Clinical trial NCT02525874
Conditions: Multiple Sclerosis, Relapsing-Remitting Multiple Sclerosis
Keywords: Tecfidera DMF dimethyl fumarate
Sponsor: Biogen
Start date: 2015-08-11; Completion date: 2018-04-23
Enrollment: 218 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of the study is to evaluate the effect of BG00012 on lymphocyte subset counts during the first year of treatment in subjects with relapsing-remitting multiple sclerosis (RRMS). A secondary objective is to evaluate the pharmacodynamic effect on absolute lymphocyte counts (ALCs) and immunoglobulins (Igs) during the first year of treatment.

Detailed description:

Arms: arm 1: 120 mg twice daily (BID) for the first 7 days and 240 mg BID thereafter
Interventions: intervention 1: dimethyl fumarate
Intervention descriptions: intervention 1: Initial oral dose for 7 days with maintenance dose thereafter

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
1 
Biogen MA Inc. 
250 Binney Street 
Cambridge, MA 02142 
United States 
PROTOCOL NUMBER: 
109MS310 / NCT02525874 
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead Berkshire 
SL6 4AY 
United Kingdom 
PHASE OF DEVELOPMENT: 
3b 
PROTOCOL TITLE:  An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With Relapsing-Remitting Multiple Sclerosis 
EUDRA CT NO: 
2015-001973-42 
DATE: 
22 January 2016 
Version 2 
FINAL 


Protocol 109MS310 
Version 2 
Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
2 
 
TABLE OF CONTENTS 
1. 
SPONSOR INFORMATION .......................................................................................8 
2. 
LIST OF ABBREVIATIONS.......................................................................................9 
3. 
SYNOPSIS .................................................................................................................11 
4. 
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR STUDY 
109MS310...................................................................................................................15 
4.1. 
Study Schematic .........................................................................................................15 
4.2. 
Schedule of Activities .................................................................................................16 
4.3. 
Additional Information ...............................................................................................21 
4.3.1. 
Site Personnel .............................................................................................................21 
4.3.2. 
Subject Management ..................................................................................................22 
5. 
INTRODUCTION ......................................................................................................23 
5.1. 
Overview of Multiple Sclerosis ..................................................................................23 
5.2. 
Current Therapies for Multiple Sclerosis ...................................................................24 
5.3. 
Profile of Previous Experience With BG00012 ..........................................................24 
5.3.1. 
Nonclinical Experience ...............................................................................................24 
5.3.2. 
Clinical Experience .....................................................................................................25 
5.4. 
Study Rationale ...........................................................................................................26 
5.5. 
Rationale for Dosing Regimen ...................................................................................26 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................27 
6.1. 
Primary Objective and Endpoint ................................................................................27 
6.2. 
Secondary Objective and Endpoints ...........................................................................27 
.27 
7. 
STUDY DESIGN .......................................................................................................29 
7.1. 
Study Overview ..........................................................................................................29 
7.2. 
Overall Study Duration and Follow-Up .....................................................................30 
7.2.1. 
Screening ....................................................................................................................30 
7.2.2. 
Treatment Period ........................................................................................................30 
7.2.3. 
Follow-Up ...................................................................................................................30 
 
30 
 
31 


Protocol 109MS310 
Version 2 
Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
3 
 
.31 
7.2.6. 
Additional Assessments if Required by Local Tecfidera Prescribing 
Information .................................................................................................................31 
7.3. 
Study Stopping Rules .................................................................................................31 
7.4. 
End of Study ...............................................................................................................32 
8. 
SELECTION OF SUBJECTS ....................................................................................33 
8.1. 
Inclusion Criteria ........................................................................................................33 
8.2. 
Exclusion Criteria .......................................................................................................33 
9. 
ENROLLMENT, REGISTRATION, AND RANDOMIZATION ............................36 
9.1. 
Screening and Enrollment ...........................................................................................36 
9.2. 
Registration of Subjects ..............................................................................................36 
9.3. 
Blinding Procedures ....................................................................................................36 
10. 
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY ...........................................37 
10.1. 
Discontinuation of Study Treatment ...........................................................................37 
10.2. 
Withdrawal of Subjects From Study ...........................................................................38 
11. 
STUDY TREATMENT USE .....................................................................................39 
11.1. 
Regimen ......................................................................................................................39 
11.2. 
Modification of Dose and/or Treatment Schedule ......................................................39 
11.2.1. 
Dosing Interruption for Abnormal Laboratory Values ...............................................39 
11.2.2. 
Resumption of Study Treatment Dosing ....................................................................40 
11.2.3. 
Subsequent Development of Additional Laboratory Abnormalities ..........................40 
11.2.4. 
Dosage Reductions .....................................................................................................41 
11.3. 
Treatment Schedule for Subjects With Abnormal Lymphocyte Count ......................41 
11.3.1. 
Schedule for Subjects With Lymphocyte Count <500/mm3.......................................41 
11.3.2. 
Schedule for Subjects With Lymphocyte Counts <LLN to ≥500/mm3 ......................44 
11.3.3. 
Schedule for Subjects Who Temporarily Withhold or Permanently 
Discontinue Study Treatment for Any Other Reason Than Lymphopenia and 
Have a Lymphocyte Count <LLN ..............................................................................44 
11.4. 
Precautions ..................................................................................................................45 
11.5. 
Compliance .................................................................................................................45 
11.6. 
Concomitant Therapy and Procedures ........................................................................46 
11.6.1. 
Concomitant Therapy .................................................................................................46 


Protocol 109MS310 
Version 2 
Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
4 
 
11.6.1.1. 
Allowed Concomitant Therapy ...................................................................................46 
11.6.1.2. 
Disallowed Concomitant Therapy ..............................................................................46 
11.6.2. 
Concomitant Procedures .............................................................................................46 
47 
11.7. 
Continuation of Treatment ..........................................................................................47 
12. 
STUDY TREATMENT MANAGEMENT ................................................................48 
12.1. 
BG00012 .....................................................................................................................48 
12.1.1. 
BG00012 Preparation .................................................................................................48 
12.1.2. 
BG00012 Storage ........................................................................................................48 
12.1.3. 
BG00012 Handling and Disposal ...............................................................................49 
12.1.4. 
BG00012 Accountability ............................................................................................49 
13. 
EFFICACY AND PHARMACODYNAMIC ASSESSMENTS ................................50 
13.1. 
Efficacy Assessments .................................................................................................50 
13.2. 
Pharmacodynamic Assessments .................................................................................50 
13.3. 
Clinical Assessments ..................................................................................................50 
14. 
SAFETY ASSESSMENTS ........................................................................................51 
14.1. 
Clinical Safety Assessments .......................................................................................51 
14.2. 
Laboratory Safety Assessments ..................................................................................51 
15. 
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................52 
15.1. 
Definitions ..................................................................................................................52 
15.1.1. 
Adverse Event .............................................................................................................52 
15.1.2. 
Serious Adverse Event ................................................................................................52 
15.1.3. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................53 
15.2. 
Safety Classifications ..................................................................................................53 
15.2.1. 
Investigator Assessment of Events .............................................................................53 
15.2.2. 
Relationship of Events to Study Treatment ................................................................54 
15.2.3. 
Severity of Events .......................................................................................................54 
15.2.4. 
Expectedness of Events ..............................................................................................54 
15.3. 
Monitoring and Recording Events ..............................................................................54 
15.3.1. 
Adverse Events ...........................................................................................................54 
15.3.2. 
Serious Adverse Events ..............................................................................................55 


Protocol 109MS310 
Version 2 
Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
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15.3.3. 
Immediate Reporting of Serious Adverse Events .......................................................55 
15.3.3.1. 
Deaths .........................................................................................................................55 
15.3.4. 
Suspected Unexpected Serious Adverse Reactions ....................................................56 
15.4. 
Procedures for Handling Special Situations ...............................................................56 
15.4.1. 
Pregnancy ...................................................................................................................56 
15.4.2. 
Overdose .....................................................................................................................56 
15.4.3. 
Medical Emergency ....................................................................................................56 
15.4.3.1. 
Unblinding for Medical Emergency ...........................................................................56 
15.5. 
Contraception Requirements ......................................................................................57 
15.6. 
Safety Responsibilities ................................................................................................58 
15.6.1. 
The Investigator ..........................................................................................................58 
15.6.2. 
Biogen .........................................................................................................................58 
16. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ...........59 
16.1. 
Pharmacokinetics ........................................................................................................59 
16.2. 
Pharmacodynamics .....................................................................................................59 
16.2.1. 
Analysis Population ....................................................................................................59 
16.2.2. 
Methods of Analysis ...................................................................................................59 
16.2.2.1. 
Analysis of the Primary Endpoint...............................................................................59 
16.2.2.2. 
Analysis of the Secondary Endpoints .........................................................................59 
 
60 
 
60 
16.4. 
Safety ..........................................................................................................................60 
16.4.1. 
Analysis Population ....................................................................................................60 
16.4.2. 
Methods of Analysis ...................................................................................................60 
16.4.2.1. 
Adverse Events ...........................................................................................................60 
16.4.2.2. 
Clinical Laboratory Results ........................................................................................60 
16.4.2.3. 
Physical Examinations ................................................................................................61 
16.4.2.4. 
Vital Signs ..................................................................................................................61 
16.4.2.5. 
ECG Data ....................................................................................................................61 
16.5. 
Clinical Assessments ..................................................................................................61 
16.5.1. 
Analysis Population ....................................................................................................61 


Protocol 109MS310 
Version 2 
Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
6 
 
.....62 
16.6. 
Interim Analyses .........................................................................................................62 
16.7. 
Sample Size Considerations .......................................................................................62 
17. 
ETHICAL REQUIREMENTS ...................................................................................64 
17.1. 
Declaration of Helsinki ...............................................................................................64 
17.2. 
Ethics Committee ........................................................................................................64 
17.3. 
Subject Information and Consent ...............................................................................64 
17.4. 
Subject Data Protection ..............................................................................................65 
17.5. 
Compensation for Injury .............................................................................................65 
17.6. 
Conflict of Interest ......................................................................................................65 
17.7. 
Registration of Study and Disclosure of Study Results ..............................................65 
18. 
ADMINISTRATIVE PROCEDURES .......................................................................66 
18.1. 
Study Site Initiation ....................................................................................................66 
18.2. 
Quality Assurance .......................................................................................................66 
18.3. 
Monitoring of the Study..............................................................................................66 
18.4. 
Study Funding .............................................................................................................66 
18.5. 
Publications .................................................................................................................66 
19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION ........................67 
19.1. 
External Contract Organizations .................................................................................67 
19.1.1. 
Contract Research Organization .................................................................................67 
19.1.2. 
Interactive Response Technology ...............................................................................67 
19.1.3. 
Electronic Data Capture ..............................................................................................67 
19.1.4. 
Central Laboratories for Laboratory Assessments .....................................................67 
19.2. 
Study Committees .......................................................................................................67 
19.3. 
Changes to Final Study Protocol ................................................................................67 
19.4. 
Ethics Committee Notification of Study Completion or Termination ........................68 
19.5. 
Retention of Study Data ..............................................................................................68 
19.6. 
Study Report Signatory...............................................................................................68 
20. 
REFERENCES ...........................................................................................................69 
21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL .........................................71 
 


Protocol 109MS310 
Version 2 
Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
7 
 
LIST OF TABLES 
Table 1: 
Study Activities for Study 109MS310 - Table 1 of 2 .................................................16 
Table 2: 
Study Activities for Study 109MS310 - Table 2 of 2 .................................................19 
Table 3: 
Laboratory Criteria Requiring Withholding or Permanent Discontinuation of 
Treatment ....................................................................................................................39 
Table 4: 
Lymphocyte Count Criteria Requiring Withholding of Study Treatment ..................41 
Table 5: 
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs ...................61 
Table 6: 
Sample Size Calculations ...........................................................................................63 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................15 
Figure 2: 
Schedule for Subjects With Lymphocyte Count <500/mm3.......................................43 
Figure 3: 
Schedule for Subjects Who Temporarily Withhold or Permanently 
Discontinue Study Treatment for Any Other Reason Than Lymphopenia* 
and Have Lymphocyte Count <LLN ..........................................................................45 
 
 


Protocol 109MS310 
Version 2 
Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
8 
 
1. 
SPONSOR INFORMATION 
The Sponsor is Biogen MA Inc. in North America and Biogen Idec Research Limited in the Rest 
of World.  Biogen MA Inc. and Biogen Idec Research Limited are referred to as Biogen in this 
protocol. 
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 
 
 
For urgent medical issues in which the study’s Medical Director should be contacted, please 
refer to the Study Reference Guide’s Official Study Contact List for complete contact 
information. 
 
Biogen may transfer any or all of its study-related responsibilities to a contract research 
organization (CRO) and other third parties; however, Biogen retains overall accountability for 
these activities. 


Protocol 109MS310 
Version 2 
Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
9 
 
2. 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALC 
absolute lymphocyte count 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
BBB 
blood-brain barrier 
BID 
twice daily 
CBC 
complete blood count 
CD 
cluster of differentiation 
CI 
confidence interval 
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization 
DHA 
Directions for Handling and Administration 
DMF 
dimethyl fumarate 
DMT 
disease modifying therapy 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
 
 
GA 
glatiramer acetate 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IFN 
interferon 
Ig 
immunoglobulin 
IV 
intravenous 
IVMP 
intravenous methylprednisolone 
IXRS 
Interactive Voice and Web Response System 
LLN 
lower limit of normal 
MMRM 
mixed model for repeated measures 
MS 
multiple sclerosis 
NK 
natural killer (cells) 
Nrf2 
nuclear factor (erythroid-derived 2)-like 2 
 
 
PML 
progressive multifocal leukoencephalopathy 
 
 
RRMS 
relapsing-remitting multiple sclerosis 
SAE 
serious adverse event 


Protocol 109MS310 
Version 2 
Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
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SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SPMS 
secondary progressive multiple sclerosis 
SUSAR 
suspected unexpected serious adverse reaction 
Treg 
T regulatory (cells) 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 
 


Protocol 109MS310 
Version 2 
Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
11 
 
3. 
SYNOPSIS 
Protocol Number: 
109MS310 
Protocol Title: 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With Relapsing-Remitting 
Multiple Sclerosis 
Version Number 
2 
Name of Study Treatment: 
BG00012 (dimethyl fumarate [DMF]; Tecfidera®) 
Study Indication: 
Multiple sclerosis (MS) 
Study Rationale 
Given the putative immunomodulatory properties of DMF 
and its observed effects on lymphocytes in humans, further 
evaluation of its effects on immune function is needed.  The 
effect of BG00012 on lymphocyte subtypes is yet unknown, 
and its evaluation may provide insights into the mechanisms 
underlying BG00012-associated lymphopenia.  This study is 
therefore being conducted to assess the effects of BG00012 
on lymphocyte subset counts and immunoglobulins (Igs) 
within the first year of treatment and until the end of the 
study. 
Phase of Development: 
3b 
Study Objectives and 
Endpoints: 
The primary objective of the study is to evaluate the effect 
of BG00012 on lymphocyte subset counts during the first 
year of treatment in subjects with relapse-remitting MS 
(RRMS). 
The primary endpoint that relates to this objective is the 
change in lymphocyte subset counts for up to 48 weeks. 
A secondary objective is to evaluate the pharmacodynamic 
effect of BG00012 on absolute lymphocyte counts (ALCs) 
and Igs during the first year of treatment.  
The endpoints that relate to this objective are the changes in 
IgG isotypes and ALCs for up to 48 weeks. 
 
 
Study Design: 
This is an open-label, multicenter study to evaluate the 


Protocol 109MS310 
Version 2 
Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
 
CONFIDENTIAL 
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Biogen MA Inc. 
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effects of BG00012 on lymphocyte subtypes and Ig 
isotypes.   
After the Screening Visit (up to 28 days), if required per 
local guidelines and if not already available within the 
previous 3 months, a magnetic resonance imaging scan 
should be performed locally before starting therapy with 
BG00012.  Subjects will then receive BG00012 treatment 
for 96 weeks twice daily (BID).  Blood samples for 
lymphocyte subset analysis, as well as blood samples for the 
determination of each subject’s complete blood count with 
differential, will be collected at Screening, Baseline (Day 1), 
and Weeks 4, 8, 12, 24, 36, 48, 60 (complete blood count 
[CBC] only), 72, 84 (CBC only), and 96.  Clinical samples 
for the analysis of blood chemistries will be collected at 
Screening, Baseline (Day 1), and Weeks 4, 8, 24, 48, and 
96.  A post-treatment follow-up visit at which safety 
assessments will be performed will occur 4 weeks after the 
final dose of BG00012.   
Subjects who develop a confirmed lymphocyte count of 
<500 cells/mm3 at any time during the study will be 
monitored every 4 weeks.  If the lymphocyte count stays 
<500 cells/mm3 for 24 weeks, the subject will temporarily 
withhold study treatment.  If the lymphocyte count does not 
recover to ≥ the lower limit of normal (LLN) within an 
additional 24 weeks while study treatment is temporarily 
withheld, study treatment will be discontinued permanently 
and the subject will continue protocol-required visits and 
assessments. 
Subjects who temporarily withhold or permanently 
discontinue study treatment for any other reason than 
lymphopenia and have a lymphocyte count <LLN will 
continue protocol-required visits and assessments and will 
also be followed 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.   
Subjects whose lymphocyte counts are <LLN at the end of 
the study (Week 96) will complete the final Follow-Up Visit 
and will then be followed up outside of this protocol at the 
Investigator’s discretion.   
Therapies directed toward the treatment of MS are 


Protocol 109MS310 
Version 2 
Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
13 
 
permitted, at the discretion of the treating physician and 
only after consulting with the Medical Monitor, for subjects 
who have permanently discontinued BG00012 for any 
reason. 
Subjects who withdraw from the study while on study 
treatment will complete the Discontinuation and/or 
Withdrawal Visit as soon as possible but no later than 
2 weeks after their last dose of study treatment and will 
complete the final Follow-Up Visit 4 weeks after their last 
dose of study treatment unless consent has been withdrawn.   
Subjects who withdraw from the study for reasons other 
than safety may be replaced at the discretion of Biogen. 
Refer to Table 1 and Table 2 for the timing of all study 
assessments. 
Study Location: 
Approximately 100 sites in North America and Europe 
Number of Planned Subjects: 
Approximately 200 subjects will be treated. 
Study Population: 
This study will be conducted in male and female subjects, 
aged 18 through 65 years, with a confirmed diagnosis of 
RRMS according to the revised McDonald criteria (2010) 
[Polman 2011]. 
Detailed criteria are described in Section 8. 
Treatment Groups: 
Approximately 200 subjects will receive oral BG00012 at a 
dose of 120 mg BID for the first 7 days and at a 
maintenance dose of 240 mg BID thereafter.  Temporary 
dose reductions to 120 mg BID may be considered for 
individuals who do not tolerate the maintenance dose due to 
flushing and/or gastrointestinal disturbances.  Within 
4 weeks, the recommended dose of 240 mg BID should be 
resumed.  


Protocol 109MS310 
Version 2 
Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
 
CONFIDENTIAL 
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Biogen MA Inc. 
14 
 
Duration of Treatment and 
Follow-up: 
The study period will consist of a Screening Visit within 
4 weeks of Baseline, a Treatment Period of 96weeks and a 
final Follow-Up Visit.  Subjects who temporarily withhold 
or permanently discontinue study treatment for any other 
reason than lymphopenia and have a lymphocyte count 
<LLN will be followed 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.  Subjects whose 
lymphocyte counts are <LLN at the end of the study 
(Week 96) will complete the final Follow-Up Visit and then 
be followed outside of this protocol at the Investigator’s 
discretion. 
Subjects will receive treatment for up to 96 weeks.  The 
total duration of subject participation will be up to 
104 weeks. 


Protocol 109MS310 
Version 2 
Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
15 
 
4. 
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR 
STUDY 109MS310 
4.1. 
Study Schematic 
The study design for Study 109MS310 is shown in Figure 1, and the study activities are shown in 
Table 1 and Table 2. 
Figure 1: 
Study Design 
 
BID = twice daily; LLN = lower limit of normal. 
*Subjects will receive oral BG00012 at a dose of 120 mg BID for the first 7 days and at a maintenance dose of 240 mg BID 
thereafter.  Temporary dose reductions to 120 mg BID may be considered (see Section 11.2.4). 
**Subjects with a lymphocyte count <LLN will continue protocol-required visits and assessments and will have additional 
lymphocyte and subset analysis (see Section 11.3). 


Protocol 109MS310 
Version 2 
Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
16 
 
4.2. 
Schedule of Activities 
Table 1: 
Study Activities for Study 109MS310 - Table 1 of 2 
Tests and 
Assessments 
Screenin
g 
Treatment Period 
Final 
Follow-Up 
Visit1 
Within 
28 days 
before 
Baseline 
Baselin
e (Day 
1) 
Week 4 
(Day 28 
±3 
days) 
Week 8 
(Day 56 
±3 
days) 
Week 
12 
(Day  
84 
±3 
days) 
Week 
24 (Day 
168 
±5 
days) 
Week 
36 (Day 
252 
±5 
days) 
Week 
48 (Day 
336 
±5 
days) 
Week 
60 (Day 
420 
±5 
days) 
Week 
72 (Day 
504 
±5 
days) 
Week 
84 (Day 
588 
±5 
days) 
Week 
96 (Day 
672 
±5 days) 
4 weeks 
±5 days 
after final 
dose 
Informed Consent2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B and C 
Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV 
Testing (As Per 
Local Guidelines)4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MRI Scan5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination6 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Vital Signs7 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
12-Lead ECG 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Hematology (CBC 
With Differential8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Chemistry 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 


Protocol 109MS310 
Version 2 
Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
 
CONFIDENTIAL 
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Tests and 
Assessments 
Screenin
g 
Treatment Period 
Final 
Follow-Up 
Visit1 
Within 
28 days 
before 
Baseline 
Baselin
e (Day 
1) 
Week 4 
(Day 28 
±3 
days) 
Week 8 
(Day 56 
±3 
days) 
Week 
12 
(Day  
84 
±3 
days) 
Week 
24 (Day 
168 
±5 
days) 
Week 
36 (Day 
252 
±5 
days) 
Week 
48 (Day 
336 
±5 
days) 
Week 
60 (Day 
420 
±5 
days) 
Week 
72 (Day 
504 
±5 
days) 
Week 
84 (Day 
588 
±5 
days) 
Week 
96 (Day 
672 
±5 days) 
4 weeks 
±5 days 
after final 
dose 
Lymphocyte 
Subset Analysis8 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Serum Pregnancy 
Test9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy 
Test9, 10 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense BG00012 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
BG00012 
Administration 
 
X 
 
Concomitant 
Therapy and 
Procedures 
 
X 
AE Recording 
 
X 
SAE Recording 
Monitor and record throughout the study. 


Protocol 109MS310 
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Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
 
CONFIDENTIAL 
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18 
 
AE = adverse event; CBC = complete blood count; DNA = deoxyribonucleic acid; ECG = electrocardiogram; 
; HIV = human 
immunodeficiency virus; Ig = immunoglobulin; LLN = lower limit of normal; MRI = magnetic resonance imaging; MS = multiple sclerosis; 
 
; SAE = serious adverse event. 
1 Subjects will have a final Follow-Up Visit 4 weeks after taking their final dose, regardless of whether they complete the treatment period or discontinue prematurely, unless they 
have a lymphocyte count <LLN.  Subjects who have a lymphocyte count <LLN will continue protocol-required visits and assessments per Section 11.3. 
2 Written informed consent must be obtained prior to performing any study-related procedures. 
3 Medical history will include gastrointestinal abnormalities within the previous 6 months, as well as duration of MS (time since diagnosis), relapse history, and treatments for MS. 
4 HIV testing will be done locally at Screening only if required, per local guidelines.   
5 If required per local guidelines and if not already available within the previous 3 months, an MRI scan should be performed locally before starting therapy with BG00012.   
6 Physical examination includes height and weight measurements, as well as a neurological examination. 
7 Vital signs will include diastolic and systolic blood pressure, heart rate, and temperature.  Subjects must be seated for 5 minutes prior to having their pulse and blood pressure 
measured. 
8 Whole blood may also be collected for lymphocyte functional tests.  Lymphocyte subset analysis will include total Ig and IgG subclasses, and may also include assays for 
 and VLA-4 expression.  In subjects with a confirmed lymphocyte count <500/mm3 lymphocyte testing must be performed every 4 weeks; if the lymphocyte count 
remains  <500/mm3 for 24 weeks, study treatment will be temporarily withheld for 24 weeks or until the lymphocyte count recovers to LLN, whichever is sooner, and testing 
continues to be every 4 weeks; if the lymphocyte count does not recover to LLN within 24 weeks while study treatment is temporarily withheld, study treatment will be withheld 
permanently, and testing will be performed every 12 weeks for an additional 24 weeks or until the lymphocyte count recovers to LLN, or until the end of the study, whichever is 
sooner. 
9 Females of childbearing potential only.  Results must be known to be negative prior to dispensing BG00012. 
10 Pregnancy test may be repeated locally at additional timepoints if needed, per local guidelines. 
11 Sample can be collected at any point during the study in subjects who have signed a separate informed consent form. 
 


Protocol 109MS310 
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Table 2: 
Study Activities for Study 109MS310 - Table 2 of 2 
Tests and Assessments 
 
 
Discontinuation and/or 
Withdrawal Visit2 
Lymphocyte Follow-Up 
Visit3 
Unscheduled Visit for 
Abnormal Laboratory 
Results (Other Than 
Lymphocytes) 
These visits can be combined.  If these visits are not combined, 
any assessment that was performed within the past 2 weeks (or 
the interval noted in the footnotes) does not need to be repeated 
unless clinically indicated. 
 
 
Physical Examination4 
X 
 
X 
 
Vital Signs5 
X 
X 
X 
 
Hematology (CBC With Differential) 
X 
X 
X 
X6 
Blood Chemistry 
X 
X 
 
X7 
Lymphocyte Subset Analysis 
 
X 
X 
 
Concomitant Therapy and Procedures 
X 
 
AE Recording 
X 
 
SAE Recording 
Monitor and record throughout the study. 
 
AE = adverse event; ALT = alanine transaminase; AST = aspartate transaminase; CBC = complete blood count; 
; LLN = lower limit of 
normal; 
; SAE = serious adverse event; ULN = upper limit of normal; WBC = white blood cell. 
 
 
2 Discontinuation refers to discontinuation of study treatment.  Withdrawal refers to withdrawal of subjects from study.  The Discontinuation and/or Withdrawal Visit should be 
conducted as soon as possible and no later than 2 weeks after their last dose of study treatment. 


Protocol 109MS310 
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3 Subjects who complete, temporarily withhold, or permanently discontinue study treatment for any reason and have a lymphocyte count <LLN will continue protocol-required 
visits and assessments and 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. 
4 Physical examination includes height and weight measurements, as well as a neurological examination. 
5 Vital signs will include diastolic and systolic blood pressure, heart rate, and temperature.  Subjects must be seated for 5 minutes prior to having their pulse and blood pressure 
measured. 
6 The Investigator should repeat the test as soon as possible.  If retest value confirms that WBC count is <2000/mm3, study treatment must be withheld.  If the value remains 
<2000/mm3 for ≥4 weeks after discontinuation of study treatment, then the subject must permanently discontinue study treatment, and the event must be recorded as an AE.  
7 The Investigator should repeat the test as soon as possible.  If the retest value confirms AST or ALT >3 × ULN or creatinine >1.2 × ULN, the study treatment must be withheld.  
If the ALT/AST value remains >3 × ULN or creatinine is >1.2 × ULN for ≥4 weeks after discontinuation of study treatment, then the subject must permanently discontinue study 
treatment, and the event must be recorded as an AE. 
 
 
 


Protocol 109MS310 
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4.3. 
Additional Information  
4.3.1. 
Site Personnel 
For each subject, the Principal Investigator of the site will designate the following investigational 
site personnel: 
 a primary and backup Neurologist 
 a primary and backup Study Nurse (or Study Coordinator) 
 a Pharmacist (or authorized designee) 
The primary and backup Neurologists must have a minimum of 2 years of neurology specialty 
training and anticipate a 2-year commitment to the study.  
 
 
  The backup Neurologist or a 
certified and trained nurse may conduct subject evaluations if the primary Neurologist is 
unavailable due to illness, vacation, or travel. 
The roles and responsibilities of the Neurologist and Study Nurse are described below.  Details 
for all roles are provided in the Study Reference Guide. 
The primary Neurologist will be responsible for the following: 
 Management of the routine neurological care of the subject. 
 Assessment (including assignment of causality) and treatment of adverse events 
(AEs) 
. 
 Review of hematology and blood chemistry results from the central laboratory to 
assess whether the subject’s study treatment should be temporarily withheld or 
permanently discontinued, as per the criteria detailed in Section 10.  
 Determination of whether new objective neurological findings have occurred (see 
Section 7.2.4). 
 
 
  
 
 
 
The Neurologist may designate other medical personnel (i.e., the backup Neurologist or the 
Study Nurse) at the investigational site to perform some of the tests and evaluations listed under 
“Neurologist.”   
Hematology and blood chemistry data will be sent to the investigational sites to aid in 
management of the subject. 


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4.3.2. 
Subject Management 
Contraception requirements are described in Section 15.5.  Study treatment dosing requirements 
and concomitant medication restrictions are described in Sections 11.1 and 11.6, respectively. 
There are no restrictions regarding diet and alcohol use.  Physical exertion atypical for the 
subject’s normal activities of daily living should be avoided for 24 hours prior to assessments.  
Subjects should not donate blood until 1 month after their last dose of study treatment in this 
study. 


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5. 
INTRODUCTION  
BG00012 is a fumarate ester drug product formulation containing the active ingredient dimethyl 
fumarate (DMF).  In 2013, BG00012 was first approved in the United States (US) under the 
propriety name Tecfidera® as a treatment for patients with relapsing MS and has since been 
approved in other countries. 
5.1. 
Overview of Multiple Sclerosis 
MS is a chronic autoimmune and neurodegenerative disorder of the central nervous system 
(CNS) that is characterized by inflammation, demyelination, and oligodendrocyte and neuronal 
loss.  It is the most common demyelinating disorder of the CNS, affecting approximately 
2.5 million people worldwide.  Its prevalence is highest among Caucasians, with higher rates 
reported in North America, Europe, Australia, New Zealand, and northern Asia [Noseworthy 
2000; Rosati 2001].   
Relapsing MS is the most common clinical presentation of the disease.  The term relapsing MS 
applies to patients with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) 
who experience relapses; both are considered part of the same disease spectrum.  In the 
relapsing/remitting phase of the disease, patients experience episodes of neurological 
dysfunction (relapses) separated by periods of relative stability.  Typical symptoms of relapse 
include weakness, sensory loss, visual loss, and imbalance.  Relapses may completely subside in 
the early stage of the disease, but recovery tends to be incomplete over time, leading to the 
accumulation of physical disability and cognitive decline.  RRMS is usually diagnosed between 
the ages of 20 and 40 years and affects twice as many women than men.  The RRMS population 
ranges from patients with relatively benign, inactive, non-inflammatory disease to patients who 
experience frequent relapse and/or persistent, active, inflammatory disease.  Most of these 
patients develop SPMS, which is characterized by progressive neurological decline with or 
without superimposed relapse; the median time to progression from RRMS to SPMS is 
approximately 10 years [Runmarker and Andersen 1993].  Approximately half of all MS patients 
are unable to walk without assistance within 15 years of their initial diagnosis [Runmarker and 
Andersen 1993; Weinshenker 1989], and more than half of patients die from MS or its 
complications [Brønnum-Hansen 2004]. 
As patients progress along the continuum from RRMS to SPMS, disability progression is more 
likely to occur independently of relapses.  The pathological changes underlying MS are thought 
to occur when activated T lymphocytes cross the blood-brain barrier (BBB) and initiate a series 
of events leading to activation of endothelial cells, recruitment of additional lymphocytes and 
monocytes, and release of pro-inflammatory cytokines.  MS lesions consisting of immune cells 
can occur throughout the CNS, but certain sites appear to be particularly vulnerable, such as the 
optic nerve, brainstem, spinal cord, and periventricular regions of the cerebrum.  The 
development of MS lesions is associated with inflammation, edema, and demyelination, and is 
often correlated with reversible disease symptoms, namely relapses, as well as oligodendrocyte 
death and axonal transection, which can be permanent and lead to disability.  Alternatively, 
oligodendrocyte and axonal loss may be due to a neurodegenerative process.  Ongoing 


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inflammatory and neurodegenerative stimuli are mediated at least in part by toxic oxidative 
stress.  Preclinical studies indicate that BG00012-dependent pharmacodynamic responses appear 
to be mediated through activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) 
transcriptional pathway, which is the primary cellular defense system for responding to a variety 
of potentially toxic stimuli through up-regulation of antioxidant response genes.  While it is not 
yet fully understood how the inflammatory cascade is initiated, adhesion and trans-endothelial 
migration of inflammatory cells from the bloodstream across the BBB and into the CNS is 
thought to be an early and critical step in this process. 
5.2. 
Current Therapies for Multiple Sclerosis 
The most commonly used first-line MS therapies are interferons (IFNs) and glatiramer acetate 
(GA) [Waldman 2011].  Relative to placebo, IFNs have been shown to reduce relapse rate by 
approximately 27% to 36% [Calabresi 2014; Jacobs 1996; PRISMS Study Group 1998; The 
IFNB Multiple Sclerosis Study Group 1993], and GA by approximately 30% [Johnson 1995].  
The interferon beta-1a (IFN -1a) products have also been shown to delay disability progression 
[Jacobs 1996; PRISMS Study Group 1998].   
Other currently approved therapies for MS include the following: 
 Natalizumab:  a humanized monoclonal antibody directed against α4 integrins 
[Polman 2006]. 
 Fingolimod:  a selective oral immunosuppressant that is metabolized to a functional 
antagonist of sphingosine 1-phosphate receptors on lymphocytes [Kappos 2010]. 
 Mitoxantrone:  a synthetic antineoplastic anthracenedione that intercalates into 
deoxyribonucleic acid (DNA) and interferes with ribonucleic acid (RNA) [Chitnis 
2012]. 
 Teriflunomide:  an immunomodulatory drug inhibiting pyrimidine synthesis by 
blocking dihydroorotate dehydrogenase [O'Connor 2011]. 
 Alemtuzumab:  a humanized monoclonal antibody targeting cluster of differentiation 
(CD) 52 antigen expressed on the surface of most leukocytes [Coles 2012]. 
5.3. 
Profile of Previous Experience With BG00012 
5.3.1. 
Nonclinical Experience 
In nonclinical studies, DMF and its primary metabolite, monomethyl fumarate, were found to 
promote stabilization and transcriptional activity of Nrf2, as well as expression of Nrf2 target 
genes in cultured human cells and in vivo [Linker 2011].  Previous ex vivo and in vivo studies 
have demonstrated a central role of the Nrf2 pathway in the protection of cells and tissues against 
oxidative, xenobiotic, and inflammatory stress.  Loss of Nrf2 function via genetic silencing has 
been shown to cause exaggerated inflammatory response and lead to development of systemic 
autoimmunity and CNS alterations, including widespread gliosis and white matter lesions.  
Conversely, pharmacological agents known to activate Nrf2 have been shown in nonclinical 
studies to exert anti-inflammatory effects, protect neurons from oxidative and excitotoxic stress-


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induced death, and improve the BBB integrity of the CNS.  Activation of the Nrf2 pathway by 
DMF in MS may contribute to inhibition of inflammation and help support CNS integrity by 
promoting cellular resistance to oxidative stress. 
See the Investigator’s Brochure for detailed information on nonclinical studies. 
5.3.2. 
Clinical Experience 
In the Phase 2 and 3 placebo-controlled safety and efficacy studies (the completed 6-month 
Phase 2 Study C-1900 Part 1 and the 2 completed 2-year Phase 3 Studies 109MS301 and 
109MS302) and/or their uncontrolled extensions (the completed 6-month Phase 2 Study C-1900 
Part 2 and the ongoing Phase 3 long-term Study 109MS303) over 2500 subjects received 
treatment with BG00012.  The overall exposure to BG00012 among these subjects was 
approximately 6100 subject-years as of September 2013.   
DMF demonstrated robust efficacy and a favorable safety profile in subjects with RRMS in the 
2 large Phase 3 studies (Study 109MS301 [DEFINE] [Gold 2012a] and Study 109MS302 
[CONFIRM] [Fox 2012]).  The benefit-risk profile of DMF was considered positive, and the 
drug has been approved. 
Both Phase 3 studies demonstrated that treatment with DMF reduced the risk of MS relapse and 
slowed progression of disability.  In an integrated analysis of DEFINE and CONFIRM, DMF 
240 mg twice daily (BID) and 3 times daily significantly reduced the annualized relapse rate at 
2 years by 49% relative to placebo (p<0.0001).  Significant reductions at 2 years were also 
observed in the proportion of subjects who relapsed (43% and 47%, respectively; p<0.0001), the 
proportion of subjects with confirmed (12-week) progression of disability (32% and 30%, 
respectively; p<0.01), and the proportion of subjects with confirmed (24-week) progression of 
disability (29% and 32%, respectively; p<0.03) [Gold 2012b].  
DMF was generally well tolerated and demonstrated an acceptable safety profile.  The most 
common AEs associated with DMF were flushing and gastrointestinal (GI) events.  In subjects 
who experienced these types of events, the events were generally mild or moderate in intensity, 
tended to decrease in incidence after the first month, and only infrequently led to treatment 
discontinuation.  There are a number of potential management strategies for these side effects.  
In the Phase 2 and 3 controlled and uncontrolled clinical studies in subjects with RRMS, 
BG00012 treatment was associated with a gradual decrease from baseline in mean leukocyte 
counts driven primarily by decreases in mean lymphocyte counts; mean lymphocyte counts 
decreased by approximately 30% of their baseline value after 1 year and then plateaued and 
remained stable through more than 6 years of follow-up.  While decreases in lymphocyte counts 
have been observed with BG00012 treatment, in the placebo controlled Phase 2 and 3 studies 
BG00012 was not associated with an increased risk of infection, serious infection, or 
opportunistic infection compared with placebo.  However, in the long-term extension study 
(109MS303), progressive multifocal leukoencephalopathy (PML) has occurred in the setting of 
severe, prolonged lymphopenia following BG00012 administration.  PML has also been reported 
in the postmarketing setting in the presence of prolonged moderate to severe lymphopenia.  The 
majority of all cases occurred in patients with lymphocyte counts <0.5 × 109/L.  With open-label 


Protocol 109MS310 
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and marketed use of BG00012, there has been no other evidence of an increased risk of 
infections, serious infections, or opportunistic infections.   
See the Investigator’s Brochure for detailed information on clinical studies. 
5.4. 
Study Rationale 
Given the putative immunomodulatory properties of DMF and its observed effects on 
lymphocytes in humans, further evaluation of its effects on lymphocytes is needed.  The effect of 
BG00012 on lymphocyte subtypes is yet unknown, and its evaluation may provide insights into 
the mechanisms underlying BG00012-associated lymphopenia.  This study is therefore being 
conducted to assess the effects of BG00012 on lymphocyte subset counts and immunoglobulins 
(Igs) within the first year of treatment and beyond.  
5.5. 
Rationale for Dosing Regimen 
The BG00012 dosage selected for this study (120 mg BID for the first 7 days and 240 mg BID 
thereafter) is the approved BG00012 dosing regimen in the US, Canada, European Union, and 
other countries around the world for the treatment of patients with MS.   
Temporary dose reductions to 120 mg BID may be considered for individuals who do not 
tolerate the maintenance dose due to flushing and/or GI disturbances.  Within 4 weeks, the 
recommended dose of 240 mg BID should be resumed. 


Protocol 109MS310 
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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Primary Objective and Endpoint 
The primary objective of the study is to evaluate the effect of BG00012 on lymphocyte subset 
counts during the first year of treatment in subjects with RRMS. 
The primary endpoint that relates to this objective is the change in lymphocyte subset counts for 
up to 48 weeks. 
6.2. 
Secondary Objective and Endpoints 
A secondary objective is to evaluate the pharmacodynamic effect of BG00012 on absolute 
lymphocyte counts (ALCs) and Igs during the first year of treatment.  
The endpoints that relate to this objective are the changes in IgG isotypes and ALCs for up to 
48 weeks. 


Protocol 109MS310 
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Protocol 109MS310 
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Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
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7. 
STUDY DESIGN 
7.1. 
Study Overview 
This is an open-label, multicenter study to evaluate the effects of BG00012 on lymphocyte 
subtypes and Ig isotypes.  Approximately 200 subjects will be treated in approximately 100 sites 
in North America and Europe. 
After the Screening Visit (up to 28 days) if required per local guidelines and if not already 
available within the previous 3 months, a magnetic resonance imaging scan should be performed 
locally before starting therapy with BG00012.  Subjects will then receive BG00012 treatment for 
96 weeks (Treatment Period).  Blood samples for lymphocyte subset analysis, as well as blood 
samples for the determination of each subject’s complete blood count with differential, will be 
collected at Screening, Baseline (Day 1), and Weeks 4, 8, 12, 24, 36, 48, 60 (complete blood 
count [CBC only]), 72, 84 (CBC only), and 96.  Clinical samples for the analysis of blood 
chemistries will be collected at Screening, Baseline (Day 1), and Weeks 4, 8, 24, 48, and 96.  A 
post-treatment follow-up visit, at which safety assessments will be performed, will occur 4 
weeks after the final dose of BG00012.   
Subjects who temporarily withhold or permanently discontinue study treatment for any other 
reason than lymphopenia and have a lymphocyte count <LLN will continue protocol-required 
visits and assessments and will also be followed 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.   
Subjects who develop a confirmed lymphocyte count of <500 cells/mm3 at any time during the 
study will be monitored every 4 weeks.  If the lymphocyte count stays <500 cells/mm3 for 
24 weeks, the subject will temporarily withhold study treatment.  If the lymphocyte count does 
not recover to LLN within 24 weeks while study treatment is temporarily withheld, study 
treatment will be discontinued permanently (see Section 11.3). 
Subjects whose lymphocyte counts remain <LLN at the end of the study (Week 96) will 
complete the final Follow-Up Visit and will then be followed up outside of this study at the 
Investigator’s discretion.   
Therapies directed toward the treatment of MS are permitted, at the discretion of the treating 
physician and only after consulting with the Medical Monitor, for subjects who have 
permanently discontinued BG00012 for any reason. 
Subjects who withdraw from the study while on study treatment will complete the 
Discontinuation and/or Withdrawal Visit as soon as possible but no later than 2 weeks after their 
last dose of study treatment and will complete the final Follow-Up Visit 4 weeks after their last 
dose of study treatment unless consent has been withdrawn.   
Subjects who withdraw from the study for reasons other than safety may be replaced at the 
discretion of Biogen. 


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See Figure 1 for a schematic of the study design.  Refer to Table 1 and Table 2 for the timing of 
all study assessments. 
7.2. 
Overall Study Duration and Follow-Up 
The study period will consist of a Screening Visit within 4 weeks of Baseline, a Treatment 
Period of 96 weeks and a final Follow-Up Visit.  Subjects will receive treatment for 96 weeks.  
The total duration of subject participation will be up to 104 weeks. 
7.2.1. 
Screening 
Subject eligibility for the study will be determined within 28 days prior to study entry.  If 
required per local guidelines and if not already available within the previous 3 months, an MRI 
scan should be performed locally before starting therapy with BG00012. 
7.2.2. 
Treatment Period 
Eligible subjects will report to the study site every 4 weeks for the first 12 weeks and every 
12 weeks thereafter for 96 weeks. 
Discontinuation and/or Withdrawal Visits 
 Visits will be 
performed as necessary.  Subjects who withdraw from the study early will be asked to return to 
complete a Discontinuation and/or Withdrawal Visit within 2 weeks of their last study treatment 
dose.   
7.2.3. 
Follow-Up 
Subjects are to return to the study site for a Follow-Up Visit 4 weeks after their last dose of study 
treatment.  The final study visit will be Week 100.  
Subjects who temporarily withhold or permanently discontinue BG00012 for any reason and 
have a lymphocyte count <LLN will be followed 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; see Section 11.3).  Subjects whose lymphocyte count remains <LLN at the end of 
the study (Week 96) will complete the final Follow-Up Visit and will then be followed up 
outside of this protocol at the Investigator’s discretion. 


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7.2.6. 
Additional Assessments if Required by Local Tecfidera Prescribing Information 
Any additional assessments that are needed to comply with the local prescribing information for 
Tecfidera should also be performed and will be reimbursed by Biogen while a subject is 
participating in this study. 
7.3. 
Study Stopping Rules 
There are no study-specific stopping rules.  Biogen may terminate this study at any time after 
informing Investigators.  Biogen will notify Investigators when the study is to be placed on hold, 
completed, or terminated. 


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7.4. 
End of Study 
The end of study is last subject, last visit for final collection of data. 


Protocol 109MS310 
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8. 
SELECTION OF SUBJECTS 
8.1. 
Inclusion Criteria 
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at enrollment or at the timepoint specified in the individual eligibility criterion listed:   
1. Ability to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use confidential health information in accordance 
with national and local subject privacy regulations.  
2. Age 18 to 65 years old, inclusive, at the time of informed consent.   
3. Subjects of childbearing potential (including female subjects who are post-menopausal 
for less than 1 year) must practice effective contraception (as determined by the 
Investigator) during the study and be willing and able to continue contraception for 
30 days after their last dose of study treatment.  For further details of contraceptive 
requirements for this study, please refer to Section 15.5. 
4. Must have a confirmed diagnosis of RRMS according to the revised McDonald criteria 
(2010) [Polman 2011]. 
8.2. 
Exclusion Criteria 
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
enrollment or at the timepoint specified in the individual criterion listed: 
Medical History 
1. History of or positive test result at Screening (if testing is required as per local 
guidelines) for human immunodeficiency virus. 
2. History of or positive test result at Screening for hepatitis C virus antibody or current 
hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] and/or 
hepatitis B core antibody [HBcAb]).  Subjects with immunity to hepatitis B from 
previous natural infection (defined as negative HBsAg, positive hepatitis B surface 
antibody IgG, and positive HBcAb) are eligible to participate in the study (US Centers 
for Disease Control and Prevention’s interpretation of the hepatitis B serology panel). 
3. History of drug or alcohol abuse (as defined by the Investigator) within 1 year prior to 
Screening. 
4. Any clinically significant (in the judgment of the Investigator) infectious illness 
(e.g., cellulitis, abscess, pneumonia, and septicemia) within 30 days prior to Screening. 
5. History of clinically significant (in the judgment of the Investigator) cardiovascular, 
dermatologic, endocrinologic, GI, hematologic, hepatic, immunologic, metabolic, 
neurologic (other than MS), psychiatric, pulmonary, renal, urologic, and/or other major 
disease that would preclude participation in a clinical study. 


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6. History of severe allergic or anaphylactic reactions or known drug hypersensitivity to 
DMF or fumaric acid esters.  
7. Any of the following abnormal blood tests at Screening that are confirmed on repeat 
testing within 2 weeks:  
 leukocytes <3500/mm3 
 ALC values ≤LLN 
 alanine transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) or 
aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) 
≥2 times the upper limit of normal (ULN) 
Treatment History 
8. Prior treatment with any of the following: 
 cladribine 
 mitoxantrone 
 total lymphoid irradiation 
 alemtuzumab 
 T-cell or T-cell receptor vaccination 
 any therapeutic monoclonal antibody, with the exception of natalizumab or 
daclizumab 
9. Treatment with any of the following medications or procedures within 6 months prior to 
Baseline (Day 1): 
 DMF (given as Fumaderm®) or BG00012; enrollment will be limited to no more 
than 40 subjects (out of 200) with prior DMF exposure 
 cyclosporine 
 azathioprine 
 methotrexate 
 mycophenolate mofetil 
 intravenous (IV) Ig 
 plasmapheresis or cytapheresis 
10. Treatment with another investigational drug or approved therapy for investigational use 
within 6 months prior to Baseline (Day 1). 
11. Treatment with steroids (IV or oral corticosteroid treatment, including agents that may 
act through the corticosteroid pathway [e.g., low-dose naltrexone]) within 4 weeks 
(28 days) prior to Baseline (Day 1). 


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Note:  Subjects who are currently using other approved disease modifying therapies (DMTs) for 
RRMS that are not excluded above may be included in the trial if all other criteria are met.  
Subjects must discontinue these other DMT treatments upon entry into the trial.  A washout 
period is not required by the protocol, but investigators should follow their local standards of 
care, taking into account the pharmacokinetic profile (ie, half-life) of the existing therapy, to 
manage the transition from the existing treatment to BG00012. 
Miscellaneous 
12. Female subjects who are currently pregnant or breastfeeding, or planning to become 
pregnant while in the study. 
13. Current enrollment or a plan to enroll in any interventional clinical study in which an 
investigational treatment or approved therapy for investigational use is administered 
within 6 months prior to the Baseline Visit. 
14. Previous enrollment in this study. 
15. Inability to comply with study requirements. 
16. Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the 
subject unsuitable for enrollment. 


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


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10. 
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY 
10.1. 
Discontinuation of Study Treatment 
A subject must permanently discontinue study treatment for any of the following reasons: 
 The subject becomes pregnant.  Study treatment must be discontinued immediately.  
Report the pregnancy according to the instructions in Section 15.4.1. 
 The subject withdraws consent to continue study treatment.   
 The subject experiences a medical emergency that necessitates permanent 
discontinuation of study treatment. 
 The subject is unable to tolerate study treatment at 240 mg BID (see Section 11.2.4). 
 The subject receives any concomitant medications not allowed by the protocol. 
 The subject experiences any of the laboratory abnormalities requiring permanent 
discontinuation of treatment defined in Table 3. 
 The subject experiences more than 1 deviation of the same laboratory parameter that 
meets the threshold limits defined in Table 3 at any time during the study.  
 The subject experiences more than 2 different deviations of laboratory parameters 
that meet the threshold limits defined in Table 3 at any time during the study.  On a 
third occasion, the subject is required to discontinue dosing for the remainder of the 
study. 
 If a subject has a lymphocyte count <500/mm3 persisting for more than 24 weeks 
consecutively, study treatment must be temporarily withheld.  Study treatment may 
be resumed after lymphocyte counts recover >LLN on 2 consecutive occasions at 
least 4 weeks apart.  If the subject develops a lymphocyte count <500/mm3 on 
1 occasion (confirmed by repeat testing) on resumption of study treatment, the subject 
must permanently discontinue study treatment and will continue protocol-required 
visits and assessments (see Section 11.3). 
 If a subject’s lymphocyte count remains <LLN for 24 weeks consecutively after study 
treatment has been temporarily withheld due to lymphocyte count <500/mm3 for 
more than 24 weeks, the subject must permanently discontinue study treatment. 
 At the discretion of the Investigator for medical reasons or for noncompliance. 
The reason for discontinuation of study treatment must be recorded in the subject’s case report 
form (CRF). 
Subjects who discontinue treatment may remain in the study and continue protocol-required tests 
and assessments. 


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10.2. 
Withdrawal of Subjects From Study 
Subjects must be withdrawn from the study for any one of the following reasons: 
 The subject is unable to tolerate study treatment at 240 mg BID (see Section 11.2.4). 
 The subject withdraws consent.   
 The subject enrolls into another interventional clinical study in which an 
investigational treatment or approved therapy for investigational use is administered. 
 The subject is unwilling or unable to comply with the protocol. 
For details regarding follow-up for subjects who discontinue study treatment or withdraw from 
the study, see Section 7.2.3. 
The reason for the subject’s withdrawal from the study must be recorded in the subject’s CRF. 
Subjects who withdraw from the study for reasons other than safety may be replaced at the 
discretion of Biogen.  


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11. 
STUDY TREATMENT USE 
11.1. 
Regimen 
Refer to and follow the Directions for Handling and Administration (DHA).  
BG00012 will be taken orally at a dose of 120 mg BID for the first 7 days and at a maintenance 
dose of 240 mg BID thereafter.  Temporary dose reductions to 120 mg BID may be considered 
for individuals who do not tolerate the maintenance dose due to flushing and/or GI disturbances.  
Within 4 weeks, the recommended dose of 240 mg BID should be resumed.  Subjects will 
receive treatment for 96 weeks. 
Missed doses should be taken within 6 hours.  If the subject does not remember to take the dose 
within 6 hours, this dose should be skipped, and the next dose should be taken as scheduled.  
Doses should not be doubled to make up for missed doses.   
11.2. 
Modification of Dose and/or Treatment Schedule 
11.2.1. 
Dosing Interruption for Abnormal Laboratory Values 
Study treatment must be temporarily withheld when any of the following laboratory values meet 
the threshold limits defined in Table 3; laboratory abnormalities that require immediate and 
permanent discontinuation of study treatment are also specified. 
Table 3: 
Laboratory Criteria Requiring Withholding or Permanent Discontinuation 
of Treatment 
Laboratory 
Parameter 
Laboratory Result 
Required Action 
AST (SGOT) 
or 
ALT (SGPT) 
>3  ULN 
The Investigator should repeat the test as soon as 
possible.  If the retest value confirms AST or ALT 
>3  ULN, the study treatment must be withheld.  If the 
value remains >3  ULN for 4 weeks after 
discontinuation of study treatment, then the subject 
must permanently discontinue study treatment, and 
the event must be recorded as an AE. 
Creatinine 
>1.2  ULN 
The Investigator should repeat the test as soon as 
possible.  If the retest value confirms that creatinine is 
>1.2  ULN, the study treatment must be withheld.  If 
the value remains >1.2  ULN for 4 weeks after 
discontinuation of study treatment, then the subject 
must permanently discontinue study treatment, and 
the event must be recorded as an AE. 


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Laboratory 
Parameter 
Laboratory Result 
Required Action 
WBC 
2000/mm3  
The Investigator should repeat the test as soon as 
possible.  If retest value confirms that WBC count is 
2000/mm3, the study treatment must be withheld.  If 
the value remains <2000/mm3 for ≥4 weeks after 
discontinuation of study treatment, then the subject 
must permanently discontinue study treatment, and 
the event must be recorded as an AE. 
AE = adverse event; ALT = alanine transaminase; AST = aspartate transaminase; SGOT = serum glutamic 
oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase; ULN = upper limit of normal; 
WBC = white blood cell. 
While dosing is withheld, subjects will continue tests and assessments according to the schedule 
defined in Section 4.2 (and may also undergo additional assessments to evaluate the laboratory 
abnormality as per the Investigator’s standard practice).  In addition, subjects (whether dosing is 
temporarily withheld or permanently discontinued) must have the abnormal laboratory result 
retested at least every 2 weeks (retests will be run at the central laboratory) until resolution or 
stabilization of the laboratory value.  Depending on the severity and clinical significance of the 
abnormality, the Investigator may need to perform the retests more frequently.   
11.2.2. 
Resumption of Study Treatment Dosing 
Resumption of study treatment is to be considered on a case-by-case basis and must be discussed 
with the Medical Monitor.  However, subjects who have abnormal laboratory values, as 
described in Table 3, sustained on 3 consecutive occasions (i.e., for more than 4 consecutive 
weeks) must permanently discontinue study treatment (Section 10.1).  Subjects who have 
temporarily withheld BG00012 due to lymphopenia may resume BG00012 according to 
Section 11.3. 
Subjects with abnormal laboratory values after Week 12 (after which clinic visits occur once 
every 3 months), who are allowed to resume study treatment dosing following a 2- to 4-week 
interruption, will restart dosing at a reduced dose for 1 week.  Subjects must also return to the 
initial every-4-week visit schedule for safety assessments (see Table 1) for 2 consecutive normal 
laboratory assessments before reverting to the every-3-month schedule.  Subjects will take 
120 mg BID for 1 week.  After 1 week at the reduced dose, subjects will take 240 mg BID. 
11.2.3. 
Subsequent Development of Additional Laboratory Abnormalities 
Subjects who develop a subsequent abnormal value for the same laboratory parameter at any 
other time during the study must permanently discontinue dosing with study treatment, i.e., only 
1 dosing interruption is allowed for each subject for the same laboratory abnormality.  However, 
subjects who subsequently experience an abnormality of a different laboratory parameter can 
have study treatment withheld again.  For example, if a subject had dosing temporarily withheld 
for an abnormal ALT/SGPT, then had dosing resumed after ALT/SGPT returned to acceptable 
limits, and subsequently developed abnormal white blood cells (WBCs), the subject may have 


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study treatment withheld again.  However, only 2 dosing interruptions are allowed for each 
subject. 
Any subject who experiences abnormal laboratory results that meet the criteria defined in 
Table 3 on a third occasion must permanently discontinue dosing. 
11.2.4. 
Dosage Reductions 
Dosage reduction will be allowed only for subjects who are unable to tolerate study treatment 
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 Sections 11.2.1, 
11.2.2, and 11.2.3).  Subjects who do not tolerate study treatment will reduce their dosage by 
taking 120 mg BID for up to 4 weeks.  Within 4 weeks at the reduced dosage, subjects will 
resume taking the full dose of 240 mg BID.  If the subject is still unable to tolerate study 
treatment, the subject must discontinue study treatment as described in Section 10.1.  Subjects 
who do not tolerate study treatment will complete the final Follow-Up Visit 4 weeks after their 
last dose of study treatment and will then be withdrawn from the study (Section 10).  
11.3. 
Treatment Schedule for Subjects With Abnormal Lymphocyte 
Count 
11.3.1. 
Schedule for Subjects With Lymphocyte Count <500/mm3 
Study treatment must be temporarily withheld when the laboratory value for lymphocyte count 
meets the threshold limits defined in Table 4. 
Table 4: 
Lymphocyte Count Criteria 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 persistently <500/mm3 for more than 
24 weeks, study treatment must be temporarily 
withheld.  If lymphocyte count is intermittently 
<500/mm3 for more than 24 weeks, the Investigator 
should contact the Medical Monitor. 
All assessments should be performed at the central 
laboratory. 
While dosing is withheld, subjects will be followed 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 (see Lymphocyte Follow-Up in Table 2).  If the lymphocyte count remains <LLN 
for ≥24 weeks consecutively after the study treatment is withheld, the subject should be 
permanently discontinued from study treatment, and the Investigator should contact the Medical 
Monitor.   


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Subjects who temporarily withhold study treatment due to decreases in lymphocyte count, as 
described in Table 4, may resume study treatment when lymphocyte counts recover (defined as a 
lymphocyte count ≥LLN on 2 consecutive occasions at least 4 weeks apart).  If the lymphocyte 
count is <500/mm3 on 1 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 
final Follow-Up Visit (whichever is sooner).  Subjects whose lymphocyte counts remain <LLN 
at the end of the study (Week 96) will complete the final Follow-Up Visit and then be followed 
outside of this study at the Investigator’s discretion. 
See Figure 2 for the treatment schedule of subjects with lymphocyte counts <500/mm3. 
 


Protocol 109MS310 
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Figure 2: 
Schedule for Subjects With Lymphocyte Count <500/mm3 
 
LLN = lower limit of normal. 


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11.3.2. 
Schedule for Subjects With Lymphocyte Counts <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.  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 Temporarily Withhold or Permanently Discontinue 
Study Treatment for Any Other Reason Than Lymphopenia and Have a 
Lymphocyte Count <LLN 
Subjects who temporarily withhold or permanently discontinue BG00012 for any other reason 
than lymphopenia (see Section 11.2) and who have a lymphocyte count <LLN will be followed 
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.  Subjects who temporarily withhold or 
permanently discontinue study treatment and have a lymphocyte count <LLN for 48 weeks 
should continue tests and assessments according to the schedule defined in Section 4 until the 
lymphocyte count recovers or until the final Follow-Up Visit (whichever is sooner).  Subjects 
whose lymphocyte counts remain <LLN at the end of the study (Week 96) will complete the 
final Follow-Up Visit and will then be followed up outside of this study at the Investigator’s 
discretion. 
See Figure 3 for a schedule of subjects who complete, temporarily withhold, or permanently 
discontinue BG00012 for any other reason and who have a lymphocyte count <LLN. 
 


Protocol 109MS310 
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Figure 3: 
Schedule for Subjects Who Temporarily Withhold or Permanently 
Discontinue Study Treatment for Any Other Reason Than Lymphopenia* 
and Have Lymphocyte Count <LLN 
 
LLN = lower limit of normal. 
*For subjects with low lymphocytes, refer to Section 11.3.1 and 11.3.2. 
11.4. 
Precautions 
Not applicable. 
11.5. 
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.   


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11.6. 
Concomitant Therapy and Procedures 
11.6.1. 
Concomitant Therapy 
A concomitant therapy is any drug or substance administered between the subject’s Screening 
Visit and the subject’s last study visit. 
11.6.1.1. Allowed Concomitant Therapy 
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 nonprescribed 
drugs, unless they have received permission from the Investigator. 
11.6.1.2. Disallowed Concomitant Therapy 
Concomitant treatment with any of the following is not allowed unless approved by the Medical 
Monitor: 
 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-β, GA, natalizumab, cyclophosphamide, methotrexate, 
azathioprine, 4-aminopyridine or related products, etc.), with the exception of acute 
management of protocol-defined relapses (Section 11.6.3). 
 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 IVMP, except for 
protocol-defined treatment of relapses (Section 11.6.3).  Steroids that are 
administered by nonsystemic routes (e.g., topical or inhaled) are allowed. 
 Total lymphoid irradiation, cladribine, T-cell or T-cell receptor vaccination, any 
therapeutic monoclonal antibody, mitoxantrone, cyclosporine, IV Ig, plasmapheresis, 
or cytapheresis. 
The use of concomitant therapies defined above must be recorded on the subject’s CRF, 
according to instructions for CRF completion.  AEs related to administration of these therapies 
must be documented on the appropriate CRF. 
Subjects should be instructed not to start taking any new medications, including non-prescribed 
drugs, unless they have received permission from the Investigator. 
11.6.2. 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
the time the subject is enrolled in the study and the subject’s last study visit. 


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The use of concomitant therapies or procedures defined above must be recorded on the subject’s 
CRF, according to the instructions for CRF completion.  AEs related to administration of these 
therapies or procedures must be documented on the appropriate CRF. 
11.7. 
Continuation of Treatment 
No further provisions are made for access to the study treatment. 


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


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12.1.3. 
BG00012 Handling and Disposal 
The Investigator must return all used and unused drug wallets of BG00012 as instructed by 
Biogen unless approved for onsite destruction. 
If any BG00012 supplies are to be destroyed at the study site, the institution or appropriate site 
personnel must obtain prior approval from Biogen/contract research organization (CRO) by 
providing, in writing, the destruction policy or details of the method of destruction.  After such 
destruction, Biogen/CRO must be notified, in writing, of the details of the study treatment 
destroyed (e.g., lot or kit numbers, quantities), the date of destruction, and proof of destruction. 
12.1.4. 
BG00012 Accountability 
Accountability for study treatment is the responsibility of the Investigator.  The study site must 
maintain accurate records demonstrating dates and amount of study treatment received, to whom 
dispensed (subject-by-subject accounting), amount returned by the subject, and accounts of any 
study treatment accidentally or deliberately destroyed or lost.   
Unless otherwise notified, all drug wallets, both used and unused, must be saved for study 
treatment accountability.  At the end of the study, reconciliation must be made between the 
amount of BG00012 supplied, dispensed, and subsequently destroyed, lost, or returned to 
Biogen.  A written explanation must be provided for any discrepancies. 


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13. 
EFFICACY AND PHARMACODYNAMIC ASSESSMENTS 
See Section 4 for the timing of all assessments. 
13.1. 
Efficacy Assessments 
Not applicable; the study is not designed to assess efficacy. 
13.2. 
Pharmacodynamic Assessments 
The following tests will be performed to assess the pharmacodynamic properties of BG00012: 
 T cells, B cells, and natural killer (NK) cells 
 total T cells:  CD4+ and CD8+ 
 total B cells 
 total NK cells 
 T regulatory (Treg) cells, resting/naïve Treg, and activated Treg 
 naïve T cells, effector T cells, central/effector memory T cells, and activated 
(expressing human leukocyte antigen [HLA] DR/CD38) T cells 
 dendritic cells, monocytes, and NK cells (CD56dim/CD56bright) 
 transitional B cells, naïve B cells, memory B cells (IgD+/IgD-), and plasmablast cells 
 
 
13.3. 
Clinical Assessments 
The following clinical assessments will be performed: 
 
 
 
 


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14. 
SAFETY ASSESSMENTS 
Refer to Section 4 for the timing of all safety assessments. 
14.1. 
Clinical Safety Assessments 
The following clinical assessments will be performed to evaluate the safety profile of BG00012: 
 AEs, SAEs, and concomitant therapy and procedures recording 
 physical examinations, including body weight and height  
 vital sign measurements, including diastolic and systolic blood pressure, heart rate, 
body temperature, and respiratory rate.  Subjects must remain in a supine or seated 
position for 5 minutes prior to having heart rate and blood pressure taken. 
 12-lead electrocardiogram (ECG) readings 
14.2. 
Laboratory Safety Assessments 
The following laboratory assessments will be performed to evaluate the safety profile of 
BG00012: 
 hematology parameters:  hemoglobin, hematocrit, red blood cell count, WBC count 
(with differential), and platelet count 
 blood chemistry parameters:  albumin, sodium, potassium, chloride, total bilirubin, 
alkaline phosphatase, ALT/SPGT, AST/SGOT, blood urea nitrogen, creatinine, 
bicarbonate, calcium, magnesium, phosphate, uric acid, and glucose 


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


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


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15.2.2. 
Relationship of Events to Study Treatment 
The following definitions should be considered when evaluating the relationship of AEs and 
SAEs to the study treatment: 
Relationship of Event to Study Treatment 
Not related 
An AE will be considered “not related” to the use of the investigational drug if there is 
not a reasonable possibility that the event has been caused by the product under 
investigation.  Factors pointing toward this assessment include but are not limited to:  the 
lack of reasonable temporal relationship between administration of the drug and the 
event, the presence of a biologically implausible relationship between the product and the 
AE, or the presence of a more likely alternative explanation for the AE. 
Related 
An AE will be considered “related” to the use of the investigational drug if there is a 
reasonable possibility that the event may have been caused by the product under 
investigation.  Factors that point toward this assessment include but are not limited to:  a 
positive rechallenge, a reasonable temporal sequence between administration of the drug 
and the event, a known response pattern of the suspected drug, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between the drug 
and the AE, or a lack of an alternative explanation for the AE. 
15.2.3. 
Severity of Events 
The following definitions should be considered when evaluating the severity of AEs and SAEs: 
Severity of Event 
Mild 
Symptoms barely noticeable to subject or does not make subject uncomfortable; does not 
influence performance or functioning; prescription drug not ordinarily needed for relief of 
symptoms but may be given because of personality of subject. 
Moderate 
Symptoms of a sufficient severity to make subject uncomfortable; performance of daily 
activity is influenced; subject is able to continue in study; treatment for symptoms may be 
needed. 
Severe 
Symptoms cause severe discomfort; symptoms cause incapacitation or significant impact 
on subject’s daily life; severity may cause cessation of treatment with study treatment; 
treatment for symptoms may be given and/or subject hospitalized. 
15.2.4. 
Expectedness of Events 
Expectedness of all AEs will be determined by Biogen according to the Investigator’s Brochure. 
15.3. 
Monitoring and Recording Events 
15.3.1. 
Adverse Events 
Any AE experienced by the subject between the time of first dose of study treatment and the 
final Follow-Up Visit is to be recorded on the CRF, regardless of the severity of the event or its 
relationship to study treatment. 


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15.3.2. 
Serious Adverse Events 
Any SAE experienced by the subject between the time of the signing of the ICF and the final 
Follow-Up Visit is to be recorded on an SAE form, regardless of the severity of the event or its 
relationship to study treatment.  SAEs must be reported to Biogen or designee within 24 hours as 
described in Section 15.3.3.  Follow-up information regarding an SAE also must be reported 
with 24 hours.  
Subjects will be followed for all SAEs until the final Follow-Up Visit.  Thereafter, the event 
should be reported to Biogen or designee only if the Investigator considers the SAE to be related 
to study treatment. 
Any SAE that is ongoing when the subject completes or discontinues the study will be followed 
by the Investigator until the event has resolved, stabilized, or returned to baseline status. 
15.3.3. 
Immediate Reporting of Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify Biogen or designee within 24 hours of the study site staff becoming aware of the 
SAE.  It is the Investigator’s responsibility to ensure that the SAE reporting information and 
procedures are used and followed appropriately. 
 
Reporting Information for SAEs 
Any SAE that occurs between the time that the subject has signed the ICF and the final 
Follow-Up Visit must be reported to Biogen or designee within 24 hours of the study site staff 
becoming aware of the event.  Thereafter, the event should be reported only if the Investigator 
considers it related to study treatment. 
A report must be submitted to Biogen or designee regardless of the following: 
 Whether or not the subject has undergone study-related procedures 
 Whether or not the subject has received study treatment 
 The severity of the event 
 The relationship of the event to study treatment 
To report initial or follow-up information on an SAE, fax a completed SAE form; refer to the 
Study Reference Guide for complete contact information. 
15.3.3.1. Deaths 
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 


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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. 
15.3.4. 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are unexpected and 
judged by the Investigator or Biogen to be related to the study treatment administered. 
Biogen or designee will report SUSARs to the appropriate regulatory authorities and 
Investigators as required, according to local law. 
15.4. 
Procedures for Handling Special Situations 
15.4.1. 
Pregnancy 
Subjects should not become pregnant or impregnate their partners during the study and 
for 30 days after their last dose of study treatment.  If a female subject becomes pregnant, 
study treatment must be discontinued immediately. 
The Investigator must report a pregnancy by faxing the appropriate form to Biogen or designee 
within 24 hours of the study site staff becoming aware of the pregnancy at the fax number 
provided in the Study Reference Guide.  The Investigator or study site staff must report the 
outcome of the pregnancy to Biogen or designee.  
Congenital abnormalities and birth defects in the offspring of male or female subjects should be 
reported as an SAE if conception occurred during the study treatment period. 
15.4.2. 
Overdose 
An overdose is any dose of study treatment administered to a subject or taken by a subject that 
exceeds the dose assigned to the subject according to the protocol.  Overdoses are not considered 
AEs and should not be recorded as an AE on the CRF; however, all overdoses must 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 must be reported to Biogen or designee even if the overdose 
does not result in an AE.  If an overdose results in an AE, the AE must be recorded.  If an 
overdose results in an SAE, both the SAE and Overdose forms must be completed and faxed to 
Biogen or designee.  All study treatment-related dosing information must be recorded on the 
dosing CRF. 
15.4.3. 
Medical Emergency 
In a medical emergency requiring immediate attention, study site staff will apply appropriate 
medical intervention, according to current standards of care.  The Investigator (or designee) 
should contact the study’s Medical Director.  Refer to the Study Reference Guide’s Official 
Study Contact List for complete contact information. 
15.4.3.1. Unblinding for Medical Emergency 
Not applicable. 


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15.5. 
Contraception Requirements 
Subjects of childbearing potential must practice effective contraception (as determined by the 
Investigator) during the study and be willing and able to continue contraception for 30 days after 
their last dose of study treatment.  In addition, male subjects should not donate sperm for the 
duration of the study and for at least 30 days after their last dose of study treatment. 
For the purposes of this study, women who do not meet one of the following criteria listed below 
are considered to be physiologically capable of becoming pregnant and are, therefore, defined as 
women of childbearing potential: 
 Postmenopausal 
o 12 months of natural (spontaneous) amenorrhea without an alternative medical 
cause and a serum follicle-stimulating hormone level >40 mIU/mL  
o 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
 Posthysterectomy 
 Female surgical sterilization (e.g., bilateral tubal ligation) 
For the purposes of the study, highly effective contraception is defined as use of 1 or more of the 
following: 
For females: 
 Established use of oral, injected, or implanted hormonal methods of contraception.  
 Placement of an intrauterine device or intrauterine system. 
 Barrier methods of contraception with use of a spermicide:  condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream suppository.  
The use of barrier contraceptives should always be supplemented with the use of a 
spermicide. 
 Male surgical sterilization (with the appropriate postvasectomy documentation of the 
absence of sperm in the ejaculate).  (For female subjects participating in the study, 
male sexual partners must have undergone surgical sterilization.) 
For males: 
 Effective male contraception includes a vasectomy with negative semen analysis at 
follow-up, or the use of condoms with spermicide. 
True abstinence, when this is consistent with the preferred and usual lifestyle of the subject, can 
be considered an acceptable method of contraception based on the evaluation of the Investigator 
who should also take into consideration the duration of the clinical trial.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not 
considered acceptable methods of contraception. 
Pregnancy reporting is described in Section 15.4.1. 


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15.6. 
Safety Responsibilities 
15.6.1. 
The Investigator 
The Investigator’s responsibilities include the following: 
 Monitor and record all AEs, including SAEs, regardless of the severity or relationship 
to study treatment. 
 Determine the seriousness, relationship, and severity of each event. 
 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. 
 Pursue AE follow-up information, if possible, until the event has resolved or has 
become stable. 
 Report SAEs to local ethics committees, as required by local law. 
15.6.2. 
Biogen 
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 is to notify all appropriate regulatory authorities, central ethics committees, 
and Investigators of SAEs, as required by local law, within required time frames. 


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16. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
The objectives of the study and the endpoints to be analyzed are listed in Section 6. 
16.1. 
Pharmacokinetics 
Not applicable. 
16.2. 
Pharmacodynamics 
16.2.1. 
Analysis Population 
The pharmacodynamic population is defined as all subjects who receive at least 1 dose of study 
treatment and have at least 1 pharmacodynamic measurement after Baseline. 
16.2.2. 
Methods of Analysis 
Statistical analyses will be 
 and descriptive in nature, with appropriate measures of 
precision provided where applicable.  There is no planned statistical hypothesis testing in this 
study.   
16.2.2.1. Analysis of the Primary Endpoint 
Counts and change from Baseline in counts for each of the lymphocyte subsets will be 
descriptively summarized at each applicable visit.  Furthermore, the primary endpoints will be 
summarized in various ALC subgroups to evaluate the nature of change in each subset in relation 
to the change in ALC.  Additionally, a mixed model for repeated measures (MMRM) will be 
used, which will be fit with the change from Baseline for each of the lymphocyte subsets as the 
dependent variable and will include ALC subgroups, visit, corresponding Baseline counts, age, 
gender, and ALC groups-by-visit interaction as fixed effects to estimate the difference between 
ALC subgroups.  Point estimates and 2-sided 90% confidence intervals (CIs) will be derived 
from the model.  Appropriate transformation may be performed based on the distribution of data. 
ALC subgroups of interest include (1) subjects who have all ALC values ≥LLN up to Week 48, 
(2) subjects who have at least 1 ALC value <LLN over 48 weeks, and (3) subjects who have at 
least 2 ALC values <LLN over 48 weeks.  Additional subgroups will be further defined in the 
Statistical Analysis Plan. 
16.2.2.2. Analysis of the Secondary Endpoints 
For the secondary endpoints (IgG isotypes and ALCs), actual values and change from Baseline 
will be descriptively summarized at each applicable visit.  In addition, the same type of MMRM 
used for analysis of primary endpoints will be employed, which will be fit with the change from 
Baseline in each of the IgG isotypes and ALCs as the dependent variable and will include visit, 
corresponding baseline value, age, and gender as fixed effects. 


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16.4. 
Safety 
16.4.1. 
Analysis Population 
The safety population is defined as all subjects who receive at least 1 dose of study treatment. 
16.4.2. 
Methods of Analysis 
All AEs, concomitant therapy and procedures, clinical laboratory results, physical examinations, 
vital signs, and 12-lead ECG readings data will be evaluated for safety. 
16.4.2.1. Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities.  Only 
treatment-emergent AEs will be presented in the summary tables.  Treatment emergent is defined 
as having an onset date on or after start of study treatment or having worsened after the start of 
study treatment. 
Subject incidences of all AEs, SAEs, AEs leading to treatment discontinuation and study 
withdrawal, and other AEs of special interest will be tabulated by system organ class and 
preferred term in descending order of frequency. 
16.4.2.2. Clinical Laboratory Results 
Clinical laboratory evaluations include hematology and blood chemistry.  Laboratory data will 
be summarized using shift tables.  Each laboratory value for each subject will be flagged as 
“low,” “normal,” or “high,” relative to the parameter’s normal range.  For each parameter, the 
number (percentage) of subjects experiencing post-Baseline shifts to “low” or “high” based on 
their minimum or maximum values at any time postdose will be summarized.  In addition, a 


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summary of laboratory values categorized based on Common Toxicity Criteria grade will also be 
generated.  Summary statistics for actual values and change from Baseline will also be presented 
for quantitative laboratory data. 
16.4.2.3. Physical Examinations 
The analyses of physical examinations will include summary statistics (actual value and change 
from Baseline for body weight and height) over time by visit. 
16.4.2.4. Vital Signs 
The analysis of vital signs will focus on 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 group.   
The definitions of these clinically relevant abnormalities are shown in Table 5.   
Table 5: 
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs 
Vital Sign 
Criteria for Abnormalities 
Temperature  
>38°C or an increase from Baseline of ≥1°C 
Pulse 
>120 bpm or an increase from Baseline of >20 bpm 
<50 bpm or a decrease from Baseline of >20 bpm 
Systolic Blood Pressure 
>180 mmHg or an increase from Baseline of >40 mmHg 
<90 mmHg or a decrease from Baseline of >30 mmHg 
Diastolic Blood Pressure 
>105 mmHg or an increase from Baseline of >30 mmHg 
<50 mmHg or a decrease from Baseline of >20 mmHg 
The analyses of vital signs will also include summary statistics (actual value and change from 
Baseline for temperature, pulse, and systolic and diastolic blood pressure) over time by visit. 
16.4.2.5. ECG Data 
A listing of subjects with abnormal ECG status will be presented.  Changes from Baseline in 
ECG will be summarized using shift tables.  The number and percentage of subjects with shifts 
to categorical values (abnormal, not AE/abnormal, AE) will be summarized. 
16.5. 
Clinical Assessments 
16.5.1. 
Analysis Population 
The evaluable population for clinical assessments is defined as all subjects who receive at least 
1 dose of study treatment and at least 1 measurement for each of the clinical assessments after 
Baseline. 


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16.6. 
Interim Analyses 
Interim analyses may be performed to support regulatory filings and/or publications and will be 
documented in the Statistical Analysis Plan. 
16.7. 
Sample Size Considerations 
The sample size for this study is not based on formal hypothesis testing but on the precision of 
the estimation of the primary endpoints and the ratios between various ALC subgroups. 
For example, the Phase 2 and 3 controlled and uncontrolled efficacy and safety studies in MS, 
based on data available as of May 2014 from 2470 subjects with at least 1 post-Baseline value 
from the interim analysis of the Integrated Summary of Safety of Tecfidera, showed that 76% of 
subjects had all ALC values ≥LLN and 24% had at least 1 ALC value <LLN up to Week 48.  
Assuming the same proportion of subjects in this study will have 1 or more ALC values <LLN, it 
is expected that approximately 137 subjects will have all ALC values ≥LLN and approximately 
43 subjects will have at least 1 ALC value <LLN at Week 48, based on a total of 180 evaluable 
subjects at Week 48.  With this sample size, the 90% CIs for the ratio of the 2 subgroups for the 
change from Baseline at Week 48 in lymphocyte subsets are illustrated below using the scenario 
of a true ratio of 0.8 (20% decrease) and 0.7 (30% decrease), respectively.  When assessing 
lymphocyte subsets between subjects with at least 2 ALC values <LLN up to the first 48 weeks 
of treatment versus subjects who have all ALC values ≥LLN throughout the study, the 90% CIs 
of the ratio would be wider, as historical data suggest that 16% of the patients treated with 
Tecfidera may have 2 or more ALC values <LLN during the first 48 weeks of treatment. 
To allow for a 10% discontinuation rate, a total of 200 subjects are planned for enrollment. 


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Table 6: 
Sample Size Calculations 
Primary 
Endpoints 
SD1 
Ratio 
90% CI for the Ratio Based on N = 180 
Subjects With At Least 1 ALC 
<LLN2 vs. Subjects With All 
ALC ≥LLN2 
Subjects With At Least 2 ALC 
<LLN2 vs. Subjects With All 
ALC ≥LLN2 
CD4 T cell 
count 
0.32 
0.8 
0.73, 0.88 
0.71, 0.90 
0.7 
0.63, 0.77 
0.63, 0.78 
CD8 T cell 
count 
0.35 
0.8 
0.72, 0.89 
0.71, 0.91 
0.7 
0.63, 0.78 
0.62, 0.79 
CD56bright NK 
cell count 
0.57 
0.8 
0.68, 0.95 
0.65, 0.98 
0.7 
0.59, 0.83 
0.57, 0.86 
Treg count 
0.95 
0.8 
0.60, 1.07 
0.57, 1.12 
0.7 
0.52, 0.93 
0.50, 0.98 
ALC = absolute lymphocyte count; CD = cluster of differentiation; CI = confidence interval; LLN = lower limit of 
normal; NK = natural killer; SD = standard deviation; Treg = T regulatory; vs. = versus. 
1 Common standard deviation for the log-transformed change from Baseline. 
2 Up to Week 48. 
 


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


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subject’s legally authorized representative).  The subject must be given sufficient time to 
consider whether to participate in the study. 
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., Protected Health Information 
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 partners and designees, ethics committees, 
and various government health agencies may inspect the records of this study.  Every effort will 
be made to keep the subject’s personal medical data confidential. 
17.5. 
Compensation for Injury 
Biogen maintains appropriate insurance coverage for clinical studies and will follow applicable 
local compensation laws. 
17.6. 
Conflict of Interest 
The Investigators should address any potential conflicts of interest (e.g., financial interest in 
Biogen) 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 screen any subjects prior to completion of a study initiation visit, 
conducted by Biogen or designee.  This initiation visit will include a detailed review of the 
protocol and study procedures. 
18.2. 
Quality Assurance 
During and/or after completion of the study, quality assurance officers named by Biogen or the 
regulatory authorities may wish to perform onsite audits or inspections.  The Investigator will be 
expected to cooperate with any audit or inspection and to provide assistance and documentation 
(including source data) as requested. 
18.3. 
Monitoring of the Study 
The Investigator must permit study-related monitoring by providing direct access to source data 
and to the subjects’ medical histories. 
The Clinical Monitor will visit the Investigator at regular intervals during the study and after the 
study has completed, as appropriate. 
During these visits, CRFs and supporting documentation related to the study will be reviewed 
and any discrepancies or omissions will be resolved.   
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure protocol adherence, quality of data, study treatment accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities. 
18.4. 
Study Funding 
Biogen is the Sponsor of the study and is funding the study.  All financial details are provided in 
the separate contracts between the institution, Investigator, and Biogen. 
18.5. 
Publications 
Details are included in the clinical trial agreement for this study. 


Protocol 109MS310 
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CONFIDENTIAL 
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Biogen MA Inc. 
67 
 
19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION 
19.1. 
External Contract Organizations 
19.1.1. 
Contract Research Organization  
A CRO, 
, will be responsible for administrative aspects of the study, including, but not 
limited to, study initiation, monitoring, medical support, and management of SAE reports and 
data management.  Before subjects are screened at each study site, 
 will review study 
responsibilities with the Investigators and other study site staff, as appropriate. 
19.1.2. 
Interactive Response Technology 
IXRS will be used in this study.  Before subjects are screened or enrolled, the IXRS vendor will 
provide each study site with the necessary training, a user manual, and access rights to the 
system. 
19.1.3. 
Electronic Data Capture 
Subject information will be captured and managed by study sites on electronic CRFs by a 
Web-based electronic data capture tool supported by iMedidata RAVE and configured by 
. 
19.1.4. 
Central Laboratories for Laboratory Assessments 
Central laboratories have been selected by Biogen to analyze the laboratory samples collected for 
this study.  
19.2. 
Study Committees 
Not applicable.  Given the established safety and efficacy of DMF via the Phase 2 and Phase 3 
studies, advisory committees were deemed not necessary for this study. 
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 
Section 17). 


Protocol 109MS310 
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CONFIDENTIAL 
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Biogen MA Inc. 
68 
 
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. 


Protocol 109MS310 
Version 2 
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CONFIDENTIAL 
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Biogen MA Inc. 
69 
 
20. 
REFERENCES 
Brønnum-Hansen H, Koch-Henriksen N, Stenager E. Trends in survival and cause of death in 
Danish patients with multiple sclerosis. Brain. 2004;127(Pt 4):844-50. 
Calabresi PA, Kieseier BC, Arnold DL, et al. Pegylated interferon beta-1a for relapsing-remitting 
multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol. 
2014;13(7):657-65. Epub 2014 Apr 30. 
Chitnis T, Tenembaum S, Banwell B, et al. Consensus statement: evaluation of new and existing 
therapeutics for pediatric multiple sclerosis. Mult Scler. 2012;18(1):116-27. 
Coles AJ, Fox E, Vladic A, et al. Alemtuzumab more effective than interferon β-1a at 5-year 
follow-up of CAMMS223 clinical trial. Neurology. 2012;78(14):1069-78. 
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. 
Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for 
relapsing multiple sclerosis. N Engl J Med. 2012a;367(12):1098-107. 
Gold R, Miller DH, Phillips JT, et al. Clinical efficacy of BG-12 in relapsing-remitting multiple 
sclerosis: an integrated analysis of the Phase 3 DEFINE and CONFIRM studies. Presented at the 
28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis 
(ECTRIMS); October 10-13, 2012; Lyons, France. 
Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease 
progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group 
(MSCRG). Ann Neurol. 1996;39(3):285-94. 
Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves 
disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-
blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 
1995;45(7):1268-76. 
Kappos L, Radue EW, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in 
relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387-401. Epub 2010 Jan 20. 
Linker RA, Lee DH, Ryan S, et al. Fumaric acid esters exert neuroprotective effects in 
neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain. 2011;134(Pt 3):678-
92. 
Noseworthy JH, Lucchinetti C, Rodriguez M, et al. Multiple sclerosis. N Engl J Med. 
2000;343(13):938-52. 


Protocol 109MS310 
Version 2 
Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
70 
 
O'Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for 
relapsing multiple sclerosis. N Engl J Med. 2011;365(14):1293-303. 
Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of 
natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899-910. 
Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 
Revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292-302. 
PRISMS Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a 
in relapsing/remitting multiple sclerosis. Lancet. 1998;352(9139):1498-504. 
Rosati G. The prevalence of multiple sclerosis in the world: an update. Neurol Sci. 
2001;22(2):117-39. 
Runmarker B, Andersen O. Prognostic factors in a multiple sclerosis incidence cohort with 
twenty-five years of follow-up. Brain. 1993;116 ( Pt 1):117-34. 
The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting 
multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-
controlled trial. Neurology. 1993;43(4):655-61. 
Waldman A, Gorman M, Rensel M, et al. Management of pediatric central nervous system 
demyelinating disorders: consensus of United States neurologists. J Child Neurol. 
2011;26(6):675-82. 
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. 
 
 


Protocol 109MS310 
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Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
CONFIDENTIAL 
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Biogen MA Inc. 
71 
 
21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL 
I have read the foregoing protocol, “An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets 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) 
 


Signature Page
Document Name: 109MS310 Protocol V2 Final 22Jan16
Document Title: An Open-Label Study to Assess the Effects of BG00012 on Lymphocyte
Subsets in Subjects With Relapsing-Remitting Multiple Sclerosis
Signed by
Role
Date / Time (UTC)
Signing as Approver
01/29/2016 18:34:34


CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
1 
Biogen MA Inc.
250 Binney Street
Cambridge, MA 02142
United States
PROTOCOL NUMBER: 
109MS310  
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead Berkshire
SL6 4AY
United Kingdom
PHASE OF DEVELOPMENT: 
3b 
PROTOCOL TITLE:  An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With Relapsing-Remitting Multiple Sclerosis 
EUDRA CT NO: 
2015-001973-42 
DATE: 
30 April 2015 
Version 1 
FINAL 






Protocol 109MS310 
Version 1 
Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
4 
 
TABLE OF CONTENTS 
1.
SPONSOR INFORMATION .....................................................................................10
2.
LIST OF ABBREVIATIONS.....................................................................................11
3.
SYNOPSIS .................................................................................................................13
4.
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR STUDY 
109MS310...................................................................................................................16
4.1.
Study Schematic .........................................................................................................16
4.2.
Schedule of Activities .................................................................................................17
4.3.
Additional Information ...............................................................................................21
4.3.1.
Site Personnel .............................................................................................................21
4.3.2.
Subject Management ..................................................................................................22
5.
INTRODUCTION ......................................................................................................23
5.1.
Overview of Multiple Sclerosis ..................................................................................23
5.2.
Current Therapies for Multiple Sclerosis ...................................................................24
5.3.
Profile of Previous Experience With BG00012 ..........................................................24
5.3.1.
Nonclinical Experience ...............................................................................................24
5.3.2.
Clinical Experience .....................................................................................................25
5.4.
Study Rationale ...........................................................................................................26
5.5.
Rationale for Dosing Regimen ...................................................................................26
6.
STUDY OBJECTIVES AND ENDPOINTS ..............................................................27
6.1.
Primary Objective and Endpoint ................................................................................27
6.2.
Secondary Objective and Endpoints ...........................................................................27
27
7.
STUDY DESIGN .......................................................................................................29
7.1.
Study Overview ..........................................................................................................29
7.2.
Overall Study Duration and Follow-Up .....................................................................29
7.2.1.
Screening ....................................................................................................................29
7.2.2.
Treatment Period and Extension Period .....................................................................30
7.2.3.
Follow-Up ...................................................................................................................30
30
31


Protocol 109MS310 
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31
7.2.6.
Additional Assessments if Required by Local Tecfidera Prescribing 
Information .................................................................................................................31
7.3.
Study Stopping Rules .................................................................................................31
7.4.
End of Study ...............................................................................................................31
8.
SELECTION OF SUBJECTS ....................................................................................32
8.1.
Inclusion Criteria ........................................................................................................32
8.2.
Exclusion Criteria .......................................................................................................32
9.
ENROLLMENT, REGISTRATION, AND RANDOMIZATION ............................35
9.1.
Screening and Enrollment ...........................................................................................35
9.2.
Registration of Subjects ..............................................................................................35
9.3.
Blinding Procedures ....................................................................................................35
10.
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY ...........................................36
10.1.
Discontinuation of Study Treatment ...........................................................................36
10.2.
Withdrawal of Subjects From Study ...........................................................................37
11.
STUDY TREATMENT USE .....................................................................................38
11.1.
Regimen ......................................................................................................................38
11.2.
Modification of Dose and/or Treatment Schedule ......................................................38
11.2.1.
Dosing Interruption for Abnormal Laboratory Values ...............................................38
11.2.2.
Resumption of Study Treatment Dosing ....................................................................39
11.2.3.
Subsequent Development of Additional Laboratory Abnormalities ..........................39
11.2.4.
Dosage Reductions .....................................................................................................40
11.3.
Treatment Schedule for Subjects With Abnormal Lymphocyte Count ......................40
11.3.1.
Schedule for Subjects With Lymphocyte Count <500/mm3.......................................40
11.3.2.
Sch
3 ......................42
11.3.3.
Schedule for Subjects Who Complete, Temporarily Withhold, or 
Permanently Discontinue Study Treatment for Any Reason and Have a 
Lymphocyte Count <LLN ..........................................................................................42
11.4.
Precautions ..................................................................................................................43
11.5.
Compliance .................................................................................................................44
11.6.
Concomitant Therapy and Procedures ........................................................................44
11.6.1.
Concomitant Therapy .................................................................................................44


Protocol 109MS310 
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11.6.1.1.
Allowed Concomitant Therapy ...................................................................................44
11.6.1.2.
Disallowed Concomitant Therapy ..............................................................................44
11.6.2.
Concomitant Procedures .............................................................................................45
45
11.7.
Continuation of Treatment ..........................................................................................45
12.
STUDY TREATMENT MANAGEMENT ................................................................46
12.1.
BG00012 .....................................................................................................................46
12.1.1.
BG00012 Preparation .................................................................................................46
12.1.2.
BG00012 Storage ........................................................................................................46
12.1.3.
BG00012 Handling and Disposal ...............................................................................47
12.1.4.
BG00012 Accountability ............................................................................................47
13.
EFFICACY AND PHARMACODYNAMIC ASSESSMENTS ................................48
13.1.
Efficacy Assessments .................................................................................................48
13.2.
Pharmacodynamic Assessments .................................................................................48
13.3.
Clinical Assessments ..................................................................................................48
14.
SAFETY ASSESSMENTS ........................................................................................49
14.1.
Clinical Safety Assessments .......................................................................................49
14.2.
Laboratory Safety Assessments ..................................................................................49
15.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................50
15.1.
Definitions ..................................................................................................................50
15.1.1.
Adverse Event .............................................................................................................50
15.1.2.
Serious Adverse Event ................................................................................................50
15.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................51
15.2.
Safety Classifications ..................................................................................................51
15.2.1.
Investigator Assessment of Events .............................................................................51
15.2.2.
Relationship of Events to Study Treatment ................................................................52
15.2.3.
Severity of Events .......................................................................................................52
15.2.4.
Expectedness of Events ..............................................................................................52
15.3.
Monitoring and Recording Events ..............................................................................52
15.3.1.
Adverse Events ...........................................................................................................52
15.3.2.
Serious Adverse Events ..............................................................................................53


Protocol 109MS310 
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Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
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15.3.3.
Immediate Reporting of Serious Adverse Events .......................................................53
15.3.3.1.
Deaths .........................................................................................................................54
15.3.4.
Suspected Unexpected Serious Adverse Reactions ....................................................54
15.4.
Procedures for Handling Special Situations ...............................................................54
15.4.1.
Pregnancy ...................................................................................................................54
15.4.2.
Overdose .....................................................................................................................54
15.4.3.
Medical Emergency ....................................................................................................55
15.4.3.1.
Unblinding for Medical Emergency ...........................................................................55
15.5.
Contraception Requirements ......................................................................................55
15.6.
Safety Responsibilities ................................................................................................56
15.6.1.
The Investigator ..........................................................................................................56
15.6.2.
Biogen .........................................................................................................................57
16.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ...........58
16.1.
Pharmacokinetics ........................................................................................................58
16.2.
Pharmacodynamics .....................................................................................................58
16.2.1.
Analysis Population ....................................................................................................58
16.2.2.
Methods of Analysis ...................................................................................................58
16.2.2.1.
Analysis of the Primary Endpoint...............................................................................58
16.2.2.2.
Analysis of the Secondary Endpoints .........................................................................58
59
59
16.4.
Safety ..........................................................................................................................59
16.4.1.
Analysis Population ....................................................................................................59
16.4.2.
Methods of Analysis ...................................................................................................59
16.4.2.1.
Adverse Events ...........................................................................................................59
16.4.2.2.
Clinical Laboratory Results ........................................................................................60
16.4.2.3.
Physical Examinations ................................................................................................60
16.4.2.4.
Vital Signs ..................................................................................................................60
16.4.2.5.
ECG Data ....................................................................................................................60
16.5.
Clinical Assessments ..................................................................................................61
16.5.1.
Analysis Population ....................................................................................................61


Protocol 109MS310 
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Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
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61
16.6.
Interim Analyses .........................................................................................................61
16.7.
Sample Size Considerations .......................................................................................61
17.
ETHICAL REQUIREMENTS ...................................................................................63
17.1.
Declaration of Helsinki ...............................................................................................63
17.2.
Ethics Committee ........................................................................................................63
17.3.
Subject Information and Consent ...............................................................................63
17.4.
Subject Data Protection ..............................................................................................64
17.5.
Compensation for Injury .............................................................................................64
17.6.
Conflict of Interest ......................................................................................................64
17.7.
Registration of Study and Disclosure of Study Results ..............................................64
18.
ADMINISTRATIVE PROCEDURES .......................................................................65
18.1.
Study Site Initiation ....................................................................................................65
18.2.
Quality Assurance .......................................................................................................65
18.3.
Monitoring of the Study..............................................................................................65
18.4.
Study Funding .............................................................................................................65
18.5.
Publications .................................................................................................................65
19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION ........................66
19.1.
External Contract Organizations .................................................................................66
19.1.1.
Contract Research Organization .................................................................................66
19.1.2.
Interactive Response Technology ...............................................................................66
19.1.3.
Electronic Data Capture ..............................................................................................66
19.1.4.
Central Laboratories for Laboratory Assessments .....................................................66
19.2.
Study Committees .......................................................................................................66
19.3.
Changes to Final Study Protocol ................................................................................66
19.4.
Ethics Committee Notification of Study Completion or Termination ........................67
19.5.
Retention of Study Data ..............................................................................................67
19.6.
Study Report Signatory...............................................................................................67
20.
REFERENCES ...........................................................................................................68
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL .........................................70
 


Protocol 109MS310 
Version 1 
Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
CONFIDENTIAL 
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Biogen MA Inc. 
9 
 
LIST OF TABLES 
Table 1:
Study Activities for Study 109MS310 - Table 1 of 2 .................................................17
Table 2:
Study Activities for Study 109MS310 - Table 2 of 2 .................................................20
Table 3:
Laboratory Criteria Requiring Withholding or Permanent Discontinuation of 
Treatment ....................................................................................................................38
Table 4:
Lymphocyte Count Criteria Requiring Withholding of Study Treatment ..................40
Table 5:
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs ...................60
Table 6:
Sample Size Calculations ...........................................................................................62
 
LIST OF FIGURES 
Figure 1:
Study Design ...............................................................................................................16
Figure 2:
Schedule for Subjects With Lymphocyte Count <500/mm3.......................................42
Figure 3:
Schedule for Subjects Who Complete, Temporarily Withhold, or 
Permanently Discontinue Study Treatment for Any Reason and Have 
Lymphocyte Count <LLN ..........................................................................................43
 
 


Protocol 109MS310 
Version 1 
Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
CONFIDENTIAL 
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Biogen MA Inc. 
10 
 
1. 
SPONSOR INFORMATION 
The Sponsor is Biogen MA Inc. in North America and Biogen Idec Research Limited in the Rest 
of World.  Biogen MA Inc. and Biogen Idec Research Limited are referred to as Biogen in this 
protocol. 
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 
 
 
refer to the 
r 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 109MS310 
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Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
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11 
 
2. 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALC 
absolute lymphocyte count 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
BBB 
blood-brain barrier 
BID 
twice daily 
CBC 
complete blood count 
CD 
cluster of differentiation 
CI 
confidence interval 
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization 
DHA 
Directions for Handling and Administration 
DMF 
dimethyl fumarate 
DMT 
disease modifying therapy 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
 
 
GA 
glatiramer acetate 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IFN 
interferon 
Ig 
immunoglobulin 
IV 
intravenous 
IVMP 
intravenous methylprednisolone 
IXRS 
Interactive Voice and Web Response System 
LLN 
lower limit of normal 
MMRM 
mixed model for repeated measures 
MS 
multiple sclerosis 
NK 
natural killer (cells) 
Nrf2 
nuclear factor (erythroid-derived 2)-like 2 
 
 
RNA 
ribonucleic acid 
RRMS 
relapsing-remitting multiple sclerosis 
SAE 
serious adverse event 
SGOT 
serum glutamic oxaloacetic transaminase 


Protocol 109MS310 
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Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
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SGPT
serum glutamic pyruvic transaminase
SPMS 
secondary progressive multiple sclerosis 
SUSAR 
suspected unexpected serious adverse reaction 
Treg 
T regulatory (cells) 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 
 


Protocol 109MS310 
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Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
CONFIDENTIAL 
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Biogen MA Inc. 
13 
 
3. 
SYNOPSIS 
Protocol Number: 
109MS310 
Protocol Title: 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With Relapsing-Remitting 
Multiple Sclerosis 
Version Number 
1 
Name of Study Treatment: 
BG00012 (dimethyl fumarate [DMF]; Tecfidera®) 
Study Indication: 
Multiple sclerosis (MS) 
Study Rationale 
Given the putative immunomodulatory properties of DMF 
and its observed effects on lymphocytes in humans, further 
evaluation of its effects on immune function is needed.  The 
effect of BG00012 on lymphocyte subtypes is yet unknown, 
and its evaluation may provide insights into the mechanisms 
underlying BG00012-associated lymphopenia.  This study is 
therefore being conducted to assess the effects of BG00012 
on lymphocyte subset counts and immunoglobulins (Igs) 
within the first year of treatment and until the end of the 
study. 
Phase of Development: 
3b 
Study Objectives and 
Endpoints: 
The primary objective of the study is to evaluate the effect 
of BG00012 on lymphocyte subset counts during the first 
year of treatment in subjects with RRMS. 
The primary endpoint that relates to this objective is the 
change in lymphocyte subset counts for up to 48 weeks. 
A secondary objective is to evaluate the pharmacodynamic 
effect of BG00012 on absolute lymphocyte counts (ALCs) 
and Igs during the first year of treatment.  
The endpoints that relate to this objective are the changes in 
IgG isotypes and ALCs for up to 48 weeks. 
 
 


Protocol 109MS310 
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Study Design: 
This is an open-label, multicenter study to evaluate the 
effects of BG00012 on lymphocyte subtypes and Ig 
isotypes.   
After the Screening Visit (up to 28 days), subjects will 
receive BG00012 treatment for 48 weeks (Treatment 
Period) and will then continue on 240 mg BG00012 twice 
daily (BID) for an additional 48 weeks (Extension Period).  
Blood samples for lymphocyte subset analysis, as well as 
complete blood count with differential, will be collected at 
Screening, Baseline (Day 1), and Weeks 4, 8, 12, 24, 36, 48, 
72, and 96.  Clinical samples for the analysis of blood 
chemistries will be collected at Screening, Baseline (Day 1), 
and Weeks 4, 8, 24, 48, and 96.  A post-treatment follow-up 
visit at which safety assessments will be performed will 
occur 4 weeks after the final dose of BG00012.   
Subjects who withdraw from the study while on study 
treatment will complete the Discontinuation and/or 
Withdrawal Visit as soon as possible but no later than 
2 weeks after their last dose of study treatment and will 
complete the final Follow-Up Visit 4 weeks after their last 
dose of study treatment unless consent has been withdrawn.  
Subjects who complete, temporarily withhold, or 
permanently discontinue study treatment for any reason and 
have a lymphocyte count <LLN will continue 
protocol-required visits and assessments and will also be 
or for 24 weeks after the last dose (whichever is sooner).  
Subjects who withdraw from the study for reasons other 
than safety may be replaced at the discretion of Biogen. 
Refer to Table 1 and Table 2 for the timing of all study 
assessments. 
Study Location: 
Approximately 100 sites in North America and Europe 
Number of Planned Subjects:
Approximately 200 subjects will be treated. 
Study Population: 
This study will be conducted in male and female subjects, 
aged 18 through 65 years, with a confirmed diagnosis of 
RRMS according to the revised McDonald criteria (2010) 
[Polman 2011]. 


Protocol 109MS310 
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Detailed criteria are described in Section 8. 
Treatment Groups: 
Approximately 200 subjects will receive oral BG00012 at a 
dose of 120 mg BID for the first 7 days and at a 
maintenance dose of 240 mg BID thereafter.  Temporary 
dose reductions to 120 mg BID may be considered for 
individuals who do not tolerate the maintenance dose due to 
flushing and/or gastrointestinal disturbances.  Within 
4 weeks, the recommended dose of 240 mg BID should be 
resumed. 
Duration of Treatment and 
Follow-up: 
The study period will consist of a Screening Visit within 
4 weeks of Baseline, a Treatment Period of 48 weeks, an 
Extension Period of 48 weeks, and a final Follow-Up Visit.  
Subjects who complete, temporarily withhold, or 
permanently discontinue study treatment for any reason and 
have a lymphocyte count <LLN will be followed every 
4 
or for 
24 weeks after the last dose (whichever is sooner).  If the 
lymphocyte count remains <LLN for 24 weeks after the last 
dose, subjects who had temporarily withheld or permanently 
discontinued study treatment will continue assessments 
specified in the protocol.  Subjects will receive treatment for 
96 weeks.  The study duration may vary from approximately 
104 to 124 weeks. 


Protocol 109MS310 
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4. 
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR 
STUDY 109MS310 
4.1. 
Study Schematic 
The study design for Study 109MS310 is shown in Figure 1, and the study activities are shown in 
Table 1 and Table 2. 
Figure 1: 
Study Design 
 
BID = twice daily; LLN = lower limit of normal. 
*Subjects will receive oral BG00012 at a dose of 120 mg BID for the first 7 days and at a maintenance dose of 
240 mg BID thereafter.  Temporary dose reductions to 120 mg BID may be considered (see Section 11.2.4). 
**Subjects with a lymphocyte count <LLN will have additional lymphocyte and subset analysis (see Section 11.3). 


Protocol 109MS310 
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17 
 
4.2. 
Schedule of Activities 
Table 1: 
Study Activities for Study 109MS310 - Table 1 of 2 
Tests and 
Assessments 
Screening 
Treatment Period 
Extension Period 
Final 
Follow-
Up 
Visit1 
Within 
28 days 
before 
Baseline 
Baseline 
(Day 1) 
Week 4 
(Day 
28 
±3 
days) 
Week 8 
(Day 
56 
±3 
days) 
Week 12 
(Day  
84 
±3 days) 
Week 24 
(Day 
168 
±5 days) 
Week 36 
(Day 
252 
±5 days) 
Week 48 
(Day 
336 
±5 days) 
Week 60 
(Day 
420 
±5 days) 
Week 72 
(Day 
504 
±5 days) 
Week 84 
(Day 
588 
±5 days) 
Week 
96 (Day 
672 
±5 days) 
4 weeks 
±5 days 
after 
final 
dose 
Informed Consent2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B and C 
Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination4 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
12-Lead ECG 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Hematology (CBC 
With Differential)6 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Blood Chemistry 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
Lymphocyte Subset 
Analysis6 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 


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Tests and 
Assessments 
Screening 
Treatment Period 
Extension Period 
Final 
Follow-
Up 
Visit1 
Within 
28 days 
before 
Baseline 
Baseline 
(Day 1) 
Week 4 
(Day 
28 
±3 
days) 
Week 8 
(Day 
56 
±3 
days) 
Week 12 
(Day  
84 
±3 days) 
Week 24 
(Day 
168 
±5 days) 
Week 36 
(Day 
252 
±5 days) 
Week 48 
(Day 
336 
±5 days) 
Week 60 
(Day 
420 
±5 days) 
Week 72 
(Day 
504 
±5 days) 
Week 84 
(Day 
588 
±5 days) 
Week 
96 (Day 
672 
±5 days) 
4 weeks 
±5 days 
after 
final 
dose 
Serum Pregnancy Test
7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test7 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Dispense BG00012 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
BG00012 
Administration 
 
X 
 
Concomitant Therapy 
and Procedures 
 
X 
AE Recording 
 
X 
SAE Recording 
Monitor and record throughout the study. 


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AE = adverse event; CBC = complete blood count; DNA = deoxyribonucleic acid; ECG = electrocardiogram; 
; LLN = lower limit of 
normal; MS = multiple sclerosis; 
; SAE = serious adverse event. 
1 Subjects will have a final Follow-Up Visit 4 weeks after taking their final dose, regardless of whether they complete the treatment period or discontinue prematurely, unless they 
have a lymphocyte count <LLN. 
2 Written informed consent must be obtained prior to performing any study-related procedures. 
3 Medical history will include gastrointestinal abnormalities within the previous 6 months, as well as duration of MS (time since diagnosis), relapse history, and treatments for MS. 
4 Physical examination includes height and weight measurements, as well as a neurological examination. 
5 Vital signs will include diastolic and systolic blood pressure, heart rate, and temperature.  Subjects must be seated for 5 minutes prior to having their pulse and blood pressure 
measured. 
6 Whole blood may also be collected for lymphocyte functional tests.  Lymphocyte subset testing must be performed every 4 weeks in subjects with lymphocyte count <500/mm3 
and followed until recovery or for 24 weeks after the last dose (whichever is sooner). 
7 Females of childbearing potential only.  Results must be known to be negative prior to dispensing BG00012. 
 
 


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Table 2: 
Study Activities for Study 109MS310 - Table 2 of 2 
Tests and Assessments 
 
Discontinuation and/or 
Withdrawal Visit2 
Lymphocyte Follow-Up Visit3 
These visits can be combined.  If these visits are not combined, any assessment 
that was performed within the past 2 weeks (or the interval noted in the 
footnotes) does not need to be repeated unless clinically indicated. 
 
Physical Examination4 
X 
 
X 
Vital Signs5 
X 
X 
X 
Hematology (CBC With Differential) 
X 
X 
X 
Blood Chemistry 
X 
X 
 
Blood for Exploratory Serum and Plasma Biomarkers 
 
X 
X 
Lymphocyte Subset Analysis 
 
X 
X 
Concomitant Therapy and Procedures 
X 
AE Recording 
X 
SAE Recording 
Monitor and record throughout the study. 
AE = adverse event; CBC = complete blood count; 
; LLN = lower limit of normal; 
 
; SAE = serious adverse event. 
 
 
2 Discontinuation refers to discontinuation of study treatment.  Withdrawal refers to withdrawal of subjects from study.  The Discontinuation and/or Withdrawal Visit should be 
conducted as soon as possible and no later than 2 weeks after their last dose of study treatment. 
3 Subjects who complete, temporarily withhold, or permanently discontinue study treatment for any reason and have a lymphocyte count <LLN will continue protocol-required 
visits and assessments and will also be followed up every 4 weeks unt
 
4 Physical examination includes height and weight measurements, as well as a neurological examination. 
5 Vital signs will include diastolic and systolic blood pressure, heart rate, and temperature.  Subjects must be seated for 5 minutes prior to having their pulse and blood pressure 
measured. 
 
 


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4.3. 
Additional Information  
4.3.1. 
Site Personnel 
For each subject, the Principal Investigator of the site will designate the following investigational 
site personnel: 
 a primary and backup Neurologist 
 a primary and backup Study Nurse (or Study Coordinator) 
 a Pharmacist (or authorized designee) 
The primary and backup Neurologists must have a minimum of 2 years of neurology specialty 
training and anticipate a 2-year commitment to the study. 
 
 
 The backup Neurologist may 
conduct subject evaluations if the primary Neurologist is unavailable due to illness, vacation, or 
travel. 
The roles and responsibilities of the Neurologist and Study Nurse are described below.  Details 
for all roles are provided in the Study Reference Guide. 
The primary Neurologist will be responsible for the following: 
 Management of the routine neurological care of the subject. 
 Assessment (including assignment of causality) and treatment of adverse events 
(AEs) 
. 
 Review of hematology and blood chemistry results from the central laboratory to 
permanently discontinued, as per the criteria detailed in Section 10.  
 Determination of whether new objective neurological findings have occurred (see 
Section 7.2.4). 
 
 
 
 
 
 


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The Neurologist may designate other medical personnel (i.e., the backup Neurologist or the 
Study Nurse) at the investigational site to perform some of the tests and evaluations listed under 
N
 
Hematology and blood chemistry data will be sent to the investigational sites to aid in 
management of the subject. 
4.3.2. 
Subject Management 
Contraception requirements are described in Section 15.5.  Study treatment dosing requirements 
and concomitant medication restrictions are described in Sections 11.1 and11.6, respectively.   
There are no restrictions regarding diet and alcohol use.  Physical exertion atypical for the 
 hours prior to assessments.  
Subjects should not donate blood until 1 month after their last dose of study treatment in this 
study. 


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5. 
INTRODUCTION  
BG00012 is a fumarate ester drug product formulation containing the active ingredient dimethyl 
fumarate (DMF).  In 2013, BG00012 was first approved in the United States (US) under the 
propriety name Tecfidera® as a treatment for patients with relapsing MS and has since been 
approved in other countries. 
5.1. 
Overview of Multiple Sclerosis 
MS is a chronic autoimmune and neurodegenerative disorder of the central nervous system 
(CNS) that is characterized by inflammation, demyelination, and oligodendrocyte and neuronal 
loss.  It is the most common demyelinating disorder of the CNS, affecting approximately 
2.5 million people worldwide.  Its prevalence is highest among Caucasians, with higher rates 
reported in North America, Europe, Australia, New Zealand, and northern Asia [Noseworthy 
2000; Rosati 2001].   
Relapsing MS is the most common clinical presentation of the disease.  The term relapsing MS 
applies to patients with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) 
who experience relapses; both are considered part of the same disease spectrum.  In the 
relapsing/remitting phase of the disease, patients experience episodes of neurological 
dysfunction (relapses) separated by periods of relative stability.  Typical symptoms of relapse 
include weakness, sensory loss, visual loss, and imbalance.  Relapses may completely subside in 
the early stage of the disease, but recovery tends to be incomplete over time, leading to the 
accumulation of physical disability and cognitive decline.  RRMS is usually diagnosed between 
the ages of 20 and 40 years and affects twice as many women than men.  The RRMS population 
ranges from patients with relatively benign, inactive, non-inflammatory disease to patients who 
experience frequent relapse and/or persistent, active, inflammatory disease.  Most of these 
patients develop SPMS, which is characterized by progressive neurological decline with or 
without superimposed relapse; the median time to progression from RRMS to SPMS is 
approximately 10 years [Runmarker and Andersen 1993].  Approximately half of all MS patients 
are unable to walk without assistance within 15 years of their initial diagnosis [Runmarker and 
Andersen 1993; Weinshenker 1989], and more than half of patients die from MS or its 
complications [Brønnum-Hansen 2004]. 
As patients progress along the continuum from RRMS to SPMS, disability progression is more 
likely to occur independently of relapses.  The pathological changes underlying MS are thought 
to occur when activated T lymphocytes cross the blood-brain barrier (BBB) and initiate a series 
of events leading to activation of endothelial cells, recruitment of additional lymphocytes and 
monocytes, and release of pro-inflammatory cytokines.  MS lesions consisting of immune cells 
can occur throughout the CNS, but certain sites appear to be particularly vulnerable, such as the 
optic nerve, brainstem, spinal cord, and periventricular regions of the cerebrum.  The 
development of MS lesions is associated with inflammation, edema, and demyelination, and is 
often correlated with reversible disease symptoms, namely relapses, as well as oligodendrocyte 


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death and axonal transection, which can be permanent and lead to disability.  Alternatively, 
oligodendrocyte and axonal loss may be due to a neurodegenerative process.  Ongoing 
inflammatory and neurodegenerative stimuli are mediated at least in part by toxic oxidative 
stress.  Preclinical studies indicate that BG00012-dependent pharmacodynamic responses appear 
to be mediated through activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) 
transcriptional pathway, which is the primary cellular defense system for responding to a variety 
of potentially toxic stimuli through up-regulation of antioxidant response genes.  While it is not 
yet fully understood how the inflammatory cascade is initiated, adhesion and trans-endothelial 
migration of inflammatory cells from the bloodstream across the BBB and into the CNS is 
thought to be an early and critical step in this process. 
5.2. 
Current Therapies for Multiple Sclerosis 
The most commonly used first-line MS therapies are interferons (IFNs) and glatiramer acetate 
(GA) [Waldman 2011].  Relative to placebo, IFNs have been shown to reduce relapse rate by 
approximately 27% to 36% [Calabresi 2014; Jacobs 1996; PRISMS Study Group 1998; The 
IFNB Multiple Sclerosis Study Group 1993], and GA by approximately 30% [Johnson 1995].  
The interferon beta-1a (IFN -1a) products have also been shown to delay disability progression 
[Jacobs 1996; PRISMS Study Group 1998].   
Other currently approved therapies for MS include the following: 
 Natalizumab:  a humanized monoclonal ant
 
[Polman 2006]. 
 Fingolimod:  a selective oral immunosuppressant that is metabolized to a functional 
antagonist of sphingosine 1-phosphate receptors on lymphocytes [Kappos 2010]. 
 Mitoxantrone:  a synthetic antineoplastic anthracenedione that intercalates into 
deoxyribonucleic acid (DNA) and interferes with ribonucleic acid (RNA) [Chitnis 
2012]. 
 Teriflunomide:  an immunomodulatory drug inhibiting pyrimidine synthesis by 
blocking dihydroorotate dehydrogenase [O'Connor 2011]. 
 Alemtuzumab:  a humanized monoclonal antibody targeting CD-52 antigen expressed 
on the surface of most leukocytes [Coles 2012]. 
5.3. 
Profile of Previous Experience With BG00012 
5.3.1. 
Nonclinical Experience 
In nonclinical studies, DMF and its primary metabolite, monomethyl fumarate, were found to 
promote stabilization and transcriptional activity of Nrf2, as well as expression of Nrf2 target 
genes in cultured human cells and in vivo [Linker 2011].  Previous ex vivo and in vivo studies 


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have demonstrated a central role of the Nrf2 pathway in the protection of cells and tissues against 
oxidative, xenobiotic, and inflammatory stress.  Loss of Nrf2 function via genetic silencing has 
been shown to cause exaggerated inflammatory response and lead to development of systemic 
autoimmunity and CNS alterations, including widespread gliosis and white matter lesions.  
Conversely, pharmacological agents known to activate Nrf2 have been shown in nonclinical 
studies to exert anti-inflammatory effects, protect neurons from oxidative and excitotoxic stress-
induced death, and improve the BBB integrity of the CNS.  Activation of the Nrf2 pathway by 
DMF in MS may contribute to inhibition of inflammation and help support CNS integrity by 
promoting cellular resistance to oxidative stress. 
 
5.3.2. 
Clinical Experience 
In the Phase 2 and 3 placebo-controlled safety and efficacy studies (the completed 6-month 
Phase 2 Study C-1900 Part 1 and the 2 completed 2-year Phase 3 Studies 109MS301 and 
109MS302) and/or their uncontrolled extensions (the completed 6-month Phase 2 Study C-1900 
Part 2 and the ongoing Phase 3 long-term Study 109MS303) over 2500 subjects received 
treatment with BG00012.  The overall exposure to BG00012 among these subjects was 
approximately 6100 subject-years as of September 2013.   
DMF demonstrated robust efficacy and a favorable safety profile in subjects with RRMS in the 
2 large Phase 3 studies (Study 109MS301 [DEFINE] [Gold 2012a] and Study 109MS302 
[CONFIRM] [Fox 2012]).  The benefit-risk profile of DMF was considered positive, and the 
drug has been approved. 
Both Phase 3 studies demonstrated that treatment with DMF reduced the risk of MS relapse and 
slowed progression of disability.  In an integrated analysis of DEFINE and CONFIRM, DMF 
240 mg twice daily (BID) and 3 times daily significantly reduced the annualized relapse rate at 
2 years by 49% relative to placebo (p<0.0001).  Significant reductions at 2 years were also 
observed in the proportion of subjects who relapsed (43% and 47%, respectively; p<0.0001), the 
proportion of subjects with confirmed (12-week) progression of disability (32% and 30%, 
respectively; p<0.01), and the proportion of subjects with confirmed (24-week) progression of 
disability (29% and 32%, respectively; p<0.03) [Gold 2012b].  
DMF was generally well tolerated and demonstrated an acceptable safety profile.  The most 
common AEs associated with DMF were flushing and gastrointestinal (GI) events.  In subjects 
who experienced these types of events, the events were generally mild or moderate in intensity, 
tended to decrease in incidence after the first month, and only infrequently led to treatment 
discontinuation.  There are a number of potential management strategies for these side effects.  
In the Phase 2 and 3 controlled and uncontrolled clinical studies in subjects with RRMS, 
BG00012 treatment was associated with a gradual decrease from baseline in mean leukocyte 
counts driven primarily by decreases in mean lymphocyte counts; mean lymphocyte counts 
decreased by approximately 30% of their baseline value after 1 year and then plateaued and 
remained stable through more than 6 years of follow-up.  While decreases in lymphocyte counts 


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have been observed with BG00012 treatment, in the placebo controlled Phase 2 and 3 studies 
BG00012 was not associated with an increased risk of infection, serious infection, or 
opportunistic infection compared with placebo.  However, in the long-term extension study 
(109MS303), progressive multifocal leukoencephalopathy has occurred in the setting of severe, 
prolonged lymphopenia following BG00012 administration.  With open-label and marketed use 
of BG00012, there has been no other evidence of an increased risk of infections, serious 
infections, or opportunistic infections.   
 
5.4. 
Study Rationale 
Given the putative immunomodulatory properties of DMF and its observed effects on 
lymphocytes in humans, further evaluation of its effects on lymphocytes is needed.  The effect of 
BG00012 on lymphocyte subtypes is yet unknown, and its evaluation may provide insights into 
the mechanisms underlying BG00012-associated lymphopenia.  This study is therefore being 
conducted to assess the effects of BG00012 on lymphocyte subset counts and immunoglobulins 
(Igs) within the first year of treatment and beyond.  
5.5. 
Rationale for Dosing Regimen 
The BG00012 dosage selected for this study (120 mg BID for the first 7 days and 240 mg BID 
thereafter) is the approved BG00012 dosing regimen in the US, Canada, European Union, and 
other countries around the world for the treatment of patients with MS.   
Temporary dose reductions to 120 mg BID may be considered for individuals who do not 
tolerate the maintenance dose due to flushing and/or GI disturbances.  Within 4 weeks, the 
recommended dose of 240 mg BID should be resumed. 


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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Primary Objective and Endpoint 
The primary objective of the study is to evaluate the effect of BG00012 on lymphocyte subset 
counts during the first year of treatment in subjects with RRMS. 
The primary endpoint that relates to this objective is the change in lymphocyte subset counts for 
up to 48 weeks. 
6.2. 
Secondary Objective and Endpoints 
A secondary objective is to evaluate the pharmacodynamic effect of BG00012 on absolute 
lymphocyte counts (ALCs) and Igs during the first year of treatment.  
The endpoints that relate to this objective are the changes in IgG isotypes and ALCs for up to 
48 weeks. 


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7. 
STUDY DESIGN 
7.1. 
Study Overview 
This is an open-label, multicenter study to evaluate the effects of BG00012 on lymphocyte 
subtypes and Ig isotypes.  Approximately 200 subjects will be treated in approximately 100 sites 
in North America and Europe. 
After the Screening Visit (up to 28 days), subjects will receive BG00012 treatment for 48 weeks 
(Treatment Period) and will then continue on 240 mg BG00012 BID for an additional 48 weeks 
(Extension Period).  Blood samples for lymphocyte subset analysis, as well as blood samples for 
the 
ted at 
Screening, Baseline (Day 1), and Weeks 4, 8, 12, 24, 36, 48, 72, and 96.  Clinical samples for the 
analysis of blood chemistries will be collected at Screening, Baseline (Day 1), and Weeks 4, 8, 
24, 48, and 96.  A post-treatment follow-up visit, at which safety assessments will be performed, 
will occur 4 weeks after the final dose of BG00012.   
Subjects who withdraw from the study while on study treatment will complete the 
Discontinuation and/or Withdrawal Visit as soon as possible but no later than 2 weeks after their 
last dose of study treatment and will complete the final Follow-Up Visit 4 weeks after their last 
dose of study treatment unless consent has been withdrawn.  Subjects who complete, temporarily 
withhold, or permanently discontinue study treatment for any reason and have a lymphocyte 
count <LLN will continue protocol-required visits and assessments and will also be followed 
for 24 weeks after the last dose (whichever 
is sooner).  If the lymphocyte count remains <LLN for 24 weeks after the last dose, subjects who 
had temporarily withheld or permanently discontinued study treatment will continue assessments 
specified in the protocol.  Subjects who withdraw from the study for reasons other than safety 
may be replaced at the discretion of Biogen. 
See Figure 1 for a schematic of the study design.  Refer to Table 1 and Table 2 for the timing of 
all study assessments. 
7.2. 
Overall Study Duration and Follow-Up 
The study period will consist of a Screening Visit within 4 weeks of Baseline, a Treatment 
Period of 48 weeks, an Extension Period of 48 weeks, and a final Follow-Up Visit.  Subjects will 
receive treatment for 96 weeks.  The study duration may vary from approximately 104 to 
124 weeks. 
7.2.1. 
Screening 
Subject eligibility for the study will be determined within 28 days prior to study entry. 


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7.2.2. 
Treatment Period and Extension Period 
Eligible subjects will report to the study site every 4 weeks for the first 12 weeks and every 
12 weeks thereafter for 96 weeks. 
Discontinuation and/or Withdrawal Visits 
 Visits will be 
performed as necessary.  Subjects who withdraw from the study early will be asked to return to 
complete a Discontinuation and/or Withdrawal Visit within 2 weeks of their last study treatment 
dose.   
7.2.3. 
Follow-Up 
Subjects are to return to the study site for a Follow-Up Visit 4 weeks after their last dose of study 
treatment.  The final study visit will be Week 100.  
Subjects who complete, temporarily withhold, or permanently discontinue BG00012 for any 
reason and have a lymphocyte count <LLN will be followed every 4 weeks until the lymphocyte 
N or for 24 weeks after the last dose (whichever is sooner; see Section 11.3).  If the 
lymphocyte count remains <LLN for 24 weeks after the last dose, subjects who had temporarily 
withheld or permanently discontinued study treatment will continue assessments specified in the 
protocol.   


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7.2.6. 
Additional Assessments if Required by Local Tecfidera Prescribing Information 
Any additional assessments that are needed to comply with the local prescribing information for 
Tecfidera should also be performed and will be reimbursed by Biogen while a subject is 
participating in this study. 
7.3. 
Study Stopping Rules 
There are no study-specific stopping rules.  Biogen may terminate this study at any time after 
informing Investigators.  Biogen will notify Investigators when the study is to be placed on hold, 
completed, or terminated. 
7.4. 
End of Study 
The end of study is last subject, last visit for final collection of data. 


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8. 
SELECTION OF SUBJECTS 
8.1. 
Inclusion Criteria 
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at enrollment or at the timepoint specified in the individual eligibility criterion listed:   
1. Ability to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use confidential health information in accordance 
with national and local subject privacy regulations.  
2. Age 18 to 65 years old, inclusive, at the time of informed consent.   
3. Subjects of childbearing potential (including female subjects who are post-menopausal 
for less than 1 year) must practice effective contraception (as determined by the 
Investigator) during the study and be willing and able to continue contraception for 
30 days after their last dose of study treatment.  For further details of contraceptive 
requirements for this study, please refer to Section 15.5. 
4. Must have a confirmed diagnosis of RRMS according to the revised McDonald criteria 
(2010) [Polman 2011]. 
8.2. 
Exclusion Criteria 
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
enrollment or at the timepoint specified in the individual criterion listed: 
Medical History 
1. History of or positive test result at Screening for human immunodeficiency virus. 
2. History of or positive test result at Screening for hepatitis C virus antibody or current 
hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] and/or 
hepatitis B core antibody [HBcAb]).  Subjects with immunity to hepatitis B from 
previous natural infection (defined as negative HBsAg, positive hepatitis B surface 
antibody IgG, and positive HBcAb) are eligible to participate in the study (US Centers 
 
3. History of drug or alcohol abuse (as defined by the Investigator) within 1 year prior to 
Screening. 
4. Any clinically significant (in the judgment of the Investigator) infectious illness 
(e.g., cellulitis, abscess, pneumonia, and septicemia) within 30 days prior to Screening. 


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5. History of clinically significant (in the judgment of the Investigator) cardiovascular, 
dermatologic, endocrinologic, GI, hematologic, hepatic, immunologic, metabolic, 
neurologic (other than MS), psychiatric, pulmonary, renal, urologic, and/or other major 
disease that would preclude participation in a clinical study. 
6. History of severe allergic or anaphylactic reactions or known drug hypersensitivity to 
DMF or fumaric acid esters.  
7. Any of the following abnormal blood tests at Screening that are confirmed on repeat 
testing within 2 weeks:  
 leukocytes <3500/mm3 
 ALC values 
LN 
 alanine transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) or 
aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) 
 times the upper limit of normal (ULN) 
Treatment History 
8. Prior treatment with any of the following: 
 cladribine 
 mitoxantrone 
 total lymphoid irradiation 
 alemtuzumab 
 T-cell or T-cell receptor vaccination 
 any therapeutic monoclonal antibody, with the exception of natalizumab or 
daclizumab 
9. Treatment with any of the following medications or procedures within 6 months prior to 
Baseline (Day 1): 
 DMF (given as Fumaderm®) or BG00012; enrollment will be limited to no more 
than 40 subjects (out of 200) with prior DMF exposure 
 cyclosporine 
 azathioprine 


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 methotrexate 
 mycophenolate mofetil 
 intravenous (IV) Ig 
 plasmapheresis or cytapheresis 
10. Treatment with another investigational drug or approved therapy for investigational use 
within 6 months prior to Baseline (Day 1). 
11. Treatment with steroids (IV or oral corticosteroid treatment, including agents that may 
act through the corticosteroid pathway [e.g., low-dose naltrexone]) within 4 weeks 
(28 days) prior to Baseline (Day 1). 
Note:  Subjects who are currently using other approved disease modifying therapies (DMTs) for 
RRMS that are not excluded above may be included in the trial if all other criteria are met.  
Subjects must discontinue these other DMT treatments upon entry into the trial.  A washout 
period is not required by the protocol, but investigators should follow their local standards of 
care to manage the transition from the existing treatment to BG00012. 
Miscellaneous 
12. Female subjects who are currently pregnant or breastfeeding, or planning to become 
pregnant while in the study. 
13. Current enrollment or a plan to enroll in any interventional clinical study in which an 
investigational treatment or approved therapy for investigational use is administered 
within 6 months prior to the Baseline Visit. 
14. Previous registration in this study. 
15. Inability to comply with study requirements. 
16. Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the 
subject unsuitable for enrollment. 


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9. 
ENROLLMENT, REGISTRATION, AND RANDOMIZATION 
9.1. 
Screening and Enrollment 
Subjects must provide informed consent before any screening tests are performed (see 
Section 17.3).  When a subject signs the informed consent form (ICF), that subject is considered 
to be enrolled in the study.  Subjects who have a nonclinically significant out-of-range laboratory 
result may be retested once to deem the eligibility per discretion of the Investigator.  
Participating study sites are required to document all screened candidates initially considered for 
inclusion in this study.  If a subject is excluded from the study, the reasons for exclusion will be 
documented in 
 
9.2. 
Registration of Subjects 
Subjects will be registered at Baseline (Day 1), after all screening assessments have been 
completed and after the Investigator has verified that the subjects are eligible per criteria in 
Sections 8.1 and 8.2.  No subject may begin treatment prior to assignment of a unique 
identification number (registration).  Any subject identification numbers that are assigned will 
not be reused even if the subject does not receive treatment. 
Refer to the Study Reference Guide for details on registration. 
9.3. 
Blinding Procedures 
Not applicable.  This is an open-label study.  


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10. 
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY 
10.1. 
Discontinuation of Study Treatment 
A subject must permanently discontinue study treatment for any of the following reasons: 
 The subject becomes pregnant.  Study treatment must be discontinued immediately.  
Report the pregnancy according to the instructions in Section 15.4.1. 
 The subject withdraws consent to continue study treatment.   
 The subject experiences a medical emergency that necessitates permanent 
discontinuation of study treatment. 
 The subject is unable to tolerate study treatment at 240 mg BID (see Section 11.2.4). 
 The subject receives any concomitant medications not allowed by the protocol. 
 The subject experiences any of the laboratory abnormalities requiring permanent 
discontinuation of treatment defined in Table 3. 
 The subject experiences more than 1 deviation of the same laboratory parameter that 
meets the threshold limits defined in Table 3 at any time during the study.  
 The subject experiences more than 2 different deviations of laboratory parameters 
that meet the threshold limits defined in Table 3 at any time during the study.  On a 
third occasion, the subject is required to discontinue dosing for the remainder of the 
study. 
 If a subject has a lymphocyte count <500/mm3 persisting for more than 24 weeks 
consecutively, study treatment must be temporarily withheld.  Study treatment may 
be resumed after lymphocyte counts recover.  If the subject develops a lymphocyte 
count <500/mm3 on 1 occasion (confirmed by repeat testing) on resumption of study 
treatment, the subject must permanently discontinue study treatment. 
 If a 
treatment has been temporarily withheld due to lymphocyte count <500/mm3 for 
more than 24 weeks, the subject must permanently discontinue study treatment. 
 At the discretion of the Investigator for medical reasons or for noncompliance. 


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form (CRF). 
Subjects who discontinue treatment may remain in the study and continue protocol-required tests 
and assessments. 
10.2. 
Withdrawal of Subjects From Study 
Subjects must be withdrawn from the study for any one of the following reasons: 
 The subject is unable to tolerate study treatment at 240 mg BID (see Section 11.2.4). 
 The subject withdraws consent.   
 The subject enrolls into another interventional clinical study in which an 
investigational treatment or approved therapy for investigational use is administered. 
 The subject is unwilling or unable to comply with the protocol. 
For details regarding follow-up for subjects who discontinue study treatment or withdraw from 
the study, see Section 7.2.3. 
 
Subjects who withdraw from the study for reasons other than safety may be replaced at the 
discretion of Biogen.  


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11. 
STUDY TREATMENT USE 
11.1. 
Regimen 
Refer to and follow the Directions for Handling and Administration (DHA).  
BG00012 will be taken orally at a dose of 120 mg BID for the first 7 days and at a maintenance 
dose of 240 mg BID thereafter.  Temporary dose reductions to 120 mg BID may be considered 
for individuals who do not tolerate the maintenance dose due to flushing and/or GI disturbances.  
Within 4 weeks, the recommended dose of 240 mg BID should be resumed.  Subjects will 
receive treatment for 96 weeks. 
Missed doses should be taken within 6 hours.  If the subject does not remember to take the dose 
within 6 hours, this dose should be skipped, and the next dose should be taken as scheduled.  
Doses should not be doubled to make up for missed doses.   
11.2. 
Modification of Dose and/or Treatment Schedule 
11.2.1. 
Dosing Interruption for Abnormal Laboratory Values 
Study treatment must be temporarily withheld when any of the following laboratory values meet 
the threshold limits defined in Table 3; laboratory abnormalities that require immediate and 
permanent discontinuation of study treatment are also specified. 
Table 3: 
Laboratory Criteria Requiring Withholding or Permanent Discontinuation 
of Treatment 
Laboratory 
Parameter 
Laboratory Result 
Required Action 
AST (SGOT) 
or 
ALT (SGPT) 
>3  ULN 
The Investigator should repeat the test as soon as 
possible.  If the retest value confirms AST or ALT 
>3  ULN, the study treatment must be withheld.  If the 
value remains >3  ULN for 4 weeks after 
discontinuation of study treatment, then the subject 
must permanently discontinue study treatment, and 
the event must be recorded as an AE. 
Creatinine 
>1.2  ULN 
The Investigator should repeat the test as soon as 
possible.  If the retest value confirms that creatinine is 
>1.2  ULN, the study treatment must be withheld.  If 
the value remains >1.2  ULN for 4 weeks after 
discontinuation of study treatment, then the subject 
must permanently discontinue study treatment, and 
the event must be recorded as an AE. 


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Laboratory 
Parameter 
Laboratory Result 
Required Action 
WBC 
2000/mm3  
The Investigator should repeat the test as soon as 
possible.  If retest value confirms that WBC count is 
2000/mm3, the study treatment must be withheld.  If 
the value remains <2000/mm3 
discontinuation of study treatment, then the subject 
must permanently discontinue study treatment, and 
the event must be recorded as an AE. 
Urine Cytology 
Positive 
Urine cytology must be performed on any subject who 
has hematuria of unknown etiology on 2 consecutive 
tests.  If urine cytology is positive, then the subject 
must permanently discontinue study treatment, and 
the event must be recorded as an AE. 
AE = adverse event; ALT = alanine transaminase; AST = aspartate transaminase; SGOT = serum glutamic 
oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase; ULN = upper limit of normal; 
WBC = white blood cell. 
While dosing is withheld, subjects will continue tests and assessments according to the schedule 
defined in Section 4.2 (and may also undergo additional assessments to evaluate the laboratory 
temporarily withheld or permanently discontinued) must have the abnormal laboratory result 
retested at least every 2 weeks (retests will be run at the central laboratory) until resolution or 
stabilization of the laboratory value.  Depending on the severity and clinical significance of the 
abnormality, the Investigator may need to perform the retests more frequently.   
11.2.2. 
Resumption of Study Treatment Dosing 
Resumption of study treatment is to be considered on a case-by-case basis and must be discussed 
with the Medical Monitor.  However, subjects who have abnormal laboratory values, as 
described in Table 3, sustained on 3 consecutive occasions (i.e., for more than 4 consecutive 
weeks) must permanently discontinue study treatment (Section 10.1).   
Subjects with abnormal laboratory values after Week 12 (after which clinic visits occur once 
every 3 months), who are allowed to resume study treatment dosing following a 2- to 4-week 
interruption, will restart dosing at a reduced dose for 1 week.  Subjects must also return to the 
initial every-4-week visit schedule for safety assessments (see Section 14 for clinical and 
laboratory safety assessments) for 2 consecutive normal laboratory assessments before reverting 
to the every-3-month schedule.  Subjects will take 120 mg BID for 1 week.  After 1 week at the 
reduced dose, subjects will take 240 mg BID. 
11.2.3. 
Subsequent Development of Additional Laboratory Abnormalities 
Subjects who develop a subsequent abnormal value for the same laboratory parameter at any 
other time during the study must permanently discontinue dosing with study treatment, i.e., only 
1 dosing interruption is allowed for each subject for the same laboratory abnormality.  However, 


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subjects who subsequently experience an abnormality of a different laboratory parameter can 
have study treatment withheld again.  For example, if a subject had dosing temporarily withheld 
for an abnormal ALT/SGPT, then had dosing resumed after ALT/SGPT returned to acceptable 
limits, and subsequently developed abnormal white blood cells (WBCs), the subject may have 
study treatment withheld again.  However, only 2 dosing interruptions are allowed for each 
subject. 
Any subject who experiences abnormal laboratory results that meet the criteria defined in 
Table 3 on a third occasion must permanently discontinue dosing. 
11.2.4. 
Dosage Reductions 
Dosage reduction will be allowed only for subjects who are unable to tolerate study treatment 
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 Sections 11.2.1, 
11.2.2, and 11.2.3).  Subjects who do not tolerate study treatment will reduce their dosage by 
taking 120 mg BID for 4 weeks.  After 4 weeks at the reduced dosage, subjects will resume 
taking the full dose of 240 mg BID.  If the subject is still unable to tolerate study treatment, the 
subject must discontinue study treatment as described in Section 10.1.  Subjects who do not 
tolerate study treatment will complete the final Follow-Up Visit 4 weeks after their last dose of 
study treatment and will then be withdrawn from the study (Section 10).  
11.3. 
Treatment Schedule for Subjects With Abnormal Lymphocyte 
Count 
11.3.1. 
Schedule for Subjects With Lymphocyte Count <500/mm3 
Study treatment must be temporarily withheld when the laboratory value for lymphocyte count 
meets the threshold limits defined in Table 4. 
Table 4: 
Lymphocyte Count Criteria 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 24 weeks, study 
treatment must be temporarily withheld.  
All assessments should be performed at the central 
laboratory. 
While dosing is withheld, subjects will be followed every 4 weeks until the lymphocyte count is 
for 24 weeks after the last dose (whichever is sooner) [see Lymphocyte Follow-Up in 
Table 2].  If the lymphocyte count remains LLN for 24 weeks consecutively after the study 


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treatment is withheld, the subject should be permanently discontinued from study treatment, and 
the Investigator should contact the Medical Monitor.   
Subjects who temporarily withhold study treatment due to decreases in lymphocyte count, as 
described in Table 4, may resume study treatment when lymphocyte counts recover (defined as a 
2 consecutive occasions at least 4 weeks apart).  If the lymphocyte 
count is <500/mm3 on 1 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 
final Follow-Up Visit (whichever is sooner). 
See Figure 2 for the treatment schedule of subjects with lymphocyte counts <500/mm3.


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Figure 2: 
Schedule for Subjects With Lymphocyte Count <500/mm3 
 
LLN = lower limit of normal. 
11.3.2. 
Schedule for Subjects W
3 
3 will have tests and assessments according 
to the schedule defined in Section 4.  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 Have a 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 
for 24 weeks after the last dose (whichever is 


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sooner).  Subjects who temporarily withhold or permanently discontinue study treatment and 
have a lymphocyte count <LLN for 24 weeks should continue tests and assessments according to 
the schedule defined in Section 4 until the lymphocyte count recovers or until the final 
Follow-Up Visit (whichever is sooner). 
See Figure 3 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 3: 
Schedule for Subjects Who Complete, Temporarily Withhold, or 
Permanently Discontinue Study Treatment for Any Reason and Have 
Lymphocyte Count <LLN 
 
LLN = lower limit of normal. 
11.4. 
Precautions 
Not applicable. 


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11.5. 
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 
11.6.1. 
Concomitant Therapy 
A concomitant therapy is any drug or substance administered between 
Visit and 
. 
11.6.1.1. Allowed Concomitant Therapy 
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 nonprescribed 
drugs, unless they have received permission from the Investigator. 
11.6.1.2. Disallowed Concomitant Therapy 
Concomitant treatment with any of the following is not allowed unless approved by the Medical 
Monitor: 
 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-
GA, natalizumab, cyclophosphamide, methotrexate, 
azathioprine, 4-aminopyridine or related products, etc.), with the exception of acute 
management of protocol-defined relapses (Section 11.6.3). 
 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 IVMP, except for 
protocol-defined treatment of relapses (Section 11.6.3).  Steroids that are 
administered by nonsystemic routes (e.g., topical or inhaled) are allowed. 
 Total lymphoid irradiation, cladribine, T-cell or T-cell receptor vaccination, any 
therapeutic monoclonal antibody, mitoxantrone, cyclosporine, IV Ig, plasmapheresis, 
or cytapheresis. 


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according to instructions for CRF completion.  AEs related to administration of these therapies 
must be documented on the appropriate CRF. 
Subjects should be instructed not to start taking any new medications, including non-prescribed 
drugs, unless they have received permission from the Investigator. 
11.6.2. 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
the time the subject is enrolled in the study and 
. 
CRF, according to the instructions for CRF completion.  AEs related to administration of these 
therapies or procedures must be documented on the appropriate CRF. 
11.7. 
Continuation of Treatment 
No further provisions are made for access to the study treatment. 


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12. 
STUDY TREATMENT MANAGEMENT 
Study site staff should follow the DHA for specific instructions on the handling, preparation, 
administration, and disposal of the study treatment.  The DHA supersedes all other references 
(e.g., protocol). 
Study treatment must be dispensed only by a pharmacist or appropriately qualified staff.  Study 
treatment is to be dispensed only to subjects enrolled in this study.  
12.1. 
BG00012 
BG00012 is a drug product formulated as enteric-coated microtablets in gelatin capsules (blue 
and white) for oral administration.  Each capsule contains 120 mg BG00012. 
Excipients for the manufacturing of the enteric-coated microtablets include microcrystalline 
cellulose, croscarmellose sodium, talc, colloidal anhydrous silica (colloidal silicon dioxide), 
magnesium stearate, triethyl citrate, methacrylic acid-methyl methacrylate copolymer, 
methacrylic acid-ethyl acrylate copolymer, simethicone, sodium lauryl sulfate, and 
polysorbate 80.  Excipients for the manufacturing of the capsule shell include gelatin, titanium 
dioxide, and indigotin. 
The contents of the study treatment label will be in accordance with all applicable regulatory 
requirements.  Do not use study treatment after the expiration date unless a written notification of 
an expiration date extension is provided by Biogen.   
12.1.1. 
BG00012 Preparation 
The individual preparing BG00012 should carefully review the instructions provided in the 
DHA. 
Drug wallets will be provided for the BG00012 treatment group to ensure that the appropriate 
treatment is provided to each subject.  Drug wallets will be supplied from an Interactive Voice 
and Web Response System (IXRS) during the study so that the appropriate wallets are correctly 
dispensed to the subjects at the required timepoints throughout the study.   
If the packaging is damaged or if there is anything unusual about the appearance or attributes of 
the drug wallet or drug, it should not be used.  The drug wallet in question should be quarantined 
at the study site, and the problem should be immediately reported to Biogen. 
12.1.2. 
BG00012 Storage 
Study treatment must be stored in a secure location.   


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BG00012 is to be stored at room temperature (15°C to 25°C or 59°F to 77°F), in a secured, 
locked cabinet with limited access.  For the most up-to-date storage requirements, follow the 
instructions provided in the DHA. 
12.1.3. 
BG00012 Handling and Disposal 
The Investigator must return all used and unused drug wallets of BG00012 as instructed by 
Biogen unless approved for onsite destruction. 
If any BG00012 supplies are to be destroyed at the study site, the institution or appropriate site 
personnel must obtain prior approval from Biogen/contract research organization (CRO) by 
providing, in writing, the destruction policy or details of the method of destruction.  After such 
destruction, Biogen/CRO must be notified, in writing, of the details of the study treatment 
destroyed (e.g., lot or kit numbers, quantities), the date of destruction, and proof of destruction. 
12.1.4. 
BG00012 Accountability 
Accountability for study treatment is the responsibility of the Investigator.  The study site must 
maintain accurate records demonstrating dates and amount of study treatment received, to whom 
dispensed (subject-by-subject accounting), amount returned by the subject, and accounts of any 
study treatment accidentally or deliberately destroyed or lost.   
Unless otherwise notified, all drug wallets, both used and unused, must be saved for study 
treatment accountability.  At the end of the study, reconciliation must be made between the 
amount of BG00012 supplied, dispensed, and subsequently destroyed, lost, or returned to 
Biogen.  A written explanation must be provided for any discrepancies. 


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13. 
EFFICACY AND PHARMACODYNAMIC ASSESSMENTS 
See Section 4 for the timing of all assessments. 
13.1. 
Efficacy Assessments 
Not applicable; the study is not designed to assess efficacy. 
13.2. 
Pharmacodynamic Assessments 
The following tests will be performed to assess the pharmacodynamic properties of BG00012: 
 T cells, B cells, and natural killer (NK) cells 
 total T cells:  CD4+ and CD8+ 
 total B cells 
 total NK cells 
 T regulatory (Treg) cells, resting/naïve Treg, and activated Treg 
 naïve T cells, effector T cells, central/effector memory T cells, and activated 
(expressing HLA DR/CD38) T cells 
 dendritic cells, monocytes, and NK cells (CD56dim/CD56bright) 
 transitional B cells, naïve B cells, memory B cells (IgD+/IgD-), and plasmablast cells 
 
 
13.3. 
Clinical Assessments 
The following clinical assessments will be performed: 
 
 
 
 


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14. 
SAFETY ASSESSMENTS 
Refer to Section 4 for the timing of all safety assessments. 
14.1. 
Clinical Safety Assessments 
The following clinical assessments will be performed to evaluate the safety profile of BG00012: 
 AEs, SAEs, and concomitant therapy and procedures recording 
 physical examinations, including body weight and height  
 vital sign measurements, including diastolic and systolic blood pressure, heart rate, 
body temperature, and respiratory rate.  Subjects must remain in a supine or seated 
position for 5 minutes prior to having heart rate and blood pressure taken. 
 12-lead electrocardiogram (ECG) readings 
14.2. 
Laboratory Safety Assessments 
The following laboratory assessments will be performed to evaluate the safety profile of 
BG00012: 
 hematology parameters:  hemoglobin, hematocrit, red blood cell count, WBC count 
(with differential), and platelet count 
 blood chemistry parameters:  albumin, sodium, potassium, chloride, total bilirubin, 
alkaline phosphatase, ALT/SPGT, AST/SGOT, blood urea nitrogen, creatinine, 
bicarbonate, calcium, magnesium, phosphate, uric acid, and glucose 


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


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 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.) 
15.1.3. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized.  The study site must document all of the following: 
 The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior t
consent to participate in the study. 
 The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the 
the procedure or treatment. 
 The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission. 
 If a subject is hospitalized due to local requirements for administration of the 
study treatment, the hospitalization should not be considered an SAE unless one 
of the requirements in Section 15.1.2 is met. 
15.2. 
Safety Classifications 
15.2.1. 
Investigator Assessment of Events 
All events must be assessed to determine the following: 
 If the event meets the criteria for an SAE as defined in Section 15.1.2 . 
 The relationship of the event to study treatment as defined in Section 15.2. 
 The severity of the event as defined in Section 15.2.3. 


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15.2.2. 
Relationship of Events to Study Treatment 
The following definitions should be considered when evaluating the relationship of AEs and 
SAEs to the study treatment: 
Relationship of Event to Study Treatment 
Not related 
not a reasonable possibility that the event has been caused by the product under 
investigation.  Factors pointing toward this assessment include but are not limited to:  the 
lack of reasonable temporal relationship between administration of the drug and the 
event, the presence of a biologically implausible relationship between the product and the 
AE, or the presence of a more likely alternative explanation for the AE. 
Related 
reasonable possibility that the event may have been caused by the product under 
investigation.  Factors that point toward this assessment include but are not limited to:  a 
positive rechallenge, a reasonable temporal sequence between administration of the drug 
and the event, a known response pattern of the suspected drug, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between the drug 
and the AE, or a lack of an alternative explanation for the AE. 
15.2.3. 
Severity of Events 
The following definitions should be considered when evaluating the severity of AEs and SAEs: 
Severity of Event 
Mild 
Symptoms barely noticeable to subject or does not make subject uncomfortable; does not 
influence performance or functioning; prescription drug not ordinarily needed for relief of 
symptoms but may be given because of personality of subject. 
Moderate 
Symptoms of a sufficient severity to make subject uncomfortable; performance of daily 
activity is influenced; subject is able to continue in study; treatment for symptoms may be 
needed. 
Severe 
Symptoms cause severe discomfort; symptoms cause incapacitation or significant impact 
treatment for symptoms may be given and/or subject hospitalized. 
15.2.4. 
Expectedness of Events 
 
15.3. 
Monitoring and Recording Events 
15.3.1. 
Adverse Events 
Any AE experienced by the subject between the time of first dose of study treatment and the 
final Follow-Up Visit is to be recorded on the CRF, regardless of the severity of the event or its 
relationship to study treatment. 


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15.3.2. 
Serious Adverse Events 
Any SAE experienced by the subject between the time of the signing of the ICF and the final 
Follow-Up Visit is to be recorded on an SAE form, regardless of the severity of the event or its 
relationship to study treatment.  SAEs must be reported to Biogen or designee within 24 hours as 
described in Section 15.3.3.  Follow-up information regarding an SAE also must be reported 
with 24 hours.  
Subjects will be followed for all SAEs until the final Follow-Up Visit.  Thereafter, the event 
should be reported to Biogen or designee only if the Investigator considers the SAE to be related 
to study treatment. 
Any SAE that is ongoing when the subject completes or discontinues the study will be followed 
by the Investigator until the event has resolved, stabilized, or returned to baseline status. 
15.3.3. 
Immediate Reporting of Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify Biogen or designee within 24 hours of the study site staff becoming aware of the 
ility to ensure that the SAE reporting information and 
procedures are used and followed appropriately. 
 
Reporting Information for SAEs 
Any SAE that occurs between the time that the subject has signed the ICF and the final 
Follow-Up Visit must be reported to Biogen or designee within 24 hours of the study site staff 
becoming aware of the event.  Thereafter, the event should be reported only if the Investigator 
considers it related to study treatment. 
A report must be submitted to Biogen or designee regardless of the following: 
 Whether or not the subject has undergone study-related procedures 
 Whether or not the subject has received study treatment 
 The severity of the event 
 The relationship of the event to study treatment 
To report initial or follow-up information on an SAE, fax a completed SAE form; refer to the 
Study Reference Guide for complete contact information. 


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15.3.3.1. Deaths 
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. 
15.3.4. 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are unexpected and 
judged by the Investigator or Biogen to be related to the study treatment administered. 
Biogen or designee will report SUSARs to the appropriate regulatory authorities and 
Investigators as required, according to local law. 
15.4. 
Procedures for Handling Special Situations 
15.4.1. 
Pregnancy 
Subjects should not become pregnant or impregnate their partners during the study and 
for 30 days after their last dose of study treatment.  If a female subject becomes pregnant, 
study treatment must be discontinued immediately. 
The Investigator must report a pregnancy by faxing the appropriate form to Biogen or designee 
within 24 hours of the study site staff becoming aware of the pregnancy at the fax number 
provided in the Study Reference Guide.  The Investigator or study site staff must report the 
outcome of the pregnancy to Biogen or designee.  
Congenital abnormalities and birth defects in the offspring of male or female subjects should be 
reported as an SAE if conception occurred during the study treatment period. 
15.4.2. 
Overdose 
An overdose is any dose of study treatment administered to a subject or taken by a subject that 
exceeds the dose assigned to the subject according to the protocol.  Overdoses are not considered 
AEs and should not be recorded as an AE on the CRF; however, all overdoses must 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 must be reported to Biogen or designee even if the overdose 
does not result in an AE.  If an overdose results in an AE, the AE must be recorded.  If an 
overdose results in an SAE, both the SAE and Overdose forms must be completed and faxed to 
Biogen or designee.  All study treatment-related dosing information must be recorded on the 
dosing CRF. 


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15.4.3. 
Medical Emergency 
In a medical emergency requiring immediate attention, study site staff will apply appropriate 
medical intervention, according to current standards of care.  The Investigator (or designee) 
Study Contact List for complete contact information. 
15.4.3.1. Unblinding for Medical Emergency 
Not applicable. 
15.5. 
Contraception Requirements 
Subjects of childbearing potential must practice effective contraception (as determined by the 
Investigator) during the study and be willing and able to continue contraception for 30 days after 
their last dose of study treatment.  In addition, male subjects should not donate sperm for the 
duration of the study and for at least 30 days after their last dose of study treatment. 
For the purposes of this study, women who do not meet one of the following criteria listed below 
are considered to be physiologically capable of becoming pregnant and are, therefore, defined as 
women of childbearing potential: 
 Postmenopausal 
 12 months of natural (spontaneous) amenorrhea without an alternative medical 
cause and a serum follicle-stimulating hormone level >40 mIU/mL  
 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
 Posthysterectomy 
 Female surgical sterilization (e.g., bilateral tubal ligation) 
For the purposes of the study, highly effective contraception is defined as use of 1 or more of the 
following: 
For females: 
 Established use of oral, injected, or implanted hormonal methods of contraception.  
 Placement of an intrauterine device or intrauterine system. 
 Barrier methods of contraception with use of a spermicide:  condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream suppository.  
The use of barrier contraceptives should always be supplemented with the use of a 
spermicide. 


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 Male surgical sterilization (with the appropriate postvasectomy documentation of the 
absence of sperm in the ejaculate).  (For female subjects participating in the study, 
male sexual partners must have undergone surgical sterilization.) 
For males: 
 Effective male contraception includes a vasectomy with negative semen analysis at 
follow-up, or the use of condoms with spermicide. 
True abstinence, when this is consistent with the preferred and usual lifestyle of the subject, can 
be considered an acceptable method of contraception based on the evaluation of the Investigator 
who should also take into consideration the duration of the clinical trial.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not 
considered acceptable methods of contraception. 
Pregnancy reporting is described in Section 15.4.1. 
15.6. 
Safety Responsibilities 
15.6.1. 
The Investigator 
 
 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. 
 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. 
 
medical records. 
 Pursue AE follow-up information, if possible, until the event has resolved or has 
become stable. 
 Report SAEs to local ethics committees, as required by local law. 


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15.6.2. 
Biogen 
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 is to notify all appropriate regulatory authorities, central ethics committees, 
and Investigators of SAEs, as required by local law, within required time frames. 


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16. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
The objectives of the study and the endpoints to be analyzed are listed in Section 6. 
16.1. 
Pharmacokinetics 
Not applicable. 
16.2. 
Pharmacodynamics 
16.2.1. 
Analysis Population 
The pharmacodynamic population is defined as all subjects who receive at least 1 dose of study 
treatment and have at least 1 pharmacodynamic measurement after Baseline. 
16.2.2. 
Methods of Analysis 
Statistical analyses will be 
 and descriptive in nature, with appropriate measures of 
precision provided where applicable.  There is no planned statistical hypothesis testing in this 
study.   
16.2.2.1. Analysis of the Primary Endpoint 
Counts and change from Baseline in counts for each of the lymphocyte subsets will be 
descriptively summarized at each applicable visit.  Furthermore, the primary endpoints will be 
summarized in various ALC subgroups to evaluate the nature of change in each subset in relation 
to the change in ALC.  Additionally, a mixed model for repeated measures (MMRM) will be 
used, which will be fit with the change from Baseline for each of the lymphocyte subsets as the 
dependent variable and will include ALC subgroups, visit, corresponding Baseline counts, age, 
gender, and ALC groups-by-visit interaction as fixed effects to estimate the difference between 
ALC subgroups.  Point estimates and 2-sided 90% confidence intervals (CIs) will be derived 
from the model.  Appropriate transformation may be performed based on the distribution of data. 
ALC subgroups of interest include (
(2) subjects who have at least 1 ALC value <LLN over 48 weeks, and (3) subjects who have at 
least 2 ALC values <LLN over 48 weeks.  Additional subgroups will be further defined in the 
Statistical Analysis Plan. 
16.2.2.2. Analysis of the Secondary Endpoints 
For the secondary endpoints (IgG isotypes and ALCs), actual values and change from Baseline 
will be descriptively summarized at each applicable visit.  In addition, the same type of MMRM 
used for analysis of primary endpoints will be employed, which will be fit with the change from 


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Baseline in each of the IgG isotypes and ALCs as the dependent variable and will include visit, 
corresponding baseline value, age, and gender as fixed effects. 
16.4. 
Safety 
16.4.1. 
Analysis Population 
The safety population is defined as all subjects who receive at least 1 dose of study treatment. 
16.4.2. 
Methods of Analysis 
All AEs, concomitant therapy and procedures, clinical laboratory results, physical examinations, 
vital signs, and 12-lead ECG readings data will be evaluated for safety. 
16.4.2.1. Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  Only 
treatment-emergent AEs will be presented in the summary tables.  Treatment emergent is defined 
as having an onset date on or after start of study treatment or having worsened after the start of 
study treatment. 
Subject incidences of all AEs, SAEs, AEs leading to treatment discontinuation and study 
withdrawal, and other AEs of special interest will be tabulated by system organ class and 
preferred term in descending order of frequency. 


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16.4.2.2. Clinical Laboratory Results 
Clinical laboratory evaluations include hematology and blood chemistry.  Laboratory data will 
be summarized using shift tables.  Each laboratory value for each subject will be flagged as 
low,  normal,  or high,  
number (percentage) of subjects experiencing post-Baseline shifts to low  or high  based on 
their minimum or maximum values at any time postdose will be summarized.  In addition, a 
summary of laboratory values categorized based on Common Toxicity Criteria grade will also be 
generated.  Summary statistics for actual values and change from Baseline will also be presented 
for quantitative laboratory data. 
16.4.2.3. Physical Examinations 
The analyses of physical examinations will include summary statistics (actual value and change 
from Baseline for body weight and height) over time by visit. 
16.4.2.4. Vital Signs 
The analysis of vital signs will focus on 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 group.   
The definitions of these clinically relevant abnormalities are shown in Table 5.   
Table 5: 
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs 
Vital Sign 
Criteria for Abnormalities 
Temperature  
>38°C or an increase from B
 
Pulse 
>120 bpm or an increase from Baseline of >20 bpm 
<50 bpm or a decrease from Baseline of >20 bpm 
Systolic Blood Pressure 
>180 mmHg or an increase from Baseline of >40 mmHg 
<90 mmHg or a decrease from Baseline of >30 mmHg 
Diastolic Blood Pressure 
>105 mmHg or an increase from Baseline of >30 mmHg 
<50 mmHg or a decrease from Baseline of >20 mmHg 
The analyses of vital signs will also include summary statistics (actual value and change from 
Baseline for temperature, pulse, and systolic and diastolic blood pressure) over time by visit. 
16.4.2.5. ECG Data 
A listing of subjects with abnormal ECG status will be presented.  Changes from Baseline in 
ECG will be summarized using shift tables.  The number and percentage of subjects with shifts 
to categorical values (abnormal, not AE/abnormal, AE) will be summarized. 


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16.5. 
Clinical Assessments 
16.5.1. 
Analysis Population 
The evaluable population for clinical assessments is defined as all subjects who receive at least 
1 dose of study treatment and at least 1 measurement for each of the clinical assessments after 
Baseline. 
16.6. 
Interim Analyses 
Interim analyses may be performed to support regulatory filings and/or publications and will be 
documented in the Statistical Analysis Plan. 
16.7. 
Sample Size Considerations 
The sample size for this study is not based on formal hypothesis testing but on the precision of 
the estimation of the primary endpoints and the ratios between various ALC subgroups. 
For example, the Phase 2 and 3 controlled and uncontrolled efficacy and safety studies in MS, 
based on data available as of May 2014 from 2470 subjects with at least 1 post-Baseline value 
from the interim analysis of the Integrated Summary of Safety of Tecfidera, showed that 76% of 
subjects had all ALC val
Assuming the same proportion of subjects in this study will have 1 or more ALC values <LLN, it 
43 subjects will have at least 1 ALC value <LLN at Week 48, based on a total of 180 evaluable 
subjects at Week 48.  With this sample size, the 90% CIs for the ratio of the 2 subgroups for the 
change from Baseline at Week 48 in lymphocyte subsets are illustrated below using the scenario 
of a true ratio of 0.8 (20% decrease) and 0.7 (30% decrease), respectively.  When assessing 
lymphocyte subsets between subjects with at least 2 ALC values <LLN up to the first 48 weeks 


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of treatment versus subjects who have all ALC 
of the ratio would be wider, as historical data suggest that 16% of the patients treated with 
Tecfidera may have 2 or more ALC values <LLN during the first 48 weeks of treatment. 
To allow for a 10% discontinuation rate, a total of 200 subjects are planned for enrollment. 
Table 6: 
Sample Size Calculations 
Primary 
Endpoints 
SD1
Ratio
90% CI for the Ratio Based on N = 180 
Subjects With At Least 1 ALC 
<LLN2 vs. Subjects With All 
2 
Subjects With At Least 2 ALC 
<LLN2 vs. Subjects With All 
2 
CD4 T cell 
count 
0.32
0.8
0.73, 0.88 
0.71, 0.90 
0.7
0.63, 0.77 
0.63, 0.78 
CD8 T cell 
count 
0.35
0.8
0.72, 0.89 
0.71, 0.91 
0.7
0.63, 0.78 
0.62, 0.79 
CD56bright NK 
cell count 
0.57
0.8
0.68, 0.95 
0.65, 0.98 
0.7
0.59, 0.83 
0.57, 0.86 
Treg count 
0.95
0.8
0.60, 1.07 
0.57, 1.12 
0.7
0.52, 0.93 
0.50, 0.98 
ALC = absolute lymphocyte count; CD = cluster of differentiation; CI = confidence interval; LLN = lower limit of 
normal; NK = natural killer; SD = standard deviation; Treg = T regulatory; vs. = versus. 
1 Common standard deviation for the log-transformed change from Baseline. 
2 Up to Week 48. 
 


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


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gal guardian), as applicable, in 
accordance with local practice and regulations.   
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the subject must be explained to the subject (or the 
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. 
edical record. 
17.4. 
Subject Data Protection 
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by local law (e.g., Protected Health Information 
authorization in North America). 
The subject will not be identified by name in the CRF or in any study reports, and these reports 
will be used for research purposes only.  Biogen, its partners and designees, ethics committees, 
and various government health agencies may inspect the records of this study.  Every effort will 
 
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 screen any subjects prior to completion of a study initiation visit, 
conducted by Biogen or designee.  This initiation visit will include a detailed review of the 
protocol and study procedures. 
18.2. 
Quality Assurance 
During and/or after completion of the study, quality assurance officers named by Biogen or the 
regulatory authorities may wish to perform onsite audits or inspections.  The Investigator will be 
expected to cooperate with any audit or inspection and to provide assistance and documentation 
(including source data) as requested. 
18.3. 
Monitoring of the Study 
The Investigator must permit study-related monitoring by providing direct access to source data 
 
The Clinical Monitor will visit the Investigator 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.   
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure protocol adherence, quality of data, study treatment accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities. 
18.4. 
Study Funding 
Biogen is the Sponsor of the study and is funding the study.  All financial details are provided in 
the separate contracts between the institution, Investigator, and Biogen. 
18.5. 
Publications 
Details are included in the clinical trial agreement for this study. 


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19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION 
19.1. 
External Contract Organizations 
19.1.1. 
Contract Research Organization  
A CRO, 
, will be responsible for administrative aspects of the study, including, but not 
limited to, study initiation, monitoring, medical support, and management of SAE reports and 
data management.  Before subjects are screened at each study site, 
 will review study 
responsibilities with the Investigators and other study site staff, as appropriate. 
19.1.2. 
Interactive Response Technology 
IXRS will be used in this study.  Before subjects are screened or enrolled, the IXRS vendor will 
provide each study site with the necessary training, a user manual, and access rights to the 
system. 
19.1.3. 
Electronic Data Capture 
Subject information will be captured and managed by study sites on electronic CRFs by a 
Web-based electronic data capture tool supported by iMedidata RAVE and configured by 
. 
19.1.4. 
Central Laboratories for Laboratory Assessments 
Central laboratories have been selected by Biogen to analyze the laboratory samples collected for 
this study.  
19.2. 
Study Committees 
Not applicable.  Given the established safety and efficacy of DMF via the Phase 2 and Phase 3 
studies, advisory committees were deemed not necessary for this study. 
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. 


Protocol 109MS310 
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67 
 
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 
Section 17). 
19.4. 
Ethics Committee Notification of Study Completion or Termination 
Where required, the regulatory authorities and ethics committees must be notified of completion 
or termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines. 
19.5. 
Retention of Study Data 
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local laws or regulations.  Prior to 
proceeding with destruction of records, the Investigator must notify Biogen in writing and 
receive written authorization from Biogen to destroy study records.  In addition, the Investigator 
must notify Biogen of any changes in the archival arrangements including but not limited to 
archival at an offsite facility or transfer of ownership if the Investigator leaves the site. 
19.6. 
Study Report Signatory 
Biogen will designate 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. 


Protocol 109MS310 
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Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
CONFIDENTIAL 
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Biogen MA Inc. 
68 
 
20. 
REFERENCES 
Brønnum-Hansen H, Koch-Henriksen N, Stenager E. Trends in survival and cause of death in 
Danish patients with multiple sclerosis. Brain. 2004;127(Pt 4):844-50. 
Calabresi PA, Kieseier BC, Arnold DL, et al. Pegylated interferon beta-1a for relapsing-remitting 
multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol. 
2014;13(7):657-65. Epub 2014 Apr 30. 
Chitnis T, Tenembaum S, Banwell B, et al. Consensus statement: evaluation of new and existing 
therapeutics for pediatric multiple sclerosis. Mult Scler. 2012;18(1):116-27. 
Coles AJ, Fox E, Vladic A, et al. 
-1a at 5-year 
follow-up of CAMMS223 clinical trial. Neurology. 2012;78(14):1069-78. 
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. 
Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for 
relapsing multiple sclerosis. N Engl J Med. 2012a;367(12):1098-107. 
Gold R, Miller DH, Phillips JT, et al. Clinical efficacy of BG-12 in relapsing-remitting multiple 
sclerosis: an integrated analysis of the Phase 3 DEFINE and CONFIRM studies. Presented at the 
28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis 
(ECTRIMS); October 10-13, 2012; Lyons, France. 
Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease 
progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group 
(MSCRG). Ann Neurol. 1996;39(3):285-94. 
Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves 
disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-
blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 
1995;45(7):1268-76. 
Kappos L, Radue EW, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in 
relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387-401. Epub 2010 Jan 20. 


Protocol 109MS310 
Version 1 
Phase 3b Study on the Effect of BG00012 on Lymphocyte Subsets and Immunoglobulins in Subjects With RRMS 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
69 
 
Linker RA, Lee DH, Ryan S, et al. Fumaric acid esters exert neuroprotective effects in 
neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain. 2011;134(Pt 3):678-
92. 
Noseworthy JH, Lucchinetti C, Rodriguez M, et al. Multiple sclerosis. N Engl J Med. 
2000;343(13):938-52. 
O'Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for 
relapsing multiple sclerosis. N Engl J Med. 2011;365(14):1293-303. 
Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of 
natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899-910. 
Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 
Revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292-302. 
PRISMS Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a 
in relapsing/remitting multiple sclerosis. Lancet. 1998;352(9139):1498-504. 
Rosati G. The prevalence of multiple sclerosis in the world: an update. Neurol Sci. 
2001;22(2):117-39. 
Runmarker B, Andersen O. Prognostic factors in a multiple sclerosis incidence cohort with 
twenty-five years of follow-up. Brain. 1993;116 ( Pt 1):117-34. 
The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting 
multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-
controlled trial. Neurology. 1993;43(4):655-61. 
Waldman A, Gorman M, Rensel M, et al. Management of pediatric central nervous system 
demyelinating disorders: consensus of United States neurologists. J Child Neurol. 
2011;26(6):675-82. 
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. 
 
 


Protocol 109MS310 
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70 
 
21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL 
I have read the foregoing 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets 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. 
 
 
 
____________________________________________________ 
 
 
 
 
Date 
 
 
____________________________________________________ 
 
 
 
 
____________________________________________________ 
Study Site (Print) 

SAP_001.pdf: 
Protocol 109MS310 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
1 
109MS310 
Biogen - BG00012 in MS 
Statistical Analysis Plan 
BIOGEN   


Statistical Analysis Plan
Version No.:  Final Version 1.0 
 Study Title: An Open-Label Study to Assess the Effects of BG00012 on Lymphocyte Subsets 
in Subjects With Relapsing-Remitting Multiple Sclerosis 
Name of Study Treatment: BG00012 
Protocol No.: 109MS310 / NCT02525874
Study Phase: Phase 3b 
Confidential Information 
The information contained in this Statistical Analysis Plan (SAP) is confidential and may not 
be reproduced or otherwise disseminated without the approval of Biogen, Inc.   




Protocol 109MS310 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
 CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen Idec MA Inc. 
3  
Table of Contents 
1 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................. 6 
1.1 
Primary Objective and Endpoint ................................................................................... 6 
1.2 
Secondary Objectives and Endpoints ............................................................................ 6 
 
 6 
2 
STUDY DESIGN ...................................................................................................................... 7 
2.1 
Study Overview ............................................................................................................ 7 
2.2 
Overall Study Duration and Follow-Up ...................................................................... 16 
2.2.1  Screening 
16 
2.2.2  Treatment Period 16 
2.2.3  Follow-Up 
16 
16 
 17 
 17 
2.2.7  Additional Assessments if Required by Local Tecfidera Prescribing Information .... 17 
2.3 
Study Stopping Rules .................................................................................................. 17 
2.4 
End of Study ............................................................................................................... 18 
3 
INTERIM ANALYSIS ............................................................................................................ 18 
4 
SAMPLE SIZE JUSTIFICATION .......................................................................................... 18 
5 
STATISTICAL ANALYSIS METHODS ............................................................................... 19 
5.1 
General consideration ................................................................................................. 19 
5.2 
Analysis of Baseline Data and Exposure to Study Drug ............................................ 20 
5.2.1  Accounting of Subjects ............................................................................................... 20 
5.2.2  Demographics and Baseline Disease Characteristics .................................................. 20 
5.2.3  Medical History and Previous MS Therapy ................................................................ 21 
5.2.4  Protocol Deviations ..................................................................................................... 21 
5.2.5  Time on Study and Treatment ..................................................................................... 21 
5.2.6  Treatment Compliance ................................................................................................ 21 
5.2.7  Concomitant Medications and Non-drug Therapies ................................................... 22 
5.3 
Pharmacodynamics ..................................................................................................... 23 
5.3.1  Analysis of the Primary Endpoint ............................................................................... 23 
5.3.2  Analysis of the Secondary Endpoints ......................................................................... 24 
5.3.3  Lymphocyte analysis during lymphocyte follow-up period ....................................... 25 
5.4 
Safety .......................................................................................................................... 26 
5.4.1  Adverse Events 
26 
5.4.2  Clinical Laboratory Results ........................................................................................ 28 
5.4.3  Physical Examinations ................................................................................................ 30 


Protocol 109MS310 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
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4  
5.4.4  Vital Signs 
30 
5.4.5  ECG Data 
31 
5.4.6  Safety analysis during lymphocyte follow-up period ................................................. 31 
 
 31 
31 
32 
 
 33 
5.7 
Changes in statistical analysis methods ...................................................................... 33 
5.7.1  Change in clinical assessment population definition .................................................. 33 
APPENDIX 1 – LIST OF REPORTABLE LYMPHOCYTE SUBSET PARAMETERS ............. 34 
APPENDIX 2 – VISIT WINDOWING RULES ............................................................................ 45 


 
Protocol 109MS310 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
 
 
 CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen Idec MA Inc. 
5  
 
List of Abbreviations 
AE 
adverse event
ALC 
absolute lymphocyte count
ALT 
alanine transaminase
AST 
aspartate transaminase
BID 
twice daily
BUN 
Blood Urea Nitrogen
CBC 
complete blood count
CD 
cluster of differentiation
CI 
confidence interval
CRF 
case report form
DMF 
dimethyl fumarate
DNA 
deoxyribonucleic acid
ECG 
electrocardiogram
GCP 
Good Clinical Practice
GGT 
Gamma-Glutamyl Transferase
HIV 
human immunodeficiency virus
ICF 
informed consent form
Ig 
immunoglobulin 
IgG 
Immunoglobulin G
IVMP 
intravenous methylprednisolone
MMRM  
mixed model for repeated measures
MRI 
magnetic resonance imaging
MS 
multiple sclerosis
NK 
natural killer
PT 
preferred term
PML 
Progressive multifocal leukoencephalopathy 
RBC 
Red blood cell
 
 
RRMS 
relapsing-remitting multiple sclerosis
SAE 
serious adverse event
SD 
standard deviation
SGOT 
serum glutamic oxaloacetic transaminase
SGPT 
serum glutamic pyruvic transaminase
SOC 
system organ class
ULN 
upper limit of normal
US 
United States
WBC 
white blood cell


 
Protocol 109MS310 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
 
  
 CONFIDENTIAL 
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Biogen Idec MA Inc. 
6  
1 
STUDY OBJECTIVES AND ENDPOINTS 
 
1.1 
Primary Objective and Endpoint 
The primary objective of the study is to evaluate the effect of BG00012 on lymphocyte subset 
counts during the first year of treatment in subjects with relapsing-remitting multiple sclerosis 
(RRMS). 
The primary endpoint that relates to this objective is the change in lymphocyte subset counts for 
up to 48 weeks.  
 
1.2 
Secondary Objectives and Endpoints 
A secondary objective is to evaluate the pharmacodynamic effect of BG00012 on absolute 
lymphocyte counts (ALCs) and immunoglobulins (Igs) during the first year of treatment.  
The endpoints that relate to this objective are the changes in Igs isotypes and ALCs for up to 48 
weeks. 
 


 
Protocol 109MS310 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
 
 
 CONFIDENTIAL 
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Biogen Idec MA Inc. 
7  
 
 
2 
STUDY DESIGN 
2.1 
Study Overview 
This is an open-label, multicenter study to evaluate the effects of BG00012 on lymphocyte 
subtypes and Ig isotypes.  Approximately 200 subjects were treated in approximately 100 sites in 
North America and Europe. 
After the Screening Visit (up to 28 days) if required per local guidelines and if not already 
available within the previous 3 months, a magnetic resonance imaging (MRI) scan should be 
performed locally before starting therapy with BG00012 as per local guidelines.  Subjects will 
then receive BG00012 treatment for 96 weeks (Treatment Period).  Blood samples for 
lymphocyte subset analysis, as well as blood samples for the determination of each subject’s 
complete blood count with differential, will be collected at Screening, Baseline (Day 1), and 
Weeks 4, 8, 12, 24, 36, 48, 60 (complete blood count [CBC only]), 72, 84 (CBC only), and 96.  
Clinical samples for the analysis of blood chemistries will be collected at Screening, Baseline 
(Day 1), and Weeks 4, 8, 24, 48, and 96.  A post-treatment follow-up visit, at which safety 
assessments will be performed, will occur 4 weeks after the final dose of BG00012.   
Subjects who temporarily withhold or permanently discontinue study treatment for any other 
reason than lymphopenia and have a lymphocyte count <LLN will continue protocol-required 
visits and assessments and will also be followed 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.   
Subjects who develop a confirmed lymphocyte count of <500 cells/mm3 at any time during the 
study will be monitored every 4 weeks.  If the lymphocyte count stays <500 cells/mm3 for 24 
weeks, the subject will temporarily withhold study treatment.  If the lymphocyte count does not 
recover to LLN within 24 weeks while study treatment is temporarily withheld, study treatment 
will be discontinued permanently. 


 
Protocol 109MS310 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
 
 
 CONFIDENTIAL 
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Biogen Idec MA Inc. 
8  
 
Subjects whose lymphocyte counts remain <LLN at the end of the study (Week 96) will 
complete the final Follow-Up Visit and will then be followed up outside of this study at the 
Investigator’s discretion.   
Therapies directed toward the treatment of MS are permitted, at the discretion of the treating 
physician and only after consulting with the Medical Monitor, for subjects who have 
permanently discontinued BG00012 for any reason. 
Subjects who withdraw from the study while on study treatment will complete the 
Discontinuation and/or Withdrawal Visit as soon as possible but no later than 2 weeks after their 
last dose of study treatment and will complete the final Follow Up Visit 4 weeks after their last 
dose of study treatment unless consent has been withdrawn.   
Subjects who withdraw from the study for reasons other than safety may be replaced at the 
discretion of Biogen. 
See Figure 1 for a schematic of the study design.  Refer to Table 1 and Table 2 for the timing of 
all study assessments. 


 
Protocol 109MS310 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
 
 
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Biogen Idec MA Inc. 
9  
 
Figure 1: 
Study Design 
 
BID = twice daily; LLN = lower limit of normal. 
*Subjects will receive oral BG00012 at a dose of 120 mg BID for the first 7 days and at a maintenance dose of 240 mg BID 
thereafter.  Temporary dose reductions to 120 mg BID may be considered. 
**Subjects with a lymphocyte count <LLN will continue protocol-required visits and assessments and will have additional 
lymphocyte and subset analysis. 


 
Protocol 109MS310 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
 
 
 
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10 
Schedule of Activities 
Table 1: 
Study Activities for Study 109MS310 - Table 1 of 2 
Tests and 
Assessments 
Screening 
Treatment Period 
Final 
Follow-Up 
Visiti) 
Within 
28 days 
before 
Baseline 
Baselin
e (Day 
1) 
Week 4
(Day 28
±3 
days) 
Week 8
(Day 56
±3 
days) 
Week 
12 
(Day  
84 
±3 
days) 
Week 
24 (Day 
168 
±5 
days) 
Week 
36 (Day 
252 
±5 
days) 
Week 
48 (Day 
336 
±5 
days) 
Week 
60 (Day 
420 
±5 
days) 
Week 
72 (Day 
504 
±5 
days) 
Week 
84 (Day 
588 
±5 
days) 
Week 
96 (Day 
672 
±5 
days) 
4 weeks 
±5 days 
after final 
dose 
Informed Consent
ii) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Historyiii) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B and C 
Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV 
Testing (As Per 
Local Guidelines)
iv) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examinationv) 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Vital Signsvi) 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
12-Lead ECG 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Hematology (CBC 
With Differential)
vii) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Chemistry 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 


 
Protocol 109MS310 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
 
 
 
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11 
Tests and 
Assessments 
Screening 
Treatment Period 
Final 
Follow-Up 
Visiti) 
Within 
28 days 
before 
Baseline 
Baselin
e (Day 
1) 
Week 4
(Day 28
±3 
days) 
Week 8
(Day 56
±3 
days) 
Week 
12 
(Day  
84 
±3 
days) 
Week 
24 (Day 
168 
±5 
days) 
Week 
36 (Day 
252 
±5 
days) 
Week 
48 (Day 
336 
±5 
days) 
Week 
60 (Day 
420 
±5 
days) 
Week 
72 (Day 
504 
±5 
days) 
Week 
84 (Day 
588 
±5 
days) 
Week 
96 (Day 
672 
±5 
days) 
4 weeks 
±5 days 
after final 
dose 
Lymphocyte 
Subset Analysis7 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Serum Pregnancy 
Testviii) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy 
Test8, 9 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense 
BG00012 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 


 
Protocol 109MS310 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
 
 
 
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The information contained herein may not be used, disclosed, or published without the written consent of Biogen Idec MA Inc. 
12 
Tests and 
Assessments 
Screening 
Treatment Period 
Final 
Follow-Up 
Visiti) 
Within 
28 days 
before 
Baseline 
Baselin
e (Day 
1) 
Week 4
(Day 28
±3 
days) 
Week 8
(Day 56
±3 
days) 
Week 
12 
(Day  
84 
±3 
days) 
Week 
24 (Day 
168 
±5 
days) 
Week 
36 (Day 
252 
±5 
days) 
Week 
48 (Day 
336 
±5 
days) 
Week 
60 (Day 
420 
±5 
days) 
Week 
72 (Day 
504 
±5 
days) 
Week 
84 (Day 
588 
±5 
days) 
Week 
96 (Day 
672 
±5 
days) 
4 weeks 
±5 days 
after final 
dose 
BG00012 
Administration 
 
X 
 
Concomitant 
Therapy and 
Procedures 
 
X 
AE Recording 
 
X 
SAE Recording 
Monitor and record throughout the study. 


 
Protocol 109MS310 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
 
 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen Idec MA Inc. 
13 
AE = adverse event; CBC = complete blood count; DNA = deoxyribonucleic acid; ECG = electrocardiogram; 
; HIV = human 
immunodeficiency virus; Ig = immunoglobulin; LLN = lower limit of normal; MRI = magnetic resonance imaging; MS = multiple sclerosis; 
 
; SAE = serious adverse event. 
1 Subjects will have a final Follow-Up Visit 4 weeks after taking their final dose, regardless of whether they complete the treatment period or discontinue prematurely, unless they 
have a lymphocyte count <LLN.  Subjects who have a lymphocyte count <LLN will continue protocol-required visits and assessments. 
2 Written informed consent must be obtained prior to performing any study-related procedures. 
3 Medical history will include gastrointestinal abnormalities within the previous 6 months, as well as duration of MS (time since diagnosis), relapse history, and treatments for MS. 
4 HIV testing will be done locally at Screening only if required, per local guidelines.   
5 Physical examination includes height and weight measurements, as well as a neurological examination. 
6 Vital signs will include diastolic and systolic blood pressure, heart rate, and temperature.  Subjects must be seated for 5 minutes prior to having their pulse and blood pressure 
measured. 
7 Whole blood may also be collected for lymphocyte functional tests.  Lymphocyte subset analysis will include total Ig and IgG subclasses, and may also include assays for 
 and VLA-4 expression.  In subjects with a confirmed lymphocyte count <500/mm3 lymphocyte testing must be performed every 4 weeks; if the lymphocyte count 
remains  <500/mm3 for 24 weeks, study treatment will be temporarily withheld for 24 weeks or until the lymphocyte count recovers to LLN, whichever is sooner, and testing 
continues to be every 4 weeks; if the lymphocyte count does not recover to LLN within 24 weeks while study treatment is temporarily withheld, study treatment will be withheld 
permanently, and testing will be performed every 12 weeks for an additional 24 weeks or until the lymphocyte count recovers to LLN, or until the end of the study, whichever is 
sooner. 
8 Females of childbearing potential only.  Results must be known to be negative prior to dispensing BG00012. 
9 Pregnancy test may be repeated locally at additional timepoints if needed, per local guidelines. 
 
 


 
Protocol 109MS310 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
 
 
 
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14 
Table 2: 
Study Activities for Study 109MS310 - Table 2 of 2 
Tests and Assessments 
 
Discontinuation and/or 
Withdrawal Visitii) 
Lymphocyte Follow-Up 
Visitiii) 
Unscheduled Visit for 
Abnormal Laboratory 
Results (Other Than 
Lymphocytes) 
These visits can be combined.  If these visits are not combined, 
any assessment that was performed within the past 2 weeks (or 
the interval noted in the footnotes) does not need to be repeated 
unless clinically indicated. 
 
 
Physical Examinationiv) 
X 
 
X 
 
Vital Signsv) 
X 
X 
X 
 
Hematology (CBC With Differential) 
X 
X 
X 
Xvi) 
Blood Chemistry 
X 
X 
 
Xvii) 
Lymphocyte Subset Analysis 
 
X 
X 
 
Concomitant Therapy and Procedures 
X 
 
AE Recording 
X 
 
SAE Recording 
Monitor and record throughout the study. 
 
AE = adverse event; ALT = alanine transaminase; AST = aspartate transaminase; CBC = complete blood count; 
; LLN = lower limit of 
normal; 
;
; SAE = serious adverse event; ULN = upper limit of normal; WBC = white blood cell. 
 
 


 
Protocol 109MS310 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
 
 
 
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15 
ii) Discontinuation refers to discontinuation of study treatment.  Withdrawal refers to withdrawal of subjects from study.  The Discontinuation and/or Withdrawal Visit should be 
conducted as soon as possible and no later than 2 weeks after their last dose of study treatment. 
iii) 
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. 
iv) Physical examination includes height and weight measurements, as well as a neurological examination. 
v) Vital signs will include diastolic and systolic blood pressure, heart rate, and temperature.  Subjects must be seated for 5 minutes prior to having their pulse and blood pressure 
measured. 
vi) 
The Investigator should repeat the test as soon as possible.  If retest value confirms that WBC count is <2000/mm3, study treatment must be withheld.  If the value 
remains <2000/mm3 for ≥4 weeks after discontinuation of study treatment, then the subject must permanently discontinue study treatment, and the event must be recorded as an 
AE.  
vii) 
The Investigator should repeat the test as soon as possible.  If the retest value confirms AST or ALT >3 × ULN or creatinine >1.2 × ULN, the study treatment must 
be withheld.  If the ALT/AST value remains >3 × ULN or creatinine is >1.2 × ULN for ≥4 weeks after discontinuation of study treatment, then the subject must permanently 
discontinue study treatment, and the event must be recorded as an AE. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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2.2 
Overall Study Duration and Follow-Up 
The study period will consist of a Screening Visit within 4 weeks of Baseline, a Treatment 
Period of 96 weeks and a final Follow-Up Visit.  Subjects will receive treatment for 96 
weeks.  The total duration of subject participation will be up to 104 weeks. 
2.2.1 Screening 
Subject eligibility for the study will be determined within 28 days prior to study entry.  If 
required per local guidelines and if not already available within the previous 3 months, an 
MRI scan should be performed locally before starting therapy with BG00012. 
2.2.2 Treatment Period  
Eligible subjects will report to the study site every 4 weeks for the first 12 weeks and every 
12 weeks thereafter for 96 weeks. 
Discontinuation and/or Withdrawal Visits 
 Visits will 
be performed as necessary.  Subjects who withdraw from the study early will be asked to 
return to complete a Discontinuation and/or Withdrawal Visit within 2 weeks of their last 
study treatment dose.   
2.2.3 Follow-Up 
Subjects are to return to the study site for a Follow-Up Visit 4 weeks after their last dose of 
study treatment.  The final study visit will be Week 100.  
Subjects who temporarily withhold or permanently discontinue BG00012 for any reason and 
have a lymphocyte count <LLN will be followed 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).  Subjects whose lymphocyte count remains <LLN at the end of 
the study (Week 96) will complete the final Follow-Up Visit and will then be followed up 
outside of this protocol at the Investigator’s discretion. 


 
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2.2.7 Additional Assessments if Required by Local Tecfidera Prescribing Information 
Any additional assessments that are needed to comply with the local prescribing information 
for Tecfidera should also be performed and will be reimbursed by Biogen while a subject is 
participating in this study. 
2.3 
Study Stopping Rules 
There are no study-specific stopping rules.  Biogen may terminate this study at any time after 
informing Investigators.  Biogen will notify Investigators when the study is to be placed on 
hold, completed, or terminated. 


 
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2.4 
End of Study 
The end of study is last subject, last visit for final collection of data. 
 
3 
INTERIM ANALYSIS 
In general, since this is an ongoing phase 3b study, interim analyses will be performed as 
needed for regulatory reporting, safety updates, publications, or as otherwise required by the 
Sponsor.  
 
4 
SAMPLE SIZE JUSTIFICATION 
The sample size for this study is not based on formal hypothesis testing but on the precision 
of the estimation of the primary endpoints and the ratios between various ALC subgroups. 
For example, the Phase 2 and 3 controlled and uncontrolled efficacy and safety studies in 
MS, based on data available as of May 2014 from 2470 subjects with at least 1 post-Baseline 
value from the interim analysis of the Integrated Summary of Safety of Tecfidera, showed 
that 76% of subjects had all ALC values ≥LLN and 24% had at least 1 ALC value <LLN up 
to Week 48.  Assuming the same proportion of subjects in this study will have 1 or more 
ALC values <LLN, it is expected that approximately 137 subjects will have all ALC values 
≥LLN and approximately 43 subjects will have at least 1 ALC value <LLN at Week 48, 
based on a total of 180 evaluable subjects at Week 48.  With this sample size, the 90% CIs 
for the ratio of the 2 subgroups for the change from Baseline at Week 48 in lymphocyte 
subsets are illustrated below using the scenario of a true ratio of 0.8 (20% decrease) and 0.7 
(30% decrease), respectively.  When assessing lymphocyte subsets between subjects with at 
least 2 ALC values <LLN up to the first 48 weeks of treatment versus subjects who have all 
ALC values ≥LLN throughout the study, the 90% CIs of the ratio would be wider, as 
historical data suggest that 16% of the patients treated with Tecfidera may have 2 or more 
ALC values <LLN during the first 48 weeks of treatment. 
To allow for a 10% discontinuation rate, a total of 200 subjects are planned for enrollment. 
Table 3: Sample Size Calculations 
Primary 
Endpoints 
SD
a) 
Ratio 
90% CI for the Ratio Based on N = 180 
Subjects With At Least 1 
ALC <LLNb) vs. Subjects 
With All ALC ≥LLNb) 
Subjects With At Least 
2 ALC <LLNb) vs. Subjects 
With All ALC ≥LLNb) 
0.32 
0.8 
0.73, 0.88 
0.71, 0.90 


 
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Primary 
Endpoints 
SD
a) 
Ratio 
90% CI for the Ratio Based on N = 180 
Subjects With At Least 1 
ALC <LLNb) vs. Subjects 
With All ALC ≥LLNb) 
Subjects With At Least 
2 ALC <LLNb) vs. Subjects 
With All ALC ≥LLNb) 
CD4 T cell 
count 
0.7 
0.63, 0.77 
0.63, 0.78 
CD8 T cell 
count 
0.35 
0.8 
0.72, 0.89 
0.71, 0.91 
0.7 
0.63, 0.78 
0.62, 0.79 
CD56bright NK 
cell count 
0.57 
0.8 
0.68, 0.95 
0.65, 0.98 
0.7 
0.59, 0.83 
0.57, 0.86 
Treg count 
0.95 
0.8 
0.60, 1.07 
0.57, 1.12 
0.7 
0.52, 0.93 
0.50, 0.98 
ALC = absolute lymphocyte count; CD = cluster of differentiation; CI = confidence interval; LLN = lower limit 
of normal; NK = natural killer; SD = standard deviation; Treg = T regulatory; vs. = versus. 
a) Common standard deviation for the log-transformed change from Baseline. 
b) Up to Week 48. 
 
5 
STATISTICAL ANALYSIS METHODS 
5.1 
General consideration 
The statistical software, SAS® ,will be used for all summaries and statistical analyses.  
This study only includes a single arm. In general, statistical analyses will be descriptive in 
nature with appropriate measures of variation provided where applicable. For continuous 
endpoints, number of subjects in the analysis population, number of subjects with non-
missing observations, mean, standard deviation (SD), median, minimum and maximum will 
be reported. For categorical endpoints, number of subjects in the analysis population, number 
with non-missing observations, and the percent of those with data in each category will be 
summarized.    
Several analysis populations are defined for different analysis purposes in this study. An 
overview of these analysis populations will be summarized. 
 Pharmacodynamic Population - it is defined as all subjects who receive at least 1 dose 
of study treatment and have at least 1 pharmacodynamic measurement after Baseline.  


 
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 Safety Population – it is defined as all subjects who receive at least 1 dose of study 
treatment.  
 
 
  
 
 
In general, for data that are summarized by visit, any early withdrawal, unscheduled or 
scheduled visits will be assigned to an appropriate scheduled visit by using a mid-point of the 
two visits windowing scheme. The date of first dose will be the reference point.  The detailed 
windowing rules for lymphocyte subsets, hematology, blood chemistry and vital signs are 
available in Appendix 2. After windowing, if there is only 1 record in the visit window, then 
this recored will be selected; if there are multiple records falling into the same visit window 
with different distance from the target day then select the one cloest to the target day; if there 
are 2 visits with the same distance from the target day, but one is before the target day and 
the other is after the target day, then select the later one; for laboratory test, if more than one 
observation falls in the same distance from the target regular scheduled visit day, the mean 
observation will be calculated and used in the summary statistics and analyses.   
No imputation will be used for missing data in this study. The observed data will be used for 
all analyses. 
 
5.2 
Analysis of Baseline Data and Exposure to Study Drug 
The baseline data and exposure to study drug will be summarized for pharmacodynamic 
population. Descriptive statistics will be presented for both continuous endpoints and 
categorical endpoints.     
5.2.1 Accounting of Subjects 
Numbers and percentages of subjects enrolled, completed the treatment, and completed the 
study, along with reasons for discontinuing treatment and withdrawing from the study, will 
be presented. 
5.2.2 Demographics and Baseline Disease Characteristics 
Demographic data, including age (years), age category (18-19, 20-29, 30-39, 40-49, 50-55, 
and > 55), gender, country, race and ethnicity will be summarized.  In addition, summary of 
height (cm), weight (kg), and BMI will be presented. A listing of demography will also be 
presented. 
Baseline disease characteristics will also be summarized descriptively.  Disease 
characteristics will include number of years since MS onset and diagnosis, 
 


 
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. 
5.2.3 Medical History and Previous MS Therapy 
Medical history will be coded by MedDRA Version 19.1 or later and summarized, as number 
and percent of subjects, by system organ class (SOC) and preferred term (PT). Prior MS 
treatment history and baseline cardiac risk factors will also be summarized.     
5.2.4 Protocol Deviations 
Protocol deviations identified in the study will be listed. 
5.2.5 Time on Study and Treatment 
The total number of days/weeks patients on study will be summarized.  Number of weeks the 
subject on the study will also be categorized into 12 week intervals and summarized.  The 
total number of days subjects on study is calculated as 
Date of study end – date of first dose + 1. 
The total number of days/weeks patients on treatment will be summarized.  Number of weeks 
the subject on treatment will also be categorized into 12 week intervals and summarized.  
The time patients on temporary drug interruption will be excluded from the time on treatment 
calculation. Therefore, the total number of days subjects on treatment is calculated as 
(Date of last dose – date of first dose + 1) - total days of temporary dose interruption if any. 
For partial study or study treatment end date, if day is missing then impute the day to 
30/31/28/29 depending on the month; if day and month are missing then impute the month 
and day  to December 31st.  
5.2.6 Treatment Compliance  
The total number of study drug capsules taken by the subject will be summarized. The 
compliance through the date of last dose of study drug and the overall 96-week compliance 
who complete the study will be summarized. The percent compliance is defined as follows 
for each subject:  
Percent Compliance = [(total number of capsules taken) / (total number of capsules subject is 
expected to take)] *100 
The total number of capsules that the subject expected to take is defined as the number of 
days the subject on the study drug multiplied by 4 (4 capsules is the expected number per 
day), except for the first week where 2 capsules a day is expected. The total number of 
capsules actually taken is calculated using total number of doses expected minus the missed 
doses.  


 
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5.2.7 Concomitant Medications and Non-drug Therapies 
Concomitant medication is defined as prescribed or over-the-counter medications used during 
the study (e.g., either started prior to the study and continued on the study or started on or after 
the first dose of study drug). If a medication had a missing start date and a missing end date, 
or had a missing start date and an end date which was after the first day the subject was on 
study drug, or a start date which was after the date of the first day the subject was on study 
drug, the medication is considered concomitant. When partial concomitant medication start or 
end date exists, before determining whether concomitant or not, the following imputation rules 
are applied.  
Partial start dates: 
If day is missing (only month and year are present) 
 If year and month are same as treatment start date then assign the day of treatment 
start date to the partial date 
 Otherwise assign the day to ‘01’ 
If only year is present 
 If year is same as treatment start date then assign the month and day of the 
treatment start date to the partial date 
 Otherwise assign the month and day to ’January-01’ 
Partial end dates: 
If day is missing (only month and year are present) 
 If year and month are same as the year and month of study end date then assign 
the day of the study end date to the partial date 
 If year and month are prior to the year and month of study end date then assign 
the last day of the month (28, 29, 30 or 31) 
If only year is present  
 If year is same as the year of study end date then assign the month and day of the 
study end date to the partial date 
 If year is prior to the year of study end date then assign ‘December-31’ to the 
partial date. 
If the study is ongoing and study end date is not available then the cut-off date will be 
used in the place of study end date 
The WHO dictionary will be used for coding concomitant medication. MedDRA is used for 
coding concomitant non-drug therapies.   


 
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The number and percentage of subjects taking concomitant medication, concomitant MS 
medication, and receiving non-drug treatments will be summarized.  Concomitant medication 
and non-drug concomitant medication will be listed. 
 
5.3 
Pharmacodynamics 
The pharmacodynamic analysis will be based on data from the pharmacodynamic population 
as defined in Section 5.1. The pharmacodynamic data includes the lymphocyte subsets, ALC, 
and isotypes (including IgA, IgM, IgG and IgG subclasses). A listing of reportable 
lymphocyte subset parameters are available in Appendix 1. The lymphocyte subsets are 
categorized into the following eight groups: 
 TBNK lymphocyte subsets 
 T cell subsets 
 B cell subsets 
 Myeloid and NK cell subsets 
 Intracellular T cell cytokines 
 VLA-4/LFA-1 expression 
 
 
 
 
Statistical analyses will be 
 and descriptive in nature, with appropriate measures 
of precision provided where applicable.  
5.3.1 Analysis of the Primary Endpoint 
The primary endpoints are the changes in lymphocyte subset counts for up to 48 weeks.The 
actual value, change and percent change from baseline in count and percent for each 
lymphocyte subset will be descriptively summarized at each applicable visit. Graphical 
display of median (Q1-25 percentile/Q3-75 percentile) of actual value and percent change 
from baseline in count and percent for each lymphocyte subset over time will also be 
presented. The Wilcoxon signed rank test will be used to test if thechange and percent change 
from baseline in count and percent for each lymphocyte subset is different from zero. 
Listings of lymphocyte subsets will also be presented. 
Furthermore, the primary endpoints will be summarized in various ALC subgroups to 
evaluate the nature of change in each subset in relation to the change in ALC.  
ALC subgroups of interest include (1) subjects who have all ALC values ≥LLN 
(0.91ൈ109/L) up to Week 48, and (2) subjects who have at least 1 ALC value <LLN over 48 
weeks. A mixed model for repeated measures (MMRM) will be used to estimate the 
difference between ALC subgroups at each post-baseline visit up to Week 48. The model 
will be fitted with the change from baseline in count up to Week 48 for each of the TBNK 
lymphocyte subset as the dependent variable and will include ALC subgroup (all ALC values 


 
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≥LLN up to Week 48; at least 1 ALC value <LLN over 48 weeks), visit, corresponding 
Baseline counts, age, gender, and ALC subgroup-by-visit interaction as fixed effects. An 
unstructured variance-covariance matrix structure will be used in the MMRM model.  Least 
squares (LS) mean, standard error, LS mean difference, 2-sided 95% confidence intervals 
(CIs) and p-values will be reported. Before the MMRM analysis, appropriate transformation 
may be performed based on the distribution of each TBNK lymphocyte subset parameter. 
The same analysis may be applied to other subsets.  
Additional subgroups based on ALC values over time are defined:  
1) ALC < 0.5ൈ109/L for ൒ 6 months (24 weeks);  
2) 0.5ൈ109/L ൑ALC <0.8ൈ109/L for ൒6 months (excluding < 0.5×109/L for ≥ 6 
months);  
3) <LLN any time (excluding < 0.8×109/L for ≥ 6 months); 
4) ALC always ൒LLN. 
Summary of actual value, change and percent change from baseline in count and percent for 
each lymphocyte subset will be presented by the ALC subgroups defined above.   
The following subgroups analyses based on ALC during the first 48 weeks will be peformed: 
1) At least 2 ALC values <LLN in the first 48 weeks; 
2) Always >= LLN or with one ALC < LLN in the first 48 weeks 
Additionally subgroups analyses based on baseline ALC quartiles will also be explored. The 
same descriptive summary on these subgroups will be applied to the count and percent for 
the TBNK lymphocyte subsets and may be applied to other subsets. Additional subgroups of 
interest may also be explored. 
The correlation between TBNK actual value and ALC will be summarized by visit and also 
presented as plots.  
 
5.3.2 Analysis of the Secondary Endpoints 
The secondary endpoints are the changes from baseline in Ig isotypes (including IgA, IgM, 
IgG and IgG subclasses) and ALCs for up to 48 weeks. The actual values, change and 
percent change from baseline for Ig isotypes and ALCs at each applicable visit will be 
descriptively summarized. Graphical display of mean (+/- SE) of actual values and percent 
change from baseline over time in Ig isotypes will be presented as well. Individual patient’s 
Ig isotypes will also be listed. 
In addition, MMRM analysis will be conducted for each Ig isotype and for ALC with the 
change from baseline up to Week 96 as the dependent variable. The model will include visit, 
corresponding baseline value, age, and gender as fixed effects and an unstructured variance-
covariance matrix structure. LS mean, standard error and 95% CIs will be reported for each 
visit. 


 
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5.3.3 Lymphocyte analysis during lymphocyte follow-up period 
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 will include subjects who have at least one 
ALC < LLN during the treatment period and have at least one ALC value during the 
lymphocyte follow-up period. 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 detailed windowing rule is available in Appendix 2. Patients who have 
any post lymphocyte follow-up baseline values will be included in the analysis. ALCs 
collected during the lymphocyte follow-up period will be analyzed. The lymphocyte subsets 
and Ig isotypes observed obvious decline over time in the treatment period will also be 
explored.  
The by-visit summary of actual value, change and percent change from 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 study baseline and lymphocyte follow-up 
baseline will be presented. The same analyses will be applied to selected lymphocyte subsets 
and Ig isotypes of interest. 
The concomitant medication, AEs, hematology, vital signs and physical examination data 
collected during the lymphocyte follow-up visits will be discussed in Section 5.4.6. 
Additional analyses exploring lymphocyte subsets and ALCs collected during the 
lymphocyte follow-up period  may be conducted.  
 


 
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5.4 
Safety 
All AEs, clinical laboratory results, physical examinations, vital signs, and 12-lead ECG 
readings data will be evaluated for safety. The data from safety population defined in Section 
5.1 will be used for safety analysis. Statistical analyses will be 
 and descriptive in 
nature.  
5.4.1 Adverse Events 
AEs will be coded using MedDRA version of 19.1 or later. Only treatment-emergent AEs 
will be analyzed.  A treatment-emergent AE is defined as any AE that has an onset date and 
time that is on or after the date of the first dose of study treatment, or that has worsened after 
the date of the first dose of study treatment.  In the case of a worsening AE, the AE is 
supposed to be recorded as a new event with an onset date after first dose of study drug.   
Therefore, all treatment emergent AEs will be captured as AEs that have an onset date that is 
on or after date of first dose of study drug.     
If an AE had a missing onset date and a missing resolution date, or had a missing onset date 
and a resolution date which was after the first day the subject was on study drug, or an onset 
date which was after the date of the first day the subject was on study drug, the event is 
considered treatment emergent.  If the onset date of the AE was the same as date of the first 
day the subject took study drug the event is considered treatment-emergent. When partial AE 
start or end date exists, before determining whether treatment-emergent or not, the following 
imputation rules are applied.  
Partial start dates:  
If day is missing (only month and year are present) 
 If year and month are same as treatment start date then assign the day of treatment 
start date to the partial date 
 Otherwise assign the day to ‘01’ 
If only year is present 
 If year is same as treatment start date then assign the month and day of the 
treatment start date to the partial date 
 Otherwise assign the month and day to ’January-01’ 
Partial end dates: 
If day is missing (only month and year are present) 
 If year and month are same as the year and month of study end date then assign 
the day of the study end date to the partial date 
 If year and month are prior to the year and month of study end date then assign 
the last day of the month (28, 29, 30 or 31) 
If only year is present  


 
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 If year is same as the year of study end date then assign the month and day of the 
study end date to the partial date 
 If year is prior to the year of study end date then assign ‘December-31’ to the 
partial date. 
If the study is ongoing and study end date is not available then the cut-off date will be 
used in the place of study end date 
 
AE overview 
The summary of treatment-emergent AEs will include the number of subjects and percentage 
for the following categories: at least one treatment-emergent AE, at least one moderate or 
severe treatment-emergent AE, at least one severe treatment-emergent AE, at least one 
related treatment-emergent AE, at least one treatment-emergent SAE, discontinuing 
treatment due to an event and withdrawing from study due to an event. A listing of all AEs 
will be presented for all subjects. 
AEs 
 The incidence of treatment-emergent AEs classified by the appropriate system organ 
class (SOC) and preferred term (PT) will be summarized.  
 The incidence of treatment-emergent AEs classified by PT will be summarized.  
 The incidence of treatment-emergent AEs considered as related to study drug 
classified by the appropriate SOC and PT will be summarized. Treatment-related is 
defined as events with a “possibly” or “related” relationship to study drug.   
 Incidence of treatment-emergent AEs by relationship to study drug will be 
summarized. In the relationship to study drug column within each SOC and PT, a 
subject was counted only once and only in the category of strongest relationship to 
study drug. 
 Incidence of treatment-emergent AEs by severity will be summarized. If a patient 
experiences an event more than once with varying severity during a study phase, 
he/she will be counted only once with the maximum severity within each SOC and 
PT. 
 The incidence of treatment-emergent AEs that led to the discontinuation of study drug 
will be presented by SOC and PT.  A listing of these AEs will also be presented.    
 The incidence of treatment-emergent AEs that led to premature withdrawal from the 
study will be presented by SOC and PT.  A listing of these AEs will also be 
presented.   
 The incidence of treatment-emergent AEs that led to temporary dose interruption will 
be presented by SOC and PT.    


 
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 The incidence of treatment-emergent AEs that led to dose reduction will be presented 
by SOC and PT.   
SAEs and severe AEs 
 The incidence of treatment-emergent SAEs will be presented by SOC and PT.  
Individual SAEs will be listed.  The information presented will include subject ID, 
treatment, SOC and PT, date of onset, severity, and relationship to and action taken 
with the study drug.    
 The incidence of treatment-emergent severe AEs classified by SOC and PT will be 
summarized.  
Infections  
The incidence of treatment-emergent infections, serious infections, and potential 
opportunistic infections by system organ class and preferred term will be summarized by 
subgroups based on the ALC values over time.  
PML  
Given that PML has been observed very rarely in patients who receive BG00012, any PML 
cases in this study will be listed. 
Pancreatitis   
Listing of events associated to pancreatitis will be presented.  
Death 
Death is classified as an outcome, not as an AE.  Therefore, cause of death will be listed as 
the AE.  Death will only be listed as an AE when the cause of death is unknown (e.g., in the 
case of sudden death).  .  The information presented will include subject ID, treatment group, 
SOC and PT, date of death, cause of death, and relationship to the study drug. 
5.4.2 Clinical Laboratory Results 
The following laboratory parameters will be analyzed: 
 Hematology:  WBC, lymphocytes, neutrophils, monocytes, eosinophils, basophils, 
RBC, hemoglobin, hematocrit, platelets. 
 Blood chemistry:  ALT/SGPT, AST/SGOT, alkaline phosphatase (ALP), total 
bilirubin, BUN/urea, creatinine, sodium, potassium, chloride, bicarbonate, calcium, 
magnesium, phosphorus, glucose, uric acid.   
Shift analyses 
Laboratory data will be summarized using shift tables.  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.  Shifts from baseline to 


 
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high/low status for hematology and blood chemistry parameters will be presented.   Subjects 
need to have at least one-post baseline evaluation in order to be included in the analysis.  In 
addition, the shift from baseline to the maximum post-baseline value will be presented for 
selected blood chemistry parameters (ALT, AST, alkaline phosphatase and total bilirubin).  
The rationale for using the maximum values or worst values is that should a treatment affect 
a laboratory value, that value could be affected at different times for different subjects.  
Therefore, the analyses present the most extreme values for each subject over time.  
In addition, summary of  maximum post-baseline values for selected blood chemistry 
parameters (ALT, AST, and total bilirubin) will be presented. For liver function tests ALT, 
AST, the number and percentage of subjects with post-baseline values classified by 
categories will be summarized.  The categories are defined as:  <= 1xULN, >1 x ULN, >= 
3xULN, >5xULN, >10xULN, and >20xULN, where ULN is the Upper Limit of the Normal 
value.  For total bilirubin, the categories are: <= 1xULN, >1 x ULN, >= 1.5xULN, and > 
2.0xULN. A graphical summary of baseline and worst post-baseline values for selected 
laboratory parameters (WBC and lymphocyte) will also be presented. 
Change from baseline analyses 
Summary of hematology and blood chemistry values and change from Baseline by visit up to 
Week 96 will be presented.  Graphical display of mean (+/- SE) of change from Baseline for 
hematology and blood chemistry parameters over time will be presented. Subject listings of 
hematology and blood chemistry will also be presented. 
Abnormality analyses 
Additional summary statistics will be presented for potentially clinically significant 
abnormalities for selected laboratory parameters.  For example, the worst post-baseline 
values for WBC, lymphocyte, platelet, RBC, neutrophils, hemoglobin, classified based on 
clinically meaningful cut-off values, will be summarized.   
Table 4: Definition for potentially clinically significant abnormalities for selected laboratory 
parameters 
Parameter (unit) 
Definition of potentially clinically significant 
abnormalities (each defined separately) 
WBC (x 109/L) 
<3.0 
>=16 
Lymphocyte  (x 109/L) 
<0.8 
<0.5 
>12 
Neutrophil  (x 109/L) 
<=1.0 


 
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<1.5 
>=12 
RBC  (x 1012/L)  
<=3.3 
>=6.8 
Hemoglobin  ( g/L) 
<=100 
Platelet count   (x 109/L) 
<=100 
>=600 
5.4.3 Physical Examinations 
The analyses of physical examinations will include summary statistics (actual value and 
change from Baseline for body weight and height) over time by visit. 
5.4.4 Vital Signs 
The analysis of vital signs will focus on clinically relevant abnormalities.  For each vital sign, 
the number of subjects evaluated and the number and percentage of subjects with the defined 
abnormality at any time post-baseline will be presented.   
The definitions of these clinically relevant abnormalities are shown in Table 4.   
Table 4: 
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs 
Vital Sign 
Criteria for Abnormalities 
Temperature  
>38°C post baseline and an increase from Baseline of ≥1°C 
Pulse 
>120 bpm post baseline or an increase from Baseline of >20 bpm 
<50 post baseline bpm or a decrease from Baseline of >20 bpm 
Systolic Blood Pressure 
>180 mmHg post baseline or an increase from Baseline of >40 mmHg 
<90 mmHg post baseline or a decrease from Baseline of >30 mmHg 
Diastolic Blood 
Pressure 
>105 mmHg post baseline or an increase from Baseline of >30 mmHg 
<50 mmHg post baseline or a decrease from Baseline of >20 mmHg 
The analyses of vital signs will also include summary statistics (actual value and change from 
Baseline for temperature, pulse, and systolic and diastolic blood pressure) over time by visit. 


 
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5.4.5 ECG Data 
A listing of subjects with abnormal ECG status will be presented.  The number and 
percentage of subjects with shifts from baseline to each of the categorical values denoting an 
abnormal scan (abnormal, not AE/abnormal, AE) will be summarized. 
5.4.6 Safety analysis during lymphocyte follow-up period 
The concomitant medication, AEs, hematology, vital signs and physical examination data 
collected during the lymphocyte follow-up period will be analyzed.    
The concomitant medication and AEs, either started prior to the lymphocyte follow-up period 
and continued during the lymphocyte follow-up period, or started on or after the lymphocyte 
follow-up period will be listed.  
Hematology, vital signs and physical examination data during the lymphocyte follow-up 
period will either be descriptively summarized or listed. The windowing rule defined in 
Section 5.3.3 will be used for visit mapping. Additional safety analyses during lymphocyte 
follow-up period may be conducted. 


 
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An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
 
 
 
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Protocol 109MS310 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
 
 
 
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5.7 
Changes in statistical analysis methods 
5.7.1 Change in clinical assessment population definition 
In protocol, the evaluable population for clinical assessments is defined as all subjects who 
receive at least 1 dose of study treatment and at least 1 measurement for each of the clinical 
assessments after Baseline. 
 
 
 
 
 
 
 


 
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Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
 
 
 
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Appendix 1 – List of reportable lymphocyte subset parameters 
 
Lab test name (LabCorp) 
Lab test code 
(LabCorp) 
Lab label 
Subset type 
%CD24hi/CD38hi [CD19+/CD3-] 
BCSB03 
Transitional B-cells (% of  B cells) 
B Cell Subsets 
%CD24hi/CD38hi/CD10+ [19+/3-] 
BCSB08 
CD10+ Transitional B cells (% of  B cells) 
B Cell Subsets 
%CD27++/CD38++ [CD19+/CD3-] 
BCSB09 
Plasmablasts (% of  B cells) 
B Cell Subsets 
%CD27++/CD38++/CD10- [19+/3-] 
BCSB10 
Plasma Cells [CD10-] (% of  B cells) 
B Cell Subsets 
%CD27++/CD38++/CD138+ [19+/3-] 
BCSB12 
CD138+ Plasma Cells (% of  B cells) 
B Cell Subsets 
%CD27+/IgD+ [CD19+/CD3-] 
BCSB07 
IgD+ Memory B cells [non-class 
switched] (% of  B cells) 
B Cell Subsets 
%CD27+/IgD- [CD19+/CD3-] 
BCSB06 
IgD- Memory B cells [class switched] (% 
of  B cells) 
B Cell Subsets 
%CD27-/IgD+ [CD19+/CD3-] 
BCSB05 
Naïve B cells (% of  B cells) 
B Cell Subsets 
Absolute 27++/38++/10-[19+/3-] 
BCSB22 
Plasma Cells [CD10-] (cells/mm3) 
B Cell Subsets 
Absolute CD24hi/CD38hi[19+/3-] 
BCSB15 
Transitional B-cells (cells/mm3) 
B Cell Subsets 
Absolute CD27++/38++[19+/3-] 
BCSB21 
Plasmablasts (cells/mm3) 
B Cell Subsets 
Absolute CD27+/IgD+ [CD19+/3-] 
BCSB19 
IgD+ Memory B cells [non-class 
switched] (cells/mm3) 
B Cell Subsets 
Absolute CD27+/IgD- [CD19+/3-] 
BCSB18 
IgD- Memory B cells [class switched] 
(cells/mm3) 
B Cell Subsets 
Absolute CD27-/IgD+ [CD19+/3-] 
BCSB17 
Naïve B cells (cells/mm3) 
B Cell Subsets 
Absolute24hi/38hi/10+[19+/3-] 
BCSB20 
CD10+ Transitional B cells (cells/mm3) 
B Cell Subsets 
Absolute27++/38++/138+[19+MNC] 
BCSB24 
CD138+ Plasma Cells (cells/mm3) 
B Cell Subsets 
%CD11a+ [CD11c++] 
A4S96 
CD11a+ (% of dendritic cells [CD11c++]) 
VLA-4/LFA-1 
Expression 
%CD11a+ [CD19+] 
A4S82 
CD11a+ (% of  B cells) 
VLA-4/LFA-1 
Expression 
%CD11a+ [CD3+] 
A4S68 
CD11a+ (% of  T cells) 
VLA-4/LFA-1 
Expression 
%CD11a+ [Lymphs] 
A4S26 
CD11a+ (% of lymphocytes) 
VLA-4/LFA-1 
Expression 
%CD11a+ [MNC] 
A4S12 
CD11a+ (% of MNC) 
VLA-4/LFA-1 
Expression 
%CD11a+ [Monos] 
A4S40 
CD11a+ (% of monocytes) 
VLA-4/LFA-1 
Expression 


 
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%CD11a+ [Neut] 
A4S54 
CD11a+ (% of neutrophils) 
VLA-4/LFA-1 
Expression 
%CD49d+ (9F10) [CD11c++] 
A4S95 
CD49d+ (% of dendritic cells [CD11c++]) 
VLA-4/LFA-1 
Expression 
%CD49d+ (9F10) [CD19+] 
A4S81 
CD49d+ (% of  B cells) 
VLA-4/LFA-1 
Expression 
%CD49d+ (9F10) [CD3+] 
A4S67 
CD49d+ (% of  T cells) 
VLA-4/LFA-1 
Expression 
%CD49d+ (9F10) [Lymphs] 
A4S25 
CD49d+ (% of lymphocytes) 
VLA-4/LFA-1 
Expression 
%CD49d+ (9F10) [MNC] 
A4S11 
CD49d+ (% of MNC) 
VLA-4/LFA-1 
Expression 
%CD49d+ (9F10) [Monos] 
A4S39 
CD49d+ (% of monocytes) 
VLA-4/LFA-1 
Expression 
%CD49d+ (9F10) [Neut] 
A4S53 
CD49d+ (% of neutrophils) 
VLA-4/LFA-1 
Expression 
MESF Total CD11a [CD11c++] 
A4S92 
CD11a+ dendritic cells [CD11c++] 
(MESF) 
VLA-4/LFA-1 
Expression 
MESF Total CD11a [CD19+] 
A4S78 
CD11a+  B cells (MESF) 
VLA-4/LFA-1 
Expression 
MESF Total CD11a [CD3+] 
A4S64 
CD11a+  T cells (MESF) 
VLA-4/LFA-1 
Expression 
MESF Total CD11a [Lymphs] 
A4S22 
CD11a+ lymphocytes (MESF) 
VLA-4/LFA-1 
Expression 
MESF Total CD11a [MNC] 
A4S08 
CD11a+ MNC (MESF) 
VLA-4/LFA-1 
Expression 
MESF Total CD11a [Monos] 
A4S36 
CD11a+ monocytes (MESF) 
VLA-4/LFA-1 
Expression 
MESF Total CD11a [Neut] 
A4S50 
CD11a+ neutrophils (MESF) 
VLA-4/LFA-1 
Expression 
MESF Total CD49d (9F10) [CD3+] 
A4S63 
CD49d+ dendritic cells [CD11c++] 
(MESF) 
VLA-4/LFA-1 
Expression 
MESF Total CD49d (9F10) [MNC] 
A4S07 
CD49d+  B cells (MESF) 
VLA-4/LFA-1 
Expression 
MESF Total CD49d (9F10) [Neut] 
A4S49 
CD49d+  T cells (MESF) 
VLA-4/LFA-1 
Expression 


 
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MESF Total CD49d [CD11c++] 
A4S91 
CD49d+ lymphocytes (MESF) 
VLA-4/LFA-1 
Expression 
MESF Total CD49d [CD19+] 
A4S77 
CD49d+ MNC (MESF) 
VLA-4/LFA-1 
Expression 
MESF Total CD49d [Lymphs] 
A4S21 
CD49d+ monocytes (MESF) 
VLA-4/LFA-1 
Expression 
MESF Total CD49d [Monos] 
A4S35 
CD49d+ neutrophils (MESF) 
VLA-4/LFA-1 
Expression 
%CD14+ [CD45+] 
DMNK02 
Total monocytes [CD14+] (% of CD45+ 
leukocytes) 
Myeloid and NK cell 
subsets 
%CD16+/CD14+dim [CD45+] 
DMNK04 
Non-classical Monocytes (% of CD45+ 
leukocytes) 
Myeloid and NK cell 
subsets 
%CD16+/CD56hi/3-/19- [Lymphs] 
DMNK10 
CD56Bright NK cells (% of lymphocytes) 
Myeloid and NK cell 
subsets 
%CD16+/CD56low/3-/19- [Lymphs] 
DMNK09 
CD56Dim NK cells (% of lymphocytes) 
Myeloid and NK cell 
subsets 
%CD16-/CD14+ [CD45+] 
DMNK03 
Classical Monocytes (% of CD45+ 
leukocytes) 
Myeloid and NK cell 
subsets 
%HLA-DR+ [MNC] 
DMNK06 
Total dendritic cells (% of MNC) 
Myeloid and NK cell 
subsets 
%HLA-DR+/CD11c+ [MNC] 
DMNK07 
Myeloid dendritic cells (% of MNC) 
Myeloid and NK cell 
subsets 
%HLA-DR+/CD123+ [MNC] 
DMNK08 
Plasmacytoid dendritic cells (% of MNC) 
Myeloid and NK cell 
subsets 
Abs CD16+/CD56hi/3-/19- Lymphs 
DMNK20 
CD56Bright NK cells (cells/mm3) 
Myeloid and NK cell 
subsets 
AbsCD16+/CD56low/3-/19- Lymphs 
DMNK19 
CD56Dim NK cells (cells/mm3) 
Myeloid and NK cell 
subsets 
Absolute CD14+ 
DMNK12 
Total monocytes [CD14+] (cells/mm3) 
Myeloid and NK cell 
subsets 
Absolute CD16+/CD14+dim 
DMNK14 
Non-classical Monocytes (cells/mm3) 
Myeloid and NK cell 
subsets 
Absolute CD16-/CD14+ 
DMNK13 
Classical Monocytes (cells/mm3) 
Myeloid and NK cell 
subsets 
Absolute HLA-DR+ [MNC] 
DMNK16 
Total dendritic cells (cells/mm3) 
Myeloid and NK cell 
subsets 


 
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Absolute HLA-DR+/CD11c+ [MNC] 
DMNK17 
Myeloid dendritic cells (cells/mm3) 
Myeloid and NK cell 
subsets 
Absolute HLA-DR+/CD123+ [MNC] 
DMNK18 
Plasmacytoid dendritic cells (cells/mm3) 
Myeloid and NK cell 
subsets 
%45+/25+/127low/- [3+/4+] 
TCTR22 
Regulatory T-cells (% of CD4+ T cells) 
T cell subsets 
%45+/25+/127low/-/45RO-[3+/4+] 
TCTR25 
Naïve Regulatory T-cells (% of CD4+ T 
cells) 
T cell subsets 
%45+/25+/127low/45RO+ [3+/4+] 
TCTR26 
Effector Regulatory T-cells (% of CD4+ T 
cells) 
T cell subsets 
%45+25+127low45RO+DR+[3+4+] 
TCTR075 
Terminal Effector Regulatory T-cells (% 
of CD4+ T cells) 
T cell subsets 
%CD38+ [3+/4+/8-] 
TCTR069 
Activated [CD38+] (% of CD4+ T cells) 
T cell subsets 
%CD38+ [3+/4-/8+] 
TCTR072 
Activated [CD38+] (% of CD8+ T cells) 
T cell subsets 
%CD38+/HLA-DR+ [CD3+/CD4+] 
TCTR14 
Activated [CD38+HLA-DR+] (% of 
CD4+ T cells) 
T cell subsets 
%CD38+/HLA-DR+ [CD3+/CD8+] 
TCTR21 
Activated [CD38+HLA-DR+] (% of 
CD8+ T cells) 
T cell subsets 
%CD4+/CD45RA+ [CD3+] 
TCTR08 
Naïve CD4+ T-cell [CD45RA+] (% of T 
cells) 
T cell subsets 
%CD4+/CD45RA- [CD3+] 
TCTR09 
Memory CD4+ T-cell [CD45RA-] (% of 
T cells) 
T cell subsets 
%CD45RA+/CCR7+ [CD3+/CD4+] 
TCTR10 
Naïve CD4+ T-cell [CD45RA+CCR7+] 
(% of CD4+ T cells) 
T cell subsets 
%CD45RA+/CCR7+ [CD3+/CD8+] 
TCTR17 
Naïve CD8+ T-cell [CD45RA+CCR7+] 
(% of CD8+ T cells) 
T cell subsets 
%CD45RA+/CCR7- [CD3+/CD4+] 
TCTR11 
Effector CD4+ T-cell [CD45RA+CCR7-] 
(% of CD4+ T cells) 
T cell subsets 
%CD45RA+/CCR7- [CD3+/CD8+] 
TCTR18 
Effector CD8+ T-cell [CD45RA+CCR7-] 
(% of CD8+ T cells) 
T cell subsets 
%CD45RA-/CCR7+ [CD3+/CD4+] 
TCTR12 
Central Memory CD4+ T-cell [CD45RA-
CCR7+] (% of CD4+ T cells) 
T cell subsets 
%CD45RA-/CCR7+ [CD3+/CD8+] 
TCTR19 
Central Memory CD8+ T-cell [CD45RA-
CCR7+] (% of CD8+T cells) 
T cell subsets 
%CD45RA-/CCR7- [CD3+/CD4+] 
TCTR13 
Effector Memory CD4+ T-cell [CD45RA-
CCR7-] (% of CD4+ T cells) 
T cell subsets 


 
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%CD45RA-/CCR7- [CD3+/CD8+] 
TCTR20 
Effector Memory CD8+ T-cell [CD45RA-
CCR7-] (% of  CD8+T cells) 
T cell subsets 
%CD8+/CD45RA+ [CD3+] 
TCTR15 
Naïve CD8+ T-cell [CD45RA+] (% of T 
cells) 
T cell subsets 
%CD8+/CD45RA- [CD3+] 
TCTR16 
Memory CD8+ T-cell [CD45RA-] (% of 
T cells) 
T cell subsets 
%CXCR3+/CCR6- [CD3+/CD4+] 
TCTR29 
Th1 phenotype (% of CD4+ T cells) 
T cell subsets 
%CXCR3+CCR6-38+HLA-DR+ 
[3+4+] 
TCTR32 
Activated Th1 phenotype (% of CD4+ T 
cells) 
T cell subsets 
%CXCR3-/CCR6+ [CD3+/CD4+] 
TCTR31 
Th17 phenotype (% of CD4+ T cells) 
T cell subsets 
%CXCR3-/CCR6- [CD3+/CD4+] 
TCTR30 
Th2-enriched phenotype (% of CD4+ T 
cells) 
T cell subsets 
%CXCR3-CCR6+38+HLA-DR+ 
[3+4+] 
TCTR34 
Activated Th17 phenotype (% of CD4+ T 
cells) 
T cell subsets 
%CXCR3-CCR6-38+HLA-DR+ 
[3+4+] 
TCTR33 
Activated Th2-enriched phenotype (% of 
CD4+ T cells) 
T cell subsets 
%HLA-DR+ [3+/4+/8-] 
TCTR068 
Activated [HLA-DR+] (% of CD4+ T 
cells) 
T cell subsets 
%HLA-DR+ [3+/4-/8+] 
TCTR071 
Activated [HLA-DR+] (% of CD8+ T 
cells) 
T cell subsets 
Abs 45+25+127low/-45RO-[3+4+] 
TCTR56 
Naïve Regulatory T-cells (cells/mm3) 
T cell subsets 
Abs 45+25+127low45RO+ [3+4+] 
TCTR57 
Effector Regulatory T-cells (cells/mm3) 
T cell subsets 
Abs 45+25+127low45RO+DR+[3+4+] 
TCTR084 
Terminal Effector Regulatory T-cells 
(cells/mm3) 
T cell subsets 
AbsCXCR3+CCR6-38+HLA-
DR+[3+4+] 
TCTR63 
Activated Th1 phenotype (cells/mm3) 
T cell subsets 
AbsCXCR3-CCR6+38+HLA-
DR+[3+4+] 
TCTR65 
Activated Th17 phenotype (cells/mm3) 
T cell subsets 
AbsCXCR3-CCR6-38+HLA-
DR+[3+4+] 
TCTR64 
Activated Th2-enriched phenotype 
(cells/mm3) 
T cell subsets 
Absolute 38+/HLA-DR+ [3+/8+] 
TCTR52 
Activated CD8+ T-cell [CD38+HLA-
DR+] (cells/mm3) 
T cell subsets 
Absolute 38+/HLA-DR+ [3+/4+] 
TCTR45 
Activated CD4+ T-cell [CD38+HLA-
DR+] (cells/mm3) 
T cell subsets 
Absolute 45+25+127low/- [3+4+] 
TCTR53 
Regulatory T-cells (cells/mm3) 
T cell subsets 


 
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Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
 
 
 
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Absolute 45RA+/CCR7+ [3+/4+] 
TCTR41 
Naïve CD4+ T-cell [CD45RA+CCR7+] 
(cells/mm3) 
T cell subsets 
Absolute 45RA+/CCR7+ [3+/8+] 
TCTR48 
Naïve CD8+ T-cell [CD45RA+CCR7+] 
(cells/mm3) 
T cell subsets 
Absolute 45RA+/CCR7- [3+/4+] 
TCTR42 
Effector CD4+ T-cell [CD45RA+CCR7-] 
(cells/mm3) 
T cell subsets 
Absolute 45RA+/CCR7- [3+/8+] 
TCTR49 
Effector CD8+ T-cell [CD45RA+CCR7-] 
(cells/mm3) 
T cell subsets 
Absolute 45RA-/CCR7+ [3+/4+] 
TCTR43 
Central Memory CD4+ T-cell [CD45RA-
CCR7+] (cells/mm3) 
T cell subsets 
Absolute 45RA-/CCR7+ [3+/8+] 
TCTR50 
Central Memory CD8+ T-cell [CD45RA-
CCR7+] (cells/mm3) 
T cell subsets 
Absolute 45RA-/CCR7- [3+/4+] 
TCTR44 
Effector Memory CD4+ T-cell [CD45RA-
CCR7-] (cells/mm3) 
T cell subsets 
Absolute 45RA-/CCR7- [3+/8+] 
TCTR51 
Effector Memory CD8+ T-cell [CD45RA-
CCR7-] (cells/mm3) 
T cell subsets 
Absolute CD38+ [3+/4+/8-] 
TCTR078 
Activated CD4+ T-cell [CD38+] 
(cells/mm3) 
T cell subsets 
Absolute CD38+ [3+/4-/8+] 
TCTR081 
Activated CD8+ T-cell [CD38+] 
(cells/mm3) 
T cell subsets 
Absolute CD4+/CD45RA+ [CD3+] 
TCTR39 
Naïve CD4+ T-cell [CD45RA+] 
(cells/mm3) 
T cell subsets 
Absolute CD4+/CD45RA- [CD3+] 
TCTR40 
Memory CD4+ T-cell [CD45RA-] 
(cells/mm3) 
T cell subsets 
Absolute CD8+/CD45RA+ [CD3+] 
TCTR46 
Naïve CD8+ T-cell [CD45RA+] 
(cells/mm3) 
T cell subsets 
Absolute CD8+/CD45RA- [CD3+] 
TCTR47 
Memory CD8+ T-cell [CD45RA-] 
(cells/mm3) 
T cell subsets 
Absolute CXCR3+/CCR6- [3+/4+] 
TCTR60 
Th1 phenotype (cells/mm3) 
T cell subsets 
Absolute CXCR3-/CCR6+ [3+/4+] 
TCTR62 
Th17 phenotype (cells/mm3) 
T cell subsets 
Absolute CXCR3-/CCR6- [3+/4+] 
TCTR61 
Th2-enriched phenotype(cells/mm3) 
T cell subsets 
Absolute HLA-DR+ [3+/4+/8-] 
TCTR077 
Activated CD4+ T-cell [HLA-DR+] 
(cells/mm3) 
T cell subsets 
Absolute HLA-DR+ [3+/4-/8+] 
TCTR080 
Activated CD8+ T-cell [HLA-DR+] 
(cells/mm3) 
T cell subsets 


 
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Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
 
 
 
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%IFNg+/ IL-17A- [3+/8+] Stim 
ICT56 
IFNg+ (% of CD8+ T cells) 
Intracellular T cell 
Cytokines 
%IFNg+/IL-17A- [CD3+/CD4+]Stim 
ICT30 
IFNg+ (% of CD4+ T cells) 
Intracellular T cell 
Cytokines 
%IFNg+/IL-17A-[3+4+8-45RA-]St 
ICT39 
IFNg+ (% of memory CD4+ T cells) 
Intracellular T cell 
Cytokines 
%IFNg+/IL-17A-[3+8+4-45RA-]St 
ICT61 
IFNg+ (% of memory CD8+ T cells) 
Intracellular T cell 
Cytokines 
%IL-17A+/IFNg- [3+/8+] Stim 
ICT58 
IL-17A+/IFNg- (% of CD8+ T cells) 
Intracellular T cell 
Cytokines 
%IL-17A+/IFNg- [CD3+/CD4+]Stim 
ICT32 
IL-17A+/IFNg- (% of CD4+ T cells) 
Intracellular T cell 
Cytokines 
%IL-17A+/IFNg-[3+4+8-45RA-]St 
ICT41 
IL-17A+/IFNg- (% of memory CD4+ T 
cells) 
Intracellular T cell 
Cytokines 
%IL-17A+/IFNg-[3+8+4-45RA-]St 
ICT63 
IL-17A+/IFNg- (% of memory CD8+ T 
cells) 
Intracellular T cell 
Cytokines 
%IL-2+ [3+/4+/8-/45RA-] Stim 
ICT42 
IL-2+ (% of memory CD4+ T cells) 
Intracellular T cell 
Cytokines 
%IL-2+ [3+8+4-45RA-]St 
ICT64 
IL-2+ (% of memory CD8+ T cells) 
Intracellular T cell 
Cytokines 
%IL-2+ [CD3+/CD4+] Stim 
ICT33 
IL-2+ (% of CD4+ T cells) 
Intracellular T cell 
Cytokines 
%IL-2+ [CD3+/CD8+] Stim 
ICT59 
IL-2+ (% of CD8+ T cells) 
Intracellular T cell 
Cytokines 
%IL-4+ [3+/4+/8-/45RA-]Stim 
ICT40 
IL-4+ (% of memory CD4+ T cells) 
Intracellular T cell 
Cytokines 
%IL-4+ [3+8+4-45RA-] Stim 
ICT62 
IL-4+ (% of memory CD8+ T cells) 
Intracellular T cell 
Cytokines 
%IL-4+ [CD3+/CD4+] Stim 
ICT31 
IL-4+ (% of CD4+ T cells) 
Intracellular T cell 
Cytokines 
%IL-4+ [CD3+/CD8+] Stim 
ICT57 
IL-4+ (% of CD8+ T cells) 
Intracellular T cell 
Cytokines 
% Granulocytes 
PGRANS 
Granulocytes (% of leukocytes) 
TBNK Lymphocyte 
Subsets 
% Lymphocytes 
PLYMPH 
Lymphocytes(% of leukocytes) 
TBNK Lymphocyte 
Subsets 


 
Protocol 109MS310 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
 
 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen Idec MA Inc. 
41 
% Monocytes 
PMONOS 
Monocytes (% of leukocytes) 
TBNK Lymphocyte 
Subsets 
%CD19+ (TBNK TruCount BD) 
CD19P1 
B cells (% of lymphocytes) 
TBNK Lymphocyte 
Subsets 
%CD3+ [Tube 1] 
CD3P1 
T cells (% of lymphocytes) 
TBNK Lymphocyte 
Subsets 
%CD3+/CD4+ 
CD4P1 
CD4+ T cells (% of lymphocytes) 
TBNK Lymphocyte 
Subsets 
%CD3+/CD8+ 
CD8P1 
CD8+ T cells (% of lymphocytes) 
TBNK Lymphocyte 
Subsets 
%CD3-/CD16+,CD56+ 
NK2P1 
NK cells (% of lymphocytes) 
TBNK Lymphocyte 
Subsets 
Abs Granulocytes 
AGRANS 
Granulocytes (cells/mm3) 
TBNK Lymphocyte 
Subsets 
Abs Monocytes 
AMONOS 
Monocytes (cells/mm3) 
TBNK Lymphocyte 
Subsets 
Absolute CD3+ [Tube 1] 
CD3A1 
T Cells (cells/mm3) 
TBNK Lymphocyte 
Subsets 
Absolute Lymphocytes [Tube 1] 
ALYMT1 
Lymphocytes (cells/mm3) 
TBNK Lymphocyte 
Subsets 
CD16,56 Absolute 
NK2A 
NK cells (cells/mm3) 
TBNK Lymphocyte 
Subsets 
CD19 Absolute 
CD19A 
B cells (cells/mm3) 
TBNK Lymphocyte 
Subsets 
CD4 Absolute 
CD4A 
CD4+ T cells (cells/mm3) 
TBNK Lymphocyte 
Subsets 
CD8 Absolute 
CD8A 
CD8+ T cells (cells/mm3) 
TBNK Lymphocyte 
Subsets 


 
Protocol 109MS310 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
 
 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen Idec MA Inc. 
42 


 
Protocol 109MS310 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
 
 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen Idec MA Inc. 
43 


 
Protocol 109MS310 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
 
 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen Idec MA Inc. 
44 
 
 
 
 
 
 
 
 
 
 
 


 
Protocol 109MS310 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
 
 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen Idec MA Inc. 
45 
Appendix 2 – Visit windowing rules 
For Blood Chemistry, window to scheduled visits using the following windows: 
Visit Name 
Target Day 
Study Day in Range Window 
Baseline 
 first dose date 
<=  first dose date 
Week 4 
Day 29 
(first dose date+1) to Day 42 
Week 8 
Day 57 
Day 43 to Day 112 
Week 24 
Day 169 
Day 113 to Day 252 
Week 48 
Day 337 
Day 253 to Day 504 
Week 96 
Day 673 
>=Day 505   
 
For Hematology parameters, window to scheduled visits using the following windows: 
Visit Name 
Target Day 
Study Day in Range Window 
Baseline 
first dose date 
<=  first dose date 
Week 4 
Day 29 
(first dose date+1) to Day 42 
Week 8 
Day 57 
Day 43 to Day 70 
Week 12 
Day 85 
Day 71 to Day 126 
Week 24 
Day 169 
Day 127 to Day 210 
Week 36 
Day 253 
Day 211 to Day 294 
Week 48 
Day 337 
Day 295 to Day 378 
Week 60 
Day 421 
Day 379 to Day 462 
Week 72 
Day 505 
Day 463 to Day 546 
Week 84 
Day 589 
Day 547 to Day 630 
Week 96 
Day 673 
>=Day 631  
 
 
 
 


 
Protocol 109MS310 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
 
 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen Idec MA Inc. 
46 
For the lymphocyte subsets, Igs and vital signs, window to scheduled visits using the 
following windows: 
Visit Name 
Target Day 
Study Day in Range Window 
Baseline 
first dose date 
<=  first dose date 
Week 4 
Day 29 
(first dose date+1) to Day 42 
Week 8 
Day 57 
Day 43 to Day 70 
Week 12 
Day 85 
Day 71 to Day 126 
Week 24 
Day 169 
Day 127 to Day 210 
Week 36 
Day 253 
Day 211 to Day 294 
Week 48 
Day 337 
Day 295 to Day 420 
Week 72 
Day 505 
Day 421 to Day 588 
Week 96 
Day 673 
>=Day 589  
 
For the physical exam (weight and height), window to scheduled visits using the 
following windows: 
Visit Name 
Target Day 
Study Day in Range Window 
Baseline 
first dose date 
<=  first dose date 
Week 48 
Day 337 
(first dose date+1) to Day 504 
Week 96 
Day 673 
>=Day 505  
 
 
 


 
Protocol 109MS310 
An Open-Label Study to Assess the Effects of BG00012 on 
Lymphocyte Subsets in Subjects With RRMS 
Final Version 1.0 
 
 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen Idec MA Inc. 
47 
For the lymphocyte subsets in the lymphocyte follow-up period, window to scheduled 
visits using the following windows: 
Visit Name 
Target Day 
Study Day in Range 
Window 
Lymphocyte FU Baseline 
lymphocyte follow-up 
start date 
<= lymphocyte follow-up 
start date 
4 weeks from Lymphocyte FU baseline 
Day 29 
Day 2 to Day 42 
8 weeks from Lymphocyte FU baseline 
Day 57 
Day 43 to  Day 70 
12 weeks from Lymphocyte FU baseline 
Day 85 
Day 71 to Day 98 
16 weeks from Lymphocyte FU baseline 
Day 113 
Day 99 to Day 126 
20 weeks from Lymphocyte FU baseline 
Day 141 
Day 127 to Day 154 
24 weeks from Lymphocyte FU baseline 
Day 169 
Day 155 to Day 210 
36 weeks from Lymphocyte FU baseline 
Day 253 
Day 211 to Day 294 
48 weeks from Lymphocyte FU baseline 
Day 337 
>= Day 295