A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study With Optional Open-Label Extension in Subjects With Relapsing Multiple Sclerosis to Evaluate the Efficacy and Safety of BIIB033 as an Add-On Therapy to Anti-Inflammatory Disease-Modifying Therapies
Phase: PHASE2
Conditions: Multiple Sclerosis
Sponsor: Biogen

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: 215MS202/NCT03222973
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead Berkshire 
SL6 4AY 
United Kingdom 
PHASE OF DEVELOPMENT: 2 
PROTOCOL TITLE: A Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Study With Optional Open-Label Extension in Subjects With Relapsing Multiple 
Sclerosis to Evaluate the Efficacy and Safety of BIIB033 as an Add-On Therapy to 
Anti-Inflammatory Disease-Modifying Therapies 
EUDRA CT NUMBER: 2017-001224-22 
DATE: 
13 February 2019 
Version 3 
FINAL 
Supersedes previous Version 2 dated 14 June 2017. 

Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
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3 
TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ....................................................................................................2 
1. 
SYNOPSIS .................................................................................................................10 
2. 
LIST OF ABBREVIATIONS.....................................................................................19 
3. 
SPONSOR INFORMATION .....................................................................................21 
4. 
INTRODUCTION ......................................................................................................22 
4.1. 
Overview of Multiple Sclerosis ..................................................................................22 
4.2. 
Current Therapies for Multiple Sclerosis ...................................................................23 
4.3. 
Profile of Previous Experience With BIIB033 ...........................................................23 
4.3.1. 
Nonclinical Experience ...............................................................................................23 
4.3.2. 
Clinical Experience .....................................................................................................24 
4.4. 
Study Rationale ...........................................................................................................26 
4.4.1. 
Rationale for Part 1 .....................................................................................................26 
4.4.2. 
Rationale for Part 2: Open-Label Extension ...............................................................26 
4.5. 
Rationale for Dose and Schedule Selection ................................................................27 
4.5.1. 
Part 1 ...........................................................................................................................27 
4.5.2. 
Part 2 ...........................................................................................................................27 
5. 
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES ..................................28 
5.1. 
Study Schematics ........................................................................................................28 
5.2. 
Part 1 – Schedule of Activities ...................................................................................30 
5.3. 
Part 2 – Schedule of Activities ...................................................................................36 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................43 
6.1. 
Part 1 Objectives and Endpoints .................................................................................43 
6.2. 
Part 2 Objectives and Endpoints .................................................................................47 
7. 
STUDY DESIGN .......................................................................................................52 
7.1. 
Study Overview ..........................................................................................................52 
7.2. 
Study Duration for Subjects ........................................................................................53 
7.2.1. 
Screening ....................................................................................................................53 
7.2.2. 
Treatment Period ........................................................................................................53 
7.2.3. 
Unscheduled Visit(s) and Treatment for Relapse .......................................................54 
7.2.4. 
Follow-Up ...................................................................................................................54 
7.3. 
Responsibilities of Study Site Personnel ....................................................................55 

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7.4. 
Study Stopping Rules .................................................................................................58 
7.5. 
End of Study ...............................................................................................................58 
8. 
SELECTION OF SUBJECTS ....................................................................................59 
8.1. 
Inclusion Criteria – Part 1 ...........................................................................................59 
8.2. 
Exclusion Criteria – Part 1 ..........................................................................................60 
8.3. 
Inclusion Criteria – Part 2 ...........................................................................................62 
8.4. 
Exclusion Criteria – Part 2 ..........................................................................................62 
9. 
SCREENING AND RANDOMIZATION .................................................................65 
9.1. 
Screening and Enrollment ...........................................................................................65 
9.2. 
Randomization ............................................................................................................66 
9.3. 
Blinding Procedures ....................................................................................................67 
10. 
DISCONTINUATION OF STUDY TREATMENT AND WITHDRAWAL 
OF SUBJECTS FROM THE STUDY ........................................................................68 
10.1. 
Discontinuation of Study Treatment ...........................................................................68 
10.2. 
Lost to Follow-Up.......................................................................................................68 
10.3. 
Withdrawal of Subjects From Study ...........................................................................69 
11. 
STUDY TREATMENT USE .....................................................................................70 
11.1. 
Regimen ......................................................................................................................70 
11.1.1. 
BIIB033 and Placebo ..................................................................................................70 
11.2. 
Modification of Dose and/or Treatment Schedule ......................................................70 
11.3. 
BIIB033 Precautions ...................................................................................................70 
11.4. 
Treatment Compliance ................................................................................................71 
11.5. 
Concomitant Therapy and Procedures ........................................................................71 
11.5.1. 
Concomitant Therapy .................................................................................................71 
11.5.1.1. 
Allowed Concomitant Therapy ...................................................................................71 
11.5.1.2. 
Disallowed Concomitant Therapy ..............................................................................72 
11.5.2. 
Concomitant Procedures .............................................................................................73 
11.6. 
Continuation of Treatment ..........................................................................................73 
12. 
STUDY TREATMENT MANAGEMENT ................................................................74 
12.1. 
BIIB033 ......................................................................................................................74 
12.1.1. 
BIIB033 Preparation ...................................................................................................74 
12.1.2. 
BIIB033 Storage .........................................................................................................75 

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12.1.3. 
BIIB033 Handling and Disposal .................................................................................75 
12.1.4. 
BIIB033 Accountability ..............................................................................................75 
12.2. 
Placebo and/or Comparator or Reference Product .....................................................75 
13. 
EFFICACY, 
, AND 
 
ASSESSMENTS.........................................................................................................76 
13.1. 
Clinical Efficacy Assessments ....................................................................................76 
 
77 
 
77 
 
78 
 
78 
 
78 
 
79 
14. 
SAFETY ASSESSMENTS ........................................................................................80 
14.1. 
Clinical Safety Assessments .......................................................................................80 
14.2. 
Laboratory Safety Assessments ..................................................................................80 
 
81 
15. 
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................82 
15.1. 
Definitions ..................................................................................................................82 
15.1.1. 
Serious Pretreatment Event .........................................................................................82 
15.1.2. 
Adverse Event .............................................................................................................82 
15.1.3. 
Serious Adverse Event ................................................................................................82 
15.1.4. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................83 
15.2. 
Safety Classifications ..................................................................................................83 
15.2.1. 
Investigator Assessment of Events .............................................................................83 
15.2.2. 
Relationship of Events to Study Treatment ................................................................84 
15.2.3. 
Severity of Events .......................................................................................................84 
15.2.4. 
Expectedness of Events ..............................................................................................85 
15.3. 
Monitoring and Recording Events ..............................................................................85 
15.3.1. 
Serious Pretreatment Events .......................................................................................85 
15.3.2. 
Adverse Events ...........................................................................................................85 
15.3.3. 
Immediate Reporting of Serious Adverse Events .......................................................85 
15.3.3.1. 
Deaths .........................................................................................................................86 

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15.3.4. 
Serious Adverse Events ..............................................................................................86 
15.3.5. 
Suspected Unexpected Serious Adverse Reactions ....................................................86 
15.4. 
Procedures for Handling Special Situations ...............................................................86 
15.4.1. 
Pregnancy ...................................................................................................................86 
15.4.2. 
Overdose .....................................................................................................................87 
15.4.3. 
Medical Emergency ....................................................................................................87 
15.4.3.1. 
Unblinding for Medical Emergency ...........................................................................87 
15.5. 
Contraception Requirements ......................................................................................87 
15.6. 
Safety Responsibilities ................................................................................................89 
15.6.1. 
The Investigator ..........................................................................................................89 
15.6.2. 
Biogen .........................................................................................................................89 
16. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ...........91 
16.1. 
Demography and Baseline Disease Characteristics ....................................................91 
16.2. 
Efficacy .......................................................................................................................91 
16.2.1. 
Analysis Population ....................................................................................................91 
16.2.2. 
Methods of Analysis ...................................................................................................91 
16.2.2.1. 
General Methods of Analysis .....................................................................................91 
16.2.2.2. 
Analysis of the Primary Endpoint in Part 1 ................................................................91 
16.2.2.3. 
Analysis of the Secondary Endpoints in Part 1 ..........................................................92 
 
92 
16.2.2.5. 
Analysis of Endpoints in Part 2 ..................................................................................92 
 
93 
 
93 
 
93 
16.4. 
Safety ..........................................................................................................................93 
16.4.1. 
Analysis Population ....................................................................................................93 
16.4.2. 
Methods of Analysis ...................................................................................................93 
16.4.2.1. 
Adverse Events ...........................................................................................................93 
16.4.2.2. 
Clinical Laboratory Results ........................................................................................94 
16.4.2.3. 
Vital Signs ..................................................................................................................94 
16.4.2.4. 
Physical Examinations ................................................................................................94 
16.4.2.5. 
Electrocardiogram .......................................................................................................94 

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Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
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16.4.2.6. 
Multiple Sclerosis Signs and Symptoms ....................................................................94 
16.4.2.7. 
Columbia Suicide Severity Rating Scale ....................................................................94 
16.5. 
Immunogenicity Data .................................................................................................95 
16.5.1. 
Analysis Population ....................................................................................................95 
16.5.2. 
Methods of Analysis ...................................................................................................95 
16.6. 
Interim Analyses .........................................................................................................95 
16.7. 
Sample Size Considerations .......................................................................................95 
17. 
ETHICAL REQUIREMENTS ...................................................................................96 
17.1. 
Declaration of Helsinki ...............................................................................................96 
17.2. 
Ethics Committee ........................................................................................................96 
17.3. 
Subject Information and Consent ...............................................................................96 
17.4. 
Subject Data Protection ..............................................................................................97 
17.5. 
Compensation for Injury .............................................................................................97 
17.6. 
Conflict of Interest ......................................................................................................98 
17.7. 
Registration of Study and Disclosure of Study Results ..............................................98 
18. 
ADMINISTRATIVE PROCEDURES .......................................................................99 
18.1. 
Study Site Initiation ....................................................................................................99 
18.2. 
Quality Control and Quality Assurance ......................................................................99 
18.3. 
Monitoring of the Study..............................................................................................99 
18.4. 
Study Funding ...........................................................................................................100 
18.5. 
Publications ...............................................................................................................100 
19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION ......................101 
19.1. 
External Contract Organizations ...............................................................................101 
19.1.1. 
Contract Research Organization ...............................................................................101 
19.1.2. 
Interactive Response Technology .............................................................................101 
19.1.3. 
Electronic Data Capture ............................................................................................101 
19.1.4. 
Central Laboratories for Laboratory Assessments ...................................................101 
19.1.5. 
Central Facility for Other Assessments ....................................................................101 
19.2. 
Study Committees .....................................................................................................102 
19.2.1. 
Independent Data Monitoring Committee (Part 1 Only) ..........................................102 
19.3. 
Changes to Final Study Protocol ..............................................................................102 
19.4. 
Ethics Committee Notification of Study Completion or Termination ......................102 

Protocol 215MS202 
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Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
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19.5. 
Retention of Study Data ............................................................................................102 
19.6. 
Study Report Signatory.............................................................................................102 
20. 
REFERENCES .........................................................................................................104 
21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL .......................................107 
 
LIST OF TABLES 
Table 1: 
Part 1 - Study Activities (Screening to Week 52) .......................................................30 
Table 2: 
Part 1 - Study Activities (Week 56 to Week 84) ........................................................33 
Table 3: 
Part 2 - Study Activities (Screening to Week 52) .......................................................36 
Table 4: 
Part 2 - Study Activities (Week 56 to Week 96) ........................................................39 
Table 5:  
 Part 1 Objectives and Endpoints ................................................................................43 
Table 6: 
Part 2 Objectives and Endpoints .................................................................................47 
Table 7: 
Criteria Used to Determine Clinically Relevant Abnormalities in Vital Signs ..........94 
 

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LIST OF FIGURES 
Figure 1: 
Part 1 - Study Schematic .............................................................................................28 
Figure 2: 
Part 2 – Study Schematic ............................................................................................29 
 

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1. 
SYNOPSIS  
Protocol Title 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study 
With Optional Open-Label Extension in Subjects With Relapsing 
Multiple Sclerosis to Evaluate the Efficacy and Safety of BIIB033 as an 
Add-On Therapy to Anti-Inflammatory Disease-Modifying Therapies  
Protocol Number 
215MS202 
Version Number 
3 
Name of Study 
Treatment 
BIIB033; opicinumab 
Study Phase 
2 
Study Indication 
Multiple Sclerosis (MS) 
Study Rationale 
The objective of this study is to evaluate the efficacy and safety of 
BIIB033 used as add-on therapy to anti-inflammatory 
disease-modifying therapies (DMTs) in subjects with relapsing multiple 
sclerosis (RMS). 
BIIB033 is a first-in-class human monoclonal antibody directed against 
LINGO-1, a negative regulator of oligodendrocyte progenitor cells 
(OPCs) differentiation and myelination. The therapeutic hypothesis is 
that BIIB033 will act in the central nervous system (CNS) to block 
LINGO-1, which is expressed on both oligodendrocytes and neurons. 
In turn, the inhibition of LINGO-1 may promote remyelination via 
differentiation of OPCs normally present in the CNS and promote 
axonal regeneration by blocking signaling from myelin debris on the 
Nogo66 receptor 1 complex in neurons. Therefore, BIIB033 treatment 
in demyelinating diseases such as MS may lead to improved CNS 
repair with corresponding beneficial effects on neurological function 
and disability.  
Three Phase 1 studies and 2 Phase 2 studies evaluating BIIB033 have 
been completed. Study 215ON201 was a 24-week, randomized, 
Phase 2 study of BIIB033 (100 mg/kg intravenous [IV] every 4 weeks) 
versus placebo in 82 subjects with acute optic neuritis. Proof of biology 
was achieved as shown by an improvement in the latency of visual 
evoked potentials.  
Study 215MS201 was a 72-week, placebo-controlled, Phase 2, 
dose-ranging study of BIIB033 (range 3 to 100 mg/kg IV every 
4 weeks) as add-on therapy to interferon beta (IFNβ) [Avonex®] in 419 

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subjects with RMS. The primary endpoint was confirmed improvement 
in 1 or more assessments of a multicomponent disability endpoint over 
72 weeks. A statistically significant linear dose-response on primary 
endpoint was not observed with BIIB033 treatment versus placebo 
(p=0.9831). Analyses showed a non-monotonic, inverted U-shaped 
dose response to BIIB033, with more favorable outcomes in the 10- 
and 30-mg/kg groups. Prespecified univariate subgroup analyses 
showed that, in general, younger subjects and those with clinical 
 
 features suggestive of more 
preserved brain tissue integrity tended to respond better to BIIB033 
treatment. 
 
 
 
 
 
 
 
 
  
BIIB033 was generally well tolerated across both Phase 2 studies 
(215ON201 and 215MS201). Hypersensitivity reactions occurred in 
2 subjects (5% of BIIB033-treated subjects) in Study 215ON201 and 
4 subjects (1% of BIIB033-treated subjects) in Study 215MS201; in 
both studies, the hypersensitivity reactions occurred at the 100-mg/kg 
dose. Postbaseline weight gain was also observed in both Phase 2 
studies. In Study 215MS201, there was a trend for dose-dependent 
weight gain over 72 weeks, with a mean increase between 0.9 and 
1.9 kg in the 4 BIIB033 dosing groups. The mechanism of the weight 
gain is not known at this time. 
The proposed study (215MS202) has 2 parts:  
• Part 1 will further investigate the efficacy and safety of 
BIIB033 as an add-on therapy in subjects with RMS who 
are on a stable dose of an anti-inflammatory DMT and with 
baseline characteristics consistent with projected enhanced 
treatment effect of BIIB033 as identified in the post hoc 
analysis from Study 215MS201.  
• The optional open-label extension (OLE) study (Part 2) will 
investigate the long-term safety and efficacy of BIIB033 
treatment as an add-on therapy to anti-inflammatory DMTs 
for approximately 2 years (96 weeks). 
 

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Study Objectives 
and Endpoints 
Part 1 
The primary objective of Part 1 of the study is to evaluate the effects of 
BIIB033 versus placebo on disability improvement over 72 weeks. 
The primary endpoint that relates to this objective is the Overall 
Response Score, assessed over 72 weeks of the study. 
The Overall Response Score is a multicomponent score based on 
4 components: Expanded Disability Status Scale (EDSS), Timed 
25-Foot Walk (T25FW), 9-Hole Peg Test in the dominant hand 
(9HPT-D), and 9HPT in the nondominant hand (9HPT-ND). It assesses 
the overall change in disability over time. Score ranges from +4 to -4. 
At each visit, each component is given a score relative to baseline: -1 
(if threshold is met for worsening), 0 (no changes meet threshold 
criteria), or +1 (if threshold is met for improvement). The thresholds 
for T25FW, 9HPT-D, and 9HPT-ND are defined by a 15% change 
from baseline (i.e., ≥15% decrease from baseline for improvement and 
≥15% increase from baseline for worsening). For EDSS, improvement 
is defined as a ≥1.0-point decrease in EDSS from a baseline score of 
≤6.0, and worsening is defined as a ≥1-point increase from a baseline 
score of ≤5.5 or a ≥0.5-point increase from a baseline score equal to 
6.0. 
The secondary objective and corresponding endpoints for Part 1 of the 
study are as follows: 
• To evaluate the effects of BIIB033 versus placebo on 
additional measures of disability improvement  
− Proportion of subjects with 12-week confirmed 
improvement (as defined above) in at least 1 of the 
following assessments: EDSS, T25FW, 9HPT-D, or 
9HPT-ND 
− Proportion of subjects with 12-week confirmed 
improvement in at least 1 of the following assessments: 
EDSS, T25FW, 9HPT-D, 9HPT-ND, or 3-Second Paced 
Auditory Serial Addition Test (PASAT-3) 
[improvement in PASAT-3 is defined as a ≥15% 
increase from baseline] 
− Proportion of subjects with 12-week confirmed 
improvement in at least 1 of the following assessments: 
EDSS, T25FW, 9HPT-D, or 9HPT-ND, and without 

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confirmed worsening in any of the 4 assessments during 
the 72 weeks of the study 
− Proportion of subjects with 12-week confirmed 
improvement in at least 1 of the following assessments: 
EDSS, T25FW, 9HPT-D, 9HPT-ND, and Symbol Digit 
Modalities Test (SDMT) [improvement in SDMT is 
defined as a ≥4-point increase from baseline] 
− Proportion of subjects with 12-week confirmed 
improvement in at least 1 of the following assessments: 
EDSS, T25FW, 9HPT-D, or 9HPT-ND (20% thresholds 
for T25FW and 9HPT)  
Part 2 
(Note: The BIIB033 Treatment Baseline in Part 2 is defined as the 
timepoint when the first dose of BIIB033 was given, i.e., Part 1/Day 1 
for subjects treated with BIIB033 in Part 1, and as Part 2/Day 1 for 
subjects treated with placebo in Part 1.)  
The primary objective of Part 2 is to evaluate the long-term safety 
profile of BIIB033 as an add-on therapy in subjects with MS. 
The primary endpoint in Part 2 of the study that relates to this objective 
is as follows: 
• Incidence of AEs and SAEs over 96 weeks in Part 2 
The secondary objective of Part 2 is to investigate long-term efficacy 
(disability improvement) and additional safety measures of BIIB033 as 
an add-on therapy in subjects with MS.  
The endpoints supporting the secondary objective are as follows: 
• Overall Response Score over 96 weeks in Part 2 
• Proportion of subjects with 24-week confirmed 
improvement in at least 1 of the following assessments: 
EDSS, T25FW, 9HPT-D, or 9HPT-ND (improvement in 
T25FW and 9HPT is defined as a ≥15% decrease from the 
BIIB033 Treatment Baseline) 
• Proportion of subjects with 24-week confirmed 
improvement in at least 1 of the following assessments: 
EDSS, T25FW, 9HPT-D, 9HPT-ND, PASAT-3 

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(improvement in PASAT-3 is defined as a ≥15% increase 
from the BIIB033 Treatment Baseline) 
• Proportion of subjects with 24-week confirmed 
improvement in at least 1 of the following assessments: 
EDSS, T25FW, 9HPT-D, 9HPT-ND, and without confirmed 
worsening in any of the 4 assessments during the 96 weeks 
of the study 
• Proportion of subjects with 24-week confirmed 
improvement in at least 1 of the following assessments: 
EDSS, T25FW, 9HPT-D, 9HPT-ND, SDMT (improvement 
in SDMT is defined as a ≥4-point increase from the 
BIIB033 Treatment Baseline) 
• Proportion of subjects with 24-week confirmed 
improvement in at least 1 of the following assessments: 
EDSS, T25FW, 9HPT-D, 9HPT-ND (20% thresholds for 
T25FW and 9HPT)  
• Potentially clinically significant abnormal laboratory, ECG, 
vital signs, and weight values over 96 weeks in Part 2 
• Columbia Suicide Severity Rating Scale (C-SSRS) over 
96 weeks in Part 2 
 
 
Study Design: 
Part 1 
Part 1 is a 72-week, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group, Phase 2 study to evaluate the 
efficacy and safety of BIIB033 (750 mg infused IV every 4 weeks) as 
an add-on therapy to a background DMT in subjects with RMS. 
Subjects enrolled must have been treated for at least 24 consecutive 
weeks prior to Day 1/Baseline on an anti-inflammatory DMT from 1 of 
the following 3 groups: IFNβ (Avonex, Plegridy®, 
Betaferon®/Betaseron®, or Rebif®), dimethyl fumarate (DMF; 
Tecfidera®), or natalizumab (Tysabri®). Subjects will continue taking 
their DMT throughout the study. Treating neurologists will manage 
DMT treatment for each subject. 
The study will include clinical assessments every 12 weeks. Each 
subject will have separate treating and examining neurologists; the 

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roles of the treating and examining neurologist are not interchangeable, 
even for different subjects. 
Part 2 
Subjects who have completed study treatment (BIIB033 or placebo) in 
Part 1 will have the option to take part in Part 2, which is a 96-week 
multicenter, OLE phase that will evaluate BIIB033-treated subjects for 
long-term safety and efficacy of BIIB033 treatment, 
 
 
. Subjects will continue the 
anti-inflammatory DMT used at the end of Part 1. DMT treatment in 
Part 2 will continue to be managed by the Investigator. The study will 
include clinical assessments every 24 weeks 
 
. 
Study treatment allocation in Part 1 will remain blinded for all Part 2 
subjects and all site staff. 
Study Location: 
Part 1: Approximately 150 sites in 15 countries are planned. 
Part 2: Approximately 95 sites in 15 countries are planned.  
Number of 
Planned Subjects: 
Part 1 
Approximately 240 subjects will be enrolled, with approximately 
120 subjects per treatment group (BIIB033; placebo).  
Subjects will be stratified by MS type (relapsing-remitting multiple 
sclerosis [RRMS] versus secondary progressive multiple sclerosis 
[SPMS]), background DMT group, 
 
. 
Part 2 
All subjects who have completed study treatment through Week 72 in 
Part 1 and have consented and are eligible to participate in Part 2 of the 
study will be enrolled. 
 
 
 
Study Population: 
Part 1 
Eligible subjects are required to be between the ages of 18 and 
58 years, inclusive, with a baseline EDSS of 2.0 to 6.0, have a 
diagnosis of RRMS per the 2010 McDonald’s criteria [Polman 2011] or 
onset of SPMS per the Lublin and Reingold criteria [Lublin 2014], and 

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should have experienced their first MS symptom(s) within the previous 
20 years.  
Subjects must have experienced at least 1 of the following within 
24 months prior to Day 1/Baseline: a clinical relapse (but not within 
24 weeks prior to Day 1/Baseline), 
 
 
 
Subjects must be on a stable dose of a protocol-specified 
anti-inflammatory DMT (IFNβ [Avonex, Plegridy, 
Betaferon/Betaseron, or Rebif], DMF [Tecfidera], or natalizumab 
[Tysabri]) for at least 24 weeks prior to enrollment. 
 
 
 
 
 
 
 
 
Part 2 
Subjects who have completed treatment with BIIB033 or placebo in 
Part 1, and who have consented and are eligible to participate in Part 2 
of the study will be enrolled. Subjects enrolling in Part 2 must meet the 
Part 2 criteria detailed in Section 8.3 and Section 8.4. Subjects will 
continue the DMT used at the end of Part 1. 
 
 
Treatment Groups: 
Part 1 
Eligible subjects will be randomized in a 1:1 ratio into 2 parallel 
treatment groups: IV infusions of 750 mg BIIB033 or placebo every 
4 weeks.  
The study treatments will be given as add-on therapy to subjects 
already stable for at least 24 consecutive weeks on a protocol-defined 
anti-inflammatory DMT. 
Part 2  
All subjects will receive IV infusions of open-label BIIB033 
750 mg once every 4 weeks as an add-on therapy to anti-inflammatory 
DMT. 

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Duration of 
Treatment and 
Follow-up: 
Part 1 
Study duration will be approximately 88 weeks for subjects 
participating in Part 1 only:  
• 4-week Screening Period 
• 72-week Treatment Period 
• 12-week Follow-up Period 
 
Subjects who enroll in Part 2 do not need to have the 12-week postdose 
follow-up (End of Study), so the study duration in Part 1 will be 
approximately 76 weeks. 
Part 2 
The duration of Part 2 will be approximately 112 weeks:  
• 4-week Screening Period 
• 96-week Treatment Period 
• 12-week Follow-up Period 
Total study duration for subjects who participate in both Part 1 and 
Part 2 will be approximately 188 weeks. 

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2. 
LIST OF ABBREVIATIONS 
4-AP 
4-aminopyridine 
 
 
9HPT-D, ND 
9-Hole Peg Test (dominant hand, nondominant hand) 
AE 
adverse event 
ALT/SGPT 
alanine aminotransferase/serum glutamate pyruvate transaminase 
AON 
acute optic neuritis 
AST/SGOT 
aspartate aminotransferase/serum glutamic oxaloacetic 
transaminase 
Cmax 
maximum observed concentration 
CNS 
central nervous system 
CRO 
contract research organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DHA 
Directions for Handling and Administration 
ADL 
Activities of Daily Living-Cognitive and Instrumental 
DMF 
dimethyl fumarate 
DMT 
disease-modifying therapy 
 
 
 
 
 
 
 
 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EDSS 
Expanded Disability Status Scale 
EMS 
Early Multiple Sclerosis 
EOS 
End of Study 
ET 
Early Termination 
FT4 
free thyroxine 
GA 
glatiramer acetate 
GCP 
Good Clinical Practice 
 
 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IDMC 
independent data monitoring committee 
IFNβ 
interferon beta 
IgG1 
immunoglobulin G subclass 1 
IRT 
interactive response technology 
ITT 
intent-to-treat 
IV 
intravenous 
 
 
LPC 
lysophosphatidylcholine 

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mAb 
monoclonal antibody 
MMRM 
Mixed Model for Repeated Measures 
MOG-EAE 
myelin oligodendrocyte glycoprotein-experimental autoimmune 
encephalomyelitis 
 
 
MS 
multiple sclerosis 
 
 
 
  
 
 
 
 
 
 
 
 
OLE 
open-label extension 
OPC 
oligodendrocyte progenitor cell 
PASAT-3 
3-Second Paced Auditory Serial Addition Test 
 
 
PK 
pharmacokinetics 
 
 
RMS 
relapsing multiple sclerosis 
 
 
RRMS 
relapsing-remitting multiple sclerosis 
SAE 
serious adverse event 
SD 
standard deviation 
 
 
SDMT 
Symbol-Digit Modalities Test 
SPMS 
secondary progressive multiple sclerosis 
SUSAR 
suspected unexpected serious adverse reaction 
 
 
 
 
T25FW 
Timed 25-Foot Walk 
T3 
triiodothyronine 
TEAE 
treatment-emergent adverse event 
TSH 
thyroid-stimulating hormone 

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21 
3. 
SPONSOR INFORMATION 
Biogen MA Inc. 
250 Binney Street 
Cambridge, MA 02142 
United States 
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead, Berkshire  
SL6 4AY 
United Kingdom 
Biogen Australia PTY Ltd. 
Suite 1, Level 3  
123 Epping Road 
North Ryde, NSW 2113 
Australia 
For urgent medical issues in which the study’s Medical Director should be contacted, please 
refer to the Study Reference Guide 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. 

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4. 
INTRODUCTION 
LINGO-1 is a cell surface glycoprotein that is selectively expressed in the human central nervous 
system (CNS) but not in non-neural tissues [Barrette 2007; Carim-Todd 2003; Llorens 2008; Mi 
2004; Okafuji and Tanaka 2005; Park and Hong 2006; Shao 2005]. It is a member of a newly 
discovered protein family comprising 3 other paralogs: LINGO-2 (GI: 12309630, 61% protein 
identity), LINGO-3 (GI: 23342615, 56% identity), and LINGO-4 (GI: 21211752, 44% identity). 
LINGO-1 is highly conserved evolutionarily with human and mouse orthologues sharing 99.5% 
identity. 
LINGO-1 is selectively expressed in both oligodendrocyte progenitor cells (OPCs) and neurons, 
where it functions as a negative regulator of OPC differentiation and myelination [Lee 2007; Mi 
2007; Mi 2005]. Its expression is developmentally regulated and is upregulated in CNS diseases 
and injury [Ji 2006; Mi 2004; Mi 2013]. Specifically, LINGO-1 expression is increased in OPCs 
from demyelinated white matter of multiple sclerosis (MS) brain tissues. LINGO-1 negatively 
regulates oligodendrocyte differentiation and myelination, neuronal survival, and axonal 
regeneration by activating ras homolog gene family member A and inhibiting Protein kinase B 
phosphorylation signaling pathways [Lee 2007; Mi 2005; Mi 2009; Mi 2013].  
BIIB033 is a first-in-class human monoclonal antibody (mAb) directed against LINGO-1. 
BIIB033 enhances differentiation of primary rat, monkey, and human oligodendrocytes in vitro 
and enhances axonal myelination in an in vitro rat dorsal root ganglion/OPC co-culture bioassay. 
Additionally, BIIB033 enhances remyelination and functional recovery in the rat 
lysophosphatidylcholine (LPC), cuprizone, myelin oligodendrocyte glycoprotein-experimental 
autoimmune encephalomyelitis (MOG-EAE), and MOG-EAE optic neuritis models [Gresle 
2016; Mi 2009]. 
The therapeutic hypothesis is that BIIB033 will act in the CNS to block LINGO-1. In turn, the 
inhibition of LINGO-1 may promote remyelination via differentiation of OPCs normally present 
in the CNS and to promote axonal regeneration. Therefore, BIIB033 treatment in demyelinating 
diseases such as MS may lead to improved CNS repair with corresponding beneficial effects on 
neurological function and disability. 
4.1. 
Overview of Multiple Sclerosis 
MS is a chronic autoimmune and neurodegenerative disorder of the 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 (RMS) is the most common clinical presentation of the disease. The term 
“relapsing MS” applies to patients with either relapsing-remitting MS (RRMS) or secondary 
progressive multiple sclerosis (SPMS) who experience relapses, which 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. 

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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 as men. As patients progress from RRMS to SPMS, they are more likely to experience 
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].  
Although CNS repair takes place early during the disease, the ability to repair the CNS 
eventually fails, leading to irreversible tissue injury and accumulation of disability. One leading 
hypothesis is that the failure of remyelination in MS is due in large part to inhibition of 
oligodendrocyte differentiation by LINGO-1. It is also hypothesized that the failure of axonal 
repair/neurite regeneration in MS is due to signaling of myelin debris on the Nogo66 receptor 1 
(NgR1)/p75/LINGO-1 and NgR1/TROY/LINGO-1 complex in damaged axons [Ji 2006; Mi 
2004]. Signaling on the NgR1 receptor complex may interfere not only with axonal regeneration 
[Yamashita 2005] but also with neuronal survival following neuroaxonal injury [Bourikas 2010; 
Fu 2008; Zhao 2008]. 
4.2. 
Current Therapies for Multiple Sclerosis 
The current standard of care in RMS employs 2 general approaches: immunomodulatory drugs 
aimed at reducing the frequency and severity of relapses as well as the accumulation of physical 
disability, which includes interferon beta (IFNβ) products (Avonex®, Plegridy®, 
Betaferon®/Betaseron®/Extavia®, and Rebif®), glatiramer acetate (GA; Copaxone®), fingolimod 
(Gilenya®), teriflunomide (Aubagio®), dimethyl fumarate (DMF; Tecfidera®), natalizumab 
(Tysabri®), alemtuzumab (Lemtrada®), daclizumab (Zinbryta®), ocrelizumab (Ocrevus®), and 
mitoxantrone (Novantrone®), and drugs that provide symptomatic treatment as needed for 
depression, bladder dysfunction, and walking impairment. 
There are currently no approved therapies to promote neurorepair in the CNS when the 
inflammatory aspects of the disease are controlled. 
4.3. 
Profile of Previous Experience With BIIB033 
See the Investigator’s Brochure for detailed information on relevant nonclinical and clinical 
studies. 
4.3.1. 
Nonclinical Experience 
BIIB033 is a fully human anti-LINGO-1 mAb that was engineered into an aglycosyl 
immunoglobulin G subclass 1 (IgG1) framework to eliminate effector function. Histological and 
functional evaluations of LINGO-1 knock-out mice have been performed, and nonclinical studies 
have demonstrated the potential for LINGO-1 antagonism to enhance CNS remyelination and 
neuroaxonal protection in animal models of (1) toxic demyelination (Cuprizone) [Mi 2009], 

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(2) chemical demyelination (LPC), (3) inflammatory demyelination (MOG-EAE) [Mi 2007], (4) 
toxic neuronal injury (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) [Inoue 2007] , and (5) 
traumatic/hypertensive optic nerve injury [Ji 2008; Ji 2006; Lv 2010]. 
The results of these studies indicate that BIIB033: 
• Binds to LINGO-1 with similar high affinity across human, monkey, rat, and mouse. 
• Is selective for LINGO-1 and does not bind the other LINGO family members, that is, 
LINGO-2, LINGO-3, or LINGO-4. 
• Promotes differentiation of primary rat, monkey, and human oligodendrocytes 
in vitro. 
• Promotes axonal myelination in an in vitro rat dorsal root ganglion/OPC co-culture 
bioassay. 
• Has significantly reduced Fc (γ) and complement effector functions compared to 
wild-type IgG1. 
• Is efficacious in animal models using biochemical and functional readouts. 
Remyelination activity has been demonstrated in the rat LPC model following 
systemic administration from 1 to 100 mg/kg. Functional recovery in the rat 
MOG-EAE model has been demonstrated following weekly systemic administration 
of 3 and 10 mg/kg. 
• Is efficacious in animal models when given in the presence of IFNβ or high-dose 
corticosteroids. 
These results support the development of BIIB033 as a potential therapy for the treatment of MS. 
4.3.2. 
Clinical Experience 
Three Phase 1 studies and 2 Phase 2 studies have been completed. The Phase 1 studies included 
Studies 215HV101 (single-ascending dose study in healthy volunteers), 215MS101 
(multiple-ascending dose study in subjects with RRMS or SPMS), and 215HV102 (single- and 
multiple-dose study in healthy Japanese volunteers). The Phase 2 studies included 
Study 215ON201 in subjects with acute optic neuritis (AON) and Study 215MS201 in subjects 
with relapsing form of MS. 
In the Phase 1 studies, BIIB033 exposure was dose proportional over the studied dose levels and 
dose ranges, with doses ranging from 0.1 to 100 mg/kg. BIIB033 was well tolerated, and 
laboratory findings revealed no clinically meaningful abnormalities. BIIB033 pharmacokinetics 
(PK) in subjects with MS was similar to that observed in healthy adults, and BIIB033 PK does 
not appear to be altered by the concurrent treatment of IFNβ or GA. Additionally, the clinical 
study portions of an additional Phase 1 study have been completed. Study 215HV103 is a single-

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dose study in healthy volunteers using study treatment from 2 different manufacturing processes 
(referred to as BIIB033-A and BIIB033-B). Preliminary data indicate that the PK parameters 
(area under the concentration-time curve from time 0 to infinity [AUCinf] and maximum 
observed concentration [Cmax]) are very similar for the BIIB033-A material and the BIIB033-B 
material. 
The completed Phase 2 Study 215ON201 was a 24-week, randomized study designed to assess 
the efficacy, safety, tolerability, and PK of BIIB033 (100 mg/kg) versus placebo in 82 subjects 
with their first episode of AON. 
• A trend in improvement was observed for the intent-to-treat (ITT) population in full-
field visual evoked potential latency of the affected eye at both Weeks 24 and 32 with 
BIIB033 over placebo, compared with the baseline of the unaffected fellow eye. This 
improvement reached statistical significance in the per-protocol population at Week 
32. These data provided proof-of-biology evidence for CNS remyelination with 
BIIB033 treatment. 
• No treatment effects were observed in retinal thinning or visual acuity tests with 
BIIB033 over placebo.  
• In this study, 100 mg/kg of BIIB033 infused IV every 4 weeks was well tolerated, 
and the overall incidence of adverse events (AEs) was the same in the placebo and 
BIIB033 groups (83%). Hypersensitivity reactions occurred in 2 subjects (5% of 
BIIB033-treated subjects who received 100-mg/kg dose), and postbaseline weight 
gain was also observed. 
The completed Phase 2 Study 215MS201 was a 72-week, multicenter, randomized, double-blind, 
parallel-group, placebo-controlled, dose-ranging study to assess the efficacy, safety, tolerability, 
and PK of BIIB033, when used concurrently with Avonex, in subjects with relapsing forms of 
MS. BIIB033 was evaluated at doses of 3, 10, 30, and 100 mg/kg. 
• The primary endpoint was confirmed improvement in 1 or more assessments of a 
multicomponent disability endpoint over 72 weeks. A statistically significant linear 
dose-response on primary endpoint was not observed with BIIB033 treatment versus 
placebo (p=0.9831). Analyses showed a non-monotonic, inverted U-shaped dose 
response to BIIB033 with more favorable outcomes in the 10- and 30-mg/kg groups. 
• Prespecified univariate subgroup analyses suggested enhanced efficacy in younger 
subjects and in those with clinical 
 features 
suggestive of more preserved brain tissue integrity. Analyses of individual functional 
assessments as well as the Overall Response Score also suggested a more pronounced 
favorable effect of BIIB033 at the 10-mg/kg dose, although there was a waning effect 
over time. 
• Post hoc multivariate analysis showed a greater and more durable efficacy in a 
subpopulation (approximately 25% to 30% of the ITT population) defined by shorter 

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disease duration and baseline MRI characteristics consistent with lower myelin 
content but higher tissue integrity in T2 lesions, especially in the 10-mg/kg group.  
• BIIB033 was generally well tolerated, with hypersensitivity reactions seen only at the 
100-mg/kg dose (4 subjects [1% of BIIB033-treated subjects]) and a trend for 
dose-dependent weight gain over 72 weeks, with a mean increase between 0.9 and 
1.9 kg in 4 BIIB033 dosing groups. 
• The study showed no change in the PK profile of BIIB033 and no new safety signals. 
The efficacy results observed in Study 215MS201, combined with the favorable safety profile 
demonstrated by the Phase 1 and Phase 2 studies as well as the proof of biology achieved in 
Study 215ON201, support the continued evaluation of BIIB033. 
4.4. 
Study Rationale 
4.4.1. 
Rationale for Part 1 
The proposed study (215MS202) will further investigate the efficacy and safety of BIIB033 as an 
add-on therapy in subjects with RMS who are on a stable dose of an anti-inflammatory 
disease-modifying therapy (DMT) and with baseline characteristics consistent with projected 
enhanced treatment effect of BIIB033 as identified in the post hoc analysis from Study 
215MS201. To reduce variability and potential confounding factors from different background 
DMTs while allowing for the evaluation of the effect of BIIB033 across a range of background 
therapies, 3 specific groups of background DMTs will be included in this study and 
randomization to treatment (BIIB033 or placebo) will be stratified by DMT group. The DMTs 
are IFNβ (Avonex, Plegridy, Betaferon/Betaseron, or Rebif), DMF (Tecfidera), and natalizumab 
(Tysabri), representing different mechanisms of action, anti-inflammatory activities, and routes 
of administration. 
4.4.2. 
Rationale for Part 2: Open-Label Extension 
The optional open-label extension study (Part 2) will investigate long-term safety and efficacy of 
BIIB033 treatment as an add-on therapy to anti-inflammatory DMTs for approximately 2 years 
(96 weeks) 
 
. Part 2 will provide the opportunity to follow the safety 
and efficacy of BIIB033 treatment for approximately 3.5 years in participants who received 
BIIB033 in Part 1, 
 
 
 
 
 
 
 
 

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4.5. 
Rationale for Dose and Schedule Selection 
4.5.1. 
Part 1 
Subjects will be randomized in a 1:1 ratio to receive either BIIB033 750 mg or placebo once 
every 4 weeks via IV infusion. 
A total of 19 doses of study treatment will be administered. 
Results from Phase 1 and Phase 2 studies suggest that IV doses of BIIB033 up to 100 mg/kg in 
healthy volunteers and MS patients were well tolerated. A total of 7 cases of hypersensitivity 
reactions all occurred in the 100-mg/kg dose group, led to discontinuation of treatment, and had 
an outcome of resolved. 
 
 
 
As described in the study rationale, Study 215MS201, a Phase 2 study evaluating BIIB033 doses 
ranging from 3 to 100 mg/kg in RRMS and SPMS subjects over 72 weeks demonstrated a 
nonmonotonic, inverted U-shaped dose response and a waning of effect over time. Positive 
signals were most consistently seen for the 10-mg/kg dose across a number of different analyses. 
In addition, the 10-mg/kg dose group also showed most pronounced efficacy in the 
subpopulation with larger and more durable efficacy in the post hoc multivariate analysis.  
BIIB033 exhibits typical PK characteristics of IgG1 mAb with an elimination half-life (t1/2) of 
approximately 2 to 3 weeks, supporting once every 4 weeks IV infusion regimens in the Phase 2 
studies. The 10-mg/kg dose regimen used in Study 215MS201 yielded mean average serum 
concentrations approximately 1.2-fold higher than the rat serum concentration at 90% of Emax 
(EC90; adjusted for ~0.1% brain penetration). A population PK simulation analysis showed that a 
750 mg fixed dose provides comparable exposure (Cmax, minimum observed concentration 
[Cmin], area under the concentration-time curve [AUC]) to the 10-mg/kg dose. In addition, 
exposure of 750 mg dosing has negligible overlap with 3 or 30 mg/kg dosing. Therefore, 
BIIB033 750 mg infused IV every 4 weeks will be the dose regimen for the current proposed 
study. 
4.5.2. 
Part 2 
The rationale for BIIB033 dose and schedule selection is the same as that in Part 1. Subjects 
participating in Part 2 will not receive placebo. 

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5.2. 
Part 1 – Schedule of Activities 
Table 1: 
Part 1 - Study Activities (Screening to Week 52) 
Tests and Assessments1 
Pretreatment 
Treatment Period 
 
Screening 
Baseline 
Visit Every 4 Weeks (±5 Days) 
Study Week (W) 
Day (D) 
W -4 to D -1 
W0 
D1 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
W52 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria check 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and prior MS treatment  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B and C screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
X2 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
T25FW, 9HPT-D, 9HPT-ND4 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
SDMT 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
EDSS5 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
PASAT-3 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
MS signs and symptoms 
X 
X2 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Weight, height6 
X 
X2 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Vital signs7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Hematology8 
X 
X2 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
Blood chemistry 
X 
X2 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
Urinalysis 
X 
X2 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
Serum FSH9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Tests and Assessments1 
Pretreatment 
Treatment Period 
 
Screening 
Baseline 
Visit Every 4 Weeks (±5 Days) 
Study Week (W) 
Day (D) 
W -4 to D -1 
W0 
D1 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
W52 
Serum pregnancy test10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test11 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-BIIB033 Ab13 
 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
X 
 
Practice tests16 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BIIB033 or placebo IV infusion19 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
AEs 
 
 
--------------AE monitoring from study treatment dosing through to EOS----------------------→ 
SAEs 
     -----------------------------------SAE monitoring from signing of ICF through to EOS--------------------------------------→ 
Concomitant therapy 
     --------------------------------Concomitant therapy monitoring from signing of ICF through to EOS----------------------→ 
9HPT-D,-ND=9-Hole Peg Test (dominant hand, nondominant hand); Ab=antibody; AE=adverse event; C-SSRS=Columbia Suicide Severity Rating Scale; 
 
 ECG=electrocardiogram; eCRF=electronic case report form; EDSS=Expanded Disability Status Scale; EMS=Early Multiple Sclerosis; EOS=End of Study; ET=Early 
Termination; FSH = follicle-stimulating hormone; Gd=gadolinium; ICF=Informed Consent Form; IV=intravenous; 
 
; MS=multiple sclerosis; 
; PASAT-3=3-Second Paced Auditory Serial 
Addition Test; 
; PT=prothrombin time; PTT=partial thromboplastin time; 
; SAE=serious adverse event; SDMT=Symbol-Digit Modalities Test; T25FW=Timed 25-Foot Walk. 
Note: See Table 2 for other study visits, including Unscheduled Visit for Relapse Assessment and ET and EOS Visits. 
1 Tests and assessments should be performed in the order listed, where possible. It is not required that all Screening tests and assessments be completed during 1 pretreatment visit.  
2 If a Screening test is performed within 7 days of Day 1/Baseline, the assessments do not need to be repeated at Day 1/Baseline. 
 
 
 
  

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4 At each visit, T25FW, 9HPT-D, and 9HPT-ND must be tested twice each. Tests should be performed in the following order where possible: T25FW, 9HPT-D, 9HPT-ND, 
, and SDMT before EDSS. 
5 EDSS score is required to be stable between Screening and Day 1/Baseline Visits. Refer to the Study Reference Guide for additional instructions. 
6 Height will be measured at Screening only. 
7 Include temperature, blood pressure, pulse rate, and respiratory rate (after being seated for at least 5 minutes). 
8 PT, PTT, and platelets will also be measured for all subjects at Screening. 
9 Required for postmenopausal female subjects only. 
10 For females of child-bearing potential. Results must be known prior to Day 1/Baseline. 
11 For females of child-bearing potential. Results must be known prior to each study treatment administration. 
 
 
 
 
 
 
 
16 Subjects should perform a separate practice test for T25FW, 9HPT-D, 9HPT-ND, and PASAT-3 at their Screening Visit. T25FW, 9HPT-D, and 9HPT-ND should be performed 
twice. The Screening and practice tests on these measurements should be separated by at least 1 hour. The Screening and Baseline tests on these measurements should be 
separated by at least 5 days. 
 
 
 
 
 
19 For subjects on natalizumab (Tysabri), natalizumab infusions and study treatment infusions may be on the same day; however, natalizumab should be administered prior to study 
treatment (BIIB033 or placebo) if given on that same day, with a minimum 1-hour interval between infusions. If any infusion reaction occurs with natalizumab, the infusion of 
BIIB033 should not be administered on that same day.

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Table 2: 
Part 1 - Study Activities (Week 56 to Week 84)  
 
Treatment Period 
 
Follow-Up 
Tests and Assessments1 
Visit Every 4 Weeks (±5 Days) 
Unscheduled Visit for 
Relapse Assessment2 
(Within 5 Days of the 
Onset) 
ET3 
EOS4 
Study Week (W) 
W56 
W60 
W64 
W68 
W725 
 
 
W84 ± 10 
days 
Informed consent for Part 26 
 
 
 
 
X 
 
 
 
Eligibility criteria check for Part 2 
 
 
 
 
X 
 
 
 
Physical examination 
 
X 
 
 
X 
X 
X 
X 
T25FW, 9HPT-D, 9HPT-ND8 
 
X 
 
 
X 
X9 
X 
X 
SDMT 
 
X 
 
 
X 
X9 
X 
X 
EDSS 
 
X 
 
 
X 
X9 
X 
X 
PASAT-3 
 
X 
 
 
X 
X9 
X 
X 
MS signs and symptoms 
 
X 
 
 
X 
X 
X 
X 
Weight 
 
X 
 
 
X 
X 
X 
X 
Vital signs10 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
 
 
 
 
X 
 
X 
X 
Hematology 
 
X 
 
 
X 
X11 
X 
X 
Blood chemistry 
 
X 
 
 
X 
X11 
X 
X 
Urinalysis 
 
X 
 
 
X 
X11 
X 
X 
Urine pregnancy test12 
X 
X 
X 
X 
X 
 
X 
X 

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Treatment Period 
 
Follow-Up 
Tests and Assessments1 
Visit Every 4 Weeks (±5 Days) 
Unscheduled Visit for 
Relapse Assessment2 
(Within 5 Days of the 
Onset) 
ET3 
EOS4 
Study Week (W) 
W56 
W60 
W64 
W68 
W725 
 
 
W84 ± 10 
days 
Anti-BIIB033 Ab14 
 
 
 
 
X 
 
X 
X 
BIIB033 or placebo IV infusion19 
X 
X 
X 
X 
X 
 
 
 
C-SSRS 
 
 
 
 
X 
 
X 
X 
AEs 
-----------------------------------AE monitoring from study treatment dosing through to EOS---------------------------------→ 
SAEs 
-------------------------------------SAE monitoring from signing of ICF through to EOS---------------------------------------→ 
Concomitant therapy 
-----------------------------Concomitant therapy monitoring from signing of ICF through to EOS-----------------------------→ 
9HPT-D, -ND=9-Hole Peg Test (dominant hand, nondominant hand); Ab=antibody; AE=adverse event; C-SSRS=Columbia Suicide Severity Rating Scale; 
ECG=electrocardiogram; eCRF=electronic case report form; EDSS=Expanded Disability Status Scale; EMS=Early Multiple Sclerosis; EOS=End of Study; ET=Early 
Termination; 
; ICF=Informed Consent Form; IV=intravenous; 
 
 PASAT-3=3-Second Paced Auditory Serial Addition Test; 
 SAE=serious adverse event; SDMT=Symbol-Digit 
Modalities Test; 
; T25FW=Timed 25-Foot Walk. 
1 Tests and assessments should be performed in the order listed where possible. 
2 If a suspected MS relapse occurs during the study, the subject should return to the study site within 5 days after onset of the event for evaluation. Unscheduled visits to be 
determined at the discretion of the Investigator for nonsuspected relapses.  
3 In the event that a subject withdraws from the study prematurely, an ET visit should be performed as soon as possible but no later than 4 weeks after the last dose of study 
treatment, to be followed by a final EOS study visit 12 weeks (±10 days) after the final dose of study treatment; all EOS assessments listed in the study schedule should be 
performed at this EOS visit. 
4 For subjects not participating in Part 2, EOS visit occurs at 12 weeks (±10 days) after administration of the last dose of study treatment. 
5 For subjects participating in Part 2, Week 72 will be the combined final Part 1 Visit and the Part 2 Screening Visit (see Table 3). 

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8 At each visit, T25FW, 9HPT-D, and 9HPT-ND must be tested twice each. Tests should be performed in the following order where possible: T25FW, 9HPT-D, 9HPT-ND, 
, and SDMT before EDSS 
9 EDSS, T25FW, 9HPT, 
, SDMT, and PASAT-3 should only be assessed at an unscheduled visit if relapse is suspected. Refer to the Study Reference Guide for additional 
instructions. 
10 Include temperature, blood pressure, pulse rate, and respiratory rate (after being seated for at least 5 minutes). 
11 To be performed only at the discretion of the treating physician if infection or metabolic disturbance is suspected to be contributing to the unscheduled visit. 
12 For females of child-bearing potential. Results must be known prior to each study treatment administration. 
14 Predose samples (sample should be taken within 1 hour prior to study treatment dosing if possible) on Day 1/Baseline and at Weeks 4,12, 24, 48, and 72 and EOS/ET. Exact 
collection times will be recorded in the eCRF. 
 
 
 
 
 
 
 
 
. 
19 For subjects on natalizumab (Tysabri), natalizumab infusions and study treatment infusions may be on the same day; however, natalizumab should be administered prior to study 
treatment (BIIB033 or placebo) if given on that same day, with a minimum 1-hour interval between infusions. If any infusion reaction occurs with natalizumab, the infusion of 
BIIB033 should not be administered on that same day.

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5.3. 
Part 2 – Schedule of Activities 
Table 3: 
Part 2 - Study Activities (Screening to Week 52)  
Tests and Assessments1 
 
Treatment Period 
 
Screening2  
Part 2/Day 13 
Visit Every 4 Weeks (±5 Days) 
Study Week (W) 
Day (D) 
W -4 to D -1 
W0 
 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
W5
2 
Informed consent4 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria check 
X 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
X 
 
 
  
 
 
X 
 
 
  
 
 
X 
 
T25FW, 9HPT-D, 9HPT-ND6 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
SDMT 
  
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
EDSS 
  
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
PASAT-3 
  
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
MS signs and symptoms 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Weight, height8 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Vital signs9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Hematology10 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Blood chemistry 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Urinalysis 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Urine pregnancy test11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Tests and Assessments1 
 
Treatment Period 
 
Screening2  
Part 2/Day 13 
Visit Every 4 Weeks (±5 Days) 
Study Week (W) 
Day (D) 
W -4 to D -1 
W0 
 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
W5
2 
Blood Sample for Anti-BIIB033 
Ab12 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Blood sample for lipid profile 
and thyroid tests 
 
 X 
 
 
 
 
 
 X 
 
 
 
 
 
X  
 
BIIB033 IV infusion17 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
AEs 
---------------------------AE monitoring from signing of the ICF through to EOS--------------------------------------→ 
SAEs 
-----------------------------------SAE monitoring from signing of ICF through to EOS---------------------------------→ 
Concomitant therapy 
--------------------------------Concomitant therapy monitoring from signing of ICF through to EOS-----------------→ 
; 9HPT-D,-ND=9-Hole Peg Test (dominant hand, nondominant hand); Ab=antibody; ADL=Activities of Daily Living-Cognitive and Instrumental; 
AE=adverse event; C-SSRS=Columbia Suicide Severity Rating Scale; D = Day; 
; 
ECG=electrocardiogram; eCRF=electronic case report form; EDSS=Expanded Disability Status Scale; EMS=Early Multiple Sclerosis; EOS=End of Study; ET=Early 
Termination; FSH = follicle-stimulating hormone; Gd=gadolinium; ICF=Informed Consent Form; IV=intravenous; 
 
; MS=multiple sclerosis; 
; 
PASAT-3=3-Second Paced Auditory Serial Addition Test; 
; PT=prothrombin time; PTT=partial 
thromboplastin time; 
; SAE=serious adverse event; SDMT=Symbol-Digit Modalities Test; T25FW=Timed 25-Foot Walk; W = Week 
1 Tests and assessments should be performed in the order listed where possible. 

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2 Screening Visit should be performed as part of Part 1/Week 72 Visit. In case the Part 2 Screening Visit is unable to be performed at Part 1/Week 72, a separate Screening Visit 
may occur within 4 weeks of Part 2/Day 1. Any test/assessment done within 28 days prior to Part 2/Day 1 will be used for screening for Part 2 and does not need to be repeated. 
3  When possible, the Part 2/Day 1 should be performed 4 weeks from the Part 1/Week 72 Visit. If not possible in 4 weeks, the maximum window is 12 weeks from 
Part 1/Week 72, and the patients should roll over into Part 2 as soon as possible within weeks 4 to 12. 
 
 
 
 
 
  
6 At each visit, T25FW, 9HPT-D, and 9HPT-ND must be tested twice each. Tests should be performed in the following order where possible: T25FW, 9HPT-D, 9HPT-ND, 
, SDMT, 
, and then EDSS. 
 
 
 
8 Height at Part 2/Day 1 only. 
9 Includes temperature, blood pressure, pulse rate, and respiratory rate (after being seated for at least 5 minutes). 
10 PT, PTT, and platelets will also be measured for all subjects on Part 2/Day 1 and at each visit when hematology is done. 
11 For females of child-bearing potential. Results must be known prior to each study treatment administration. 
12 The period between predose sample collection and administering of the study treatment should not exceed 24 hours, and the exact time and date at which the sample was 
collected should be recorded in the eCRF. 
 
 
 
 
 
 
 
 
  
 
17 For subjects on natalizumab (Tysabri), natalizumab infusions and study treatment infusions may be on the same day; however, natalizumab should be administered prior to 
BIIB033 infusion if given on that same day, with a minimum 1-hour interval between infusions. If any infusion reaction occurs with natalizumab, the infusion of BIIB033 should 
not be administered on that same day. 
 
  
 

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Table 4: 
Part 2 - Study Activities (Week 56 to Week 96)  
Tests and 
Assessments1 
Treatment Period 
 
Follow 
Up 
 
Visit Every 4 Weeks (±5 Days) 
Unscheduled 
Visit for 
Relapse 
Assessment2 
(Within 5 
Days of the 
Onset) 
ET3 
EOS4 
Study Week (W) 
W56 
W60 
W64 
W68 
W72 
W76 
W80 
W84 
W88 
W92 
W96 
 
 
W108± 
10d 
Physical 
examination 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
T25FW, 9HPT-D, 
9HPT-ND6 
 
 
 
 
X 
 
 
 
 
 
X 
X6 
X 
X 
SDMT 
 
 
 
 
X 
 
 
 
 
 
X 
X6 
X 
X 
EDSS 
 
 
 
 
X 
 
 
 
 
 
X 
X6 
X 
X 
PASAT-3 
 
 
 
 
X 
 
 
 
 
 
X 
X6 
X 
X 
MS signs and 
symptoms 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
Weight 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
Vital signs8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
Hematology 
 
X 
 
 
X 
 
 
X 
 
 
X 
X9 
X 
X 
Blood chemistry 
 
X 
 
 
X 
 
 
X 
 
 
X 
X9 
X 
X 

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Tests and 
Assessments1 
Treatment Period 
 
Follow 
Up 
 
Visit Every 4 Weeks (±5 Days) 
Unscheduled 
Visit for 
Relapse 
Assessment2 
(Within 5 
Days of the 
Onset) 
ET3 
EOS4 
Study Week (W) 
W56 
W60 
W64 
W68 
W72 
W76 
W80 
W84 
W88 
W92 
W96 
 
 
W108± 
10d 
Urinalysis 
 
X 
 
 
X 
 
 
X 
 
 
X 
X9 
X 
X 
Urine pregnancy 
test10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Blood sample for 
Anti-BIIB033 
Ab11 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
Blood sample for 
lipid profile and 
thyroid tests 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 

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Tests and 
Assessments1 
Treatment Period 
 
Follow 
Up 
 
Visit Every 4 Weeks (±5 Days) 
Unscheduled 
Visit for 
Relapse 
Assessment2 
(Within 5 
Days of the 
Onset) 
ET3 
EOS4 
Study Week (W) 
W56 
W60 
W64 
W68 
W72 
W76 
W80 
W84 
W88 
W92 
W96 
 
 
W108± 
10d 
BIIB033 IV 
infusion16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
C-SSRS 
 
 
 
 
X17 
 
 
 
 
 
X 
 
X 
X 
AEs 
-----------------------------------AE monitoring from signing of Part 2 ICF through to EOS---------------------------------→ 
SAEs 
-------------------------------------SAE monitoring from signing of Part 2 ICF through to EOS---------------------------------------→ 
Concomitant 
therapy 
-----------------------------Concomitant therapy monitoring from signing of Part 2 ICF through to EOS-----------------------------→ 
; 9HPT-D, -ND=9-Hole Peg Test (dominant hand, nondominant hand); Ab=antibody; ADL=Activities of Daily Living-Cognitive and Instrumental; 
AE=adverse event; C-SSRS=Columbia Suicide Severity Rating Scale; ECG=electrocardiogram; eCRF=electronic case report form; 
 
EDSS=Expanded Disability Status Scale; EMS=Early Multiple Sclerosis; EOS=End of Study; ET=Early Termination; hbA1C = glycated hemoglobin; 
 
ICF=Informed Consent Form; IV=intravenous; 
; mmEP = multi-modal evoked potential; 
; PASAT-3=3-Second Paced Auditory Serial Addition Test; 
 
; SAE=serious adverse event; SDMT=Symbol-Digit Modalities Test; T25FW=Timed 25-Foot Walk; W = Week 
 
  
1 Tests and assessments should be performed in the order listed where possible. 
2 If a suspected MS relapse occurs during the study, the subject should return to the study site within 5 days after onset of the event for evaluation. Unscheduled visits to be 
determined at the discretion of the Investigator for nonsuspected relapses.  
3 In the event that a subject withdraws from the study prematurely, an ET Visit should be performed as soon as possible but no later than 4 weeks after the last dose of study 
treatment. 
4 EOS Visit occurs at 12 weeks (±10 days) after administration of the last dose of study treatment. All EOS assessments listed in the study schedule should be performed at this 
EOS Visit. 
 
 
 
 

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6 At each visit, T25FW, 9HPT-D, and 9HPT-ND must be tested twice each. Tests should be performed in the following order where possible: T25FW, 9HPT-D, 9HPT-ND, 
, SDMT, 
, and then EDSS. 
 
 
.  
8 Includes temperature, blood pressure, pulse rate, and respiratory rate (after being seated for at least 5 minutes). 
9 To be performed only at the discretion of the treating physician if infection or metabolic disturbance is suspected to be contributing to the unscheduled visit. 
10 For females of child-bearing potential. Results must be known prior to each study treatment administration. 
11 The period between predose sample collection and administering of the study treatment should not exceed 24 hours, and the exact time and date at which the sample was 
collected should be recorded in the eCRF. 
 
 
 
 
 
 
 
 
 
16 For subjects on natalizumab (Tysabri), natalizumab infusions and study treatment infusions may be on the same day; however, natalizumab should be administered prior to study 
treatment (BIIB033 or placebo) if given on that same day, with a minimum 1-hour interval between infusions. If any infusion reaction occurs with natalizumab, the infusion of 
BIIB033 should not be administered on that same day. 
  

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9HPT-D=9-Hole Peg Test, dominant hand; 9HPT-ND=9-Hole Peg Test, nondominant hand; AE=adverse events; 
C-SSRS=Columbia Suicide Severity Rating Scale; 
; ECG=electrocardiogram; EDSS=Expanded 
Disability Status Scale; EMS=Early Multiple Sclerosis; 
 
; MS=multiple sclerosis; 
 
; PASAT-3=3-Second Paced Auditory Serial Addition Test; 
 
 SAE=serious adverse event; 
SDMT=Symbol-Digit Modalities Test; T25FW=Timed 25-Foot Walk 
1 For T25FW, 9HPT-D, 9HPT-ND, and PASAT-3, 15% thresholds (i.e., ≥15% change from baseline) are used to measure 
improvement or worsening unless otherwise specified. For EDSS, improvement is defined as a ≥1.0-point decrease in EDSS 
from a baseline score of ≤6.0, and worsening is defined as a ≥1-point increase from a baseline score of ≤5.5 or a ≥0.5-point 
increase from a baseline score equal to 6.0. For SDMT, improvement is defined as a ≥4-point increase from baseline, and 
worsening is defined as a ≥4-point decrease from baseline.

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50 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
; 9HPT=9-Hole Peg Test; 9HPT-D=9-Hole Peg Test, dominant hand; 9HPT-ND=9-Hole Peg Test, 
nondominant hand; ADL=Activities of Daily Living; AE=adverse events; C-SSRS=Columbia Suicide Severity Rating Scale; 
; 

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ECG=electrocardiogram; EDSS=Expanded Disability Status Scale; EMS=Early Multiple Sclerosis; FT4=free thyroxine; 
; MS=multiple sclerosis; 
 
; PASAT-3=3-Second Paced Auditory Serial Addition Test; 
 
; SAE=serious adverse event; SDMT=Symbol-Digit Modalities Test; 
 
; T25FW=Timed 25-Foot Walk; T3=triiodothyronine; TSH=thyroid-stimulating hormone 

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7. 
STUDY DESIGN 
7.1. 
Study Overview 
This is a Phase 2 multicenter study conducted in 2 parts. Part 1 is a 72-week, multicenter, 
randomized, double-blind, placebo-controlled, parallel-group, Phase 2 study to evaluate the 
efficacy and safety of BIIB033 (750 mg infused IV every 4 weeks) as an add-on therapy to a 
background DMT in subjects with RMS. Part 2 is a 96-week open-label extension that will 
assess long-term safety and efficacy of BIIB033 administered for approximately 24 additional 
months.  
In Part 1 of the study, approximately 240 eligible subjects will be randomized into the active 
treatment group (BIIB033 750 mg) or placebo in a 1:1 ratio at approximately 150 sites in 
approximately 25 countries. Randomization will be stratified by MS type (RRMS versus SPMS), 
background DMT group, 
 
 
The study treatment in Part 1 includes BIIB033 or placebo, administered once every 4 weeks by 
IV infusion for a total of 19 doses over 72 weeks. All enrolled subjects must have been treated 
for at least 24 consecutive weeks prior to enrollment on an anti-inflammatory DMT (as defined 
in Section 4.4) and will continue taking their DMT throughout the study. 
Each subject in Part 1 will have a total of 21 scheduled study visits: 
• Screening (pretreatment) 
• Treatment Period: 1 visit every 4 weeks between Baseline/Day 1 and Week 72 
(19 visits) 
• Follow-up Period (Post-treatment): End of Study (EOS) Visit (Week 84) for subjects 
who do not participate in Part 2. 
Part 1 of the study will include clinical assessments every 12 weeks. Each subject will have 
separate treating and examining neurologists; the roles of the treating and examining neurologist 
are not interchangeable even for different subjects. 
In Part 2 of the study, subjects who have completed study treatment (BIIB033 or placebo) in 
Part 1, have consented and are eligible to participate in Part 2 of the study will be enrolled.  
Subjects enrolled in Part 2 of the study will receive BIIB033 by IV infusion once every 4 weeks 
for a period of approximately 96 weeks. All subjects in Part 2 will continue the 
anti-inflammatory DMT used at the end of Part 1. The maximum allowed time for rollover into 
Part 2 of the study (Day 1) is 12 weeks after the Part 1/Week 72 Visit. Clinic visits will be 
conducted once every 24 weeks, 
  

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Study treatment allocation in Part 1 will remain blinded for all Part 2 subjects and all site staff. 
See Figure 1 and Figure 2 for a schematic of the study design for Part 1 and Part 2, respectively. 
7.2. 
Study Duration for Subjects 
The total duration of study participation in Part 1 for each subject will be up to approximately 88 
weeks; this consists of a Screening Period of up to 4 weeks, a Treatment Period of 72 weeks, and 
a Follow-up Period of 12 weeks. Subjects who enroll in Part 2 do not need to have the 12-week 
postdose follow-up (EOS); thus, the study duration in Part 1 will be approximately 76 weeks. 
The total duration of study participation in Part 2 for each subject will be up to approximately 
112 weeks; this consists of a Screening Period of up to 4 weeks, a Treatment Period of 96 weeks, 
and a Follow-up Period of 12 weeks. 
The total duration for subjects who participate in both Part 1 and Part 2 will be approximately 
188 weeks.  
7.2.1. 
Screening 
For Part 1, subject eligibility for the study will be determined at Screening within 28 days prior 
to Day 1/Baseline.  
For subjects participating in Part 2, Part 1/Week 72 will be the combined Part 1 Final Visit and 
the Part 2 Screening Visit. In case the Part 2 Screening Visit is unable to be performed at 
Part 1/Week 72, a separate visit may occur within 4 weeks prior to Part 2/Day 1 (see 
Section 5.3). 
7.2.2. 
Treatment Period 
Part 1 
Study treatment with BIIB033 or placebo will be initiated on Day 1 after all baseline assessments 
are completed. 
The Treatment Period will consist of 19 study visits beginning with Day 1/Baseline and then 
every 4 weeks at Weeks 4 through Week 72 with a visit window of ±5 days (see Section 5).  
Subjects who do not enroll in Part 2 will return to the study site for a post-treatment EOS Visit at 
Week 84, 12 weeks±10 days after the last dose of BIIB033 or placebo.  
Part 2 

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Study treatment with BIIB033 will be initiated on Day 1 after all Part 2/Day 1 assessments are 
completed. 
The Treatment Period will consist of 25 study visits beginning with Day 1 and then every 
4 weeks at Weeks 4 through Week 96 with a visit window of ±5 days (see Table 3 and Table 4). 
7.2.3. 
Unscheduled Visit(s) and Treatment for Relapse 
If an MS relapse is suspected during the study, the subject should return to the study site for an 
unscheduled visit and be evaluated as soon as possible (within 5 days after onset of the event) for 
confirmation and to determine the severity of the relapse. Relapses will be documented in the 
relapse assessment form. 
An MS relapse will be defined as the onset of new or recurrent neurological symptoms lasting at 
least 24 hours, accompanied by new objective abnormalities on a neurological exam, and not 
explained solely by non-MS processes such as fever, infection, severe stress, or drug toxicity 
(adapted from [Schumacher 1965]). 
The subject must have objective signs confirming the event on the examining neurologist’s 
examination. 
New or recurrent neurological symptoms that occur less than 30 days following the onset of a 
protocol-defined relapse should be considered as part of the same relapse. New or recurrent 
neurologic symptoms that evolve gradually over months should not be considered an acute 
relapse and should not be treated with high-dose corticosteroids. Laboratory tests to investigate 
possible causes of pseudorelapse can be done at the discretion of the Investigator.  
Treatment of a protocol-defined relapse may proceed at the discretion of the Investigator 
according to local standards of care and will not affect the subject’s eligibility to continue in the 
study. At the discretion of the Investigator, treatment may include 1000 mg IV 
methylprednisolone administered daily for 3 to 5 days with or without an oral prednisone taper 
(up to 15 days).  
 
 
 
 
7.2.4. 
Follow-Up 
Part 1 
Subjects who enroll in Part 1 but not Part 2 will return to the study site for an End of Part 1 
Evaluation approximately 12 weeks after the last dose of study treatment (Part 1/Week 72 Visit). 
Subjects who enroll in Part 2 do not need to have the Part 1 12-week postdose follow-up (EOS) 
Visit. 

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Part 2 
Subjects will return to the study site for a post-treatment EOS Visit at Week 108, 
12 weeks±10 days after the last dose of BIIB033.  
7.3. 
Responsibilities of Study Site Personnel  
For each subject in Part 1 and Part 2, the Principal Investigator of the site will designate the 
following investigational site personnel: 
• A primary and backup treating neurologist 
• A treating nurse (or study coordinator; may be performed by treating neurologist) 
• A primary and backup examining neurologist 
• An examining technician (may be performed by examining neurologist) 
 
 
• An unblinded pharmacist (or unblinded authorized designee) 
Both the examining neurologist and the treating neurologist must have a minimum of 2 years of 
neurology specialty training and, at study initiation, do not anticipate to leave the study within at 
least 1 year. Where specified, evaluations described in this section must be performed only by 
the personnel indicated. Treating neurologists may review neurological exam results obtained by 
examining neurologists. The examining neurologist and examining technician should not 
administer study treatment. 
The primary treating neurologist will be responsible for the following: 
• Management of the routine neurological care of the subject, including the 
management of background DMT treatment and associated safety monitoring 
• Assessment (including assignment of causality) and treatment of AEs and MS 
relapses 
• Review of hematology and blood chemistry results from the central laboratory to 
assess whether the subject’s study treatment should be discontinued as per the criteria 
detailed in Section 10 
• The treating neurologist may designate the backup treating neurologist or the 
treating nurse at the investigational site to perform some of the tests and evaluations 
listed under “treating neurologist.” If there is more than 1 treating neurologist 
available at a given site such that each one is assigned to particular subjects, then 
these treating neurologists may act as backup for each other. 

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• Hematology and blood chemistry data will be sent to the investigational sites to aid in 
the management of the subject. As with other laboratory and clinical information, 
these data should NOT be reviewed by the examining neurologist, the backup 
examining neurologist, or the examining technician. 
The primary treating nurse (or study coordinator; may be performed by treating neurologist) 
will be responsible for the following: 
• Assisting the treating neurologist in subject management, including the treatment of 
AEs, the treatment and assessment of disease relapses, and the recording of AEs and 
concomitant medications 
• 
 
 
 
 
 
• Administering the Columbia Suicide Severity Rating Scale (C-SSRS) 
• Collecting blood samples and obtaining vital signs  
The examining neurologist will be responsible for the following: 
• Obtaining an Expanded Disability Status Scale (EDSS) score based on a detailed 
neurological examination at the scheduled timepoints required in the protocol 
• Obtaining an EDSS score at every Unscheduled Relapse Assessment Visit if referred 
by the treating neurologist when there is the possibility of a relapse 
• The following guidelines must be strictly followed: 
− The examining neurologist must not be involved with any other aspect of subject 
care and management. Further, the examining neurologist is not to serve as 
treating neurologist for any subjects at a given investigational site.  
− The examining neurologist must remain blinded to AEs, concomitant 
medications, laboratory data, 
, and any other data that have the 
potential of revealing the treatment assignment. 
− To ensure consistency across sites, examining neurologists and the backup 
examining neurologist must receive standardized training and obtain certification 
of EDSS scoring prior to enrollment of subjects at their site.  
− The backup examining neurologist will conduct subject evaluations ONLY if the 
primary examining neurologist is unavailable due to illness, vacation, or travel. 

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All sites should attempt to maintain the same examining neurologist throughout 
the study.  
− If an examining neurologist has to be replaced, the new examining neurologist 
must receive standardized training and obtain certification of EDSS scoring prior 
to performing an EDSS assessment.  
− The communication of new findings on the neurological examination from the 
examining neurologist to the treating neurologist is permitted (because findings 
on the neurological examination may be important in the routine care of the 
subject, e.g., medical management of relapses).  
− The roles of the treating and examining neurologists (primary and backup) are 
NOT interchangeable even for different subjects.  
− The examining neurologist may also act as the examining technician (see below).  
− After receiving approval from the Biogen Medical Director or designee, nurse 
practitioners or physician assistants who have at least 2 years of practice 
experience in a neurology clinic and have prior experience and certification in 
EDSS scoring may function as examining neurologists in this study. 
The examining technician (or the examining neurologist) will be responsible for the following: 
• Administering the Timed 25-Foot Walk (T25FW), 9HPT-D, 9HPT-ND, 3-Second 
Paced Auditory Serial Addition Test (PASAT-3), Symbol-Digit Modalities Test 
(SDMT), 
, 
 at each scheduled 
timepoint required in the protocol  
• These guidelines must be strictly followed: 
− The examining technician must remain blinded to AEs, concomitant medications, 
laboratory data, 
, and any other data that have the potential of 
revealing the treatment assignment.  
− To ensure consistency across sites, examining technicians must undergo a 
standardized training session prior to enrollment of subjects at their site.  
− All sites should attempt to maintain the same examining technician throughout the 
study. 
− If an examining technician has to be replaced, the new examining technician must 
undergo a training session prior to performing any study assessment.  

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The unblinded pharmacist (or unblinded authorized designee) will be responsible for the 
following: 
• Receipt, storage, distribution, and accountability of study treatment 
• Storage and security of unblinding documentation related to study treatment, dose 
preparation, and study treatment assignment. All treatment assignment or study 
treatment preparation information must be maintained strictly confidential at all 
times. Measures to prevent inadvertent unblinding must be followed. 
• Preparation of study treatments for IV infusion 
7.4. 
Study Stopping Rules 
For Part 1 and Part 2 of the study, 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. 
Conditions that may warrant termination of the study include, but are not limited to, the 
following:  
• The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled 
in the study.  
• A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product. 
7.5. 
End of Study 
The End of Study is last subject, last visit. 

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8. 
SELECTION OF SUBJECTS 
8.1. 
Inclusion Criteria – Part 1 
To be eligible to participate in this study, subjects must meet the following eligibility criteria at 
Screening or at the timepoint specified in the individual eligibility criterion listed:  
1. Ability of the subject 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 58 years old, inclusive, at the time of informed consent. 
3. Diagnosis of RRMS per the 2010 McDonald’s criteria [Polman 2011] or onset of SPMS 
per the Lublin and Reingold criteria [Lublin 2014]. 
4. Baseline EDSS score of 2.0 to 6.0. 
5. MS disease duration of ≤20 years from first MS symptom(s). 
6. Must have at least one of the following occurring within 24 months prior to 
Day 1/Baseline:  
• Clinical relapse(s) [but not within 24 weeks prior to Day 1/Baseline] 
• Gadolinium (Gd)-enhancing lesion(s) on brain or spinal cord MRI 
• New T2 lesion(s) on brain or spinal cord MRI 
7. Must have been taking one of the following DMTs at a stable dose for at least 24 weeks 
prior to Day 1/Baseline: 
• IFNβ (Avonex, Plegridy, Betaferon/Betaseron, or Rebif [at 44 µg by subcutaneous 
injection 3 times per week]) 
• DMF (Tecfidera) 

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• Natalizumab (Tysabri) 
Subjects who missed no more than a single dose of natalizumab during the 24-week 
period may still enter the study. 
8. At enrollment, subject is not anticipated to require switching of background 
anti-inflammatory DMT, in the opinion of the Investigator. 
9. All subjects must meet the following MRI criteria on the Screening/Baseline brain MRI:  
• MTR in T2 lesions ≤-0.17 normalized MTR unit (nMTRu) 
and  
• DTI – radial diffusivity (DTI-RD) in T2 lesions ≤0.98 × 10-3 mm2/s 
10. All female subjects of childbearing potential and all male subjects must practice effective 
contraception during the study and continue contraception for at least 24 weeks after their 
last dose of study treatment (BIIB033 or placebo). In addition, subjects should not donate 
sperm or eggs during the study and for at least 24 weeks after their last dose of study 
treatment. For further details of contraceptive requirements for this study, refer to 
Section 15.5. 
8.2. 
Exclusion Criteria – Part 1 
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
Screening or at the timepoint specified in the individual criterion listed: 
1. Primary progressive MS [Polman 2011]. 
2. T25FW >30 seconds (based on an average of 2 consecutive trials at Screening). 
3. An MS relapse that has occurred within 24 weeks prior to Day 1/Baseline or the subject 
has not stabilized from a previous relapse at the time of Screening. 
4. A history of clinically significant persistent neutralizing antibody against IFNβ or 
natalizumab, in the opinion of the Investigator, for subjects treated with an interferon or 
with natalizumab, respectively. 
5. Prior exposure to BIIB033 (opicinumab). 
6. Treatment with any chemotherapeutic agents (e.g., mitoxantrone, cyclophosphamide, 
cladribine), cell-depleting mAbs (e.g., rituximab, ocrelizumab, alemtuzumab), total 
lymphoid irradiation, T-cell or T-cell receptor vaccination, or teriflunomide within 1 year 
prior to Day 1/Baseline. 
7. Treatment with other anti-inflammatory DMTs (e.g., GA, fingolimod, daclizumab) or 
plasmapheresis within 24 weeks prior to Day1/Baseline. 

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8. Treatment with Botox for limb spasticity within 24 weeks before Day 1/Baseline. 
9. Treatment with any investigational drug within 24 weeks or 5 t1/2 (whichever is longer) 
prior to Day 1/Baseline. 
10. Treatment with 4-aminopyridine (4-AP) within 30 days prior to Day 1/Baseline, unless a 
stable dose has been maintained for at least 30 days prior to Day 1/Baseline and will be 
continued for the course of this study. Treatment with medical marijuana for MS 
symptoms is not exclusionary, if it is consistent with local MS treatment guidelines and 
local regulations. 
11. Treatment with high-dose oral or IV steroids within 30 days before Day 1/Baseline. 
12. Contraindications to MRI, for example, presence of pacemakers or other implanted metal 
devices (excluding dental braces), an allergy to Gd, renal impairment, or claustrophobia 
that cannot be medically managed. 
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 5 half-lives of the agent prior to the Baseline Visit. Participation in a 
noninterventional study can be allowed as long as this participation does not interfere 
with this protocol or is not likely to affect the subject’s ability to comply with the 
protocol. 
14. History of suicidal ideation or an episode of clinically severe depression (as determined 
by the Investigator) within 12 weeks of enrollment. Note: Subjects receiving ongoing 
antidepressant therapy will not be excluded from the study unless the medication has 
been increased within 24 weeks prior to enrollment. 
15. History of human immunodeficiency virus or other immunodeficient conditions. 
16. Positive test result at Screening for hepatitis C virus antibody or hepatitis B virus (defined 
as positive for hepatitis B surface antigen or hepatitis B core antibody). 
17. History of malignancy; however, subjects with a history of excised or treated basal cell 
carcinoma or fewer than 3 squamous cell carcinomas are eligible to participate in this 
study. 
18. History of drug or alcohol abuse (as defined by the Investigator) within 2 years prior to 
Day 1/Baseline. 
19. History of abnormal laboratory results that, in the opinion of the Investigator, are 
indicative of a significant cardiac, endocrine, hematologic, immunologic, metabolic, 
urologic, pulmonary, gastrointestinal, dermatologic, psychiatric, renal, neurologic (other 
than MS), and/or other major diseases. 

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20. Any of the following abnormal blood tests at Screening: 
• hemoglobin ≤9.0 g/dL  
• platelets ≤100 × 109/L  
• lymphocytes ≤1.0 × 109/L  
• neutrophils ≤1.5 × 109/L  
• alanine aminotransferase/serum glutamate pyruvate transaminase (ALT/SGPT), 
aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT), or 
gamma-glutamyl-transferase ≥2 times the upper limit of normal 
• creatinine clearance <60 mL/min (estimated by Cockcroft-Gault equation) 
21. Female subjects who have a positive pregnancy test result, are pregnant, or are currently 
breast feeding. 
22. Plans to undergo elective major procedures/surgeries at any time during the study. 
23. Inability to comply with study requirements. 
24. Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the 
subject unsuitable for enrollment. 
8.3. 
Inclusion Criteria – Part 2  
 
1. Ability of the subject 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. Subjects who complete study treatment (BIIB033 or placebo) at Part 1/Week 72 Visit. 
3. All female subjects of childbearing potential and all male subjects must practice effective 
contraception during the study and continue contraception for at least 24 weeks after their 
last dose of BIIB033. In addition, subjects should not donate sperm or eggs during the 
study and for at least 24 weeks after their last dose of study treatment. For further details 
of contraceptive requirements for this study, refer to Section 15.5. 
8.4. 
Exclusion Criteria – Part 2  
Candidates will be excluded from the Part 2 if they meet any of the following exclusion criterion 
at the Part 2 screening: 
1. Subjects who did not complete study treatment in Part 1/Week 72 Visit 

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2. Subjects who have a duration >12 weeks between their Part 1/Week 72 Visit and Part 
2/Day 1.  
3. Any significant change in clinical status that would make the subject unsuitable to 
participate in Part 2, in the opinion of the Investigator. The Investigator must reassess the 
subject’s medical fitness for participation and consider any diseases that would preclude 
study treatment. 
4. A history of clinically significant and persistent neutralizing antibody against IFNβ or 
natalizumab, in the opinion of the Investigator, for subjects treated with an interferon or 
with natalizumab, respectively. 
5. Treatment with any investigational drug within 12 weeks prior to Part 2/Day 1. 
6. Treatment with 4-aminopyridine (4-AP) within 30 days prior to Part 2/Day 1, unless a 
stable dose has been maintained for at least 30 days prior to Part 2/Day 1. Treatment with 
medical marijuana for MS symptoms is not exclusionary, if it is consistent with local MS 
treatment guidelines and local regulations. 
7. Treatment with high-dose oral or IV steroids within 30 days before Part 2/Day 1. 
8. Contraindications to MRI, for example, presence of pacemakers or other implanted metal 
devices (excluding dental braces), an allergy to Gd, renal impairment, or claustrophobia 
that cannot be medically managed. 
9. Current enrollment or a plan to enroll in any interventional clinical study (except 
215MS202) in which an investigational treatment or approved therapy for investigational 
use is administered within 12 weeks prior to the Part 2/Day 1. Participation in a 
noninterventional study can be allowed as long as this participation does not interfere 
with this protocol or is not likely to affect the subject’s ability to comply with the 
protocol. 
10. History of suicidal ideation or an episode of clinically severe depression (as determined 
by the Investigator) within 12 weeks prior to Part 2/Day 1.  
11. History of human immunodeficiency virus or other immunodeficient conditions not 
related to DMT treatment. 
12. History of malignancy unless enrollment is approved by the Sponsor; subjects with a 
history of excised or treated basal cell carcinoma or fewer than 3 squamous cell 
carcinomas are eligible to participate in this study. 
13. History of drug or alcohol abuse (as defined by the Investigator) during Part 1 of the 
study or within 12 weeks prior to Part 2/Day 1. 
14. History of abnormal laboratory results that, in the opinion of the Investigator, are 
indicative of a significant cardiac, endocrine, hematologic, immunologic, metabolic, 

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urologic, pulmonary, gastrointestinal, dermatologic, psychiatric, renal, neurologic (other 
than MS), and/or other major diseases. 
15. Any of the following abnormal blood tests at Part 2 Screening: 
• alanine aminotransferase/serum glutamate pyruvate transaminase (ALT/SGPT), 
aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT), or 
gamma-glutamyl-transferase ≥2 times the upper limit of normal 
• creatinine clearance <60 mL/min (estimated by Cockcroft-Gault equation) 
16. Female subjects who have a positive pregnancy test result, are pregnant, or are currently 
breast feeding. 
17. Plans to undergo elective major procedures/surgeries at any time during the study. 
18. Inability to comply with study requirements. 
19. Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the 
subject unsuitable for enrollment. 

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9. 
SCREENING AND RANDOMIZATION 
9.1. 
Screening and Enrollment 
Part 1 
Subjects must provide informed consent before any Screening tests are performed (see 
Section 17.3). At the time of consent, the subject will be enrolled into the study. Subjects who 
are not eligible for participation at Screening due to a nonclinically significant out-of-range 
laboratory result(s) or a temporary condition (e.g., acute infection) may be rescreened 1 time 
only, at the discretion of the Investigator.  
Participating study sites are required to document all screened candidates initially considered for 
inclusion in the 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. A minimal set of 
Screening failure information is required to ensure transparent reporting of Screening failure 
participants to meet the Consolidated Standards of Reporting Trials publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
Screening failure details, eligibility criteria, and any serious adverse events (SAEs).  
It is not required that all Screening tests and assessments be completed during 1 pretreatment 
visit. Subjects must perform a separate practice test for T25FW, 9HPT-D, 9HPT-ND, and 
PASAT-3 at their Screening Visit (T25FW, 9HPT-D, and 9HPT-ND should be performed 
twice). The Screening and practice tests on these measurements should be separated by at least 
1 hour. The Screening and baseline tests on these measurements should be separated by at least 
5 days from each. 
 
 
 
 
 
Part 2 
Subjects must provide informed consent before any Part 2 assessments are performed (see 
Section 5.3). 
 
 
For subjects participating in Part 2, Part 1/Week 72 will be the combined Part 1 Final Visit and 
the Part 2 Screening Visit. In case the Part 2 Screening Visit is unable to be performed at 
Part 1/Week 72, a separate visit may occur within 4 weeks prior to Part 2/Day 1. The 
Part 2/Day 1 Visit should be performed as early as possible within 4 to 12 weeks from the 
Part 1/Week 72 Visit. Part 2/Day 1 must be within 12 weeks from Part 1/Week 72. 

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Subjects who are not eligible for participation at Screening due to a nonclinically significant out-
of-range laboratory result(s) or a temporary condition (e.g., acute infection), or treatment with 
high dose steroids for a relapse, may be rescreened 1 time only, at the discretion of the 
Investigator.  
The tests and assessments completed at the Part 1 Week 72 Visit may be used as Part 2 
screening, and do not need to be repeated, if the subject enrolls in Part 2 within 4 weeks (+ 5 
days) of the Part 1 Week 72 Visit.  
Participating study sites are required to document all screened candidates initially considered for 
inclusion in the 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. A minimal set of 
Screening failure information is required to ensure transparent reporting of Screening failure 
participants to meet the Consolidated Standards of Reporting Trials publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
Screening failure details, eligibility criteria, and any serious adverse events (SAEs).  
9.2. 
Randomization 
Part 1 
Randomization will take place across all study sites using a centralized interactive response 
technology (IRT; see Section 19.1.2 for IRT vendor and training). Subjects will be randomized 
to receive BIIB033 or placebo in a 1:1 ratio. 
Subjects will be randomized after all Screening assessments have been completed, including a 
stable pretreatment EDSS score, and after the Investigator has verified that the subjects are 
eligible per criteria in Sections 8.1 and 8.2. Subjects will be assigned a unique 6-digit subject 
identification number (the first segment of the number represents the study site and the second 
segment of the number represents the subject at that study site) that will be used on study-related 
documents pertaining to the subject. Any subject identification numbers that are assigned will 
not be reused even if the subject does not receive treatment or continue in the study.  
Randomization will be stratified by MS type (RRMS versus SPMS), background DMT group, 
. 
Subjects will be randomized via IRT. Each background DMT group should be represented by at 
least 10%, but no more than 45%, of the study population at enrollment. 
 
 
 
 
 
Subjects with RMS (RRMS and relapsing SPMS) will be enrolled in the study. It is estimated 
that 15% of enrolled subjects or fewer will have a diagnosis of relapsing SPMS. 

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Part 2 
There will be no randomization in Part 2, the OLE phase of the study in which all subjects 
receive BIIB033. 
Refer to the Study Reference Guide for details on randomization and enrollment. 
9.3. 
Blinding Procedures 
Part 1 
All study staff will be blinded to the subject treatment assignments (BIIB033 or placebo), with 
the exception of the unblinded pharmacist or unblinded designee, who is responsible for 
preparing study treatments, and the unblinded Pharmacy Monitor. To maintain the study blind, it 
is imperative that subject treatment assignments are not shared with the subjects, their families, 
or any member of the study team, either at the study site or at Biogen, except the unblinded 
Pharmacist or designee and the unblinded Pharmacy Monitor. In addition, the Sponsor staff 
conducting the study along with the study Data Manager and study Statistician will also be 
blinded to the treatment allocations while the study is ongoing. Unblinded documentation will be 
clearly marked as containing unblinding information. Unblinded documentation will be stored in 
a secure location that will be inaccessible to blinded staff. 
See Section 15.4.3.1 for instructions on unblinding in the event of a medical emergency.  
All efficacy assessments and neurological examinations will be performed by an examining 
neurologist and/or examining technician blinded to treatment assignment. It is imperative that 
subject treatment assignments and any information (such as laboratory results, AE reports, 
clinical records, etc.) that may reveal the identity of the assigned treatment are not shared with 
the examining neurologist or examining technician.  
The examining neurologist, examining technician, and subjects will be instructed to keep 
conversation to a minimum during evaluations and, in particular, not to discuss the potential side 
effects of study treatment. Similarly, there should be no access to patient records or prior 
assessments. 
 
Part 2 
Study treatment allocation in Part 1 will remain blinded for all Part 2 subjects and all site staff. 
At the end of Part 2 (i.e., once the clinical study report is finalized), if unblinding will not 
jeopardize the results of ongoing related studies, Biogen will provide the randomization codes to 
Investigators, who then can inform their subjects about the treatment received. Unblinded 
documents from Part 1 will not be accessible to subjects or blinded site study staff before Part 2 
ends. 

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10. 
DISCONTINUATION OF STUDY TREATMENT AND 
WITHDRAWAL OF SUBJECTS FROM THE STUDY 
10.1. 
Discontinuation of Study Treatment 
A subject must permanently discontinue study treatment (BIIB033 or placebo) for any of the 
following reasons: 
• The subject withdraws consent. 
• The subject becomes pregnant. Study treatment must be discontinued immediately. 
• The subject experiences a medical emergency that necessitates permanent discontinuation 
and/or unblinding of study treatment. 
• At the discretion of the Investigator for medical reasons or for noncompliance. 
The primary reason for discontinuation of study treatment must be recorded in the subject’s 
electronic case report form (eCRF). 
In Part 1 of the study, subjects who discontinue study treatment may remain in the study and 
continue protocol-required tests and assessments.  
In Part 2, subjects who discontinue study treatment will be required to withdraw from the study. 
10.2. 
Lost to Follow-Up 
Subjects will be considered lost to follow-up if they repeatedly fail to return for scheduled visits 
and are unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether the subject wishes to and/or should continue in the 
study. 
• In cases in which the subject is deemed lost to follow-up, the Investigator or designee 
must make every effort to regain contact with the subject. These contact attempts 
should be documented in the subject’s medical record. 
• Should the subject continue to be unreachable, that subject will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 

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10.3. 
Withdrawal of Subjects From Study 
Subjects must be withdrawn from the study for any one of the following reasons: 
• 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. 
• The subject discontinues study treatment in Part 2. 
The primary reason for the subject’s withdrawal from the study must be recorded in the subject’s 
eCRF. 
In Part 1 and Part 2, subjects who withdraw from the study prematurely should complete an ET 
visit as soon as possible but no later than 4 weeks after the last dose of study treatment and an 
EOS Visit 12 weeks (±10 days) after the last dose of BIIB033 or placebo administration. 
Subjects who withdraw from Part 1 of the study may not be replaced unless the dropout rate is 
higher than the expected rate. 

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11. 
STUDY TREATMENT USE 
Biogen will provide BIIB033 to the study sites.  
Refer to Section 12 (Study Treatment Management) for specifics on the preparation, storage, 
handling, disposal, and accountability of the study treatment. 
11.1. 
Regimen 
11.1.1. 
BIIB033 and Placebo 
Refer to and follow the Directions for Handling and Administration (DHA).  
Part 1 
BIIB033 or placebo will be administered as an IV infusion once every 4 weeks for 72 weeks at 
the study site.  
Subjects will receive BIIB033 or placebo at 19 study visits (Day 1/Baseline, Week 4, Week 8, 
Week 12, Week 16, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, 
Week 48, Week 52, Week 56, Week 60, Week 64, Week 68, and Week 72). 
BIIB033 or placebo should be administered within the ±5-day window period of the scheduled 
visit. If a subject misses the planned dose (i.e., outside of the ±5-day window), the missed dose 
should be administered as soon as possible unless it is within 2 weeks of the next scheduled dose 
(i.e., do not administer the missed dose if it is ≤2 weeks to the next scheduled dose).  
Part 2 
In Part 2 of the study, each subject will receive BIIB033 as an IV infusion once every 4 weeks 
(within ±5 day window of the scheduled visit) for 96 weeks, as specified in Table 3 and Table 4.  
11.2. 
Modification of Dose and/or Treatment Schedule 
Not applicable. 
11.3. 
BIIB033 Precautions 
Following BIIB033 or placebo administration, subjects will be required to remain at the study 
site for at least 1 hour for monitoring of any unexpected infusion reactions. Medications for the 
treatment of severe hypersensitivity reactions (e.g., epinephrine for subcutaneous injections, 
diphenhydramine for injection) should be available for immediate use. 
Please refer to the DHA for detailed instructions.  

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11.4. 
Treatment Compliance 
All doses of study treatment will be administered by the clinical staff. 
11.5. 
Concomitant Therapy and Procedures 
11.5.1. 
Concomitant Therapy 
A concomitant therapy is any drug or substance administered between signing of the Informed 
Consent Form (ICF) and the EOS/ET Visit (Part 1, Week 84 ± 10 days; Part 2, Week 
108 ± 10 days). Prior MS treatment should be recorded in the eCRF at Screening and 
Day 1/Baseline for Part 1.  
11.5.1.1. Allowed Concomitant Therapy 
11.5.1.1.1. Background Anti-Inflammatory DMTs for Use with Study Treatment 
During the study period, subjects will take the same protocol-specified anti-inflammatory DMT 
they have been treated with for at least 24 weeks prior to Day 1/Baseline of Part 1. In Part 2, the 
subject will continue the anti-inflammatory background DMT used at the end of Part 1. 
DMTs are not provided by Biogen and are managed by the treating neurologist. Treating 
neurologists will be responsible for the prescription of background DMT treatment and safety 
monitoring according to the local label and regulations.  
For subjects on natalizumab (Tysabri), natalizumab infusions and study treatment infusions may 
be on the same day; however, natalizumab should be administered prior to study treatment 
(BIIB033 or placebo) if given on that same day, with a minimum 1-hour interval between 
infusions. If any infusion reaction occurs with natalizumab, the infusion of BIIB033 should not 
be administered on that same day. Subsequent infusions of natalizumab should be managed in 
accordance with its label. BIIB033 can be administered again on the same day if no infusion 
reaction occurs during subsequent natalizumab infusions. 
Administration of background DMTs may continue after the study Treatment Period ends, at the 
discretion of the treating neurologist. 
Based on the clinical judgment of the treating neurologist, subjects can switch to another 
marketed DMT during the study (not limited to protocol-defined DMTs) or may discontinue the 
DMT altogether. These subjects should remain in the study and continue study treatment 
(BIIB033 or placebo). The reason for the change and the DMT that the subject switched to (if 
applicable) must be recorded in the subject’s eCRF. Investigators continue to be responsible for 
managing DMT treatment and safety monitoring after a switch. 
The Medical Monitor should be notified of any DMT switches. 

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11.5.1.1.2. Other Allowed Concomitant Therapy 
Subjects should be instructed not to start taking any new medications, including nonprescribed 
drugs, unless they have received permission from the Investigator.  
Concomitant therapy with the following is allowed as long as the exclusion criteria listed in 
Section 8.2 and Section 8.4 are observed:  
• Oral contraceptives at a stable dose for women of childbearing potential.  
• Acetaminophen/paracetamol for pain relief or treatment of flu-like symptoms.  
• 4-AP, if used per label and maintained on a stable regimen for at least 30 days prior to 
Part 1/Baseline or Part 2/Day 1, and throughout the study.  
• Medications used to treat MS symptoms, such as spasticity, bladder impairment, pain, 
or depression (such symptomatic therapy 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). Medical marijuana is allowed for treatment of MS 
symptoms if it is consistent with local MS treatment guidelines and local regulations, 
is maintained on a stable regimen for at least 30 days prior to Part 2/Day 1, and 
throughout the study. 
• Steroid treatment of a protocol-defined relapse at the discretion of the treating 
neurologist according to local standards of care (refer to Section 7.2.3). 
• Corticosteroids that are administered by nonsystemic routes (e.g., topical, inhaled).  
11.5.1.2. Disallowed Concomitant Therapy 
Concomitant treatment with any of the following is not allowed while receiving study treatment, 
unless as otherwise described in this protocol:  
• While subjects are permitted to switch from their protocol-defined background DMT 
to another marketed background DMT at the discretion of their treating neurologist, 
subjects are not allowed to take more than 1 background DMT at any time; this 
includes any chronic immunosuppressant or immunomodulatory therapy.  
• Any investigational product, including investigational symptomatic therapies for MS 
and investigational therapies for non-MS indications  
• Any systemic steroid therapy without prior approval from the Sponsor. This includes, 
but is not limited to, oral corticosteroids (e.g., prednisone) or periodic (e.g., every 4 
weeks) treatment with IV methylprednisolone, except for protocol-defined treatment 
of relapses (Section 7.2.3). Steroids that are administered by nonsystemic routes (e.g., 
topical, inhaled) are allowed.  

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Subjects who receive any of these restricted medications may be required to permanently 
discontinue study treatment and withdraw from the study (Sections 10.1 and 10.3). Contact 
Sponsor or designee for approval if specific medical conditions necessitate the use of any 
disallowed concomitant medications.  
The use of concomitant therapies defined above must be recorded on the subject’s eCRF, 
according to instructions for eCRF completion. AEs related to the administration of these 
therapies or procedures must be documented on the appropriate eCRF.  
11.5.2. 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
the time the subject is enrolled in the study (i.e., has signed the ICF) and the EOS/ET Visit 
unless the subject is being followed for study-related toxicity. 
Total lymphoid irradiation, T-cell or T-cell receptor vaccination, plasmapheresis, or cytapheresis 
are not allowed during the study period. 
Subjects who receive any of these restricted procedures may be required to permanently 
discontinue study treatment and may be withdrawn from the study as described in Sections 10.1 
and 10.3. 
The use of concomitant procedures defined above must be recorded on the subject’s eCRF, 
according to instructions for eCRF completion. AEs related to the administration of these 
therapies or procedures must be documented on the appropriate eCRF. 
11.6. 
Continuation of Treatment 
Given that this is a Phase 2 study intended to provide proof of concept, no further provisions of 
the study treatment are made beyond the protocol-specified treatment duration.  

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12. 
STUDY TREATMENT MANAGEMENT 
Study treatment will be manufactured, handled, and stored in accordance with applicable Good 
Manufacturing Practice. Study treatment (BIIB033) will be stored in a limited-access area, out 
of sight and view to blinded site staff. Daily minimum/maximum temperature logs should be 
maintained at the study sites. Accountability for study treatment is the responsibility of the 
unblinded pharmacist (or unblinded authorized designee). More details concerning this 
responsibility are included in Section 12.1.4. 
Study treatment must be dispensed only by an unblinded pharmacist (Part 1 only) or 
appropriately qualified staff. Study treatment is to be dispensed only to subjects enrolled in this 
study. Once study treatment is prepared for a subject, it can be administered only to that subject. 
Study treatments are for one-time use only; do not use any study treatment remaining in the vial 
for another subject. 
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). 
12.1. 
BIIB033 
The BIIB033 used in this study will be BIIB033-B, whose production reflects process changes 
for improved efficiency and productivity relative to the BIIB033-A product used in previous 
clinical studies (see Section 4.3.2 [Study 215HV103] and the Investigator’s Brochure for more 
details). 
BIIB033 is supplied as a liquid drug product containing 200 mg/mL opicinumab in 20 mM 
L-histidine, 160 mM L-arginine hydrochloride, 10 mM L-methionine, 0.05% (w/v) polysorbate 
80, pH 6.5. It is provided in glass vials, each containing 1000 mg BIIB033. BIIB033 is to be 
administered by IV infusion following dilution into saline as specified in the DHA.  
The contents of the BIIB033 label will be in accordance with all applicable regulatory 
requirements. At a minimum, the study treatment label will include a study reference code, drug 
identifier, number of dosage units, lot number, expiry or use-by date, and other pertinent 
information in accordance with local law. The expiry or use-by date is also stored in the IRT 
system, and printable assignment reports are available to the unblinded pharmacist (or unblinded 
authorized designee). BIIB033 should not be used after the expiry or use-by date. 
12.1.1. 
BIIB033 Preparation 
The individual preparing BIIB033 should carefully review the instructions provided in the DHA 
and ensure the study blind is maintained. 
If the packaging is damaged, or if there is anything unusual about the appearance or attributes of 
the vials or study treatment, do not use the study treatment. The vial in question should be saved 
at the study site and the problem immediately reported to Biogen. 

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12.1.2. 
BIIB033 Storage 
Study treatment must be stored in a secure location. 
BIIB033 vials are to be stored at 2°C to 8°C (36°F to 46°F) in a locked refrigerator with limited 
access. BIIB033 vials are to be protected from light, protected from freezing, and should not be 
shaken. If BIIB033 is frozen, the Sponsor should be notified immediately and the drug should be 
quarantined until further notice from the Sponsor. 
For the most up-to-date storage requirements, follow the instructions provided in the DHA 
located in the Pharmacy Manual and Study Reference Guide. 
12.1.3. 
BIIB033 Handling and Disposal 
The unblinded pharmacist (or unblinded authorized designee) must return all used and unused 
vials of BIIB033 as instructed by Biogen unless approved for onsite destruction. 
If any BIIB033 supplies are to be destroyed at the site, the institution or appropriate site 
personnel must obtain prior approval from Biogen, by providing, in writing, the destruction 
policy or details of the method of destruction. After such destruction, Biogen must be notified, in 
writing, of the details of the study treatment destroyed (e.g., lot or kit numbers, quantities), the 
date of destruction, and proof of destruction. 
12.1.4. 
BIIB033 Accountability 
Accountability for study treatment is the responsibility of the unblinded pharmacist (or unblinded 
authorized designee). The study site must maintain accurate records demonstrating dates and 
amount of study treatment received, to whom dispensed (subject-by-subject accounting), and 
accounts of any study treatment accidentally or deliberately destroyed or lost.  
Unless otherwise notified, all vials both used and unused, must be saved for study treatment 
accountability. By the end of the study, reconciliation must be made between the amount of 
BIIB033 supplied, dispensed, and subsequently destroyed or returned to Biogen. A written 
explanation must be provided for any discrepancies. 
12.2. 
Placebo and/or Comparator or Reference Product 
The placebo (control agent) to be used in this study will be sterile normal saline (0.9% sodium 
chloride for IV administration). The manufacturer’s directions for material storage and handling 
are to be followed, as are standard clinical practices for ensuring sterility of the material. 

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13. 
EFFICACY, 
 
 ASSESSMENTS 
See Section 5 for the timing of all assessments. 
Tests and evaluations affecting primary endpoints and/or analyses may need to be repeated if the 
original results are lost or damaged. In these cases, subjects will be asked to return to the clinic to 
have the evaluations repeated. 
13.1. 
Clinical Efficacy Assessments 
The following clinical assessments will be performed to evaluate the efficacy of BIIB033: 
• EDSS 
• T25FW  
• 9HPT-D and 9HPT-ND (the right and left hands both tested, with the dominant hand 
tested before the nondominant hand) 
• PASAT-3 
• SDMT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Refer to Table 1, Table 2, Table 3, and Table 4 for the timing of assessments. 

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14. 
SAFETY ASSESSMENTS 
Refer to Section 5 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 BIIB033: 
• Medical history and prior MS treatment  
• Continuous AE and SAE monitoring  
• MS signs and symptoms (including relapses) 
• Physical examination  
• Vital sign measurements: temperature, pulse rate, systolic and diastolic blood 
pressure, and respiratory rate 
• Body weight measurements 
• 12-Lead electrocardiograms (ECGs) 
• C-SSRS 
• Concomitant therapy and procedure recording 
14.2. 
Laboratory Safety Assessments 
Samples will be analyzed using Good Laboratory Practice-validated assays. 
The following laboratory assessments will be performed to evaluate the safety profile of 
BIIB033: 
• Hematology: complete blood count with differential and platelet count, and absolute 
neutrophil count. Prothrombin time, partial thromboplastin time, and platelets will 
also be measured for all subjects at Screening.  
• Blood chemistry: total protein, albumin, creatinine, blood urea nitrogen, uric acid, 
bilirubin (total and direct), alkaline phosphatase, ALT/SGPT, AST/SGOT, 
gamma-glutamyl-transferase, glucose, calcium, phosphorus, bicarbonate, chloride, 
sodium, potassium, and follicle-stimulating hormone (FSH; for postmenopausal 
female subjects only). 
• Urinalysis: blood, protein, and glucose (microscopic examination, if abnormal). 
• Serum and urine pregnancy test (women of childbearing potential only). 

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15. 
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES 
Throughout the course of the study, every effort must be made to remain alert to possible AEs. If 
an AE occurs, the first concern should be for the safety of the subject. If necessary, appropriate 
medical intervention should be provided. 
At the signing of the ICF, each subject or his/her legally authorized representative must be given 
the names and telephone numbers of study site staff for reporting AEs and medical emergencies. 
15.1. 
Definitions 
15.1.1. 
Serious Pretreatment Event 
A serious pretreatment event is any event that meets the criteria for SAE reporting (as defined in 
Section 15.1.3) and occurs after the subject signs the ICF but before administration of study 
treatment (BIIB033 or placebo). 
15.1.2. 
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, vital sign result, and/or ECG result 
meets the definition of an AE will be made by the Investigator. Abnormal results are not 
considered AEs unless one or more of the following criteria are met: 
• The result meets the criteria for an SAE 
• The result requires the subject to receive specific corrective therapy 
• The result is considered by the Investigator to be clinically significant 
15.1.3. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that: 
• 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 

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• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect 
• Is a medically important event 
A medically important event is an AE 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. 
15.1.4. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized. The study site must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining the subject’s 
consent to participate in the study. 
• 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. 
o 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 15.1.3 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 15.1.3. 
• The relationship of the event to study treatment as defined in Section 15.2.2. 
• The severity of the event as defined in Section 15.2.3. 

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• The severity of the event 
• The relationship of the event to study treatment 
To report initial or follow-up information on an SAE, fax or email 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 eCRF. All causes of death must be reported as SAEs within 24 hours of the site 
becoming aware of the event. The Investigator should make every effort to obtain and send death 
certificates and autopsy reports to Biogen 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. 
Serious Adverse Events 
Any SAE experienced by the subject between the time of the signing of the ICF and EOS 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 within 24 hours.  
Subjects will be followed for all SAEs until the EOS 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. 
15.3.5. 
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. 
Appropriate personnel at Biogen will unblind SUSARs for the purpose of regulatory reporting. 
Biogen or designee will submit SUSARs (in blinded or unblinded fashion) to regulatory agencies 
according to local law. Biogen or designee will submit SUSARs to Investigators in a blinded 
fashion. 
15.4. 
Procedures for Handling Special Situations 
15.4.1. 
Pregnancy 
Subjects should not become pregnant or impregnate their partners during the study or for 
24 weeks after their last dose of study treatment (BIIB033 or placebo). If a female subject 
becomes pregnant, study treatment must be discontinued immediately. 

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Any pregnancy that occurs between the first dose and 24 weeks after the last dose of study 
treatment (BIIB033 or placebo) must be reported. 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. Refer to the Study Reference Guide for complete contact 
information. The Investigator or study site staff must report the outcome of the pregnancy to 
Biogen or designee. A pregnancy is not considered an AE and should not be recorded on the AE 
eCRF. 
Congenital abnormalities and birth defects in the offspring of male or female subjects should be 
reported as an SAE if conception occurred during the study Treatment Period. 
15.4.2. 
Overdose 
An overdose is any dose of study treatment administered to a subject or taken by a subject that 
exceeds the dose assigned to the subject according to the protocol. Overdoses are not considered 
AEs and should not be recorded as an AE on the eCRF; however, all overdoses must be recorded 
on an Overdose form and faxed to Biogen 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 eCRF. 
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 for complete 
contact information.  
15.4.3.1. Unblinding for Medical Emergency 
In a medical emergency when knowledge of the subject’s treatment assignment may influence 
the subject’s clinical care, the Investigator may access the subject’s treatment assignment by 
IRT. The Investigator must document the reasons for unblinding in the subject’s source 
documents. The Investigator is strongly advised not to divulge the subject’s treatment 
assignment to any individual not directly involved in managing the medical emergency, or to 
personnel involved with the analysis and conduct of the study. The Investigator can contact 
Biogen or designee to discuss such situations. 
15.5. 
Contraception Requirements 
All women of childbearing potential and all men must ensure that effective contraception is used 
during the study and for at least 24 weeks after their last dose of study treatment (BIIB033 or 
placebo). In addition, subjects should not donate sperm or eggs for the duration of the study and 
for at least 24 weeks after their last dose of study treatment. 

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For the purposes of this study, women who do not meet one of the following criteria are 
considered to be physiologically capable of becoming pregnant and are, therefore, defined as 
women of childbearing potential: 
• Postmenopausal 
− 12 continuous months of natural (spontaneous) amenorrhea without an alternative 
medical cause and a serum FSH 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, effective contraception is defined as use of one of the following:  
For females: 
• Established use of oral, intravaginal, or transdermal combined (estrogen and 
progestogen containing) hormonal methods of contraception associated with the 
inhibition of ovulation. 
• Established use of oral, injected, or implanted hormonal methods of contraception  
• Placement of an intrauterine device or intrauterine hormone-releasing system. 
• Bilateral tubal occlusion.  
• 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.  
• Sex with a male who uses the methods described for males below.  
For males: 
• Vasectomy with negative semen analysis at follow-up, or the use of condoms with 
spermicide.  
• Sex with a female who uses the methods described for females if she is of 
childbearing potential. 
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 

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(e.g., calendar, ovulation, symptothermal, and postovulation methods) and withdrawal are not 
considered acceptable methods of contraception. 
For DMTs, contraceptive requirements per label must be followed. 
Pregnancy reporting is described in Section 15.4.1. 
15.6. 
Safety Responsibilities 
15.6.1. 
The Investigator 
The Investigator’s responsibilities include the following: 
• Monitor and record all AEs, including SAEs, on the eCRF 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. Follow up on any ongoing 
SAE until the event has resolved, stabilized, or returned to baseline status. 
• Monitor and record all pregnancies and follow up on the outcome of all pregnancies. 
• 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 become 
stable. Record AE follow-up information, including resolution, on the eCRF, as 
applicable. 
• Report SAEs to local ethics committees, as required by local law. 
15.6.2. 
Biogen  
Biogen’s responsibilities include the following: 
• Before a site can enroll any subjects, the Clinical Monitor is responsible for reviewing 
with study site staff the definitions of AE and SAE, as well as the instructions for 
monitoring, recording, and reporting AEs and SAEs. 

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• 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 Part 1 and Part 2 objectives/endpoints are listed in Section 6 Table 5 and Table 6, 
respectively.  
16.1. 
Demography and Baseline Disease Characteristics 
Demographic and baseline disease characteristic data will be summarized by treatment group 
with summary statistics (mean, standard deviation [SD], median, interquartile range, and overall 
range) for continuous variables or with number and percentages for categorical variables. 
16.2. 
Efficacy 
16.2.1. 
Analysis Population 
The efficacy endpoints will be analyzed for the ITT population. The ITT population includes all 
randomized subjects who receive at least 1 dose of study treatment. Subjects will be analyzed in 
the groups to which they were randomized. 
16.2.2. 
Methods of Analysis 
16.2.2.1. General Methods of Analysis 
Data will be collected and analyzed in 2 phases: 
1. After the Part 1 placebo-controlled phase is completed, the efficacy and safety analysis 
will be performed. All data will be summarized by treatment group (BIIB033 750 mg and 
placebo). 
2. Analyses will be performed as needed during the Part 2 OLE. Descriptive statistics will 
be used to evaluate the long-term safety and efficacy data of BIIB033. 
Summary statistics will be presented. For continuous endpoints, the summary statistics will 
generally include the number of subjects with data, mean, SD, median, interquartile range, and 
overall range. For categorical endpoints, the summary statistics will generally include the 
number of subjects with available data and the percent of subjects with data in each category.  
In the analysis of Part 1 efficacy variables, comparisons will be made between the active dose 
group (BIIB033 750 mg) versus the placebo group.  
16.2.2.2. Analysis of the Primary Endpoint in Part 1 
The primary efficacy endpoint of Overall Response Score will be summarized using descriptive 
statistics by treatment groups and visits. A Mixed Model for Repeated Measures (MMRM) will 
be used as the primary analysis to analyze the Overall Response Score up to week 72. Treatment, 
visit, treatment by visit interaction, baseline component measurements (EDSS, T25FW, 9HPT), 

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and stratification factors will be included in MMRM as fixed effects. The primary hypothesis test 
for treatment comparison (BIIB033 750 mg versus placebo) will be based on the main effect 
over 72 weeks derived from the model. If the main effect is significant at an α level of 0.05 (2-
sided), treatment difference at individual timepoints (visits) will also be assessed based on the 
same model. Subgroup analyses will be performed as supportive analyses with subgroups 
defined a priori in the statistical analysis plan.  
16.2.2.3. Analysis of the Secondary Endpoints in Part 1 
Treatment comparison with respect to secondary endpoints will be made in sequential order for 
the endpoints listed in Section 6. The proportion of patients with confirmed improvement will be 
analyzed using logistic regression. The time from randomization to confirmed improvement will 
be analyzed using the Cox proportional hazards model. Where appropriate, baseline component 
measurements (EDSS, T25FW, 9HPT-D, 9HPT-ND, PASAT-3, and SDMT) and stratification 
factors will be included in both logistic regression and Cox model as covariates. The odds ratio 
from logistic regression and the hazard ratio from the Cox model will be derived with 95% 
confidence interval. 
 
 
 
 
 
 
 
 
 
 
 
16.2.2.5. Analysis of Endpoints in Part 2 
Descriptive statistics will be used to evaluate the long-term safety and efficacy data of BIIB033. 
Additional analyses of the efficacy endpoints for combined data from Part 1 and Part 2 may be 
performed based on randomization treatment group in Part 1. Additional analyses of Part 2 
efficacy endpoints may be performed by using Part 1/Day1 as baseline for all subjects. The 
statistical methods will be specified in detail in the statistical analysis plan. 
 
 
 
 
  

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16.4. 
Safety 
16.4.1. 
Analysis Population 
For Part 1, the safety population is defined as all subjects who receive at least 1 dose of study 
treatment in Part 1. 
For Part 2, the safety population is defined as all subjects who receive at least 1 dose of study 
treatment in Part 2. 
16.4.2. 
Methods of Analysis 
All AEs, clinical laboratory abnormalities, vital signs, physical examinations, ECG, MS signs 
and symptoms, and C-SSRS will be evaluated for safety. 
16.4.2.1. Adverse Events 
Only treatment-emergent adverse events (TEAEs) will be summarized. Treatment emergent is 
defined as having an onset date that is on or after the first dose of double-blind treatment, or as 
worsening after the first dose of double-blind treatment.  
The incidence of clinical TEAEs will be summarized by treatment group, severity, and by 
relationship to the study treatment. The summary tables will include incidence estimates for 
overall system organ class as well as for preferred terms within each system organ class. AEs 
will be coded using the Medical Dictionary for Regulatory Activities. 

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16.4.2.2. Clinical Laboratory Results 
Clinical laboratory evaluations include hematology, blood chemistry, and urinalysis. Laboratory 
data will be summarized using shift tables. Shifts from baseline to high/low status for 
hematology and blood chemistry parameters and shifts from baseline to high/positive status for 
urinalysis will be presented. Also, summaries of laboratory values categorized based on 
potentially clinically significant abnormalities will be created. Summary statistics for actual 
values and change from baseline will be presented for quantitative laboratory data. 
16.4.2.3. Vital Signs 
The analysis of vital signs will focus on clinically relevant abnormalities. 
The definitions of these clinically relevant abnormalities are shown in Table 7.  
Table 7: 
Criteria Used to Determine Clinically Relevant Abnormalities in Vital Signs 
Vital Sign 
Criteria for Abnormalities 
Temperature  
>38°C or an increase from baseline of at least 1°C 
Pulse 
>100 beats per minute (bpm) or an increase from baseline of >30 bpm 
<40 bpm or a decrease from baseline of >20 bpm 
Systolic Blood Pressure 
>160 mmHg or an increase from baseline of >40 mmHg 
<90 mmHg or a decrease from baseline of >30 mmHg 
Diastolic Blood Pressure 
>100 mmHg or an increase from baseline of >30 mmHg 
<45 mmHg or a decrease from baseline of >20 mmHg 
16.4.2.4. Physical Examinations 
Clinically significant abnormal findings will be reported as AEs and included in the AE analyses. 
16.4.2.5. Electrocardiogram 
The number and percentage of subjects with shifts to the categorical values (abnormal not AE, or 
abnormal AE) will be summarized by treatment group.  
16.4.2.6. Multiple Sclerosis Signs and Symptoms 
The changes from baseline will be summarized by treatment group. 
16.4.2.7. Columbia Suicide Severity Rating Scale 
The C-SSRS data will be summarized by treatment group. 

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16.5. 
Immunogenicity Data 
16.5.1. 
Analysis Population 
The analysis population for immunogenicity is defined as all subjects in the safety population 
who have at least 1 postdose immunogenicity sample collected. 
For Part 1, the analysis population for immunogenicity is defined as all subjects in the safety 
population who have at least 1 postdose immunogenicity sample collected.  
For Part 2, samples will only be collected and stored. Immunogenicity assessment may be 
performed at sponsor’s discretion.  
16.5.2. 
Methods of Analysis 
The incidence of anti-BIIB033 serum antibodies will be summarized by treatment group.  
16.6. 
Interim Analyses 
In Part 1, an interim analysis may be performed by a small, independent team for futility 
assessment when a minimum of 50% of subjects have completed at least their Week 24 Visit. 
The futility criteria will be specified in detail in the statistical analysis plan. This study may be 
terminated early if the prespecified futility criteria are met at interim analysis. The study 
management team, Investigators, and subjects will remain blinded. The analyses to be performed 
when Part 1 is completed are not considered as interim analysis. 
In Part 2, interim analysis may be performed as needed. Subject level data from Part 1 will 
remain blinded for all subjects and site investigator/staff while Part 2 is ongoing. 
16.7. 
Sample Size Considerations 
In Part 1, a sample size of 120 subjects per treatment group will have approximately 80% power 
to detect a true mean treatment difference of 0.354 in the main effect of Overall Response Score 
over 72 weeks. This power calculation is based on a 1-sided 2-sample t-test assuming equal 
variance with a significance level of 0.025, an SD of 0.85, and a drop-out rate of 20%. The 
assumed mean difference of 0.354 between the 2 treatment groups is based on the 90% one-sided 
lower confidence bound of the estimated treatment difference in the target population of 
Study 215MS201. 
In Part 2, the actual sample size, 
, is 
dependent on the enrollment rate; therefore, a sample size calculation is not needed.  

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17. 
ETHICAL REQUIREMENTS 
Biogen, 
, and the Investigator must comply with all instructions, regulations, and 
agreements in this protocol and applicable International Council for Harmonisation (ICH) and 
Good Clinical Practice (GCP) guidelines and conduct the study according to local regulations. 
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines. The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated. The Investigator 
is responsible for supervising those individuals and for implementing procedures to ensure the 
integrity of the tasks performed and any data generated. 
17.1. 
Declaration of Helsinki 
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki. 
17.2. 
Ethics Committee 
The Investigator must obtain ethics committee approval of the protocol, ICF, and other required 
study documents prior to starting the study. Biogen will submit documents on behalf of the 
investigational sites in countries other than the United States. 
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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or subject’s legally authorized representative (e.g., parent or legal guardian), as applicable, in 
accordance with local practice and regulations.  
Written informed consent must be obtained from subjects electing to enroll in Part 2 before any 
Part 2 assessments are performed. 
 
 
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 
subject’s legally authorized representative). The subject must be given sufficient time to consider 
whether to participate in the study. 
Subjects will be informed that their race and ethnicity will be collected and will be used during 
analysis of study results (unless not permitted by local law).  
A copy of the signed and dated ICF must be given to the subject. The original 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). 
During the study, subjects’ race and ethnicity will be collected (unless not permitted by local 
law). These data will be used in the analysis of the safety and/or 
 of the study 
treatment. It is unknown whether the effects of the study treatment are influenced by race or 
ethnicity.  
Study reports will be used for research purposes only. The subject will not be identified by name 
in eCRFs, study-related forms, study reports, or any related publications. 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. 

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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. This initiation visit will include a detailed review of the protocol and study 
procedures. 
18.2. 
Quality Control and Quality Assurance 
Quality control procedures will be implemented at each stage of data handling to ensure that all 
data are reliable and have been processed correctly. Data anomalies will be communicated to the 
sites for clarification and resolution, as appropriate.  
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. Source data must be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data must be traceable, 
not obscure the original entry, and be explained if necessary (e.g., with an audit trail). The 
Investigator should maintain a record of the location(s) of essential documents. 
The Clinical Monitor will visit the study site at regular intervals during the study and after the 
study has completed, as appropriate. A clinical site monitoring plan will detail who performs the 
monitoring, how often, and the extent of review. It also will provide the monitoring strategy, 
with emphasis on subject safety, data integrity, and critical data and processes. 
During these visits, eCRFs, supporting documentation, and essential documentation related to the 
study will be reviewed and any discrepancies or omissions will be resolved. Documentation of 
results will be provided to Biogen or designee in a timely fashion to allow follow-up and 
verification of compliance with the monitoring plan. Remote evaluation of data (centralized 
monitoring) may also be conducted and reported as defined in the monitoring plan. 
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure the protection of subject rights and well-being, protocol adherence, quality of data 
(accurate, complete, and verifiable), study treatment accountability, compliance with regulatory 
requirements, and continued adequacy of the investigational site and its facilities. 

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18.4. 
Study Funding 
Biogen is the Sponsor of the study and is funding the study. All financial details are provided in 
the separate contracts between the institution, Investigator, and Biogen.  
18.5. 
Publications 
Details are included in the clinical trial agreement for this study. 
 

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19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION 
19.1. 
External Contract Organizations 
Biogen will ensure oversight of any study-related duties and functions carried out on its behalf 
and will specify in writing all duties and functions that are transferred.  
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, and management of SAE reports and data management. Before 
subjects are screened at each study site, the CRO will review study responsibilities with the 
Investigators and other study site staff, as appropriate. 
19.1.2. 
Interactive Response Technology 
IRT will be used in this study. Before subjects are screened or enrolled, the IRT 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 eCRFs by a web-based 
electronic data capture (EDC) tool developed by a CRO and configured by the EDC vendor. 
PROs will be completed by the subject on paper forms and subsequently entered into the EDC 
tool by site staff. 
19.1.4. 
Central Laboratories for Laboratory Assessments 
A central laboratory has been selected by Biogen to analyze all blood chemistry, hematology, 
and urine samples collected for this study. 
 and other samples will be analyzed at a laboratory 
selected by Biogen. 
 
 
 
 
 
 
 

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19.2. 
Study Committees 
19.2.1. 
Independent Data Monitoring Committee (Part 1 Only)  
An independent data monitoring committee (IDMC) will be formed to review ongoing safety 
data during the course of Part 1 only. A charter will be written for this IDMC. 
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 17.3). 
19.4. 
Ethics Committee Notification of Study Completion or Termination 
Where required, the regulatory authorities and ethics committees must be notified of completion 
or termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines. 
19.5. 
Retention of Study Data 
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local, national, or regional 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 Investigators as a signatory for the study report. 
This determination will be made by several factors including but not limited to the Investigator’s 
experience and reputation in the studied indication; the Investigator’s contribution to the study in 
terms of design, management, and/or subject enrollment; or by other factors determined to be 
relevant by Biogen. 

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Biogen will follow all applicable local regulations pertaining to study report signatories. 

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20. 
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inhibitors of axonal regeneration in the intact and injured mouse central nervous system. 
Molecular and cellular neurosciences. 2007;34(4):519-38. 
Bourikas D, Mir A, Walmsley AR. LINGO-1-mediated inhibition of oligodendrocyte 
differentiation does not require the leucine-rich repeats and is reversed by p75(NTR) antagonists. 
Molecular and cellular neurosciences. 2010;45(4):363-9. 
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. 
Carim-Todd L, Escarceller M, Estivill X, et al. LRRN6A/LERN1 (leucine-rich repeat neuronal 
protein 1), a novel gene with enriched expression in limbic system and neocortex. The European 
journal of neuroscience. 2003;18(12):3167-82. 
Fu QL, Hu B, Wu W, et al. Blocking LINGO-1 function promotes retinal ganglion cell survival 
following ocular hypertension and optic nerve transection. Invest Ophthalmol Vis Sci. 
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Gresle MM, Liu Y, Kilpatrick TJ, et al. Blocking LINGO-1 in vivo reduces degeneration and 
enhances regeneration of the optic nerve. Multiple Sclerosis Journal - Experimental, 
Translational and Clinical. 2016;2:1-13. 
Inoue H, Lin L, Lee X, et al. Inhibition of the leucine-rich repeat protein LINGO-1 enhances 
survival, structure, and function of dopaminergic neurons in Parkinson's disease models. Proc 
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Ji B, Case LC, Liu K, et al. Assessment of functional recovery and axonal sprouting in 
oligodendrocyte-myelin glycoprotein (OMgp) null mice after spinal cord injury. Molecular and 
cellular neurosciences. 2008;39(2):258-67. 
Ji B, Li M, Wu WT, et al. LINGO-1 antagonist promotes functional recovery and axonal 
sprouting after spinal cord injury. Molecular and cellular neurosciences. 2006;33(3):311-20. 
Lee X, Yang Z, Shao Z, et al. NGF regulates the expression of axonal LINGO-1 to inhibit 
oligodendrocyte differentiation and myelination. J Neurosci. 2007;27(1):220-5. 
Llorens F, Gil V, Iraola S, et al. Developmental analysis of Lingo-1/Lern1 protein expression in 
the mouse brain: interaction of its intracellular domain with Myt1l. Developmental neurobiology. 
2008;68(4):521-41. 
Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 
2013 revisions. Neurology. 2014;83(3):278-86. 

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Lv J, Xu RX, Jiang XD, et al. Passive immunization with LINGO-1 polyclonal antiserum 
afforded neuroprotection and promoted functional recovery in a rat model of spinal cord injury. 
Neuroimmunomodulation. 2010;17(4):270-8. 
Mi S, Hu B, Hahm K, et al. LINGO-1 antagonist promotes spinal cord remyelination and axonal 
integrity in MOG-induced experimental autoimmune encephalomyelitis. Nat Med. 
2007;13(10):1228-33. 
Mi S, Lee X, Shao Z, et al. LINGO-1 is a component of the Nogo-66 receptor/p75 signaling 
complex. Nat Neurosci. 2004;7(3):221-8. 
Mi S, Miller RH, Lee X, et al. LINGO-1 negatively regulates myelination by oligodendrocytes. 
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Mi S, Miller RH, Tang W, et al. Promotion of central nervous system remyelination by induced 
differentiation of oligodendrocyte precursor cells. Ann Neurol. 2009;65(3):304-15. 
Mi S, Pepinsky RB, Cadavid D. Blocking LINGO-1 as a therapy to promote CNS repair: from 
concept to the clinic. CNS Drugs. 2013;27(7):493-503. 
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chick embryo. Gene Expr Patterns. 2005;6(1):57-62. 
Park S, Hong YW. Transcriptional regulation of artemin is related to neurite outgrowth and actin 
polymerization in mature DRG neurons. Neuroscience letters. 2006;404(1-2):61-6. 
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. 
Rosati G. The prevalence of multiple sclerosis in the world: an update. Neurol Sci. 
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Runmarker B, Andersen O. Prognostic factors in a multiple sclerosis incidence cohort with 
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sclerosis: Report by the Panel on the Evaluation of Experimental Trials of Therapy in Multiple 
Sclerosis. Ann NY Acad Sci. 1965;122(1):552-568. 
Shao Z, Browning JL, Lee X, et al. TAJ/TROY, an orphan TNF receptor family member, binds 
Nogo-66 receptor 1 and regulates axonal regeneration. Neuron. 2005;45(3):353-9. 
Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a 
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Yamashita T, Fujitani M, Yamagishi S, et al. Multiple signals regulate axon regeneration through 
the Nogo receptor complex. Molecular neurobiology. 2005;32(2):105-11. 
Zhao XH, Jin WL, Wu J, et al. Inactivation of Glycogen Synthase Kinase-3beta and Up-
regulation of LINGO-1 are Involved in LINGO-1 Antagonist Regulated Survival of Cerebellar 
Granular Neurons. Cell Mol Neurobiol. 2008;28:727-735. 
 

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21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL 
I have read the foregoing protocol, “A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study With Optional Open-Label Extension in Subjects With Relapsing 
Multiple Sclerosis to Evaluate the Efficacy and Safety of BIIB033 as an Add-On Therapy to 
Anti-Inflammatory Disease-Modifying Therapies,” 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 SignatureDate 
 
 
____________________________________________________ 
Investigator’s Name (Print) 
 
 
 
____________________________________________________ 
Study Site (Print) 
 

CONFIDENTIAL
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Biogen MA Inc.
1
Biogen MA Inc.
225 Binney Street
Cambridge, MA 02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead Berkshire
SL6 4AY
United Kingdom
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 215MS202
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study With Optional 
Open-Label Extension in Subjects With Relapsing Multiple Sclerosis to Evaluate the Efficacy 
and Safety of BIIB033 as an Add-On Therapy to Anti-Inflammatory Disease-Modifying 
Therapies
Version 3
Date: 13 February 2019
EUDRA CT Number: 2017-001224-22
Version 3 of the protocol has been prepared for this amendment, which supersedes Version 2

Protocol 215MS202, Version 3
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4
Section 7.2.2, Treatment Period
Part 1
Study treatment with BIIB033 or placebo will be initiated on Day 1 after all baseline assessments 
are completed.
The Treatment Period will consist of 19 study visits beginning with Day 1/Baseline and then 
every 4 weeks at Weeks 4 through Week 72 with a visit window of ±5 days (see Section 5).
Subjects who do not enroll in Part 2 will return to the study site for a post-treatment EOS Visit 
at Week 84, 12 weeks±10 days after the last dose of BIIB033 or placebo. 
Part 2
Study treatment with BIIB033 will be initiated on Day 1 after all Part 2/Day 1 assessments 
are completed.
The Treatment Period will consist of 25 study visits beginning with Day 1 and then every 
4 weeks at Weeks 4 through Week 96 with a visit window of ±5 days (see Table 3 and Table 
4).
⋮
Section 7.2.4, Follow-Up (new section)
Part 1
Subjects who enroll in Part 1 but not Part 2 will return to the study site for an End of 
Part 1 Evaluation approximately 12 weeks after the last dose of study treatment 
(Part 1/Week 72 Visit). Subjects who enroll in Part 2 do not need to have the Part 1 
12-week postdose follow-up (EOS) Visit.
Part 2
Subjects will return to the study site for a post-treatment EOS Visit at Week 108, 
12 weeks±10 days after the last dose of BIIB033. 
Section 7.3, Responsibilities of Study Site Personnel 
For each subject in Part 1 and Part 2, the Principal Investigator of the site will designate the 
following investigational site personnel:
⋮
The examining technician (or the examining neurologist) will be responsible for the following:

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
Section 8.1, Inclusion Criteria – Part 1

Section 8.2, Exclusion Criteria – Part 1

Section 8.3, Inclusion Criteria – Part 2 (new section)

Section 8.4, Exclusion Criteria – Part 2 (new section)

Section 9.1, Screening and Enrollment

Section 9.2, Randomization

Section 9.3, Blinding Procedures

Section 10.1, Discontinuation of Study Treatment

Section 10.3, Withdrawal of Subjects From Study

Section 11.1.1, BIIB033 and Placebo

Section 11.5.1.1.1 Background Anti-Inflammatory DMTs for Use with Study 
Treatment

Section 11.5.1.1.2, Other Allowed Concomitant Therapy

Section 13.1, Clinical Efficacy Assessments




Section 16.2, Efficacy


Section 16.4.1, Safety Analysis Population

Section 16.5, Immunogenicity Data

Section 16.6, Interim Analyses

Section 16.7, Sample Size Considerations

Section 17.3, Subject Information and Consent

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

Section 19.2.1, Independent Data Monitoring Committee (Part 1 Only)

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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL
Changes to the protocol are presented chronologically. New text is shown in bold type; deleted 
text is shown with a strikethrough.
Section 1, Synopsis
The Synopsis was revised to reflect changes made throughout the protocol.
Section 5.2, Part 1 - Schedule of Activities
Change: In footnote 19 to Table 1, the interval between natalizumab infusion and BIIB033 or 
placebo infusion was changed from a minimum of 2 hours to a minimum of 1 hour if given on 
the same day.
Now reads:
19For subjects on natalizumab (Tysabri), natalizumab infusions and study treatment infusions 
may be on the same day; however, natalizumab should be administered prior to study treatment 
(BIIB033 or placebo) if given on that same day, with a minimum 2 1-hour interval between 
infusions. If any infusion reaction occurs with natalizumab, the infusion of BIIB033 should not 
be administered on that same day.
Rationale: This change was made for consistency with the established 1-hour observation period 
performed after natalizumab infusion, as described in the United States Prescribing Information
and European Union Summary of Product Characteristics.
This change also affects Section 5.2, Part 1 – Schedule of Activities, Table 2, footnote 19; and 
Section 11.5.1.1.1, Background Anti-Inflammatory DMTs for Use with Study Treatment.
Section 11.5.1.1.2, Other Allowed Concomitant Therapy
Change: Medical marijuana was added as an allowed treatment of MS symptoms.
Now reads:

Medications used to treat MS symptoms, such as spasticity, bladder impairment, pain, 
or depression (such symptomatic therapy 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). Medical marijuana is allowed for treatment of MS 
symptoms if it is consistent with local MS treatment guidelines and local 
regulations, is maintained on a stable regimen for at least 30 days prior to Part 
2/Day 1, and throughout the study.

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Rationale: Although MS symptomatic medications are allowed, there have been questions from 
sites about whether medical marijuana is allowed as concomitant medication. This change 
clarifies the scope of allowed medical marijuana treatment for this study.
Section 15.5, Contraception Requirements
Change: Barrier methods of contraception with use of a spermicide were added as effective 
contraception for female subjects.
Now reads:

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. 
Rationale: BIIB033 showed no evidence of teratogenicity/fetotoxicity in nonclinical 
reproductive toxicology studies at all doses studied, and thus is unlikely to have a risk of human 
teratogenicity/fetotoxicity. Therefore, barrier methods of contraception with use of a spermicide 
were added to contraceptive requirements for female subjects for consistency with the definition 
of effective contraception and with the BIIB033 Investigator’s Brochure.

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1
Biogen MA Inc.
250 Binney Street
Cambridge, MA  02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead Berkshire
SL6 4AY
United Kingdom
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 215MS202
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study in Subjects With 
Relapsing Multiple Sclerosis to Evaluate the Efficacy and Safety of BIIB033 as an Add-On 
Therapy to Anti-Inflammatory Disease-Modifying Therapies
Version 2
Date:  14 June 2017
EUDRA CT Number:  2017-001224-22
Version 2 of the protocol has been prepared for this amendment, which supersedes Version 1.

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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL
Changes to the protocol are presented chronologically.  New text is shown in bold type; deleted 
text is shown with a strikethrough.
Section 1, Synopsis
The Synopsis was revised to reflect changes made throughout the protocol
Section 3, Sponsor Information
Change:  To update to the safety reporting sections of the protocol for accurate representation of 
medical emergency reporting responsibilities.
Now reads:  
For urgent medical issues in which the 
study’s Medical MonitorDirector should be 
contacted, please refer to the Study Reference Guide for complete contact information.
Rationale:  
The contact details for reporting urgent medical issues were not accurately defined. This change 
was required to define urgent medical issues accurately, and the sites should refer to the Study 
Reference Guide for complete contact information.
Section 8.1, Inclusion Criteria
Change:  To update to the inclusion criterion regarding donation of sperm or eggs.
Now reads:  
All female subjects of childbearing potential and all male subjects must practice effective 
contraception during the study and be willing and able to continue contraception for at least 
24 weeks after their last dose of study treatment (BIIB033 or placebo).  In addition, subjects 
should not donate sperm or eggs during the study and for at least 90 days 24 weeks after their 
last dose of study treatment.  For further details of contraceptive requirements for this study, 
please refer to Section 15.5.
Rationale:  
The inclusion criterion regarding donation of sperm or eggs was updated to at least 24 weeks to 
align with the requirement for effective contraception (i.e., 24 weeks after last dose of study 
treatment [BIIB033 or placebo]).

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This change also affects Section 15.5, Contraception Requirements.