Clinical trial NCT03222973
Conditions: Multiple Sclerosis
Keywords: Remyelination Re-myelination DMT LINGO-1 Anti-LINGO-1 Opicinumab
Sponsor: Biogen
Start date: 2017-11-15; Completion date: 2021-02-12
Enrollment: 263 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of Part 1 of this study is to evaluate the effects of BIIB033 versus placebo on disability improvement over 72 weeks. The primary objective of Part 2 of this study is to evaluate the long-term safety profile of BIIB033 as an add-on therapy in participants with MS.

The secondary objective of Part 1 is to evaluate the effects of BIIB033 versus placebo on additional measures of disability improvement. 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 participants with MS.

Detailed description:

Arms: arm 1: Participants with relapsing multiple sclerosis (RMS) will receive BIIB033 750 milligram (mg) intravenously (IV) as an add-on therapy to a background disease-modifying therapy (DMT) once every 4 weeks over 72 weeks in Part 1 and once every 4 weeks over 96 weeks in Part 2. arm 2: Participants with RMS will receive placebo IV as an add-on therapy to a background DMT once every 4 weeks over 72 weeks in Part 1 and BIIB033 once every 4 weeks over 96 weeks in Part 2. The placebo looks like BIIB033 but does not contain the active ingredient that is thought to have an effect on MS disease. The placebo used in this study is sterile normal saline (water with a small amount of sodium chloride \[salt\]).
Interventions: intervention 1: BIIB033 (opicinumab) intervention 2: Placebo
Intervention descriptions: intervention 1: Administered as specified in the treatment arm intervention 2: Administered as specified in the treatment arm

Protocol documents:
Prot_002.pdf: 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
1 
Biogen MA Inc. 
250 Binney Street 
Cambridge, MA 02142 
United States 
PROTOCOL NUMBER: 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 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
3 
TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ....................................................................................................2 
1. 
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 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
4 
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 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
5 
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 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
6 
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 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
7 
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 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
8 
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 
 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
9 
LIST OF FIGURES 
Figure 1: 
Part 1 - Study Schematic .............................................................................................28 
Figure 2: 
Part 2 – Study Schematic ............................................................................................29 
 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
10 
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 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
11 
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). 
 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
12 
 
 
 
 
  


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
13 
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 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
14 
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 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
15 
(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 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
16 
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 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
17 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
18 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
19 
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 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
20 
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 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
22 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
23 
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], 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
24 
(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-


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
25 
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 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
26 
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, 
 
 
 
 
 
 
 
 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
27 
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. 






Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
30 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
31 
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. 
 
 
 
  


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
32 
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.


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
33 
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 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
34 
 
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). 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
35 
 
 
 
 
 
 
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.


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
36 
 
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 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
37 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
38 
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. 
 
  
 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
39 
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 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
40 
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 
 
 
 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
41 
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. 
 
 
 
 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
42 
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. 
  






Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
45 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
46 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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.






Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
49 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
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; 
; 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
51 
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 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
52 
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, 
  


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
53 
 
  
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 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
54 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
55 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
56 
• 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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
57 
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.  


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
58 
  
 
 
 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
59 
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) 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
60 
• 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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
61 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
62 
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 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
63 
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, 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
64 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
65 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
66 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
67 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
68 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
69 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
70 
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.  


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
71 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
72 
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.  


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
73 
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.  


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
74 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
75 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
76 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
77 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
78 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
79 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
80 
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). 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
81 
 
 
 
 
 
 
 
  
 
  
 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
82 
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 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
83 
• 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. 






Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
86 
• 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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
87 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
88 
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 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
89 
(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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
90 
• Biogen is to notify all appropriate regulatory authorities, central ethics committees, 
and Investigators of SAEs, as required by local law, within required time frames. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
91 
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), 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
92 
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. 
 
 
 
 
  


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
93 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
94 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
95 
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.  


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
96 
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 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
97 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
98 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
99 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
100 
18.4. 
Study Funding 
Biogen is the Sponsor of the study and is funding the study. All financial details are provided in 
the separate contracts between the institution, Investigator, and Biogen.  
18.5. 
Publications 
Details are included in the clinical trial agreement for this study. 
 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
101 
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. 
 
 
 
 
 
 
 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
102 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
103 
Biogen will follow all applicable local regulations pertaining to study report signatories. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
104 
20. 
REFERENCES 
Barrette B, Vallieres N, Dube M, et al. Expression profile of receptors for myelin-associated 
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. 
2008;49(3):975-85. 
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 
Natl Acad Sci U S A. 2007;104(36):14430-5. 
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. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
105 
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. 
Nat Neurosci. 2005;8(6):745-51. 
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. 
Noseworthy JH, Lucchinetti C, Rodriguez M, et al. Multiple sclerosis. The New England journal 
of medicine. 2000;343(13):938-52. 
Okafuji T, Tanaka H. Expression pattern of LINGO-1 in the developing nervous system of the 
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. 
2001;22(2):117-39. 
Runmarker B, Andersen O. Prognostic factors in a multiple sclerosis incidence cohort with 
twenty-five years of follow-up. Brain. 1993;116(Pt 1):117-34. 
Schumacher G, Beebe G, Kibler R, et al. Problems of experimental trials of therapy in multiple 
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 
geographically based study. I. Clinical course and disability. Brain. 1989;112(Pt 1):133-146. 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
106 
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. 
 


Protocol 215MS202 
Version 3 
Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory DMTs 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
107 
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
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
1
Biogen MA Inc.
225 Binney Street
Cambridge, MA 02142
United States
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
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
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:






Protocol 215MS202, Version 3
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
7

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


Protocol 215MS202, Version 3
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
8


Section 19.2.1, Independent Data Monitoring Committee (Part 1 Only)


Protocol 215MS202, Version 3
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
9
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.


Protocol 215MS202, Version 3
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
10
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.




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
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.




Protocol 215MS202, Version 2
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
3
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]).


Protocol 215MS202, Version 2
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
4
This change also affects Section 15.5, Contraception Requirements.



SAP_003.pdf: 
Product: BIIB033 
Study: 215MS202
Statistical Analysis Plan 
Version: 2.0
Page 1
STATISTICAL ANALYSIS PLAN 
Version No.: 2.0 
Date: 31 July 2020 
 Author: 
Study 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 
Name of Study Treatment: BIIB033 
Protocol No.: 215MS202/NCT03222973
Study Phase: Phase II 
Confidential Information 
The information contained in this Statistical Analysis Plan (SAP) is confidential and may not be 
reproduced or otherwise disseminated without the approval of Biogen, Inc.   




Product: BIIB033 
Study: 215MS202
Statistical Analysis Plan 
Version: 2.0
 
 
Page 3
 
 
 
VERSION HISTORY 
SAP Version 
Date 
Primary Reasons for 
Amendment 
Draft version 1.0 
03-August-2018 
Draft version. 
Stable version 1.0 
28-September-2018 
Stable version. 
Final version 1.0 
01-September-2019 
Finalized version 1. 
Final version 2.0 
31-July-2020 
Finalized version 2. to use 
new SAP template and 
some amendment to 
planned analyses including 
additional supportive 
endpoints for clinical 
disability measures. 
 
 
 


Product: BIIB033 
Study: 215MS202
Statistical Analysis Plan 
Version: 2.0
 
 
Page 4
 
 
TABLE OF CONTENTS 
 
STATISTICAL ANALYSIS PLAN ............................................................................................................. 1 
APPROVAL ................................................................................................................................................. 2 
VERSION HISTORY ................................................................................................................................... 3 
LIST OF ABBREVIATIONS ....................................................................................................................... 7 
1. 
Introduction ........................................................................................................................................... 9 
2. 
Study Overview .................................................................................................................................... 9 
2.1. 
Study Objectives and Endpoints ............................................................................................... 9 
2.1.1. 
Primary Objective ................................................................................................................. 9 
2.1.2. 
Primary Endpoint .................................................................................................................. 9 
2.1.3. 
Secondary Objective ............................................................................................................. 9 
2.1.4. 
Secondary Endpoints............................................................................................................. 9 
10 
10 
2.2. 
Study Design ........................................................................................................................... 16 
2.3. 
Study Duration for Subjects .................................................................................................... 20 
2.4. 
Sample Size Considerations .................................................................................................... 20 
3. 
Definitions ........................................................................................................................................... 20 
3.1. 
Study Treatment ...................................................................................................................... 20 
3.2. 
Dates and Points of Reference ................................................................................................ 21 
3.3. 
Study Periods .......................................................................................................................... 23 
3.4. 
Key Derived Variables ............................................................................................................ 23 
3.4.1. 
Thresholds for Improvement and Worsening ..................................................................... 23 
3.4.2. 
Definitions of Confirmed Disability Improvement and Confirmed Disability Worsening . 24 
31 
3.5. 
Stratification Factors and Subgroup Variables ....................................................................... 33 
3.5.1. 
Stratification Factors ........................................................................................................... 33 
3.5.2. 
Subgroup Variables ............................................................................................................. 33 
3.6. 
Analysis Population ................................................................................................................ 34 
4. 
List of Planned Study Analyses .......................................................................................................... 35 
4.1. 
Interim Analysis ...................................................................................................................... 35 


Product: BIIB033 
Study: 215MS202
Statistical Analysis Plan 
Version: 2.0
 
 
Page 5
 
 
4.2. 
Primary Analysis ..................................................................................................................... 35 
 36 
5. 
Statistical Methods for Planned Analyses ........................................................................................... 36 
5.1. 
General Principles ................................................................................................................... 36 
5.2. 
Handling of Missing Data ....................................................................................................... 36 
5.2.1. 
T25FW, 9HPT-D, 9HPT-ND, PASAT-3 and SDMT ......................................................... 36 
5.2.2. 
Adverse Event and Concomitant Medication ..................................................................... 37 
5.2.3. 
MS Relapse ......................................................................................................................... 38 
5.3. 
Accounting of Subjects ........................................................................................................... 39 
5.4. 
Demographic and Baseline Characteristics ............................................................................. 39 
5.5. 
Protocol Deviations ................................................................................................................. 40 
5.6. 
Study Treatment Exposure and Concomitant Medications ..................................................... 40 
5.7. 
Efficacy Endpoints .................................................................................................................. 41 
5.7.1. 
General Analysis Methods for Efficacy Endpoints ............................................................. 41 
5.7.2. 
Primary Efficacy Endpoint .................................................................................................. 43 
5.7.3. 
Secondary Efficacy Endpoints and Related Time to Event Endpoints ............................... 45 
 47 
5.8. 
Safety Endpoints ..................................................................................................................... 53 
5.8.1. 
General Analysis Methods for Safety Endpoints ................................................................ 53 
5.8.2. 
Adverse Events ................................................................................................................... 53 
5.8.3. 
MS Relapse ......................................................................................................................... 55 
5.8.4. 
Clinical Laboratory Abnormalities ..................................................................................... 56 
5.8.5. 
Vital Sign Measurements .................................................................................................... 59 
5.8.6. 
Physical Examination .......................................................................................................... 60 
5.8.7. 
12-lead ECG Readings ........................................................................................................ 60 
5.8.8. 
Columbia Suicide Severity Rating Scale (C-SSRS) ........................................................... 60 
5.8.9. 
MS Signs and Symptoms .................................................................................................... 62 
 62 
 62 
 63 
5.10. 
Immunogenicity (Anti-BIIB033 Antibodies) .......................................................................... 63 
5.11. 
Statistical Considerations for Interim Analysis ....................................................................... 63 


Product: BIIB033 
Study: 215MS202
Statistical Analysis Plan 
Version: 2.0
 
 
Page 6
 
 
5.11.1. 
Futility Criteria .................................................................................................................... 63 
5.11.2. 
Interim Analysis .................................................................................................................. 64 
5.11.3. 
Regular Safety Analysis by DMC ....................................................................................... 64 
64 
6. 
Changes from Protocol-Specified Analyses........................................................................................ 64 
7. 
Summary of Changes from the Previous Version of the SAP ............................................................ 65 
8. 
References ........................................................................................................................................... 66 
APPENDICES ............................................................................................................................................ 68 
Appendix I Visit Window Mapping........................................................................................................ 68 
 72 
 74 
Appendix IV Study Activities ................................................................................................................. 80 
 
 
 






Product: BIIB033 
Study: 215MS202
Statistical Analysis Plan 
Version: 2.0
 
 
Page 9
 
 
1. Introduction 
The purpose of this SAP is to delineate the statistical analyses as outlined in the 215MS202 
Protocol V3, with details focusing on the study primary analysis, i.e., the Study Part 1 analysis.  
 
2. Study Overview 
2.1. Study Objectives and Endpoints 
2.1.1. Primary Objective 
The primary objective of the study is to evaluate the effects of BIIB033 versus placebo on disability 
improvement over 72 weeks. 
2.1.2. Primary Endpoint 
The primary endpoint is the Overall Response Score (ORS), assessed over 72 weeks of the study.  
The ORS is a multicomponent score based on 4 components: EDSS, T25FW, 9HPT-D, and 9HPT-
ND. It assesses overall changes in disability over time.  
At each visit, each assessment is given a score compared to baseline. Meeting or exceeding the 
threshold for improvement in an assessment results in a +1 score for that assessment; meeting or 
exceeding the threshold for worsening in an assessment results in a -1 score for that assessment; 
no change or subthreshold changes in an assessment results in a score of 0 for that assessment. The 
scores of individual assessments are summed up to provide a total ORS that ranges from +4 to -4 
for each visit. 
2.1.3. Secondary Objective 
The secondary objective of this study is to evaluate the effects of BIIB033 versus placebo on 
additional measures of disability improvement. 
2.1.4. Secondary Endpoints 
The secondary endpoints are as follows: 
 Proportion of subjects with 12-week confirmed improvement (CDI) in at least 1 of the 
following assessments: EDSS, T25FW, 9HPT-D and 9HPT-ND. 
 Proportion of subjects with 12-week CDI in at least 1 of the following assessments: EDSS, 
T25FW, 9HPT-D, 9HPT-ND and PASAT-3.  
 Proportion of subjects with 12-week CDI in at least 1 of the following assessments: EDSS, 
T25FW, 9HPT-D, 9HPT-ND, and without confirmed disability worsening in any of the 4 
assessments during the 72 weeks of the study. 
 Proportion of subjects with 12-week CDI in at least 1 of the following assessments: EDSS, 
T25FW, 9HPT-D, 9HPT-ND and SDMT. 
 Proportion of subjects with 12-week CDI in at least 1 of the following assessments: EDSS, 
T25FW, 9HPT-D and 9HPT-ND (20% thresholds for T25FW and 9HPT). 


Product: BIIB033 
Study: 215MS202
Statistical Analysis Plan 
Version: 2.0
 
 
Page 10
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


Product: BIIB033 
Study: 215MS202
Statistical Analysis Plan 
Version: 2.0
 
 
Page 11
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Product: BIIB033 
Study: 215MS202
Statistical Analysis Plan 
Version: 2.0
 
 
Page 12
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Product: BIIB033 
Study: 215MS202
Statistical Analysis Plan 
Version: 2.0
 
 
Page 13
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Product: BIIB033 
Study: 215MS202
Statistical Analysis Plan 
Version: 2.0
 
 
Page 14
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


Product: BIIB033 
Study: 215MS202
Statistical Analysis Plan 
Version: 2.0
 
 
Page 15
 
 
o 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Product: BIIB033 
Study: 215MS202
Statistical Analysis Plan 
Version: 2.0
 
 
Page 16
 
 
o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.2. Study Design 
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 


Product: BIIB033 
Study: 215MS202
Statistical Analysis Plan 
Version: 2.0
 
 
Page 17
 
 
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 and will continue 
taking their DMT throughout the study. Based on the clinical judgment of the treating neurologist, 
subjects can switch to another marketed DMT during the study or may discontinue the DMT 
altogether. 
Each subject in Part 1 will have a total of 21 scheduled study visits:  
 Screening (pre-treatment)  
 Treatment Period: 1 visit every 4 weeks between Day 1/Baseline 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, 
. 
 
 
  
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. 






Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 20
 
 
2.3. 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 enrolled in Part 2 do not need to have the 12-week 
follow-up (EOS) after the last dose of study treatment in Part 1; 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. 
For details about Screening, Treatment Period, unscheduled visits(s) and treatment for relapse and 
Follow-up, please see protocol Section 7.2. 
2.4. Sample Size Considerations   
In Part 1, a sample size of 120 subjects per treatment group will have approximately 80% power 
to detect a treatment effect of 0.354 in ORS over 72 weeks comparing to placebo. 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 treatment effect of 0.354 is 
effect in the target 
population of Study 215MS201. 
 
 
3. Definitions 
3.1. Study Treatment 
Study treatment in this SAP, unless otherwise specified, refers to the blinded treatment in Part 1 
of either BIIB033 750 mg or placebo, administered once every 4 weeks (Q4W) by intravenous 
(IV) infusion for the planned a total of 19 doses over 72 weeks, added on to anti-inflammatory 
DMT. Throughout this SAP, study treatment and study drug are equivalent and used 
interchangeably. 
To facilitate illustration in the analysis plan, treatment groups are listed below with short names: 
Table 1: 
Treatment Groups 
Part 1 Analyses (Interim Analysis, Primary Analysis):  
Study Treatment
Short name
 Blinded BIIB033 750 mg IV infusion Q4W
BIIB033
Blinded Placebo IV infusion Q4W
Placebo
 
 




Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 22
 
 
COVID-19 phase refers to the time period during which conduct of this study is impacted by 
COVID-19 infection or COVID-19 pandemic measures. The start date of the COVID-19 phase 
for this study is March 15, 2020. 
COVID-19 Pandemic Measures 
Refer to any action or challenges arising due to COVID-19 that may impact study conduct, 
including quarantines, site closures, travel limitation, interruptions to the supply chain for the 
investigational product, or other considerations if site personnel become infected with COVID-19. 
Study Day 
o For a date on or after Study Day 1 
Study Day = (Date of Interest)  (Study Day 1) + 1 
o For a date before Study Day 1 
Study Day = (Date of Interest)  (Study Day 1) 
Visit Window Mapping 
For data that are summarized by visit and longitudinal analysis, assessment from all scheduled 
visits including ET visits and EOS visits, and all unscheduled visits in Part 1 will be mapped to an 
appropriate analysis visit using a windowing scheme. The analysis visit windows are defined in 
Table 5 for different endpoints. To define the analysis visit window, the target visit day is 
calculated as (week number×7+1). The lower bound of the visit window is calculated as (target 
visit day + (target visit day of the previous visit))/2+1, except for the first post-baseline visit 
window whose lower bound is set as Day 2; the upper bound of the visit window is calculated as 
(target visit day + (target visit day of the next visit))/2; the upper bound of the last visit in Part 1 is 
the date of the EOS/ET visit in Part 1 for subjects who are not enrolled in Part 2, or (Part 2 Day 1) 
 1 for those who are enrolled in Part 2 of the study.  
If more than one assessment is within the same analysis visit window other than ET or EOS visits, 
the assessment closest to the target visit day will be used for the analysis.  If more than one 
assessment falls in the same distance from the target visit day other than ET or EOS visits, the last 
one will be used for the analysis. If more than one assessment is on the same day other than ET or 
EOS visits, the average value for the quantitative parameters and the worst value for the qualitative 
parameters will be used for the analysis. 
If the ET visit is mapped to the same analysis visit as a prior visit (either scheduled or unscheduled 
visit), then the ET visit will be remapped to the next analysis visit. If EOS visit is mapped to an 
analysis visit and a prior visit, e.g. ET visit, is mapped to the same analysis visit, then EOS visit 
will be remapped to the next analysis visit. The latest analysis visit for the ET visit can be up to 
Week 72 and for the EOS visit can be up to Week 84. 
As Part 2 Screening visit should be performed as part of Part 1 Week 72 visit but a separate Part 
2 Screening visit is allowed, for subjects who have screening for Part 2 but do not rollover to 
Part 2, they may not have a separate Part 2 Screening visit or may have Part 2 Screening visit as 
a separate visit after Week 72 visit; for subjects who have screening for Part 2 and rollover to 
Part 2, they will have Part 2 Day 1 visit, in addition, they may not have a separate Part 2 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 23
 
 
Screening visit or may have Part 2 Screening visit as a separate visit after Week 72 visit. We do 
not map Part 2 screening visit and Part 2 Day 1 visit.  
3.3. Study Periods 
Study Baseline Period and Baseline Data 
The study baseline period is defined as the period from screening visit to the day prior to first 
administration of study treatment.  
Unless stated otherwise, study baseline data are defined as the data collected prior to the first dose, 
which is usually at the Day 1/Baseline visit. If there is more than one value on or before the first 
dose, the non-missing value closest to and prior to the first dose will be used as the baseline value. 
Actual Treatment Period in Study Part 1  
Actual treatment period in Part 1 of the study is defined as the period from the first infusion of 
study treatment to 28 days after the last infusion of study treatment in Part 1. 
Treatment Emergent 
An adverse event in Part 1 is defined as the event that has onset date/time prior to Part 2 Day 1 
infusion day. If a subject is not enrolled in Part 2 or is enrolled in Part 2 but never receives 
infusion of study treatment in Part 2, all adverse events will be considered as occurring in Part 1. 
An adverse event is regarded as treatment emergent in Part 1 of the study if the event has onset 
date/time on or after the first dose date/time of study treatment, or was reported prior to the first 
dose and subsequently worsens in severity after first dose date. Additional criteria to determine 
treatment emergent are described in Section 5.8.2. Unless otherwise specified, the phrase 
 in this SAP refers to 
 
3.4. Key Derived Variables 
3.4.1. Thresholds for Improvement and Worsening 
The thresholds are defined as following: 
 Thresholds for EDSS 
o Improvement is defined as a  1.0-point decrease in EDSS from a baseline score of 
6.0.  
o Worsening is defined as a 1.0-point increase from a baseline score of 5.5 or a 
0.5-point increase from a baseline score equal to 6.0 
 15% Thresholds for T25FW, 9HPT-D and 9HPT-ND 
o Improvement is defined as 15% decrease from baseline in time (seconds)  
o Worsening is defined as 15% increase from baseline in time (seconds) 
Throughout this SAP document, unless otherwise specified, 15% is used as the threshold 
for T25FW, 9HPT-D, and 9HPT-ND. 
 20% Thresholds for T25FW, 9HPT-D and 9HPT-ND  


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 24
 
 
o Improvement is defined as 20% decrease from baseline in time (seconds)  
o Worsening is defined as 20% increase from baseline in time (seconds) 
20% thresholds for T25FW and 9HPT
and the SAP refers to 
the case that 20% being used as the threshold for T25FW, 9HPT-D, and 9HPT-ND. 
 Threshold for PASAT-3  
o Improvement is defined as 15% decrease from baseline in score 
 Threshold for SDMT 
o Improvement is defined as a 4-point increase from baseline 
 
 
 
 
3.4.2. Definitions of Confirmed Disability Improvement and Confirmed Disability 
Worsening 
3.4.2.1. Confirmed Disability Improvement (CDI) 
CDI is assessed for each of the efficacy components (EDSS, T25FW, 9HPT-D, 9HPT-ND, 
PASAT-3, SDMT, 
) in the first place using the improvement threshold for each of the 
components defined in Section 3.4.1; then CDI in a multicomponent endpoint (MCE) is 
determined based on the CDI results of the components that constitute the MCE. Improvement in 
T25FW, 9HPT-D, 9HPT-ND and PASAT-3 will be derived after the imputation rules described in 
Section 5.2.1 are applied.  
60-day Relapse Window 
A 60-day relapse window is employed for some conditions in the CDI and CDW derivations. A 
subject is regarded as having a relapse for at least 60 days after the onset of a protocol-defined 
relapse. At each (unscheduled) relapse visit, the investigator will evaluate whether the subject 
experiences a protocol-defined MS relapse. A visit is considered as within the 60-day relapse 
window if (date of the visit  onset date of the protocol-defined MS relapse) <60 days. 
Potential Improvement and Tentative Improvement  
For each component, a potential improvement is observed at a given visit if the improvement 
threshold is met at this visit but is not met at the previous visit, and no CDI has been identified up 
to this visit since study Day 1.  
Assessment at any unscheduled visit will not be used for either potential improvement or 
improvement confirmation.  
To be eligible for evaluation of CDI, potential improvement must start in the actual treatment 
period defined in Section 3.3. Visits outside of the actual treatment period can only be used to 
confirm potential improvements that start within the actual treatment period. If a potential 
improvement is observed in the actual treatment period but there is no later assessment in the 
remaining study period, then the improvement cannot be confirmed, and the potential 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 25
 
 
improvement in this case is termed as tentative improvement. Alternative approaches considering 
tentative improvement may be used as supportive analyses (Section 5.7.3.2). 
Confirmed disability improvement will be assessed as follows. 
12-week CDI 
The 12-week confirmation visit in default refers to the visit that should occur, per schedule of 
events (Appendix IV), 12 weeks after the visit with a potential improvement observed. If the 
default confirmation visit is missing, the next scheduled visit that actually occurs will be used as 
the 12-week confirmation visit. 
For each component, a 12-week CDI is identified if the improvement threshold for the same 
component is met again at the 12-week confirmation visit that is 74 days after the visit with the 
potential improvement. The 74 days is the minimum distance between 2 consecutive scheduled 
visits with a target distance of 84 days and a protocol allowed ±5-day visit window. In the event 
that the improvement at 12-week confirmation visit is <74 days apart from the potential 
improvement, or that the result at this visit fails to meet the improvement threshold but is assessed 
within a 60-day relapse window, the next scheduled visit subsequent to this 12-week confirmation 
visit can confirm the potential improvement if having an improvement observed. 
The ET and EOS visits are treated as scheduled visits and the corresponding assessments can be 
used to confirm the potential improvement observed at the latest scheduled visit prior to ET or 
EOS regardless of the 74-day requirement. For example, if a subject has a potential improvement 
followed by an ET visit and an EOS visit, both with non-missing results, then the result at the ET 
visit will be used to confirm the potential improvement regardless of the number of days between 
the potential improvement and the ET visit.  
24-week CDI 
The 24-week confirmation visit in default refers to the visit that should occur, per schedule of 
events (Appendix IV), 24 weeks after the visit with a potential improvement observed. If the 
default confirmation visit is missing, the next scheduled visit that actually occurs will be used as 
the 24-week confirmation visit. 
For each component, a 24-week CDI is identified if the improvement threshold for the same 
component is met at the 24-week confirmation visit, and is also met at any scheduled visit between 
the potential improvement and 24-week confirmation visit unless the scheduled visit in between is 
within a 60-day relapse window.  
The improvement at 24-week confirmation visit is required to be 
potential improvement to be confirmed. The 158 days is the minimum distance between 2 
scheduled visits with a target distance of 24 weeks (168 days) and a protocol allowed ±5-day visit 
window. In the event that the improvement at 24-week confirmation visit is <158 days apart from 
the potential improvement, or that the result at this visit fails to meet the improvement threshold 
but is assessed within a 60-day relapse window, the next scheduled visit subsequent to this 24-
week confirmation visit can confirm the potential improvement if having an improvement 
observed. 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 26
 
 
The ET and EOS visits are treated as scheduled visits and the corresponding assessments can be 
used to confirm the potential improvement observed at the latest 2 scheduled visits (assessments 
are taken every 12 weeks per protocol schedule) prior to ET or EOS regardless of the 158-day 
requirement. For example, if a subject has a potential improvement followed by an ET visit and 
an EOS visit, both with non-missing results, then the result at the ET visit will be used to confirm 
the potential improvement regardless of the number of days between the potential improvement 
and the ET visit. In this case, CDI is identified if improvement threshold is met at the ET visit, as 
well as at the scheduled visit, if there is any, between the potential improvement and the ET visit. 
CDI in an Individual Component  
For a disability assessment (e.g., EDSS, T25FW) that may be used to constitute an MCE together 
with other disability assessments, if a subject has a potential improvement that is later confirmed 
following the criteria aforementioned in this section, then the subject is considered as with CDI in 
this component, and the potential improvement that gets later confirmed is assigned as the actual 
CDI event of the component. 
Time to CDI in an Individual Component 
For a given individual component, the time to CDI in this component is defined as the number of 
days from the study Day 1 to the date of the CDI event of this component as defined above. For 
subjects without CDI in this component, the time to CDI in this component is censored at the 
date of the 
latest scheduled visit in the actual treatment period at which the result is 
non-missing, including the case that the subject is unable to complete this component assessment 
due to MS-related physical limitations. If a subject has missing value of the individual 
component at the Day 1/Baseline visit, for example, the subject has no assessment at Day 1, or 
the result of the assessment at Day 1 is not available due to any other reason, then the censoring 
date will be set as Day 1. Assessment at any unscheduled visit will not be used to determine the 
censoring time. 
CDI in a Multicomponent Endpoint (MCE) 
If a subject is with CDI in one or more components that constitute an MCE, then the subject is 
considered as with CDI in this MCE, and the first CDI event of any component is assigned as the 
actual CDI event of the MCE. 
Time to CDI in an MCE 
The time to CDI in an MCE is defined as the number of days from the study Day 1 to the date of 
the first CDI event of the MCE as defined above. For subjects without CDI in this MCE, the time 
to CDI in this MCE is censored at the latest date among the 
censoring dates for each 
component constituting this MCE. 
3.4.2.2. Confirmed Disability Worsening (CDW) 
CDW is assessed for each of the efficacy components (EDSS, T25FW, 9HPT-D and 9HPT-ND) 
in the first place using the threshold for each of the components defined in Section 3.4.1; then 
CDW in an MCE is determined based on the CDW results of the components that constitute this 
MCE. Worsening in T25FW, 9HPT-D and 9HPT-ND will be derived after the imputation rules 
described in Section 5.2.1 are applied.  


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 27
 
 
In any case, disability worsening cannot be confirmed if there is a recent relapse and the visit 
used for confirmation is within a 60-day relapse window as defined in Section 3.4.2.1. 
Potential Worsening and Tentative Worsening  
For each component, a potential worsening is observed at a given visit if worsening threshold is 
met at this visit but is not met at the previous visit, and no CDW has been identified up to this 
visit since study Day 1.  
An unscheduled visit associated with a protocol-defined MS relapse can be used to identify 
potential worsening, but cannot be used to confirm a worsening itself. Instead, if following a 
potential worsening the worsening threshold is met again at this unscheduled relapse visit, then 
the next visit subsequent to this unscheduled relapse visit will be used for worsening 
confirmation. 
To be eligible for evaluation of CDW, potential worsening must start in the actual treatment 
period defined in Section 3.3. Visits outside the actual treatment period can only be used to 
confirm potential worsening events that start within the actual treatment period. If a potential 
worsening is observed in the actual treatment period but there is no later assessment in the 
remaining study period, then the worsening cannot be confirmed, and the potential improvement 
in this case is termed as tentative worsening.  
Confirmed disability worsening will be assessed as follows. 
12-week CDW 
The 12-week confirmation visit in default refers to the visit that should occur, per schedule of 
events (Appendix IV), 12 weeks after the visit with a potential worsening observed. If the default 
confirmation visit is missing, the next scheduled visit or unscheduled relapse visit that actually 
occurs will be used as the 12-week confirmation visit.  
For each component, a 12-week CDW is identified if the worsening threshold for the same 
component is met again at the 12-week confirmation visit, which is 74 days after the visit with 
the potential worsening and not within a 60-day relapse window. In the event that the worsening 
at the 12-week confirmation visit is <74 days apart from the potential worsening or within a 60-
day relapse window, the next visit subsequent to this 12-week confirmation visit can confirm the 
potential worsening if having a worsening observed and not within a 60-day relapse window. 
The ET and EOS visits are treated as scheduled visits and the corresponding assessment can be 
used to confirm a previous potential worsening if there is no scheduled visit between the 
potential worsening and the ET or EOS regardless of the 74-day requirement. For example, if a 
subject has a potential worsening followed by an ET visit and an EOS visit, both with non-
missing results and not within a 60-day relapse window, then the result at ET visit will be used to 
confirm the potential worsening regardless of the number of days between the potential 
worsening and the ET visit.  
24-week CDW 
The 24-week confirmation visit in default refers to the visit that should occur, per schedule of 
events (Appendix IV), 24 weeks after the visit with a potential worsening observed. If the default 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 28
 
 
confirmation visit is missing, the next scheduled visit or unscheduled relapse visit that actually 
occurs will be used as the 24-week confirmation visit. 
For each component, a 24-week CDW is identified if the worsening threshold for the same 
component is met at the 24-week confirmation visit, and is also met at any scheduled visit 
between the potential worsening and the 24-week confirmation visit.  
The worsening at the 24-week confirmation visit is required to be 
 days apart from the 
potential worsening to be confirmed. In the event that the worsening at 24-week confirmation 
visit is <158 days apart from the potential worsening or within a 60-day relapse window, the next 
visit subsequent to this 24-week confirmation visit can confirm the potential worsening if having 
a worsening observed and not within a 60-day relapse window. 
The ET and EOS visits are treated as scheduled visits and the corresponding assessment can be 
used to confirm the potential worsening observed at the latest 2 scheduled visits (assessments are 
taken every 12 weeks per protocol schedule) prior to ET or EOS regardless of the 158-day 
requirement. For example, if a subject has a potential worsening followed by an ET visit and an 
EOS visit, both with non-missing results, then the result at the ET visit will be used to confirm 
the potential worsening regardless of the number of days between the potential worsening and 
the ET visit. In this case, CDW is identified if worsening threshold is met at the ET visit, as well 
as at any other visit, if there is any, between the potential worsening and the ET visit. 
CDW in an Individual Component  
For a disability assessment (e.g., EDSS, T25FW) that may be used to constitute an MCE together 
with other disability assessments, if a subject has a potential worsening that is later confirmed 
following the criteria aforementioned in this section, then the subject is considered as with CDW 
in this component, and the potential worsening that gets later confirmed is assigned as the actual 
CDW event of the component. 
Time to CDW in an Individual Component 
For a given individual component, the time to CDW in this component is defined as the number 
of days from the study Day 1 to the date of the CDW event of this component as defined above. 
For subjects without CDW in this component, the time to CDW in this component is censored at 
the date of the subjec
visit (considering all scheduled visits and unscheduled visit where 
a protocol-defined MS relapse is asserted) in the actual treatment period at which the result is 
non-missing, including the case that the subject is unable to complete this component assessment 
due to MS-related physical limitations. If a subject has missing value of the individual 
component at the Day 1/Baseline visit, for example, the subject has no assessment at Day 1, or 
the result of the assessment at Day 1 is not available due to any other reason, then the censoring 
date will be set as Day 1.  
CDW in an MCE 
If a subject is with CDW in one or more components that constitute an MCE, then the subject is 
considered as with CDW in this MCE, and the first CDW event of any component is assigned as 
the actual CDW event of the MCE. 
Time to CDW in an MCE 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 29
 
 
The time to CDW in an MCE is defined as the number of days from the study Day 1 to the date 
of the first CDW event of this MCE as defined above. For subjects without CDW in this MCE, 
the time to CDW in this MCE is censored at the latest date among the subjec
for each component constituting the MCE. 
3.4.2.3. CDI Without Confirmed Disability Worsening 
Unless otherwise specified, this refers to the 12-week CDI in at least 1 of the following 4 
assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND, and without confirmed disability worsening 
in any of these 4 assessments during the 72 weeks of the study.  
Essentially, this CDI without confirmed disability worsening defines a subset of subjects with 
CDI, with the condition further selecting subjects who are without CDW during the 72 weeks of 
the study. For the subset of subjects identified as having CDI without confirmed disability 
worsening, the assignment of the event and the time to event for this endpoint are the same as 
that of the assignment of CDI event and time to CDI as defined in Section 3.4.2.1. The rest of 
subjects are considered as not with this CDI without confirmed disability worsening. For such 
subjects the censoring date is the date of the subjec
scheduled visit in the actual 
treatment period at which the result is non-missing, including the case that the subject is unable 
to complete this component assessment due to MS-related physical limitations. 
3.4.2.4. CDW Without Confirmed Disability Improvement 
Unless otherwise specified, this refers to the 12-week CDW in at least 1 of the following 
assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND, and without confirmed disability 
improvement in any of the 4 assessments during the 72 weeks of the study.  
Essentially, this CDW without confirmed disability improvement defines a subset of subjects 
with CDW, with the condition further selecting subjects who are without CDI during the 72 
weeks of the study. For the subset of subjects identified as having CDW without confirmed 
disability improvement, the assignment of the event and the time to event for this endpoint are 
the same as that of the assignment of CDW event and time to CDW as defined in Section 3.4.2.2. 
The rest of subjects are considered as not with this CDW without confirmed disability 
improvement. For such subjects the censoring date is the date of the subjec
visit 
(considering all scheduled visits and unscheduled visit where a protocol-defined MS relapse is 
asserted) in the actual treatment period at which the result is non-missing, including the case that 
the subject is unable to complete this component assessment due to MS-related physical 
limitations. 
3.4.2.5. CDI in Two or More Components 
A subject is considered with CDI in two or more components if the subject has 12-week CDI in 
two or more of the assessments during the 72 weeks of study: EDSS, T25FW and 9HPT either 
hand. The CDI in 9HPT is only counted as one assessment here. Specifically, subjects with CDI 
in two or more components include 
 Subjects with 12-week CDI in EDSS and 12-week CDI in T25FW 
 Subjects with 12-week CDI in EDSS and 12-week CDI in 9HPT either hand (12-
week CDI in 9HPT-D or 12-week CDI in 9HPT-ND) 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 30
 
 
 Subjects with 12-week CDI in T25FW and 12-week CDI in 9HPT either hand (12-
week CDI in 9HPT-D or 12-week CDI in 9HPT-ND) 
 Subjects with 12-week CDI in EDSS, 12-week CDI in T25FW and 12-week CDI in 
9HPT either hand (12-week CDI in 9HPT-D or 12-week CDI in 9HPT-ND) 
Again, there are three components considered here: EDSS, T25FW and 9HPT either hand. The 
time to CDI in EDSS or T25FW follows the time to CDI in individual component defined in 
Section 3.4.2.1. For 9HPT either hand, if a subject has CDI in both hands, then the hand with the 
earlier CDI is used to set the time to CDI in 9HPT either hand.  
For subjects with the event of CDI in two or more components, the time to event is calculated as 
the number of days between the first dose date and the second CDI date of the two or more 
individual components that achieve CDI:  
 The date of CDI in EDSS 
 The date of CDI in T25FW 
 The date of CDI in 9HPT (based on the hand with the earlier CDI date if CDI is achieved 
in both hands) 
For example, if a subject has a CDI in both EDSS and T25FW, and thus this subject has a CDI in 
two or more components. Suppose time to CDI in EDSS is 84 days, and the time to CDI in 
T25FW is 112 days, then the time to confirmed improvement is 112 days.  
For a subject who does not have CDI in two or more components, the time to this endpoint is 
censored at the latest date among the subjec
(EDSS, 
T25FW, 9HPT-D and 9HPT-ND). Here the date of CDI and censoring date of CDI in individual 
component all follow Section 3.4.2.1. 
3.4.2.6. CDI Excluding Data after DMT Switch 
CDI excluding data after DMT switch will be used for some supportive analyses, which will not 
consider data collected after DMT switch date for subjects who switch DMT during the actual 
treatment period. A subject is considered as having this event defined here if the subject achieves 
CDI and does not switch DMT or if he/she switches DMT during actual treatment period but 
achieves CDI before the DMT switch date. 
If a subject has CDI excluding data after DMT switch, the event date is the date of the CDI, 
otherwise the subject will be censored at the CDI censoring date, or the date of the 
latest scheduled visit with non-missing result (including the case that the subject is unable to 
complete this component assessment due to MS-related physical limitations) before the DMT 
switch date, whichever comes earlier. The CDI event date and censoring date are as defined in 
Section 3.4.2.1, and DMT switch date is as defined in Section 3.2. 
3.4.2.7. Tentative Improvement in Two or More Components at Week 72 
If a subject has no CDI and has tentative improvement in two or more components at Week 72, 
but the Week 84/EOS result is missing and therefore the tentative improvement cannot be 
confirmed, then the subject is considered to achieve this MCE at Week 72. The time to event for 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 31
 
 
this subject is the number of days from the first dose date to the first time when tentative 
improvement is achieved for a component at the Week 72 visit. 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 32
 
 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 33
 
 
3.5. Stratification Factors and Subgroup Variables 
3.5.1. Stratification Factors 
The randomization stratification factors are listed as follows. 
 MS type:  
o Relapsing-remitting MS (RRMS) 
o Secondary progressive MS (SPMS) 
 Background DMT group:  
o IFN-  (Avonex, Plegridy®, Betaferon®/ Betaseron®, or Rebif®) 
o dimethyl fumarate (DMF; Tecfidera®) 
o natalizumab (Tysabri®) 
Unless otherwise specified, the background DMT refers to the baseline DMT according 
to randomization stratification 
 
  
 
 
 
 
 
 
 
 
3.5.2. Subgroup Variables 
3.5.2.1. Baseline Characteristics Subgroup Variables 
 Age at baseline ( 40 and <40 years) 
 Regions (North America, Eastern Europe, Western Europe and other regions) 
o North America: Canada, United States 
o Eastern Europe: Czech Republic, Hungary, Poland 
o Western Europe and other regions: Belgium, United Kingdom, Germany, France, 
Switzerland, Italy, Netherlands, Spain, Australia, Israel 
 Baseline EDSS ( 3 and <3) 
 Disease duration between onset of the first MS symptoms and randomization ( 6 years 
and <6 years) 
 
 
 
 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 34
 
 
 
 
 
 
 
 
 
 
 
3.5.2.3. DMT Subgroups 
 1-DMT groups: subjects with background DMT as 1) IFN- , 2) Dimethyl fumarate, and 
3) Natalizumab 
 
2-DMT groups: subjects with background DMT as 1) IFN-  or Dimethyl fumarate, 2) 
IFN-  or Natalizumab, and 3) Dimethyl fumarate or Natalizumab  
3.6. Analysis Population 
Intention-to-treat (ITT) population, per-protocol population, 
, safety population, 
immunogenicity population, and interim analysis (IA) cohort are defined as follows: 
 ITT population 
The ITT population is defined as all randomized subjects who received at least 1 dose of 
study treatment. In analyses performed on the ITT population, subjects will be analyzed 
according to their randomized treatment assignment regardless of actual treatment 
received. 
 Per-protocol population 
The per-protocol population is defined as subjects from the ITT population who received 
80% of planned study treatment during the period from the first dose to the ET visit 
date, or the last dose of study treatment in Part 1 for those who did not early terminate, 
did not early terminate due to sites GCP deviation, and did not have major protocol 
deviations that would impact the efficacy assessments. The major protocol deviations that 
will lead to exclusion from the per-protocol population include: 
o 
 
 
 
 
o 
 
 
 
 
 
 
o meeting exclusion criterion #14 (history of suicidal ideation or an episode of 
clinically severe depression as determined by the Investigator within 12 weeks of 
enrollment; subjects receiving ongoing antidepressant therapy will not be 
excluded from the study unless the medication has been increased within 24 
weeks prior to enrollment). 
o unblinding. 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 35
 
 
Subjects will be analyzed according to the actual treatment allocation.   
 
 
 
  
 Safety population 
The safety population is defined as all subjects who received at least 1 dose of study 
treatment. Although treatment assignment error is not expected, if some subjects received 
different study treatment than the randomization allocation, the safety analyses will be 
based on the actual treatment allocation. The actual treatment in Study Part 1 will be 
BIIB033 if the subject received any active dose of BIIB033; otherwise, the actual 
treatment will be placebo. 
 Immunogenicity population 
The immunogenicity population is defined as all subjects in the safety population who 
had at least 1 post-dose sample evaluated for immunogenicity. 
 IA cohort  
The IA Cohort is defined as the first 80% participants dosed in the study who have had 
the opportunity to complete Week 36 assessments in Study Part 1. 
 
4. List of Planned Study Analyses 
4.1. Interim Analysis 
According to the protocol, in Part 1, an interim analysis (IA) 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. This study may be terminated early if the prespecified futility criteria 
are met at the interim analysis. In 2019, the actual IA was performed by the Data Monitoring 
Committee (DMC) for futility assessment once the first 80% participants dosed in the study have 
had the opportunity to complete Week 36 assessments in Study Part 1. According to the 
prespecified criteria, futility was evaluated based on treatment effect of ORS at Week 36, as well 
as the overall trend and totality of data. Following the IA, the study was not stopped for futility 
and continued without modification. The study management team, investigators, and subjects 
remain blinded. 
4.2. Primary Analysis 
The primary analysis (PA) of the study will be conducted at the end of the placebo-controlled 
phase, i.e., Study Part 1, once all subjects have had the opportunity to complete the EOS visit in 
Part 1 or Part 2 Day 1 visit after the 72 weeks of blinded study treatment in Part 1. The PA aims 
to address all study objectives of Part 1, to evaluate the effects of BIIB033 versus placebo on 
disability improvement over 72 weeks, and assess the overall efficacy and safety of BIIB033 as 
an add-on therapy to anti-inflammatory DMT during this blinded, placebo-controlled study 
phase. 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 36
 
 
Unless otherwise specified, all the analyses specified in Section 5 are focusing on the PA in this 
version of the SAP.  
 
 
 
 
 
 
 
5. Statistical Methods for Planned Analyses 
5.1.  General Principles  
Descriptive summary statistics will be presented for all study primary, secondary 
 
endpoints collected. For continuous endpoints, descriptive summary statistics will generally 
include number of subjects with data, the mean, standard deviation, median, interquartile range 
(Q1, Q3) and range (minimum, maximum). For categorical endpoints, this will generally include 
number and the percent of subjects with data in each category.  
The statistical software, SAS® version 9.4 or above, will be used for all summaries and 
statistical analyses.  
This Statistical Analysis Plan (SAP) document supersedes the statistical section in the protocol 
and provides details for those analyses pre-specified before any planned study unblinding. 
Additional ad hoc analyses may be conducted if needed after data unblinding and if there are any 
significant modification on SAP after data unblinding, those must be documented in clinical 
study report (CSR) accordingly.  
5.2. Handling of Missing Data  
5.2.1. T25FW, 9HPT-D, 9HPT-ND, PASAT-3 and SDMT  
The following rules will be applied to handle missing data in T25FW, 9HPT and PASAT-3 
before any further analyses or derivations of disability improvement/worsening endpoints. 
At each visit, the T25FW assessment has 2 trials and the average time from the 2 trials will be 
used for statistical analyses.  
(1) If a subject misses 1 trial due to reasons other than MS-related physical limitations, the 
result from the other trial will be used for that visit in the analyses.  
(2) If results from both trials are missing due to reasons other than MS-related physical 
limitations, the T25FW assessment for that visit will be set as missing.  
(3) If a subject misses either trial due to MS-related physical limitations, the assessment 
result (time in seconds) will be imputed as 13.7×SD (reference) + MEAN (reference), 
where the MEAN (reference) and SD (reference) are the mean and standard deviation of 
the averaged time from two trials of baseline assessments based on the reference 
population. The reference population is defined as all subjects dosed with non-missing 
baseline assessments for at least 1 trial. The baseline assessments used for calculating the 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 37
 
 
average time do not include any trials that are missing due to MS-related physical 
limitations. 
At each visit, the 9HPT assessment will be evaluated on the dominant hand and non-dominant 
hand separately, and 2 trials will be performed on each hand. For each hand, the average time 
from the 2 trials will be used for statistical analyses.  
(1) If a subject misses 1 trial on one hand due to reasons other than MS-related physical 
limitations, the result from the other trial will be used for that visit in the analyses.  
(2) If results from both trials on one hand are missing due to reasons other than MS-related 
physical limitations, the 9HPT assessment for that hand will be set as missing at that 
visit.  
(3) If a subject misses either trial on one hand due to MS-related physical limitations, 777 
seconds (Fischer, J. et al. (2001)) will be assigned as 9HPT test assessment for the 
disabled hand at that visit.  
When the average of dominant and non-dominant hand is calculated for the combined 9HPT 
assessment, if the assessment for one hand is missing, the average will be the assessment of the 
other hand. 
PASAT-3 assessments are the number of correct answers. If the assessment is missing due to MS 
disease limitation, the assessment will be imputed as a score of 0; otherwise the assessment will 
be set as missing.  
Symbol Digit Modality Test (SDMT) score is assessed at each visit. Measurements will not be 
imputed if SDMT is missing. 
Additional considerations on dealing with missing data including supportive analyses are 
provided in Section 5.7. 
5.2.2. Adverse Event and Concomitant Medication 
For completely missing start dates of AEs, assign the first dose date of study treatment. No 
imputation will be performed for completely missing start dates of concomitant medications. The 
partial start dates will be imputed as follows:  
 If only the day is missing and month and year are present, then assign to the first day of 
the month; 
 If only the year is present and month and day are missing, then assign to January 1st. The 
imputed start date will be compared to the first dose date of study treatment. If the 
imputed start date is earlier than the first dose date, then the first dose date will be 
chosen. 
No imputation will be performed for completely missing end dates of AEs and concomitant 
medications. The partial end dates will be imputed as follows: 
 If only the day is missing and month and year are present, then assign to the last day of the 
month; 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 38
 
 
 If only the year is present and month and day are missing, then assign to December 31st.The 
imputed end date will be compared to the last day in Part 1. If the imputed end date is later 
than the last day in Part 1, then the last day in Part 1 will be chosen. 
5.2.3. MS Relapse 
For all relapses, retrieve relapses onset date from relapse assessment data and adverse event 
termed Multiple sclerosis relapse data. All relapses from relapse assessment data will be used. 
If there is an adverse event termed Multiple sclerosis relapse  and the start date is different from 
all relapse onset dates from relapse assessment of the subject, this is considered as a subjective 
relapse of this subject and the start date of such adverse event is considered as the relapse onset 
date of a subjective relapse. 
The following rules will be used to impute the completely missing or partial onset dates of all 
relapses: 
 If the onset date is from relapse assessment: 
o If the date is completely missing, then assign to the day after the first dose date of 
study treatment; 
o If only the day is missing and month and year are present, then assign to the first 
day of the month; 
o If only the year is present and month and day are missing, then assign to January 
1st; 
o The imputed onset date will be compared to the day after the first dose date. If the 
imputed onset date is earlier than the day after the first dose date, then the day 
after first dose day will be chosen. 
 If the onset date is from adverse event termed Multiple sclerosis relapse : 
o If the date is completely missing, then assign to the first dose date of study 
treatment; 
o If only the day is missing and month and year are present, then assign to the first 
day of the month; 
o If only the year is present and month and day are missing, then assign to January 
1st. 
o The imputed start date will be compared to the first dose date of study treatment. 
If the imputed start date is earlier than the first dose date, then the first dose date 
will be chosen. 
Protocol-defined relapse is also used for efficacy analysis. Since the protocol-defined relapse 
date is from relapse assessment data, the imputation will follow the rule above for imputing the 
onset date if the onset date is from relapse assessment. 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 39
 
 
5.3. Accounting of Subjects  
The summary of subject disposition will include: subjects randomized, subjects randomized but 
not dosed; subjects dosed; subjects who completed the treatment in study Part 1; subjects who 
completed the study Part 1 (including those who completed the 72 weeks of treatment in Part 1 
and signed consent for Part 2, and those who completed Week 84 visit in Part 1 and did not roll 
over to Part 2); subjects who completed the study Part 1 but missed one or more doses; subjects 
who discontinued study treatment and the reasons for discontinuation; and subjects who 
withdrew from study and the reasons for withdrawal. A listing of those subjects who 
discontinued study treatment/withdraw from study and the associated reasons for 
discontinuation/withdrawal will be presented by treatment group. Number of subjects in each 
analysis population will also be summarized. In addition, number of subjects dosed, number of 
subjects who completed the study in each treatment group will be summarized by country and 
sites. Number of subjects by background DMT group and by region will be presented by 
treatment groups and overall. 
The summary of subjects on stratification factors (MS type, background DMT group and core 
group population/non-core group population) will be summarized separately by treatment groups 
and overall. 
The number of subjects whose visits are impacted by the pandemic, including missing or out-of-
window study treatment and key efficacy assessments will be summarized, according to 
information recorded in the study protocol deviation listing. Due to COVID-19 pandemic 
measures, there may be challenges to conduct on-site monitoring visits and thereof result in some 
study data pending source data verification (SDV). The number of subjects who have any 
pending SDV data and the number of study visits without SDV performed will be presented.   
5.4.  Demographic and Baseline Characteristics 
All demographics and baseline disease characteristics will be summarized for ITT population 
and per-protocol population separately. 
Demographic data, including age (in years), age category (<18, 18-30, 31-40, 41-50, 51-58, >58) 
and (<40, 40), and gender will be summarized by treatment groups and overall, also by 
treatment groups and background DMT group.  
Baseline MS disease history will be summarized by treatment groups and overall, using 
descriptive statistics. Time since onset of MS symptoms (in years), time since MS diagnosis (in 
years), number of subjects with secondary progressive MS (SPMS), time since onset of 
secondary progressive MS (in months, for subjects with SPMS only), time since the most recent 
relapse prior to Day 1 (in months), 
 
, number of relapses within the past 12 months, 2 years 
and 3 years of enrollment will be summarized. 
 
 
 
Number and percentage of subjects with any MS treatment history will be summarized by 
treatment groups and overall. Specifically, number and percentage of subjects who have taken 
approved DMTs and others will also be displayed by treatment groups and overall. Approved 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 40
 
 
DMTs include alemtuzumab, cladribine, daclizumab, dimethyl fumarate, fingolimod, glatiramer 
acetate, interferons (Interferon Beta-1A(AVONEX), Interferon Beta-1A (REBIF), Interferon 
Beta-1B (EXTAVIA)), Interferon Beta-1B (BETASERON), Peginterferon Beta-1A 
(PLEGRIDY)), natalizumab, ocrelizumab, and teriflunomide.  
 
 
 
 
Medical history will be coded using the latest version of MedDRA (version 23.0 or later if updated) 
and number and percentage of subjects with each history will be presented using the preferred 
term.  
5.5.  Protocol Deviations 
Protocol deviations identified during site monitoring will be captured in a protocol deviation log 
and categorized as major or minor deviations. Number and percentage of subjects with at least 
one major deviation will be summarized by category. All protocol deviations related to COVID-
19 pandemic measures will be provided in a listing with all available details.  
5.6. Study Treatment Exposure and Concomitant Medications 
Extent of exposure to study treatment will be summarized for both the ITT and the per-protocol 
populations. Number of infusions taken will be summarized as both continuous and category 
variables (>=12, >=16, >=18). The overall study drug compliance and study drug compliance 
during treatment phase will be provided. Subjects will also be categorized and summarized by 
 
Overall study drug compliance 
Defined as the percentage of study drug infusions actually received over 19 planned doses for 72 
weeks, will be summarized regardless of study completion for all subjects.  
Study drug compliance during treatment phase 
Defined as number of infusions actually received divided by the number of expected; the 
expected infusions is the total 19 planned doses for those who completed 72 weeks of study 
treatment, and is the total number of planned doses before early termination visit date for those 
who early terminated. 
In the study Part 1, no subject with study treatment administration is impacted by COVID-19 
infection or COVID-19 pandemic measures. Therefore, no additional summary on the extent of 
exposure to study treatment will provided for COVID-19 impact. 
The total number of weeks on study drug for each subject will be summarized as a continuous 
variable and presented in groups of 12-week intervals. Weeks on study drug are calculated as the 
number of weeks from the first dose date to the last dose date plus 4 weeks. Days on study drug 
are calculated as the number of days from the first dose date to the last dose date plus 28 days.  
Concomitant therapy will be summarized for both the ITT and the per-protocol populations. 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 41
 
 
All concomitant medications will be coded using the World Health Organization (WHO) 
medication dictionary (WHODD GLOBAL version B3 March 2020, or later if updated). 
Concomitant medication is any drug or substance administered between the time the subject 
signed the ICF and the EOS date. A concomitant non-drug treatment is any therapeutic 
interventions or diagnostic assessment performed between the time the subject signed the ICF 
and the EOS date.  
A medication in Part 1 refers to a medication that starts prior to the study treatment infusion in 
Part 2 Day 1 visit. If a subject is not enrolled in Part 2 or is enrolled in Part 2 but never receives 
infusion of study treatment in Part 2, all t medications will be considered as occurring in Part 1. 
A medication and/or non-drug treatments in Part 1 is regarded as concomitant with study 
treatment in Part 1 of the study if the stop date/time is on or after the first dose date/time of study 
treatment. In order to determine whether medication and/or non-drug treatments with missing 
stop dates are concomitant, the following additional criteria will be used: 
 If stop date of a particular therapy has year, month available but day missing and the year 
and month of the stop date is on/after the first dose date, then the therapy will be 
considered as concomitant; 
 If stop date of a particular therapy has year available but month and day missing and the 
year is on/after the first dose date, then the therapy will be considered as concomitant. 
If stop date of a particular therapy is missing, then the therapy will be considered as concomitant. 
The number and percent of subjects taking concomitant medication and non-drug treatments will 
be summarized separately by treatment group and overall.  
5.7. Efficacy Endpoints 
5.7.1. General Analysis Methods for Efficacy Endpoints 
All efficacy endpoints will be evaluated in the ITT population as defined in Section 3.6. The 
primary and secondary efficacy endpoints will also be analyzed in the per-protocol population as 
supportive analysis. 
Subjects who early terminated due to sites GCP deviation will not be used for any efficacy 
analysis. 
For data that are analyzed by longitudinal analysis, efficacy endpoint assessments at unscheduled 
visits can be used. This includes the primary endpoint ORS 
 in which 
data are analyzed by longitudinal analysis. It is possible that the assessments at an unscheduled 
visit can be used for summary by visit through mapping visit windows (Section 3.2). For efficacy 
data that are summarized by visit and used in longitudinal analysis, assessments from all 
scheduled visits including ET visit and EOS visit, as well as all unscheduled visits, will be 
mapped to an appropriate analysis visit using a windowing scheme (Section 3.2).                                                   
Study protocol specifies that disallowed concomitant therapies include: 1) more than one 
background DMT at any time, including any chronic immunosuppressant or immunomodulatory 
therapy; 2) any investigational product; 3) any systemic steroid therapy without prior approval 
from the Sponsor, except for protocol-defined treatment of relapses. The blinded clinical review 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 42
 
 
of all concomitant therapies data collected during Part 1 of the study shows that one subject 
received immunosuppressant treatment (methotrexate) as a concomitant medication during the 
Part 1. No subject received investigational therapy. Although in Part 1 there were subjects who 
received systemic steroid treatments for various medical reasons but not for protocol-defined 
relapses, all cases were a single course for one week or less during the entire Part 1, which were 
considered to have minimal impact on the efficacy analyses. Therefore, in the efficacy analyses, 
only immunosuppressant treatment (methotrexate) is considered as prohibited concomitant 
therapy in Part 1. Data on efficacy endpoints of a study subject collected after the use of 
methotrexate will not be included in any efficacy analyses for this subject. 
In general, baseline disability measurements used in model covariates refer to the continuous 
variables of baseline results of the disability assessments that serve as the independent 
component endpoint or constitute the MCE to be used as the dependent variable in the models 
(MMRM, logistic regression, Cox proportional hazard model, etc.). For analyses of primary and 
secondary MCEs, baseline EDSS, baseline T25FW time, baseline 9HPT-D time, baseline 9HPT-
ND time, baseline PASAT-3 score and baseline SDMT score as continuous covariates will be 
included in the statistical model when the model dependent variable includes the corresponding 
disability assessments. The exception is that in the supportive analysis of repeating MMRM 
analysis on the overall response score using ITT population with combined 9HPT, the average of 
baseline 9HPT-D time and baseline 9HPT-ND time as a continuous covariate will be included in 
the statistical model, instead of including both baseline 9HPT-D time and baseline 9HPT-ND 
time. For analyses of individual components, the corresponding baseline measurement (EDSS, 
T25FW, 9HPT-D, 9HPT-ND, PASAT-3, SDMT, 
) will be used as 
continuous covariate in the model. Unless otherwise specified, all analysis models are adjusted 
for stratification (categorical) variables of background DMT group 
 
. Though MS type was also used as a stratification factor in the randomization, it will 
not be included in any statistical models as an adjusted covariate. This is because after 
completion of randomization of all subjects, only two out of all 263 enrolled subjects are with 
SPMS, therefore, including such adjustment will have minimal impact on the statistical analysis 
results.  
Mixed Model for Repeated Measures (MMRM) will be used to analyze longitudinal assessment 
for continuous endpoints. MMRM will have treatment, visit, treatment-by-visit interaction as 
independent variables, adjusting for baseline disability measurements and stratification variables 
of background DMT group 
. Least-squares (LS) adjusted mean 
is constructed using observed margin. An unstructured (UN) covariance matrix will be assumed 
to model the within-subject variability. Model convergence will be checked.  If the MMRM with 
unstructured covariance matrix fails to converge, a compound symmetry (CS) structure will be 
used. LS adjusted mean and its 95% CI of each treatment group as well as treatment differences 
between BIIB033 vs. placebo will be displayed with 95% CI and p-values.  
Logistic regression will be used to analyze and compare the proportion of CDI (defined in 
Section 3.4.2.1) or CDW (defined in Section 3.4.2.2) with logit link function. The model will 
have treatment as independent variable, adjusting for baseline disability measurements and 
stratification variables of background DMT group 
. Odds ratio 
of BIIB033 group vs. placebo group with 95% confidence interval (CI) and p-value will be 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 43
 
 
presented. In the situation that logistic regression model fails to converge, stratification variables 
(background DMT group 
) will be removed from the covariate 
list and the logistic regression model will be fitted again. If the logistic regression model still 
fails to converge, the p-
regression model estimates. Ordinal logistic regression will be used for ordinal data, which will 
adjust for variables similar as described above for logistic regression. Odds ratio of BIIB033 vs. 
Placebo with 95% CI and p-value will be presented. 
Cox proportional hazards model will be used to analyze and compare time to the first CDI or 
CDW assuming the hazard ratio is constant over time. The model will include treatment as 
independent variable, adjusting for baseline disability measurements, and stratification variables 
of background DMT group 
. Hazard ratio of each BIIB033 vs. 
placebo with 95% CI and p-value will also be presented. In the situation that Cox proportional 
hazards model fails to converge, stratification variables (background DMT group 
 
) will be removed from the covariate list and the Cox proportional hazards 
model will be fitted again.  
Analysis of covariance (ANCOVA) model will be used to analyze and compare change from 
baseline for some continuous endpoints. The model will have treatment as the independent 
variable, adjusting for baseline disability measurements and stratification variables (background 
DMT group 
). Based on Type III sum of squares, LS adjusted 
mean of each treatment group as well as treatment difference between BIIB033 vs. placebo will 
be presented with 95% CI and p-values.  
There are no missing data through Week 72 due to COVID-19 or COVID-19 pandemic 
measures. A small number of subjects have missing assessments at the Week 84 or Part 2 Day 1 
visit, which would be used to confirm any tentative improvement or worsening events in the 
treatment period. In the main analysis, subjects with tentative improvement or worsening events 
before Week 84 or Part 2 Day 1 visit will not be considered as having a confirmed event. 
Supportive analysis will be conducted by considering these subjects having a confirmed event. 
Data with pending SDV due to COVID-19 will be included in analysis. 
5.7.2. Primary Efficacy Endpoint 
5.7.2.1. Main Analysis of Primary Efficacy Endpoint 
For each subject at each post-baseline visit during the treatment period (Weeks 12, 24, 36, 48, 60 
and 72), an overall response score (ORS) as defined in Section 2.1.2 will be determined based on 
all components (EDSS, T25FW, 9HPT-D and 9HPT-ND). 
The ORS will be summarized using descriptive summary statistics by visit. MMRM will be used 
to analyze the overall response scores up to Week 72. The MMRM model will include treatment, 
visit, treatment-by-visit interaction, baseline disability measurements (EDSS, T25FW, 9HPT-D 
and 9HPT-ND), background DMT group 
 as fixed effects. LS 
adjusted mean of each treatment group and the treatment difference between BIIB033 vs. 
placebo will be presented with associated 95% CI and p-value at Weeks 12, 24, 36, 48, 60 and 
72. LS adjusted means by treatment group will also be displayed graphically by visit. The 
treatment effect between BIIB033 vs. placebo over 72 weeks will be estimated as the average 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 44
 
 
treatment effect across the visits through 72 weeks derived from the model, based on which the 
p-value using the T-test statistic for the primary null hypothesis will be reported. If the average 
-sided), treatment difference at individual 
timepoints (visits) will also be assessed based on the same model.  
For the interim analysis of the overall response score, see Section 5.11 for details. 
5.7.2.2. Supportive Analyses for Primary Efficacy Endpoint 
The following supportive analyses will be conducted. Since all subjects would have had their 
Week 72 assessments done before start of the COVID-19 pandemic measures, no supportive 
analysis will be performed related to COVID-19.  
(1) The same MMRM analysis for the ORS as described in Section 5.7.2.1 will be repeated 
for the per-protocol population. 
(2) The same MMRM analysis for the ORS will be repeated in the ITT population with 
combined 9HPT scores from the dominant and non-dominant hand. The average of 
9HPT-D and 9HPT-ND is calculated for 9HPT assessment, considering the high 
correlation between two hands. Then the range of overall response score will be -3 to +3. 
If the assessment for one hand is missing after imputation rule is applied, the average will 
be the assessment of the other hand. 
(3) The same MMRM analysis for the ORS will be repeated using 20% thresholds for 
improvement and worsening in T25FW, 9HPT-D and 9HPT-ND. 
(4) MMRM analysis on the ORS will be repeated in the ITT population with multiple 
imputation for missing values of EDSS, T25FW, 9HPT-D and 9HPT-ND over 72 weeks 
of treatment under the assumptions of missing at random. Each individual component in 
the composite overall response will be multiply imputed as a continuous variable with 
treatment group, randomization stratification factors (excluding MS type) and baseline 
scores of EDSS, T25FW, 9HPT-D and 9HPT-ND assessments included in the imputation 
model. The missing baseline value will be imputed by the mean baseline in 
corresponding treatment group. Multiple imputations will be performed using PROC MI 
in SAS assuming the scores at post-baseline visits following a joint multivariate normal 
distribution. After imputing the individual component scores, the overall response score 
at each visit will then be calculated using the imputed component scores in each imputed 
data set following the definition in Section 2.1.2. A set of 500 imputed data sets will be 
generated with 200 burn-in iterations and the relative efficiency parameter will be 
checked to ensure no extreme values are sampled. The multiply imputed datasets will be 
analyzed using the same MMRM model for the ORS, and the estimates from all imputed 
datasets will be combined for an 
 
(5) The same MMRM analysis for the ORS will be repeated in the ITT population by 
excluding data collected after the end of actual treatment period (i.e., after treatment 
discontinuation) for subjects discontinued study treatment early but still stayed in the 
study and continued with study assessments.  


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 45
 
 
(6) The same MMRM analysis for the ORS will be repeated in the ITT population by 
excluding data collected after DMT switch date for subjects who switched DMT during 
the actual treatment period. 
5.7.2.3. Subgroup Analysis of Primary Efficacy Endpoint 
Subgroup analysis will be performed for the primary efficacy endpoint on the subgroups defined 
in Section 3.5.2, including baseline characteristics subgroups, 
 
, DMT subgroups. All the subgroup analyses will be performed in each subgroup 
separately. A subgroup variable will not be used in the model covariates for the analysis 
performed on the subgroups defined by that subgroup variable. Within each subgroup, the 
MMRM analysis for the ORS will be performed as described in Section 5.7.2.1. Subgroup 
analyses aim to assess the consistency of treatment effect across subgroups. 
 
  
5.7.3. Secondary Efficacy Endpoints and Related Time to Event Endpoints 
5.7.3.1. Main Analysis for Proportion of CDI on MCE 
The number and percentage of subjects with CDI for the secondary MCE based on EDSS, 
T25FW, 9HPT-D and 9HPT-ND, as defined in Section 3.4.2.1, will be displayed by treatment 
groups. 
A logistic regression model for proportion of CDI will be performed with treatment as 
independent variable, adjusting for baseline disability measurements and stratification variables 
of background DMT group 
. The odds ratios of BIIB033 vs. 
placebo from the logistic regression model will be presented with 95% CI and p-value. 
5.7.3.2. Supportive Analyses for Proportion of CDI in MCEs 
The following supportive analyses will be conducted on secondary endpoints: proportion of 
subjects with 12-week CDI in MCEs based on EDSS, T25FW, 9HPT-D, 9HPT-ND, with default 
threshold (15%) and with 20% thresholds for T25FW and 9HPT. 
(1) The main analysis as described in Section 5.7.3.1 will be repeated for the per-protocol 
population. 
(2) The main analysis will be repeated by including CDI and tentative improvement in two or 
more components at Week 72 (defined in Section 3.4.2.7) 
(3) The main analysis will be repeated for proportion of subjects with CDI in two or more 
components (defined in Section 3.4.2.5) 
(4) Confirmed improvement extent analysis:  
The confirmed improvement extent endpoint is defined as the number of CDI per subject 
based on whether a subject has CDI in EDSS, T25FW, 9HPT-D, or 9HPT-ND (using the 
same criteria defined in Section 3.4.2.1). Specifically, the confirmed improvement extent 
is defined as follows:  
 Extent=0: CDI in none of the 4 components 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 46
 
 
 Extent=1: CDI in 1 of the 4 components 
 Extent=2: CDI in 2 or more of the 4 components 
The number and percentage of subjects by confirmed improvement extent will be 
displayed. The ordinal logistic regression will be used to analyze the probability of 
different confirmed improvement extent. Proportional odds assumption is assumed. That 
is, the effect of covariates and treatment is the same for different logit function (extent=0 
vs. extent=1 or 2, or extent=1 or 2 vs. extent=0). The common odds ratio of BIIB033 vs. 
placebo will be displayed with 95% CI and p-value.  
(5) The main analysis will be repeated for CDI considering unconfirmed events due to 
COVID-19. To evaluate COVID-19 impact, if the subject has tentative improvement in at 
least one component at Week 72, but the subsequent planned visit to be used for 
confirmation (Week 84/EOS or Part 2 Day 1) is not conducted, or the corresponding 
disability assessment is not done due to COVID-19 or COVID-19 pandemic measures, 
then tentative improvement would be assumed to be confirmed for the component and 
hence for the MCE.  
(6) The main analysis will be repeated for CDI excluding data after DMT switch (defined in 
Section 3.4.2.6). 
5.7.3.3. Subgroup Analysis for Proportion of CDI in MCEs 
Subgroup analysis will be performed for the secondary efficacy endpoints: proportion of subjects 
with 12-week CDI in MCEs based on EDSS, T25FW, 9HPT-D and 9HPT-ND, with default 
threshold (15%) and with 20% thresholds for T25FW and 9HPT separately, on the pre-defined 
subgroups in Section 3.5.2. 
Logistic regression will be used for all subgroup analyses on secondary MCEs. The probability 
of CDI will be analyzed and compared in each subgroup. The logistic regression model will be 
similar to the one used in the main analysis for CDI in MCE, except that a subgroup variable will 
be excluded from the model covariates for the analysis performed on the subgroups defined by 
that subgroup variable. In subgroup analysis of two DMT groups, the background DMT to be 
included in the model covariates is the actual DMT at baseline instead of background DMT per 
randomization stratification. Odds ratio of BIIB033 vs. placebo for each subgroup will be 
displayed with 95% CI and p-value. 
5.7.3.4. Main Analysis for Time to CDI and CDW 
For the time to CDI and time to CDW endpoints described in Section 2.1.6.2 supporting analyses 
on other clinical disability measures, the following analyses will be performed. The Kaplan-
Meier (K-M) curve will be used to display distribution of time to CDI (or CDW) event. 
Treatment effect on time to first CDI (or CDW) event will also be analyzed based on a Cox 
proportional hazards model with treatment as the independent variable, adjusting for baseline 
component measurements, and stratification variables of background DMT and baseline 
MTR/DTI category. Hazard ratio of BIIB033 vs. placebo will be displayed with 95% CI and p-
value. 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 47
 
 
5.7.3.5. Supportive Analyses for Time to CDI in MCEs 
The following supportive analyses will be conducted on time to 12-week CDI in MCEs based on 
EDSS, T25FW, 9HPT-D and 9HPT-ND, with default threshold (15%) and with 20% thresholds 
for T25FW and 9HPT, separately.  
(1) The main analysis described in Section 5.7.3.4 will be conducted using per-protocol 
population. 
(2) The main analysis will be repeated by including CDI and tentative improvement in two or 
more components at Week 72 (defined in Section 3.4.2.7). 
(3) The main analysis will be repeated based on the CDI in two or more component defined 
in Section 3.4.2.5.  
(4) The main analysis will be repeated for CDI considering unconfirmed events due to 
COVID-19. To evaluate COVID-19 impact, if the subjects have tentative improvement 
on at least one component at week 72, but the subsequent planned visit to be used for 
confirmation (Week 84/EOS or Part 2 Day 1) is not conducted, or the corresponding 
disability assessment is not done due to COVID-19 or COVID-19 pandemic measures, 
then tentative improvement would be assumed to be confirmed for the component and 
hence for the MCE.  
(5) The main analysis will be repeated for CDI excluding data after DMT switch (defined in 
Section 3.4.2.6). 
5.7.3.6. Subgroup Analysis for Time to CDI 
Subgroup analysis will be performed for the time to event endpoints for 12-week CDI for MCEs 
based on EDSS, T25FW, 9HPT-D, 9HPT-ND, with default threshold (15%) and with 20% 
thresholds for T25FW and 9HPT separately, on the pre-defined subgroups in Section 3.5.2. 
The analysis similar to the main analysis described in Section 5.7.3.4 will be performed in each 
subgroup. The Cox regression model will be similar to the one used in the main analysis for time 
to CDI in MCE, except that a subgroup variable will be excluded from the model covariates or 
strata variables for the analysis performed on the subgroups defined by that subgroup variable. In 
subgroup analysis of two DMT groups, the background DMT group to be included in the model 
covariates is the actual background DMT group instead of background DMT group used for 
randomization/stratification. Hazards ratio of BIIB033 group vs. placebo group will be displayed 
with 95% CI and p-value. 
 
 
 
 
 
 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
Page 48
 
 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 49
 
 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 50
 
 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
Page 51
 
 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 52
 
 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 53
 
 
 
 
5.8. Safety Endpoints 
5.8.1. General Analysis Methods for Safety Endpoints 
All safety endpoints will be evaluated in the safety population (all subjects dosed) as defined in 
Section 3.6.  
All treatment emergent adverse events (TEAEs) and serious adverse events (SAEs), clinical 
laboratory abnormalities, vital sign measurements, physical examination findings, 12-lead ECG 
readings, MS signs and symptoms, annualized relapse rate, body weight and Columbia Suicide 
Severity Rating Scale (C-SSRS) will be evaluated for safety. Safety data collected by Follow-up 
visit (EOS visit (Week 84 or earlier for early termination subjects) for those who are not enrolled 
in Part 2, or Part 2 Day 1 visit for those who enroll in Part 2 of the study) will be summarized 
using descriptive statistics by treatment groups. For subjects who do not enroll in Part 2, the 
safety data collected by EOS visit will all be used; for subjects who are enrolled in Part 2, if a 
safety data has both date and time, the date and time will be compared with Part 2 Day 1 infusion 
day and time and any data that is collected on or after the Part 2 Day 1 infusion day and time is 
excluded from analysis; if a safety data has date but does not have time, the data that is collected 
on or after Part 2 Day1 is excluded from analysis. If a subject is enrolled in Part 2 but does not 
receive Part 2 Day 1 infusion, all safety data up to Part 2 Day 1 visit last date will be used.   
For safety data that are summarized by visit, assessments from all scheduled visits, ET visit, EOS 
visit and unscheduled visits in Part 1 will be mapped to an appropriate analysis visit using a 
windowing scheme (Section 3.2). 
5.8.2. Adverse Events 
For this study, any TEAE experienced by the subject between the time of first dose of study 
treatment (Day 1/Baseline) and the EOS visit in Part 1 for those who do not enroll in Part 2 or 
Part 2 Day 1 - 1 for those who enroll in Part 2 is to be recorded on the CRF, regardless of the 
severity of the event or its relationship to study treatment. Any SAE experienced by the subject 
between the time the subject has signed the ICF and the EOS visit in Part 1 for those who do not 
enroll in Part 2 or Part 2 Day 1 - 1 for those who enroll in Part 2 is to be recorded, regardless of 
the severity of the event or its relationship to study treatment.   
All AEs will be coded using MedDRA (version 23.0 or later if updated) and will be analyzed 
based on the principle of treatment emergence.  
In order to define treatment-emergent AEs with completely missing/partial start or end dates, the 
following additional criteria will be used: 
 If both the start and end dates for a particular event are completely missing, then that 
event is considered treatment emergent; 
 If the start date for a particular event is completely missing, then the end date/time will be 
compared to the first dose date: 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 54
 
 
o If the end date/time is complete and is on or after the first dose date/time, then 
that event is considered as treatment emergent; 
o If the end time is missing, but the end date is present and is on or after the first 
dose date, then that event is considered as treatment emergent; 
o If the end day is missing, but the year/month of end date is present and is on or 
after that of the first dose date, then that event is considered as treatment 
emergent; 
o If only the year of end date is present and is on or after that of the first dose date, 
then that event is considered as treatment emergent; 
 If the start date for a particular event is partially missing, and the year/month/day of the 
event date will be compared to that of the first dose date: 
o If the start time is missing and year/month/day of the start date falls after that of 
the first dose date, then that event is considered treatment emergent; 
o If the start day is missing and year/month of the start date falls after that of the 
first dose date, then that event is considered treatment emergent; 
o If only the year of the start date is present and falls after that of the first dose date, 
then that event is considered as treatment emergent. 
o If the partial start date is the same as that of the first dose date, then the end 
date/time will be compared to the first dose date following the logic above. 
The overall summary table of TEAEs will present the number of subjects with the following 
events by treatment groups. A subject is counted only once in each category. All treatment-
emergent adverse event and treatment-emergent serious adverse events will be presented and 
summarized. 
 Any TEAE; 
 
 
 
 
 Current DMT related TEAE; 
 Study treatment related TEAE; 
 Any SAE; 
 Current DMT related SAE; 
 Study treatment related SAE; 
 AE leading to discontinuation of study treatment; 
 AE leading to withdrawal from study. 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 55
 
 
The incidence of TEAEs will be summarized using the primary system organ class (SOC) and 
preferred term (PT). Preferred terms are presented by decreasing incidence in the BIIB033 
column within each system organ class.  
The incidence of TEAEs will also be summarized by event severity and by relationship to study 
drug using system organ class and preferred term. Within each system organ class or/and 
preferred term, the same subject will be counted only once.  Under the same system organ class 
or/and preferred term, the occurrence of the adverse event with the greatest severity will be used 
in the calculation of incidence by severity; the occurrence of the adverse event with the strongest 
relationship to study drug will be used in summarizing incidence by relationship to study drug.  
Additionally, the incidence of TEAEs will be summarized by using preferred term only, and 
preferred terms will be ordered by decreasing frequency of AEs in the BIIB033 column.  
The incidence of treatment-emergent SAEs will also be summarized by primary system organ 
class, preferred term and treatment group as well.   
Listings of AEs, SAEs, AEs that led to study drug discontinuation, and AEs that led to study 
withdrawal will be presented. Listing of death will be provided if applicable. 
In some AE/SAE listings, complete AE start and end dates are needed to calculate the relative 
study days of AE start and end. Therefore, any partial date will be imputed for these listings as 
described in Section 5.2.2.  
AEs around the time of infusion 
The incidence of AEs around the time of the infusion (within 4 hours and 24 hours post start of 
infusion respectively) will be summarized by preferred term and visit for each treatment group. 
At each visit, the same subject will be counted only once within each preferred term. Preferred 
terms will be ordered by decreasing frequency of AEs in the BIIB033 column. 
Listings of such AEs around the time of the infusion (within 4 hours and 24 hours after infusion 
start respectively) will be provided by treatment group.  
5.8.3. MS Relapse 
If an MS relapse is suspected during the study, an unscheduled visit should be performed to 
confirm the relapse and assess the severity, which will be documented in the relapse assessment 
form.  
Summary will be made for all relapse (including protocol-defined, non-protocol-defined, and 
subjective relapse) as well as protocol-defined relapse only. A summary table will be displayed 
with the number of subjects with 0, 1, 2, 3 or >3 relapse by treatment groups. The total number 
of relapse and subject-years followed will be shown in the table. Total number of subject-year is 
defined as the sum of number of days of all subjects in the study divided by 365.25. Unadjusted 
annualized relapse rate is the total number of relapses of all subjects in the study divided by the 
total subject-year. 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 56
 
 
5.8.4. Clinical Laboratory Abnormalities 
The following clinical laboratory parameters are assessed at all study visits as stated in Section 5 
and Section 14.2 of the protocol (except that baseline assessments do not need to be repeated if 
Screening is within 7 days of Baseline): 
 Hematology:  complete blood count with differential and platelet count, and absolute 
neutrophil count. Prothrombin time (PT), partial thromboplastin time (PTT) 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, alanine aminotransferase (ALT or 
SGPT), aspartate aminotransferase (AST or SGOT), gamma-glutamyl-transferase (GGT), 
glucose, calcium, phosphorus, bicarbonate, chloride, sodium, potassium and follicle-
stimulating hormone (FSH: for postmenopausal female subjects only) 
 Urinalysis:  dipstick for blood, protein, and glucose (microscopic examination, if 
abnormal) 
 Serum and urine pregnancy test (women of child-bearing potential only) 
Baseline value is defined as in Section 5.1. 
Shift analyses 
Laboratory data (except coagulation) will be summarized using shift tables where appropriate.  
hematology and blood chemistry parameters, and shifts from baseline to high or positive status 
for urinalysis will be presented.    
In the hematology and blood chemistry shift summary tables, entries are numbers of subjects 
shift to low (or high) divide by number of subjects at risk followed by corresponding 
percentages. Number at risk for shifting to low (or high) is the number of subjects whose 
baseline value was not low (or high) and who had at least one post-baseline evaluation. Shift to 
low includes normal to low, high to low, and unknown to low. Shift to high includes normal to 
high, low to high, and unknown to high.  
In the urinalysis shift summary table, entries are numbers of subjects shift to high or positive 
divided by number of subjects at risk followed by corresponding percentages. Number at risk for 
shift to high or positive is the number of subjects whose baseline value was not high or positive 
and who had at least one post-baseline evaluation. Shift to high or positive includes low to high, 
normal or negative to high or positive and unknown to high or positive.  
 
 
as Normal/Negative; 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 57
 
 
 For other urine tests, if te
 
A listing will be presented for all subjects with post-baseline urinalysis shifts. In this listing, each 
 will be 
listed with shifts labeled. 
Liver function laboratory tests 
For liver function laboratory tests (ALT, AST, and total bilirubin), count and percentage of 
maximal post-baseline values by following categories will be provided: 
For ALT or AST,  
 
 Upper Limit of Normal (ULN),  
 >ULN,  
 
 3x ULN,  
 >5x ULN,  
 >10x ULN,  
 >20x ULN. 
For total bilirubin,  
 
 ULN,  
 >ULN,  
 
 1.5x ULN,  
 >2x ULN. 
For more than one liver function test 
 ALT or AST  3x ULN and total bilirubin  1.5x ULN at the same time point, 
 ALT or AST  3x ULN and total bilirubin >2x ULN at the same time point. 
A subject listing will be presented for all subjects with any post-baseline ALT or AST  3x 
lkaline 
phosphatase, ALT/SGPT, AST/SGOT, GGT) from screening to last study visit will be listed with 
abnormal records labeled. 
Summary and listings of actual values and change from baseline  
Actual laboratory values, changes from baseline and percent changes from baseline in selected 
quantitative laboratory values will be summarized using descriptive statistics by treatment group 
and visit. Box and whisker plots displaying values and changes from baseline by visit will also 
be presented. 
Potentially clinically significant (PCS) abnormalities 






Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 60
 
 
A summary table for subjects with any clinically relevant post-baseline abnormalities will be 
provided. In the summary table, entries are numbers of subjects with an abnormality divided by 
number of subjects evaluated followed by corresponding percentages. Number evaluated is the 
number of subjects who had a baseline assessment and at least one post-baseline assessment for 
that vital sign.  
The number and percentage of subjects with post-baseline weight change of greater than 7% 
from baseline will be summarized by treatment group and visit. A subject listing of post-baseline 
weight change of greater than 7% from baseline will be presented. 
For temperature, pulse, systolic blood pressure, diastolic blood pressure, respiratory rate and 
weight, actual values and changes from baseline will be summarized using descriptive statistics 
by treatment group and visit. Box and whisker plots displaying values and changes from baseline 
by visit will also be presented. 
A subject listing will be presented for subjects with any post-baseline clinically relevant 
screening to last study visit will be listed with abnormalities labeled. 
5.8.6. Physical Examination 
Physical examination is performed every 12 weeks from Week 0 to Week 72 and at unscheduled 
visits. The result collected on CRF at scheduled visits will be listed as performed or not 
performed, and abnormality will be reported as AE. 
5.8.7. 12-lead ECG Readings 
ECG is assessed at Screening, Week 24, Week 48, Week 72, ET, and Follow-up visit (EOS visit 
(Week 84 or earlier for early termination subjects) for those who do not enroll in Part 2, or Part 2 
Day 1 visit for those who enroll in Part 2 of the study). 
 
Status change in ECG from screening at Week 24, Week 48, Week 72, and Follow-up visit will 
be summarized using shift tables.  The number and percent of subjects with shifts from normal to 
summarized by treatment group.  
A listing of details for abnormal ECG findings will also be presented. 
5.8.8. Columbia Suicide Severity Rating Scale (C-SSRS) 
The Columbia Suicide Severity Rating Scale (C-SSRS) is an assessment that evaluates suicidal 
ideation and behavior. C-
 
Week 24, 48, 72, 
ET and Follow-up Visit.  
-baseline visits. Five questions on 
suicidal ideation and five questions on suicidal behavior are re-ordered and follow increasing 
severity order respectively as shown in Table 4; another question on self-injurious behavior 
without suicidal intent is listed separately. In particular, only subjects 
 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 61
 
 
question is used to record if subject had committed suicide in post-baseline visits.  
Table 4: 
C-SSRS re-ordered questions 
Suicidal Ideation 
Question 1 
Wish to be dead 
Question 2 
Non-specific active suicidal thoughts 
Question 3 
Active suicidal ideation with any methods (not plan) 
without intent to act 
Question 4 
Active suicidal ideation with some intent to act, without 
specific plan 
Question 5 
Active suicidal ideation with specific plan and intent 
Suicidal Behavior 
Question 6 
Preparatory acts or behavior 
Question 7 
Aborted attempt 
Question 8 
Interrupted attempt 
Question 9 
Actual attempt 
Question 10 
Suicidal behavior 
Question 11 (post-baseline visit 
only) 
Suicide 
Self-Injurious Behavior without Suicidal Intent 
Question 12 
Self-injurious behavior without suicidal intent 
 
A subject is considered to have suicidal ideation 
to any of the five suicidal ideation questions (Question 1-5). A subject is considered to have 
suicidal behavior 
behavior questions (Question 6-
behavior questions (Question 6-11) at post-baseline visit.  
Suicidal Ideation Score is defined as the maximal suicidal ideation question number 
(maximal of 1-5) wit
treatment-emergent suicidal ideation if the subject had either new or worsening suicidal ideation.  


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 62
 
 
increased at any post-baseline visit compared to a score 0 at baseline. A subject is considered to 
Suicidal Ideation Score increased at any post-
baseline visit compared to a positive score at baseline. 
A subject is considered to have treatment-emergent suicidal behavior if the subject answered 
-baselin
suicidal behavior questions at baseline.  
The following analyses on C-SSRS measurements will be conducted: 
 
-12 as well as 
subjects who had suicidal ideation or suicidal behavior at baseline and at any post-
baseline visit. The denominator for baseline summary is the number of subjects who were 
dosed and had baseline assessment; the denominator for post-baseline summary is the 
number of subjects who were dosed and had at least one post-baseline assessment for 
each question. 
 Descriptive summary of subjects who had treatment-emergent suicidal ideation, subjects 
who had new suicidal ideation as well as subjects who had worsening suicidal ideation. 
The denominator is the number of dosed subjects with both baseline and at least one post-
baseline suicidal ideation assessment. 
 Descriptive summary of subjects who had treatment-emergent suicidal behavior. The 
 to all suicidal behavior 
questions at baseline and had at least one post-baseline suicidal behavior assessment.  
Listing of subjects having treatment-emergent suicidal ideation will be provided. Subjects who 
had new suicidal ideation and subjects who had worsening suicidal ideation will be flagged. The 
listing will display both baseline and post-baseline Suicidal Ideation Scores for each subject. 
Listing of subjects having treatment-emergent suicidal behavior will also be provided.  
5.8.9. MS Signs and Symptoms 
Typical MS signs and symptoms are evaluated at screening, baseline and every 12 weeks until 
Week 72, and at unscheduled visit, ET visit, Follow-up visit. MS signs and symptoms are listed 
in 7 classes as well as sensory disturbances and motor disturbances. Number and percentage of 
subjects having each listed MS signs and symptoms at each visit will be displayed by treatment 
groups. 
 
 
 
  
  
 
 
 
 
 
 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 63
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
5.10. Immunogenicity (Anti-BIIB033 Antibodies) 
Immunogenicity may affect PK and the blood levels could be lower in those study subjects who 
develop anti-drug antibodies.  The anti-BIIB033 antibody presence will be presented in subject 
listings as mentioned in Section 5.9.2. Additional analysis may be conducted and will be 
included in a separated report from CPP.  
5.11. Statistical Considerations for Interim Analysis 
5.11.1. Futility Criteria 
The futility criteria are determined by balancing and controlling the false negative rate (FNR) 
and false positive rate (FPR), and considering the overall trend of the IA data. The proposed 
futility threshold is the observed treatment difference in ORS at W
futility 
threshold is met if the observed treatment effect (treatment difference of ORS at week 36 in 
BIIB033 compare to placebo) is not large than 0.3. The minimum observed treatment difference 
is based on statistical simulation, with assumption of true treatment difference of 0.5 which is 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 64
 
 
based on the data from SYNERGY study while controlling FNR at 10% and FPR at 3%. The 
futility criteria take into account of the observed treatment effect set by the futility threshold, as 
well as the overall trend and totality of data at the IA. 
5.11.2. Interim Analysis 
Main analysis for the primary and secondary endpoints will be conducted for interim analysis, 
with endpoints defined over 36 weeks (based on the data maturity at the planned IA) instead of 
over 72 weeks that is designed for the PA, and the analysis methods applied are as described in 
Section 5.7.2.1, Section 5.7.3.1 and Section 5.7.3.4. The futility threshold will be based on the 
LS adjusted means of treatment difference between BIIB033 vs. Placebo at week 36 from 
MMRM model. Plot of the LS adjusted mean of each treatment group with 95% CI at each visit 
will be provided to assess the ORS trend over time. The revised version of the supportive 
analysis in secondary endpoints considering tentative improvement assumed to be confirmed if 
no visits after Week 36 (Section 5.7.3.2 and Section 5.7.3.5) will also be performed to support 
the IA data interpretation. 
5.11.3. Regular Safety Analysis by DMC 
Safety data will be reviewed on an ongoing basis by the Data Monitoring Committee (DMC) 
during Part 1. Safety data are reviewed on a quarterly basis by DMC.  
All adverse events (AEs) and serious adverse events (SAEs), MS relapse, clinical laboratory 
abnormalities, vital sign measurements, physical examination findings, 12-lead ECG readings, MS 
signs and symptoms, body weight and Columbia Suicide Severity Rating Scale (C-SSRS) will be 
evaluated for safety at interim analysis.  
 
 
 
 
 
   
 
 
  
 
 
6. Changes from Protocol-Specified Analyses 
COVID-19 Related Analyses 
In 2020 there is a worldwide outbreak of respiratory disease named as Coronavirus Disease 
2019  (COVID-19). It has been recognized that this COVID-19 public health emergency may 
impact the conduct of clinical trials of medical products and the challenges caused by the 
COVID-19 pandemic may lead to difficulties in meeting protocol-specified procedures, 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 65
 
 
including administering the investigational product or adhering to protocol-mandated visits and 
laboratory/diagnostic testing (FDA 2020 and EMA 2020).  
For this study 215MS202, no subject in the study Part 1 had COVID-19 infection. Majority of 
the study Part 1 conduct and data collection have completed by the time of the COVID-19 
outbreak. No subject visit from Day 1 to Week 72 is impacted by the COVID-19 pandemic, 
however, there are small number of subjects whose Week 84/EOS or Part 2 Day 1 visits are 
impacted. There were also challenges to conduct on-site monitoring visits and thereof result in 
some study data pending source data verification (SDV).  
Therefore, the following analyses are added to assess the impact of COVID-19 pandemic. 
Supportive analyses on CDI and CDW MCEs are added by including tentative events that were 
unable to be confirmed due to missing Week 84/EOS or Part 2 Day 1 visits impacted by COVID-
19 pandemic. Summaries of study subjects with early withdrawal, protocol deviation, missing or 
out-of-window key disability assessments due to COVID-19 pandemic are to be provided. The 
incomplete SDV on dosing information and key disability assessments due to the pandemic will 
also be summarized by visit.  
 
 
 
 
 
 
 
 
7. Summary of Changes from the Previous Version of the SAP 
Document Format Change 
This SAP document is reformatted to follow the suggested content and structure in the Biogen 
Statistical Analysis Plan Template version 1.0 released in January 2020. 
Updates Following Protocol Amendment 
In this study 215MS202 protocol version 3, an open-label extension, i.e., Study Part 2, is added. 
Accordingly, in this version of the SAP, amendments have been made to reflect this change in 
study design, with corresponding updates in study procedures and data collection, as well as 
planned analyses. 
Additional Endpoints and Analyses about MCEs of CDI and CDW 
As discussed in Section 6, additional MCEs of CDI and CDW based on alternative definitions 
are added for supportive analyses to aid the interpretation of treatment effect on clinical 
disability. 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 66
 
 
Changes in Planned Analysis Methods 
A few changes are made to the planned analysis methods to best suit the characteristics of the 
data to be analyzed, as well as to focus on the most relevant analyses addressing the trial 
objectives and scientific questions of interest. These changes include the following. For analyses 
related to brain imaging lesion count data over time, MMRM is replaced by Negative Binomial 
regression. For analyses related to brain imaging lesion volume over time, MMRM is replaced 
by 
. GEE and WLW approaches for supportive analyses on proportion and 
time to CDI are removed. Supportive analyses using multiple imputation for ORS over 72 weeks 
are added. Supportive analyses are added on CDI by removing data after DMT switch. The 
definition of per-protocol population is also updated by adding the consideration of some major 
protocol deviations that could potentially impact efficacy results. 
COVID-19 Related Analyses  
As discussed in Section 6, additional analyses are added in the SAP to assess impact of the 
COVID-19 pandemic and ensure the robustness of the primary analysis results. 
 
8. References 
[1] Dmitrienko, A., Chuang-Stein, C., & D'Agostino, R. B. (2007). Pharmaceutical statistics 
using SAS: a practical guide. SAS Institute.  
[2] EMA Points to consider on implications of the Coronavirus Disease (COVID-19) on 
methodological aspects of ongoing clinical trials (2020) 
[3] FDA Guidance for Industry: Statistical considerations for clinical trials during the COVID-
19 public health emergency (2020) 
 
  
[5] Liang, K. Y., & Zeger, S. L. (1986). Longitudinal data analysis using generalized linear 
models. Biometrika, 13-22.  
[6] Lublin, F. D., & Reingold, S. C. (1996). Defining the clinical course of multiple sclerosis 
results of an international survey. Neurology, 46(4), 907-911.  
[7] Polman, C. H et al. (2005). Diagnostic criteria for multiple sclerosis: 2005 revisions to the 
 Annals of neurology, 58(6), 840-846. 
[8] Wei, L. J., Lin, D. Y., & Weissfeld, L. (1989). Regression analysis of multivariate 
incomplete failure time data by modeling marginal distributions. Journal of the 
American statistical association, 84(408), 1065-1073.  
[9] Williamson, J. M., Datta, S., & Satten, G. A. (2003). Marginal analyses of clustered data 
when cluster size is informative. Biometrics, 59(1), 36-42.  
 
 
 
 


Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 67
 
 
 
 
 
 
 
 
 
 
 
 














Product: BIIB033 
Study: 215MS202
         Statistical Analysis Plan 
           Version: 2.0
 
 
Page 74
 
 
 
 
 
 
 
 
  
 
  
      
 
 
 
 
 
 
  
 
 
 
 
 
 
    
 
 
  
 
  
  
 
 
  
 
 
 






















Product: BIIB033 
Study: 215MS202 
         Statistical Analysis Plan  
           Version: 2.0 
 
 
Page 85 
 
 
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 Part 2  Schedule of Activities 
Table 9). 
6 Informed consent for the optional substudy is obtained at Week 72 for subjects participating in Part 2. 
 
  
 
 
. 
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, LCVA, 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. 
 
 
 


Product: BIIB033 
Study: 215MS202 
         Statistical Analysis Plan  
           Version: 2.0 
 
 
Page 86 
 
 
Part 2  Schedule of Activities 
Table 9: 
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 








Product: BIIB033 
Study: 215MS202 
         Statistical Analysis Plan  
           Version: 2.0 
 
 
Page 90 
 
 
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 
Blood chemistry 
 
X 
 
 
X 
 
 
X 
 
 
X 
X10 
X 
X 
Urinalysis 
 
X 
 
 
X 
 
 
X 
 
 
X 
X11 
X 
X 
Urine pregnancy 
test12 
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 
 
 
 




Product: BIIB033 
Study: 215MS202 
         Statistical Analysis Plan  
           Version: 2.0 
 
 
Page 92 
 
 
 
  
 
 
 
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, 6MWT, 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. 
 
 






 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 












 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 


o
o
o
o
o


















study Day 1
study Day 1 in Part 2
 first dose date
last dose date in Part 1
 first dose date in Part 2 
 last dose date in Part 2
EOT in Part 1 date
EOT in 
Part 2 date
ET visit in Part 1 date
ET visit 
in Part 2 date
The EOS date




 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
  
  
 
 
 
 
 
 
  
 
  
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
  
 
 
 
 
 
  
  
  
 
 
 
 
 
  
 
 
 
  
  
 
  
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
  
 
  
 
  
 
  
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
  
 
  
 
 
 
  
  
 
  
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 


Unless stated otherwise, Study baseline data
Study baseline data in Part 2


treatment emergent in Part 2
o
o
o
o
o
o


60-day relapse window
potential improvement
tentative improvement


12-week confirmation visit
12-week CDI 


with CDI in this component
CDI event of the component
with CDI in this MCE
CDI event of the MCE
potential worsening


tentative 
worsening
12-week confirmation visit
12-week CDW 


with CDW 
in this component
CDW event of the component
with CDW in this MCE
CDW event of the MCE




o
o
o
o
o
o




 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


o
o
o
o
o
o






 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
  
 
 
 
  
 
  
  
 
  
 
 
  
 
  
 
 
 
 
 
 
 
  
  
 
 
  
  
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 








o
o
o
o
o
o
o
o