A Randomized, Controlled, Open-Label, Rater-Blinded, Phase 3b Study of the Efficacy, Safety, and Tolerability of 6-Week Extended Interval Dosing (EID) of Natalizumab (BG00002) in Subjects With Relapsing-Remitting Multiple Sclerosis Switching From Treatment With 4-Week Natalizumab Standard Interval Dosing (SID) in Relation to Continued SID Treatment - Followed by an Open-Label Crossover Extension Study Comprising Subcutaneous and Intravenous Natalizumab Administration
Phase: PHASE3
Conditions: Multiple Sclerosis, Relapsing-Remitting
Sponsor: Biogen

COVER PAGE 
Official Title: A Randomized, Controlled, Open-Label, Rater-Blinded, Phase 3b 
Study of the Efficacy, Safety, and Tolerability of 6-Week Extended 
Interval Dosing (EID) of Natalizumab (BG00002) in Subjects With 
Relapsing-Remitting Multiple Sclerosis Switching From Treatment 
With 4-Week Natalizumab Standard Interval Dosing (SID) in Relation 
to Continued SID Treatment - Followed by an Open-Label Crossover 
Extension Study Comprising Subcutaneous and Intravenous 
Natalizumab Administration 
NCT Number: 
NCT03689972 
Document Date: 
Protocol version 4.0: 20 Aug 2020 

CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
1
Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
United States
PROTOCOL NUMBER:
101MS329
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead Berkshire
SL6 4AY
United Kingdom
PHASE OF DEVELOPMENT:
3b
PROTOCOL TITLE: A Randomized, Controlled, Open-Label, Rater-Blinded, Phase 3b 
Study of the Efficacy, Safety, and Tolerability of 6-Week Extended Interval Dosing (EID) 
of Natalizumab (BG00002) in Subjects With Relapsing-Remitting Multiple Sclerosis 
Switching From Treatment With 4-Week Natalizumab Standard Interval Dosing (SID) in 
Relation to Continued SID Treatment - Followed by an Open-Label Crossover Extension
Study Comprising Subcutaneous and Intravenous Natalizumab Administration
EUDRA CT NUMBER:
2018-002145-11
DATE:
20 August 2020
Version 4.0
FINAL
Supersedes previous Version 3.0 dated 08 July 2020

Protocol 101MS329
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TABLE OF CONTENTSTABLE OF CONTENTS
SPONSOR SIGNATURE PAGE ....................................................................................................2
1.
SYNOPSIS ...................................................................................................................9
2.
LIST OF ABBREVIATIONS.....................................................................................15
3.
SPONSOR INFORMATION .....................................................................................17
4.
INTRODUCTION......................................................................................................18
4.1.
Overview of Multiple Sclerosis..................................................................................18
4.2.
Current Therapies for Multiple Sclerosis ...................................................................19
4.3.
Profile of Previous Experience With Natalizumab.....................................................19
4.3.1.
Nonclinical Experience...............................................................................................19
4.3.2.
Clinical Experience.....................................................................................................19
4.4.
Benefit-Risk Assessment............................................................................................20
4.5.
Study Rationale...........................................................................................................21
5.
SCHEDULE OF ACTIVITIES ..................................................................................22
5.1.
Part 1 – Schedule of Activities ...................................................................................22
5.2.
Part 2 – Schedule of Activities ...................................................................................32
6.
STUDY OBJECTIVES AND ENDPOINTS..............................................................42
6.1.
Part 1 Objectives and Endpoints.................................................................................42
6.2.
Part 2 Objectives and Endpoints.................................................................................44
7.
STUDY DESIGN .......................................................................................................47
7.1.
Study Duration for Subjects........................................................................................49
7.1.1.
Study Duration for Subjects Enrolled Only in Part 1 .................................................49
7.1.2.
Study Duration for Subjects Enrolled in Part 1 and Part 2.........................................49
7.2.
Responsibilities of Study Site Staff............................................................................49
7.2.1.
General Staff Responsibilities During Part 1 and Part 2 ............................................49
7.2.2.
Changes in Responsibilities During Part 2.................................................................52
7.3.
Unscheduled Visits and Treatment for MS Relapses .................................................52
7.3.1.
Unscheduled Visits in Part 1.......................................................................................53
7.3.2.
Unscheduled Visits in Part 2.......................................................................................53
7.4.
Study Stopping Rules .................................................................................................53
7.5.
End of Study ...............................................................................................................53
8.
SELECTION OF SUBJECTS ....................................................................................54

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8.1.
Part 1 Inclusion Criteria..............................................................................................54
8.2.
Part 1 Exclusion Criteria.............................................................................................54
8.3.
Part 2 Inclusion Criteria..............................................................................................56
8.4.
Part 2 Exclusion Criteria.............................................................................................56
8.5.
Part 2 Inclusion Criteria for New Subjects.................................................................56
8.6.
Part 2 Exclusion Criteria for New Subjects................................................................57
9.
SCREENING AND RANDOMIZATION .................................................................58
9.1.
Screening ....................................................................................................................58
9.1.1.
Part 1 Screening..........................................................................................................58
9.1.2.
Part 2 Screening..........................................................................................................58
9.2.
Randomization............................................................................................................59
9.2.1.
Part 1 Randomization .................................................................................................59
9.2.2.
Part 2 Randomization .................................................................................................59
9.3.
Blinding Procedures....................................................................................................59
9.3.1.
Part 1 Blinding............................................................................................................59
9.3.2.
Part 2 Blinding............................................................................................................59
10.
DISCONTINUATION OF STUDY TREATMENT AND WITHDRAWAL 
OF SUBJECTS FROM THE STUDY........................................................................60
10.1.
Discontinuation of Study Treatment...........................................................................60
10.2.
Lost to Follow-Up.......................................................................................................61
10.3.
Withdrawal of Subjects From Study...........................................................................61
11.
STUDY TREATMENT USE .....................................................................................62
11.1.
Regimen......................................................................................................................62
11.1.1.
Part 1 Regimen ...........................................................................................................62
11.1.2.
Part 2 Regimen ...........................................................................................................62
11.2.
Modification of Dose and Treatment Schedule..........................................................62
11.2.1.
Modification of Dose..................................................................................................62
11.2.2.
Modification of Treatment Schedule..........................................................................62
11.2.2.1.
Part 1 Modification of Treatment ...............................................................................62
11.2.2.2.
Part 2 Modification of Treatment ...............................................................................63
11.3.
Precautions..................................................................................................................63
11.4.
Compliance.................................................................................................................63

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11.5.
Concomitant Therapy and Procedures........................................................................63
11.5.1.
Concomitant Therapy .................................................................................................63
11.5.1.1.
Allowed Concomitant Therapy...................................................................................63
11.5.1.2.
Disallowed Concomitant Therapy..............................................................................64
11.5.2.
Concomitant Procedures.............................................................................................64
11.5.2.1.
Disallowed Concomitant Procedures..........................................................................64
11.6.
Continuation of Treatment..........................................................................................65
12.
STUDY TREATMENT MANAGEMENT................................................................66
12.1.
Natalizumab................................................................................................................66
12.1.1.
Natalizumab Preparation ............................................................................................66
12.1.2.
Natalizumab Storage...................................................................................................66
12.1.3.
Natalizumab Handling and Disposal ..........................................................................67
12.1.4.
Natalizumab Accountability.......................................................................................67
13.
EFFICACY, PHARMACOKINETIC, AND PHARMACODYNAMIC 
ASSESSMENTS.........................................................................................................68
13.1.
Clinical Efficacy Assessments....................................................................................68
13.1.1.
Part 1 Efficacy Assessments.......................................................................................68
13.1.2.
Part 2 Efficacy Assessments.......................................................................................69
13.2.
Pharmacokinetic Assessments....................................................................................69
13.3.
Pharmacodynamic Assessments.................................................................................69
13.3.2.
Part 2 Pharmacodynamic Assessments.......................................................................70
14.
SAFETY ASSESSMENTS ........................................................................................71
14.1.
Clinical Safety Assessments.......................................................................................71
14.2.
Laboratory Safety Assessments..................................................................................71
14.3.
Natalizumab Safety Assessments ...............................................................................71
15.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................72
15.1.
Definitions ..................................................................................................................72
15.1.1.
Adverse Event.............................................................................................................72
15.1.2.
Serious Adverse Event................................................................................................72
15.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments................73

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15.2.
Safety Classifications..................................................................................................73
15.2.1.
Investigator Assessment of Events.............................................................................73
15.2.2.
Relationship of Events to Study Treatment................................................................73
15.2.3.
Severity of Events.......................................................................................................74
15.2.4.
Expectedness of Events ..............................................................................................74
15.3.
Monitoring and Recording Events..............................................................................74
15.3.1.
Adverse Events ...........................................................................................................74
15.3.2.
Serious Adverse Events..............................................................................................75
15.3.3.
Immediate Reporting of Serious Adverse Events.......................................................75
15.3.3.1.
Deaths .........................................................................................................................75
15.3.4.
Suspected Unexpected Serious Adverse Reactions....................................................76
15.4.
Procedures for Handling Special Situations ...............................................................76
15.4.1.
Progressive Multifocal Leukoencephalopathy ...........................................................76
15.4.2.
Pregnancy ...................................................................................................................76
15.4.3.
Overdose.....................................................................................................................76
15.4.4.
Medical Emergency....................................................................................................77
15.5.
Contraception Requirements ......................................................................................77
15.6.
Safety Responsibilities................................................................................................78
15.6.1.
The Investigator..........................................................................................................78
15.6.2.
Biogen.........................................................................................................................78
16.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........79
16.1.
Efficacy.......................................................................................................................79
16.1.1.
Analysis Population....................................................................................................79
16.1.2.
General Methods of Analysis .....................................................................................79
16.1.3.
Part 1 Statistical Analysis...........................................................................................79
16.1.3.1.
Analysis of the Primary Endpoint in Part 1................................................................79
16.1.3.2.
Primary and Secondary Estimands and Handling of Intercurrent Events in 
Part 1...........................................................................................................................80
16.1.3.3.
Analysis of the Secondary Endpoints in Part 1 ..........................................................81
16.1.3.5.
Subgroup Analyses in Part 1.......................................................................................82
16.1.4.
Part 2 Statistical Analysis...........................................................................................83

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16.1.4.1.
Analysis of the Primary Endpoint in Part 2................................................................83
16.1.4.2.
Analysis of the Secondary Endpoint in Part 2............................................................83
16.2.
Pharmacokinetics........................................................................................................86
16.2.1.
Analysis Population....................................................................................................86
16.2.2.
Methods of Analysis...................................................................................................86
16.3.
Pharmacodynamics.....................................................................................................86
16.3.1.
Analysis Population....................................................................................................86
16.3.2.
Methods of Analysis...................................................................................................86
16.5.
Safety..........................................................................................................................87
16.5.1.
Analysis Population....................................................................................................87
16.5.2.
Methods of Analysis...................................................................................................87
16.5.2.1.
Adverse Events ...........................................................................................................87
16.5.2.2.
Clinical Laboratory Results........................................................................................88
16.5.2.3.
Vital Signs ..................................................................................................................88
16.5.2.4.
C-SSRS.......................................................................................................................88
16.6.
Antigenicity/Immunogenicity Data ............................................................................88
16.6.1.
Analysis Population....................................................................................................88
16.6.2.
Methods of Analysis...................................................................................................88
16.7.
Interim Analyses.........................................................................................................88
16.8.
Sample Size Considerations .......................................................................................89
17.
ETHICAL REQUIREMENTS ...................................................................................90
17.1.
Declaration of Helsinki...............................................................................................90
17.2.
Ethics Committee........................................................................................................90
17.3.
Subject Information and Consent ...............................................................................90
17.4.
Subject Data Protection ..............................................................................................91
17.5.
Compensation for Injury.............................................................................................91
17.6.
Conflict of Interest......................................................................................................92
17.7.
Registration of Study and Disclosure of Study Results..............................................92

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18.
ADMINISTRATIVE PROCEDURES.......................................................................93
18.1.
Study Site Initiation....................................................................................................93
18.2.
Quality Control and Quality Assurance......................................................................93
18.3.
Monitoring of the Study..............................................................................................93
18.4.
Study Funding.............................................................................................................93
18.5.
Publications.................................................................................................................94
19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION........................95
19.1.
External Contract Organizations.................................................................................95
19.1.1.
Contract Research Organization.................................................................................95
19.1.2.
Interactive Response Technology...............................................................................95
19.1.3.
Electronic Data Capture..............................................................................................95
19.1.4.
Central Facility for MRI Scans...................................................................................95
19.2.
Study Committees.......................................................................................................95
19.2.1.
Advisory Committee...................................................................................................95
19.2.2.
Independent Neurology Evaluation Committee .........................................................96
19.3.
Changes to Final Study Protocol ................................................................................96
19.4.
Ethics Committee Notification of Study Completion or Termination........................96
19.5.
Retention of Study Data..............................................................................................96
19.6.
Study Report Signatory...............................................................................................96
20.
REFERENCES ...........................................................................................................97
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL.........................................98
LIST OF TABLES
Table 1:
Part 1 Schedule of Activities – SID............................................................................23
Table 2:
Part 1 Schedule of Activities – EID............................................................................28
Table 3:
Part 2 Schedule of Activities – EID SC vs. IV OLE for Subjects Who 
Participated in Part 1...................................................................................................33
Table 4:
Part 2 Schedule of Activities – EID SC vs. IV OLE for New Subjects .....................37
LIST OF FIGURES
Figure 1:
Design for Study 101MS329 with Open-Label Extension.........................................48

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1.
SYNOPSIS
Protocol Title:
A Randomized, Controlled, Open-Label, Rater-Blinded, Phase 3b 
Study of the Efficacy, Safety, and Tolerability of 6-Week Extended 
Interval Dosing (EID) of Natalizumab (BG00002) in Subjects With 
Relapsing-Remitting Multiple Sclerosis Switching From Treatment 
With 4-Week Natalizumab Standard Interval Dosing (SID) in Relation 
to Continued SID Treatment - Followed by an Open-Label Crossover 
Extension Study Comprising Subcutaneous and Intravenous
Natalizumab Administration
Protocol Number:
101MS329
Version Number:
4.0
Name of Study 
Treatment:
BG00002 (natalizumab; Tysabri®)
Study Phase:
3b
Study Indication:
Relapsing-remitting multiple sclerosis (RRMS)
Study Rationale:
Extending the dosing interval of natalizumab (e.g., to 6 weeks) has 
been practiced by some physicians in anti-John Cunningham virus
antibody-positive patients with the intention of improving the 
benefit/risk of the treatment by reducing the exposure-dependent risk of 
progressive multifocal leukoencephalopathy while maintaining 
efficacy. Whether extending the dosing interval of natalizumab can 
potentially improve benefit/risk for some patients remains to be 
established as there are no prospective, randomized, controlled studies 
assessing the efficacy of extended interval dosing (EID). This study 
aims to assess the following: the initial efficacy, safety, and tolerability 
of switching to EID (dosing interval every 6 weeks [Q6W]) after at 
least 12 months of disease stability on standard interval dosing (SID) 
[dosing interval every 4 weeks (Q4W)] compared to the continuation of 
SID; and the long-term efficacy, safety, and tolerability of EID when 
natalizumab is delivered by subcutaneous (SC) or intravenous (IV) 
administration. This study has 2 parts.

Part 1 is a randomized, controlled, rater-blinded analysis
designed to compare the efficacy, safety, and tolerability of 
natalizumab EID and SID outcomes.

Part 2 is a randomized open-label extension (OLE) designed to 
assess subject preference for SC natalizumab EID treatment 

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and explore long-term efficacy, safety, and tolerability of EID.
Study Objectives 
and Endpoints:
Part 1
The primary objective of Part 1 of the study is to evaluate the efficacy 
of natalizumab EID in subjects who have previously been treated with 
natalizumab SID for at least 12 months, in relation to continued SID 
treatment, with the goal of estimating the difference between SID and 
EID, with high precision and a narrow 95% confidence interval, to 
support the treatment decision based on individualized benefit/risk 
assessments.

The primary endpoint that relates to this objective is the 
number of new or newly enlarging T2 hyperintense lesions at 
Week 72.
Secondary objectives and endpoints for Part 1 of the study are as 
follows:

To evaluate additional relapse-based clinical efficacy measures 
of natalizumab EID in subjects who have previously been 
treated with natalizumab SID for at least 12 months, in relation 
to continued SID treatment.
o
Time to first relapse (relapses will be adjudicated by an 
Independent Neurology Evaluation Committee)
o
Annualized relapse rate at Week 72

To evaluate disability worsening of natalizumab EID in 
subjects who have previously been treated with natalizumab 
SID for at least 12 months, in relation to continued SID 
treatment.
o
Time to Expanded Disability Status Scale (EDSS) 
worsening (confirmed after at least 24 weeks)

To evaluate additional magnetic resonance imaging 
(MRI)-lesion efficacy measures of natalizumab EID in subjects 
who have previously been treated with natalizumab SID for at 
least 12 months, in relation to continued SID treatment.
o
Number of new or newly enlarging T2 hyperintense lesions 
at Week 24 and Week 48
o
Number of new gadolinium (Gd)-enhancing and new 
T1 hypointense lesions at Weeks 24, 48, and 72

To evaluate the safety of natalizumab EID in subjects who have 
previously been treated with natalizumab SID for at least 
12 months in relation to continued SID treatment.

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up visit or follow-up safety phone call 24 weeks after the last dose of 
study treatment in Part 1.
Part 2 
Study duration for subjects enrolled in Part 2 after completing Part 1 
and for new subjects will be approximately 108 weeks, comprising the 
following: 

36-week period of IV Q6W treatment

48-week randomized crossover treatment period comprising 
24 weeks SC Q6W and 24 weeks IV Q6W

12-week follow-up period

Follow-up safety phone call 12 weeks after the follow-up 
period (24 weeks after the last dose of study treatment)
The total duration of study participation for subjects who participate in 
both Part 1 and Part 2 will be approximately 186 weeks.
The Part 2 Screening, informed consent, and eligibility assessment 
should be performed during Week 72 of Part 1. In the event that the 
Part 2 Screening cannot be performed at that time, a separate Part 2 
Screening may occur within 6 weeks prior to Week 78 or Week 84, 
whichever visit and infusion is the first Part 2 administration of study 
treatment to the subject. Subject randomization to crossover sequence 
in Part 2 will occur at the Week 108 visit to confirm crossover 
treatment allocation.
After Week 84, subjects are not eligible for enrollment in Part 2 of the 
study.

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2.
LIST OF ABBREVIATIONS
AE
adverse event
CI
confidence interval
CNS
central nervous system
CRF
case report form
CRO
contract research organization
C-SSRS
Columbia Suicide Severity Rating Scale
Ctrough
trough serum concentration of natalizumab
DHA
Directions for Handling and Administration
DNA
deoxyribonucleic acid
EDSS
Expanded Disability Status Scale
EID
extended interval dosing
EOS
end of study
ET
early termination
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
Gd
gadolinium
Hep
hepatitis
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
INEC
Independent Neurology Evaluation Committee
IRT
interactive response technology
IV
intravenous(ly)
JCV
John Cunningham virus
KM
Kaplan-Meier
mAb
monoclonal antibody
mITT
modified intent to treat
MMRM
mixed model of repeated measures
MRI
magnetic resonance imaging
MS
multiple sclerosis
D

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OLE
open-label extension
PBMC
peripheral blood mononuclear cell
PBVC
percentage of brain volume change
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
PPQ
Patient Preference Questionnaire
PRO
patient-reported outcome
Q4W
every 4 weeks
Q6W
every 6 weeks
RNA
ribonucleic acid
RRMS
relapsing-remitting multiple sclerosis
SAE
serious adverse event
SC
subcutaneous
SID
standard interval dosing
SUSAR
suspected unexpected serious adverse reaction
TSQM
Treatment Satisfaction Questionnaire for Medication
USA
United States
VCAM-1
vascular cell adhesion molecule 1

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

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4.
INTRODUCTION 
Natalizumab is a recombinant humanized anti-α4 integrin antibody, derived from a monoclonal 
antibody (mAb) [AN100226m] raised against human α4 integrin. The murine mAb 
(AN100226m) was humanized by complementarity-determining region grafting of the 
hypervariable region of the gene encoding AN100226m onto a human immunoglobulin G4 
framework, producing the humanized immunoglobulin G4/kappa antibody, natalizumab.
Natalizumab has been approved under the propriety name Tysabri® and was licensed for use in 
relapsing forms of multiple sclerosis (MS) by the United States (US) Food and Drug 
Administration on 23 November 2004. Natalizumab was authorized in the US on 05 June 2006, 
in the European Union on 27 June 2006 (Austria, Belgium, Bulgaria, Croatia 
[15 December 2008], Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, 
Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, the Netherlands, Poland, 
Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, and the United Kingdom), and in 
multiple other countries in the rest of the world (Algeria, Argentina, Australia, Azerbaijan, 
Bahrain, Bosnia and Herzegovina, Brazil, Canada, Chile, Colombia, Costa Rica, Dominican 
Republic, El Salvador, Georgia, Guatemala, Honduras, Hong Kong, Iceland, India, Israel, Japan, 
Jordan, Kazakhstan, Kuwait, Lebanon, Libya, Malaysia, Mexico, Morocco, New Zealand, 
Norway, Oman, Panama, Peru, Qatar, Russia, Serbia, Singapore, South Africa, South Korea, 
Switzerland, Syria, Taiwan, Tunisia, Ukraine, the United Arab Emirates, Uruguay, and 
Venezuela).
4.1.
Overview of Multiple Sclerosis
MS is a progressive, degenerative disease of the central nervous system (CNS) characterized by 
a variety of clinical courses. Approximately 90% of patients present with episodic neurological 
symptoms and will have bouts of disease activity (exacerbations) separated by periods of total or 
partial remission (relapsing-remitting phase). A typical patient will have 1 or 2 exacerbations per 
year with variable duration, lasting from several weeks to more than a month. This 
relapsing-remitting phase may last many years but, in most patients, is eventually followed by a 
period of chronic progressive decline (secondary progression), with increasing disability and 
with or without exacerbations. Approximately 10% of patients will have progression from the 
onset of the disease (primary progression), without acute exacerbations.
MS is an inflammatory disease of the CNS characterized by areas of demyelination (lesions), 
which give rise to the clinical symptoms of the disease. Although lesions can occur throughout 
the CNS, certain sites seem particularly vulnerable, such as the optic nerve, brainstem, spinal 
cord, and periventricular regions. Lesions are believed to occur when activated T lymphocytes 
cross the blood-brain barrier and, once in the parenchyma, initiate a series of events leading to 
activation of endothelial cells, recruitment of additional lymphocytes and monocytes, release of 
proinflammatory cytokines, and subsequent demyelination [Ffrench-Constant 1994].  
Trafficking of leukocytes across the blood-brain barrier involves interaction of the cell adhesion 
molecule α4 integrin, expressed on lymphocytes and monocytes, with its counter receptors 
vascular cell adhesion molecule 1 (VCAM-1) and fibronectin on brain endothelial cells. In 

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19
particular, VCAM-1 is expressed on inflamed brain endothelial cells and on activated microglial 
cells, while fibronectin is expressed around inflamed brain microvessels [Hartung 1995].
Blockade of these cell adhesion interactions is assumed to either prevent trafficking of 
leukocytes across the vascular endothelium, into parenchyma tissue, and subsequently into 
inflamed tissue; or prevent their activation by ligands in the parenchyma. It is believed that the 
clinical progression of MS is related to the demyelination caused by leukocyte injury to the 
myelin sheaths. Thus, inhibiting or preventing leukocyte entry into the CNS and subsequent 
leukocyte activation is expected to be of therapeutic benefit in MS.
4.2.
Current Therapies for Multiple Sclerosis
Approved therapies for MS include the following: 

interferon 

glatiramer acetate

dimethyl fumarate

teriflunomide

alemtuzumab

fingolimod

ocrelizumab

cladribine

mitoxantrone

natalizumab

diroximel fumarate

siponimod

ozanimod
4.3.
Profile of Previous Experience With Natalizumab
See the Investigator’s Brochure (IB) for detailed information on relevant nonclinical and clinical
studies.
4.3.1.
Nonclinical Experience
The pharmacology, pharmacokinetics (PK), and toxicology of natalizumab have been 
characterized in nonclinical in vitro and in vivo experimental systems. Nonclinical studies are 
outlined in the accompanying natalizumab IB.
4.3.2.
Clinical Experience
Natalizumab has been used extensively in relapsing-remitting multiple sclerosis (RRMS) and 
Crohn’s disease, both in clinical studies as well as in the postmarketing setting.

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As of 07 August 2017, natalizumab has been administered for MS to approximately 
5064 subjects in clinical studies and approximately 171,630 patients in the postmarketing setting. 
Approximately 1639 and 1688 subjects have received natalizumab for Crohn’s disease in clinical 
studies and in the postmarketing setting, respectively. Additionally, subjects have received 
natalizumab in clinical studies for rheumatoid arthritis (231 subjects), acute ischemic stroke 
(210 subjects), and multiple myeloma (6 subjects).
The efficacy of natalizumab in subjects with relapsing forms of MS has been established in 
3 controlled studies: a Phase 2 dose-comparison study as well as 2 Phase 3 efficacy and safety 
studies. These studies show that treatment with natalizumab has a profound impact on disability 
worsening and relapse rate and markedly attenuates brain magnetic resonance imaging (MRI) 
measures of inflammation and tissue destruction in subjects with relapsing forms of MS. 
Moreover, the data indicate that efficacy is realized early and persists throughout the treatment 
period.
4.4.
Benefit-Risk Assessment
After more than 10 years of postmarketing experience, natalizumab continues to demonstrate a 
high level of efficacy with a well-characterized safety profile and a significant beneficial impact 
on the quality of life in patients with RRMS. In pivotal clinical studies, natalizumab 
demonstrated a 67% reduction in annualized relapse rate and a 42% reduction in the risk of 
disability progression over 2 years. Since the marketing of natalizumab, publications from 
multiple independent groups, as well as publications from the Sponsor, have further 
demonstrated the clinical effectiveness of natalizumab when used in patients with MS with high 
disease activity despite treatment with first-line therapies [Belachew 2011; Morrow 2010; Oturai 
2009; Sangalli 2011].
Extensive safety data from clinical studies and the postmarketing setting have resulted in a 
well-characterized safety profile for natalizumab. Infusion and hypersensitivity reactions and 
anti-natalizumab antibody production are important safety concerns; however, they are 
manageable in routine clinical practice. Serious herpes infections and hepatic events are 
additional safety concerns that are also included in product labeling; however, the incidence of 
these adverse events (AEs) is low.
The most important AE affecting natalizumab benefit-risk assessment is the occurrence of 
progressive multifocal leukoencephalopathy (PML). Three established risk factors for the 
development of PML have been identified and are currently included in the product labeling: that 
PML risk is increased with the presence of anti-John Cunningham virus (JCV) antibodies, 
treatment duration (especially beyond 2 years of therapy), and prior use of an 
immunosuppressant therapy. These 3 risk factors, as well as information about anti-JCV 
antibody index in anti-JCV antibody-positive patients without any prior immunosuppressant use, 
can be utilized to further stratify the risk of PML and therefore provide an important tool for 
physicians and patients when making individual benefit-risk decisions regarding initiation or 
continuation of natalizumab therapy. 
Overall, the benefit-risk ratio for natalizumab in treating RRMS remains positive.

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4.5.
Study Rationale
The safety and efficacy of the currently recommended dose (300 mg natalizumab administered 
intravenously [IV] every 4 weeks [Q4W]) has been well established through clinical trials and in 
real-world clinical practice.  
Extending the dosing interval of natalizumab (e.g., to every 6 weeks [Q6W]) has been practiced 
by some physicians in anti-JCV antibody-positive patients with the intention of improving the 
benefit/risk of the treatment by reducing the exposure-dependent risk of PML while maintaining 
efficacy. In a prespecified, retrospective analysis of anti-JCV antibody-positive patients treated 
with natalizumab in the US TOUCH (Tysabri® Outreach: United Commitment to Health) 
program (n = 18,755), the risk of PML was compared between patients treated with standard 
interval dosing (SID) and patients treated with extended interval dosing (EID) for at least 
6 months (300 mg with an average dosing interval of 5 to 6 weeks). The majority of patients 
were treated with SID for at least 1 year before switching to EID (median of 25 SID infusions 
prior to switch). The analysis demonstrated a clinically and statistically significant reduction in 
the risk of PML in patients treated with EID. Whether extending the dosing interval of 
natalizumab can potentially improve benefit/risk for some patients remains to be established as 
there are no prospective, randomized, controlled studies assessing efficacy of EID.
This study will be conducted in 2 parts: Part 1 is a randomized, controlled, rater-blinded, 
analysis designed to assess the efficacy, safety, and tolerability of switching to EID (Q6W 
dosing) after at least 12 months of disease stability on SID (Q4W dosing);Part 2 is a randomized
open-label extension (OLE) designed to assess preference for SC natalizumab EID treatment and 
explore long-term efficacy, safety, and tolerability of EID.

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Table 1:
Part 1 Schedule of Activities – SID
Tests and assessments are listed in the recommended order. At each visit, assessments should be performed as follows:
, 2) clinical and neurological assessments, 
, and 4) dose administration. 
It is not required that all screening tests and assessments be completed during 1 visit.
Study Week
Screening
Visit1
-6 to -1
Baseline 
Visit
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68 722 Follow 
Up 
EOS 
Visit
84
Follow 
Up 
Safety 
Phone 
Call
963
ET 
Visit4 Unscheduled 
Visit 
(Neurological 
Worsening 
and Relapse 
Assessment)5
Study Day
-42 to -1
0
28
(-2/
+5)
56
(-2/
+5)
84
(-2/
+5)
112
(-2/
+5)
140
(-2/
+5)
168
(-2/
+5)
196
(-2/
+5)
224
(-2/
+5)
252
(-2/
+5)
280
(-2/
+5)
308
(-2/
+5)
336
(-2/
+5)
364
(-2/
+5)
392
(-2/
+5)
420
(-2/
+5)
448
(-2/
+5)
476
(-2/
+5)
504
(-2/
+5)
588
(±10)
672
(±10)
Informed Consent 
Form 
X
Eligibility Criteria 
Check
X
X
Randomization
X
Medical History
X
Physical 
Examination
X
X6
X
X
X
X
X
X
Body Weight
X
X6
X
X
X
X
X
X
Vital Signs7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV, Hep B, and 
Hep C Testing
X

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Study Week
Screening
Visit1
-6 to -1
Baseline 
Visit
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68 722 Follow 
Up 
EOS 
Visit
84
Follow 
Up 
Safety 
Phone 
Call
963
ET 
Visit4 Unscheduled 
Visit 
(Neurological 
Worsening 
and Relapse 
Assessment)5
Study Day
-42 to -1
0
28
(-2/
+5)
56
(-2/
+5)
84
(-2/
+5)
112
(-2/
+5)
140
(-2/
+5)
168
(-2/
+5)
196
(-2/
+5)
224
(-2/
+5)
252
(-2/
+5)
280
(-2/
+5)
308
(-2/
+5)
336
(-2/
+5)
364
(-2/
+5)
392
(-2/
+5)
420
(-2/
+5)
448
(-2/
+5)
476
(-2/
+5)
504
(-2/
+5)
588
(±10)
672
(±10)
C-SSRS8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
EDSS
X
X
X
X
X
X
X
Neurological 
Examination (MS 
Signs & Symptoms)
X
X
X
X
X
X
X
Blood Hematology9
X
X
X
X
X
X
Blood Chemistry10
X
X
X
Serum Pregnancy 
Test11
X
Serum FSH12
X
Urine Pregnancy 
Test13
X

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9
Sample to be collected prior to dosing.
10 If a subject experiences signs and symptoms suggestive of liver injury (such as jaundice, vomiting, anorexia, nausea, fatigue, and right upper abdominal 
discomfort), liver function tests (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, bilirubin, and 
albumin) must be performed at the local laboratory on an expedited basis.
11 Required for women of childbearing potential. Results must be known prior to Day 0/Baseline.
12 For postmenopausal subjects only.
13 Required for women of childbearing potential. Follow-up testing throughout the study will be done at the discretion of the Investigator or as required by local 
law. In each case of delayed menstruation (over 1 month between menstrual periods), a urine pregnancy test should be performed.
15 The screening MRI must be performed at least 2 weeks prior to the Baseline Visit to confirm eligibility. All postbaseline MRIs, with the exception of the one 
conducted at the Neurological Worsening and Relapse Assessment, are to be completed within a 7-day window of the dosing visit. MRIs conducted at the 
Neurological Worsening and Relapse Assessment must be completed prior to dosing with rescue therapy, but can be completed on the same day. If a subject's 
MRI is scheduled to occur <4 weeks after the last dose of steroid treatment for relapse, the MRI should be rescheduled so that it is performed either before the 
steroid treatment of between 4 and 8 weeks after the last dose of steroid treatment. MRI does not need to be performed at the ET Visit if the last MRI was 
performed within the previous 4 weeks. In the event of an early study termination for a pregnancy, a Gd-enhancing MRI should not be conducted.
16
Please refer to the Directions for Handling and Administration (DHA) located in the Study Reference Guide for details of postdose observation requirements.
17 Subjects should be contacted by phone 24 weeks after the last dose of study treatment to discuss if there has been any new development of any new 
neurological symptoms. PML or new neurological symptoms indicative of PML (e.g., new or sudden change in thinking, vision, balance, or strength 
persisting over several days) must be immediately reported as an SAE.
P

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Table 2:
Part 1 Schedule of Activities – EID
Tests and assessments are listed in the recommended order. At each visit, assessments should be performed as follows:
, 
2) clinical and neurological assessments, 
, and 4) dose administration. It is not required that all 
screening tests and assessments be completed during 1 visit.
Study Week
Screening 
Visit1
-6 to -1
Baseline 
Visit
0
6
12
18
24
30
36
42
48
54
60
66
722
Follow
Up EOS 
Visit
84
Follow Up 
Safety 
Phone 
Call3
96
ET 
Visit4
Unscheduled 
Visit 
(Neurological 
Worsening 
and Relapse 
Assessment)5
Study Day
-42 to -1
0
42
(-2/
+5)
84
(-2/
+5)
126
(-2/
+5)
168
(-2/
+5)
210
(-2/
+5)
252
(-2/
+5)
294
(-2/
+5)
336
(-2/
+5)
378
(-2/
+5)
420
(-2/
+5)
462
(-2/
+5)
504
(-2/
+5)
588
(±10)
672
(±10)
Informed Consent Form
X
Eligibility Criteria Check
X
X
Randomization
X
Medical History
X
Physical Examination
X
X6
X
X
X
X
X
X
Body Weight
X
X6
X
X
X
X
X
X
Vital Signs7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV, Hep B, and Hep C 
Testing
X
C-SSRS8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

Protocol 101MS329
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Study Week
Screening 
Visit1
-6 to -1
Baseline 
Visit
0
6
12
18
24
30
36
42
48
54
60
66
722
Follow
Up EOS 
Visit
84
Follow Up 
Safety 
Phone 
Call3
96
ET 
Visit4
Unscheduled 
Visit 
(Neurological 
Worsening 
and Relapse 
Assessment)5
Study Day
-42 to -1
0
42
(-2/
+5)
84
(-2/
+5)
126
(-2/
+5)
168
(-2/
+5)
210
(-2/
+5)
252
(-2/
+5)
294
(-2/
+5)
336
(-2/
+5)
378
(-2/
+5)
420
(-2/
+5)
462
(-2/
+5)
504
(-2/
+5)
588
(±10)
672
(±10)
EDSS
X
X
X
X
X
X
X
Neurological Examination 
(MS Signs & Symptoms)
X
X
X
X
X
X
X
Blood Hematology9
X
X
X
X
X
X
Blood Chemistry10
X
X
X
Serum Pregnancy Test11
X
Serum FSH12
X
Urine Pregnancy Test13
X

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3
Subjects should have a follow-up safety phone call 24 weeks after their last dose of study treatment.
4
If a subject chooses to withdraw from the study, an ET Visit should occur as soon as possible but no later than 4 weeks after the last dose of study treatment, 
to be followed by a final EOS Visit at 12 weeks (± 10 days) and the follow-up safety phone call at 24 weeks after the final dose of study treatment.
5
Subjects who suspect that they are experiencing new or worsening neurological symptoms, including possible relapse, need to phone the Investigator within 
72 hours of the onset of the symptoms. The subject is to be evaluated by the neurologist within 5 days of the onset of symptoms. Relapses should be 
documented in the relapse assessment form. The maximum number of samples eligible for collection and analysis are 2 (1 for each unscheduled visit). The 
samples will be named NW1 and NW2.
6
If a screening test is performed within 7 days of the Baseline Visit, the assessment does not need to be repeated at Baseline.
7
Vital signs collected at each of the specified timepoints include temperature, systolic and diastolic blood pressures, pulse rate, and respiratory rate. Vital signs 
collected as part of the subject’s standard of care on the same day as a study visit do not need to be repeated for the study if Biogen has access to the 
information and data are recorded in the subject’s CRF. Vital signs taken on a study treatment day must be performed prior to study treatment administration.
8
The “baseline/screening” C-SSRS must be completed at the Screening Visit; at all other visits, the “since last visit” C-SSRS must be used.
9
Sample to be collected prior to dosing.
10 If a subject experiences signs and symptoms suggestive of liver injury (such as jaundice, vomiting, anorexia, nausea, fatigue, and right upper abdominal 
discomfort), liver function tests (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, bilirubin, and 
albumin) must be performed at the local laboratory on an expedited basis.
11 Required for women of childbearing potential. Results must be known prior to Day 0/Baseline.
12 For postmenopausal subjects only.
13 Required for women of childbearing potential. Follow-up testing throughout the study will be done at the discretion of the Investigator or as required by local 
law. In each case of delayed menstruation (over 1 month between menstrual periods), a urine pregnancy test should be performed.
15 The screening MRI must be performed at least 2 weeks prior to the Baseline Visit to confirm eligibility. All postbaseline MRIs, with the exception of the one 
conducted at the Neurological Worsening and Relapse Assessment, are to be completed within a 7-day window of the dosing visit. MRIs conducted at the 
Neurological Worsening and Relapse Assessment must be completed prior to dosing with rescue therapy, but can be completed on the same day. If a subject’s 
MRI is scheduled to occur < 4 weeks after the last dose of steroid treatment for relapse, the MRI should be rescheduled so it is performed either before the 
steroid treatment or between 4 and 8 weeks after the last dose of steroid treatment. MRI does not need to be performed at the ET Visit if the previous MRI 
was performed within the previous 4 weeks. In the event of an early study termination for a pregnancy, a Gd-enhancing MRI should not be conducted.
16 Subjects are to continue with their natalizumab SID until they have received their baseline dose. Please refer to the DHA located in the Study Reference 
Guide for details of postdose observation requirements.
17 Subjects should be contacted by phone 24 weeks after the last dose of study treatment to discuss if there has been any new development of any new 
neurological symptoms. PML or new neurological symptoms indicative of PML (e.g., new or sudden change in thinking, vision, balance, or strength 
persisting over several days) must be immediately reported as an SAE.
P

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5.2.
Part 2 – Schedule of Activities
For subjects who completed Part 1 treatment and enrolled in Part 2, the schedule of activities for 
Part 2 (Table 3) does not differ for subjects randomized to SC/IV or IV/SC with the exception of 
the order of treatment administration during the crossover period.
For new subjects enrolled in Part 2, the initial screening, inclusive of select assessments, differs 
from those subjects who participated in Part 1 but is otherwise the same beginning at Week 78 
through the end of Part 2 (Table 4).

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Table 3:
Part 2 Schedule of Activities – EID SC vs. IV OLE for Subjects Who Participated in Part 1
Tests and assessments are listed in the recommended order. At each visit, assessments should be performed as follows:
, 
2) clinical and neurological assessments, 3) PK/PD 
 collection, and 4) dose administration. It is not required that all 
screening tests and assessments be completed during 1 visit.
Study Week
78
841
90
96
102
108
114
120
126
132
138
144
150
156
Follow-
Up EOS 
Visit
168
ET 
Visit2
Unscheduled 
Visit 
(Neurological 
Worsening and 
Relapse 
Assessment)3
Follow-Up 
Safety 
Phone Call
1804
Study Day
546
(-2/
+5)
588
(-2/
+5)
630
(-2/
+5)
672
(-2/
+5)
714
(-2/
+5)
756
(-2/
+5)
798
(-2/
+5)
840
(-2/
+5)
882
(-2/
+5)
924
(-2/
+5)
966
(-2/
+5)
1008
(-2/
+5)
1050
(-2/
+5)
1092
(-2/
+5)
1176
(±10)
-
-
1260
(±10)
Informed 
Consent Form 
for Part 25
---- X ----
Eligibility 
Criteria Check 
for Part 25
---- X ----
Randomization
X
Vital signs6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
Examination1
X
X
X
X
X
X
X
Body Weight1
X
X
X
X
C-SSRS1,7
X
TSQM
X
X
X

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Study Week
78
841
90
96
102
108
114
120
126
132
138
144
150
156
Follow-
Up EOS 
Visit
168
ET 
Visit2
Unscheduled 
Visit 
(Neurological 
Worsening and 
Relapse 
Assessment)3
Follow-Up 
Safety 
Phone Call
1804
Study Day
546
(-2/
+5)
588
(-2/
+5)
630
(-2/
+5)
672
(-2/
+5)
714
(-2/
+5)
756
(-2/
+5)
798
(-2/
+5)
840
(-2/
+5)
882
(-2/
+5)
924
(-2/
+5)
966
(-2/
+5)
1008
(-2/
+5)
1050
(-2/
+5)
1092
(-2/
+5)
1176
(±10)
-
-
1260
(±10)
EDSS
X
X
X
X
X
X
Neurological 
Examination 
(MS Signs &
Symptoms)
X
X
X
X
X
X
Blood 
Hematology8
X
X
X
X
X
X
X
Blood 
Chemistry9
X
X
X
X
Urine Pregnancy 
Test10
PD Assessments 
(whole blood)8
X
X
X
X
X
X
X
X
X
X
PK Natalizumab 
Concentration 
(serum)8
X
X
X
X
X
X
X
X
X
X
Anti-
natalizumab 
Antibodies8
X
X
X
X
X
X
Brain MRI11
X
X
X
X

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to crossover study treatment should be done at the Week 108 visit to confirm crossover treatment allocation. After Week 84, subjects are not eligible for 
enrollment in Part 2 of the study.
6
Vital signs collected at each of the specified timepoints include temperature, systolic and diastolic blood pressure, pulse rate, and respiratory rate. Vital signs 
collected as part of the subject's standard of care on the same day as a study visit do not need to be repeated for the study if Biogen has access to the 
information and data recorded in the subject's CRF. Vital signs on a study treatment day must be performed prior to the administration of study treatment.
7
The Part 1 "baseline/screening" C-SSRS must be completed at the Part 1 screening Visit; at all other visits, the "since last visit" C-SSRS must be used.
8
Sample to be collected prior to dosing.
9
If a subject experiences signs and symptoms suggestive of liver failure (such as jaundice, vomiting, anorexia, nausea, fatigue, and right upper abdominal 
discomfort), liver function tests (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, bilirubin, and 
albumin) must be performed at the local laboratory on an expedited basis.
10 Follow-up testing for women of childbearing potential throughout the study will be done at the discretion of the Investigator or as required by local law. In 
each case of delayed menstruation (more than 1 month between menstrual periods), a urine pregnancy test should be performed.
11 All postbaseline MRIs are to be completed within a 7-day window of the dosing visit. If a subject's MRI is scheduled to occur < 4 weeks after the last dose of 
steroid treatment for relapse, the MRI should be rescheduled so it is performed either before the steroid treatment or between 4 and 8 weeks after the last dose 
of steroid treatment. MRI does not need to be performed at the ET Visit if the last MRI was performed within the previous 4 weeks. In the event of an early 
termination for a pregnancy, a Gd-enhancing MRI should not be conducted.
12 The time required for drug preparation and drug administration should be recorded in detail for each occasion of treatment administration during the crossover 
period. Please refer to the DHA located in the Study Reference Guide for details of postdose observation requirements.
13 Subjects in Part 2 will receive a final dose of natalizumab 300 mg by SC injection or IV infusion at the Week 156 visit with the route of administration being 
the subject’s choice.
14 PPQ assessments at Week 138 and Week 150 must be collected after study treatment administration.

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Table 4:
Part 2 Schedule of Activities – EID SC vs. IV OLE for New Subjects
Tests and assessments are listed in the recommended order. At each visit, assessments should be performed as follows:
, 
2) clinical and neurological assessments, 3) PK/PD 
 collection, and 4) dose administration. It is not required that all 
screening tests and assessments be completed during 1 visit. This Schedule of Activities is identical to the Schedule in Table 3 after 
the Week 84 visit.
Nominal
Study Week
Screen1
Baseline 
Visit
72
78
842
90
96
102
108
114
120
126
132
138
144
150
156
Follow-
Up EOS 
Visit
168
ET 
Visit3
Unscheduled 
Visit 
(Neurological 
Worsening 
and Relapse 
Assessment)4
Follow-
Up Safety 
Phone 
Call5
180
Nominal
Study Day
-42 to
-1
504
(-2/
+5)
546
(-2/
+5)
588
(-2/
+5)
630
(-2/
+5)
672
(-2/
+5)
714
(-2/
+5)
756
(-2/
+5)
798
(-2/
+5)
840
(-2/
+5)
882
(-2/
+5)
924
(-2/
+5)
966
(-2/
+5)
1008
(-2/
+5)
1050
(-2/
+5)
1092
(-2/
+5)
1176
(±10)
-
-
1260
(±10)
Informed 
Consent Form 
for Part 21
X
Eligibility 
Criteria Check 
for Part 21
X
X
Randomization
X
Medical 
History1
X
Physical 
Examination1
X
X
X
X
X
X
X
X
X
Body Weight1
X
X
X
X
X
X
Vital signs6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV, Hep B, 
and Hep C 
Testing
X
TSQM
X
X
X
X

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Nominal
Study Week
Screen1
Baseline 
Visit
72
78
842
90
96
102
108
114
120
126
132
138
144
150
156
Follow-
Up EOS 
Visit
168
ET 
Visit3
Unscheduled 
Visit 
(Neurological 
Worsening 
and Relapse 
Assessment)4
Follow-
Up Safety 
Phone 
Call5
180
Nominal
Study Day
-42 to
-1
504
(-2/
+5)
546
(-2/
+5)
588
(-2/
+5)
630
(-2/
+5)
672
(-2/
+5)
714
(-2/
+5)
756
(-2/
+5)
798
(-2/
+5)
840
(-2/
+5)
882
(-2/
+5)
924
(-2/
+5)
966
(-2/
+5)
1008
(-2/
+5)
1050
(-2/
+5)
1092
(-2/
+5)
1176
(±10)
-
-
1260
(±10)
EDSS
X
X
X
X
X
X
X
Neurological 
Examination 
(MS Signs &
Symptoms)
X
X
X
X
X
X
X
Blood 
Hematology7
X
X
X
X
X
X
X
X
Blood 
Chemistry8,7
X
X
X
X
X
Serum 
Pregnancy Test9
X
Serum FSH10
X
Urine Pregnancy 
Test11
X
PD Assessments 
(whole blood)7
X
X
X
X
X
X
X
X
X
X
X
PK Natalizumab 
Concentration 
(serum)7
X
X
X
X
X
X
X
X
X
X
X

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Nominal
Study Week
Screen1
Baseline 
Visit
72
78
842
90
96
102
108
114
120
126
132
138
144
150
156
Follow-
Up EOS 
Visit
168
ET 
Visit3
Unscheduled 
Visit 
(Neurological 
Worsening 
and Relapse 
Assessment)4
Follow-
Up Safety 
Phone 
Call5
180
Nominal
Study Day
-42 to
-1
504
(-2/
+5)
546
(-2/
+5)
588
(-2/
+5)
630
(-2/
+5)
672
(-2/
+5)
714
(-2/
+5)
756
(-2/
+5)
798
(-2/
+5)
840
(-2/
+5)
882
(-2/
+5)
924
(-2/
+5)
966
(-2/
+5)
1008
(-2/
+5)
1050
(-2/
+5)
1092
(-2/
+5)
1176
(±10)
-
-
1260
(±10)
Anti-
natalizumab 
Antibodies7
X
X
X
X
X
X
X
Brain MRI12
X
X
X
X
X
Natalizumab 
EID IV infusion
X
X
X
X
X
X
X
Natalizumab 
EID SC-IV 
Crossover13
X
X
X
X
X
X
X
X
X14
PPQ15
X
X
X
Safety (AEs, 
SAEs)
Record as per Section 15.3 of the protocol
Concomitant 
Therapy and 
Procedures
Record as per Section 11.5 of the protocol
X
Assessment of 
New 
Neurological 
Symptoms16
X
AE = adverse event; CRF = case report form; EDSS = Expanded Disability Status Scale; EID = extended interval dosing; EOS = end of study; 
 
; ET = early termination; FSH = follicle stimulating hormone; Gd = gadolinium; Hep = hepatitis; HIV = human immunodeficiency virus; 

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15 PPQ assessments at Week 138 and Week 150 must be collected after study treatment administration.
16 Subjects should be contacted by phone 24 weeks after the last dose of study treatment to discuss if there has been any new development of neurological 
symptoms. PML or new neurological symptoms indicative of PML (new or sudden change in thinking, vision, balance, or strength persisting over several 
days) must be immediately reported as a SAE.

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To evaluate drug preparation and 
administration time between SC and IV 
routes of natalizumab administration.
Mean time for drug preparation and 
administration.
To evaluate the safety and immunogenicity of 
SC versus IV routes of natalizumab 
administration.
All endpoints will be assessed between
6 months of SC and 6 months IV in the 
randomized, crossover period.

The proportion of subjects with 
treatment emergent AEs

The proportion of subjects who develop 
anti-natalizumab antibodies 
To evaluate the efficacy of SC versus IV 
routes of natalizumab administration.
All endpoints will be assessed between
6 months of SC and 6 months IV in the 
randomized, crossover period.

Number of new or newly enlarging 
T2 hyperintense lesions

Time to first relapse

Annualized relapse rate

Change in EDSS score

Number of new Gd-enhancing lesions

Number of new T1 hypointense lesions

PBVC and change in cortical and 
thalamic brain region volume
To characterize PK and PD of SC versus IV 
routes of natalizumab administration.
All endpoints will be assessed between
6 months of SC and 6 months IV in the 
randomized, crossover period.

Ctrough

Trough α4 integrin saturation

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7.
STUDY DESIGN
This study will be conducted in 2 parts. Part 1 is a prospective, randomized, interventional, 
controlled, open-label, rater-blinded, Phase 3b study in subjects with RRMS who have been 
receiving natalizumab SID for at least 12 months without relapses in the last 12 months. All MRI 
scans will be read at a central facility with raters blinded to subject assignment. Approximately 
480 subjects are expected to be enrolled at approximately 100 sites in North America, Europe, 
and Australia. Subjects will be randomly assigned to continue to receive natalizumab in 1 of the 
following 2 groups:

SID:  approximately 240 subjects will receive natalizumab as a 300 mg IV infusion 
every 4 weeks (28 [-2/+5 days]).

EID:  approximately 240 subjects will receive natalizumab as a 300 mg IV infusion 
every 6 weeks (42 [-2/+5 days]). 
Randomization will be stratified by country/region (North America [includes USA and Canada], 
United Kingdom, Europe and Israel [includes Belgium, France, Germany, Israel, Italy, 
Netherlands, and Spain], and Australia), body weight (≤80 kg versus > 80 kg), and duration of 
natalizumab exposure (≤3 years versus > 3 years). Subjects will receive open-label natalizumab 
at their assigned frequency throughout the 72 weeks of the study.
At the completion of their 72-week treatment period, subjects in Part 1 who cannot participate, or 
elect not to participate, in Part 2 will enter a 12-week follow-up period, and will receive a 
follow-up safety phone call 12 weeks later (i.e., 24 weeks after the last dose of study treatment) 
before completing the study.
Part 2 is a 108-week OLE for approximately 200 subjects at approximately 45 sites in Canada, 
the United Kingdom, Europe, Israel, and Australia who complete their randomized treatment in 
Part 1, provide consent, and are eligible to participate immediately following completion of the 
72-week treatment period.
Subjects who did not participate in Part 1 but provide consent and satisfy the inclusion-exclusion 
and eligibility requirements of Part 1, including treatment with natalizumab SID for at least 
12 months without relapses in the last 12 months, may also be enrolled in Part 2 as new subjects
to ensure adequate sample size for the Part 2 analysis.
Subjects enrolled in Part 2 will receive natalizumab 300 mg by IV infusion once every 6 weeks 
(42 ± 7 days) for a period of 36 weeks and be randomized to an additional 48 weeks of crossover
treatment comprising 24 weeks EID SC Q6W and 24 weeks EID IV Q6W. All MRI scans will be 
read at a central facility by blinded raters.
At the completion of their 48-week crossover treatment period, subjects in Part 2 will receive a 
final dose of natalizumab 300 mg by SC injection or IV infusion at Week 156 with the route of 
administration being the subject’s choice, proceed to the 12-week follow-up period, and receive 
a follow-up safety phone call 12 weeks later (i.e., 24 weeks after the last dose of study treatment) 
before completing the study.
The design of this study, inclusive of Parts 1 and 2, is presented in Figure 1.

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7.1.
Study Duration for Subjects
7.1.1.
Study Duration for Subjects Enrolled Only in Part 1
The total duration of study participation in Part 1 for subjects who do not participate in Part 2 
will be up to 102 weeks. This comprises a screening period of up to 6 weeks; a treatment period 
of 72 weeks; a follow-up period of 12 weeks; and a follow-up safety phone call 12 weeks after 
the follow-up period (i.e., 24 weeks after the last dose of study treatment).
The end of study (EOS) date for a subject in Part 1 may be the last study visit, the follow-up 
safety phone call, or last protocol-specified assessment; if the subject has ongoing AEs that are 
being followed, then the date may be the date of AE resolution.
7.1.2.
Study Duration for Subjects Enrolled in Part 1 and Part 2
The total duration of study participation in Part 1 for subjects who also participate in Part 2 will 
be up to 78 weeks, comprising a screening period of up to 6 weeks and the randomized SID or 
EID treatment period of 72 weeks.
The total duration of study participation in Part 2 for these subjects will be approximately 
108 weeks. This comprises EID IV treatment for 36 weeks; a randomized EID SC vs. EID IV
crossover treatment period of 48 weeks; a follow-up period of 12 weeks; and a follow-up safety 
phone call 12 weeks after the follow-up period (i.e., 24 weeks after the last dose of study 
treatment).  The total duration of study participation for subjects who participate in both Part 1 
and Part 2 will be approximately 186 weeks.
The EOS date for subjects participating in Part 1 and Part 2 may be the last study visit, the 
follow-up safety phone call, or last protocol-specified assessment; if the subject has ongoing AEs 
that are being followed, then the date may be the date of AE resolution.
7.2.
Responsibilities of Study Site Staff
7.2.1.
General Staff Responsibilities During Part 1 and Part 2
For each subject in Part 1 and Part 2, the Investigator of the study site will designate the 
following study site staff:

A primary and backup unblinded treating neurologist

An unblinded treating nurse (or study coordinator; may be performed by treating 
neurologist)

A primary and backup blinded examining neurologist

A blinded examining technician (may be performed by blinded examining 
neurologist) (see Section 7.2.2 for changes in Part 2)

An unblinded MRI technician

An unblinded pharmacist (or unblinded authorized designee)

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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 leaving 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 examination 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 physical 
examination, management of treatment, and associated safety monitoring.

Assessment (including assignment of causality) and treatment of AEs, SAEs, and MS 
relapses.

Assessing 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 study 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 
study site such that each one is assigned to particular subjects, then these treating 
neurologists may act as backup for each other.

Review of hematology and blood chemistry data from the central laboratory 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/SAEs and concomitant medications.

Administering the PROs (TSQM, 
 

Collecting blood samples.

Obtaining vital signs.
The examining neurologist will be responsible for the following:

Obtaining an EDSS score and MS signs and symptoms based on a detailed
neurological examination at the scheduled timepoints required in the protocol.

Obtaining an EDSS score at every unscheduled Neurological Worsening and Relapse 
Assessment Visit, if referred by the treating neurologist when there is the possibility 
of a relapse.

The following guidelines must be strictly followed:

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
If an examining technician has to be replaced, the new examining technician must 
undergo a training session prior to performing any study assessment. 
The MRI technician will be responsible for the following:

Performing a brain MRI scan with and without contrast, in accordance with the 
study-specific MRI manual, at all protocol-required timepoints.
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 documentation related to study treatment, dose preparation, 
and study treatment assignment. All treatment assignment or study treatment 
preparation information must be maintained strictly confidential from the examining 
neurologist and examining technician at all times. Measures to prevent inadvertent 
unblinding must be followed.

Preparation of study treatments for IV infusion.
7.2.2.
Changes in Responsibilities During Part 2
The role of examining technician is no longer required in Part 2. The blinded examining 
technician will need to remain blinded until the Week 84 visit has been completed for all subjects 
who enrolled in Part 1, all queries have been addressed, and protection of the associated database 
secured. The Sponsor will confirm when the blinded examining technician can be unblinded. The 
primary and backup blinded examining neurologist along with the central MRI rater will remain 
blinded throughout the study. All other roles as presented in Section 7.2.1 will remain unchanged 
in Part 2.
7.3.
Unscheduled Visits and Treatment for MS Relapses
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 examination, and 
not explained solely by non-MS processes such as fever, infection, severe stress, or drug toxicity 
(adapted from [Schumacher 1965]).
The Unscheduled Visit for Neurological Worsening and Relapse Assessment should not modify 
or replace the subjects’ visit schedule. If a subject’s study MRI is scheduled to occur < 4 weeks 
after the last dose of steroid treatment for relapse, the MRI should be rescheduled so that it is 
performed either before the steroid treatment or between 4 and 8 weeks after the last dose of 
steroid treatment. MRI does not need to be performed at the ET Visit if the previous MRI was 
performed within the previous 4 weeks.

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New or recurrent neurological symptoms that occur < 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 be considered disability progression, not 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.
7.3.1.
Unscheduled Visits in Part 1
In Part 1, an unscheduled visit for a suspected relapse should be recorded at a Neurological 
Worsening and Relapse Assessment Visit, with the relapse reported on the relapse assessment 
form and not reported as an AE. A brain MRI should be performed before treatment of a 
protocol-defined relapse. The potential abnormalities must then be reviewed and confirmed by 
the INEC for the purposes of confirming the secondary endpoint (see Section 19.2.2). Treatment 
of a protocol-defined relapse may proceed at the discretion of the Investigator prior to INEC 
confirmation according to local standard of care and will not affect the subject’s eligibility to 
continue in the study. At the discretion of the Investigator, treatment may include 
methylprednisolone 1000 mg IV administered daily for 3 to 5 days with or without an oral
prednisone taper (up to 15 days).
7.3.2.
Unscheduled Visits in Part 2
In Part 2, an unscheduled visit for a suspected relapse should be recorded at a Neurological 
Worsening and Relapse Assessment Visit with the relapse reported on the relapse assessment 
form and not reported as an AE. The Investigator is responsible for determining whether a 
protocol-defined relapse has occurred. After all Part 2 unscheduled visit assessments have been 
performed, relapse treatment can proceed per local standard of care without INEC review.
7.4.
Study Stopping Rules
The study will be stopped if the interim futility analysis shows a statistically significant 
worsening of efficacy in Part 1 as gauged by new or newly enlarging T2 hyperintense lesions in
the EID group relative to the SID group.
Biogen will notify Investigators when the study is to be placed on hold, completed, or 
terminated.
7.5.
End of Study
The EOS is defined as the last subject, last visit for final collection of data during the study.

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8.
SELECTION OF SUBJECTS
8.1.
Part 1 Inclusion Criteria
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at the time of randomization, 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. Aged 18 to 60 years old, inclusive, at the time of informed consent.
3. Diagnosis of RRMS according to the McDonald criteria [Thompson 2018].
4. Treatment with natalizumab as disease-modifying monotherapy for RRMS that is 
consistent with the approved dosing for a minimum of 12 months prior to randomization. 
The subject must have received at least 11 doses of natalizumab in the 12 months prior to 
randomization with no missed doses in the 3 months prior to randomization.
5. EDSS score ≤5.5 at Screening.
6. No relapses in the last 12 months prior to randomization, as determined by the enrolling 
Investigator.
7. All women of childbearing potential must practice highly effective contraception during 
the study and for 3 months after their last dose of study treatment. For further details of 
contraceptive requirements for this study, see Section 15.5.
8.2.
Part 1 Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
the time of randomization, or at the timepoint specified in the individual criterion listed:
1. Primary- and secondary-progressive MS.
2. MRI positive for Gd-enhancing lesions at Screening.
3. Subjects for whom MRI is contraindicated (e.g., have a contraindicated pacemaker or 
other contraindicated implanted metal device, have suffered, or are at risk for, side effects 
from Gd, or have claustrophobia that cannot be medically managed).
4. History of any clinically significant (as determined by the Investigator) cardiac, 
endocrinologic, hematologic, hepatic, immunologic, metabolic (including diabetes), 
urologic, pulmonary, neurologic (except for RRMS), dermatologic, psychiatric, renal, or 
other major disease that would preclude participation in a clinical study, in the opinion of 
the Investigator.
5. History of human immunodeficiency virus or positive test result at Screening, or history 
of other immunodeficient conditions. The requirement for testing at Screening may be 
omitted if it is not permitted by local regulations.

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6. Known history of hepatitis C (test for hepatitis C virus antibody) or hepatitis B virus (test 
for hepatitis B surface antigen and/or hepatitis B core antibody).
7. History of malignant disease, including solid tumors and hematologic malignancies (with 
the exception of basal cell and squamous cell carcinomas of the skin that have been 
completely excised and are considered cured).
8. History of transplantation or any antirejection therapy.
9. History of severe allergic or anaphylactic reactions or known hypersensitivity to any 
antibody drug therapy.
10. A clinically significant infectious illness (e.g., cellulitis, abscess, pneumonia, septicemia) 
within 30 days prior to Screening, or PML or other opportunistic infections at any time.
11. Presence of anti-natalizumab antibodies at Screening.
12. Signs or symptoms suggestive of any serious infection, based on medical history, 
physical examination, or laboratory testing, as determined by the Investigator.
Treatment History
13. Prior treatment with cladribine, mitoxantrone, T-cell or T-cell receptor vaccination, 
cyclophosphamide, cyclosporine, azathioprine, methotrexate, or mycophenolate mofetil.
14. Prior treatment with any therapeutic mAb other than natalizumab within 24 months prior 
to randomization.
15. Prior treatment with total lymphoid irradiation.
16. Prior treatment with IV immunoglobulin, plasmapheresis, or cytapheresis within 
12 months prior to randomization.
17. Treatment with IV or oral corticosteroids (topical or inhaled corticosteroids are 
acceptable) or related products (e.g., Acthar®) within 3 months prior to randomization.
Miscellaneous
18. History of drug or alcohol abuse within 2 years prior to entry, per Investigator judgment.
19. 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 30 days (or 5 half-lives of the agent, whichever is longer) prior to the Baseline 
Visit or at any time during this study.
20. Inability to comply with study requirements.
21. Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the 
subject unsuitable for enrollment.
22. Women who are pregnant or breastfeeding, and women intending to become pregnant 
during the study.

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8.3.
Part 2 Inclusion Criteria
To be eligible to participate in Part 2, candidates previously enrolled in Part 1 must meet the 
following eligibility criteria 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 for Part 2 and authorization to use confidential health 
information in accordance with national and local subject privacy regulations.
2. Completed Part 1 Week 72 visit while remaining on their randomized treatment 
assignment of SID or EID.
8.4.
Part 2 Exclusion Criteria
Candidates who completed Part 1 will be excluded from Part 2 entry if any of the following 
exclusion criteria exist at the timepoint specified in the individual criterion listed:
1. Subject treated with natalizumab EID was reverted to natalizumab SID by choice or as 
rescue treatment in Part 1.
2. Subject received treatment with any MS disease-modifying therapy other than 
natalizumab in Part 1 or in the period between Part 1 and Part 2.
3. History of any clinically significant (as determined by the Investigator) cardiac, 
endocrinologic, hematologic, hepatic, immunologic, metabolic (including diabetes), 
urologic, pulmonary, neurologic (except for RRMS), dermatologic, psychiatric, renal, or 
other major disease that would preclude participation in a clinical study, in the opinion of 
the Investigator.
4. History of human immunodeficiency virus or history of other immunodeficient 
conditions. 
5. History of malignant disease, including solid tumors and hematologic malignancies (with 
the exception of basal cell and squamous cell carcinomas of the skin that have been 
completely excised and are considered cured).
6. 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 30 days (or 5 half-lives of the agent, whichever is longer) prior to the Baseline 
Visit or at any time during this study.
7. Inability to comply with study requirements.
8. Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the 
subject unsuitable for enrollment.
9. Women who are pregnant or breastfeeding, and women intending to become pregnant 
during the study.
8.5.
Part 2 Inclusion Criteria for New Subjects
The inclusion criteria for new subjects who did not participate in Part 1 of the study are the same 
as those for subjects who did participate in Part 1, as presented in Section 8.1.

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8.6.
Part 2 Exclusion Criteria for New Subjects
The exclusion criteria for new subjects who did not participate in Part 1 of the study are the same 
as those for subjects who did participate in Part 1, as presented in Section 8.2.

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9.
SCREENING AND RANDOMIZATION
9.1.
Screening 
9.1.1.
Part 1 Screening
Subjects must provide informed consent before any screening tests are performed (see 
Section 17.3). Participating study sites are required to document all screened candidates initially 
considered for inclusion in the study.
Screen failures are defined as subjects who sign the informed consent form (ICF) but are not 
subsequently randomized. If a subject is considered a screen failure, the reasons for exclusion 
must be documented in the subject’s source documents and on the screening log. A minimal set 
of screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAEs. Subjects who fail screening due to 
clinically nonsignificant laboratory result(s) or transient infection can be rescreened once, at the 
discretion of the Investigator.
It is not required that all screening tests and assessments be completed during 1 pretreatment 
visit; however, some tests and assessments must be completed immediately prior to subjects 
receiving their last prestudy dose of natalizumab. Other assessments can occur anytime between 
the subjects receiving their last prestudy dose of natalizumab and baseline (see Section 5).
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 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 SAEs.
9.1.2.
Part 2 Screening
Subjects must provide informed consent before any Part 2 assessments are performed (see 
Section 17.3). Participating study sites are required to document all screened candidates initially 
considered for inclusion in the study. New subjects enrolling in Part 2 of the study should follow 
all guidance with respect to screening as described in Section 9.1.1. New subjects who fail 
screening due to a clinically nonsignificant laboratory result(s) or transient infection can be 
rescreened once at the discretion of the Investigator.
Part 2 Screening Visit will be performed during the Week 72 visit if possible or within 6 weeks 
prior to Week 78 or Week 84, whichever visit/infusion is the first Part 2 study treatment 
administration to the subject.
Subjects who meet Part 2 inclusion/exclusion criteria and provide informed consent will be 
enrolled and will receive their first Part 2 study treatment at Week 78. In the event that a subject 

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cannot be enrolled at Week 78 for any reason, the subject can enroll up to a maximum of 
12 weeks after their Week 72 visit, provided that the subject has continued to receive treatment 
with natalizumab between the end of Part 1 and the beginning of Part 2.
9.2.
Randomization 
9.2.1.
Part 1 Randomization
Subjects will be randomized after all screening assessments have been completed and after the 
Investigator has verified that the subjects are eligible per criteria in Sections 8.1 and 8.2. Subjects 
will be assigned a unique identification number 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 continue in the study.
Randomization will be performed using interactive response technology (IRT). Subjects will be 
randomized to receive natalizumab SID or natalizumab EID in a 1:1 ratio. The randomization 
will be stratified by country/region (North America [includes USA and Canada], United 
Kingdom, Europe and Israel [includes Belgium, France, Germany, Israel, Italy, Netherlands, and 
Spain], and Australia), body weight (≤80 kg versus > 80 kg), and duration of natalizumab 
exposure (≤3 years versus > 3 years).
Refer to the Study Reference Guide for details on randomization.
9.2.2.
Part 2 Randomization
Subjects will be randomized in a 1:1 ratio, stratified by their treatment assignment in Part 1 (SID, 
EID, new subjects) to receive SC/IV or IV/SC before the first dose of crossover treatment in 
Part 2 of the study.
9.3.
Blinding Procedures
9.3.1.
Part 1 Blinding
The designated examining neurologist, backup examining neurologist, and examining technician 
will be blinded to treatment assignments; however, the subjects, Investigator, Biogen, and 
IQVIA will know the subject’s treatment assignment. The central MRI rater will remain blinded 
throughout the study. To maintain the rater blinding, it is imperative that subject treatment 
assignments, infusion dates, and laboratory data are not shared with the examining neurologist, 
backup examining neurologist, or examining technician.
9.3.2.
Part 2 Blinding
All blinding procedures will be maintained in Part 2 until all Part 1 Week 84 data have been 
entered, checked, and secured. The Sponsor will notify the sites when the Part 1 examining 
technician can be unblinded. The examining neurologist, backup examining neurologist, and 
central MRI rater will remain blinded throughout the study.

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10.
DISCONTINUATION OF STUDY TREATMENT AND 
WITHDRAWAL OF SUBJECTS FROM THE STUDY
10.1.
Discontinuation of Study Treatment
A subject must permanently discontinue study treatment for any of the following reasons:

The subject becomes pregnant. Study treatment must be discontinued immediately. 
Report the pregnancy according to the instructions in Section 15.4.2.

The subject develops persistent anti-natalizumab antibodies (2 consecutive readings).

The subject develops PML or another serious opportunistic infection.

The subject withdraws consent to continue study treatment.

The subject experiences an AE or SAE that necessitates permanent discontinuation of 
study treatment.

The subject experiences hypersensitivity or suspected allergic reaction to study 
treatment.

The subject experiences a medical emergency that necessitates permanent 
discontinuation of study treatment.

The subject is unwilling or unable to comply with the protocol.

At the discretion of the Investigator for medical reasons.

At the discretion of the Investigator or Sponsor for noncompliance.
The primary reason for discontinuation of study treatment must be recorded in the subject’s case 
report form (CRF).
In Part 1, subjects who discontinue treatment may remain in the study and continue 
protocol-required tests and assessments. Of note, subjects who discontinue natalizumab do not 
need to return for visits at which only vital signs and Columbia Suicide Severity Rating Scale 
(C-SSRS) assessments are performed. Subjects who discontinue natalizumab should continue 
visits at 12-week intervals (e.g., Weeks 12, 24, 36, 48, 60, and 72).
If a subject chooses to withdraw from the study, an Early Termination (ET) Visit should occur as 
soon as possible but no later than 4 weeks after the last dose of study treatment; in addition, all 
EOS assessments should be conducted at a separate EOS visit 12 weeks (± 10 days) after the 
final dose of study treatment is received. A follow-up safety phone call will be performed 
24 weeks after the last dose of study treatment.
In Part 2, subjects who discontinue study treatment will be required to withdraw from the study. 
If a subject chooses to withdraw from the study, an ET Visit should occur as soon as possible but 
no later than 4 weeks after the last dose of study treatment. In addition, all EOS assessments 
should be conducted at a separate EOS Visit 12 weeks (± 10 days) after the final dose of study 
treatment. A follow-up safety phone call will be performed 24 weeks after the last dose of study 
treatment.

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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 study site for a required 
study visit:
1. The study 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.
2. 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 records.
3. 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.
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 
CRF.
Subjects must undergo an ET Visit unless withdrawal is due to death or withdrawal of consent.
Subjects who withdraw from the study may not be replaced.

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11.
STUDY TREATMENT USE
11.1.
Regimen
Refer to and follow the DHA for natalizumab IV infusion in both Parts 1 and 2 of the study; refer 
to the DHA for natalizumab SC injection in Part 2 of the study.
11.1.1.
Part 1 Regimen
Subjects will continue to receive natalizumab either SID (300 mg IV infusion Q4W) or EID 
(300 mg IV infusion Q6W) for a period of 72 weeks.
11.1.2.
Part 2 Regimen
Subjects will initially receive natalizumab 300 mg IV Q6W beginning on Week 78. During the 
treatment period beginning on Week 108, subjects will receive natalizumab 300 mg Q6W for 
24 weeks by SC injection and natalizumab 300 mg by IV infusion for 24 weeks in a randomized 
crossover
11.2.
Modification of Dose and Treatment Schedule
11.2.1.
Modification of Dose
The dosage of natalizumab cannot be modified.
11.2.2.
Modification of Treatment Schedule
11.2.2.1.
Part 1 Modification of Treatment
If a subject treated with natalizumab EID experiences any of the following conditions, the 
Investigator will have the option of reverting to natalizumab SID as a rescue treatment. If a 
subject treated with SID experiences any of the following conditions, the Investigator will have 
the option of selecting another disease-modifying therapy that is available to the subject per local 
standard of care. Rescue treatment decisions are to occur within 4 weeks of either the date of 
MRI that showed the disease activity or confirmation of EDSS score worsening for at least 
24 weeks, at the Investigator’s discretion:

Two or more new or enlarging T2 hyperintense lesions of any size, compared with a 
previous scan performed as part of this study.

An EDSS worsening compared with previous assessment and confirmed at least 
24 weeks after the initial increase meeting any of the following criteria:  1) an 
increase of ≥1.0 in EDSS as compared with previous assessment if previous EDSS 
was ≤5.5 and > 0; or 2) an increase of ≥1.5 in EDSS if previous EDSS was 0; or 3) 
an increase of ≥0.5 in EDSS if previous EDSS was ≥6.0.

A clinical relapse with new or recurrent neurological symptoms, not associated with 
fever or infection, having a minimum duration of 24 hours and any of the following:  
1) an increase of ≥1 grade in ≥2 functional scales of the EDSS; or 2) an increase of 

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≥2 grades in 1 functional scale of the EDSS; or 3) an increase of ≥1 in the EDSS if 
the previous EDSS was ≤5.5, or ≥0.5 if the previous EDSS was ≥6 (an increase of 
≥1.5 in EDSS if previous EDSS was equal to 0).
Subjects who receive rescue treatment with natalizumab SID should remain in the study and 
follow the schedule of activities for SID. Subjects who receive rescue treatment different from 
natalizumab SID may remain in the study and follow the schedule of activities with exception of 
natalizumab administration. Note, for subjects who experience acute clinical relapse, high dose 
corticosteroid treatment as per local standard of care (up to 5 days) for relapse treatment may be 
administered (see Section 7.3).
11.2.2.2.
Part 2 Modification of Treatment
In Part 2, there will be no protocol-defined rescue treatment; subjects who discontinue study 
treatment in Part 2 for any reason will be withdrawn from the study and will be treated as per 
local standard of care.
11.3.
Precautions
Please refer to the DHA located in the Study Reference Guide for details on postdose observation 
requirements.
11.4.
Compliance
All doses of study treatment will be administered by the study site staff.
11.5.
Concomitant Therapy and Procedures
11.5.1.
Concomitant Therapy
A concomitant therapy is any drug or substance administered between the time of the subject’s 
written consent and the subject’s last study visit.
11.5.1.1.
Allowed Concomitant Therapy
Concomitant treatment with any of the following is allowed so long as the exclusionary criteria 
described in Section 8.2 are observed:

Medications necessary for the treatment of AEs.

4-aminopyridine if used per label and maintained on a stable regimen for at least 
30 days prior to randomization and throughout the study.

Medications used to treat MS symptoms such as spasticity, bladder impairment, pain, 
fatigue, or depression.

Short courses of high-dose corticosteroids per local standard of care in the treatment 
of protocol-defined relapse of MS disease (see Section 7.3).

Corticosteroids that are administered by nonsystemic routes (e.g., topical, inhaled).

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
In Part 2 only, corticosteroids administered via systemic routes (e.g., oral, injected, 
and intravenous) are also allowed.
11.5.1.2.
Disallowed Concomitant Therapy
Subjects should be instructed to contact their Investigators before taking any new medications, 
including nonprescription drugs and herbal preparations.
Concomitant treatment with any of the following is not allowed while receiving study treatment, 
unless as otherwise described in this protocol:

Any nonstudy treatments directed toward the treatment of MS such as chronic 
immunosuppressant therapy or other immunomodulatory treatments. This includes, 
but is not limited to interferon, glatiramer acetate, dimethyl fumarate, diroximel 
fumarate, cyclophosphamide, methotrexate, azathioprine, cladribine, mitoxantrone, 
IV immunoglobulin, mycophenolate mofetil, fingolimod, siponimod, ozanimod, 
daclizumab, rituximab, ocrelizumab, or any therapeutic mAb. 

Any investigational product, including investigational symptomatic therapies for MS 
and investigational therapies for non-MS indications.

In Part 1 only, systemic steroid therapy including, but not limited to, oral 
corticosteroids (e.g., prednisone) or periodic (e.g., monthly) treatment with IV 
methylprednisolone, except for protocol-defined treatment of relapses as described in 
Section 7.3. These therapies are allowed in Part 2 only.
Subjects who receive any of these restricted treatments may be required to discontinue study 
treatment permanently and may be withdrawn from the study as outlined in Section 10.1.
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 culture) performed between the 
time of the subject’s written consent and the subject’s last study visit, unless the subject is being 
followed up for study-related toxicity.
11.5.2.1.
Disallowed Concomitant Procedures
Treatment with any of the following concomitant procedures is not allowed while receiving 
study treatment, unless as otherwise described in this protocol:

total lymphoid irradiation

T-cell or T-cell receptor vaccination

plasmapheresis

cytapheresis
Subjects who receive treatment with any of these restricted procedures may be required to 
permanently discontinue study treatment and may be withdrawn from the study as outlined in 
Section 10.1.

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The use of concomitant therapies or procedures defined above must be recorded in the subject’s 
CRF, according to the instructions for CRF completion. AEs related to the administration of 
these therapies or procedures must be documented in the appropriate CRF.
11.6.
Continuation of Treatment
There is no provision to provide study treatment after the study. Natalizumab is available 
commercially and subjects/Investigators can continue Tysabri treatment via a commercial 
source. Once subjects have completed the Part 1 or Part 2 treatment period in the study, it is up 
to the treating physician and subject as to what the most appropriate treatment plan is for that 
subject per local practice.

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12.
STUDY TREATMENT MANAGEMENT
Study treatment will be manufactured, handled, and stored in accordance with applicable Good 
Manufacturing Practice.
Study site staff should follow the DHA for specific instructions on the handling, preparation, 
administration, and disposal of the study treatment. The DHA supersedes all other references 
(e.g., protocol).
Study treatment must be dispensed only by a pharmacist or appropriately qualified staff. Study 
treatment is to be dispensed only to subjects enrolled in this study. 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.
12.1.
Natalizumab
Natalizumab is a recombinant, humanized anti-α4 integrin antibody manufactured by Biogen.
Natalizumab for IV infusion is supplied as a liquid in 15 mL vials containing 300 mg of 
natalizumab per vial and excipient materials (sodium phosphate monobasic monohydrate, 
sodium phosphate dibasic heptahydrate, sodium chloride, and polysorbate 80).
Natalizumab for SC injection is provided in a 1 mL prefilled syringe containing 150 mg 
natalizumab and excipient materials (sodium phosphate, sodium chloride, polysorbate 80, 
pH 6.0); 2 injections in succession are required to administer 300 mg.
The contents of the natalizumab label will be in accordance with all applicable regulatory 
requirements. At a minimum, the label will include a study reference code, study treatment 
identifier, quantity of dosage units, lot number, and other pertinent information in accordance 
with local law. The expiry or use-by date will be stored in the IRT system, and printable 
assignment reports will be available to study site staff. Study treatment should not be used after 
the expiration, expiry, or use-by date.
12.1.1.
Natalizumab Preparation
The individual preparing natalizumab should carefully review the instructions provided in the 
DHA.
If the packaging is damaged, or if there is anything unusual about the appearance or attributes of 
the container closure system or study treatment, do not use the study treatment. The drug product
in question should be saved at the study site and the problem immediately reported to Biogen. 
Information on reporting product issues can be found in the Study Reference Guide, Pharmacy 
Manual, and DHA.
12.1.2.
Natalizumab Storage
Study treatment must be stored in a secure location.

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Natalizumab is to be stored at 2C to 8C (36F to 46F), protected from light, in a monitored 
and locked refrigerator with limited access. Study treatment is not to be frozen. For the most 
up-to-date storage requirements, follow the instructions provided in the DHA.
12.1.3.
Natalizumab Handling and Disposal
The Investigator must return all used and unused natalizumab study treatment as instructed by 
Biogen unless approved for onsite destruction.
If any natalizumab supplies are to be destroyed at the study site, the institution or appropriate 
study site staff 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.
Natalizumab Accountability
Accountability for study treatment is the responsibility of the Investigator. The study site must 
maintain accurate records demonstrating the dates and amount of study treatment received, to 
whom study treatment was dispensed (subject-by-subject accounting), and accounts of any study 
treatment accidentally or deliberately destroyed or lost.
Unless otherwise notified, all study treatment both used and unused must be saved for 
accountability. By the end of the study, reconciliation must be made between the amount of 
natalizumab supplied, dispensed, and subsequently destroyed, lost, or returned to Biogen. A 
written explanation must be provided for any discrepancies.

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14.
SAFETY ASSESSMENTS
See 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 
natalizumab:
In Part 1 only:

C-SSRS
In Part 1 and for new subjects in Part 2 only,

Medical history
In Part 1 and Part 2:

Physical examination

Body weight

Vital sign measurements: temperature, systolic and diastolic blood pressures, pulse 
rate, and respiratory rate

Concomitant therapy and procedure recording

AE and SAE recording
14.2.
Laboratory Safety Assessments
Samples will be analyzed using Good Laboratory Practice-validated assays in Part 1 and Part 2.
The following laboratory assessments will be performed to evaluate the safety profile of 
natalizumab:

Hematology: complete blood count with differential and platelet count and absolute 
neutrophil count

Blood chemistry: total protein, albumin, creatinine, blood urea nitrogen, uric acid, 
bilirubin (total and direct), alkaline phosphatase, alanine aminotransferase, aspartate 
aminotransferase, gamma-glutamyl transferase, glucose, calcium, phosphorus, 
bicarbonate, chloride, sodium, and potassium 
14.3.
Natalizumab Safety Assessments
The following assessments will be performed to determine the safety of natalizumab in 
 Part 2:

Anti-natalizumab antibodies


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

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

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15.3.4.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are unexpected and 
judged by the Investigator or Biogen to be related to the study treatment administered.
Biogen will report SUSARs to the appropriate regulatory authorities and Investigators as 
required, according to local law.
15.4.
Procedures for Handling Special Situations
15.4.1.
Progressive Multifocal Leukoencephalopathy
Due to the risk of PML in natalizumab-treated subjects, if neurological symptoms or MRIs 
indicate a possible pathology other than MS, the following diagnostic procedures are 
recommended:

Careful evaluation of MRI, including comparison with previous MRI scans.

.

Timely discontinuation of treatment.  If the Investigator is unable exclude PML or 
other opportunistic infections (viral, bacterial, or fungal), natalizumab must be 
discontinued.
If, in the opinion of the Investigator, a subject’s individualized risk for PML requires more 
frequent MRI monitoring than is performed as part of this study, additional MRIs to monitor for 
PML may be performed at the Investigator’s discretion.
15.4.2.
Pregnancy
Subjects should not become pregnant after the first dose in this study and for at least 
3 months after their last dose of study treatment. If a female subject becomes pregnant, study 
treatment must be discontinued immediately. In the event of early study termination for a 
pregnancy, an EOS Gd-enhancing MRI should not be conducted.
The Investigator must report a pregnancy occurring in a female subject between the first dose of 
study treatment and 3 months after the last dose of study treatment by faxing the appropriate 
form to Biogen within 24 hours of the study site staff becoming aware of the pregnancy. Refer to 
the Study Reference Guide’s Official Study Contact List for complete contact information. The 
Investigator or study site staff must report the outcome of the pregnancy to Biogen. A pregnancy 
is not considered an AE and should not be recorded in the AE CRF.
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.
15.4.3.
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 in the CRF; however, all overdoses must be recorded 
on an Overdose form and faxed to Biogen within 24 hours of the study site becoming aware of 
the overdose. An overdose must be reported to Biogen even if the overdose does not result in an 

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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. All study 
treatment-related dosing information must be recorded in the dosing CRF.
15.4.4.
Medical Emergency
In a medical emergency requiring immediate attention, study site staff will apply appropriate 
medical intervention, according to current standard of care. The Investigator (or designee) should 
contact the study’s Medical Director. Refer to the Study Reference Guide’s Official Study 
Contact List for complete contact information.
15.5.
Contraception Requirements
All women of childbearing potential must ensure that highly effective contraception is used 
during the study and for at least 3 months after their last dose of study treatment.
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
o
12 continuous months of natural (spontaneous) amenorrhea without an alternative 
medical cause 
o
6 weeks after surgical bilateral oophorectomy with or without hysterectomy

Posthysterectomy

Female surgical sterilization (e.g., bilateral tubal ligation)
For the purposes of the study, highly effective contraception is defined as contraception that 
achieves a failure rate of < 1% when used consistently and correctly, and includes 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 progestogen-only hormonal methods of 
contraception associated with the inhibition of ovulation.

Placement of an intrauterine device or intrauterine hormone-releasing system.

Bilateral tubal occlusion.
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 study. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not 
considered acceptable methods of contraception.
Pregnancy reporting is described in Section 15.4.2.

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15.6.
Safety Responsibilities
15.6.1.
The Investigator
The Investigator’s responsibilities include the following:

Monitor and record all AEs, including SAEs, in the CRF regardless of the severity or 
relationship to study treatment.

Determine the seriousness, relationship, and severity of each event.

Determine the onset and resolution dates of each event.

Monitor and record all pregnancies in female subjects and follow up on the outcome 
of all pregnancies.

Complete an SAE form for each SAE and fax it to Biogen 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 within 24 hours of the study site staff becoming aware of 
new information.

Ensure that 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, in the CRF, 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 study 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.

Biogen is to notify all appropriate regulatory authorities, central ethics committees, 
and Investigators of SAEs, as required by local law, within the required time frames.

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16.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
The objectives of the study and the endpoints to be analyzed are listed in Section 6.
In this more detailed description of the associated statistical methods, the endpoints are presented 
in relationship to categorical assessment. The associated endpoints of primary, secondary, 
 importance are specifically identified under each of these categories.
16.1.
Efficacy
16.1.1.
Analysis Population
The modified intent-to-treat (mITT) population, defined as all randomized subjects who receive 
at least 1 dose of study treatment and have at least 1 postbaseline efficacy assessment, will be 
used for all efficacy analyses. Subjects will be analyzed in the groups to which they are 
randomized.
16.1.2.
General Methods of Analysis
Data will be collected and analyzed in 2 parts:
1. After the completion of the randomized phase in Part 1, the primary efficacy and safety 
analyses will be performed. All data will be summarized by randomized treatment group 
(SID and EID).
2. After the completion of the randomized phase in Part 2, analyses of all Part 2 endpoints 
will be performed. Data from Part 1 will be combined with data from Part 2 to evaluate 
the long-term efficacy and safety data of natalizumab EID.
For the continuous endpoints, the summary statistics will generally include the number of 
subjects with data, mean, standard deviation, median, interquartile range, and overall range. For 
categorical endpoints, the summary statistics will generally include the number of subjects with 
available data and the percentage of subjects with data in each category. 
In the analysis of Part 1 efficacy variables, comparisons will be made between the EID group 
and the SID group.
16.1.3.
Part 1 Statistical Analysis
16.1.3.1.
Analysis of the Primary Endpoint in Part 1
The primary endpoint, the number of new or newly enlarging T2 hyperintense lesions at 
Week 72, will be analyzed using negative binomial regression models with treatment as the 
classification variable and baseline body weight (≤80 kg versus > 80 kg), duration of 
natalizumab exposure at baseline (≤3 years versus > 3 years), and region (North America 
[includes USA and Canada], United Kingdom, Europe, and Israel [includes Belgium, France, 
Germany, Israel, Italy, Netherlands, and Spain], and Australia) as covariates. The ratio of mean 
lesion numbers of EID versus SID (EID/SID) will be derived from the model with a 95% CI and 

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associated p-value. The treatment will be considered different if the lower limit of the 95% CI is 
above 1. As a secondary inference, the possibility of a 2-fold increase in the mean lesion number 
in the EID group as compared with the SID group will be considered ruled out if the upper limit 
of 95% CI is no greater than 2. The proportion of subjects with no new or newly enlarging 
T2 hyperintense lesions will be analyzed using logistic regression models with the same 
covariates as those described above.
16.1.3.2.
Primary and Secondary Estimands and Handling of Intercurrent Events in 
Part 1
The study plans to make every effort to retain subjects in the study and to continue the follow-up 
in the cases with the initiation of rescue medication, switch to different dosing frequency, 
treatment discontinuation due to AEs, lack of efficacy, or for other reasons. This will allow 
continuing assessments of subjects’ MS disease activity. Efforts will also be made to obtain 
details of withdrawals in the generic categories of “lost to follow-up” or “other” whenever 
possible. Classification of the withdrawals in these nonspecific categories into “possibly efficacy 
related,” “possibly safety-related,” or “no information” will be made based on all available 
information by independent Sponsor personnel who are blinded to the treatment regimen and 
will be documented prior to database lock.
The proposed primary estimand will be based on a treatment policy strategy, in which the study 
is intended to estimate the difference of a potential treatment decision of switching subjects from 
SID to EID compared with keeping subjects on SID over the next 72 weeks in a realistic clinical 
setting, where switching to a different dosing regimen or different medication may occur 
depending on disease activity. Therefore, the primary analysis will utilize all measurements 
regardless of whether subjects remain on randomized treatment. For subjects who withdraw from 
the study for reasons related to the efficacy or an AE or who have a “possibly related” 
withdrawal, as described above, the missing values will be imputed by the worst observed value 
of the subjects on study treatment at the given timepoint. For withdrawals classified as “no 
information,” the missing values will be treated as missing at random and will be addressed 
using multiple imputations. The number and proportion of subjects with intercurrent events and 
the time to intercurrent event will also be tabulated and compared between randomized groups. 
Sensitivity analysis may be conducted using tipping point analysis. Supplementary analyses by 
imputing all missing values by treating all as missing at random using multiple imputations will 
also be conducted.
The secondary estimand will be based on a hypothetical strategy, in which the difference in the 
efficacy of EID versus SID over the 72 weeks following randomization if no intercurrent events 
occurred will be the target of estimation. The primary analysis for this estimand will treat the 
data obtained post-intercurrent event as missing values. For treatment discontinuation or 
switching due to efficacy as well as a withdrawal that is due to efficacy or is “possibly efficacy 
related,” the missing values will be imputed by the worst observed values of the subjects on 
study treatment at the given timepoint. For intercurrent events due to other reasons, the resulting 
missing values will be addressed using multiple imputations. Sensitivity analysis may be 
conducted using tipping point analysis.

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
Country/region (North America [includes USA and Canada], United Kingdom, 
Europe and Israel [includes Belgium, France, Germany, Israel, Italy, Netherlands, and 
Spain], and Australia)

Baseline weight (40 to 59 kg, 60 to 79 kg, 80 to 89 kg, and ≥90 kg)
In addition, subgroup analysis of the primary and key secondary endpoints will be evaluated in 
subgroups defined by prior disease activity, the number and type of therapies prior to 
natalizumab, quartiles of the Ctrough values, and α-integrin saturation levels at Weeks 24, 48 and 
72.
16.1.4.
Part 2 Statistical Analysis
In Part 2, the mITT population is defined as all randomized subjects in Part 2 who received at 
least 1 dose of SC natalizumab and completed at least the first question in the PPQ on 1 
occasion.
During Part 2, the baseline of each period is defined as the last assessment before the first dose 
administration during that period.
16.1.4.1.
Analysis of the Primary Endpoint in Part 2
Proportion of subjects indicating preference for SC versus IV administration at the end of Part 2.
For each subject, the last answer in the PPQ will be used to derive the primary endpoint of 
Part 2. The proportion of subjects preferring SC natalizumab at the end of Part 2 will be 
estimated, and the 95% CI will be calculated using the exact Binomial method. Additionally, the 
proportion of subjects preferring SC will be summarized by randomized arms during Part 2, 
i.e., the group receiving SC followed by IV and that receiving IV followed by SC.
16.1.4.2.
Analysis of the Secondary Endpoint in Part 2
Mean score on TSQM.
Total TSQM value will be summarized by route of administration during Part 2. No formal 
comparison is planned.
Mean time for drug preparation and administration between SC and IV routes of administration.
Mean time for drug preparation and administration will be summarized by route of 
administration during Part 2. No formal comparison is planned.
For the remaining secondary endpoints, analysis will be performed by using data, respectively, 
during the first period, the second period, and both periods.
Number of new or newly enlarging T2 hyperintense lesions.
In Part 2, the number of new or newly enlarging T2 hyperintense lesions will be summarized by 
route of administration.
Time to first relapse
In Part 2, if a subject withdraws from the study prior to the end of either period in the crossover 
design and did not experience a relapse reported prior to withdrawal, the subject will be censored 

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on the last day in the period. The start date for time to first relapse or censoring is defined as the 
start date of each period.
The proportion of relapsed subjects will be estimated using the KM product limit method and be 
presented as KM curves over time by route of administration.
The comparisons of route will be based on Cox regression models with route of administration as 
the classification variable and treatment arm during Part 1 and period during Part 2 as covariates. 
The hazard ratio of relapse of SC versus IV (SC/IV) will be derived from the Cox model with a 
95% CI and associated p-value.
Annualized relapse rate
During each period of the crossover design in Part 2, all relapses reported prior to the end of each 
period will be included in the analysis for this endpoint.
The relapse rate for each route will be calculated as the total number of relapses experienced for
the administration route divided by the total number of subject-years on study at the end of each 
period for the route of administration. This is the unadjusted relapse rate.
In addition, the relapse rate for an individual subject will be calculated as the number of relapses
for that subject in each period divided by the duration of the subject on study in years at the end 
of each period. Based on these individual relapse rates, the mean and median for each route will 
be presented. This is called the subject relapse rate.
The annualized relapse rate at the end of each period will be analyzed using a negative binomial 
regression model, with route of administration as the classification variable and the treatment 
arm during Part 1 and period during Part 2 as covariates. The logarithmic transformation of the 
number of years in the study at the end of each period will be included in the model as the 
“offset” parameter. The ratio of mean annualized relapse rate of SC/IV will be derived from the 
model with a 95% CI and associated p-value. If negative binomial regression model does not 
converge, a Poisson regression model with the same classification variable and covariates will be 
used instead.
Change in EDSS score
During each period of the crossover design in Part 2, the change in EDSS score from the start 
date of a period to the end date of the same period will be calculated and summarized by route of 
administration.
Number of new Gd-enhancing lesions
The same method for the analysis of new or newly enlarging T2 hyperintense lesions will be 
applied.
Number of new T1 hypointense lesions
The same method for the analysis of new or newly enlarging T2 hyperintense lesions will be 
applied.
PBVC and change in cortical and thalamic brain region volume
The same method for the analysis of new or newly enlarging T2 hyperintense lesions will be 
applied.

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covariates. The ratio of mean lesion numbers of EID versus SID (EID/SID) will be derived from 
the model with a 95% CI. The study may be stopped for futility if the lower limit of the 95% CI 
is > 2 and a 2-fold increase in mean lesion numbers in the EID group can be concluded with 
97.5% confidence.
In Part 2, no formal interim analysis will be performed; however, there may be intermittent 
analyses of the data as needed.
16.8.
Sample Size Considerations
Historical data on MS treatments, including a meta-analysis on the relationship between new or 
newly enlarging T2 lesions and relapses, suggest little or no clinical relevance of a difference of 
0.2 to 0.3 in mean lesion numbers over 72 weeks [Sormani and Bruzzi 2013].  With the planned 
sample size of N = 200/group, the precision of the estimated mean lesion numbers is sufficient to 
allow > 80% probability to observe the lower limit of the 95% CI for the ratio of EID to SID in 
the estimated mean lesion number above 1 if the true mean is 0.5 and 0.3 in the EID and SID 
group, respectively. If the true mean is 0.6 and 0.3 in the EID and SID group, respectively, the 
probability will be approximately 90%. In the other direction, the sample size provides a 
precision that allows approximately 90% probability to observe the upper limit of the 95% CI to 
be ≤2 if the true mean lesion numbers in both groups are 0.3. Approximately 480 subjects will 
be enrolled to account for a drop-out rate of approximately 17%.
For Part 2, in the absence of EID SC natalizumab data, it is assumed that the proportion of 
subjects who would prefer SC natalizumab is 75%, with a 7.5% margin of error; therefore, a 
sample size of 130 subjects for the 95% CIs to be within 67.5% and 82.5%. Approximately 
160 subjects are needed to allow for 20% of subjects who do not provide an evaluable preference 
assessment (calculated by nQuery Advisor Version 7).

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17.
ETHICAL REQUIREMENTS
Biogen, IQVIA, 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 is responsible for endorsing all data on completed CRFs electronically, prior to 
any interim lock or database lock.
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 or designee will submit documents on behalf 
of the study sites in countries other than the US.
If the Investigator makes any changes to the ICF, Biogen must approve the changes before the 
ICF is submitted to the ethics committee. A copy of the approved ICF must be provided to 
Biogen. After approval, the ICF must not be altered without the agreement of the relevant ethics 
committee and Biogen.
It is the responsibility of the Investigators to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations.
Biogen must receive a letter documenting ethics committee approval, which specifically 
identifies the protocol, protocol number, and ICF, prior to the initiation of the study. Protocol 
amendments will be subject to the same requirements as those in 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 study site must submit a close-out letter to the 
ethics committee and Biogen.
17.3.
Subject Information and Consent
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the subject 

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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 the outcome on a publicly
accessible website in accordance with the applicable laws and regulations.

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18.
ADMINISTRATIVE PROCEDURES
18.1.
Study Site Initiation
The Investigator must not screen any subjects prior to completion of a study initiation visit, 
conducted by Biogen. This initiation visit will include a detailed review of the protocol and study 
procedures.
18.2.
Quality Control and Quality Assurance
Quality control procedures will be implemented at each stage of data handling to ensure that all 
data are reliable and have been processed correctly. Data anomalies will be communicated to the 
study sites for clarification and resolution, as appropriate. The Investigator is responsible for 
endorsing all CRF data prior to any interim or final database lock.
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, CRFs, 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 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 study site and its facilities.
18.4.
Study Funding
Biogen is the Sponsor of the study and is funding the study. All financial details are provided in 
the separate contracts between the institution, Investigator, and Biogen.

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18.5.
Publications
Details are included in the clinical trial agreement for this study.

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19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION
19.1.
External Contract Organizations
Biogen will ensure oversight of any study-related duties and functions carried out on its behalf 
and will specify in writing all duties and functions that are transferred.
19.1.1.
Contract Research Organization 
A CRO will be responsible for administrative aspects of the study including but not limited to 
study initiation, monitoring, 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 in electronic CRFs by a 
web-based electronic data capture tool configured by the CRO and hosted by the electronic data 
capture vendor. PROs will be completed by the subject on paper forms and subsequently entered 
into the electronic CRF by study site staff.
19.1.4.
Central Facility for MRI Scans
A central MRI reader has been selected by Biogen to read and interpret all MRI scans for this 
study. All study sites will need to perform a dummy scan for the qualification of the study site’s
MRI machine; a separate ICF will be used for this scan. If there is a change in the MRI machine 
during the study, this process will need to be repeated. The MRI central reader will be blinded to 
treatment allocation.
19.2.
Study Committees
An Independent Data Monitoring Committee will not be used for this study because the 
Investigators and treating staff are not blinded to the subjects’ treatment assignment, natalizumab 
has a well-established safety profile, and the study has built-in rescue criteria and a futility 
analysis to check efficacy failure.
19.2.1.
Advisory Committee
An advisory committee will be formed to provide scientific and medical direction for the study 
and to oversee the administrative progress of the study. The advisory committee will meet at 
least annually to monitor subject accrual and to monitor compliance with the protocol at 
individual study sites. The advisory committee will be blinded to subject treatment assignments.

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Members of the advisory committee will include the Medical Director, Clinical Operations Lead, 
and Project Statistician from Biogen, and participating Investigators. Biogen will designate one 
of the participating Investigators to be the chairperson of the advisory committee.
19.2.2.
Independent Neurology Evaluation Committee
An INEC will be formed to review and confirm potential abnormalities related to suspected 
relapses for the purposes of confirming the Part 1 secondary endpoint.
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 the 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).
19.4.
Ethics Committee Notification of Study Completion or Termination
Where required, the regulatory authorities and ethics committees must be notified of the 
completion or termination of this study and sent a copy of the study synopsis in accordance with 
the necessary timelines.
19.5.
Retention of Study Data
The minimum retention time for study records will meet the strictest standard applicable to that 
study site, as dictated by any institutional requirements or local, national, or regional laws or 
regulations. Prior to proceeding with the 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 study 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 101MS329
Version 4.0
Phase 3b Efficacy Study of Natalizumab EID After Switch From Natalizumab SID in Subjects With RRMS
CONFIDENTIAL
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97
20.
REFERENCES
Belachew S, Phan-Ba R, Bartholomé E, et al. Natalizumab induces a rapid improvement of 
disability status and ambulation after failure of previous therapy in relapsing-remitting multiple 
sclerosis. Eur J Neurol. 2011;18(2):240-245.
Calabresi PA, Mellion M, Edwards KR, et al. Efficacy Results From the Phase 2b SYNERGY 
Study: Treatment of Disabling Multiple Sclerosis with the Anti-LING0-1 Monoclonal Antibody 
Opicinumab. Presented at the 2017 American Academy of Neurology Annual Meeting.
Ffrench-Constant C. Pathogenesis of multiple sclerosis. Lancet. 1994;343(8892):271-5.
Hartung HP, Archelos JJ, Zielasek J, et al. Circulating adhesion molecules and inflammatory 
mediators in demyelination: a review. Neurology. 1995;45(6 Suppl 6):S22-S32.
Morrow SA, O'Connor PW, Polman CH, et al. Evaluation of the symbol digit modalities test 
(SDMT) and MS neuropsychological screening questionnaire (MSNQ) in natalizumab-treated 
MS patients over 48 weeks. Mult Scler. 2010;16(11):1385-92.
Oturai AB, Koch-Henriksen N, Petersen T, et al. Efficacy of natalizumab in multiple sclerosis 
patients with high disease activity: a Danish nationwide study. Eur J Neurol. 2009;16(3):420-3.
Sangalli F, Moiola L, Bucello S, et al. Efficacy and tolerability of natalizumab in relapsing–
remitting multiple sclerosis patients: a post-marketing observational study. Neurol Sci. 
2011;31(0):299-302.
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.
Sormani MP, Bruzzi P. MRI lesions as a surrogate for relapses in multiple sclerosis: a meta-
analysis of randomised trials. Lancet Neurol. 2013;12(7):669-76.
Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of 
the McDonald criteria. Lancet Neurol. 2018;17(2):162-173. Epub 2017/12/21.

Protocol 101MS329
Version 4.0
Phase 3b Efficacy Study of Natalizumab EID After Switch From Natalizumab SID in Subjects With RRMS
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98
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “A Randomized, Controlled, Open-Label, Rater-Blinded, 
Phase 3b Study of the Efficacy, Safety, and Tolerability of 6-Week Extended Interval Dosing of 
Natalizumab (BG00002) in Subjects With Relapsing-Remitting Multiple Sclerosis Switching 
From Treatment With 4-Week Natalizumab Standard Interval Dosing (SID) in Relation to 
Continued SID Treatment - Followed by an Open-Label Crossover Extension Study Comprising 
Subcutaneous and Intravenous Natalizumab Administration” and agree to conduct the study 
according to the protocol and the applicable ICH guidelines and GCP regulations, and to inform 
all who assist me in the conduct of this study of their responsibilities and obligations.
____________________________________________________
Investigator’s Signature
        Date (dd - MONTH - yyyy)
____________________________________________________
Investigator’s Name (Print)
____________________________________________________
Study Site (Print)

CONFIDENTIAL
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Biogen MA Inc.
1
Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead, Berkshire
SL6 4AY
United Kingdom
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 101MS329
A Randomized, Controlled, Open-Label, Rater-Blinded, Phase 3b Study of the Efficacy, 
Safety, and Tolerability of 6-Week Extended Interval Dosing (EID) of Natalizumab (BG00002) 
in Subjects With Relapsing-Remitting Multiple Sclerosis Switching From Treatment With 
4-Week Natalizumab Standard Interval Dosing (SID) in Relation to Continued SID Treatment -
Followed by an Open-Label EID Crossover Extension Study Comprising Subcutaneous and 
Intravenous Natalizumab Administration
Version 4.0
Date: 20 August 2020
EUDRA CT Number: 2018-002145-11
Version 4.0 of the protocol has been prepared for this amendment, which supersedes Version 3.0.

Amendment Summary for Protocol 101MS329, Version 4.0
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
2
PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol 101MS329 is the addition of details
regarding the Screening visit for new participants who did not participate in Part 1 of the study 
and are being enrolled in Part 2.
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 5.2, Part 2 - Schedule of Activities, Table 4, footnote 1
Now reads:
1
The Part 2 Screening, informed consent, and eligibility assessment for a new subject should 
be performed within 6 weeks of the Baseline Visit.Informed consent can be obtained any 
time between Day -42 and the day of the last prestudy dose of natalizumab. The last 
prestudy dose of natalizumab must occur between Days -33 and -26 from the baseline 
visit. Some screening assessments must be performed immediately prior to the last 
prestudy dose of natalizumab (see footnote 7). All other screening assessments can 
occur any time between the day of the last prestudy natalizumab dose and baseline.
Randomization to crossover study treatment should be done at the Week 108 visit to confirm 
crossover treatment allocation.
Rationale: The change was made to clarify the timing of the last prestudy dose of natalizumab
and screening requirements for new participants being enrolled in the open-label extension, as 
well as the assessments that must be completed prior to the last prestudy dose of natalizumab.

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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 5.1, Part 1 - Schedule of Activities, Table 1
Change: In footnote 16, instructions for postdosing observation requirements were revised
Now reads:
16
Subjects must be observed for 1 hour after completion of infusion. Please refer to the 
Directions for Handling and Administration (DHA) located in the Study Reference 
Guide for details of postdose observation requirements.
Rationale: Biogen has elected to specify requirements for postdosing observation in the DHA of 
natalizumab rather than the study protocol.
This change also affects Section 5.1, Part 1 - Schedule of Activities (Table 2, footnote 16); 
Section 5.2, Part 2 - Schedule of Activities (Table 3, footnote 12); Section 5.2, Part 2 - Schedule 
of Activities (Table 4, footnote 13); and Section 11.3, Precautions.
Section 5.2, Part 2 - Schedule of Activities, Table 4
Change: The Nominal Study Day for the Screening visit was revised.
Now reads:
-4142 to -1
Rationale: This revision was required to align with the change in footnote 1 of this table.
Section 5.2, Part 2 - Schedule of Activities, Table 4
Change: Reference to footnote 7 was added to the Blood Chemistry assessment schedule.
Now reads:  
Blood Chemistry8,7
Rationale: The need for reference to footnote 7 was overlooked in the previous version.

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4
SUMMARY OF MINOR CHANGES TO THE PROTOCOL
The following minor changes were made to the protocol, as appropriate:

The version number and date were updated throughout the protocol.

The Sponsor Signature Page was revised.

Amendment Summary for Protocol 101MS329, Version 4.0
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5
LIST OF ABBREVIATIONS
DHA
Directions for Handling and Administration

CONFIDENTIAL
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Biogen MA Inc.
1
Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead, Berkshire
SL6 4AY
United Kingdom
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 101MS329
A Randomized, Controlled, Open-Label, Rater-Blinded, Phase 3b Study of the Efficacy, 
Safety, and Tolerability of 6-Week Extended Interval Dosing (EID) of Natalizumab (BG00002) 
in Subjects With Relapsing-Remitting Multiple Sclerosis Switching From Treatment With 
4-Week Natalizumab Standard Interval Dosing (SID) in Relation to Continued SID Treatment -
Followed by an Open-Label EID Crossover Extension Study Comprising Subcutaneous and 
Intravenous Natalizumab Administration
Version 3
Date: 08 July 2020
EUDRA CT Number: 2018-002145-11
Version 3 of the protocol has been prepared for this amendment, which supersedes Version 2.

Amendment Summary for Protocol 101MS329, Version 3
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
2
PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol 101MS329 is the addition of an OLE 
comprising a crossover analysis of natalizumab administered by IV infusion and SC injection
under EID.
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 7, Study Design
Now reads:
This study will be conducted in 2 parts. Part 1 is a prospective, randomized, interventional, 
controlled, open-label, rater-blinded, Phase 3b study in subjects with RRMS who have been 
receiving natalizumab SID for at least 12 months without relapses in the last 12 months. All MRI 
scans will be read at a central facility with raters blinded to subject assignment. Approximately 
480 subjects are expected to be enrolled at approximately 100 sites in North America, Europe, 
and Australia. Subjects will be randomly assigned to continue to receive natalizumab in 1 of the 
following 2 armsgroups:

SID: approximately 240 subjects will receive natalizumab as a 300 mg IV infusion 
every 4 weeks (28 [-2/+5 days]).

EID:  approximately 240 subjects will receive natalizumab as a 300 mg IV infusion 
every 6 weeks (42 [-2/+5 days]). 
Randomization will be stratified by country/region (North America [includes USA and Canada], 
United Kingdom, Europe and Israel [includes Belgium, France, Germany, Israel, Italy, 
Netherlands, and Spain], and Australia), body weight (≤80 kg versus > 80 kg), and duration of 
natalizumab exposure (≤3 years versus > 3 years). Subjects will receive open-label natalizumab 
at their assigned frequency throughout the 72 weeks of the study.
At the completion of their 72-week treatment period, subjects in Part 1 who cannot 
participate, or elect not to participate, in Part 2 will enter a 12-week follow-up, and will 
receive a follow-up safety phone call 12 weeks later (i.e., 24 weeks after the last dose of 
study treatment) before completing the study.
See Figure 1 for a schematic of the study design.

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3
Figure 1:
Study Design
Part 2 is a 108-week OLE for approximately 200 subjects at approximately 45 sites in 
Canada, the United Kingdom, Europe, Israel, and Australia who complete their 
randomized treatment in Part 1, provide consent, and are eligible to participate 
immediately following completion of the 72-week treatment period.
Subjects who did not participate in Part 1 but provide consent and satisfy the inclusion-
exclusion and eligibility requirements of Part 1, including treatment with natalizumab SID 
for at least 12 months without relapses in the last 12 months, may also be enrolled in Part 2 
as new subjects to ensure adequate sample size for the Part 2 analysis.
Subjects enrolled in Part 2 will receive natalizumab 300 mg by IV infusion once every 
6 weeks (42 ± 7 days) for a period of 36 weeks and be randomized to an additional 48 weeks 
of crossover treatment comprising 24 weeks EID SC Q6W and 24 weeks EID IV Q6W. All 
MRI scans will be read at a central facility by blinded raters.
At the completion of their 48-week crossover treatment period, subjects in Part 2 will 
receive a final dose of natalizumab 300 mg by IV infusion at Week 156, proceed to the 12-
week follow-up, and receive a further safety follow-up by telephone 12 weeks later (i.e., 
24 weeks after the last dose of study treatment) before completing the study.
The design of this study, inclusive of Parts 1 and 2, is presented in Figure 1.

Amendment Summary for Protocol 101MS329, Version 3
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6
…
15
The screening MRI must be performed at least 2 weeks prior to the Baseline Visit to confirm eligibility. All 
postbaseline MRIs, with the exception of the one conducted at the Neurological Worsening and Relapse 
Assessment, are to be completed within a 7-day window of the dosing visit. MRIs conducted at the 
Neurological Worsening and Relapse Assessment must be completed prior to dosing with rescue therapy, but 
can be completed on the same day. If a subject's MRI is scheduled to occur <4 weeks after the last dose of 
steroid treatment for relapse, the MRI should be rescheduled so that it is performed either before the steroid 
treatment of between 4 and 8 weeks after the last dose of steroid treatment. MRI does not need to be 
performed at the ET Visit if the last MRI was performed within the previous 4 weeks. In the event of an 
early study termination for a pregnancy, a Gd-enhancing MRI should not be conducted.
In Section 5.2:

Introductory text was added to Section 5.2, Part 2 – Schedule of Activities.

Table 3: Part 2 Schedule of Activities – EID SC vs. IV OLE for Subjects Who 
Participated in Part 1 was added, with supporting footnotes.

Table 4: Part 2 Schedule of Activities – EID SC vs. IV OLE for New Subjects was 
added, with supporting footnotes.
Now reads:
5.2.
Part 2 – Schedule of Activities
For subjects who completed Part 1 treatment and enrolled in Part 2, the schedule of 
activities for Part 2 (Table 3) does not differ for subjects randomized to SC/IV or IV/SC 
with the exception of the order of treatment administration during the crossover period.
For new subjects enrolled in Part 2, the initial screening, inclusive of select assessments, 
differs from those subjects who participated in Part 1 but is otherwise the same beginning 
at Week 78 through the end of Part 2 (Table 4).

Amendment Summary for Protocol 101MS329, Version 3
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7
Table 1:
Part 2 Schedule of Activities – EID SC vs. IV OLE for Subjects Who Participated in Part 1
Tests and assessments are listed in the recommended order. At each visit, assessments should be performed as follows:
 
 2) clinical and neurological assessments, 3) PK/PD 
 collection, and 4) dose administration. It is not 
required that all screening tests and assessments be completed during 1 visit.
Study Week
78
841
90
96
102
108
114
120
126
132
138
144
150
156
Follow-
Up EOS 
Visit
168
ET 
Visit2
Unscheduled Visit
(Neurological 
Worsening and 
Relapse 
Assessment)3
Follow-Up 
Safety 
Phone Call
1804
Study Day
546
(-2/
+5)
588
(-2/
+5)
630
(-2/
+5)
672
(-2/
+5)
714
(-2/
+5)
756
(-2/
+5)
798
(-2/
+5)
840
(-2/
+5)
882
(-2/
+5)
924
(-2/
+5)
966
(-2/
+5)
1008
(-2/
+5)
1050
(-2/
+5)
1092
(-2/
+5)
1176
(±10)
-
-
1260
(±10)
Informed 
Consent Form 
for Part 25
---- X ----
Eligibility 
Criteria Check 
for Part 25
---- X ----
Randomization
X
Vital signs6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
Examination1
X
X
X
X
X
X
X
Body Weight1
X
X
X
X
C-SSRS1,7
X
TSQM
X
X
X
EDSS
X
X
X
X
X
X

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8
Study Week
78
841
90
96
102
108
114
120
126
132
138
144
150
156
Follow-
Up EOS 
Visit
168
ET 
Visit2
Unscheduled Visit
(Neurological 
Worsening and 
Relapse 
Assessment)3
Follow-Up 
Safety 
Phone Call
1804
Study Day
546
(-2/
+5)
588
(-2/
+5)
630
(-2/
+5)
672
(-2/
+5)
714
(-2/
+5)
756
(-2/
+5)
798
(-2/
+5)
840
(-2/
+5)
882
(-2/
+5)
924
(-2/
+5)
966
(-2/
+5)
1008
(-2/
+5)
1050
(-2/
+5)
1092
(-2/
+5)
1176
(±10)
-
-
1260
(±10)
Neurological 
Examination 
(MS Signs & 
Symptoms)
X
X
X
X
X
X
Blood 
Hematology8
X
X
X
X
X
X
X
Blood 
Chemistry9
X
X
X
X
Urine Pregnancy 
Test10
PD Assessments 
(whole blood)8
X
X
X
X
X
X
X
X
X
X
PK Natalizumab 
Concentration 
(serum)8
X
X
X
X
X
X
X
X
X
X
Anti-
natalizumab 
Antibodies8
X
X
X
X
X
X
Brain MRI11
X
X
X
X
Natalizumab 
EID IV infusion
X
X
X
X
X
X

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10
6
Vital signs collected at each of the specified timepoints include temperature, systolic and diastolic blood pressure, pulse rate, and respiratory rate. 
Vital signs collected as part of the subject's standard of care on the same day as a study visit do not need to be repeated for the study if Biogen has 
access to the information and data recorded in the subject's CRF. Vital signs on a study treatment day must be performed prior to the 
administration of study treatment.
7
The Part 1 "baseline/screening" C-SSRS must be completed at the Part 1 screening Visit; at all other visits, the "since last visit" C-SSRS must be 
used.
8
Sample to be collected prior to dosing.
9
If a subject experiences signs and symptoms suggestive of liver failure (such as jaundice, vomiting, anorexia, nausea, fatigue, and right upper 
abdominal discomfort), liver function tests (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl 
transferase, bilirubin, and albumin) must be performed at the local laboratory on an expedited basis.
10 Follow-up testing for women of childbearing potential throughout the study will be done at the discretion of the Investigator or as required by local 
law. In each case of delayed menstruation (more than 1 month between menstrual periods), a urine pregnancy test should be performed.
11 All postbaseline MRIs are to be completed within a 7-day window of the dosing visit. If a subject's MRI is scheduled to occur < 4 weeks after the last 
dose of steroid treatment for relapse, the MRI should be rescheduled so it is performed either before the steroid treatment or between 4 and 8 weeks 
after the last dose of steroid treatment. MRI does not need to be performed at the ET Visit if the last MRI was performed within the previous 
4 weeks. In the event of an early termination for a pregnancy, a Gd-enhancing MRI should not be conducted.
12 The time required for drug preparation and drug administration should be recorded in detail for each occasion of treatment administration during 
the crossover period. Subjects must be observed for 1 hour after completion of the SC injection or IV infusion.
13 Subjects in Part 2 will receive a final dose of natalizumab 300 mg by SC injection or IV infusion at the Week 156 visit with the route of 
administration being the subject’s choice.
14 PPQ assessments at Week 138 and Week 150 must be collected after study treatment administration.

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11
Table 2:
Part 2 Schedule of Activities – EID SC vs. IV OLE for New Subjects
Tests and assessments are listed in the recommended order. At each visit, assessments should be performed as follows:
 
, 2) clinical and neurological assessments, 3) PK/PD 
 collection, and 4) dose administration. It is not 
required that all screening tests and assessments be completed during 1 visit. This Schedule of Activities is identical to the 
Schedule in Table 3 after the Week 84 visit.
Nominal
Study Week
Screen1
Baseline 
Visit
72
78
842
90
96
102
108
114
120
126
132
138
144
150
156
Follow-
Up EOS 
Visit
168
ET 
Visit3
Unscheduled 
Visit 
(Neurological 
Worsening 
and Relapse 
Assessment)4
Follow-
Up Safety 
Phone 
Call5
180
Nominal
Study Day
-41 to -
1
504
(-2/
+5)
546
(-2/
+5)
588
(-2/
+5)
630
(-2/
+5)
672
(-2/
+5)
714
(-2/
+5)
756
(-2/
+5)
798
(-2/
+5)
840
(-2/
+5)
882
(-2/
+5)
924
(-2/
+5)
966
(-2/
+5)
1008
(-2/
+5)
1050
(-2/
+5)
1092
(-2/
+5)
1176
(±10)
-
-
1260
(±10)
Informed
Consent Form 
for Part 21
X
Eligibility 
Criteria Check 
for Part 21
X
X
Randomization
X
Medical 
History1
X
Physical 
Examination1
X
X
X
X
X
X
X
X
X
Body Weight1
X
X
X
X
X
X
Vital signs6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV, Hep B, and 
Hep C Testing
X
TSQM
X
X
X
X
P
D

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12
Nominal
Study Week
Screen1
Baseline 
Visit
72
78
842
90
96
102
108
114
120
126
132
138
144
150
156
Follow-
Up EOS 
Visit
168
ET 
Visit3
Unscheduled 
Visit 
(Neurological 
Worsening 
and Relapse 
Assessment)4
Follow-
Up Safety 
Phone 
Call5
180
Nominal
Study Day
-41 to -
1
504
(-2/
+5)
546
(-2/
+5)
588
(-2/
+5)
630
(-2/
+5)
672
(-2/
+5)
714
(-2/
+5)
756
(-2/
+5)
798
(-2/
+5)
840
(-2/
+5)
882
(-2/
+5)
924
(-2/
+5)
966
(-2/
+5)
1008
(-2/
+5)
1050
(-2/
+5)
1092
(-2/
+5)
1176
(±10)
-
-
1260
(±10)
EDSS
X
X
X
X
X
X
X
Neurological 
Examination 
(MS Signs & 
Symptoms)
X
X
X
X
X
X
X
Blood 
Hematology7
X
X
X
X
X
X
X
X
Blood 
Chemistry8
X
X
X
X
X
Serum 
Pregnancy Test9
X
Serum FSH10
X
Urine Pregnancy 
Test11
X
PD Assessments 
(whole blood)7
X
X
X
X
X
X
X
X
X
X
X
PK Natalizumab 
Concentration 
(serum)7
X
X
X
X
X
X
X
X
X
X
X
Anti-
natalizumab 
Antibodies7
X
X
X
X
X
X
X

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Nominal
Study Week
Screen1
Baseline 
Visit
72
78
842
90
96
102
108
114
120
126
132
138
144
150
156
Follow-
Up EOS 
Visit
168
ET 
Visit3
Unscheduled 
Visit 
(Neurological 
Worsening 
and Relapse 
Assessment)4
Follow-
Up Safety 
Phone 
Call5
180
Nominal
Study Day
-41 to -
1
504
(-2/
+5)
546
(-2/
+5)
588
(-2/
+5)
630
(-2/
+5)
672
(-2/
+5)
714
(-2/
+5)
756
(-2/
+5)
798
(-2/
+5)
840
(-2/
+5)
882
(-2/
+5)
924
(-2/
+5)
966
(-2/
+5)
1008
(-2/
+5)
1050
(-2/
+5)
1092
(-2/
+5)
1176
(±10)
-
-
1260
(±10)
Brain MRI12
X
X
X
X
X
Natalizumab 
EID IV infusion
X
X
X
X
X
X
X
Natalizumab 
EID SC-IV 
Crossover13
X
X
X
X
X
X
X
X
X14
PPQ14
X
X
X
Safety (AEs, 
SAEs)
Record as per Section 15.3 of the protocol
Concomitant 
Therapy and 
Procedures
Record as per Section 11.5 of the protocol
X
Assessment of 
New 
Neurological 
Symptoms15
X
AE = adverse event; CRF = case report form; EDSS = Expanded Disability Status Scale; EID = extended interval dosing; EOS = end of study; 
 ET = early termination; FSH = follicle stimulating hormone; Gd = gadolinium; Hep = hepatitis; HIV = 
human immunodeficiency virus; IV=intravenous; MRI = magnetic resonance imaging; MS = multiple sclerosis; 
 
; OLE = open-label extension; PD = pharmacodynamic; PK = pharmacokinetic; PPQ = Patient Preference 
Questionnaire; SAE = serious adverse event; SC = subcutaneous; Sg = Screening; TSQM = Treatment Satisfaction Questionnaire for Medication.

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1
The Part 2 Screening, informed consent, and eligibility assessment for new subjects should be performed within 6 weeks of the Baseline Visit. 
Randomization to crossover study treatment should be done at the Week 108 visit to confirm crossover treatment allocation.
2
The Part 1 and Part 2 assessments at Week 84 are the same and should be performed only once.
3
If a subject chooses to withdraw from the study, an ET Visit should occur as soon as possible but no later than 4 weeks after the last dose of study 
treatment, to be followed by a final EOS Visit at 12 weeks (± 10 days) and the safety follow-up phone call at 24 weeks after the last dose of study 
treatment.
4
Subjects who suspect that they are experiencing new or worsening neurological symptoms, including possible relapse, need to phone the Investigator 
within 72 hours of the onset of symptoms. The subject is to be evaluated by the neurologist within 5 days of the onset of symptoms. Relapses should 
be documented in the relapse assessment form. The maximum number of samples eligible for collection and analysis are 2 (1 for each unscheduled 
visit).
5
Subjects should have a follow-up safety phone call 24 weeks after their last dose of study treatment.
6
Vital signs collected at each of the specified timepoints include temperature, systolic and diastolic blood pressure, pulse rate, and respiratory rate. 
Vital signs collected as part of the subject's standard of care on the same day as a study visit do not need to be repeated for the study if Biogen has 
access to the information and data recorded in the subject's CRF. Vital signs taken on a study treatment day must be performed prior to the 
administration of study treatment.
7
Sample to be collected prior to dosing.
8
If a subject experiences signs and symptoms suggestive of liver failure (such as jaundice, vomiting, anorexia, nausea, fatigue, and right upper 
abdominal discomfort), liver function tests (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, bilirubin, and 
albumin) must be performed at the local laboratory on an expedited basis.
9
Required for women of childbearing potential. Results must be known prior to Baseline.
10 For postmenopausal subjects only.
11 Follow-up testing for women of childbearing potential throughout the study will be done at the discretion of the Investigator or as required by local 
law. In each case of delayed menstruation (more than 1 month between menstrual periods), a urine pregnancy test should be performed.
12 The screening MRI must be performed at least 2 weeks prior to the Baseline Visit to confirm eligibility. All postbaseline MRIs are to be completed 
within a 7-day window of the dosing visit. If a subject's MRI is scheduled to occur < 4 weeks after the last dose of steroid treatment for relapse, the 
MRI should be rescheduled so it is performed either before the steroid treatment or between 4 and 8 weeks after the last dose of steroid treatment. 
MRI does not need to be performed at the ET Visit if the last MRI was performed within the previous 4 weeks. In the event of an early termination 
for a pregnancy, a Gd-enhancing MRI should not be conducted.
13 The time required for drug preparation and drug administration should be recorded in detail for each occasion of treatment administration during 
the crossover period. Subjects must be observed for 1 hour after completion of the IV infusion or the SC injection.
14 Subjects in Part 2 will receive a final dose of natalizumab 300 mg by SC injection or IV infusion at the Week 156 visit with the route of 
administration being the subject’s choice.
15 PPQ assessments at Week 138 and Week 150 must be collected after study treatment administration.

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15 Subjects should be contacted by phone 24 weeks after the last dose of study treatment to discuss if there has been any new development of 
neurological symptoms. PML or new neurological symptoms indicative of PML (new or sudden change in thinking, vision, balance, or strength 
persisting over several days) must be immediately reported as a SAE.

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17
To evaluate the efficacy of SC versus IV 
routes of natalizumab administration.
All endpoints will be assessed between 
6 months of SC and 6 months IV in the 
randomized, crossover period.

Number of new or newly enlarging 
T2 hyperintense lesions

Time to first relapse

Annualized relapse rate

Change in EDSS score

Number of new Gd-enhancing lesions

Number of new T1 hypointense lesions

PBVC and change in cortical and 
thalamic brain region volume
To characterize PK and PD of SC versus 
IV routes of natalizumab administration.
All endpoints will be assessed between 
6 months of SC and 6 months IV in the 
randomized, crossover period.

Ctrough

Trough α4 integrin saturation

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Rationale: The objective of the OLE is to evaluate subject preference for, and satisfaction, with 
SC injection and IV infusion of natalizumab under EID, and to develop long-term efficacy and 
safety data with regard to natalizumab administration in general under the EID regimen.
This change also substantially affects Section 13, Efficacy, Pharmacokinetic, and 
Pharmacodynamic Assessments; and Section 16, Statistical Methods and Determination of 
Sample Size.
Section 7.1, Study Duration for Subjects
Change: Section 7 was revised to comprise Section 7.1.1, Study Duration for Subjects Enrolled 
Only in Part 1, and Section 7.1.2, Study Duration for Subjects Enrolled in Part 1 and Part 2. 
Now reads:
7.1.1. Study Duration for Subjects Enrolled Only in Part 1
The total duration of study participation in Part 1 for each subjects who do not participate in 
Part 2 will be up to 102 weeks;. tThis consists of comprises a screening period of up to 
6 weeks,; a treatment period of 72 weeks,; and a follow-up period of 12 weeks; and .  Aa
follow-up safety phone call will be performed 2412 weeks after the follow-up period 
(i.e., 24 weeks after the last dose of study treatment).
The end of study (EOS) date for a subject in Part 1 may be the last study visit, last the follow-up 
safety phone conversationcall, or last protocol-specified assessment,; or if the subject has 
ongoing AEs that are being followed up, then the date may be the date of AE resolution.
7.1.2
Study Duration for Subjects Enrolled in Part 1 and Part 2
The total duration of study participation in Part 1 for subjects who also participate in Part 
2 will be up to 78 weeks, comprising a screening period of up to 6 weeks and the 
randomized SID or EID treatment period of 72 weeks.

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The total duration of study participation in Part 2 for these subjects will be approximately 
108 weeks. This comprises EID IV treatment for 36 weeks; a randomized EID SC vs. IV 
crossover-treatment period of 48 weeks; a follow-up period of 12 weeks; and a follow-up 
safety phone call 12 weeks after the follow-up period (i.e., 24 weeks after the last dose of 
study treatment).  The total duration of study participation for subjects who participate in 
both Part 1 and Part 2 will be approximately 186 weeks.
The EOS date for subjects participating in Part 1 and Part 2 may be the last study visit, the 
follow-up safety phone call, or last protocol-specified assessment; if the subject has ongoing 
AEs that are being followed, then the date may be the date of AE resolution.
Rationale: Revision of this section was required to differentiate the duration of study for 
subjects who participate in Part 1 only, in both Part 1 and Part 2, as well as for new subjects who 
participate in Part 2 of the study without having participated in Part 1.
This change also substantially affects Section 7.3, Unscheduled Visits and Treatment for MS 
Relapses; Section 7.5, End of Study; Section 9, Screening and Randomization; Section 10, 
Discontinuation of Study Treatment and Withdrawal of Subjects from the Study; and Section 11, 
Study Treatment Use.

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SUMMARY OF MINOR CHANGES TO THE PROTOCOL
The following minor changes were made to the protocol, as appropriate:

The title, version number, and date were updated throughout the protocol.

Section 2, List of Abbreviations, was updated.

In Section 4.2, current therapies for multiple sclerosis were updated.

Typographical errors and formatting were corrected.

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21
LIST OF ABBREVIATIONS
AE
adverse event
CRF
case report form
C-SSRS
Columbia Suicide Severity Rating Scale
Ctrough
trough serum concentration of natalizumab
DNA
deoxyribonucleic acid
EDSS
Expanded Disability Status Scale
EID
extended interval dosing
EOS
end of study
ET
early termination
FSH
follicle stimulating hormone
Gd
gadolinium
Hep
hepatitis
HIV
human immunodeficiency virus
IV
intravenous(ly)
JCV
John Cunningham virus
MRI
magnetic resonance imaging
MS
multiple sclerosis
OLE
open-label extension
PBMC
peripheral blood mononuclear cell
PBVC
percentage of brain volume change
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
PPQ
Patient Preference Questionnaire
PRO
patient-reported outcome
Q4W
every 4 weeks
Q6W
every 6 weeks
RNA
ribonucleic acid
RRMS
relapsing-remitting multiple sclerosis
SAE
serious adverse event
D

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SC
subcutaneous
SID
standard interval dosing
TSQM
Treatment Satisfaction Questionnaire for Medication
USA
United States
VCAM-1
vascular cell adhesion molecule 1

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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 101MS329
A Randomized, Controlled, Open-Label, Rater-Blinded, Phase 3b Study of the Efficacy, Safety, 
and Tolerability of 6-Week Extended Interval Dosing of Natalizumab (BG00002) in Subjects 
With Relapsing-Remitting Multiple Sclerosis Switching From Treatment With 4-Week 
Natalizumab Standard Interval Dosing (SID) in Relation to Continued SID Treatment
Version 2.0
Date: 28 February 2019
EUDRA CT Number: 2018-002145-11
Version 2.0 of the protocol has been prepared for this amendment, which supersedes Version 1.0.

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who have previously been treated with 
natalizumab SID for at least 12 months, in 
relation to continued SID treatment.
and Week 7248

Number of new gadolinium 
(Gd)-enhancing and new 
T1 hypointense lesions at Weeks 24, 
48, and 72
…
…
Rationale: The timing of the primary efficacy endpoint was changed to Week 72 to allow the 
collection of efficacy data over a 48-week period after stable trough concentrations have been 

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5
withdrawal will be summarized by treatment group.  Clinically relevant abnormalities for 
laboratory parameters will be identified by treatment group.
16.1.1.
Analysis Population
The modified intent-to-treat population, defined as all randomized subjects who receive at least 
1 dose of study treatment and have at least 1 postbaseline efficacy assessment, will be used for 
all efficacy analyses.  Subjects will be analyzed in the groups to which they are randomized.
16.1.2.
Methods of Analysis
16.1.2.1.
Analysis of the Primary Endpoint
The primary endpoint, the number of new or newly enlarging T2 hyperintense lesions at 
Week 4872, will be analyzed using negative binomial regression models with treatment as the 
classification variable and baseline body weight (≤90 80 kg versus >90 80 kg), EDSS,duration 
of natalizumab exposure at baseline (≤3 years versus > 3 years), and region (North America 
[includes USA and Canada], United Kingdom, Europe and Israel [includes Belgium, 
France, Germany, Israel, Italy, Netherlands, and Spain], and Australia) as covariates.  The 
ratio of mean lesion numbers of EID versus SID (EID/SID) will be derived from the model with 
a 95% CI and associated p-value.  The treatment will be considered different if the p value 
(2 sided) is less than 0.05.  Thelower limit of the 95% CI is above 1.  As a secondary 
inference, the possibility of a 2-fold increase in the mean lesion number in the EID group as 
compared with the SID group will be considered ruled out if the upper limit of 95% CI is lessno 
greater than 2.  The proportion of subjects with no new or newly enlarging T2 hyperintense 
lesions will be analyzed using logistic regression models with the same covariates as those 
described above.
For subjects who withdraw or receive rescue SID natalizumab prior to Week 48, the Week 48 
number of lesions may be imputed using the MMRM.
16.1.2.2.
Primary and Secondary Estimands and Handling of Intercurrent Events
The study plans to make every effort to retain subjects in the study and to continue 
follow-up in the cases of the initiation of rescue medication, switching to different dosing 
frequency, and treatment discontinuation due to AEs, lack of efficacy, or for other reasons.  
This will allow continuing assessments of subjects’ MS disease activity.  Efforts will also be 
made to obtain details of withdrawals in the generic categories of “lost to follow-up” or 
“other” whenever possible.  Classification of the withdrawals in these nonspecific 
categories into “possibly efficacy related”, “possibly safety related”, or “no information” 
will be made based on all available information by independent Sponsor personnel who are 
blinded to treatment regimen and will be documented prior to database lock. 
The proposed primary estimand will be based on a treatment policy strategy, in which the 
study is intended to estimate the difference of a potential treatment decision of switching 
subjects from SID to EID compared with keeping subjects on SID over the next 72 weeks in 

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a realistic clinical setting, where switching to a different dosing regimen or different 
medication may occur depending on disease activity.  Therefore, the primary analysis will 
utilize all measurements regardless of whether subjects remain on randomized treatment.  
For subjects who withdraw from the study for reasons related to efficacy or an AE or who 
have a “possibly related” withdrawal, as described above, the missing values will be 
imputed by the worst observed value of the subjects on study treatment at the given 
timepoint.  For withdrawals classified as “no information”, the missing values will be 
treated as missing at random and will be addressed using multiple imputation.  The 
number and proportion of subjects with intercurrent events and the time to intercurrent 
event will also be tabulated and compared between randomized groups.  Sensitivity 
analysis may be conducted using tipping point analysis.  Supplementary analyses by 
imputing all missing values by treating all as missing at random using multiple imputation 
will also be conducted. 
The secondary estimand will be based on a hypothetical strategy, in which the difference in 
the efficacy of EID versus SID over the 72 weeks following randomization if no 
intercurrent events occurred will be the target of estimation.  The primary analysis for this 
estimand will treat the data obtained post-intercurrent event as missing values.  For 
treatment discontinuation or switching due to efficacy as well as withdrawal that is due to 
efficacy or is “possibly efficacy related”, the missing values will be imputed by the worst 
observed values of the subjects on study treatment at the given timepoint.  For intercurrent 
events due to other reasons, the resulting missing values will be addressed using multiple 
imputation.  Sensitivity analysis may be conducted using tipping point analysis.
16.1.2.216.1.2.3.
Analysis of the Secondary Endpoints
…
Annualized Relapse Rate
The annualized relapse rate at Week 48 and Week 72 will be analyzed at each timepoint using 
negative binomial regression models with treatment as the classification variable and baseline 
body weight (≤90 80 kg versus >90 80 kg), EDSS,duration of natalizumab exposure at 
baseline (≤3 years versus > 3 years), and region (North America [includes USA and 
Canada], United Kingdom, Europe and Israel [includes Belgium, France, Germany, Israel, 
Italy, Netherlands, and Spain], and Australia) as covariates.  The ratio of mean lesion 
numbers of EID versus SID (EID/SID) will be derived from the model with a 95% CI and 
associated p-value.
EDSS Worsening
Confirmed EDSS worsening is defined as an increase of at least 1.0 point from a baseline 
EDSS score ≥ 1.0 or an increase of at least 1.5 points from a baseline EDSS score of 0 that is 
confirmed after at least 24 weeks.  Time to EDSS worsening will be analyzed using KM 
estimates and Cox regression models similar to the method described above for time to first 
relapse.

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…
16.7.
Interim Analyses
An interim futility analysis, based on the number of new or newly enlarging T2 hyperintense 
lesions at 24 weeks, will be conducted when 50% of subjects have at least 6 months of 
randomized treatment.  The interim futility analysis is designed to ensure that if clinically 
meaningful loss of efficacy is occurring in the EID group, the study can be stopped early to 
prevent unnecessary risk to the study participants of uncontrolled MS disease activity as a result 
of potential efficacy failure on EIDThe interim data will be analyzed using negative binomial 
regression models with treatment as the classification variable and baseline body weight 
(≤80 kg versus > 80 kg), duration of natalizumab exposure at baseline (≤3 years versus 
> 3 years), and region (North America [includes USA and Canada], United Kingdom, 
Europe and Israel [includes Belgium, France, Germany, Israel, Italy, Netherlands, and 
Spain], and Australia) as covariates.  The ratio of mean lesion numbers of EID versus SID 
(EID/SID) will be derived from the model with a 95% CI.  The study may be stopped for 
futility if the lower limit of the 95% CI is > 2 and a 2-fold increase in mean lesion numbers 
in the EID group can be concluded with 97.5% confidence.
16.8.
Sample Size Considerations
To detect an increase in the mean number of new or newly enlarging T2 hyperintense lesions 
over 48 weeks at the alpha level of 0.05 (2 sided), a sample size of 400 subjects (200 subjects per 
arm) will provide the following:

>80% power to detect an increase from a mean of 0.3 (expected efficacy of 
SID dosing arm in this population) to 0.5.

≥90% power to detect an increase from a mean of 0.3 to 0.6.
Historical data on MS treatments, including meta analyses on the relationship between new or 
newly enlarging T2 hyperintense lesions and relapses, suggest little or no clinical relevance of a 
difference smaller than 0.2 in mean new or newly enlarging T2 hyperintense lesions over 
48 weeks.Historical data on MS treatments, including a meta-analysis on the relationship 
between new or newly enlarging T2 lesions and relapses, suggest little or no clinical 
relevance of a difference of 0.2 to 0.3 in mean lesion numbers over 72 weeks [Sormani and 
Bruzzi 2013].  With the planned sample size of N = 200/group, the precision of the 
estimated mean lesion numbers is sufficient to allow > 80% probability to observe the 
lower limit of the 95% CI for the ratio of EID to SID in the estimated mean lesion number 
above 1 if the true mean is 0.5 and 0.3 in the EID and SID group, respectively.  If the true 
mean is 0.6 and 0.3 in the EID and SID group, respectively, the probability will be 
approximately 90%.  In the other direction, the sample size provides a precision that allows 
approximately 90% probability to observe the upper limit of the 95% CI to be ≤2 if the 
true mean lesion numbers in both groups are 0.3.  Approximately 480 subjects will be 
enrolled to account for a drop-out rate of approximately 17%.

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Rationale: The text describing the overview of statistical analysis for efficacy in Section 16.1 
was revised per regulatory advice, and detailed rationales for each section are provided below. 
The timing of the primary efficacy endpoint was changed to Week 72 to allow the collection of 
efficacy data over a 48-week period after stable trough concentrations have been reached. 
Stratification on the factor “country/region” was clarified per EMA request because it was not 
clear whether stratification would be based on regions, countries, or a mixture of the two. A 
lower cutoff for body weight (i.e., 80 kg) was used because at weight > 80 kg, a decrease in 
efficacy was suggested based on the PK/PD modelling data and per EMA request. Duration of 
natalizumab exposure was added as a covariate in place of EDSS per EMA request and guidance 
that any factor utilized in randomization stratification should also be utilized as a model 
covariate.  Detailed inference criteria for the primary analysis were edited to avoid the potential 
misinterpretation that the study was designed to test the superiority of EID over SID and to better 
reflect the study goal of estimating the difference between SID and EID, with high precision and 
a narrow 95% confidence interval (CI), to support the treatment decision based on individualized 
benefit/risk assessments, as discussed and agreed upon with the EMA.
The analysis plan was revised to include primary and secondary estimands based on International 
Council for Harmonisation E9 (R1) Draft Addendum on estimands 
EMA/CHMP/ICH/436221/2017 and per request from the EMA that these statistical details be 
included in the protocol rather than only in the study statistical analysis plan.
With the primary endpoint changed to Week 72, the corresponding secondary endpoint timing 
was changed to Week 48 and there will no longer be an efficacy analysis performed at Week 48;
.  EDSS 
worsening was further defined, consistent with the reprioritization of EDSS worsening as a 
secondary endpoint. 
Time to EDSS worsening was prioritized as a secondary endpoint;
 
Subgroup analyses are useful for assessing heterogeneity and might further stress or refute the 
need for individualized benefit/risk assessments. The EMA requested that information on 
prespecified subgroup analyses be included in the protocol rather than only in the statistical 
analysis plan.
Interim analysis text was updated to clarify that the study may be stopped for a degree of inferior 
efficacy that would discourage the use of EID in all settings. Consultation with leading 
neurologists treating MS led to an empirical consensus view that a change from 0.3 with SID to 
0.6 (a 2-fold increase) with EID at a population level would represent an unacceptable disease 
activity for considering EID as a reasonable PML risk mitigation strategy. The EMA requested 
that details of the analysis planned for assessment of futility be included in the protocol rather 
than only in the statistical analysis plan.
Sample size considerations were revised to avoid the potential misinterpretation that the study 
was designed to test superiority of EID over SID and to better reflect the study goal of estimating 

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the difference between SID and EID, with high precision and a narrow 95% CI, to support the 
treatment decision based on individualized benefit/risk assessments, as discussed and agreed 
upon with the EMA. Text was added to address the sample size appropriateness for both the 
primary and secondary analyses discussed with the EMA, i.e., to check if there is a difference 
between EID and SID and to exclude the worsening of efficacy with EID at a level that would 
discourage the use of EID in most clinical settings.

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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL
Changes to the protocol are presented chronologically. New text is shown in bold type; deleted 
text is shown with a strikethrough.
Section 1, Synopsis
The Synopsis was revised to reflect changes made throughout the protocol.
Section 5, Schedule of Activities
Change: The screening period was extended to Days -42 to -1, and a new footnote (Footnote 1) 
was added to clarify the screening timing. 
Week 84 EDSS and neurological examination assessments as well as Week 60 assessments for 
anti-natalizumab antibodies were added.
Footnote 9 of Table 1 was added to include language on liver function testing in the event of a 
subject experiencing signs and symptoms suggestive of liver injury.
Footnote 12 of Table 1 was updated to include language on delayed menstrual period and 
pregnancy testing. 

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Now reads:
Table 1:
Schedule of Activities – SID
Study Week
Screening 
Visit
41
-6 to -1
Baseline 
Visit
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72 Follow 
Up 
EOS 
Visit
84
Follow 
Up 
Safety 
Phone 
Call12
96 
ET 
Visit23 Unscheduled 
Visit 
(Neurological 
Worsening 
and Relapse 
Assessment)34
Study Day
-2842 to -1
1
28
(-2/
+5)
56
(-2/
+5)
84
(-2/
+5)
112
(-2/
+5)
140
(-2/
+5)
168
(-2/
+5)
196
(-2/
+5)
224
(-2/
+5)
252
(-2/
+5)
280
(-2/
+5)
308
(-2/
+5)
336
(-2/
+5)
364
(-2/
+5)
392
(-2/
+5)
420
(-2/
+5)
448
(-2/
+5)
476
(-2/
+5)
504
(-2/
+5)
588
(±10)
672
(±10)
Informed Consent 
Form
X
Eligibility Criteria 
Check
X
X
Randomization
X
Medical History
X
Physical 
Examination
X
X45
X
X
X
X
X
X
Body Weight
X
X45
X
X
X
X
X
X
Vital Signs56
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV, Hep B, and 
Hep C Testing
X

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Study Week
Screening 
Visit
41
-6 to -1
Baseline 
Visit
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72 Follow 
Up 
EOS 
Visit
84
Follow 
Up 
Safety 
Phone 
Call12
96 
ET 
Visit23 Unscheduled 
Visit 
(Neurological 
Worsening 
and Relapse 
Assessment)34
Study Day
-2842 to -1
1
28
(-2/
+5)
56
(-2/
+5)
84
(-2/
+5)
112
(-2/
+5)
140
(-2/
+5)
168
(-2/
+5)
196
(-2/
+5)
224
(-2/
+5)
252
(-2/
+5)
280
(-2/
+5)
308
(-2/
+5)
336
(-2/
+5)
364
(-2/
+5)
392
(-2/
+5)
420
(-2/
+5)
448
(-2/
+5)
476
(-2/
+5)
504
(-2/
+5)
588
(±10)
672
(±10)
C-SSRS67
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
EDSS
X
X
X
X
X
X
X
Neurological 
Examination
X
X
X
X
X
X
X
Blood 
Hematology78
X
X
X
X
X
X
Blood Chemistry9
X
X
X
Serum Pregnancy 
Test810
X
Serum FSH911
X
Urine Pregnancy 
Test1012
X

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89If a subject experiences signs and symptoms suggestive of liver injury (such as jaundice, vomiting, anorexia, nausea, fatigue, and right upper 
abdominal discomfort), liver function tests (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl 
transferase, bilirubin, and albumin) must be performed at the local laboratory on an expedited basis.
10Required for women of childbearing potential.  Results must be known prior to Day 1/Baseline.
911
For postmenopausal subjects only.
1012
Required for women of childbearing potential.  Follow-up testing throughout the study will be done at the discretion of the Investigator or as required by 
local law. In each case of delayed menstrual period (over 1 month between menstruations), a urine pregnancy test should be performed.
1214
The screening MRI must be performed at least 2 weeks prior to the Baseline Visit to confirm eligibility.  All postbaseline MRIs, with the exception of 
the one conducted at the Neurological Worsening and Relapse Assessment, are to be completed within a 7-day window of the dosing visit.  MRIs conducted at 
the Neurological Worsening and Relapse Assessment must be completed prior to dosing with rescue therapy, but can be completed on the same day.  If a 
subject’s MRI is scheduled to occur less than< 4 weeks after the last dose of steroid treatment for relapse, the MRI should be rescheduled so it is performed 
either before the steroid treatment or between 4 and 8 weeks after the last dose of steroid treatment.
1315
Subjects must be observed for 1 hour after completion of infusion.
1416
Subjects should be contacted by phone 24 weeks after the last dose of study treatment to discuss if there has been any new development of any new 
neurological symptoms.  PML or new neurological symptoms indicative of PML (e.g., new or sudden change in thinking, vision, balance, or strength persisting 
over several days) must be immediately reported as an SAE.
P

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Rationale: The screening period was extended to Days -42 to -1 to improve logistics for sites in 
the collection of informed consents. 
EDSS and neurological examination assessments were added at Week 84 to confirm the 
Week 72 secondary endpoint. Anti-natalizumab antibodies assessment at Week 60 was added to 
make the schedule consistent with the existing text in the protocol and the ICF. 
Footnote 9 of Table 1 was added to include information on the monitoring of liver function to 
make the global protocol consistent with the local protocol amendment required in France.
Footnote 12 of Table 1 was updated to include pregnancy testing consistent with Heads of 
Medicines Agencies Clinical Trial Facilitation Group guidance and to make the global protocol 
consistent with the local protocol amendment required in the UK. 
This change also affects Table 2, Schedule of Activities – EID, Figure 1, Study Design, and 
Section 7.1, Study Duration for Subjects.
Section 7, Study Design
Change: Text was updated to clarify stratification on the factor “country/region” and to use a 
lower cut-off for body weight. 
Now reads: Randomization will be stratified by country/region (North America [includes 
USA and Canada], United Kingdom, Europe and Israel [includes Belgium, France, 
Germany, Israel, Italy, Netherlands, and Spain], and Australia), body weight (≤90 80 kg 
versus >90 80 kg), and duration of natalizumab exposure (≤3 years versus > 3 years).  Subjects 
will receive open-label natalizumab at their assigned frequency throughout the 72 weeks of the 
study.
Rationale: Clarified stratification on the factor “country/region” because it was not clear 
whether stratification would be based on regions, countries, or a mixture of the two. A lower 
cut-off for body weight (i.e., 80 kg) was used because at weight > 80 kg, a decrease in efficacy 
was suggested based on the PK/PD modelling data and per the request of the EMA. 
This change also affects Section 9.2, Randomization, Section 16.1.2.1, Analysis of the Primary 
Endpoint, and Section 16.1.2.3, Analysis of the Secondary Endpoints.
Section 11.6, Continuation of Treatment
Change: Text related to continuation of treatment after 72-week randomized treatment period 
was clarified. 
Now reads: There is no provision to provide study treatment after the study.  Natalizumab is 
available commercially and subjects/Investigators can continue Tysabri treatment via a 
commercial source.  Once subjects have completed the randomized 72-week treatment 

Protocol 101MS329, Version 2.0
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Now reads: Expectedness of all AEs will be determined by Biogen according to the local label
natalizumab Investigator’s Brochure.
Rationale: This change was made for consistency in using the reference safety information 
contained in the Investigator’s Brochure to determine the expectedness of all adverse events.
Section 15.4.2, Pregnancy
Change: Text related to reporting of pregnancy events was updated. 
Now reads: The Investigator must report a pregnancy occurring in a female subject between 
the first dose of study treatment and 3 months after the last dose of study treatment by 
faxing the appropriate form to Biogen within 24 hours of the study site staff becoming aware of 
the pregnancy.  Refer to the Study Reference Guide’s Official Study Contact List for complete 
contact information.  The Investigator or study site staff must report the outcome of the 
pregnancy to Biogen.  A pregnancy is not considered an AE and should not be recorded in the 
AE CRF.
Rationale: Text was revised to specify the pregnancy events collection period. 
Section 15.5, Contraception Requirements
Change: Text related to contraception for males and the donation of eggs/sperm for all subjects 
was removed.
Now reads: All women of childbearing potential and all men must ensure that highly effective 
contraception is used during the study and for at least 3 months after their last dose of study 
treatment.  In addition, subjects should not donate sperm or eggs for the duration of the study and 
for at least 3 months after their last dose of study treatment.
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
o
12 continuous months of natural (spontaneous) amenorrhea without an alternative 
medical cause 
o
6 weeks after surgical bilateral oophorectomy with or without hysterectomy

Posthysterectomy

Female surgical sterilization (e.g., bilateral tubal ligation)
For the purposes of the study, highly effective contraception is defined as contraception that 
achieves a failure rate of less than< 1% when used consistently and correctly, and includes the 
following:

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Biogen MA Inc.
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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 progestogen-only hormonal methods of 
contraception associated with the inhibition of ovulation.

Placement of an intrauterine device or intrauterine hormone-releasing system.

Bilateral tubal occlusion.
For males:

Vasectomy with negative semen analysis at follow up.

Sex with a woman 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 study.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not 
considered acceptable methods of contraception.
Pregnancy reporting is described in Section 15.4.2.
Rationale:  The deletions make this section consistent with the inclusion/exclusion criteria.

Protocol 101MS329, Version 2.0
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Biogen MA Inc.
21
SUMMARY OF MINOR CHANGES TO THE PROTOCOL
The following minor changes were made to the protocol, as appropriate:

The version number and date were updated throughout the protocol.

Typographical errors and formatting were corrected.