Clinical trial NCT02657915
Conditions: Acute Optic Neuritis
Keywords: FF-VEP mfVEP Human anti-LINGO-1 BIIB033 AON
Sponsor: Biogen
Start date: 2016-03-10; Completion date: 2017-01-23
Enrollment: 52 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to assess full-field visual evoked potential (FF-VEP) latency in subjects who were enrolled in Study NCT01721161 2 years (+ up to 12 months) after the last study visit. The secondary objective is to assess clinical progression and severity of central nervous system (CNS) demyelinating disease in subjects who were enrolled in Study NCT01721161 2 years (+ up to 12 months) after the last study visit. Intervention was administered in the previous study. The participants, investigator and outcome assessors remain blinded in this follow-up study.

Detailed description:

Arms: arm 1: This was a follow-up study, investigational product was administered in the previous study. Participants in the placebo arm have received at least 1 dose of placebo. arm 2: This was a follow-up study, investigational product was administered in the previous study. Participants in the BIIB033 arm have received at least 1 dose of 100 mg/kg BIIB033.
Interventions: intervention 1: Placebo intervention 2: BIIB033 100mg/Kg
Intervention descriptions: intervention 1: Administered as specified in the treatment arm. intervention 2: Administered as specified in the treatment arm.

Protocol documents:
Prot_001.pdf: 
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
1
Biogen MA Inc.
250 Binney Street
Cambridge, MA 02142
United States
PROTOCOL NUMBER:
215ON203 / NCT02657915
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead Berkshire
SL6 4AY
United Kingdom
PHASE OF DEVELOPMENT:
2
PROTOCOL TITLE:  A Multicenter, Follow-Up Study to Assess Long-Term 
Electrophysiologic and Clinical Outcomes in Subjects Previously Enrolled in Study 
215ON201
EUDRA CT NO:
2015-003618-26
DATE:
08 June 2016
Version 4
Final
Supersedes previous Version 3.0 dated 16 November 2015




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TABLE OF CONTENTS
1.
SPONSOR INFORMATION .......................................................................................7
2.
LIST OF ABBREVIATIONS.......................................................................................8
3.
SYNOPSIS .................................................................................................................10
4.
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR STUDY 
215ON203...................................................................................................................15
4.1.
Study Schematic .........................................................................................................15
4.2.
Schedule of Activities.................................................................................................16
5.
INTRODUCTION......................................................................................................18
5.1.
Overview of Acute Optic Neuritis..............................................................................18
5.2.
Current Therapies for Acute Optic Neuritis ...............................................................19
5.3.
Overview of Multiple Sclerosis..................................................................................19
5.4.
Current Therapies for Multiple Sclerosis ...................................................................20
5.5.
Profile of Previous Experience with BIIB033............................................................20
5.5.1.
Nonclinical Experience...............................................................................................20
5.5.2.
Clinical Experience.....................................................................................................21
5.6.
Study Rationale...........................................................................................................23
5.7.
Rationale for Dosing Regimen ...................................................................................23
6.
STUDY OBJECTIVES AND ENDPOINTS..............................................................24
6.1.
Primary Objective and Endpoint ................................................................................24
6.2.
Secondary Objectives and Endpoints .........................................................................24
24
7.
STUDY DESIGN .......................................................................................................27
7.1.
Study Overview ..........................................................................................................27
7.2.
Overall Study Duration...............................................................................................27
7.2.1.
Screening ....................................................................................................................27
7.2.2.
Treatment....................................................................................................................27
7.2.3.
Visit Schedule.............................................................................................................27
7.3.
Study Stopping Rules .................................................................................................28
7.4.
End of Study ...............................................................................................................28
8.
SELECTION OF SUBJECTS ....................................................................................29


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8.1.
Inclusion Criteria ........................................................................................................29
8.2.
Exclusion Criteria.......................................................................................................29
9.
ENROLLMENT AND REGISTRATION .................................................................30
9.1.
Enrollment ..................................................................................................................30
9.2.
Registration of Subjects..............................................................................................30
9.3.
Blinding Procedures....................................................................................................30
10.
WITHDRAWAL OF SUBJECTS FROM THE STUDY...........................................31
10.1.
Withdrawal of Subjects From Study...........................................................................31
11.
FOLLOW-UP ASSESSMENTS ................................................................................32
11.1.
One-Day Visit Assessments .......................................................................................32
12.
SAFETY ASSESSMENTS ........................................................................................34
12.1.
Safety Assessments.....................................................................................................34
12.2.
Vital Signs ..................................................................................................................34
13.
SAFETY DEFINITIONS, CLASSIFICATIONS, RECORDING, 
REPORTING, AND RESPONSIBILITIES ...............................................................35
13.1.
Definition....................................................................................................................35
13.1.1.
Adverse Event.............................................................................................................35
13.1.2.
Serious Adverse Event................................................................................................35
13.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments................36
13.2.
Safety Classifications..................................................................................................36
13.2.1.
Investigator Assessment of Events.............................................................................36
13.2.2.
Relationship of Events to Study Procedure(s) and Prior Treatment With 
Investigational Drug ...................................................................................................37
13.2.3.
Severity of Events.......................................................................................................37
13.2.4.
Expectedness of Events ..............................................................................................37
13.3.
Monitoring and Recording Events..............................................................................38
13.3.1.
Adverse Events ...........................................................................................................38
13.3.2.
Serious Adverse Events..............................................................................................38
13.3.3.
Immediate Reporting of Serious Adverse Events.......................................................38
13.3.3.1.
Deaths .........................................................................................................................38
13.3.4.
Suspected Unexpected Serious Adverse Reactions....................................................39
13.3.5.
Medical Emergency....................................................................................................39


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13.4.
Safety Responsibilities................................................................................................39
13.4.1.
The Investigator..........................................................................................................39
13.4.2.
Biogen.........................................................................................................................40
14.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........41
14.1.
Efficacy.......................................................................................................................41
14.1.1.
Analysis Population....................................................................................................41
14.1.2.
General Methods of Analysis .....................................................................................41
14.1.2.1.
Analysis of the Primary Endpoint...............................................................................41
14.1.2.2.
Analysis of the Secondary Endpoints.........................................................................41
42
14.2.
Safety..........................................................................................................................42
14.2.1.
Analysis Population....................................................................................................42
14.2.2.
Methods of Analysis...................................................................................................42
14.2.2.1.
Adverse Events ...........................................................................................................42
14.2.2.2.
Vital Signs ..................................................................................................................42
14.3.
Interim Analyses.........................................................................................................42
14.4.
Sample Size Considerations .......................................................................................43
15.
ETHICAL REQUIREMENTS ...................................................................................44
15.1.
Declaration of Helsinki...............................................................................................44
15.2.
Ethics Committee........................................................................................................44
15.3.
Subject Information and Consent ...............................................................................44
15.4.
Subject Data Protection ..............................................................................................45
15.5.
Compensation for Injury.............................................................................................45
15.6.
Conflict of Interest......................................................................................................45
15.7.
Registration of Study and Disclosure of Study Results..............................................45
16.
ADMINISTRATIVE PROCEDURES.......................................................................46
16.1.
Study Site Initiation....................................................................................................46
16.2.
Quality Assurance.......................................................................................................46
16.3.
Monitoring of the Study..............................................................................................46
16.4.
Study Funding.............................................................................................................46
16.5.
Publications.................................................................................................................46


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17.
FURTHER REQUIREMENTS AND GENERAL INFORMATION........................47
17.1.
External Contract Organizations.................................................................................47
17.1.1.
Contract Research Organization.................................................................................47
17.1.2.
Electronic Data Capture..............................................................................................47
17.1.3.
Central Facility for Other Assessments ......................................................................47
17.2.
Changes to Final Study Protocol ................................................................................47
17.3.
Ethics Committee Notification of Study Completion or Termination........................48
17.4.
Retention of Study Data..............................................................................................48
17.5.
Study Report Signatory...............................................................................................48
18.
REFERENCES ...........................................................................................................49
19.
SIGNED AGREEMENT OF THE STUDY PROTOCOL.........................................52
LIST OF TABLES
Table 1:
Schedule of Activities.................................................................................................16
Table 2:
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs ...................34
LIST OF FIGURES
Figure 1:
Study Design...............................................................................................................15


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1.
SPONSOR INFORMATION
Biogen MA Inc.
250 Binney Street
Cambridge, MA 02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead, Berkshire 
SL6 4AY
United Kingdom
Biogen Australia Pty Ltd
Suite 1, Level 3
123 Epping Road
North Ryde NSW 2113
Australia
For urgent medical issues in which the study’s Medical Director should be contacted, please 
refer to the Study Reference Manual for the full contact information of the Medical Monitor.
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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2.
LIST OF ABBREVIATIONS
9HPT
9-Hole Peg Test
AE
adverse event
ANCOVA
analysis of covariance
AON
acute optic neuritis
CDMS
clinically definite multiple sclerosis
CI
confidence interval
CIS
clinically isolated syndrome
CNS
central nervous system
CRF
case report form
CRO
contract research organization
CSF
cerebrospinal fluid
EDSS
Expanded Disability Status Scale
FITC-BIIB033
fluorescein isothiocyanate-conjugated BIIB033
FF-VEP
full-field visual evoked potential
GCP
Good Clinical Practice
Gd
gadolinium
IB
Investigator’s Brochure
IP
Investigational product
HCVA
high-contrast visual acuity
ICF
informed consent form
ICH
International Conference on Harmonisation
IFN-β
interferon-beta
IgG1
immunoglobulin G1
ITT
intent-to-treat
IV
intravenous
LCLA
low-contrast letter acuity
MAD
multiple-ascending dose 
MFD
maximum feasible dose
MMRM
mixed model for repeated measures
MRI
magnetic resonance imaging
MS
multiple sclerosis
MSFC
multiple sclerosis functional composite
 
 
NEI-VFQ-25
25-item National Eye Institute Visual Function Questionnaire


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PASAT
(3-Second) Paced Auditory Serial Addition Test 
PK
pharmacokinetic(s)
RGCL
retinal ganglion cell layer
RNFL
retinal nerve fiber layer
RRMS
relapsing-remitting multiple sclerosis
SAD
single-ascending dose 
SAE
serious adverse event
SC
subcutaneous
SDMT
Symbol-Digit Modalities Test
SPMS
secondary progressive multiple sclerosis
SUSAR
suspected unexpected serious adverse reaction
T25FW
Timed 25-Foot Walk


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3.
SYNOPSIS
Protocol Number:
215ON203
Protocol Title:
A Multicenter, Follow-Up Study to Assess Long-Term 
Electrophysiologic and Clinical Outcomes in Subjects 
Previously Enrolled in Study 215ON201
Version Number:
4.0
Study Indication:
Acute optic neuritis (AON)
Study Rationale:
BIIB033 (human anti-LINGO-1 monoclonal antibody) is an 
investigational product with the potential of enhancing 
remyelination and neuroaxonal protection.
In Study 215ON201, treatment of patients with AON with 
BIIB033 displayed evidence of functional remyelination in 
the affected eye by demonstrating significant improvement 
in visual evoked potential latency over treatment with 
placebo.  The electrophysiologic differences between the 
treatment and placebo groups were first observed at 
Week 12 during the dosing period and persisted throughout 
the subsequent monthly dosing visits.  More interestingly, 
this trend continued for an additional 3 months through the 
Follow-Up Visit at Week 32 despite subjects completing the 
dosing period at Week 20. 
Study 215ON201 also showed that all subjects, regardless of 
assigned treatment, recovered clinically to a large extent 
regardless of treatment assignment or severity of injury to 
the retina or the optic nerve; however, not all subjects 
demonstrated complete functional recovery upon 
electrophysiologic examination.  The rationale for the 
discrepancy between clinical recovery and 
electrophysiological improvement is unclear and requires 
further investigation. 
Given these data, the proposed follow-up study is necessary 
to assess the long-term electrophysiologic and clinical 
outcomes of this patient population with past randomized 
exposure to remyelinating therapy versus placebo and also 
to explore potential mechanism(s) by which patients recover 


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from previous AON.  This information will be critical in 
ongoing clinical development of remyelinating therapies so 
that they can be optimally evaluated and utilized for 
maximal benefit.  
Phase of Development:
2
Study Objectives and 
Endpoints:
The primary objective of this study is to assess full-field 
visual evoked potential (FF-VEP) latency in subjects who 
were enrolled in Study 215ON201 at 2 years (+ up to 
12 months) after the last study visit.
The primary endpoint that is related to this objective is the
change in FF-VEP latency of the affected eye as compared 
to the baseline of the fellow eye at 2 years (+ up to 
12 months) after the last study visit assessment (Week 32 or 
projected Week 32 visit) in Study 215ON201.
The secondary objective is to assess clinical progression and 
severity of central nervous system (CNS) demyelinating 
disease in subjects who were enrolled in Study 215ON201 
at 2 years (+ up to 12 months) after the last study visit.
The endpoints that relate to this objective are as follows:

Evaluate incidence of clinically definite multiple 
sclerosis (CDMS) and time to diagnosis of 
CDMS.

Evaluate severity of CNS demyelinating disease 
with Expanded Disability Status Scale (EDSS), 
Symbol-Digit Modalities Test (SDMT), and 
multiple sclerosis functional composite (MSFC).  
The MSFC includes the following: 

Timed 25-Foot Walk (T25FW) 

9-Hole Peg Test (9HPT) [dominant and 
nondominant hands]

(3-Second) Paced Auditory Serial Addition 
Test (PASAT)

Evaluate change in disease activity from baseline 
with brain magnetic resonance imaging (MRI) 


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with and without gadolinium (Gd).  MRI analysis 
will include the following:

Number of Gd-enhanced lesions

Volume of T2 lesions
Study Design:
This is a blinded, multicenter, follow-up study to determine 
the long-term electrophysiologic and clinical outcomes in 
subjects previously enrolled in Study 215ON201.
One group is planned, with eligible subjects (previously
enrolled in Study 215ON201) having been already 
administered at least 1 study treatment (BIIB033 100 mg/kg 
or placebo) by intravenous infusion once every 4 weeks for 
20 weeks (a total of 6 doses).  Dosing was completed 
2 years (+ up to 12 months) prior to enrollment in this 
follow-up study.  No additional study drug or placebo will 
be administered.
Study Location:
Approximately 33 sites globally are planned.
Number of Planned Subjects:
A maximum of 82 subjects will be eligible for enrollment
(determined from the number of subjects who received at 
least 1 dose of BIIB033 100 mg/kg or placebo in 
Study 215ON201).
Study Population:
This study will be conducted in subjects who have 
participated in and received at least 1 dose of BIIB033 or 
placebo in Study 215ON201.  
Detailed criteria are described in Section 8.
Duration of Follow-up:
Eligible subjects will be enrolled at 2 years (+ up to
12 months) after their last study visit (Week 32 or projected
Week 32 visit) if the subject did not complete all visits in 
Study 215ON201.  Enrollment in Study 215ON203 will end 
no later than approximately 2 years after the last patient’s 
Week 32 visit (or projected Week 32 visit) in the parent
study, Study 215ON201.  Subjects will perform 1 set of 
follow-up assessments at this timepoint.


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Evaluations:
Safety:
Assessments evaluating the safety profile will include 
physical examinations, vital sign measurements, and adverse 
events (AEs)/serious adverse events (SAEs).
Any AE or SAE experienced by the subject after informed 
consent form sign-off through the end-of-study visit is to be 
recorded on the case report form or SAE form, respectively, 
regardless of the severity of the event or its relationship to 
study procedure(s) and/or to prior treatment with 
investigational drug (administered in Study 215ON201).
Subjects will be followed for all SAEs until the event has 
resolved, stabilized, or returned to baseline status.  
Statistical Analysis Methods:
The primary analysis will be on the change in FF-VEP 
latency of the affected eye as compared to the baseline 
(measured prior to dosing in Study 215ON201) of the fellow 
eye at 2 years (+ up to 12 months) after the last study visit 
assessment (Week 32 or projected Week 32 visit) in Study 
215ON201.  The ANCOVA model will be used to test the 
difference between the 2 original treatment groups from 
Study 215ON201, adjusting for the baseline of the 
unaffected fellow eye.
The secondary endpoints will include the time to diagnosis 
of CDMS; severity of disease evaluated by EDSS, SDMT, 
and MSFC (including T25FW, 9HPT, and PASAT); and 
brain MRI results.  Number and percentage of subjects with 
diagnosis of CDMS will be summarized, and descriptive 
statistics of time to diagnosis of CDMS will be presented.  
EDSS, SDMT, MSFC, and brain MRI outcomes will also be 
summarized using descriptive statistics.
Statistical testing for efficacy endpoints will be made 
between the BIIB033 group and the placebo group. There 
will be no multiple comparison adjustments.
Unless stated otherwise, all statistical tests will be 2-sided 
with statistical significance level of 0.05. 


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Interim Analysis:
An interim analysis will be performed when approximately 
50% of potentially projected available subjects have been 
enrolled into the study to provide information to assist the 
interpretation and design of ongoing clinical development of 
BIIB033 and other potential CNS remyelinating therapies.  
Given that there is no intervention in this study, study 
stoppage does not apply. No stopping or continuation rules 
will be applied for the interim analysis.


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4.
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR 
STUDY 215ON203
4.1.
Study Schematic
Figure 1:
Study Design
IP = investigational product.
Note: All assessments should be performed on the same day where possible or within a +5-day window of the 1-day 
visit.


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4.2.
Schedule of Activities
Table 1:
Schedule of Activities
Tests and Assessments1
Day 12: 
(2 Years + up to 12 Months After Week 32 Visit in Study 215ON201 or Projected
Week 32 Visit if the Subject Did Not Complete All Visits)
Informed Consent
X
Eligibility Criteria Check
X
Medical History3
X
Multiple Sclerosis Diagnosis
X
Multiple Sclerosis Signs and Symptoms 
X
Concomitant Therapy and Procedures Recording
X
Vital Signs4
X
Physical Examination
X
Expanded Disability Status Scale5
X
Symbol-Digit Modalities Test
X
Multiple Sclerosis Functional Composite Including

Timed 25-Foot Walk 

9-Hole Peg Test (Dominant and Nondominant Hands)

(3-Second) Paced Auditory Serial Addition Test  
X


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Tests and Assessments1
Day 12: 
(2 Years + up to 12 Months After Week 32 Visit in Study 215ON201 or Projected
Week 32 Visit if the Subject Did Not Complete All Visits)
Full-Field Visual Evoked Potential7
X
Adverse Event/Serious Adverse Event Recording12
X
 MRI = magnetic resonance imaging.
1 All assessments should be performed on the same day and in the order listed, when possible (or within a +5-day window of the 1-day visit).
2 Completion of the Day 1 visit assessments constitutes the end-of-study visit.
3 Medical history will be taken from after last study visit in Study 215ON201.
4 Vital signs include temperature, systolic and diastolic blood pressure, pulse rate, body weight, and respiratory rate (after sitting for at least 5 minutes).
5 Expanded Disability Status Scale should be performed by a study certified rater.  Where applicable, refer to study manual for instructions.
6
 
 
7 Sites and technicians must be qualified and approved by the central reader to perform 
, full-field visual evoked 
potential, and 
.
 
 
12Adverse event/serious adverse event monitoring will be recorded after informed consent form sign-off through the end-of-study visit. 


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5.
INTRODUCTION
BIIB033, a first-in-class human monoclonal antibody directed against LINGO-1, is a negative 
regulator of myelination and axonal growth. Antagonizing LINGO-1 with BIIB033 has the 
potential to enhance remyelination and neuroaxonal protection in the central nervous system 
(CNS). 
LINGO-1 is a cell surface glycoprotein that is selectively expressed in the adult CNS in neurons 
and oligodendrocytes [Barrette 2007; Carim-Todd 2003; Llorens 2008; Mi 2004; Park 2005; 
Shao 2005]. It functions as a negative regulator of oligodendrocyte differentiation, myelination, 
and remyelination [Lee 2007; Mi 2005; Mi 2009; Mi 2008]. Axonal and neuronal expression of 
LINGO-1 increases after injury [Ji 2006; Mi 2004]. LINGO-1 expression prevents myelination 
of axons by oligodendrocytes. 
Several nonclinical studies have demonstrated the potential for LINGO-1 antagonism to enhance 
CNS remyelination and neuroaxonal protection in animal models of toxic (cuprizone plus 
rapamycin) [Mi 2009], chemical (lysophosphatidylcholine), and inflammatory (myelin 
oligodendrocyte glycoprotein-experimental autoimmune encephalomyelitis) [Mi 2007]
demyelination and of toxic (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neuronal [Inoue 
2007] and traumatic/hypertensive optic nerve [Fu 2008] and spinal cord [Ji 2008; Ji 2006] injury. 
The leading hypothesis for this clinical development program is that antagonism of LINGO-1 
with BIIB033 will enhance remyelination and neuroaxonal protection in CNS demyelinating 
diseases such as multiple sclerosis (MS) and acute optic neuritis (AON), leading to CNS 
improvement with corresponding beneficial effects on neurological function and disability. 
Additional details may be found in the BIIB033 Investigator’s Brochure (IB). 
5.1.
Overview of Acute Optic Neuritis 
The anterior visual pathway, particularly the optic nerve and its retinal nerve fiber layer (RNFL) 
and retinal ganglion cell layer (RGCL), is affected by AON and is a potential target for 
therapeutic compounds with properties to enhance remyelination and neuroaxonal protection. In 
a study of the long-term effects of AON in the context of MS, the RNFL was decreased to an 
average of 83 microns [Costello 2006; Talman 2010]. This corresponds to an average loss of 
~20 microns or 20% of nerve fibers relative to unaffected eyes in patients with AON or to a loss 
of ~13 microns relative to eyes in patients with MS without history or presence of AON [Talman 
2010]. Costello et al [Costello 2006] found that 74% of patients had 20% or greater thinning of 
the RNFL following AON. As also noted by Henderson et al [Henderson 2011 Aug], this RNFL 
thinning begins early (between 1 and 2 months after onset of AON), and nearly all of the 
eventual RNFL loss is complete by 6 months. This loss of RNFL is associated with a clinically 
important loss of visual function, as shown by a decrease of low-contrast letter acuity (LCLA) to 
an average of 21 letters out of 60 or a loss of 14 letters relative to unaffected MS eyes. There is 
also a permanent loss of visual motion perception in most patients affected by AON [Raz 2011].


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Motion processing impairments in AON may be highly disruptive to the ability of patients to 
ambulate, drive, and navigate [Duffy 2011a; Duffy 2011b]. The permanent loss of visual 
function in AON is clinically important as reflected by a vision-related quality of life score of 84 
on the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25), which is 8 
points lower than in unaffected patients [Balcer 2012]. This 8-point loss on the NEI-VFQ-25 is 
higher than the currently accepted 4-point threshold for clinically important changes in vision-
related quality of life [Mowry 2009; Submacular Surgery Trials Research Group 2007]. 
5.2.
Current Therapies for Acute Optic Neuritis 
The only currently available treatment for AON is high-dose intravenous (IV) steroids (e.g., 
methylprednisolone) followed by an oral prednisone taper, which speeds up the recovery of 
symptoms (e.g., ocular pain) and high-contrast visual acuity (HCVA) primarily in the first 
2 weeks after an attack, but has no long-term beneficial effects on the ultimate recovery of visual 
function [Beck 1992] nor is there evidence that it affects the degree of axonal loss or conduction 
velocity in the optic nerve pathway. 
Despite treatment with high-dose steroids, over 60% of patients with AON are left with loss of 
visual function [Kupersmith 2007].
5.3.
Overview of Multiple Sclerosis
MS is a chronic disabling neurological disease that affects an estimated 1 million people in North 
America and Western Europe.  It is a disease of young adults, primarily women, with disease 
onset typically occurring between the ages of 20 and 40 years [Weinshenker 1989]. It is the 
most frequent cause of nontraumatic neurological disability affecting young adults in the 
Western world.  Although the etiology is uncertain, evidence suggests that MS is, in part, an 
autoimmune disease directed against protein components of myelin.  The diagnosis of clinically 
definite multiple sclerosis (CDMS) has traditionally been made on the basis of clinical criteria 
and requires that a patient experience at least 2 neurologic events consistent with demyelination, 
separated both in time and in location in the CNS [Poser 1983].  More recent diagnostic criteria 
have allowed for less than 2 neurologic attacks, when there is supportive laboratory evidence 
based on magnetic resonance imaging (MRI) or cerebrospinal fluid (CSF) results [McDonald 
2001].  The majority of patients with MS start out with a clinical course characterized by 
episodes or attacks (relapses) of neurologic dysfunction, which occur over many years.  This 
phase of the disease is called relapsing-remitting multiple sclerosis (RRMS).  Symptoms of such 
relapses include loss of vision or double vision, numbness or tingling sensation in the 
extremities, muscle weakness, slurred speech, difficulty with coordination, and bladder 
dysfunction.  Patients having the first clinical attack are referred to as clinically isolated 
syndrome (CIS).  The most common CIS types are AON, transverse myelitis, and brainstem 
attack.  Patients with CIS with characteristic brain MRI lesions are considered to be having MS 
by the most recent diagnostic McDonald criteria [Polman 2011].  Patients with CIS without brain 
lesions are at low risk of developing MS.  Early in the course of relapsing MS, the signs and 
symptoms tend to subside completely after each attack.  Over time, there tends to be incomplete 
recovery from such attacks.  The majority of patients with relapsing MS accumulate some 


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disability, and about half are unable to walk without assistance within 15 years of their initial 
diagnosis [Runmarker and Andersen 1993; Weinshenker 1989].  The majority of patients with 
RRMS eventually enter the secondary progressive phase of the disease (secondary progressive 
multiple sclerosis [SPMS]), characterized by steady worsening of disability independently of 
relapses.  About 15% of the patients go into this progressive phase without prior development of 
a relapsing-remitting phase and are referred to as having a primary progressive MS.
5.4.
Current Therapies for Multiple Sclerosis
Available therapies for the treatment of relapsing MS target the immunomodulation of 
inflammatory activity and include interferon-beta (IFN-β)1a, pegylated IFN-β1a, IFN-β1b, 
natalizumab, mitoxantrone, glatiramer acetate, teriflunomide, dimethyl fumarate, alemtuzumab, 
and fingolimod.  There is also 1 available symptomatic MS therapy to improve walking, 
prolonged-release fampridine, known as dalfampridine extended release in the United States. 
5.5.
Profile of Previous Experience with BIIB033
5.5.1.
Nonclinical Experience
BIIB033 is a fully human aglycosylated immunoglobulin G1 (IgG1) monoclonal antibody that 
binds LINGO-1 with high affinity.  As LINGO-1 is a cell surface glycoprotein selectively 
expressed in CNS oligodendrocytes and neurons that prevents myelination of axons by 
oligodendrocytes, a blockade of LINGO-1 may enhance remyelination and repair in CNS 
demyelinated lesions.  
BIIB033 binds LINGO-1 with high affinity in humans, monkeys, rats, and mice; has high 
specificity for LINGO-1 and does not cross react with other LINGO family members; enhances 
differentiation of primary rat, monkey, and human oligodendrocytes in vitro; enhances axonal 
myelination in an in vitro rat dorsal root ganglion/oligodendrocyte precursor cell co-culture 
bioassay; has reduced Fcγ and complement effector functions compared to wild-type IgG1; and 
is efficacious in animal models using biochemical and functional readouts.  These data suggest 
that BIIB033 will be an effective therapy to enhance remyelination in patients with MS.  
An assessment of BIIB033 toxicology has been carried out in repeated-dose studies in rats and 
cynomolgus monkeys, as these species are considered pharmacologically relevant based on 
sequence homology with LINGO-1 and/or similarity in binding and in vitro functional activity 
with LINGO 1.  Toxicology studies of up to 6 months in duration did not identify any adverse 
treatment-related effects or any effect on neurobehavioral assessments with weekly IV 
administrations of BIIB033 at up to a maximum feasible dose (MFD) of 316 mg/kg or 3-time-per
week subcutaneous (SC) doses at up to 32 mg/kg.  Effects on the CNS and respiratory system 
were transient, and none were considered adverse responses to BIIB033.  In embryo-fetal
toxicology studies in rats and rabbits, BIIB033 was shown to be not causing fetal abnormalities 
at maternal doses up to 316 mg/kg.  Maternal toxicity and morbidity were noted in 1 rabbit given 
316 mg/kg, but the relationship to BIIB033 treatment was unclear; no maternal toxicity was 
observed in rats at any dose. 


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Immunohistochemical analyses have identified target and nontarget antigen-specific 
cross-reactivity by fluorescein isothiocyanate-conjugated BIIB033 (FITC-BIIB033)-specific 
staining in a range of human, cynomolgus monkey, and rat tissues, including those of neural, 
epithelial, neuroendocrine, and connective tissue origins.  Consistent BIIB033-specific 
immunostaining using 2 concentrations of FITC-BIIB033 was observed in the brain (primarily, 
the cerebral cortex) and spinal cord across all 3 species, and the pattern of FITC-BIIB033-
specific staining was consistent with that of LINGO-1 protein localization, as previously 
observed in rodents.  Additional non-neural tissues with inconsistent binding patterns across 
species were evaluated within the repeated-dose toxicology studies and were not identified as 
target organs of toxicity associated with BIIB033 administration up to an MFD dose over 
6 months of treatment.  The exposure-based safety margin for the highest dose planned for 
chronic dosing in the clinic (100 mg/kg/month) is projected to be 4- to 6-fold lower relative to 
exposures at the no-observed-adverse-effect level in toxicology species after 6 months of dosing.  
Together, these data support ongoing evaluations of BIIB033 in Phase 2 studies.  
See the IB for detailed information on nonclinical studies.
5.5.2.
Clinical Experience
As of 07 May 2015, 72 healthy volunteers (54 BIIB033 and 18 placebo) have been dosed in a 
single-ascending-dose (SAD) clinical study (Study 215HV101), 47 subjects with MS 
(32 BIIB033 and 15 placebo) have been dosed in a multiple-ascending-dose (MAD) clinical 
study (Study 215MS101), 82 subjects with AON (41 BIIB033 and 41 placebo) have been dosed 
in a Phase 2 Study 215ON201, and 418 subjects with MS (treatment groups still blinded) have 
been dosed in the ongoing Phase 2 Study 215MS201.
Overall, BIIB033 has been well tolerated in clinical studies.  In the completed Study 215HV101 
(SAD), which evaluated the safety, tolerability, and pharmacokinetics (PK) of BIIB033 in 
healthy volunteers, doses ranging from 0.1 to 100 mg/kg BIIB033 were administered to a total of 
54 healthy adult volunteers.  There were no serious adverse events (SAEs) in the SAD study.  
Most adverse events (AEs) considered related to study treatment in the SAD study were mild,
except for 3 moderate events (2 cases of headache and 1 case of gastroenteritis).  The most 
common AEs with an incidence of ≥5% reported by subjects receiving BIIB033 were headache 
(10 subjects [19%]), upper respiratory tract infection (6 subjects [11%]), nasopharyngitis 
(4 subjects [7%]), and gastroenteritis (3 subjects [6%]).  Overall, the frequency of AEs was 
similar between the BIIB033 and placebo groups.
In the completed Study 215MS101 (MAD), which evaluated the safety, tolerability, and PK of 
BIIB033 in subjects with RRMS or SPMS, multiple doses ranging from 0.3 to 100 mg/kg 
BIIB033 were administered to a total of 32 subjects.  There were no SAEs in the MAD study.  
The frequency of AEs was similar in BIIB033-treated subjects compared with placebo-treated 
subjects.  The most common AEs with an incidence of ≥5% reported by subjects receiving 
BIIB033 were headache and urinary tract infection (5 subjects [16%] each), upper respiratory 


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tract infection and MS relapse (3 subjects [9%] each), and postlumbar puncture headache 
(2 subjects [6%]). 
The completed Phase 2 Study 215ON201 was designed to assess the efficacy, safety, tolerability, 
and PK of BIIB033 in subjects with their first episode of AON.  In this study, the dose of 
100 mg/kg BIIB033 was well tolerated, and the overall incidence of AEs was the same in the
placebo and BIIB033 groups (34 subjects [83%] in each group).  The most common AEs with an 
incidence of ≥10% reported by subjects receiving BIIB033 were nasopharyngitis (12 subjects 
[29%]), headache (11 subjects [27%]), fatigue (6 subjects [15%]), nausea (5 subjects [12%]), and 
paresthesia (4 subjects [10%]).  There were 7 of 82 subjects (9%) who experienced SAEs, 
5 subjects (12%) in the BIIB033 treatment group and 2 subjects (5%) in the placebo group.  In 
the BIIB033 treatment group, 3 subjects had SAEs that were considered related to study 
treatment by the Investigator:  2 subjects with hypersensitivity reactions occurring during study 
treatment infusions and 1 subject with asymptomatic increased aspartate aminotransferase, 
increased alanine aminotransferase, and liver disorder.  Two subjects in the BIIB033 treatment 
group experienced SAEs considered not related to study treatment.  These included 1 subject 
with MS relapse and 1 subject with optic neuritis.  All of the SAEs in the BIIB033 treatment 
group were reported as resolved.  No anti-BIIB033 antibodies were seen in Study 215ON201, 
except for 1 subject who tested positive at predose baseline.
The reported events of hypersensitivity (serious and nonserious) in the clinical studies have 
occurred after the start of either the first or the second study treatment infusion in both Phase 1 
and 2 studies.  In all cases, the infusions were stopped, appropriate treatment was administered, 
and all events resolved.
The Phase 2 Study, 215MS201, was designed to assess the efficacy, safety, tolerability, and PK 
of BIIB033 in subjects with relapsing forms of MS when used concurrently with Avonex and is 
currently ongoing.  In this study, the most common AEs with an incidence of ≥10% in the 
combined BIIB033 and placebo treatment groups are influenza like illness (175 subjects [42%]), 
MS relapse (123 subjects [29%]), headache (68 subjects [16%]), upper respiratory tract infection 
(51 subjects [12%]), urinary tract infection (46 subjects [11%]), pyrexia (44 subjects [11%]), and 
nasopharyngitis (40 subjects [10%]).  Fifty of 418 subjects enrolled (12%) reported SAEs as of 
07 May 2015.  SAEs that were reported in more than 1 subject included MS relapse (27 subjects 
[6%]), urinary tract infection (3 subjects [<1%]), and hypersensitivity (4 subjects [<1%]).  As 
this study is still ongoing, the treatment codes are blinded, and it is not known if the events 
occurred in subjects treated with BIIB033 or placebo.
BIIB033 PK following a single dose (IV and SC) up to 100 mg/kg in healthy volunteers and 
2 repeated IV doses up to 100 mg/kg in subjects with MS was characterized in the SAD and 
MAD studies, respectively.  BIIB033 PK appears to be similar between healthy volunteers and 
subjects with MS.  In general, BIIB033 PK was linear with small volume of distribution at steady 
state, minimal target-mediated clearance, and an elimination half-life of approximately 2 to 
3 weeks.  As expected, the CSF/serum concentration ratio for BIIB033 in humans is estimated to 
be approximately 0.1%.  In the Phase 2 Study 215ON201, the preliminary PK results suggest that 


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the predicted BIIB033 pharmacological exposure at 100 mg/kg was achieved in subjects with 
AON, and BIIB033 PK appears to be similar to healthy adults and subjects with MS.
Please refer to the BIIB033 IB for additional details and results on clinical studies.
5.6.
Study Rationale
A biological effect of BIIB033 was shown in Study 215ON201 in subjects with AON.  In this 
study, subjects received 6 doses of 100 mg/kg BIIB033 or placebo administered via IV infusion 
every 4 weeks up to Week 20, with Follow-Up Visits at Weeks 24 and 32.  Efficacy results 
showed an improvement in mean change in full-field visual evoked potential (FF-VEP) latency 
values of the affected eye from the baseline of the fellow eye at Week 24 in the BIIB033 group 
compared with placebo in the intent-to-treat population (-3.48 [95% confidence interval (CI):
-10.61, 3.65] msec, analysis of covariance [ANCOVA]).  The treatment effect was more 
pronounced in the per-protocol population (-7.55 [95% CI:  -15.12, 0.01] msec, ANCOVA). The 
electrophysiologic differences between the treatment and placebo groups, first observed at 
Week 12 during the dosing period, persisted throughout the subsequent monthly dosing visits.  
The change in FF-VEP latency in the affected eye versus the baseline of the unaffected fellow 
eye by mixed model for repeated measures (MMRM) showed a greater treatment effect at 
Week 32 than at Week 24 for both the intent-to-treat (ITT) and per-protocol populations, despite 
subjects completing the dosing period at Week 20.  In the ITT population, an improvement of 
-6.06 msec over placebo was seen in the BIIB033 group at Week 32 by MMRM (p = 0.0711).  A 
significant improvement of -9.13 msec over placebo was seen in the BIIB033 group at Week 32 
in the per-protocol population by MMRM (p = 0.0112).  
Study 215ON201 also showed that all subjects, regardless of assigned treatment, recovered 
clinically to a large extend regardless of treatment assignment or severity of injury to the retina 
or the optic nerve; however, not all subjects demonstrated complete functional recovery upon 
electrophysiologic examination.  The rationale for the discrepancy between clinical recovery and 
electrophysiological improvement is unclear and requires further investigation.  
Given these data, the proposed follow-up study is necessary to assess the long-term 
electrophysiologic and clinical outcomes of this patient population with past randomized 
exposure to remyelinating therapy versus placebo, but also to explore potential mechanism(s) by 
which patients recover from previous AON.  This information will be critical in the ongoing 
clinical development of remyelinating therapies so that they can be optimally evaluated and 
utilized for maximal benefit.  
Please refer to the BIIB033 IB for additional details and results on Study 215ON201.
5.7.
Rationale for Dosing Regimen
No study drug dosing is planned for this follow-up study.


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6.
STUDY OBJECTIVES AND ENDPOINTS
6.1.
Primary Objective and Endpoint
The primary objective of the study is to assess FF-VEP latency in subjects who were enrolled in 
Study 215ON201 at 2 years (+ up to 12 months) after the last study visit.
The primary endpoint that is related to this objective is the change in FF-VEP latency of the 
affected eye as compared to the baseline of the fellow eye at 2 years (+ up to 12 months) after the 
last study visit assessment (Week 32 or the projected Week 32 visit) in Study 215ON201.
6.2.
Secondary Objectives and Endpoints
The secondary objective is to assess clinical progression and severity of CNS demyelinating 
disease in subjects who were enrolled in Study 215ON201 at 2 years (+ up to 12 months) after 
the last study visit. 
The endpoints that relate to this objective are as follows:

Evaluate incidence of CDMS and time to diagnosis of CDMS.

Evaluate severity of CNS demyelinating disease with Expanded Disability Status 
Scale (EDSS), Symbol-Digit Modalities Test (SDMT), and multiple sclerosis 
functional composite (MSFC).  MSFC includes the following:

Timed 25-Foot Walk (T25FW) 

9-Hole Peg Test (9HPT) [dominant and nondominant hands]

(3-Second) Paced Auditory Serial Addition Test (PASAT) 

Evaluate change in disease activity from baseline with brain MRI with and without 
gadolinium (Gd).  MRI analysis will include the following:

Number of Gd-enhanced lesions

Volume of T2 lesions


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7.
STUDY DESIGN
7.1.
Study Overview
This blinded, multicenter, follow-up study will determine the long-term electrophysiologic and 
clinical outcomes in subjects previously enrolled in Study 215ON201.
One group is planned, with eligible subjects (previously enrolled in Study 215ON201) having 
been already administered at least 1 study treatment (BIIB033 100 mg/kg or placebo) by 
IV infusion once every 4 weeks for 20 weeks (a total of 6 doses).  Dosing was completed 2 years 
(+ up to 12 months) prior to enrollment in this follow-up study.  A maximum of 82 subjects 
(determined from the number of subjects who received at least 1 dose of BIIB033 or placebo in 
Study 215ON201) will be included in this study.  There is no formal sample size calculation.  
The number of subjects eligible for this study is determined by the number of subjects who 
participated in Study 215ON201.
See Figure 1 for a schematic of the study design.
7.2.
Overall Study Duration
The study period will consist of an approximately 1-day visit (with a +5-day window of the 
1-day visit) that is dependent on the scanner capabilities and equipment availability at each 
clinical site.  Enrollment in Study 215ON203 will end no later than approximately 2 years after 
the last patient’s Week 32 visit (or projected Week 32 visit) in Study 215ON201.
7.2.1.
Screening
Subject eligibility for the study will be determined by the date of 2 years (+ up to 12 months) 
after the last study visit (Week 32) or projected Week 32 visit, if the subject did not complete all 
visits in Study 215ON201.  There is no screening visit in this study.
7.2.2.
Treatment
No study drug dosing is planned for this study.
7.2.3.
Visit Schedule
Each subject will have approximately 1 scheduled study visit (with a +5-day window of the 
1-day visit) that is dependent on the scanner capabilities and equipment availability at each 
clinical site.


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7.3.
Study Stopping Rules
Biogen will notify Investigators when the study is to be placed on hold, completed, or 
terminated.
7.4.
End of Study
The end of study is last subject, last visit for final collection of data.


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8.
SELECTION OF SUBJECTS
8.1.
Inclusion Criteria
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at the time of Day 1 visit or at the timepoint specified in the individual eligibility criterion listed:  
1. Must have participated in Study 215ON201 and received at least 1 dose of BIIB033 or 
placebo, as per protocol, within 2 years (+ up to 12 months) from Day 1 of this study 
(2 years from Week 32 or projected Week 32 visit, if the subject did not complete all 
visits in Study 215ON201).
2. 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.  
8.2.
Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist prior 
to enrolment, or at the timepoint specified in the individual criterion listed:
1. Not previously enrolled in Study 215ON201.
2. Inability to comply with study requirements.
3. Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the 
subject unsuitable for enrollment.
4. Subjects with recent kidney function, such as serum creatinine above upper limit of 
normal range, will not be allowed to receive administration of Gd but will otherwise be 
allowed to participate in the study, including MRI assessments not requiring the use of 
Gd.
5. Female subjects must have had a recent pregnancy test and must not be breastfeeding
prior to MRI assessments with Gd.


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9.
ENROLLMENT AND REGISTRATION
9.1.
Enrollment
Subjects (or their legally authorized representative [e.g., parent or legal guardian], where 
applicable) must provide informed consent before any study-related tests are performed (see 
Section 15.3).  When a subject signs the informed consent form (ICF), that subject is considered 
to be enrolled 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 enrolment log.
9.2.
Registration of Subjects
Subjects will be registered at 2 years (+ up to 12 months) after their last study visit (Week 32) or 
projected Week 32 visit, if the subjects did not complete all visits in Study 215ON201, and after 
the Investigator has verified that the subjects are eligible per criteria in Sections 8.1 and 8.2.  
Refer to the Study Reference Guide for details on registration.
9.3.
Blinding Procedures
This is a follow-up study with no investigational product.  To maintain the blind from 
Study 215ON201, the treatment disclosure for Study 215ON201 will not be shared with sites or 
patients until the end of this study.  Maintenance of the blind will reduce the risk of bias on the 
follow-up assessments.  


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10.
WITHDRAWAL OF SUBJECTS FROM THE STUDY
10.1.
Withdrawal of Subjects From Study
Subjects must be withdrawn from the study for any of the following reasons:

The subject withdraws consent. 

The subject is unwilling or unable to comply with the protocol.

At the discretion of the Sponsor or Investigator for medical reasons or for 
noncompliance.
The reason for the subject’s withdrawal from the study must be recorded in the subject’s case 
report form (CRF).


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11.
FOLLOW-UP ASSESSMENTS
See Section 4 for the timing of all assessments.
11.1.
One-Day Visit Assessments
This study will assess the electrophysiological function of the visual pathway using FF-VEP. 
The various electrophysiologic and imaging measurements will be made to assess feasibility of
being utilized as potential clinical endpoints sensitive to remyelination therapy in multicenter 
clinical studies (Table 1).  Clinical progression and severity of disease will be assessed by the 
following:

Medical history, including date of diagnosis of CDMS

MS diagnosis

MS signs and symptoms

Concomitant therapy and procedures recording

Vital signs

Physical examination

EDSS

SDMT

MSFC (including T25FW, 9HPT, and PASAT)



FF-VEP

 




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



AE and SAE recording


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12.
SAFETY ASSESSMENTS
Refer to Section 4 for the timing of all safety assessments.
12.1.
Safety Assessments
The following safety assessments will be performed:

Physical examinations

Vital sign measurements:  temperature, pulse rate, systolic and diastolic blood 
pressure, body weight, and respiratory rate 

AE and SAE recording
12.2.
Vital Signs
The analysis of vital signs will focus on clinically relevant abnormalities. The definitions of 
these clinically relevant abnormalities are shown in Table 2.
Table 2:
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs
Vital Sign
Criteria for Abnormalities
Temperature
>38°C
Pulse rate
>100 bpm
<40 bpm
Systolic Blood Pressure
>160 mmHg
<90 mmHg
Diastolic Blood Pressure
>100 mmHg
<45 mmHg
bpm = beats per minute.


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13.
SAFETY DEFINITIONS, CLASSIFICATIONS, 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.
13.1.
Definition
13.1.1.
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.
13.1.2.
Serious Adverse Event
An SAE is any untoward medical occurrence that at any dose:

Results in death.

In the view of the Investigator, places the subject at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred 
in a more severe form, might have caused death.

Requires inpatient hospitalization or prolongation of existing hospitalization.

Results in persistent or significant disability/incapacity.

Results in a congenital anomaly/birth defect.
An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above.  (Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or convulsions occurring at home that do not 
require an inpatient hospitalization.)


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13.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized.  The study site must document all of the following:

The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining the subject’s 
consent to participate in the study.

The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the subject’s consent to participate in the study and the time of 
the procedure or treatment.

The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission.

If a subject is hospitalized due to local requirements for administration of the 
study treatment, the hospitalization should not be considered an SAE unless one 
of the requirements in Section 13.1.2 is met.
13.2.
Safety Classifications
13.2.1.
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 13.1.2.

The relationship of the event to the study procedure(s) and to prior treatment with 
investigational drug (administered in Study 215ON201) as defined in Section 13.2.2.

The severity of the event as defined in Section 13.2.3.


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13.2.2.
Relationship of Events to Study Procedure(s) and Prior Treatment With 
Investigational Drug
The following definitions should be considered when evaluating the relationship of AEs and 
SAEs to the study procedure(s) and to prior treatment with investigational drug:
Relationship of Event to Study Procedure(s) and to Prior Treatment With Investigational Drug 
(Administered in Study 215ON201)
Not related
An AE will be considered “not related” to the study procedure(s) and/or investigational 
drug (administered in Study 215ON201) if there is not a reasonable possibility that the 
event has been caused by the study procedure(s) and/or investigational drug.  Factors 
pointing toward this assessment include but are not limited to:  the lack of reasonable 
temporal relationship between study procedure(s) and/or investigational drug and the 
event, the presence of a biologically implausible relationship between the study 
procedure(s) and/or investigational drug and the AE, or the presence of a more likely 
alternative explanation for the AE.
Related
An AE will be considered “related” to the study procedure(s) and/or investigational drug 
(administered in Study 215ON201) if there is a reasonable possibility that the event may 
have been caused by the study procedure(s) and/or investigational drug.  Factors that 
point toward this assessment include but are not limited to:  a positive rechallenge, a 
reasonable temporal sequence between study procedure(s) and/or investigational drug and 
the event, a known response pattern of the study procedure(s) and/or investigational drug, 
a biologically plausible relationship between the study procedure(s) and/or investigational 
drug and the AE, or a lack of an alternative explanation for the AE.
13.2.3.
Severity of Events
The following definitions should be considered when evaluating the severity of AEs and SAEs:
Severity of Event
Mild
Symptoms barely noticeable to subject or does not make subject uncomfortable; does not 
influence performance or functioning; prescription drug not ordinarily needed for relief of 
symptoms but may be given because of personality of subject.
Moderate
Symptoms of a sufficient severity to make subject uncomfortable; performance of daily 
activity is influenced; subject is able to continue in study; treatment for symptoms may be 
needed.
Severe
Symptoms cause severe discomfort; symptoms cause incapacitation or significant impact 
on subject’s daily life; severity may cause cessation of study procedure(s); treatment for 
symptoms may be given and/or subject hospitalized.
13.2.4.
Expectedness of Events
Expectedness of all AEs due to previous exposure to BIIB033 will be determined by Biogen 
according to the IB.


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13.3.
Monitoring and Recording Events
13.3.1.
Adverse Events
Any AE experienced by the subject after ICF sign-off through the end-of-study visit is to be 
recorded on the CRF, regardless of the severity of the event or its relationship to study 
procedure(s) and/or to prior treatment with the investigational drug (administered in 
Study 215ON201).
13.3.2.
Serious Adverse Events
Any SAE experienced by a subject after ICF sign-off through the end-of-study visit is to be 
recorded on an SAE form, regardless of the severity of the event or its relationship to study 
procedure(s) and/or to prior treatment with the investigational drug (administered in 
Study 215ON201). SAEs must be reported to 
 within 24 hours as 
described in Section 13.3.3.  Follow-up information regarding an SAE also must be reported 
within 24 hours. 
Subjects will be followed for all SAEs until the event has resolved, stabilized, or returned to 
baseline status.  
13.3.3.
Immediate Reporting of Serious Adverse Events
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify 
 within 24 hours of the study site staff becoming aware 
of the SAE.  It is the Investigator’s responsibility to ensure that the SAE reporting information 
and procedures are used and followed appropriately.
Reporting Information for SAEs
Any SAE that occurs after ICF sign-off through the end-of-study visit must be reported to 
 within 24 hours of the study site staff becoming aware of the event. 
After the end-of-study visit, the SAE should only be reported if the Investigator considers it 
related to investigational drug (administered in Study 215ON201).  In this circumstance, the 
SAE should be reported per Study 215ON201 protocol.
To report initial or follow-up information on an SAE, fax a completed SAE form; refer to the 
Study Reference Guide for country-specific
 fax number or email 
13.3.3.1.
Deaths
Death is an outcome of an event.  The event that resulted in death should be recorded on the 
appropriate CRF and reported as an SAE within 24 hours of the site becoming aware of the 
event.  The Investigator should make every effort to obtain and send death certificates and 


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autopsy reports to 
.  The term death should be reported as an SAE only 
if the cause of death is not known and cannot be determined.
13.3.4.
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 study treatment (administered in 
Study 215ON201). 
Biogen or designee will report SUSARs to the appropriate regulatory authorities and 
Investigators as required, according to local law.
13.3.5.
Medical Emergency
In a medical emergency requiring immediate attention, study site staff will apply appropriate 
medical intervention, according to current standards of care.  The Investigator (or designee) 
should contact the study’s Medical Director.  Refer to the Study Reference Guide’s Official 
Study Contact List for complete contact information.
13.4.
Safety Responsibilities
13.4.1.
The Investigator
The Investigator’s responsibilities include the following:

Monitor and record all AEs and SAEs.

Determine the relationship to study procedure(s) and to prior treatment with 
investigational drug (administered in Study 215ON201) and the severity of each 
event.

Determine the onset and resolution dates of each event.

Complete an SAE form for each SAE and fax it to 
within 
24 hours of the study site staff becoming aware of the event.

Pursue SAE follow-up information actively and persistently until the event has 
resolved or become stable.  Follow-up information must be reported to 
within 24 hours of the study site staff becoming aware of new 
information.

Ensure all AE and SAE reports are supported by documentation in the subjects’ 
medical records.

Pursue AE follow-up information, if possible, until the event has resolved or become 
stable.


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
Report SAEs to local ethics committees, as required by local law.
13.4.2.
Biogen
Biogen’s responsibilities include the following:

Before study site activation and subject enrollment, the Clinical Monitor is 
responsible for reviewing with study site staff the definition of AE and SAE, as well 
as the instructions for monitoring, recording, and reporting AEs and SAEs.

Biogen or designee is to notify all appropriate regulatory authorities, central ethics 
committees, central institutional review boards, and Investigators of SAEs, as 
required by local law, within required time frames.


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14.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The objectives of the study and the endpoints to be analyzed are listed in Section 6.
14.1.
Efficacy
14.1.1.
Analysis Population
Analysis of efficacy endpoints will be based on all enrolled subjects who complete the 1-day 
assessments.
14.1.2.
General Methods of Analysis
Descriptive summary statistics will be presented for all study primary, secondary, and 
 endpoints collected.
Unless stated otherwise, summary statistics will be presented by original treatment groups and 
overall.  For continuous endpoints, the summary statistics will generally include number of 
subjects enrolled, number of subjects evaluated, mean, standard deviation, median, and range
(minimum, maximum).  For categorical endpoints, the summary statistics will generally include 
number of subjects enrolled, number of subjects evaluated, and the percent of subjects in each 
category.
Statistical testing for efficacy endpoints will be made between the BIIB033 group and the 
placebo group. There will be no multiple comparison adjustments.
Unless stated otherwise, all statistical tests will be 2-sided with statistical significance level of 
0.05.
14.1.2.1.
Analysis of the Primary Endpoint
The primary analysis will be on the change in FF-VEP latency of the affected eye as compared to 
the baseline (measured prior to dosing in Study 215ON201) of the fellow eye at 2 years (+ up to
12 months) after the last study visit assessment (Week 32 or the projected Week 32 visit) in 
Study 215ON201.  The ANCOVA model will be used to test the difference between the 2 
original treatment groups from Study 215ON201, adjusting for the baseline of the unaffected 
fellow eye.
14.1.2.2.
Analysis of the Secondary Endpoints
The secondary endpoints will include the time to diagnosis of CDMS; severity of disease 
evaluated by EDSS, SDMT, and MSFC (including T25FW, 9HPT, and PASAT); and brain MRI 
results.  Number and percentage of subjects with diagnosis of CDMS will be summarized, and 


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descriptive statistics of time to diagnosis of CDMS will be presented. EDSS, SDMT, MSFC, 
and brain MRI outcomes will also be summarized using descriptive statistics.
14.2.
Safety
14.2.1.
Analysis Population
The safety population is defined as all enrolled subjects who complete the 1-day assessments.
14.2.2.
Methods of Analysis
All AEs, clinical laboratory abnormalities, vital sign measurements, and physical examination 
findings will be evaluated for safety.
14.2.2.1.
Adverse Events
AEs will be coded using the Medical Dictionary for Regulatory Activities.  The incidence of 
clinical AEs will be summarized by severity and by relationship to study procedure(s) and to 
prior treatment with investigational drug (administered in Study 215ON201).  The summary 
tables will include incidence estimates for overall system organ class as well as for preferred 
terms within each system organ class.
14.2.2.2.
Vital Signs
The analysis of vital signs will focus on clinically relevant abnormalities.  The definitions of 
these clinically relevant abnormalities are shown in Table 2.
14.3.
Interim Analyses
An interim analysis will be performed when approximately 50% of potential projected subjects 
have been enrolled into the study to provide information to assist the interpretation and design of 
ongoing clinical development of BIIB033 and other potential CNS remyelinating therapies.  
Statistical analyses listed in Section 14.1 will be performed on primary, secondary, and 
endpoints at the interim analysis.  Given that there is no intervention in this study,
study stoppage does not apply. No stopping or continuation rules will be applied for the interim 
analysis.


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14.4.
Sample Size Considerations
The sample size is based on the number of subjects who participated in Study 215ON201 
(approximately 82) rather than statistical considerations.  The subjects eligible for this study 
must have participated in Study 215ON201.  


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15.
ETHICAL REQUIREMENTS
Biogen,
, and the Investigator must comply with all instructions, regulations, and 
agreements in this protocol and applicable International Conference on Harmonisation (ICH) and 
Good Clinical Practice (GCP) guidelines and conduct the study according to local regulations.
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines.  The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated.
15.1.
Declaration of Helsinki
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki.
15.2.
Ethics Committee
The Investigator must obtain ethics committee approval of the protocol, ICF, and other required 
study documents prior to starting the study.  Biogen will submit documents on behalf of the 
investigational sites in all countries where subjects are enrolled.
If the Investigator makes any changes to the ICF, Biogen must approve the changes before the 
ICF is submitted to the ethics committee.  A copy of the approved ICF must be provided to 
Biogen.  After approval, the ICF must not be altered without the agreement of the relevant ethics 
committee and Biogen.
It is the responsibility of the Investigators to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations.
Biogen must receive a letter documenting ethics committee approval, which specifically 
identifies the protocol, protocol number, and ICF, prior to the initiation of the study.  Protocol 
amendments will be subject to the same requirements as the original protocol.
A progress report must be submitted to the ethics committee at required intervals and not less 
than annually.
At the completion or termination of the study, the investigational site must submit a close-out 
letter to the ethics committee and Biogen.
15.3.
Subject Information and Consent
Prior to performing any study-related activities under this protocol, including study-related tests 
and assessments, written informed consent with the approved ICF must be obtained from the 


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subject or subject’s legally authorized representative (e.g., parent or legal guardian), as 
applicable, in accordance with local practice and regulations.  
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the subject must be explained to the subject (or the 
subject’s legally authorized representative).  The subject must be given sufficient time to 
consider whether to participate in the study.
A copy of the signed and dated ICF must be given to the subject.  The signed and dated ICF will 
be retained with the study records.  Local regulations must be complied with in respect to the 
final disposition of the original (wet signature) and copies of the signed and dated ICFs.
Confirmation of informed consent must also be documented in the subject’s medical record.
15.4.
Subject Data Protection
Prior to any testing under this protocol, including assessments, candidates must also provide all 
authorizations required by local law (e.g., Protected Health Information authorization in North 
America).
The subject will not be identified by name in the CRF or in any study reports, and these reports 
will be used for research purposes only.  Biogen, its partners and designees, ethics committees, 
and various government health agencies may inspect the records of this study.  Every effort will 
be made to keep the subject’s personal medical data confidential.
15.5.
Compensation for Injury
Biogen maintains appropriate insurance coverage for clinical studies and will follow applicable 
local compensation laws.
15.6.
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.
15.7.
Registration of Study and Disclosure of Study Results
Biogen will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations.


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16.
ADMINISTRATIVE PROCEDURES
16.1.
Study Site Initiation
The Investigator must not enroll any subjects prior to completion of an on-site or remote study 
initiation visit, conducted by Biogen or designee.  This initiation visit will include a detailed 
review of the protocol and study procedures.
16.2.
Quality Assurance
During and/or after completion of the study, quality assurance officers named by Biogen or the 
regulatory authorities may wish to perform onsite audits or inspections.  The Investigator will be 
expected to cooperate with any audit or inspection and to provide assistance and documentation 
(including source data) as requested.
16.3.
Monitoring of the Study
No site may initiate the 1-day assessments until Biogen or its designee representatives have 
concluded protocol-specific training and approved assessment technician(s).
Biogen or its designee representatives may conduct on-site visits at the study facilities for the 
purpose of monitoring various aspects of the study.  The Investigator must agree to 
Sponsor-authorized personnel having direct access to subject (or associated) source files for the 
purpose of verifying entries made in the CRF and assist with their activities, if requested.  
Adequate space and time for monitoring visits should be made available by the Investigator or 
study staff.  The site must complete the CRFs in a timely manner and on an ongoing basis to 
allow regular review by the study team.
During these visits, CRFs and supporting documentation related to the study will be reviewed 
and any discrepancies or omissions will be resolved.  
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure protocol adherence, quality of data, compliance with regulatory requirements, and 
continued adequacy of the investigational site and its facilities.
16.4.
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. 
16.5.
Publications
Details are included in the clinical study agreement for this study.


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17.
FURTHER REQUIREMENTS AND GENERAL INFORMATION
17.1.
External Contract Organizations
Biogen will be responsible for all administrative aspects of this study, including but not limited 
to, study initiation, monitoring, management of AEs, and data management.
17.1.1.
Contract Research Organization 
, a contract research organization (CRO), will be responsible for administrative aspects 
of the study, including but not limited to, study initiation, monitoring, and management of AE 
reports and data management.  Before subjects are enrolled at each study site, the CRO will
review study responsibilities with the Investigators and other study site staff, as appropriate.
17.1.2.
Electronic Data Capture
Subject information will be captured and managed by study sites on CRFs via an appropriate
Web-based electronic remote data capture tool.
17.1.3.
Central Facility for Other Assessments
A central facility has been selected by Biogen to be a central reader for 
, FF-VEP, and 
 for this study. A separate central facility has been selected by Biogen to read and 
interpret all MRI results for this study.
17.2.
Changes to Final Study Protocol
All protocol amendments must be submitted to the ethics committee and regulatory authorities if 
required by local law.  Protocol modifications that affect subject safety, the scope of the 
investigation, or the scientific quality of the study must be approved by the ethics committee 
before implementation of such modifications to the conduct of the study.  If required by local 
law, such modifications must also be approved by the appropriate regulatory agency prior to 
implementation.
However, Biogen may, at any time, amend this protocol to eliminate an apparent immediate 
hazard to a subject.  In this case, the appropriate regulatory authorities will be notified 
subsequent to the modification.
In the event of a protocol modification, the ICF may require similar modifications (see 
Section 15).


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17.3.
Ethics Committee Notification of Study Completion or Termination
Where required, the regulatory authorities and ethics committees must be notified of completion 
or termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines.
17.4.
Retention of Study Data
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local laws or regulations.  Prior to 
proceeding with destruction of records, the Investigator must notify Biogen in writing and 
receive written authorization from Biogen to destroy study records.  In addition, the Investigator 
must notify Biogen of any changes in the archival arrangements including but not limited to 
archival at an offsite facility or transfer of ownership if the Investigator leaves the site.
17.5.
Study Report Signatory
Biogen will designate one of the participating Study Investigators as a signatory for the study 
report.  This determination will be made by several factors, including but not limited to, the 
Investigator's experience and reputation in the studied indication; the Investigator's contribution 
to the study in terms of design, management, and/or subject enrollment; or by other factors 
determined to be relevant by Biogen.
Biogen will follow all applicable local regulations pertaining to study report signatories.


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18.
REFERENCES
Balcer LJ, Galetta SL, Polman CH, et al. Low-contrast acuity measures visual improvement in 
phase 3 trial of natalizumab in relapsing MS. J Neurol Sci. 2012;318(1-2):119-24.
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Beck RW, Cleary PA, Anderson MM, Jr., et al. A randomized, controlled trial of corticosteroids 
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Carim-Todd L, Escarceller M, Estivill X, et al. LRRN6A/LERN1 (leucine-rich repeat neuronal 
protein 1), a novel gene with enriched expression in limbic system and neocortex. Eur J 
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Duffy CJ. The consequences of optic neuritis: more than meets the eye. Neurology. 
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Duffy LM, Chapman AL, Shaw PJ, et al. Review: The role of mitochondria in the pathogenesis 
of amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol. 2011b;37(4):336-52.
Fu QL, Hu B, Wu W, et al. Blocking LINGO-1 function promotes retinal ganglion cell survival 
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Henderson A, Altmann D, Anand T, et al. Early factors associated with axonal loss after optic 
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Inoue H, Lin L, Lee X, et al. Inhibition of the leucine-rich repeat protein LINGO-1 enhances 
survival, structure, and function of dopaminergic neurons in Parkinson's disease models. Proc 
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Ji B, Case LC, Liu K, et al. Assessment of functional recovery and axonal sprouting in 
oligodendrocyte-myelin glycoprotein (OMgp) null mice after spinal cord injury. Mol Cell 
Neurosci. 2008;39(2):258-67.
Ji B, Li M, Wu WT, et al. LINGO-1 antagonist promotes functional recovery and axonal 
sprouting after spinal cord injury. Mol Cell Neurosci. 2006;33(3):311-20.
Kupersmith MJ, Gal RL, Beck RW, et al. Visual function at baseline and 1 month in acute optic 
neuritis: predictors of visual outcome. Neurology. 2007;69(6):508-14.
Lee X, Yang Z, Shao Z, et al. NGF regulates the expression of axonal LINGO-1 to inhibit 
oligodendrocyte differentiation and myelination. J Neurosci. 2007;27(1):220-5.


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Llorens F, Gil V, Iraola S, et al. Developmental analysis of Lingo-1/Lern1 protein expression in 
the mouse brain: interaction of its intracellular domain with Myt1l. Dev Neurobiol. 
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Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a 
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19.
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “A Multicenter, Follow-Up Study to Assess Long-Term 
Electrophysiologic and Clinical Outcomes in Subjects Previously Enrolled in Study 215ON201,”
and agree to conduct the study according to the protocol and the applicable ICH guidelines and 
GCP regulations, and to inform all who assist me in the conduct of this study of their 
responsibilities and obligations.
____________________________________________________
Investigator’s Signature
Date
____________________________________________________
Investigator’s Name (Print)
____________________________________________________
Study Site (Print)


CONFIDENTIAL
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Biogen MA Inc.
1
Biogen MA Inc.
250 Binney Street
Cambridge, MA 02142
United States
PROTOCOL NUMBER:
215ON203
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead Berkshire
SL6 4AY
United Kingdom
PHASE OF DEVELOPMENT:
2
PROTOCOL TITLE:  A Multicenter, Follow-Up Study to Assess Long-Term 
Electrophysiologic and Clinical Outcomes in Subjects Previously Enrolled in Study 
215ON201
EUDRA CT NO:
2015-003618-26
DATE:
16 November 2015
Version 3.0
Final
Supersedes previous Version 2 dated 01 September 2015


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Long-Term Assessment of Remyelinating Therapy
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TABLE OF CONTENTS
1.
SPONSOR INFORMATION .......................................................................................6
2.
LIST OF ABBREVIATIONS.......................................................................................7
3.
SYNOPSIS ...................................................................................................................9
4.
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR STUDY 
215ON203...................................................................................................................13
4.1.
Study Schematic .........................................................................................................13
4.2.
Schedule of Activities.................................................................................................14
5.
INTRODUCTION......................................................................................................16
5.1.
Overview of Acute Optic Neuritis..............................................................................16
5.2.
Current Therapies for Acute Optic Neuritis ...............................................................17
5.3.
Overview of Multiple Sclerosis..................................................................................17
5.4.
Current Therapies for Multiple Sclerosis ...................................................................18
5.5.
Profile of Previous Experience with BIIB033............................................................18
5.5.1.
Nonclinical Experience...............................................................................................18
5.5.2.
Clinical Experience.....................................................................................................19
5.6.
Study Rationale...........................................................................................................21
5.7.
Rationale for Dosing Regimen ...................................................................................21
6.
STUDY OBJECTIVES AND ENDPOINTS..............................................................22
6.1.
Primary Objective and Endpoint ................................................................................22
6.2.
Secondary Objectives and Endpoints .........................................................................22
22
7.
STUDY DESIGN .......................................................................................................25
7.1.
Study Overview ..........................................................................................................25
7.2.
Overall Study Duration...............................................................................................25
7.2.1.
Screening ....................................................................................................................25
7.2.2.
Treatment....................................................................................................................25
7.2.3.
Visit Schedule.............................................................................................................25
7.3.
Study Stopping Rules .................................................................................................25
7.4.
End of Study ...............................................................................................................26
8.
SELECTION OF SUBJECTS ....................................................................................27


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8.1.
Inclusion Criteria ........................................................................................................27
8.2.
Exclusion Criteria.......................................................................................................27
9.
ENROLLMENT AND REGISTRATION .................................................................28
9.1.
Enrollment ..................................................................................................................28
9.2.
Registration of Subjects..............................................................................................28
9.3.
Blinding Procedures....................................................................................................28
10.
WITHDRAWAL OF SUBJECTS FROM THE STUDY...........................................29
10.1.
Withdrawal of Subjects From Study...........................................................................29
11.
FOLLOW-UP ASSESSMENTS ................................................................................30
11.1.
One-Day Visit Assessments .......................................................................................30
12.
SAFETY ASSESSMENTS ........................................................................................32
12.1.
Safety Assessments.....................................................................................................32
12.2.
Vital Signs ..................................................................................................................32
13.
SAFETY DEFINITIONS, CLASSIFICATIONS, RECORDING, 
REPORTING, AND RESPONSIBILITIES ...............................................................33
13.1.
Definition....................................................................................................................33
13.1.1.
Adverse Event.............................................................................................................33
13.1.2.
Serious Adverse Event................................................................................................33
13.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments................34
13.2.
Safety Classifications..................................................................................................34
13.2.1.
Investigator Assessment of Events.............................................................................34
13.2.2.
Relationship of Events to Study Procedure(s) and Prior Treatment With 
Investigational Drug ...................................................................................................35
13.2.3.
Severity of Events.......................................................................................................35
13.2.4.
Expectedness of Events ..............................................................................................35
13.3.
Monitoring and Recording Events..............................................................................36
13.3.1.
Adverse Events ...........................................................................................................36
13.3.2.
Serious Adverse Events..............................................................................................36
13.3.3.
Immediate Reporting of Serious Adverse Events.......................................................36
13.3.3.1.
Deaths .........................................................................................................................36
13.3.4.
Suspected Unexpected Serious Adverse Reactions....................................................37
13.3.5.
Medical Emergency....................................................................................................37


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13.4.
Safety Responsibilities................................................................................................37
13.4.1.
The Investigator..........................................................................................................37
13.4.2.
Biogen.........................................................................................................................38
14.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........39
14.1.
Efficacy.......................................................................................................................39
14.1.1.
Analysis Population....................................................................................................39
14.1.2.
General Methods of Analysis .....................................................................................39
14.1.2.1.
Analysis of the Primary Endpoint...............................................................................39
14.1.2.2.
Analysis of the Secondary Endpoints.........................................................................39
39
14.2.
Safety..........................................................................................................................40
14.2.1.
Analysis Population....................................................................................................40
14.2.2.
Methods of Analysis...................................................................................................40
14.2.2.1.
Adverse Events ...........................................................................................................40
14.2.2.2.
Vital Signs ..................................................................................................................40
14.3.
Interim Analyses.........................................................................................................40
14.4.
Sample Size Considerations .......................................................................................40
15.
ETHICAL REQUIREMENTS ...................................................................................41
15.1.
Declaration of Helsinki...............................................................................................41
15.2.
Ethics Committee........................................................................................................41
15.3.
Subject Information and Consent ...............................................................................41
15.4.
Subject Data Protection ..............................................................................................42
15.5.
Compensation for Injury.............................................................................................42
15.6.
Conflict of Interest......................................................................................................42
15.7.
Registration of Study and Disclosure of Study Results..............................................42
16.
ADMINISTRATIVE PROCEDURES.......................................................................43
16.1.
Study Site Initiation....................................................................................................43
16.2.
Quality Assurance.......................................................................................................43
16.3.
Monitoring of the Study..............................................................................................43
16.4.
Study Funding.............................................................................................................43
16.5.
Publications.................................................................................................................43


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17.
FURTHER REQUIREMENTS AND GENERAL INFORMATION........................44
17.1.
External Contract Organizations.................................................................................44
17.1.1.
Contract Research Organization.................................................................................44
17.1.2.
Electronic Data Capture..............................................................................................44
17.1.3.
Central Facility for Other Assessments ......................................................................44
17.2.
Changes to Final Study Protocol ................................................................................44
17.3.
Ethics Committee Notification of Study Completion or Termination........................45
17.4.
Retention of Study Data..............................................................................................45
17.5.
Study Report Signatory...............................................................................................45
18.
REFERENCES ...........................................................................................................46
19.
SIGNED AGREEMENT OF THE STUDY PROTOCOL.........................................49
LIST OF TABLES
Table 1:
Schedule of Activities.................................................................................................14
Table 2:
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs ...................32
LIST OF FIGURES
Figure 1:
Study Design...............................................................................................................13


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1.
SPONSOR INFORMATION
Biogen MA Inc.
250 Binney Street
Cambridge, MA 02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead, Berkshire 
SL6 4AY
United Kingdom
Biogen Australia Pty Ltd
Suite 1, Level 3
123 Epping Road
North Ryde NSW 2113
Australia
For urgent medical issues in which the study’s Medical Director should be contacted, please 
refer to the Study Reference Manual for the full contact information of the Medical Monitor.
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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2.
LIST OF ABBREVIATIONS
9HPT
9-Hole Peg Test
AE
adverse event
ANCOVA
analysis of covariance
AON
acute optic neuritis
CDMS
clinically definite multiple sclerosis
CI
confidence interval
CIS
clinically isolated syndrome
CNS
central nervous system
CRF
case report form
CRO
contract research organization
CSF
cerebrospinal fluid
EDSS
Expanded Disability Status Scale
FITC-BIIB033
fluorescein isothiocyanate-conjugated BIIB033
FF-VEP
full-field visual evoked potential
GCP
Good Clinical Practice
Gd
gadolinium
IB
Investigator’s Brochure
IP
Investigational product
HCVA
high-contrast visual acuity
ICF
informed consent form
ICH
International Conference on Harmonisation
IFN-β
interferon-beta
IgG1
immunoglobulin G1
ITT
intent-to-treat
IV
intravenous
LCLA
low-contrast letter acuity
MAD
multiple-ascending dose 
MFD
maximum feasible dose
MMRM
mixed model for repeated measures
MRI
magnetic resonance imaging
MS
multiple sclerosis
MSFC
multiple sclerosis functional composite
 
 
 
NEI-VFQ-25
25-item National Eye Institute Visual Function Questionnaire


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PASAT
(3-Second) Paced Auditory Serial Addition Test 
PK
pharmacokinetic(s)
RGCL
retinal ganglion cell layer
RNFL
retinal nerve fiber layer
RRMS
relapsing-remitting multiple sclerosis
SAD
single-ascending dose 
SAE
serious adverse event
SC
subcutaneous
SDMT
Symbol-Digit Modalities Test
SPMS
secondary progressive multiple sclerosis
SUSAR
suspected unexpected serious adverse reaction
T25FW
Timed 25-Foot Walk


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3.
SYNOPSIS
Protocol Number:
215ON203
Protocol Title:
A Multicenter, Follow-Up Study to Assess Long-Term 
Electrophysiologic and Clinical Outcomes in Subjects 
Previously Enrolled in Study 215ON201
Version Number:
3.0
Study Indication:
Acute optic neuritis (AON)
Study Rationale:
BIIB033 (human anti-LINGO-1 monoclonal antibody) is an 
investigational product with the potential of enhancing 
remyelination and neuroaxonal protection.
In Study 215ON201, treatment of patients with AON with 
BIIB033 displayed evidence of functional remyelination in 
the affected eye by demonstrating significant improvement 
in visual evoked potential latency over treatment with 
placebo.  The electrophysiologic differences between the 
treatment and placebo groups were first observed at 
Week 12 during the dosing period and persisted throughout 
the subsequent monthly dosing visits.  More interestingly, 
this trend continued for an additional 3 months through the 
Follow-Up Visit at Week 32 despite subjects completing the 
dosing period at Week 20. 
Study 215ON201 also showed that all subjects, regardless of 
assigned treatment, recovered clinically to a large extent 
regardless of treatment assignment or severity of injury to 
the retina or the optic nerve; however, not all subjects 
demonstrated complete functional recovery upon 
electrophysiologic examination.  The rationale for the 
discrepancy between clinical recovery and 
electrophysiological improvement is unclear and requires 
further investigation. 
Given these data, the proposed follow-up study is necessary 
to assess the long-term electrophysiologic and clinical 
outcomes of this patient population with past randomized 
exposure to remyelinating therapy versus placebo and also 
to explore potential mechanism(s) by which patients recover 


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from previous AON.  This information will be critical in 
ongoing clinical development of remyelinating therapies so 
that they can be optimally evaluated and utilized for 
maximal benefit.  
Phase of Development:
2
Study Objectives and 
Endpoints:
The primary objective of this study is to assess full-field 
visual evoked potential (FF-VEP) latency in subjects who 
were enrolled in Study 215ON201 2 years (+ 4 months) 
after the last study visit.
The primary endpoint that is related to this objective is the
change in FF-VEP latency of the affected eye as compared 
to the baseline of the fellow eye at 2 years (+ 4 months) 
after the last study visit assessment (Week 32) in 
Study 215ON201.
The secondary objective is to assess clinical progression and 
severity of central nervous system (CNS) demyelinating 
disease in subjects who were enrolled in Study 215ON201 
2 years (+ 4 months) after the last study visit.
The endpoints that relate to this objective are as follows:

Evaluate incidence of clinically definite multiple 
sclerosis (CDMS) and time to diagnosis of 
CDMS.

Evaluate severity of CNS demyelinating disease 
with Expanded Disability Status Scale (EDSS), 
Symbol-Digit Modalities Test (SDMT), and 
multiple sclerosis functional composite (MSFC).  
The MSFC includes the following: 

Timed 25-Foot Walk (T25FW) 

9-Hole Peg Test (9HPT) [dominant and 
nondominant hands]

(3-Second) Paced Auditory Serial Addition 
Test (PASAT)

Evaluate change in disease activity from baseline 
with brain magnetic resonance imaging (MRI) 


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with and without gadolinium (Gd).  MRI analysis 
will include the following:

Number of Gd-enhanced lesions

Volume of T2 lesions
 
Study Design:
This is a multicenter, follow-up study to determine the 
long-term electrophysiologic and clinical outcomes in 
subjects previously enrolled in Study 215ON201.
One group is planned, with eligible subjects (previously
enrolled in Study 215ON201) having been already 
administered at least 1 study treatment (BIIB033 100 mg/kg 
or placebo) by intravenous infusion once every 4 weeks for 
20 weeks (a total of 6 doses).  Dosing was completed 
2 years (+ 4 months) prior to enrollment in this follow-up 
study.  No additional study drug or placebo will be 
administered.
Study Location:
Approximately 33 sites globally are planned.
Number of Planned Subjects:
A maximum of 82 subjects will be eligible for enrollment
(determined from the number of subjects who received at 
least 1 dose of BIIB033 100 mg/kg or placebo in 
Study 215ON201).
Study Population:
This study will be conducted in subjects who have 
participated in and received at least 1 dose of BIIB033 or 
placebo in Study 215ON201.  
Detailed criteria are described in Section 8.
Duration of Follow-up:
Eligible subjects will be enrolled at 2 years after their last
study visit (Week 32) or projected Week 32 (+ 4 months) 
visit if the subject did not complete all visits in 
Study 215ON201.  Subjects will perform 1 set of follow-up 
assessments at this timepoint.
Evaluations:
Safety:
Assessments evaluating the safety profile will include 
physical examinations, vital sign measurements, and adverse 


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events (AEs)/serious adverse events (SAEs).
Any AE or SAE experienced by the subject after informed 
consent form sign-off through the end-of-study visit is to be 
recorded on the case report form or SAE form, respectively, 
regardless of the severity of the event or its relationship to 
study procedure(s) and/or to prior treatment with 
investigational drug (administered in Study 215ON201).
Subjects will be followed for all SAEs until the event has 
resolved, stabilized, or returned to baseline status.  
Statistical Analysis Methods:
The primary analysis will be on the change in FF-VEP 
latency of the affected eye as compared to the baseline 
(measured prior to dosing in Study 215ON201) of the fellow 
eye at 2 years (+ 4 months) after the last study visit 
assessment (Week 32) in Study 215ON201.  The ANCOVA 
model will be used to test the difference between the 
2 original treatment groups from Study 215ON201, 
adjusting for the baseline of the unaffected fellow eye.
The secondary endpoints will include the time to diagnosis 
of CDMS; severity of disease evaluated by EDSS, SDMT, 
and MSFC (including T25FW, 9HPT, and PASAT); and 
brain MRI results.  Number and percentage of subjects with 
diagnosis of CDMS will be summarized, and descriptive 
statistics of time to diagnosis of CDMS will be presented.  
EDSS, SDMT, MSFC, and brain MRI outcomes will also be 
summarized using descriptive statistics.
 
Interim Analysis:
An interim analysis will be performed when approximately 
50% of potentially projected available subjects have been 
enrolled into the study to provide information to assist the 
interpretation and design of ongoing clinical development of 
CNS remyelinating therapies.  


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4.
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR 
STUDY 215ON203
4.1.
Study Schematic
Figure 1:
Study Design
IP = investigational product; MRI= magnetic resonance imaging.
Note: All assessments should be performed on the same day where possible or within a + 5-day window of the 
1-day visit.


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4.2.
Schedule of Activities
Table 1:
Schedule of Activities
Tests and Assessments1
Day 12: 
(2 Years + 4 Months After Week 32 Visit in Study 215ON201 or Projected Week 32 
Visit if the Subject Did Not Complete All Visits)
Informed Consent
X
Eligibility Criteria Check
X
Medical History3
X
Multiple Sclerosis Diagnosis
X
Multiple Sclerosis Signs and Symptoms 
X
Concomitant Therapy and Procedures Recording
X
Vital Signs4
X
Physical Examination
X
Expanded Disability Status Scale5
X
Symbol-Digit Modalities Test
X
Multiple Sclerosis Functional Composite Including

Timed 25-Foot Walk 

9-Hole Peg Test (Dominant and Nondominant Hands)

(3-Second) Paced Auditory Serial Addition Test  
X


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Tests and Assessments1
Day 12: 
(2 Years + 4 Months After Week 32 Visit in Study 215ON201 or Projected Week 32 
Visit if the Subject Did Not Complete All Visits)
Full-Field Visual Evoked Potential7
X
Adverse Event/Serious Adverse Event Recording12
X
; MRI = magnetic resonance imaging.
1 All assessments should be performed on the same day and in the order listed, when possible (or within a + 5-day window of the 1-day visit).
2 Completion of the Day 1 visit assessments constitutes the end-of-study visit.
3 Medical history will be taken from after last study visit in Study 215ON201.
4 Vital signs include temperature, systolic and diastolic blood pressure, pulse rate, body weight, and respiratory rate (after sitting for at least 5 minutes).
5 Expanded Disability Status Scale should be performed by a study certified rater.  Where applicable, refer to study manual for instructions.
 
 
7 Sites and technicians must be qualified and approved by the central reader to perform 
, full-field visual evoked 
potential, and 
.
  
 
12Adverse event/serious adverse event monitoring will be recorded after informed consent form sign-off through the end-of-study visit. 


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5.
INTRODUCTION
BIIB033, a first-in-class human monoclonal antibody directed against LINGO-1, is a negative 
regulator of myelination and axonal growth. Antagonizing LINGO-1 with BIIB033 has the 
potential to enhance remyelination and neuroaxonal protection in the central nervous system 
(CNS). 
LINGO-1 is a cell surface glycoprotein that is selectively expressed in the adult CNS in neurons 
and oligodendrocytes [Barrette 2007; Carim-Todd 2003; Llorens 2008; Mi 2004; Park 2005; 
Shao 2005]. It functions as a negative regulator of oligodendrocyte differentiation, myelination, 
and remyelination [Lee 2007; Mi 2005; Mi 2009; Mi 2008]. Axonal and neuronal expression of 
LINGO-1 increases after injury [Ji 2006; Mi 2004]. LINGO-1 expression prevents myelination 
of axons by oligodendrocytes. 
Several nonclinical studies have demonstrated the potential for LINGO-1 antagonism to enhance 
CNS remyelination and neuroaxonal protection in animal models of toxic (cuprizone plus 
rapamycin) [Mi 2009], chemical (lysophosphatidylcholine), and inflammatory (myelin 
oligodendrocyte glycoprotein-experimental autoimmune encephalomyelitis) [Mi 2007]
demyelination and of toxic (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neuronal [Inoue 
2007] and traumatic/hypertensive optic nerve [Fu 2008] and spinal cord [Ji 2008; Ji 2006] injury. 
The leading hypothesis for this clinical development program is that antagonism of LINGO-1 
with BIIB033 will enhance remyelination and neuroaxonal protection in CNS demyelinating 
diseases such as multiple sclerosis (MS) and acute optic neuritis (AON), leading to CNS 
improvement with corresponding beneficial effects on neurological function and disability. 
Additional details may be found in the BIIB033 Investigator’s Brochure (IB). 
5.1.
Overview of Acute Optic Neuritis 
The anterior visual pathway, particularly the optic nerve and its retinal nerve fiber layer (RNFL) 
and retinal ganglion cell layer (RGCL), is affected by AON and is a potential target for 
therapeutic compounds with properties to enhance remyelination and neuroaxonal protection. In 
a study of the long-term effects of AON in the context of MS, the RNFL was decreased to an 
average of 83 microns [Costello 2006; Talman 2010]. This corresponds to an average loss of 
~20 microns or 20% of nerve fibers relative to unaffected eyes in patients with AON or to a loss 
of ~13 microns relative to eyes in patients with MS without history or presence of AON [Talman 
2010]. Costello et al [Costello 2006] found that 74% of patients had 20% or greater thinning of 
the RNFL following AON. As also noted by Henderson et al [Henderson 2011 Aug], this RNFL 
thinning begins early (between 1 and 2 months after onset of AON), and nearly all of the 
eventual RNFL loss is complete by 6 months. This loss of RNFL is associated with a clinically 
important loss of visual function, as shown by a decrease of low-contrast letter acuity (LCLA) to 
an average of 21 letters out of 60 or a loss of 14 letters relative to unaffected MS eyes. There is 
also a permanent loss of visual motion perception in most patients affected by AON [Raz 2011].


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Motion processing impairments in AON may be highly disruptive to the ability of patients to 
ambulate, drive, and navigate [Duffy 2011a; Duffy 2011b]. The permanent loss of visual 
function in AON is clinically important as reflected by a vision-related quality of life score of 84 
on the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25), which is 8 
points lower than in unaffected patients [Balcer 2012]. This 8-point loss on the NEI-VFQ-25 is 
higher than the currently accepted 4-point threshold for clinically important changes in vision-
related quality of life [Mowry 2009; Submacular Surgery Trials Research Group 2007]. 
5.2.
Current Therapies for Acute Optic Neuritis 
The only currently available treatment for AON is high-dose intravenous (IV) steroids (e.g., 
methylprednisolone) followed by an oral prednisone taper, which speeds up the recovery of 
symptoms (e.g., ocular pain) and high-contrast visual acuity (HCVA) primarily in the first
2 weeks after an attack, but has no long-term beneficial effects on the ultimate recovery of visual 
function [Beck 1992] nor is there evidence that it affects the degree of axonal loss or conduction 
velocity in the optic nerve pathway. 
Despite treatment with high-dose steroids, over 60% of patients with AON are left with loss of 
visual function [Kupersmith 2007].
5.3.
Overview of Multiple Sclerosis
MS is a chronic disabling neurological disease that affects an estimated 1 million people in North 
America and Western Europe.  It is a disease of young adults, primarily women, with disease 
onset typically occurring between the ages of 20 and 40 years [Weinshenker 1989]. It is the 
most frequent cause of nontraumatic neurological disability affecting young adults in the 
Western world.  Although the etiology is uncertain, evidence suggests that MS is, in part, an 
autoimmune disease directed against protein components of myelin.  The diagnosis of clinically 
definite multiple sclerosis (CDMS) has traditionally been made on the basis of clinical criteria 
and requires that a patient experience at least 2 neurologic events consistent with demyelination, 
separated both in time and in location in the CNS [Poser 1983].  More recent diagnostic criteria 
have allowed for less than 2 neurologic attacks, when there is supportive laboratory evidence 
based on magnetic resonance imaging (MRI) or cerebrospinal fluid (CSF) results [McDonald 
2001].  The majority of patients with MS start out with a clinical course characterized by 
episodes or attacks (relapses) of neurologic dysfunction, which occur over many years.  This 
phase of the disease is called relapsing-remitting multiple sclerosis (RRMS).  Symptoms of such 
relapses include loss of vision or double vision, numbness or tingling sensation in the 
extremities, muscle weakness, slurred speech, difficulty with coordination, and bladder 
dysfunction.  Patients having the first clinical attack are referred to as clinically isolated 
syndrome (CIS).  The most common CIS types are AON, transverse myelitis, and brainstem 
attack.  Patients with CIS with characteristic brain MRI lesions are considered to be having MS 
by the most recent diagnostic McDonald criteria [Polman 2011].  Patients with CIS without brain 
lesions are at low risk of developing MS.  Early in the course of relapsing MS, the signs and 
symptoms tend to subside completely after each attack.  Over time, there tends to be incomplete 
recovery from such attacks.  The majority of patients with relapsing MS accumulate some 


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disability, and about half are unable to walk without assistance within 15 years of their initial 
diagnosis [Runmarker and Andersen 1993; Weinshenker 1989].  The majority of patients with 
RRMS eventually enter the secondary progressive phase of the disease (secondary progressive 
multiple sclerosis [SPMS]), characterized by steady worsening of disability independently of 
relapses.  About 15% of the patients go into this progressive phase without prior development of 
a relapsing-remitting phase and are referred to as having a primary progressive MS.
5.4.
Current Therapies for Multiple Sclerosis
Available therapies for the treatment of relapsing MS target the immunomodulation of 
inflammatory activity and include interferon-beta (IFN-β)1a, pegylated IFN-β1a, IFN-β1b, 
natalizumab, mitoxantrone, glatiramer acetate, teriflunomide, dimethyl fumarate, alemtuzumab, 
and fingolimod.  There is also 1 available symptomatic MS therapy to improve walking, 
prolonged-release fampridine, known as dalfampridine extended release in the United States. 
5.5.
Profile of Previous Experience with BIIB033
5.5.1.
Nonclinical Experience
BIIB033 is a fully human aglycosylated immunoglobulin G1 (IgG1) monoclonal antibody that 
binds LINGO-1 with high affinity.  As LINGO-1 is a cell surface glycoprotein selectively 
expressed in CNS oligodendrocytes and neurons that prevents myelination of axons by 
oligodendrocytes, a blockade of LINGO-1 may enhance remyelination and repair in CNS 
demyelinated lesions.  
BIIB033 binds LINGO-1 with high affinity in humans, monkeys, rats, and mice; has high 
specificity for LINGO-1 and does not cross react with other LINGO family members; enhances 
differentiation of primary rat, monkey, and human oligodendrocytes in vitro; enhances axonal 
myelination in an in vitro rat dorsal root ganglion/oligodendrocyte precursor cell co-culture 
bioassay; has reduced Fcγ and complement effector functions compared to wild-type IgG1; and 
is efficacious in animal models using biochemical and functional readouts.  These data suggest 
that BIIB033 will be an effective therapy to enhance remyelination in patients with MS.  
An assessment of BIIB033 toxicology has been carried out in repeated-dose studies in rats and 
cynomolgus monkeys, as these species are considered pharmacologically relevant based on 
sequence homology with LINGO-1 and/or similarity in binding and in vitro functional activity 
with LINGO 1.  Toxicology studies of up to 6 months in duration did not identify any adverse 
treatment-related effects or any effect on neurobehavioral assessments with weekly IV 
administrations of BIIB033 at up to a maximum feasible dose (MFD) of 316 mg/kg or 3-time-per
week subcutaneous (SC) doses at up to 32 mg/kg.  Effects on the CNS and respiratory system 
were transient, and none were considered adverse responses to BIIB033.  In embryo-fetal
toxicology studies in rats and rabbits, BIIB033 was shown to be not causing fetal abnormalities 
at maternal doses up to 316 mg/kg.  Maternal toxicity and morbidity were noted in 1 rabbit given 
316 mg/kg, but the relationship to BIIB033 treatment was unclear; no maternal toxicity was 
observed in rats at any dose. 


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Immunohistochemical analyses have identified target and nontarget antigen-specific 
cross-reactivity by fluorescein isothiocyanate-conjugated BIIB033 (FITC-BIIB033)-specific 
staining in a range of human, cynomolgus monkey, and rat tissues, including those of neural, 
epithelial, neuroendocrine, and connective tissue origins.  Consistent BIIB033-specific 
immunostaining using 2 concentrations of FITC-BIIB033 was observed in the brain (primarily, 
the cerebral cortex) and spinal cord across all 3 species, and the pattern of FITC-BIIB033-
specific staining was consistent with that of LINGO-1 protein localization, as previously 
observed in rodents.  Additional non-neural tissues with inconsistent binding patterns across 
species were evaluated within the repeated-dose toxicology studies and were not identified as 
target organs of toxicity associated with BIIB033 administration up to an MFD dose over 
6 months of treatment.  The exposure-based safety margin for the highest dose planned for 
chronic dosing in the clinic (100 mg/kg/month) is projected to be 4- to 6-fold lower relative to 
exposures at the no-observed-adverse-effect level in toxicology species after 6 months of dosing.  
Together, these data support ongoing evaluations of BIIB033 in Phase 2 studies.  
See the IB for detailed information on nonclinical studies.
5.5.2.
Clinical Experience
As of 07 May 2015, 72 healthy volunteers (54 BIIB033 and 18 placebo) have been dosed in a 
single-ascending-dose (SAD) clinical study (Study 215HV101), 47 subjects with MS 
(32 BIIB033 and 15 placebo) have been dosed in a multiple-ascending-dose (MAD) clinical 
study (Study 215MS101), 82 subjects with AON (41 BIIB033 and 41 placebo) have been dosed 
in a Phase 2 Study 215ON201, and 418 subjects with MS (treatment groups still blinded) have 
been dosed in the ongoing Phase 2 Study 215MS201.
Overall, BIIB033 has been well tolerated in clinical studies.  In the completed Study 215HV101 
(SAD), which evaluated the safety, tolerability, and pharmacokinetics (PK) of BIIB033 in 
healthy volunteers, doses ranging from 0.1 to 100 mg/kg BIIB033 were administered to a total of 
54 healthy adult volunteers.  There were no serious adverse events (SAEs) in the SAD study.  
Most adverse events (AEs) considered related to study treatment in the SAD study were mild,
except for 3 moderate events (2 cases of headache and 1 case of gastroenteritis).  The most 
common AEs with an incidence of ≥5% reported by subjects receiving BIIB033 were headache 
(10 subjects [19%]), upper respiratory tract infection (6 subjects [11%]), nasopharyngitis 
(4 subjects [7%]), and gastroenteritis (3 subjects [6%]).  Overall, the frequency of AEs was 
similar between the BIIB033 and placebo groups.
In the completed Study 215MS101 (MAD), which evaluated the safety, tolerability, and PK of 
BIIB033 in subjects with RRMS or SPMS, multiple doses ranging from 0.3 to 100 mg/kg 
BIIB033 were administered to a total of 32 subjects.  There were no SAEs in the MAD study.  
The frequency of AEs was similar in BIIB033-treated subjects compared with placebo-treated 
subjects.  The most common AEs with an incidence of ≥5% reported by subjects receiving 
BIIB033 were headache and urinary tract infection (5 subjects [16%] each), upper respiratory 


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tract infection and MS relapse (3 subjects [9%] each), and postlumbar puncture headache 
(2 subjects [6%]). 
The completed Phase 2 Study 215ON201 was designed to assess the efficacy, safety, tolerability, 
and PK of BIIB033 in subjects with their first episode of AON.  In this study, the dose of 
100 mg/kg BIIB033 was well tolerated, and the overall incidence of AEs was the same in the 
placebo and BIIB033 groups (34 subjects [83%] in each group).  The most common AEs with an 
incidence of ≥10% reported by subjects receiving BIIB033 were nasopharyngitis (12 subjects 
[29%]), headache (11 subjects [27%]), fatigue (6 subjects [15%]), nausea (5 subjects [12%]), and 
paresthesia (4 subjects [10%]).  There were 7 of 82 subjects (9%) who experienced SAEs, 
5 subjects (12%) in the BIIB033 treatment group and 2 subjects (5%) in the placebo group.  In 
the BIIB033 treatment group, 3 subjects had SAEs that were considered related to study 
treatment by the Investigator:  2 subjects with hypersensitivity reactions occurring during study 
treatment infusions and 1 subject with asymptomatic increased aspartate aminotransferase, 
increased alanine aminotransferase, and liver disorder.  Two subjects in the BIIB033 treatment 
group experienced SAEs considered not related to study treatment.  These included 1 subject 
with MS relapse and 1 subject with optic neuritis.  All of the SAEs in the BIIB033 treatment 
group were reported as resolved.  No anti-BIIB033 antibodies were seen in Study 215ON201, 
except for 1 subject who tested positive at predose baseline.
The reported events of hypersensitivity (serious and nonserious) in the clinical studies have 
occurred after the start of either the first or the second study treatment infusion in both Phase 1 
and 2 studies.  In all cases, the infusions were stopped, appropriate treatment was administered, 
and all events resolved.
The Phase 2 Study, 215MS201, was designed to assess the efficacy, safety, tolerability, and PK 
of BIIB033 in subjects with relapsing forms of MS when used concurrently with Avonex and is 
currently ongoing.  In this study, the most common AEs with an incidence of ≥10% in the 
combined BIIB033 and placebo treatment groups are influenza like illness (175 subjects [42%]), 
MS relapse (123 subjects [29%]), headache (68 subjects [16%]), upper respiratory tract infection 
(51 subjects [12%]), urinary tract infection (46 subjects [11%]), pyrexia (44 subjects [11%]), and 
nasopharyngitis (40 subjects [10%]).  Fifty of 418 subjects enrolled (12%) reported SAEs as of 
07 May 2015.  SAEs that were reported in more than 1 subject included MS relapse (27 subjects 
[6%]), urinary tract infection (3 subjects [<1%]), and hypersensitivity (4 subjects [<1%]).  As 
this study is still ongoing, the treatment codes are blinded, and it is not known if the events 
occurred in subjects treated with BIIB033 or placebo.
BIIB033 PK following a single dose (IV and SC) up to 100 mg/kg in healthy volunteers and 
2 repeated IV doses up to 100 mg/kg in subjects with MS was characterized in the SAD and 
MAD studies, respectively.  BIIB033 PK appears to be similar between healthy volunteers and 
subjects with MS.  In general, BIIB033 PK was linear with small volume of distribution at steady 
state, minimal target-mediated clearance, and an elimination half-life of approximately 2 to 
3 weeks.  As expected, the CSF/serum concentration ratio for BIIB033 in humans is estimated to 
be approximately 0.1%.  In the Phase 2 Study 215ON201, the preliminary PK results suggest that 


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the predicted BIIB033 pharmacological exposure at 100 mg/kg was achieved in subjects with 
AON, and BIIB033 PK appears to be similar to healthy adults and subjects with MS.
Please refer to the BIIB033 IB for additional details and results on clinical studies.
5.6.
Study Rationale
A biological effect of BIIB033 was shown in Study 215ON201 in subjects with AON.  In this 
study, subjects received 6 doses of 100 mg/kg BIIB033 or placebo administered via IV infusion 
every 4 weeks up to Week 20, with Follow-Up Visits at Weeks 24 and 32.  Efficacy results 
showed an improvement in mean change in full-field visual evoked potential (FF-VEP) latency 
values of the affected eye from the baseline of the fellow eye at Week 24 in the BIIB033 group 
compared with placebo in the intent-to-treat population (-3.48 [95% confidence interval (CI):
-10.61, 3.65] msec, analysis of covariance [ANCOVA]).  The treatment effect was more 
pronounced in the per-protocol population (-7.55 [95% CI:  -15.12, 0.01] msec, ANCOVA). The 
electrophysiologic differences between the treatment and placebo groups, first observed at 
Week 12 during the dosing period, persisted throughout the subsequent monthly dosing visits.  
The change in FF-VEP latency in the affected eye versus the baseline of the unaffected fellow 
eye by mixed model for repeated measures (MMRM) showed a greater treatment effect at 
Week 32 than at Week 24 for both the intent-to-treat (ITT) and per-protocol populations, despite 
subjects completing the dosing period at Week 20.  In the ITT population, an improvement of 
-6.06 msec over placebo was seen in the BIIB033 group at Week 32 by MMRM (p = 0.0711).  A 
significant improvement of -9.13 msec over placebo was seen in the BIIB033 group at Week 32 
in the per-protocol population by MMRM (p = 0.0112).  
Study 215ON201 also showed that all subjects, regardless of assigned treatment, recovered 
clinically to a large extend regardless of treatment assignment or severity of injury to the retina 
or the optic nerve; however, not all subjects demonstrated complete functional recovery upon 
electrophysiologic examination.  The rationale for the discrepancy between clinical recovery and 
electrophysiological improvement is unclear and requires further investigation.  
Given these data, the proposed follow-up study is necessary to assess the long-term 
electrophysiologic and clinical outcomes of this patient population with past randomized 
exposure to remyelinating therapy versus placebo, but also to explore potential mechanism(s) by 
which patients recover from previous AON.  This information will be critical in the ongoing 
clinical development of remyelinating therapies so that they can be optimally evaluated and 
utilized for maximal benefit.  
Please refer to the BIIB033 IB for additional details and results on Study 215ON201.
5.7.
Rationale for Dosing Regimen
No study drug dosing is planned for this follow-up study.


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6.
STUDY OBJECTIVES AND ENDPOINTS
6.1.
Primary Objective and Endpoint
The primary objective of the study is to assess FF-VEP latency in subjects who were enrolled in 
Study 215ON201 2 years (+ 4 months) after the last study visit.
The primary endpoint that is related to this objective is the change in FF-VEP latency of the 
affected eye as compared to the baseline of the fellow eye at 2 years (+ 4 months) after the last 
study visit assessment (Week 32) in Study 215ON201.
6.2.
Secondary Objectives and Endpoints
The secondary objective is to assess clinical progression and severity of CNS demyelinating 
disease in subjects who were enrolled in Study 215ON201 2 years (+ 4 months) after the last 
study visit. 
The endpoints that relate to this objective are as follows:

Evaluate incidence of CDMS and time to diagnosis of CDMS.

Evaluate severity of CNS demyelinating disease with Expanded Disability Status 
Scale (EDSS), Symbol-Digit Modalities Test (SDMT), and multiple sclerosis 
functional composite (MSFC).  MSFC includes the following:

Timed 25-Foot Walk (T25FW) 

9-Hole Peg Test (9HPT) [dominant and nondominant hands]

(3-Second) Paced Auditory Serial Addition Test (PASAT) 

Evaluate change in disease activity from baseline with brain MRI with and without 
gadolinium (Gd).  MRI analysis will include the following:

Number of Gd-enhanced lesions

Volume of T2 lesions


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7.
STUDY DESIGN
7.1.
Study Overview
This multicenter, follow-up study will determine the long-term electrophysiologic and clinical 
outcomes in subjects previously enrolled in Study 215ON201.
One group is planned, with eligible subjects (previously enrolled in Study 215ON201) having 
been already administered at least 1 study treatment (BIIB033 100 mg/kg or placebo) by 
IV infusion once every 4 weeks for 20 weeks (a total of 6 doses).  Dosing was completed 2 years 
(+ 4 months) prior to enrollment in this follow-up study.  A maximum of 82 subjects (determined 
from the number of subjects who received at least 1 dose of BIIB033 or placebo in Study 
215ON201) will be included in this study.  There is no formal sample size calculation.  The 
number of subjects eligible for this study is determined by the number of subjects who 
participated in Study 215ON201.
See Figure 1 for a schematic of the study design.
7.2.
Overall Study Duration 
The study period will consist of an approximately 1-day visit (with a + 5-day window of the 
1-day visit) that is dependent on the scanner capabilities and equipment availability at each 
clinical site.
7.2.1.
Screening
Subject eligibility for the study will be determined by the date of 2 years (+ 4 months) after the 
last study visit (Week 32) or projected Week 32 visit, if the subject did not complete all visits in 
Study 215ON201.  There is no screening visit in this study.
7.2.2.
Treatment
No study drug dosing is planned for this study.
7.2.3.
Visit Schedule
Each subject will have approximately 1 scheduled study visit (with a + 5-day window of the 
1-day visit) that is dependent on the scanner capabilities and equipment availability at each 
clinical site.
7.3.
Study Stopping Rules
Biogen will notify Investigators when the study is to be placed on hold, completed, or 
terminated.


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


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8.
SELECTION OF SUBJECTS
8.1.
Inclusion Criteria
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at the time of Day 1 visit or at the timepoint specified in the individual eligibility criterion listed:  
1. Must have participated in Study 215ON201 and received at least 1 dose of BIIB033 or 
placebo, as per protocol, within 2 years (+ 4 months) from Day 1 of this study (2 years 
from Week 32 or projected Week 32 visit, if the subject did not complete all visits in 
Study 215ON201).
2. 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.  
8.2.
Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist prior 
to enrolment, or at the timepoint specified in the individual criterion listed:
1. Not previously enrolled in Study 215ON201.
2. Inability to comply with study requirements.
3. Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the 
subject unsuitable for enrollment.
4. Subjects with recent kidney function, such as serum creatinine above upper limit of 
normal range, will not be allowed to receive administration of Gd but will otherwise be 
allowed to participate in the study, including MRI assessments not requiring the use of 
Gd.
5. Female subjects must have had a recent pregnancy test and must not be breastfeeding
prior to MRI assessments with Gd.


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9.
ENROLLMENT AND REGISTRATION
9.1.
Enrollment
Subjects (or their legally authorized representative [e.g., parent or legal guardian], where 
applicable) must provide informed consent before any study-related tests are performed (see 
Section 15.3).  When a subject signs the informed consent form (ICF), that subject is considered 
to be enrolled 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 enrolment log.
9.2.
Registration of Subjects
Subjects will be registered at 2 years (+ 4 months) after their last study visit (Week 32) or 
projected Week 32 visit, if the subjects did not complete all visits in Study 215ON201, and after 
the Investigator has verified that the subjects are eligible per criteria in Sections 8.1 and 8.2. 
Refer to the Study Reference Guide for details on registration.
9.3.
Blinding Procedures
This is a follow-up study with no investigational product, therefore blinding is not applicable.  
As much as possible, the treatment disclosure for Study 215ON201 should not be shared with 
sites or patients until the end of this study to reduce the risk of bias on the follow on assessments
based on knowledge of treatment.  


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10.
WITHDRAWAL OF SUBJECTS FROM THE STUDY
10.1.
Withdrawal of Subjects From Study
Subjects must be withdrawn from the study for any of the following reasons:

The subject withdraws consent.  

The subject is unwilling or unable to comply with the protocol.

At the discretion of the Sponsor or Investigator for medical reasons or for 
noncompliance.
The reason for the subject’s withdrawal from the study must be recorded in the subject’s case 
report form (CRF).


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11.
FOLLOW-UP ASSESSMENTS
See Section 4 for the timing of all assessments.
11.1.
One-Day Visit Assessments
This study will assess the electrophysiological function of the visual pathway using FF-VEP. 
The various electrophysiologic and imaging measurements will be made to assess feasibility of
being utilized as potential clinical endpoints sensitive to remyelination therapy in multicenter 
clinical studies (Table 1).  Clinical progression and severity of disease will be assessed by the 
following:

Medical history, including date of diagnosis of CDMS

MS diagnosis

MS signs and symptoms

Concomitant therapy and procedures recording

Vital signs 

Physical examination

EDSS

SDMT

MSFC (including T25FW, 9HPT, and PASAT)



FF-VEP

 




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



AE and SAE recording


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12.
SAFETY ASSESSMENTS
Refer to Section 4 for the timing of all safety assessments.
12.1.
Safety Assessments
The following safety assessments will be performed:

Physical examinations

Vital sign measurements:  temperature, pulse rate, systolic and diastolic blood 
pressure, body weight, and respiratory rate 

AE and SAE recording
12.2.
Vital Signs
The analysis of vital signs will focus on clinically relevant abnormalities. The definitions of 
these clinically relevant abnormalities are shown in Table 2.
Table 2:
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs
Vital Sign
Criteria for Abnormalities
Temperature
>38°C 
Pulse
>100 bpm
<40 bpm 
Systolic Blood Pressure
>160 mmHg 
<90 mmHg 
Diastolic Blood Pressure
>100 mmHg 
<45 mmHg 
bpm = beats per minute.


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13.
SAFETY DEFINITIONS, CLASSIFICATIONS, 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.
13.1.
Definition
13.1.1.
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.
13.1.2.
Serious Adverse Event
An SAE is any untoward medical occurrence that at any dose:

Results in death.

In the view of the Investigator, places the subject at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred 
in a more severe form, might have caused death.

Requires inpatient hospitalization or prolongation of existing hospitalization.

Results in persistent or significant disability/incapacity.

Results in a congenital anomaly/birth defect.
An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above.  (Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or convulsions occurring at home that do not 
require an inpatient hospitalization.)


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13.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized.  The study site must document all of the following:

The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining the subject’s 
consent to participate in the study.

The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the subject’s consent to participate in the study and the time of 
the procedure or treatment.

The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission.

If a subject is hospitalized due to local requirements for administration of the 
study treatment, the hospitalization should not be considered an SAE unless one 
of the requirements in Section 13.1.2 is met.
13.2.
Safety Classifications
13.2.1.
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 13.1.2.

The relationship of the event to the study procedure(s) and to prior treatment with 
investigational drug (administered in Study 215ON201) as defined in Section 13.2.2.

The severity of the event as defined in Section 13.2.3.


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13.2.2.
Relationship of Events to Study Procedure(s) and Prior Treatment With 
Investigational Drug
The following definitions should be considered when evaluating the relationship of AEs and 
SAEs to the study procedure(s) and to prior treatment with investigational drug:
Relationship of Event to Study Procedure(s) and to Prior Treatment With Investigational Drug 
(Administered in Study 215ON201)
Not related
An AE will be considered “not related” to the study procedure(s) and/or investigational 
drug (administered in Study 215ON201) if there is not a reasonable possibility that the 
event has been caused by the study procedure(s) and/or investigational drug.  Factors 
pointing toward this assessment include but are not limited to:  the lack of reasonable 
temporal relationship between study procedure(s) and/or investigational drug and the 
event, the presence of a biologically implausible relationship between the study 
procedure(s) and/or investigational drug and the AE, or the presence of a more likely 
alternative explanation for the AE.
Related
An AE will be considered “related” to the study procedure(s) and/or investigational drug 
(administered in Study 215ON201) if there is a reasonable possibility that the event may 
have been caused by the study procedure(s) and/or investigational drug.  Factors that 
point toward this assessment include but are not limited to:  a positive rechallenge, a 
reasonable temporal sequence between study procedure(s) and/or investigational drug and 
the event, a known response pattern of the study procedure(s) and/or investigational drug, 
a biologically plausible relationship between the study procedure(s) and/or investigational 
drug and the AE, or a lack of an alternative explanation for the AE.
13.2.3.
Severity of Events
The following definitions should be considered when evaluating the severity of AEs and SAEs:
Severity of Event
Mild
Symptoms barely noticeable to subject or does not make subject uncomfortable; does not 
influence performance or functioning; prescription drug not ordinarily needed for relief of 
symptoms but may be given because of personality of subject.
Moderate
Symptoms of a sufficient severity to make subject uncomfortable; performance of daily 
activity is influenced; subject is able to continue in study; treatment for symptoms may be 
needed.
Severe
Symptoms cause severe discomfort; symptoms cause incapacitation or significant impact 
on subject’s daily life; severity may cause cessation of study procedure(s); treatment for 
symptoms may be given and/or subject hospitalized.
13.2.4.
Expectedness of Events
Expectedness of all AEs due to previous exposure to BIIB033 will be determined by Biogen 
according to the IB.


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13.3.
Monitoring and Recording Events
13.3.1.
Adverse Events
Any AE experienced by the subject after ICF sign-off through the end-of-study visit is to be 
recorded on the CRF, regardless of the severity of the event or its relationship to study 
procedure(s) and/or to prior treatment with the investigational drug (administered in 
Study 215ON201).
13.3.2.
Serious Adverse Events
Any SAE experienced by a subject after ICF sign-off through the end-of-study visit is to be 
recorded on an SAE form, regardless of the severity of the event or its relationship to study 
procedure(s) and/or to prior treatment with the investigational drug (administered in 
Study 215ON201). SAEs must be reported to 
 within 24 hours as 
described in Section 13.3.3.  Follow-up information regarding an SAE also must be reported 
within 24 hours. 
Subjects will be followed for all SAEs until the event has resolved, stabilized, or returned to 
baseline status.  
13.3.3.
Immediate Reporting of Serious Adverse Events
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify 
 within 24 hours of the study site staff becoming aware 
of the SAE.  It is the Investigator’s responsibility to ensure that the SAE reporting information 
and procedures are used and followed appropriately.
Reporting Information for SAEs
Any SAE that occurs after ICF sign-off through the end-of-study visit must be reported to 
 within 24 hours of the study site staff becoming aware of the event. 
After the end-of-study visit, the SAE should only be reported if the Investigator considers it 
related to investigational drug (administered in Study 215ON201).  In this circumstance, the 
SAE should be reported per Study 215ON201 protocol.
To report initial or follow-up information on an SAE, fax a completed SAE form; refer to the 
Study Reference Guide for country-specific 
 fax number or email 
.
13.3.3.1.
Deaths
Death is an outcome of an event.  The event that resulted in death should be recorded on the 
appropriate CRF and reported as an SAE within 24 hours of the site becoming aware of the 
event.  The Investigator should make every effort to obtain and send death certificates and 


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autopsy reports to 
.  The term death should be reported as an SAE only 
if the cause of death is not known and cannot be determined.
13.3.4.
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 study treatment (administered in 
Study 215ON201). 
Biogen or designee will report SUSARs to the appropriate regulatory authorities and 
Investigators as required, according to local law.
13.3.5.
Medical Emergency
In a medical emergency requiring immediate attention, study site staff will apply appropriate 
medical intervention, according to current standards of care.  The Investigator (or designee) 
should contact the study’s Medical Director.  Refer to the Study Reference Guide’s Official 
Study Contact List for complete contact information.
13.4.
Safety Responsibilities
13.4.1.
The Investigator
The Investigator’s responsibilities include the following:

Monitor and record all AEs and SAEs.

Determine the relationship to study procedure(s) and to prior treatment with 
investigational drug (administered in Study 215ON201) and the severity of each 
event.

Determine the onset and resolution dates of each event.

Complete an SAE form for each SAE and fax it to 
within 
24 hours of the study site staff becoming aware of the event.

Pursue SAE follow-up information actively and persistently until the event has 
resolved or become stable.  Follow-up information must be reported to 
within 24 hours of the study site staff becoming aware of new 
information.

Ensure all AE and SAE reports are supported by documentation in the subjects’ 
medical records.

Pursue AE follow-up information, if possible, until the event has resolved or become 
stable.


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
Report SAEs to local ethics committees, as required by local law.
13.4.2.
Biogen
Biogen’s responsibilities include the following:

Before study site activation and subject enrollment, the Clinical Monitor is 
responsible for reviewing with study site staff the definition of AE and SAE, as well 
as the instructions for monitoring, recording, and reporting AEs and SAEs.

Biogen or designee is to notify all appropriate regulatory authorities, central ethics 
committees, central institutional review boards, and Investigators of SAEs, as 
required by local law, within required time frames.


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14.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The objectives of the study and the endpoints to be analyzed are listed in Section 6.
14.1.
Efficacy
14.1.1.
Analysis Population
Analysis of efficacy endpoints will be based on all enrolled subjects who complete the 1-day
assessments.
14.1.2.
General Methods of Analysis
Unless stated otherwise, summary statistics will be presented by original treatment groups and 
overall.  For continuous endpoints, the summary statistics will generally include number of 
subjects enrolled, number of subjects evaluated, mean, standard deviation, median, and range.  
For categorical endpoints, the summary statistics will generally include number of subjects 
enrolled, number of subjects evaluated, and the percent of subjects in each category.
14.1.2.1.
Analysis of the Primary Endpoint
The primary analysis will be on the change in FF-VEP latency of the affected eye as compared to 
the baseline (measured prior to dosing in Study 215ON201) of the fellow eye at 2 years (+ 
4 months) after the last study visit assessment (Week 32) in Study 215ON201.  The ANCOVA
model will be used to test the difference between the 2 original treatment groups from 
Study 215ON201, adjusting for the baseline of the unaffected fellow eye.
14.1.2.2.
Analysis of the Secondary Endpoints
The secondary endpoints will include the time to diagnosis of CDMS; severity of disease 
evaluated by EDSS, SDMT, and MSFC (including T25FW, 9HPT, and PASAT); and brain MRI 
results.  Number and percentage of subjects with diagnosis of CDMS will be summarized, and 
descriptive statistics of time to diagnosis of CDMS will be presented. EDSS, SDMT, MSFC, 
and brain MRI outcomes will also be summarized using descriptive statistics.


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14.2.
Safety
14.2.1.
Analysis Population
The safety population is defined as all enrolled subjects who complete the 1-day assessments.
14.2.2.
Methods of Analysis
All AEs, clinical laboratory abnormalities, vital sign measurements, and physical examination 
findings will be evaluated for safety.
14.2.2.1.
Adverse Events
AEs will be coded using the Medical Dictionary for Regulatory Activities.  The incidence of 
clinical AEs will be summarized by severity and by relationship to study procedure(s) and to 
prior treatment with investigational drug (administered in Study 215ON201).  The summary 
tables will include incidence estimates for overall system organ class as well as for preferred 
terms within each system organ class.
14.2.2.2.
Vital Signs
The analysis of vital signs will focus on clinically relevant abnormalities.  The definitions of 
these clinically relevant abnormalities are shown in Table 2.
14.3.
Interim Analyses
An interim analysis will be performed when approximately 50% of potentially projected 
available subjects have been enrolled into the study to provide information to assist the 
interpretation and design of ongoing clinical development of CNS remyelinating therapies.  
Statistical analyses listed in Section 14.1 will be performed on primary, secondary, and 
 endpoints at the interim analysis.
14.4.
Sample Size Considerations
The sample size is based on the number of subjects who participated in Study 215ON201 
(approximately 82) rather than statistical considerations.  The subjects eligible for this study 
must have participated in Study 215ON201.  


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15.
ETHICAL REQUIREMENTS
Biogen,
, and the Investigator must comply with all instructions, regulations, and 
agreements in this protocol and applicable International Conference on Harmonisation (ICH) and 
Good Clinical Practice (GCP) guidelines and conduct the study according to local regulations.
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines.  The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated.
15.1.
Declaration of Helsinki
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki.
15.2.
Ethics Committee
The Investigator must obtain ethics committee approval of the protocol, ICF, and other required 
study documents prior to starting the study.  Biogen will submit documents on behalf of the 
investigational sites in all countries where subjects are enrolled.
If the Investigator makes any changes to the ICF, Biogen must approve the changes before the 
ICF is submitted to the ethics committee.  A copy of the approved ICF must be provided to 
Biogen.  After approval, the ICF must not be altered without the agreement of the relevant ethics 
committee and Biogen.
It is the responsibility of the Investigators to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations.
Biogen must receive a letter documenting ethics committee approval, which specifically 
identifies the protocol, protocol number, and ICF, prior to the initiation of the study.  Protocol 
amendments will be subject to the same requirements as the original protocol.
A progress report must be submitted to the ethics committee at required intervals and not less 
than annually.
At the completion or termination of the study, the investigational site must submit a close-out 
letter to the ethics committee and Biogen.
15.3.
Subject Information and Consent
Prior to performing any study-related activities under this protocol, including study-related tests 
and assessments, written informed consent with the approved ICF must be obtained from the 


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subject or subject’s legally authorized representative (e.g., parent or legal guardian), as 
applicable, in accordance with local practice and regulations.  
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the subject must be explained to the subject (or the 
subject’s legally authorized representative).  The subject must be given sufficient time to 
consider whether to participate in the study.
A copy of the signed and dated ICF must be given to the subject.  The signed and dated ICF will 
be retained with the study records.  Local regulations must be complied with in respect to the 
final disposition of the original (wet signature) and copies of the signed and dated ICFs.
Confirmation of informed consent must also be documented in the subject’s medical record.
15.4.
Subject Data Protection
Prior to any testing under this protocol, including assessments, candidates must also provide all 
authorizations required by local law (e.g., Protected Health Information authorization in North 
America).
The subject will not be identified by name in the CRF or in any study reports, and these reports 
will be used for research purposes only.  Biogen, its partners and designees, ethics committees, 
and various government health agencies may inspect the records of this study.  Every effort will 
be made to keep the subject’s personal medical data confidential.
15.5.
Compensation for Injury
Biogen maintains appropriate insurance coverage for clinical studies and will follow applicable 
local compensation laws.
15.6.
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.
15.7.
Registration of Study and Disclosure of Study Results
Biogen will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations.


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16.
ADMINISTRATIVE PROCEDURES
16.1.
Study Site Initiation
The Investigator must not enroll any subjects prior to completion of an on-site or remote study 
initiation visit, conducted by Biogen or designee.  This initiation visit will include a detailed 
review of the protocol and study procedures.
16.2.
Quality Assurance
During and/or after completion of the study, quality assurance officers named by Biogen or the 
regulatory authorities may wish to perform onsite audits or inspections.  The Investigator will be 
expected to cooperate with any audit or inspection and to provide assistance and documentation 
(including source data) as requested.
16.3.
Monitoring of the Study
No site may initiate the 1-day assessments until Biogen or its designee representatives have 
concluded protocol-specific training and approved assessment technician(s).
Biogen or its designee representatives may conduct on-site visits at the study facilities for the 
purpose of monitoring various aspects of the study.  The Investigator must agree to 
Sponsor-authorized personnel having direct access to subject (or associated) source files for the 
purpose of verifying entries made in the CRF and assist with their activities, if requested.  
Adequate space and time for monitoring visits should be made available by the Investigator or 
study staff.  The site must complete the CRFs in a timely manner and on an ongoing basis to 
allow regular review by the study team.
During these visits, CRFs and supporting documentation related to the study will be reviewed 
and any discrepancies or omissions will be resolved.  
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure protocol adherence, quality of data, compliance with regulatory requirements, and 
continued adequacy of the investigational site and its facilities.
16.4.
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. 
16.5.
Publications
Details are included in the clinical study agreement for this study.


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17.
FURTHER REQUIREMENTS AND GENERAL INFORMATION
17.1.
External Contract Organizations
Biogen will be responsible for all administrative aspects of this study, including but not limited 
to, study initiation, monitoring, management of AEs, and data management.
17.1.1.
Contract Research Organization 
, a contract research organization (CRO), will be responsible for administrative aspects 
of the study, including but not limited to, study initiation, monitoring, and management of AE 
reports and data management.  Before subjects are enrolled at each study site, the CRO will 
review study responsibilities with the Investigators and other study site staff, as appropriate.
17.1.2.
Electronic Data Capture
Subject information will be captured and managed by study sites on CRFs via an appropriate
Web-based electronic remote data capture tool.
17.1.3.
Central Facility for Other Assessments
A central facility has been selected by Biogen to be a central reader for SD-OCT, FF-VEP, and 
mfVEP for this study. A separate central facility has been selected by Biogen to read and 
interpret all MRI results for this study.
17.2.
Changes to Final Study Protocol
All protocol amendments must be submitted to the ethics committee and regulatory authorities if 
required by local law.  Protocol modifications that affect subject safety, the scope of the 
investigation, or the scientific quality of the study must be approved by the ethics committee 
before implementation of such modifications to the conduct of the study.  If required by local 
law, such modifications must also be approved by the appropriate regulatory agency prior to 
implementation.
However, Biogen may, at any time, amend this protocol to eliminate an apparent immediate 
hazard to a subject.  In this case, the appropriate regulatory authorities will be notified 
subsequent to the modification.
In the event of a protocol modification, the ICF may require similar modifications (see 
Section 15).


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17.3.
Ethics Committee Notification of Study Completion or Termination
Where required, the regulatory authorities and ethics committees must be notified of completion 
or termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines.
17.4.
Retention of Study Data
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local laws or regulations.  Prior to 
proceeding with destruction of records, the Investigator must notify Biogen in writing and 
receive written authorization from Biogen to destroy study records.  In addition, the Investigator 
must notify Biogen of any changes in the archival arrangements including but not limited to 
archival at an offsite facility or transfer of ownership if the Investigator leaves the site.
17.5.
Study Report Signatory
Biogen will designate one of the participating Study Investigators as a signatory for the study 
report.  This determination will be made by several factors, including but not limited to, the 
Investigator's experience and reputation in the studied indication; the Investigator's contribution 
to the study in terms of design, management, and/or subject enrollment; or by other factors 
determined to be relevant by Biogen.
Biogen will follow all applicable local regulations pertaining to study report signatories.


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18.
REFERENCES
Balcer LJ, Galetta SL, Polman CH, et al. Low-contrast acuity measures visual improvement in 
phase 3 trial of natalizumab in relapsing MS. J Neurol Sci. 2012;318(1-2):119-24.
Barrette B, Vallieres N, Dube M, et al. Expression profile of receptors for myelin-associated 
inhibitors of axonal regeneration in the intact and injured mouse central nervous system. Mol 
Cell Neurosci. 2007;34(4):519-38.
Beck RW, Cleary PA, Anderson MM, Jr., et al. A randomized, controlled trial of corticosteroids 
in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med. 
1992;326(9):581-8.
Carim-Todd L, Escarceller M, Estivill X, et al. LRRN6A/LERN1 (leucine-rich repeat neuronal 
protein 1), a novel gene with enriched expression in limbic system and neocortex. Eur J 
Neurosci. 2003;18(12):3167-82.
Costello F, Coupland S, Hodge W, et al. Quantifying axonal loss after optic neuritis with optical 
coherence tomography. Ann Neurol. 2006;59(6):963-9.
Duffy CJ. The consequences of optic neuritis: more than meets the eye. Neurology. 
2011a;76(24):2052-3.
Duffy LM, Chapman AL, Shaw PJ, et al. Review: The role of mitochondria in the pathogenesis 
of amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol. 2011b;37(4):336-52.
Fu QL, Hu B, Wu W, et al. Blocking LINGO-1 function promotes retinal ganglion cell survival 
following ocular hypertension and optic nerve transection. Invest Ophthalmol Vis Sci. 
2008;49(3):975-85.
Henderson A, Altmann D, Anand T, et al. Early factors associated with axonal loss after optic 
neuritis. Ann Neurol [Internet]. 2011 Aug:[16 p.]. Available from: 
http://onlinelibrary.wiley.com/doi/10.1002/ana.22554/pdf.
Inoue H, Lin L, Lee X, et al. Inhibition of the leucine-rich repeat protein LINGO-1 enhances 
survival, structure, and function of dopaminergic neurons in Parkinson's disease models. Proc 
Natl Acad Sci U S A. 2007;104(36):14430-5.
Ji B, Case LC, Liu K, et al. Assessment of functional recovery and axonal sprouting in 
oligodendrocyte-myelin glycoprotein (OMgp) null mice after spinal cord injury. Mol Cell 
Neurosci. 2008;39(2):258-67.
Ji B, Li M, Wu WT, et al. LINGO-1 antagonist promotes functional recovery and axonal 
sprouting after spinal cord injury. Mol Cell Neurosci. 2006;33(3):311-20.
Kupersmith MJ, Gal RL, Beck RW, et al. Visual function at baseline and 1 month in acute optic 
neuritis: predictors of visual outcome. Neurology. 2007;69(6):508-14.
Lee X, Yang Z, Shao Z, et al. NGF regulates the expression of axonal LINGO-1 to inhibit 
oligodendrocyte differentiation and myelination. J Neurosci. 2007;27(1):220-5.


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Long-Term Assessment of Remyelinating Therapy
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The information contained herein may not be used, disclosed, or published without the written consent of 
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47
Llorens F, Gil V, Iraola S, et al. Developmental analysis of Lingo-1/Lern1 protein expression in 
the mouse brain: interaction of its intracellular domain with Myt1l. Dev Neurobiol. 
2008;68(4):521-41.
McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple 
sclerosis: guidelines from the International panel on the diagnosis of multiple sclerosis. Annals 
of Neurology. 2001;50(1):121-127.
Mi S, Hu B, Hahm K, et al. LINGO-1 antagonist promotes spinal cord remyelination and axonal 
integrity in MOG-induced experimental autoimmune encephalomyelitis. Nat Med.
2007;13(10):1228-33.
Mi S, Lee X, Shao Z, et al. LINGO-1 is a component of the Nogo-66 receptor/p75 signaling 
complex. Nat Neurosci. 2004;7(3):221-8.
Mi S, Miller RH, Lee X, et al. LINGO-1 negatively regulates myelination by oligodendrocytes. 
Nat Neurosci. 2005;8(6):745-51.
Mi S, Miller RH, Tang W, et al. Promotion of central nervous system remyelination by induced 
differentiation of oligodendrocyte precursor cells. Ann Neurol. 2009;65(3):304-15.
Mi S, Sandrock A, Miller RH. LINGO-1 and its role in CNS repair. Int J Biochem Cell Biol. 
2008.
Mowry EM, Loguidice MJ, Daniels AB, et al. Vision related quality of life in multiple sclerosis: 
correlation with new measures of low and high contrast letter acuity. J Neurol Neurosurg 
Psychiatry. 2009;80(7):767-72.
Park JB, Yiu G, Kaneko S, et al. A TNF receptor family member, TROY, is a coreceptor with 
Nogo receptor in mediating the inhibitory activity of myelin inhibitors. Neuron. 2005;45(3):345-
51.
Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 
Revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292-302.
Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: 
guidelines for research protocols. Ann Neurol. 1983;13(3):227-31.
Raz N, Dotan S, Benoliel T, et al. Sustained motion perception deficit following optic neuritis: 
Behavioral and cortical evidence. Neurology. 2011;76(24):2103-11.
Runmarker B, Andersen O. Prognostic factors in a multiple sclerosis incidence cohort with 
twenty-five years of follow-up. Brain. 1993;116 ( Pt 1):117-34.
Shao Z, Browning JL, Lee X, et al. TAJ/TROY, an orphan TNF receptor family member, binds 
Nogo-66 receptor 1 and regulates axonal regeneration. Neuron. 2005;45(3):353-9.
Submacular Surgery Trials Research Group. Evaluation of minimum clinically meaningful 
changes in scores on the National Eye Institute Visual Function Questionnaire (NEI-VFQ) SST 
Report Number 19. Ophthalmic Epidemiol. 2007;14(4):205-15.
Talman LS, Bisker ER, Sackel DJ, et al. Longitudinal study of vision and retinal nerve fiber 
layer thickness in multiple sclerosis. Ann Neurol. 2010;67(6):749-60.


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Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a 
geographically based study. I. Clinical course and disability. Brain. 1989;112:133-146.


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19.
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “A Multicenter, Follow-Up Study to Assess Long-Term 
Electrophysiologic and Clinical Outcomes in Subjects Previously Enrolled in Study 215ON201,”
and agree to conduct the study according to the protocol and the applicable ICH guidelines and 
GCP regulations, and to inform all who assist me in the conduct of this study of their 
responsibilities and obligations.
____________________________________________________
Investigator’s Signature
Date
____________________________________________________
Investigator’s Name (Print)
____________________________________________________
Study Site (Print)


Signature Page
Document Name: 215ON203 Protocol V3 Final 16Nov15
Document Title: A Multicenter, Follow-Up Study to Assess Long Term Electrophysiologic
and Clinical Outcomes in Subjects Previously Enrolled in Study 215ON201
Signed by
Role
Date / Time (UTC)
Signing as Approver
16-Nov-2015 19:57:07


CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
1 
Biogen MA Inc. 
250 Binney Street 
Cambridge, MA 02142 
United States 
PROTOCOL NUMBER: 
215ON203
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead Berkshire 
SL6 4AY 
United Kingdom 
PHASE OF DEVELOPMENT: 
2 
PROTOCOL TITLE:  A Multicenter, Follow-Up Study to Assess Long-Term 
Electrophysiologic and Clinical Outcomes in Subjects Previously Enrolled in Study 
215ON201 
EUDRA CT NO: 
2015-003618-26 
DATE: 
01 September 2015 
Version 2.0 
Final 




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TABLE OF CONTENTS 
1. 
SPONSOR INFORMATION .......................................................................................7 
2. 
LIST OF ABBREVIATIONS.......................................................................................8 
3. 
SYNOPSIS .................................................................................................................10 
4. 
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR STUDY 
215ON203 ...................................................................................................................14 
4.1. 
Study Schematic .........................................................................................................14 
4.2. 
Schedule of Activities .................................................................................................15 
5. 
INTRODUCTION ......................................................................................................17 
5.1. 
Overview of Acute Optic Neuritis ..............................................................................17 
5.2. 
Current Therapies for Acute Optic Neuritis ...............................................................18 
5.3. 
Overview of Multiple Sclerosis ..................................................................................18 
5.4. 
Current Therapies for Multiple Sclerosis ...................................................................19 
5.5. 
Profile of Previous Experience with BIIB033 ............................................................19 
5.5.1. 
Nonclinical Experience ...............................................................................................19 
5.5.2. 
Clinical Experience .....................................................................................................20 
5.6. 
Study Rationale ...........................................................................................................22 
5.7. 
Rationale for Dosing Regimen ...................................................................................22 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................23 
6.1. 
Primary Objective and Endpoint ................................................................................23 
6.2. 
Secondary Objectives and Endpoints .........................................................................23 
 
23 
7. 
STUDY DESIGN .......................................................................................................26 
7.1. 
Study Overview ..........................................................................................................26 
7.2. 
Overall Study Duration ...............................................................................................26 
7.2.1. 
Screening ....................................................................................................................26 
7.2.2. 
Treatment ....................................................................................................................26 
7.2.3. 
Visit Schedule .............................................................................................................26 
7.3. 
Study Stopping Rules .................................................................................................26 
7.4. 
End of Study ...............................................................................................................27 
8. 
SELECTION OF SUBJECTS ....................................................................................28 


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8.1. 
Inclusion Criteria ........................................................................................................28 
8.2. 
Exclusion Criteria .......................................................................................................28 
9. 
ENROLLMENT AND REGISTRATION .................................................................29 
9.1. 
Enrollment ..................................................................................................................29 
9.2. 
Registration of Subjects ..............................................................................................29 
9.3. 
Blinding Procedures ....................................................................................................29 
10. 
WITHDRAWAL OF SUBJECTS FROM THE STUDY ...........................................30 
10.1. 
Withdrawal of Subjects From Study ...........................................................................30 
11. 
FOLLOW-UP ASSESSMENTS ................................................................................31 
11.1. 
One-Day Visit Assessments .......................................................................................31 
12. 
SAFETY ASSESSMENTS ........................................................................................33 
12.1. 
Safety Assessments .....................................................................................................33 
12.2. 
Vital Signs ..................................................................................................................33 
13. 
SAFETY DEFINITIONS, CLASSIFICATIONS, RECORDING, 
REPORTING, AND RESPONSIBILITIES ...............................................................34 
13.1. 
Definition ....................................................................................................................34 
13.1.1. 
Serious Adverse Event ................................................................................................34 
13.2. 
Safety Classifications ..................................................................................................34 
13.2.1. 
Investigator Assessment of Events .............................................................................34 
13.2.2. 
Relationship of Events to Study Procedure(s) ............................................................35 
13.2.3. 
Severity of Events .......................................................................................................35 
13.3. 
Monitoring and Recording Events ..............................................................................35 
13.3.1. 
Serious Adverse Events ..............................................................................................35 
13.3.2. 
Immediate Reporting of Serious Adverse Events .......................................................36 
13.3.2.1. 
Deaths .........................................................................................................................36 
13.3.3. 
Suspected Unexpected Serious Adverse Reactions ....................................................36 
13.3.4. 
Medical Emergency ....................................................................................................36 
13.4. 
Safety Responsibilities ................................................................................................36 
13.4.1. 
The Investigator ..........................................................................................................36 
13.4.2. 
Biogen .........................................................................................................................37 
14. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ...........38 
14.1. 
Efficacy .......................................................................................................................38 


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14.1.1. 
Analysis Population ....................................................................................................38 
14.1.2. 
General Methods of Analysis .....................................................................................38 
14.1.2.1. 
Analysis of the Primary Endpoint...............................................................................38 
14.1.2.2. 
Analysis of the Secondary Endpoints .........................................................................38 
 
38 
14.2. 
Safety ..........................................................................................................................39 
14.2.1. 
Analysis Population ....................................................................................................39 
14.2.2. 
Methods of Analysis ...................................................................................................39 
14.2.2.1. 
Serious Adverse Events ..............................................................................................39 
14.2.2.2. 
Vital Signs ..................................................................................................................39 
14.3. 
Interim Analyses .........................................................................................................39 
14.4. 
Sample Size Considerations .......................................................................................39 
15. 
ETHICAL REQUIREMENTS ...................................................................................40 
15.1. 
Declaration of Helsinki ...............................................................................................40 
15.2. 
Ethics Committee ........................................................................................................40 
15.3. 
Subject Information and Consent ...............................................................................40 
15.4. 
Subject Data Protection ..............................................................................................41 
15.5. 
Compensation for Injury .............................................................................................41 
15.6. 
Conflict of Interest ......................................................................................................41 
15.7. 
Registration of Study and Disclosure of Study Results ..............................................41 
16. 
ADMINISTRATIVE PROCEDURES .......................................................................42 
16.1. 
Study Site Initiation ....................................................................................................42 
16.2. 
Quality Assurance .......................................................................................................42 
16.3. 
Monitoring of the Study..............................................................................................42 
16.4. 
Study Funding .............................................................................................................42 
16.5. 
Publications .................................................................................................................42 
17. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION ........................43 
17.1. 
External Contract Organizations .................................................................................43 
17.1.1. 
Contract Research Organization .................................................................................43 
17.1.2. 
Electronic Data Capture ..............................................................................................43 
17.1.3. 
Central Facility for Other Assessments ......................................................................43 


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17.2. 
Changes to Final Study Protocol ................................................................................43 
17.3. 
Ethics Committee Notification of Study Completion or Termination ........................44 
17.4. 
Retention of Study Data ..............................................................................................44 
17.5. 
Study Report Signatory...............................................................................................44 
18. 
REFERENCES ...........................................................................................................45 
19. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL .........................................48 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities .................................................................................................15 
Table 2: 
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs ...................33 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................14 
 
 


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1. 
SPONSOR INFORMATION 
Biogen MA Inc. 
250 Binney Street 
Cambridge, MA 02142 
United States 
 
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead, Berkshire  
SL6 4AY 
United Kingdom 
Biogen Australia Pty Ltd 
Suite 1, Level 5 
123 Epping Road 
North Ryde NSW 2113 
Australia 
 
For urgent medical issues in which the study’s Medical Director should be contacted, please 
refer to the Study Reference Manual for the full contact information of the Medical Monitor.  
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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2. 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ANCOVA 
analysis of covariance 
AON 
acute optic neuritis 
CDMS 
clinically definite multiple sclerosis 
CI 
confidence interval 
CIS 
clinically isolated syndrome 
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
 
 
EDSS 
Expanded Disability Status Scale 
FITC-BIIB033 
fluorescein isothiocyanate-conjugated BIIB033 
FF-VEP 
full-field visual evoked potential 
 
 
GCP 
Good Clinical Practice 
Gd 
gadolinium 
IB 
Investigator’s Brochure 
IP 
Investigational product 
HCVA 
high-contrast visual acuity 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IFN-β 
interferon-beta 
IgG1 
immunoglobulin G1 
ITT 
intent-to-treat 
IV 
intravenous 
LCLA 
low-contrast letter acuity 
MAD 
multiple-ascending dose  
MFD 
maximum feasible dose 
 
 
MMRM 
mixed model for repeated measures 
MRI 
magnetic resonance imaging 
MS 
multiple sclerosis 
MSFC 
multiple sclerosis functional composite 
 
  
 
 
 
 
NEI-VFQ-25 
25-item National Eye Institute Visual Function Questionnaire 
 
 
PK 
pharmacokinetic(s) 


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RGCL 
retinal ganglion cell layer 
RNFL 
retinal nerve fiber layer 
 
 
RRMS 
relapsing-remitting multiple sclerosis 
SAD 
single-ascending dose  
SAE 
serious adverse event 
SC 
subcutaneous 
 
 
SPMS 
secondary progressive multiple sclerosis 


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3. 
SYNOPSIS 
Protocol Number: 
215ON203 
Protocol Title: 
A Multicenter, Follow-Up Study to Assess Long-Term 
Electrophysiologic and Clinical Outcomes in Subjects 
Previously Enrolled in Study 215ON201 
Version Number: 
2.0 
Study Indication: 
Acute optic neuritis (AON) 
Study Rationale: 
BIIB033 (human anti-LINGO-1 monoclonal antibody) is an 
investigational product with the potential of enhancing 
remyelination and neuroaxonal protection. 
In Study 215ON201, treatment of patients with AON with 
BIIB033 displayed evidence of functional remyelination in 
the affected eye by demonstrating significant improvement 
in visual evoked potential latency over treatment with 
placebo.  The electrophysiologic differences between the 
treatment and placebo groups were first observed at 
Week 12 during the dosing period and persisted throughout 
the subsequent monthly dosing visits.  More interestingly, 
this trend continued for an additional 3 months through the 
Follow-Up Visit at Week 32 despite subjects completing the 
dosing period at Week 20.  
Study 215ON201 also showed that all subjects, regardless of 
assigned treatment, recovered clinically to a large extent 
regardless of treatment assignment or severity of injury to 
the retina or the optic nerve; however, not all subjects 
demonstrated complete functional recovery upon 
electrophysiologic examination.  The rationale for the 
discrepancy between clinical recovery and 
electrophysiological improvement is unclear and requires 
further investigation.   
Given these data, the proposed follow-up study is necessary 
to assess the long-term electrophysiologic and clinical 
outcomes of this patient population with past randomized 
exposure to remyelinating therapy versus placebo and also 
to explore potential mechanism(s) by which patients recover 


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from previous AON.  This information will be critical in 
ongoing clinical development of remyelinating therapies so 
that they can be optimally evaluated and utilized for 
maximal benefit.   
Phase of Development: 
2 
Study Objectives and 
Endpoints: 
The primary objective of this study is to assess full-field 
visual evoked potential (FF-VEP) latency in subjects who 
were enrolled in Study 215ON201 2 years (+ 4 months) 
after the last study visit. 
The primary endpoint that is related to this objective is the 
change in FF-VEP latency of the affected eye as compared 
to the baseline of the fellow eye at 2 years (+ 4 months) 
after the last study visit assessment (Week 32) in 
Study 215ON201. 
The secondary objective is to assess clinical progression and 
severity of central nervous system (CNS) demyelinating 
disease in subjects who were enrolled in Study 215ON201 
2 years (+ 4 months) after the last study visit. 
The endpoints that relate to this objective are as follows: 
 Evaluate incidence of clinically definite multiple 
sclerosis (CDMS) and time to diagnosis of 
CDMS. 
 Evaluate severity of CNS demyelinating disease 
with Expanded Disability Status Scale (EDSS) 
and multiple sclerosis functional composite 
(MSFC). 
 Evaluate change in disease activity from baseline 
with brain magnetic resonance imaging (MRI) 
with and without gadolinium (Gd).  MRI analysis 
will include the following: 
 Number of Gd-enhanced lesions 
 Volume of T2 lesions 
 
 


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Study Design: 
This is a multicenter, follow-up study to determine the 
long-term electrophysiologic and clinical outcomes in 
subjects previously enrolled in Study 215ON201. 
One group is planned, with eligible subjects (previously 
enrolled in Study 215ON201) having been already 
administered at least 1 study treatment (BIIB033 100 mg/kg 
or placebo) by intravenous infusion once every 4 weeks for 
20 weeks (a total of 6 doses).  Dosing was completed 
2 years (+ 4 months) prior to enrollment in this follow-up 
study.  No additional drug or placebo will be administered. 
Study Location: 
Approximately 33 sites globally are planned. 
Number of Planned Subjects: 
A maximum of 82 subjects will be eligible for enrollment 
(determined from the number of subjects who received at 
least 1 dose of BIIB033 100 mg/kg or placebo in 
Study 215ON201). 
Study Population: 
This study will be conducted in subjects who have 
participated in and received at least 1 dose of BIIB033 or 
placebo in Study 215ON201.   
Detailed criteria are described in Section 8. 
Duration of Follow-up: 
Eligible subjects will be enrolled at 2 years after their last 
study visit (Week 32) or projected Week 32 (+ 4 months) 
visit if the subject did not complete all visits in 
Study 215ON201.  Subjects will perform 1 set of follow-up 
assessments at this timepoint. 
Evaluations: 
 
Safety: 
Assessments evaluating the safety profile related to study 
procedure(s) will include physical examinations, vital sign 
measurements, and serious adverse events (SAEs). 
Any SAE experienced by a subject post informed consent 
form sign-off through end-of-study visit and considered by 
the Investigator to be related to study procedure(s) is to be 
recorded on an SAE form, regardless of the severity of the 
event.  Information on SAEs related to study procedure(s) 
must be reported to 
 within 
24 hours. 


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Subjects will be followed for all SAEs until the event has 
resolved, stabilized, or returned to baseline status.   
Statistical Analysis Methods: 
The primary analysis will be on the change in FF-VEP 
latency of the affected eye as compared to the baseline 
(measured prior to dosing in Study 215201) of the fellow 
eye at 2 years (+ 4 months) after the last study visit 
assessment (Week 32) in Study 215ON201.  The ANCOVA 
model will be used to test the difference between the 
2 original treatment groups from Study 215ON201, 
adjusting for the baseline of the unaffected fellow eye. 
The secondary endpoints will include the time to diagnosis 
of CDMS, severity of disease evaluated by EDSS and 
MSFC, and brain MRI results.  Number and percentage of 
subjects with diagnosis of CDMS will be summarized, and 
descriptive statistics of time to diagnosis of CDMS will be 
presented.  EDSS, MSFC, and brain MRI outcomes will also 
be summarized using descriptive statistics. 
 
  
Interim Analysis: 
An interim analysis will be performed when approximately 
50% of potentially projected available subjects have been 
enrolled into the study to provide information to assist the 
interpretation and design of ongoing clinical development of 
CNS remyelinating therapies.   


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4. 
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR 
STUDY 215ON203 
4.1. 
Study Schematic 
Figure 1: 
Study Design 
 
IP = investigational product; MRI= magnetic resonance imaging. 
Note:  All assessments should be performed on the same day where possible or within a + 5 day window of the 
1-day visit. 


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4.2. 
Schedule of Activities 
Table 1: 
Schedule of Activities 
Tests and Assessments1 
Day 1:  
(2 Years + 4 Months After Week 32 Visit in Study 215ON201 or Projected Week 32 
Visit if the Subject Did Not Complete All Visits) 
Informed Consent 
X 
Eligibility Criteria Check 
X 
Medical History2 
X 
Multiple Sclerosis Diagnosis 
X 
Multiple Sclerosis Signs and Symptoms  
X 
Concomitant Therapy and Procedures Recording 
X 
Vital Signs3 
X 
Physical Examination 
X 
Expanded Disability Status Scale4 
X 
Multiple Sclerosis Functional Composite 
X 
Full-Field Visual Evoked Potential6 
X 


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Tests and Assessments1 
Day 1:  
(2 Years + 4 Months After Week 32 Visit in Study 215ON201 or Projected Week 32 
Visit if the Subject Did Not Complete All Visits) 
Serious Adverse Events Related to Study Procedure(s) Reporting11 
X 
; MRI = magnetic resonance imaging. 
1 All assessments should be performed on the same day and in the order listed, when possible (or within a + 5 day window of the 1-day visit). 
2 Medical history will be taken from after last study visit in Study 215ON201. 
3 Vital signs include temperature, systolic and diastolic blood pressure, pulse rate, and respiratory rate (after sitting down for at least 5 minutes). 
4 Expanded Disability Status Scale should be performed by a study certified rater.  Where applicable, refer to study manual for instructions. 
 
 
 
 
6 Sites and technicians must be qualified and approved by the central reader to perform 
, full-field visual evoked 
potential, and 
. 
 
   
 
 
 
 
  
11 Serious adverse events monitoring for events related to study procedure(s) will be reported post informed consent form sign-off through end-of-study visit.  
 
 


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5. 
INTRODUCTION  
BIIB033, a first-in-class human monoclonal antibody directed against LINGO-1, is a negative 
regulator of myelination and axonal growth.  Antagonizing LINGO-1 with BIIB033 has the 
potential to enhance remyelination and neuroaxonal protection in the central nervous system 
(CNS).  
LINGO-1 is a cell surface glycoprotein that is selectively expressed in the adult CNS in neurons 
and oligodendrocytes [Barrette 2007; Carim-Todd 2003; Llorens 2008; Mi 2004; Park 2005; 
Shao 2005].  It functions as a negative regulator of oligodendrocyte differentiation, myelination, 
and remyelination [Lee 2007; Mi 2005; Mi 2009; Mi 2008].  Axonal and neuronal expression of 
LINGO-1 increases after injury [Ji 2006; Mi 2004].  LINGO-1 expression prevents myelination 
of axons by oligodendrocytes.  
Several nonclinical studies have demonstrated the potential for LINGO-1 antagonism to enhance 
CNS remyelination and neuroaxonal protection in animal models of toxic (cuprizone plus 
rapamycin) [Mi 2009], chemical (lysophosphatidylcholine), and inflammatory (myelin 
oligodendrocyte glycoprotein-experimental autoimmune encephalomyelitis) [Mi 2007] 
demyelination and of toxic (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neuronal [Inoue 
2007] and traumatic/hypertensive optic nerve [Fu 2008] and spinal cord [Ji 2008; Ji 2006] injury.  
The leading hypothesis for this clinical development program is that antagonism of LINGO-1 
with BIIB033 will enhance remyelination and neuroaxonal protection in CNS demyelinating 
diseases such as multiple sclerosis (MS) and acute optic neuritis (AON), leading to CNS 
improvement with corresponding beneficial effects on neurological function and disability.  
Additional details may be found in the BIIB033 Investigator’s Brochure (IB).  
5.1. 
Overview of Acute Optic Neuritis  
The anterior visual pathway, particularly the optic nerve and its retinal nerve fiber layer (RNFL) 
and retinal ganglion cell layer (RGCL), is affected by AON and is a potential target for 
therapeutic compounds with properties to enhance remyelination and neuroaxonal protection.  In 
a study of the long-term effects of AON in the context of MS, the RNFL was decreased to an 
average of 83 microns [Costello 2006; Talman 2010].  This corresponds to an average loss of 
~20 microns or 20% of nerve fibers relative to unaffected eyes in patients with AON or to a loss 
of ~13 microns relative to eyes in patients with MS without history or presence of AON [Talman 
2010].  Costello et al [Costello 2006] found that 74% of patients had 20% or greater thinning of 
the RNFL following AON.  As also noted by Henderson et al [Henderson 2011 Aug], this RNFL 
thinning begins early (between 1 and 2 months after onset of AON), and nearly all of the 
eventual RNFL loss is complete by 6 months.  This loss of RNFL is associated with a clinically 
important loss of visual function, as shown by a decrease of low-contrast letter acuity (LCLA) to 
an average of 21 letters out of 60 or a loss of 14 letters relative to unaffected MS eyes.  There is 
also a permanent loss of visual motion perception in most patients affected by AON [Raz 2011].  


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Motion processing impairments in AON may be highly disruptive to the ability of patients to 
ambulate, drive, and navigate [Duffy 2011a; Duffy 2011b].  The permanent loss of visual 
function in AON is clinically important as reflected by a vision-related quality of life score of 84 
on the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25), which is 8 
points lower than in unaffected patients [Balcer 2012].  This 8-point loss on the NEI-VFQ-25 is 
higher than the currently accepted 4-point threshold for clinically important changes in vision-
related quality of life [Mowry 2009; Submacular Surgery Trials Research Group 2007].  
5.2. 
Current Therapies for Acute Optic Neuritis  
The only currently available treatment for AON is high-dose intravenous (IV) steroids (e.g., 
methylprednisolone) followed by an oral prednisone taper, which speeds up the recovery of 
symptoms (e.g., ocular pain) and high-contrast visual acuity (HCVA) primarily in the first 
2 weeks after an attack, but has no long-term beneficial effects on the ultimate recovery of visual 
function [Beck 1992] nor is there evidence that it affects the degree of axonal loss or conduction 
velocity in the optic nerve pathway.  
Despite treatment with high-dose steroids, over 60% of patients with AON are left with loss of 
visual function [Kupersmith 2007]. 
5.3. 
Overview of Multiple Sclerosis  
MS is a chronic disabling neurological disease that affects an estimated 1 million people in North 
America and Western Europe.  It is a disease of young adults, primarily women, with disease 
onset typically occurring between the ages of 20 and 40 years [Weinshenker 1989].  It is the 
most frequent cause of nontraumatic neurological disability affecting young adults in the 
Western world.  Although the etiology is uncertain, evidence suggests that MS is, in part, an 
autoimmune disease directed against protein components of myelin.  The diagnosis of clinically 
definite multiple sclerosis (CDMS) has traditionally been made on the basis of clinical criteria 
and requires that a patient experience at least 2 neurologic events consistent with demyelination, 
separated both in time and in location in the CNS [Poser 1983].  More recent diagnostic criteria 
have allowed for less than 2 neurologic attacks, when there is supportive laboratory evidence 
based on magnetic resonance imaging (MRI) or cerebrospinal fluid (CSF) results [McDonald 
2001].  The majority of patients with MS start out with a clinical course characterized by 
episodes or attacks (relapses) of neurologic dysfunction, which occur over many years.  This 
phase of the disease is called relapsing-remitting multiple sclerosis (RRMS).  Symptoms of such 
relapses include loss of vision or double vision, numbness or tingling sensation in the 
extremities, muscle weakness, slurred speech, difficulty with coordination, and bladder 
dysfunction.  Patients having the first clinical attack are referred to as clinically isolated 
syndrome (CIS).  The most common CIS types are AON, transverse myelitis, and brainstem 
attack.  Patients with CIS with characteristic brain MRI lesions are considered to be having MS 
by the most recent diagnostic McDonald criteria [Polman 2011].  Patients with CIS without brain 
lesions are at low risk of developing MS.  Early in the course of relapsing MS, the signs and 
symptoms tend to subside completely after each attack.  Over time, there tends to be incomplete 
recovery from such attacks.  The majority of patients with relapsing MS accumulate some 


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disability, and about half are unable to walk without assistance within 15 years of their initial 
diagnosis [Runmarker and Andersen 1993; Weinshenker 1989].  The majority of patients with 
RRMS eventually enter the secondary progressive phase of the disease (secondary progressive 
multiple sclerosis [SPMS]), characterized by steady worsening of disability independently of 
relapses.  About 15% of the patients go into this progressive phase without prior development of 
a relapsing-remitting phase and are referred to as having a primary progressive MS. 
5.4. 
Current Therapies for Multiple Sclerosis 
Available therapies for the treatment of relapsing MS target the immunomodulation of 
inflammatory activity and include interferon-beta (IFN-β)1a, pegylated IFN-β1a, IFN-β1b, 
natalizumab, mitoxantrone, glatiramer acetate, teriflunomide, dimethyl fumarate, alemtuzumab, 
and fingolimod.  There is also 1 available symptomatic MS therapy to improve walking, 
prolonged-release fampridine, known as dalfampridine extended release in the United States.  
5.5. 
Profile of Previous Experience with BIIB033 
5.5.1. 
Nonclinical Experience 
BIIB033 is a fully human aglycosylated immunoglobulin G1 (IgG1) monoclonal antibody that 
binds LINGO-1 with high affinity.  As LINGO-1 is a cell surface glycoprotein selectively 
expressed in CNS oligodendrocytes and neurons that prevents myelination of axons by 
oligodendrocytes, a blockade of LINGO-1 may enhance remyelination and repair in CNS 
demyelinated lesions.   
BIIB033 binds LINGO-1 with high affinity in humans, monkeys, rats, and mice; has high 
specificity for LINGO-1 and does not cross react with other LINGO family members; enhances 
differentiation of primary rat, monkey, and human oligodendrocytes in vitro; enhances axonal 
myelination in an in vitro rat dorsal root ganglion/oligodendrocyte precursor cell co-culture 
bioassay; has reduced Fcγ and complement effector functions compared to wild-type IgG1; and 
is efficacious in animal models using biochemical and functional readouts.  These data suggest 
that BIIB033 will be an effective therapy to enhance remyelination in patients with MS.   
An assessment of BIIB033 toxicology has been carried out in repeated-dose studies in rats and 
cynomolgus monkeys, as these species are considered pharmacologically relevant based on 
sequence homology with LINGO-1 and/or similarity in binding and in vitro functional activity 
with LINGO 1.  Toxicology studies of up to 6 months in duration did not identify any adverse 
treatment-related effects or any effect on neurobehavioral assessments with weekly IV 
administrations of BIIB033 at up to an maximum feasible dose (MFD) of 316 mg/kg or 
3-time-per week subcutaneous (SC) doses at up to 32 mg/kg.  Effects on the CNS and respiratory 
system were transient, and none were considered adverse responses to BIIB033.  In embryo-fetal 
toxicology studies in rats and rabbits, BIIB033 was shown to be not causing fetal abnormalities 
at maternal doses up to 316 mg/kg.  Maternal toxicity and morbidity were noted in 1 rabbit given 
316 mg/kg, but the relationship to BIIB033 treatment was unclear; no maternal toxicity was 
observed in rats at any dose.  


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Immunohistochemical analyses have identified target and nontarget antigen-specific 
cross-reactivity by fluorescein isothiocyanate-conjugated BIIB033 (FITC-BIIB033)-specific 
staining in a range of human, cynomolgus monkey, and rat tissues, including those of neural, 
epithelial, neuroendocrine, and connective tissue origins.  Consistent BIIB033-specific 
immunostaining using 2 concentrations of FITC-BIIB033 was observed in the brain (primarily, 
the cerebral cortex) and spinal cord across all 3 species, and the pattern of FITC-BIIB033-
specific staining was consistent with that of LINGO-1 protein localization, as previously 
observed in rodents.  Additional non-neural tissues with inconsistent binding patterns across 
species were evaluated within the repeated-dose toxicology studies and were not identified as 
target organs of toxicity associated with BIIB033 administration up to an MFD dose over 
6 months of treatment.  The exposure-based safety margin for the highest dose planned for 
chronic dosing in the clinic (100 mg/kg/month) is projected to be 4- to 6-fold lower relative to 
exposures at the no-observed-adverse-effect level in toxicology species after 6 months of dosing.   
Together, these data support ongoing evaluations of BIIB033 in Phase 2 studies.   
See the IB for detailed information on nonclinical studies. 
5.5.2. 
Clinical Experience 
As of 07 May 2015, 72 healthy volunteers (54 BIIB033 and 18 placebo) have been dosed in a 
single-ascending-dose (SAD) clinical study (Study 215HV101), 47 subjects with MS 
(32 BIIB033 and 15 placebo) have been dosed in a multiple-ascending-dose (MAD) clinical 
study (Study 215MS101), 82 subjects with AON (41 BIIB033 and 41 placebo) have been dosed 
in a Phase 2 Study 215ON201, and 418 subjects with MS (treatment groups still blinded) have 
been dosed in the ongoing Phase 2 Study 215MS201. 
Overall, BIIB033 has been well tolerated in clinical studies.  In the completed Study 215HV101 
(SAD), which evaluated the safety, tolerability, and pharmacokinetics (PK) of BIIB033 in 
healthy volunteers, doses ranging from 0.1 to 100 mg/kg BIIB033 were administered to a total of 
54 healthy adult volunteers.  There were no serious adverse events (SAEs) in the SAD study.  
Most adverse events (AEs) considered related to study treatment in the SAD study were mild, 
except for 3 moderate events (2 cases of headache and 1 case of gastroenteritis).  The most 
common AEs with an incidence of ≥5% reported by subjects receiving BIIB033 were headache 
(10 subjects [19%]), upper respiratory tract infection (6 subjects [11%]), nasopharyngitis 
(4 subjects [7%]), and gastroenteritis (3 subjects [6%]).  Overall, the frequency of AEs was 
similar between the BIIB033 and placebo groups. 
In the completed Study 215MS101 (MAD), which evaluated the safety, tolerability, and PK of 
BIIB033 in subjects with RRMS or SPMS, multiple doses ranging from 0.3 to 100 mg/kg 
BIIB033 were administered to a total of 32 subjects.  There were no SAEs in the MAD study.  
The frequency of AEs was similar in BIIB033-treated subjects compared with placebo-treated 
subjects.  The most common AEs with an incidence of ≥5% reported by subjects receiving 
BIIB033 were headache and urinary tract infection (5 subjects [16%] each), upper respiratory 


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tract infection and MS relapse (3 subjects [9%] each), and postlumbar puncture headache 
(2 subjects [6%]).  
The completed Phase 2 Study 215ON201 was designed to assess the efficacy, safety, tolerability, 
and PK of BIIB033 in subjects with their first episode of AON.  In this study, the dose of 
100 mg/kg BIIB033 was well tolerated, and the overall incidence of AEs was the same in the 
placebo and BIIB033 groups (34 subjects [83%] in each group).  The most common AEs with an 
incidence of ≥10% reported by subjects receiving BIIB033 were nasopharyngitis (12 subjects 
[29%]), headache (11 subjects [27%]), fatigue (6 subjects [15%]), nausea (5 subjects [12%]), and 
paresthesia (4 subjects [10%]).  There were 7 of 82 subjects (9%) who experienced SAEs, 
5 subjects (12%) in the BIIB033 treatment group and 2 subjects (5%) in the placebo group.  In 
the BIIB033 treatment group, 3 subjects had SAEs that were considered related to study 
treatment by the Investigator:  2 subjects with hypersensitivity reactions occurring during study 
treatment infusions and 1 subject with asymptomatic increased aspartate aminotransferase, 
increased alanine aminotransferase, and liver disorder.  Two subjects in the BIIB033 treatment 
group experienced SAEs considered not related to study treatment.  These included 1 subject 
with MS relapse and 1 subject with optic neuritis.  All of the SAEs in the BIIB033 treatment 
group were reported as resolved.  No anti-BIIB033 antibodies were seen in Study 215ON201, 
except for 1 subject who tested positive at predose baseline. 
The reported events of hypersensitivity (serious and nonserious) in the clinical studies have 
occurred after the start of either the first or the second study treatment infusion in both Phase 1 
and 2 studies.  In all cases, the infusions were stopped, appropriate treatment was administered, 
and all events resolved. 
The Phase 2 Study, 215MS201, was designed to assess the efficacy, safety, tolerability, and PK 
of BIIB033 in subjects with relapsing forms of MS when used concurrently with Avonex and is 
currently ongoing.  In this study, the most common AEs with an incidence of ≥10% in the 
combined BIIB033 and placebo treatment groups are influenza like illness (175 subjects [42%]), 
MS relapse (123 subjects [29%]), headache (68 subjects [16%]), upper respiratory tract infection 
(51 subjects [12%]), urinary tract infection (46 subjects [11%]), pyrexia (44 subjects [11%]), and 
nasopharyngitis (40 subjects [10%]).  Fifty of 418 subjects enrolled (12%) reported SAEs as of 
07 May 2015.  SAEs that were reported in more than 1 subject included MS relapse (27 subjects 
[6%]), urinary tract infection (3 subjects [<1%]), and hypersensitivity (4 subjects [<1%]).  As 
this study is still ongoing, the treatment codes are blinded, and it is not known if the events 
occurred in subjects treated with BIIB033 or placebo. 
BIIB033 PK following a single dose (IV and SC) up to 100 mg/kg in healthy volunteers and 
2 repeated IV doses up to 100 mg/kg in subjects with MS was characterized in the SAD and 
MAD studies, respectively.  BIIB033 PK appears to be similar between healthy volunteers and 
subjects with MS.  In general, BIIB033 PK was linear with small volume of distribution at steady 
state, minimal target-mediated clearance, and an elimination half-life of approximately 2 to 
3 weeks.  As expected, the CSF/serum concentration ratio for BIIB033 in humans is estimated to 
be approximately 0.1%.  In the Phase 2 Study 215ON201, the preliminary PK results suggest that 


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the predicted BIIB033 pharmacological exposure at 100 mg/kg was achieved in subjects with 
AON, and BIIB033 PK appears to be similar to healthy adults and subjects with MS. 
Please refer to the BIIB033 IB for additional details and results on clinical studies. 
5.6. 
Study Rationale 
A biological effect of BIIB033 was shown in Study 215ON201 in subjects with AON.  In this 
study, subjects received 6 doses of 100 mg/kg BIIB033 or placebo administered via IV infusion 
every 4 weeks up to Week 20, with Follow-Up Visits at Weeks 24 and 32.  Efficacy results 
showed an improvement in mean change in full-field visual evoked potential (FF-VEP) latency 
values of the affected eye from the baseline of the fellow eye at Week 24 in the BIIB033 group 
compared with placebo in the intent-to-treat population (-3.48 [95% confidence interval (CI): 
-10.61, 3.65] msec, analysis of covariance [ANCOVA]).  The treatment effect was more 
pronounced in the per-protocol population (-7.55 [95% CI:  -15.12, 0.01] msec, ANCOVA).  The 
electrophysiologic differences between the treatment and placebo groups, first observed at 
Week 12 during the dosing period, persisted throughout the subsequent monthly dosing visits.   
The change in FF-VEP latency in the affected eye versus the baseline of the unaffected fellow 
eye by mixed model for repeated measures (MMRM) showed a greater treatment effect at 
Week 32 than at Week 24 for both the intent-to-treat (ITT) and per-protocol populations, despite 
subjects completing the dosing period at Week 20.  In the ITT population, an improvement of 
-6.06 msec over placebo was seen in the BIIB033 group at Week 32 by MMRM (p = 0.0711).  A 
significant improvement of -9.13 msec over placebo was seen in the BIIB033 group at Week 32 
in the per-protocol population by MMRM (p = 0.0112).   
Study 215ON201 also showed that all subjects, regardless of assigned treatment, recovered 
clinically to a large extend regardless of treatment assignment or severity of injury to the retina 
or the optic nerve; however, not all subjects demonstrated complete functional recovery upon 
electrophysiologic examination.  The rationale for the discrepancy between clinical recovery and 
electrophysiological improvement is unclear and requires further investigation.   
Given these data, the proposed follow-up study is necessary to assess the long-term 
electrophysiologic and clinical outcomes of this patient population with past randomized 
exposure to remyelinating therapy versus placebo, but also to explore potential mechanism(s) by 
which patients recover from previous AON.  This information will be critical in the ongoing 
clinical development of remyelinating therapies so that they can be optimally evaluated and 
utilized for maximal benefit.   
Please refer to the BIIB033 IB for additional details and results on Study 215ON201. 
5.7. 
Rationale for Dosing Regimen 
No study drug dosing is planned for this follow-up study. 


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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Primary Objective and Endpoint 
The primary objective of the study is to assess FF-VEP latency in subjects who were enrolled in 
Study 215ON201 2 years (+ 4 months) after the last study visit. 
The primary endpoint that is related to this objective is the change in FF-VEP latency of the 
affected eye as compared to the baseline of the fellow eye at 2 years (+ 4 months) after the last 
study visit assessment (Week 32) in Study 215ON201. 
6.2. 
Secondary Objectives and Endpoints 
The secondary objective is to assess clinical progression and severity of CNS demyelinating 
disease in subjects who were enrolled in Study 215ON201 2 years (+ 4 months) after the last 
study visit.  
The endpoints that relate to this objective are as follows: 
 Evaluate incidence of CDMS and time to diagnosis of CDMS. 
 Evaluate severity of CNS demyelinating disease with Expanded Disability Status 
Scale (EDSS) and multiple sclerosis functional composite (MSFC). 
 Evaluate change in disease activity from baseline with brain MRI with and without 
gadolinium (Gd).  MRI analysis will include the following: 
 Number of Gd-enhanced lesions 
 Volume of T2 lesions 


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7. 
STUDY DESIGN 
7.1. 
Study Overview 
This multicenter, follow-up study will determine the long-term electrophysiologic and clinical 
outcomes in subjects previously enrolled in Study 215ON201. 
One group is planned, with eligible subjects (previously enrolled in Study 215ON201) having 
been already administered at least 1 study treatment (BIIB033 100 mg/kg or placebo) by 
IV infusion once every 4 weeks for 20 weeks (a total of 6 doses).  Dosing was completed 2 years 
(+ 4 months) prior to enrollment in this follow-up study.  A maximum of 82 subjects (determined 
from the number of subjects who received at least 1 dose of BIIB033 or placebo in Study 
215ON201) will be included in this study.  There is no formal sample size calculation.  The 
number of subjects eligible for this study is determined by the number of subjects who 
participated in Study 215ON201. 
See Figure 1 for a schematic of the study design. 
7.2. 
Overall Study Duration  
The study period will consist of an approximately 1-day visit (with a +5-day window of the 
1-day visit) that is dependent on the scanner capabilities and equipment availability at each 
clinical site. 
7.2.1. 
Screening 
Subject eligibility for the study will be determined by the date of 2 years (+ 4 months) after the 
last study visit (Week 32) or projected Week 32 visit, if the subject did not complete all visits in 
Study 215ON201.  There is no screening visit in this study. 
7.2.2. 
Treatment 
No study drug dosing is planned for this study. 
7.2.3. 
Visit Schedule 
Each subject will have approximately 1 scheduled study visit (with a +5-day window of the 
1-day visit) that is dependent on the scanner capabilities and equipment availability at each 
clinical site. 
7.3. 
Study Stopping Rules 
Biogen will notify Investigators when the study is to be placed on hold, completed, or 
terminated. 


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


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8. 
SELECTION OF SUBJECTS 
8.1. 
Inclusion Criteria 
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at the time of Day 1 visit or at the timepoint specified in the individual eligibility criterion listed:   
1. Must have participated in Study 215ON201 and received at least 1 dose of BIIB033 or 
placebo, as per protocol, within 2 years (+ 4 months) from Day 1 of this study (2 years 
from Week 32 or projected Week 32 visit, if the subject did not complete all visits in 
Study 215ON201). 
2. 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.   
8.2. 
Exclusion Criteria 
Candidates will be excluded from study entry if any of the following exclusion criteria exist prior 
to enrolment, or at the timepoint specified in the individual criterion listed: 
1. Not previously enrolled in Study 215ON201. 
2. Inability to comply with study requirements. 
3. Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the 
subject unsuitable for enrollment. 
4. Subjects with recent kidney function, such as serum creatinine above upper limit of 
normal range, will not be allowed to receive administration of Gd but will otherwise be 
allowed to participate in the study, including MRI assessments not requiring the use of 
Gd. 
5. Female subjects must have had a recent pregnancy test and must not be breastfeeding 
prior to MRI assessments with Gd. 


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9. 
ENROLLMENT AND REGISTRATION 
9.1. 
Enrollment 
Subjects (or their legally authorized representative [e.g., parent or legal guardian], where 
applicable) must provide informed consent before any study-related tests are performed (see 
Section 15.3).  When a subject signs the informed consent form (ICF), that subject is considered 
to be enrolled 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 enrolment log. 
9.2. 
Registration of Subjects 
Subjects will be registered at 2 years (+ 4 months) after their last study visit (Week 32) or 
projected Week 32 visit, if the subjects did not complete all visits in Study 215ON201, and after 
the Investigator has verified that the subjects are eligible per criteria in Sections 8.1 and 8.2.   
Refer to the Study Reference Guide for details on registration. 
9.3. 
Blinding Procedures 
This is a follow-up study with no investigational product, therefore blinding is not applicable.  
As much as possible, the treatment disclosure for Study 215ON201 should not be shared with 
sites or patients until the end of this study to reduce the risk of bias on the follow on assessments 
based on knowledge of treatment.   
 
 


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10. 
WITHDRAWAL OF SUBJECTS FROM THE STUDY 
10.1. 
Withdrawal of Subjects From Study 
Subjects must be withdrawn from the study for any of the following reasons: 
 The subject withdraws consent.   
 The subject is unwilling or unable to comply with the protocol. 
 At the discretion of the Sponsor or Investigator for medical reasons or for 
noncompliance. 
The reason for the subject’s withdrawal from the study must be recorded in the subject’s case 
report form (CRF). 


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11. 
FOLLOW-UP ASSESSMENTS 
See Section 4 for the timing of all assessments. 
11.1. 
One-Day Visit Assessments 
This study will assess the electrophysiological function of the visual pathway using FF-VEP.  
The various electrophysiologic and imaging measurements will be made to assess feasibility of 
being utilized as potential clinical endpoints sensitive to remyelination therapy in multicenter 
clinical studies (Table 1).  Clinical progression and severity of disease will be assessed by the 
following: 
 Medical history, including date of diagnosis of CDMS 
 MS diagnosis 
 MS signs and symptoms 
 Concomitant therapy and procedures recording 
 Vital signs  
 Physical examination 
 EDSS 
 MSFC 
 
 
 
 
 FF-VEP 
 
 
 
 
 
 
 
 
 
 


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 
 
 
 
 SAEs related to study procedure(s) reporting 


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12. 
SAFETY ASSESSMENTS 
Refer to Section 4 for the timing of all safety assessments. 
12.1. 
Safety Assessments 
The following assessments will be performed to evaluate the safety profile related to study 
procedure(s): 
 Physical examinations 
 Vital sign measurements:  temperature, pulse rate, systolic and diastolic blood 
pressure, and respiratory rate  
 SAEs related to study procedure(s)  
12.2. 
Vital Signs 
The analysis of vital signs will focus on clinically relevant abnormalities.  The definitions of 
these clinically relevant abnormalities are shown in Table 2. 
Table 2: 
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs 
Vital Sign 
Criteria for Abnormalities 
Temperature 
>38°C  
Pulse 
>100 bpm 
<40 bpm  
Systolic Blood Pressure 
>160 mmHg  
<90 mmHg  
Diastolic Blood Pressure 
>100 mmHg  
<45 mmHg  
bpm = beats per minute. 


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13. 
SAFETY DEFINITIONS, CLASSIFICATIONS, RECORDING, 
REPORTING, AND RESPONSIBILITIES 
Throughout the course of the study, every effort must be made to remain alert to possible SAEs 
related to study procedure(s).  If an SAE 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 SAEs and medical emergencies. 
13.1. 
Definition 
13.1.1. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death. 
 In the view of the Investigator, places the subject at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred 
in a more severe form, might have caused death. 
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
 Results in persistent or significant disability/incapacity. 
 Results in a congenital anomaly/birth defect. 
An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above.  (Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or convulsions occurring at home that do not 
require an inpatient hospitalization.) 
13.2. 
Safety Classifications 
13.2.1. 
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 13.1.1. 
 The relationship of the event to the study procedure(s). 


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 The severity of the event as defined in Section 13.2.3. 
13.2.2. 
Relationship of Events to Study Procedure(s) 
The following definitions should be considered when evaluating the relationship of SAEs to the 
study procedure(s). 
Relationship of Event to Study Procedure(s) 
Not related 
An SAE will be considered “not related” to the study procedure(s) if there is not a 
reasonable possibility that the event has been caused by the study procedure(s).  Factors 
pointing toward this assessment include but are not limited to:  the lack of reasonable 
temporal relationship between study procedure(s) and the event, the presence of a 
biologically implausible relationship between the study procedure(s) and the SAE, or the 
presence of a more likely alternative explanation for the SAE. 
Related 
An SAE will be considered “related” to the study procedure(s) if there is a reasonable 
possibility that the event may have been caused by the study procedure(s).  Factors that 
point toward this assessment include but are not limited to:  a positive rechallenge, a 
reasonable temporal sequence between study procedure(s) and the event, a known 
response pattern of the study procedure(s), a biologically plausible relationship between 
the study procedure(s) and the SAE, or a lack of an alternative explanation for the SAE. 
 
13.2.3. 
Severity of Events 
The following definitions should be considered when evaluating the severity SAEs: 
Severity of Event 
Mild 
Symptoms barely noticeable to subject or does not make subject uncomfortable; does not 
influence performance or functioning; prescription drug not ordinarily needed for relief of 
symptoms but may be given because of personality of subject. 
Moderate 
Symptoms of a sufficient severity to make subject uncomfortable; performance of daily 
activity is influenced; subject is able to continue in study; treatment for symptoms may be 
needed. 
Severe 
Symptoms cause severe discomfort; symptoms cause incapacitation or significant impact 
on subject’s daily life; severity may cause cessation of study procedure(s); treatment for 
symptoms may be given and/or subject hospitalized. 
13.3. 
Monitoring and Recording Events 
13.3.1. 
Serious Adverse Events 
Any SAE experienced by a subject post ICF sign-off through end-of-study visit and considered 
by the Investigator to be related to study procedure(s) is to be recorded on an SAE form, 
regardless of the severity of the event.  Information on SAEs related to study procedure(s) must 


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be reported to 
 within 24 hours as described in Section 13.3.2.  
Follow-up information regarding an SAE also must be reported with 24 hours.  
Subjects will be followed for all SAEs until the event has resolved, stabilized, or returned to 
baseline status.   
13.3.2. 
Immediate Reporting of Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify 
 within 24 hours of the study site staff becoming aware 
of the SAE.  It is the Investigator’s responsibility to ensure that the SAE reporting information 
and procedures are used and followed appropriately. 
Reporting Information for SAEs 
Any SAE related to study procedure that occurs between post ICF sign-off through end-of-study 
visit must be reported to 
 within 24 hours of the study site staff 
becoming aware of the event.  
To report initial or follow-up information on an SAE, fax a completed SAE form; refer to the 
Study Reference Guide for complete contact information. 
13.3.2.1. Deaths 
Death is an outcome of an event.  The procedure-related event that resulted in death should be 
recorded on the appropriate CRF and reported as an SAE within 24 hours of the site becoming 
aware of the event.  The Investigator should make every effort to obtain and send death 
certificates and autopsy reports to
.  The term death should be reported 
as an SAE only if the cause of death is not known and cannot be determined. 
13.3.3. 
Suspected Unexpected Serious Adverse Reactions 
Not applicable as no study treatment will be administered. 
13.3.4. 
Medical Emergency 
In a medical emergency requiring immediate attention, study site staff will apply appropriate 
medical intervention, according to current standards of care.  The Investigator (or designee) 
should contact the study’s Medical Director.  Refer to the Study Reference Guide’s Official 
Study Contact List for complete contact information. 
13.4. 
Safety Responsibilities 
13.4.1. 
The Investigator 
The Investigator’s responsibilities include the following: 


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 Monitor and record all SAEs that are deemed to be related to the study procedure(s). 
 Determine the relationship and severity of each event. 
 Determine the onset and resolution dates of each event. 
 Complete an SAE form for each procedure-related SAE and fax it to 
 
 within 24 hours of the study site staff becoming aware of the event. 
 Pursue SAE follow-up information actively and persistently until the event has 
resolved or become stable.  Follow-up information must be reported to 
 
 within 24 hours of the study site staff becoming aware of new 
information. 
 Ensure all SAE reports are supported by documentation in the subjects’ medical 
records. 
 Report SAEs to local ethics committees, as required by local law. 
13.4.2. 
Biogen 
Biogen’s responsibilities include the following: 
 Before study site activation and subject enrollment, the Clinical Monitor is 
responsible for reviewing with study site staff the definition of SAEs, as well as the 
instructions for monitoring, recording, and reporting procedure-related SAEs. 
 Biogen is to notify all appropriate regulatory authorities, central ethics committees, 
and Investigators of procedure-related SAEs, as required by local law, within required 
time frames. 


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14. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
The objectives of the study and the endpoints to be analyzed are listed in Section 6. 
14.1. 
Efficacy 
14.1.1. 
Analysis Population 
Analysis of efficacy endpoints will be based on all enrolled subjects who complete the 1-day 
assessments. 
14.1.2. 
General Methods of Analysis 
Unless stated otherwise, summary statistics will be presented by original treatment groups and 
overall.  For continuous endpoints, the summary statistics will generally include number of 
subjects enrolled, number of subjects evaluated, mean, standard deviation, median, and range.  
For categorical endpoints, the summary statistics will generally include number of subjects 
enrolled, number of subjects evaluated, and the percent of subjects in each category. 
14.1.2.1. Analysis of the Primary Endpoint 
The primary analysis will be on the change in FF-VEP latency of the affected eye as compared to 
the baseline (measured prior to dosing in Study 215201) of the fellow eye at 2 years (+ 4 months) 
after the last study visit assessment (Week 32) in Study 215ON201.  The ANCOVA model will 
be used to test the difference between the 2 original treatment groups from Study 215ON201, 
adjusting for the baseline of the unaffected fellow eye. 
14.1.2.2. Analysis of the Secondary Endpoints 
The secondary endpoints will include the time to diagnosis of CDMS, severity of disease 
evaluated by EDSS and MSFC, and brain MRI results.  Number and percentage of subjects with 
diagnosis of CDMS will be summarized, and descriptive statistics of time to diagnosis of CDMS 
will be presented.  EDSS, MSFC, and brain MRI outcomes will also be summarized using 
descriptive statistics. 


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14.2. 
Safety 
14.2.1. 
Analysis Population 
The safety population is defined as all enrolled subjects who complete the 1-day assessments. 
14.2.2. 
Methods of Analysis 
All SAEs, clinical laboratory abnormalities, vital sign measurements, and physical examination 
findings will be evaluated for safety. 
14.2.2.1. Serious Adverse Events 
SAEs will be coded using the Medical Dictionary for Regulatory Activities.  The incidence of 
clinical SAEs will be summarized by severity and by relationship to study procedure(s).  The 
summary tables will include incidence estimates for overall system organ class as well as for 
preferred terms within each system organ class. 
14.2.2.2. Vital Signs 
The analysis of vital signs will focus on clinically relevant abnormalities.  The definitions of 
these clinically relevant abnormalities are shown in Table 2.  
14.3. 
Interim Analyses 
An interim analysis will be performed when approximately 50% of potentially projected 
available subjects have been enrolled into the study to provide information to assist the 
interpretation and design of ongoing clinical development of CNS remyelinating therapies.  
Statistical analyses listed in Section 14.1 will be performed on primary, secondary, and 
 endpoints at the interim analysis. 
14.4. 
Sample Size Considerations 
The sample size is based on the number of subjects who participated in Study 215ON201 
(approximately 82) rather than statistical considerations.  The subjects eligible for this study 
must have participated in Study 215ON201.   


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15. 
ETHICAL REQUIREMENTS 
Biogen, 
, and the Investigator must comply with all instructions, regulations, and 
agreements in this protocol and applicable International Conference on Harmonisation (ICH) and 
Good Clinical Practice (GCP) guidelines and conduct the study according to local regulations. 
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines.  The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated. 
15.1. 
Declaration of Helsinki 
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki. 
15.2. 
Ethics Committee 
The Investigator must obtain ethics committee approval of the protocol, ICF, and other required 
study documents prior to starting the study.  Biogen will submit documents on behalf of the 
investigational sites in all countries where subjects are enrolled. 
If the Investigator makes any changes to the ICF, Biogen must approve the changes before the 
ICF is submitted to the ethics committee.  A copy of the approved ICF must be provided to 
Biogen.  After approval, the ICF must not be altered without the agreement of the relevant ethics 
committee and Biogen. 
It is the responsibility of the Investigators to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations. 
Biogen must receive a letter documenting ethics committee approval, which specifically 
identifies the protocol, protocol number, and ICF, prior to the initiation of the study.  Protocol 
amendments will be subject to the same requirements as the original protocol. 
A progress report must be submitted to the ethics committee at required intervals and not less 
than annually. 
At the completion or termination of the study, the investigational site must submit a close-out 
letter to the ethics committee and Biogen. 
15.3. 
Subject Information and Consent 
Prior to performing any study-related activities under this protocol, including study-related tests 
and assessments, written informed consent with the approved ICF must be obtained from the 


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subject or subject’s legally authorized representative (e.g., parent or legal guardian), as 
applicable, in accordance with local practice and regulations.   
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the subject must be explained to the subject (or the 
subject’s legally authorized representative).  The subject must be given sufficient time to 
consider whether to participate in the study. 
A copy of the signed and dated ICF must be given to the subject.  The signed and dated ICF will 
be retained with the study records.  Local regulations must be complied with in respect to the 
final disposition of the original (wet signature) and copies of the signed and dated ICFs. 
Confirmation of informed consent must also be documented in the subject’s medical record. 
15.4. 
Subject Data Protection 
Prior to any testing under this protocol, including assessments, candidates must also provide all 
authorizations required by local law (e.g., Protected Health Information authorization in North 
America). 
The subject will not be identified by name in the CRF or in any study reports, and these reports 
will be used for research purposes only.  Biogen, its partners and designees, ethics committees, 
and various government health agencies may inspect the records of this study.  Every effort will 
be made to keep the subject’s personal medical data confidential. 
15.5. 
Compensation for Injury 
Biogen maintains appropriate insurance coverage for clinical studies and will follow applicable 
local compensation laws. 
15.6. 
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. 
15.7. 
Registration of Study and Disclosure of Study Results 
Biogen will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations. 


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42 
 
16. 
ADMINISTRATIVE PROCEDURES 
16.1. 
Study Site Initiation 
The Investigator must not enroll any subjects prior to completion of an on-site or remote study 
initiation visit, conducted by Biogen or designee.  This initiation visit will include a detailed 
review of the protocol and study procedures. 
16.2. 
Quality Assurance 
During and/or after completion of the study, quality assurance officers named by Biogen or the 
regulatory authorities may wish to perform onsite audits or inspections.  The Investigator will be 
expected to cooperate with any audit or inspection and to provide assistance and documentation 
(including source data) as requested. 
16.3. 
Monitoring of the Study 
No site may initiate the 1-day assessments until Biogen or its designee representatives have 
concluded protocol-specific training and approved assessment technitian(s). 
Biogen or its designee representatives may conduct on-site visits at the study facilities for the 
purpose of monitoring various aspects of the study.  The Investigator must agree to 
Sponsor-authorized personnel having direct access to subject (or associated) source files for the 
purpose of verifying entries made in the CRF and assist with their activities, if requested.  
Adequate space and time for monitoring visits should be made available by the Investigator or 
study staff.  The site must complete the CRFs in a timely manner and on an ongoing basis to 
allow regular review by the study team. 
During these visits, CRFs and supporting documentation related to the study will be reviewed 
and any discrepancies or omissions will be resolved.   
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure protocol adherence, quality of data, compliance with regulatory requirements, and 
continued adequacy of the investigational site and its facilities. 
16.4. 
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.  
16.5. 
Publications 
Details are included in the clinical study agreement for this study. 


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43 
 
17. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION 
17.1. 
External Contract Organizations 
Biogen will be responsible for all administrative aspects of this study, including but not limited 
to, study initiation, monitoring, management of SAEs, and data management. 
17.1.1. 
Contract Research Organization  
, a contract research organization (CRO), will be responsible for administrative aspects 
of the study, including but not limited to, study initiation, monitoring, and management of SAE 
reports and data management.  Before subjects are enrolled at each study site, the CRO will 
review study responsibilities with the Investigators and other study site staff, as appropriate. 
17.1.2. 
Electronic Data Capture 
Subject information will be captured and managed by study sites on CRFs via an appropriate 
Web-based electronic remote data capture tool. 
17.1.3. 
Central Facility for Other Assessments 
A central facility has been selected by Biogen to be a central reader for 
, FF-VEP, and 
 for this study.  A separate central facility has been selected by Biogen to read and 
interpret all MRI results for this study. 
17.2. 
Changes to Final Study Protocol 
All protocol amendments must be submitted to the ethics committee and regulatory authorities if 
required by local law.  Protocol modifications that affect subject safety, the scope of the 
investigation, or the scientific quality of the study must be approved by the ethics committee 
before implementation of such modifications to the conduct of the study.  If required by local 
law, such modifications must also be approved by the appropriate regulatory agency prior to 
implementation. 
However, Biogen may, at any time, amend this protocol to eliminate an apparent immediate 
hazard to a subject.  In this case, the appropriate regulatory authorities will be notified 
subsequent to the modification. 
In the event of a protocol modification, the ICF may require similar modifications (see 
Section 15). 


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17.3. 
Ethics Committee Notification of Study Completion or Termination 
Where required, the regulatory authorities and ethics committees must be notified of completion 
or termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines. 
17.4. 
Retention of Study Data 
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local laws or regulations.  Prior to 
proceeding with destruction of records, the Investigator must notify Biogen in writing and 
receive written authorization from Biogen to destroy study records.  In addition, the Investigator 
must notify Biogen of any changes in the archival arrangements including but not limited to 
archival at an offsite facility or transfer of ownership if the Investigator leaves the site. 
17.5. 
Study Report Signatory 
Biogen will designate one of the participating Study Investigators as a signatory for the study 
report.  This determination will be made by several factors, including but not limited to, the 
Investigator's experience and reputation in the studied indication; the Investigator's contribution 
to the study in terms of design, management, and/or subject enrollment; or by other factors 
determined to be relevant by Biogen. 
Biogen will follow all applicable local regulations pertaining to study report signatories. 


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45 
 
18. 
REFERENCES 
Balcer LJ, Galetta SL, Polman CH, et al. Low-contrast acuity measures visual improvement in 
phase 3 trial of natalizumab in relapsing MS. J Neurol Sci. 2012;318(1-2):119-24. 
Barrette B, Vallieres N, Dube M, et al. Expression profile of receptors for myelin-associated 
inhibitors of axonal regeneration in the intact and injured mouse central nervous system. Mol 
Cell Neurosci. 2007;34(4):519-38. 
Beck RW, Cleary PA, Anderson MM, Jr., et al. A randomized, controlled trial of corticosteroids 
in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med. 
1992;326(9):581-8. 
Carim-Todd L, Escarceller M, Estivill X, et al. LRRN6A/LERN1 (leucine-rich repeat neuronal 
protein 1), a novel gene with enriched expression in limbic system and neocortex. Eur J 
Neurosci. 2003;18(12):3167-82. 
Costello F, Coupland S, Hodge W, et al. Quantifying axonal loss after optic neuritis with optical 
coherence tomography. Ann Neurol. 2006;59(6):963-9. 
Duffy CJ. The consequences of optic neuritis: more than meets the eye. Neurology. 
2011a;76(24):2052-3. 
Duffy LM, Chapman AL, Shaw PJ, et al. Review: The role of mitochondria in the pathogenesis 
of amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol. 2011b;37(4):336-52. 
Fu QL, Hu B, Wu W, et al. Blocking LINGO-1 function promotes retinal ganglion cell survival 
following ocular hypertension and optic nerve transection. Invest Ophthalmol Vis Sci. 
2008;49(3):975-85. 
Henderson A, Altmann D, Anand T, et al. Early factors associated with axonal loss after optic 
neuritis. Ann Neurol [Internet]. 2011 Aug:[16 p.]. Available from: 
http://onlinelibrary.wiley.com/doi/10.1002/ana.22554/pdf. 
Inoue H, Lin L, Lee X, et al. Inhibition of the leucine-rich repeat protein LINGO-1 enhances 
survival, structure, and function of dopaminergic neurons in Parkinson's disease models. Proc 
Natl Acad Sci U S A. 2007;104(36):14430-5. 
Ji B, Case LC, Liu K, et al. Assessment of functional recovery and axonal sprouting in 
oligodendrocyte-myelin glycoprotein (OMgp) null mice after spinal cord injury. Mol Cell 
Neurosci. 2008;39(2):258-67. 
Ji B, Li M, Wu WT, et al. LINGO-1 antagonist promotes functional recovery and axonal 
sprouting after spinal cord injury. Mol Cell Neurosci. 2006;33(3):311-20. 
Kupersmith MJ, Gal RL, Beck RW, et al. Visual function at baseline and 1 month in acute optic 
neuritis: predictors of visual outcome. Neurology. 2007;69(6):508-14. 
Lee X, Yang Z, Shao Z, et al. NGF regulates the expression of axonal LINGO-1 to inhibit 
oligodendrocyte differentiation and myelination. J Neurosci. 2007;27(1):220-5. 


Protocol 215ON203 
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Long-Term Assessment of Remyelinating Therapy 
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The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
46 
 
Llorens F, Gil V, Iraola S, et al. Developmental analysis of Lingo-1/Lern1 protein expression in 
the mouse brain: interaction of its intracellular domain with Myt1l. Dev Neurobiol. 
2008;68(4):521-41. 
McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple 
sclerosis: guidelines from the International panel on the diagnosis of multiple sclerosis. Annals 
of Neurology. 2001;50(1):121-127. 
Mi S, Hu B, Hahm K, et al. LINGO-1 antagonist promotes spinal cord remyelination and axonal 
integrity in MOG-induced experimental autoimmune encephalomyelitis. Nat Med. 
2007;13(10):1228-33. 
Mi S, Lee X, Shao Z, et al. LINGO-1 is a component of the Nogo-66 receptor/p75 signaling 
complex. Nat Neurosci. 2004;7(3):221-8. 
Mi S, Miller RH, Lee X, et al. LINGO-1 negatively regulates myelination by oligodendrocytes. 
Nat Neurosci. 2005;8(6):745-51. 
Mi S, Miller RH, Tang W, et al. Promotion of central nervous system remyelination by induced 
differentiation of oligodendrocyte precursor cells. Ann Neurol. 2009;65(3):304-15. 
Mi S, Sandrock A, Miller RH. LINGO-1 and its role in CNS repair. Int J Biochem Cell Biol. 
2008. 
Mowry EM, Loguidice MJ, Daniels AB, et al. Vision related quality of life in multiple sclerosis: 
correlation with new measures of low and high contrast letter acuity. J Neurol Neurosurg 
Psychiatry. 2009;80(7):767-72. 
Park JB, Yiu G, Kaneko S, et al. A TNF receptor family member, TROY, is a coreceptor with 
Nogo receptor in mediating the inhibitory activity of myelin inhibitors. Neuron. 2005;45(3):345-
51. 
Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 
Revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292-302. 
Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: 
guidelines for research protocols. Ann Neurol. 1983;13(3):227-31. 
Raz N, Dotan S, Benoliel T, et al. Sustained motion perception deficit following optic neuritis: 
Behavioral and cortical evidence. Neurology. 2011;76(24):2103-11. 
Runmarker B, Andersen O. Prognostic factors in a multiple sclerosis incidence cohort with 
twenty-five years of follow-up. Brain. 1993;116 ( Pt 1):117-34. 
Shao Z, Browning JL, Lee X, et al. TAJ/TROY, an orphan TNF receptor family member, binds 
Nogo-66 receptor 1 and regulates axonal regeneration. Neuron. 2005;45(3):353-9. 
Submacular Surgery Trials Research Group. Evaluation of minimum clinically meaningful 
changes in scores on the National Eye Institute Visual Function Questionnaire (NEI-VFQ) SST 
Report Number 19. Ophthalmic Epidemiol. 2007;14(4):205-15. 
Talman LS, Bisker ER, Sackel DJ, et al. Longitudinal study of vision and retinal nerve fiber 
layer thickness in multiple sclerosis. Ann Neurol. 2010;67(6):749-60. 


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Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a 
geographically based study. I. Clinical course and disability. Brain. 1989;112:133-146. 
 
 


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19. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL 
I have read the foregoing protocol, “A Multicenter, Follow-Up Study to Assess Long-Term 
Electrophysiologic and Clinical Outcomes in Subjects Previously Enrolled in Study 215ON201,” 
and agree to conduct the study according to the protocol and the applicable ICH guidelines and 
GCP regulations, and to inform all who assist me in the conduct of this study of their 
responsibilities and obligations. 
 
 
 
____________________________________________________ 
Investigator’s Signature 
 
 
 
Date 
 
 
____________________________________________________ 
Investigator’s Name (Print) 
 
 
 
____________________________________________________ 
Study Site (Print) 
 
 


CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
1 
Biogen MA Inc. 
250 Binney Street 
Cambridge, MA 02142 
United States 
PROTOCOL NUMBER: 
215ON203
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead Berkshire 
SL6 4AY 
United Kingdom 
PHASE OF DEVELOPMENT: 
2 
PROTOCOL TITLE:  A Multicenter, Follow-Up Study to Assess Long-Term 
Electrophysiologic and Clinical Outcomes in Subjects Previously Enrolled in Study 
215ON201 
EUDRA CT NO: 
2015-003618-26 
DATE: 
26 August 2015 
Version 1.0 
Final 




Protocol 215ON203 
 
Version 1.0 
Long-Term Assessment of Remyelinating Therapy 
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3 
 
TABLE OF CONTENTS 
1. 
SPONSOR INFORMATION .......................................................................................7 
2. 
LIST OF ABBREVIATIONS.......................................................................................8 
3. 
SYNOPSIS .................................................................................................................10 
4. 
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR STUDY 
215ON203 ...................................................................................................................14 
4.1. 
Study Schematic .........................................................................................................14 
4.2. 
Schedule of Activities .................................................................................................15 
5. 
INTRODUCTION ......................................................................................................17 
5.1. 
Overview of Acute Optic Neuritis ..............................................................................17 
5.2. 
Current Therapies for Acute Optic Neuritis ...............................................................18 
5.3. 
Overview of Multiple Sclerosis ..................................................................................18 
5.4. 
Current Therapies for Multiple Sclerosis ...................................................................19 
5.5. 
Profile of Previous Experience with BIIB033 ............................................................19 
5.5.1. 
Nonclinical Experience ...............................................................................................19 
5.5.2. 
Clinical Experience .....................................................................................................20 
5.6. 
Study Rationale ...........................................................................................................22 
5.7. 
Rationale for Dosing Regimen ...................................................................................22 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................23 
6.1. 
Primary Objective and Endpoint ................................................................................23 
6.2. 
Secondary Objectives and Endpoints .........................................................................23 
 
23 
7. 
STUDY DESIGN .......................................................................................................26 
7.1. 
Study Overview ..........................................................................................................26 
7.2. 
Overall Study Duration ...............................................................................................26 
7.2.1. 
Screening ....................................................................................................................26 
7.2.2. 
Treatment ....................................................................................................................26 
7.2.3. 
Visit Schedule .............................................................................................................26 
7.3. 
Study Stopping Rules .................................................................................................26 
7.4. 
End of Study ...............................................................................................................27 
8. 
SELECTION OF SUBJECTS ....................................................................................28 


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8.1. 
Inclusion Criteria ........................................................................................................28 
8.2. 
Exclusion Criteria .......................................................................................................28 
9. 
ENROLLMENT AND REGISTRATION .................................................................29 
9.1. 
Enrollment ..................................................................................................................29 
9.2. 
Registration of Subjects ..............................................................................................29 
9.3. 
Blinding Procedures ....................................................................................................29 
10. 
WITHDRAWAL OF SUBJECTS FROM THE STUDY ...........................................30 
10.1. 
Withdrawal of Subjects From Study ...........................................................................30 
11. 
FOLLOW-UP ASSESSMENTS ................................................................................31 
11.1. 
One-Day Visit Assessments .......................................................................................31 
12. 
SAFETY ASSESSMENTS ........................................................................................33 
12.1. 
Safety Assessments .....................................................................................................33 
12.2. 
Vital Signs ..................................................................................................................33 
13. 
SAFETY DEFINITIONS, CLASSIFICATIONS, RECORDING, 
REPORTING, AND RESPONSIBILITIES ...............................................................34 
13.1. 
Definition ....................................................................................................................34 
13.1.1. 
Serious Adverse Event ................................................................................................34 
13.2. 
Safety Classifications ..................................................................................................34 
13.2.1. 
Investigator Assessment of Events .............................................................................34 
13.2.2. 
Relationship of Events to Study Procedure(s) ............................................................35 
13.2.3. 
Severity of Events .......................................................................................................35 
13.3. 
Monitoring and Recording Events ..............................................................................35 
13.3.1. 
Serious Adverse Events ..............................................................................................35 
13.3.2. 
Immediate Reporting of Serious Adverse Events .......................................................36 
13.3.2.1. 
Deaths .........................................................................................................................36 
13.3.3. 
Suspected Unexpected Serious Adverse Reactions ....................................................36 
13.3.4. 
Medical Emergency ....................................................................................................36 
13.4. 
Safety Responsibilities ................................................................................................36 
13.4.1. 
The Investigator ..........................................................................................................36 
13.4.2. 
Biogen .........................................................................................................................37 
14. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ...........38 
14.1. 
Efficacy .......................................................................................................................38 


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14.1.1. 
Analysis Population ....................................................................................................38 
14.1.2. 
General Methods of Analysis .....................................................................................38 
14.1.2.1. 
Analysis of the Primary Endpoint...............................................................................38 
14.1.2.2. 
Analysis of the Secondary Endpoints .........................................................................38 
 
38 
14.2. 
Safety ..........................................................................................................................39 
14.2.1. 
Analysis Population ....................................................................................................39 
14.2.2. 
Methods of Analysis ...................................................................................................39 
14.2.2.1. 
Serious Adverse Events ..............................................................................................39 
14.2.2.2. 
Vital Signs ..................................................................................................................39 
14.3. 
Interim Analyses .........................................................................................................39 
14.4. 
Sample Size Considerations .......................................................................................39 
15. 
ETHICAL REQUIREMENTS ...................................................................................40 
15.1. 
Declaration of Helsinki ...............................................................................................40 
15.2. 
Ethics Committee ........................................................................................................40 
15.3. 
Subject Information and Consent ...............................................................................40 
15.4. 
Subject Data Protection ..............................................................................................41 
15.5. 
Compensation for Injury .............................................................................................41 
15.6. 
Conflict of Interest ......................................................................................................41 
15.7. 
Registration of Study and Disclosure of Study Results ..............................................41 
16. 
ADMINISTRATIVE PROCEDURES .......................................................................42 
16.1. 
Study Site Initiation ....................................................................................................42 
16.2. 
Quality Assurance .......................................................................................................42 
16.3. 
Monitoring of the Study..............................................................................................42 
16.4. 
Study Funding .............................................................................................................42 
16.5. 
Publications .................................................................................................................42 
17. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION ........................43 
17.1. 
External Contract Organizations .................................................................................43 
17.1.1. 
Contract Research Organization .................................................................................43 
17.1.2. 
Electronic Data Capture ..............................................................................................43 
17.1.3. 
Central Facility for Other Assessments ......................................................................43 


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17.2. 
Changes to Final Study Protocol ................................................................................43 
17.3. 
Ethics Committee Notification of Study Completion or Termination ........................44 
17.4. 
Retention of Study Data ..............................................................................................44 
17.5. 
Study Report Signatory...............................................................................................44 
18. 
REFERENCES ...........................................................................................................45 
19. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL .........................................48 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities .................................................................................................15 
Table 2: 
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs ...................33 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................14 
 
 


Protocol 215ON203 
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1. 
SPONSOR INFORMATION 
Biogen MA Inc. 
250 Binney Street 
Cambridge, MA 02142 
United States 
 
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead, Berkshire  
SL6 4AY 
United Kingdom 
 
 
For urgent medical issues in which the study’s Medical Director should be contacted, please 
refer to the Study Reference Manual for the full contact information of the Medical Monitor.  
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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2. 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ANCOVA 
analysis of covariance 
AON 
acute optic neuritis 
CDMS 
clinically definite multiple sclerosis 
CI 
confidence interval 
CIS 
clinically isolated syndrome 
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
 
 
EDSS 
Expanded Disability Status Scale 
FITC-BIIB033 
fluorescein isothiocyanate-conjugated BIIB033 
FF-VEP 
full-field visual evoked potential 
 
 
GCP 
Good Clinical Practice 
Gd 
gadolinium 
IB 
Investigator’s Brochure 
IP 
Investigational product 
HCVA 
high-contrast visual acuity 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IFN-β 
interferon-beta 
IgG1 
immunoglobulin G1 
ITT 
intent-to-treat 
IV 
intravenous 
LCLA 
low-contrast letter acuity 
MAD 
multiple-ascending dose  
MFD 
maximum feasible dose 
 
 
MMRM 
mixed model for repeated measures 
MRI 
magnetic resonance imaging 
MS 
multiple sclerosis 
MSFC 
multiple sclerosis functional composite 
 
  
 
 
 
 
NEI-VFQ-25 
25-item National Eye Institute Visual Function Questionnaire 
 
 
PK 
pharmacokinetic(s) 


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RGCL 
retinal ganglion cell layer 
RNFL 
retinal nerve fiber layer 
 
 
RRMS 
relapsing-remitting multiple sclerosis 
SAD 
single-ascending dose  
SAE 
serious adverse event 
SC 
subcutaneous 
 
 
SPMS 
secondary progressive multiple sclerosis 


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3. 
SYNOPSIS 
Protocol Number: 
215ON203 
Protocol Title: 
A Multicenter, Follow-Up Study to Assess Long-Term 
Electrophysiologic and Clinical Outcomes in Subjects 
Previously Enrolled in Study 215ON201 
Version Number: 
1.0 
Study Indication: 
Acute optic neuritis (AON) 
Study Rationale: 
BIIB033 (human anti-LINGO-1 monoclonal antibody) is an 
investigational product with the potential of enhancing 
remyelination and neuroaxonal protection. 
In Study 215ON201, treatment of patients with AON with 
BIIB033 displayed evidence of functional remyelination in 
the affected eye by demonstrating significant improvement 
in visual evoked potential latency over treatment with 
placebo.  The electrophysiologic differences between the 
treatment and placebo groups were first observed at 
Week 12 during the dosing period and persisted throughout 
the subsequent monthly dosing visits.  More interestingly, 
this trend continued for an additional 3 months through the 
Follow-Up Visit at Week 32 despite subjects completing the 
dosing period at Week 20.  
Study 215ON201 also showed that all subjects, regardless of 
assigned treatment, recovered clinically to a large extent 
regardless of treatment assignment or severity of injury to 
the retina or the optic nerve; however, not all subjects 
demonstrated complete functional recovery upon 
electrophysiologic examination.  The rationale for the 
discrepancy between clinical recovery and 
electrophysiological improvement is unclear and requires 
further investigation.   
Given these data, the proposed follow-up study is necessary 
to assess the long-term electrophysiologic and clinical 
outcomes of this patient population with past randomized 
exposure to remyelinating therapy versus placebo and also 
to explore potential mechanism(s) by which patients recover 


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from previous AON.  This information will be critical in 
ongoing clinical development of remyelinating therapies so 
that they can be optimally evaluated and utilized for 
maximal benefit.   
Phase of Development: 
2 
Study Objectives and 
Endpoints: 
The primary objective of this study is to assess full-field 
visual evoked potential (FF-VEP) latency in subjects who 
were enrolled in Study 215ON201 2 years (+ 4 months) 
after the last study visit. 
The primary endpoint that is related to this objective is the 
change in FF-VEP latency of the affected eye as compared 
to the baseline of the fellow eye at 2 years (+ 4 months) 
after the last study visit assessment (Week 32) in 
Study 215ON201. 
The secondary objective is to assess clinical progression and 
severity of central nervous system (CNS) demyelinating 
disease in subjects who were enrolled in Study 215ON201 
2 years (+ 4 months) after the last study visit. 
The endpoints that relate to this objective are as follows: 
 Evaluate incidence of clinically definite multiple 
sclerosis (CDMS) and time to diagnosis of 
CDMS. 
 Evaluate severity of CNS demyelinating disease 
with Expanded Disability Status Scale (EDSS) 
and multiple sclerosis functional composite 
(MSFC). 
 Evaluate change in disease activity from baseline 
with brain magnetic resonance imaging (MRI) 
with and without gadolinium (Gd).  MRI analysis 
will include the following: 
 Number of Gd-enhanced lesions 
 Volume of T2 lesions 
 
 


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Study Design: 
This is a multicenter, follow-up study to determine the 
long-term electrophysiologic and clinical outcomes in 
subjects previously enrolled in Study 215ON201. 
One group is planned, with eligible subjects (previously 
enrolled in Study 215ON201) having been already 
administered at least 1 study treatment (BIIB033 100 mg/kg 
or placebo) by intravenous infusion once every 4 weeks for 
20 weeks (a total of 6 doses).  Dosing was completed 
2 years (+ 4 months) prior to enrollment in this follow-up 
study.  No additional drug or placebo will be administered. 
Study Location: 
Approximately 33 sites globally are planned. 
Number of Planned Subjects: 
A maximum of 82 subjects will be eligible for enrollment 
(determined from the number of subjects who received at 
least 1 dose of BIIB033 100 mg/kg or placebo in 
Study 215ON201). 
Study Population: 
This study will be conducted in subjects who have 
participated in and received at least 1 dose of BIIB033 or 
placebo in Study 215ON201.   
Detailed criteria are described in Section 8. 
Duration of Follow-up: 
Eligible subjects will be enrolled at 2 years after their last 
study visit (Week 32) or projected Week 32 (+ 4 months) 
visit if the subject did not complete all visits in 
Study 215ON201.  Subjects will perform 1 set of follow-up 
assessments at this timepoint. 
Evaluations: 
 
Safety: 
Assessments evaluating the safety profile related to study 
procedure(s) will include physical examinations, vital sign 
measurements, and serious adverse events (SAEs). 
Any SAE experienced by a subject post informed consent 
form sign-off through end-of-study visit and considered by 
the Investigator to be related to study procedure(s) is to be 
recorded on an SAE form, regardless of the severity of the 
event.  Information on SAEs related to study procedure(s) 
must be reported to 
 within 
24 hours. 


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Subjects will be followed for all SAEs until the event has 
resolved, stabilized, or returned to baseline status.   
Statistical Analysis Methods: 
The primary analysis will be on the change in FF-VEP 
latency of the affected eye as compared to the baseline 
(measured prior to dosing in Study 215201) of the fellow 
eye at 2 years (+ 4 months) after the last study visit 
assessment (Week 32) in Study 215ON201.  The ANCOVA 
model will be used to test the difference between the 
2 original treatment groups from Study 215ON201, 
adjusting for the baseline of the unaffected fellow eye. 
The secondary endpoints will include the time to diagnosis 
of CDMS, severity of disease evaluated by EDSS and 
MSFC, and brain MRI results.  Number and percentage of 
subjects with diagnosis of CDMS will be summarized, and 
descriptive statistics of time to diagnosis of CDMS will be 
presented.  EDSS, MSFC, and brain MRI outcomes will also 
be summarized using descriptive statistics. 
 
  
Interim Analysis: 
An interim analysis will be performed when approximately 
50% of potentially projected available subjects have been 
enrolled into the study to provide information to assist the 
interpretation and design of ongoing clinical development of 
CNS remyelinating therapies.   


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4. 
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR 
STUDY 215ON203 
4.1. 
Study Schematic 
Figure 1: 
Study Design 
 
IP = investigational product; MRI= magnetic resonance imaging. 
Note:  All assessments should be performed on the same day where possible or within a + 5 day window of the 
1-day visit. 


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4.2. 
Schedule of Activities 
Table 1: 
Schedule of Activities 
Tests and Assessments1 
Day 1:  
(2 Years + 4 Months After Week 32 Visit in Study 215ON201 or Projected Week 32 
Visit if the Subject Did Not Complete All Visits) 
Informed Consent 
X 
Eligibility Criteria Check 
X 
Medical History2 
X 
Multiple Sclerosis Diagnosis 
X 
Multiple Sclerosis Signs and Symptoms  
X 
Concomitant Therapy and Procedures Recording 
X 
Vital Signs3 
X 
Physical Examination 
X 
Expanded Disability Status Scale4 
X 
Multiple Sclerosis Functional Composite 
X 
Full-Field Visual Evoked Potential6 
X 


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Tests and Assessments1 
Day 1:  
(2 Years + 4 Months After Week 32 Visit in Study 215ON201 or Projected Week 32 
Visit if the Subject Did Not Complete All Visits) 
Serious Adverse Events Related to Study Procedure(s) Reporting11 
X 
; MRI = magnetic resonance imaging. 
1 All assessments should be performed on the same day and in the order listed, when possible (or within a + 5 day window of the 1-day visit). 
2 Medical history will be taken from after last study visit in Study 215ON201. 
3 Vital signs include temperature, systolic and diastolic blood pressure, pulse rate, and respiratory rate (after sitting down for at least 5 minutes). 
4 Expanded Disability Status Scale should be performed by a study certified rater.  Where applicable, refer to study manual for instructions. 
 
 
 
 
6 Sites and technicians must be qualified and approved by the central reader to perform 
, full-field visual evoked 
potential, and 
. 
 
 
 
 
 
 
  
11 Serious adverse events monitoring for events related to study procedure(s) will be reported post informed consent form sign-off through end-of-study visit.  
 
 


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5. 
INTRODUCTION  
BIIB033, a first-in-class human monoclonal antibody directed against LINGO-1, is a negative 
regulator of myelination and axonal growth.  Antagonizing LINGO-1 with BIIB033 has the 
potential to enhance remyelination and neuroaxonal protection in the central nervous system 
(CNS).  
LINGO-1 is a cell surface glycoprotein that is selectively expressed in the adult CNS in neurons 
and oligodendrocytes [Barrette 2007; Carim-Todd 2003; Llorens 2008; Mi 2004; Park 2005; 
Shao 2005].  It functions as a negative regulator of oligodendrocyte differentiation, myelination, 
and remyelination [Lee 2007; Mi 2005; Mi 2009; Mi 2008].  Axonal and neuronal expression of 
LINGO-1 increases after injury [Ji 2006; Mi 2004].  LINGO-1 expression prevents myelination 
of axons by oligodendrocytes.  
Several nonclinical studies have demonstrated the potential for LINGO-1 antagonism to enhance 
CNS remyelination and neuroaxonal protection in animal models of toxic (cuprizone plus 
rapamycin) [Mi 2009], chemical (lysophosphatidylcholine), and inflammatory (myelin 
oligodendrocyte glycoprotein-experimental autoimmune encephalomyelitis) [Mi 2007] 
demyelination and of toxic (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neuronal [Inoue 
2007] and traumatic/hypertensive optic nerve [Fu 2008] and spinal cord [Ji 2008; Ji 2006] injury.  
The leading hypothesis for this clinical development program is that antagonism of LINGO-1 
with BIIB033 will enhance remyelination and neuroaxonal protection in CNS demyelinating 
diseases such as multiple sclerosis (MS) and acute optic neuritis (AON), leading to CNS 
improvement with corresponding beneficial effects on neurological function and disability.  
Additional details may be found in the BIIB033 Investigator’s Brochure (IB).  
5.1. 
Overview of Acute Optic Neuritis  
The anterior visual pathway, particularly the optic nerve and its retinal nerve fiber layer (RNFL) 
and retinal ganglion cell layer (RGCL), is affected by AON and is a potential target for 
therapeutic compounds with properties to enhance remyelination and neuroaxonal protection.  In 
a study of the long-term effects of AON in the context of MS, the RNFL was decreased to an 
average of 83 microns [Costello 2006; Talman 2010].  This corresponds to an average loss of 
~20 microns or 20% of nerve fibers relative to unaffected eyes in patients with AON or to a loss 
of ~13 microns relative to eyes in patients with MS without history or presence of AON [Talman 
2010].  Costello et al [Costello 2006] found that 74% of patients had 20% or greater thinning of 
the RNFL following AON.  As also noted by Henderson et al [Henderson 2011 Aug], this RNFL 
thinning begins early (between 1 and 2 months after onset of AON), and nearly all of the 
eventual RNFL loss is complete by 6 months.  This loss of RNFL is associated with a clinically 
important loss of visual function, as shown by a decrease of low-contrast letter acuity (LCLA) to 
an average of 21 letters out of 60 or a loss of 14 letters relative to unaffected MS eyes.  There is 
also a permanent loss of visual motion perception in most patients affected by AON [Raz 2011].  


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Motion processing impairments in AON may be highly disruptive to the ability of patients to 
ambulate, drive, and navigate [Duffy 2011a; Duffy 2011b].  The permanent loss of visual 
function in AON is clinically important as reflected by a vision-related quality of life score of 84 
on the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25), which is 8 
points lower than in unaffected patients [Balcer 2012].  This 8-point loss on the NEI-VFQ-25 is 
higher than the currently accepted 4-point threshold for clinically important changes in vision-
related quality of life [Mowry 2009; Submacular Surgery Trials Research Group 2007].  
5.2. 
Current Therapies for Acute Optic Neuritis  
The only currently available treatment for AON is high-dose intravenous (IV) steroids (e.g., 
methylprednisolone) followed by an oral prednisone taper, which speeds up the recovery of 
symptoms (e.g., ocular pain) and high-contrast visual acuity (HCVA) primarily in the first 
2 weeks after an attack, but has no long-term beneficial effects on the ultimate recovery of visual 
function [Beck 1992] nor is there evidence that it affects the degree of axonal loss or conduction 
velocity in the optic nerve pathway.  
Despite treatment with high-dose steroids, over 60% of patients with AON are left with loss of 
visual function [Kupersmith 2007]. 
5.3. 
Overview of Multiple Sclerosis  
MS is a chronic disabling neurological disease that affects an estimated 1 million people in North 
America and Western Europe.  It is a disease of young adults, primarily women, with disease 
onset typically occurring between the ages of 20 and 40 years [Weinshenker 1989].  It is the 
most frequent cause of nontraumatic neurological disability affecting young adults in the 
Western world.  Although the etiology is uncertain, evidence suggests that MS is, in part, an 
autoimmune disease directed against protein components of myelin.  The diagnosis of clinically 
definite multiple sclerosis (CDMS) has traditionally been made on the basis of clinical criteria 
and requires that a patient experience at least 2 neurologic events consistent with demyelination, 
separated both in time and in location in the CNS [Poser 1983].  More recent diagnostic criteria 
have allowed for less than 2 neurologic attacks, when there is supportive laboratory evidence 
based on magnetic resonance imaging (MRI) or cerebrospinal fluid (CSF) results [McDonald 
2001].  The majority of patients with MS start out with a clinical course characterized by 
episodes or attacks (relapses) of neurologic dysfunction, which occur over many years.  This 
phase of the disease is called relapsing-remitting multiple sclerosis (RRMS).  Symptoms of such 
relapses include loss of vision or double vision, numbness or tingling sensation in the 
extremities, muscle weakness, slurred speech, difficulty with coordination, and bladder 
dysfunction.  Patients having the first clinical attack are referred to as clinically isolated 
syndrome (CIS).  The most common CIS types are AON, transverse myelitis, and brainstem 
attack.  Patients with CIS with characteristic brain MRI lesions are considered to be having MS 
by the most recent diagnostic McDonald criteria [Polman 2011].  Patients with CIS without brain 
lesions are at low risk of developing MS.  Early in the course of relapsing MS, the signs and 
symptoms tend to subside completely after each attack.  Over time, there tends to be incomplete 
recovery from such attacks.  The majority of patients with relapsing MS accumulate some 


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disability, and about half are unable to walk without assistance within 15 years of their initial 
diagnosis [Runmarker and Andersen 1993; Weinshenker 1989].  The majority of patients with 
RRMS eventually enter the secondary progressive phase of the disease (secondary progressive 
multiple sclerosis [SPMS]), characterized by steady worsening of disability independently of 
relapses.  About 15% of the patients go into this progressive phase without prior development of 
a relapsing-remitting phase and are referred to as having a primary progressive MS. 
5.4. 
Current Therapies for Multiple Sclerosis 
Available therapies for the treatment of relapsing MS target the immunomodulation of 
inflammatory activity and include interferon-beta (IFN-β)1a, pegylated IFN-β1a, IFN-β1b, 
natalizumab, mitoxantrone, glatiramer acetate, teriflunomide, dimethyl fumarate, alemtuzumab, 
and fingolimod.  There is also 1 available symptomatic MS therapy to improve walking, 
prolonged-release fampridine, known as dalfampridine extended release in the United States.  
5.5. 
Profile of Previous Experience with BIIB033 
5.5.1. 
Nonclinical Experience 
BIIB033 is a fully human aglycosylated immunoglobulin G1 (IgG1) monoclonal antibody that 
binds LINGO-1 with high affinity.  As LINGO-1 is a cell surface glycoprotein selectively 
expressed in CNS oligodendrocytes and neurons that prevents myelination of axons by 
oligodendrocytes, a blockade of LINGO-1 may enhance remyelination and repair in CNS 
demyelinated lesions.   
BIIB033 binds LINGO-1 with high affinity in humans, monkeys, rats, and mice; has high 
specificity for LINGO-1 and does not cross react with other LINGO family members; enhances 
differentiation of primary rat, monkey, and human oligodendrocytes in vitro; enhances axonal 
myelination in an in vitro rat dorsal root ganglion/oligodendrocyte precursor cell co-culture 
bioassay; has reduced Fcγ and complement effector functions compared to wild-type IgG1; and 
is efficacious in animal models using biochemical and functional readouts.  These data suggest 
that BIIB033 will be an effective therapy to enhance remyelination in patients with MS.   
An assessment of BIIB033 toxicology has been carried out in repeated-dose studies in rats and 
cynomolgus monkeys, as these species are considered pharmacologically relevant based on 
sequence homology with LINGO-1 and/or similarity in binding and in vitro functional activity 
with LINGO 1.  Toxicology studies of up to 6 months in duration did not identify any adverse 
treatment-related effects or any effect on neurobehavioral assessments with weekly IV 
administrations of BIIB033 at up to an maximum feasible dose (MFD) of 316 mg/kg or 
3-time-per week subcutaneous (SC) doses at up to 32 mg/kg.  Effects on the CNS and respiratory 
system were transient, and none were considered adverse responses to BIIB033.  In embryo-fetal 
toxicology studies in rats and rabbits, BIIB033 was shown to be not causing fetal abnormalities 
at maternal doses up to 316 mg/kg.  Maternal toxicity and morbidity were noted in 1 rabbit given 
316 mg/kg, but the relationship to BIIB033 treatment was unclear; no maternal toxicity was 
observed in rats at any dose.  


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Immunohistochemical analyses have identified target and nontarget antigen-specific 
cross-reactivity by fluorescein isothiocyanate-conjugated BIIB033 (FITC-BIIB033)-specific 
staining in a range of human, cynomolgus monkey, and rat tissues, including those of neural, 
epithelial, neuroendocrine, and connective tissue origins.  Consistent BIIB033-specific 
immunostaining using 2 concentrations of FITC-BIIB033 was observed in the brain (primarily, 
the cerebral cortex) and spinal cord across all 3 species, and the pattern of FITC-BIIB033-
specific staining was consistent with that of LINGO-1 protein localization, as previously 
observed in rodents.  Additional non-neural tissues with inconsistent binding patterns across 
species were evaluated within the repeated-dose toxicology studies and were not identified as 
target organs of toxicity associated with BIIB033 administration up to an MFD dose over 
6 months of treatment.  The exposure-based safety margin for the highest dose planned for 
chronic dosing in the clinic (100 mg/kg/month) is projected to be 4- to 6-fold lower relative to 
exposures at the no-observed-adverse-effect level in toxicology species after 6 months of dosing.   
Together, these data support ongoing evaluations of BIIB033 in Phase 2 studies.   
See the IB for detailed information on nonclinical studies. 
5.5.2. 
Clinical Experience 
As of 07 May 2015, 72 healthy volunteers (54 BIIB033 and 18 placebo) have been dosed in a 
single-ascending-dose (SAD) clinical study (Study 215HV101), 47 subjects with MS 
(32 BIIB033 and 15 placebo) have been dosed in a multiple-ascending-dose (MAD) clinical 
study (Study 215MS101), 82 subjects with AON (41 BIIB033 and 41 placebo) have been dosed 
in a Phase 2 Study 215ON201, and 418 subjects with MS (treatment groups still blinded) have 
been dosed in the ongoing Phase 2 Study 215MS201. 
Overall, BIIB033 has been well tolerated in clinical studies.  In the completed Study 215HV101 
(SAD), which evaluated the safety, tolerability, and pharmacokinetics (PK) of BIIB033 in 
healthy volunteers, doses ranging from 0.1 to 100 mg/kg BIIB033 were administered to a total of 
54 healthy adult volunteers.  There were no serious adverse events (SAEs) in the SAD study.  
Most adverse events (AEs) considered related to study treatment in the SAD study were mild, 
except for 3 moderate events (2 cases of headache and 1 case of gastroenteritis).  The most 
common AEs with an incidence of ≥5% reported by subjects receiving BIIB033 were headache 
(10 subjects [19%]), upper respiratory tract infection (6 subjects [11%]), nasopharyngitis 
(4 subjects [7%]), and gastroenteritis (3 subjects [6%]).  Overall, the frequency of AEs was 
similar between the BIIB033 and placebo groups. 
In the completed Study 215MS101 (MAD), which evaluated the safety, tolerability, and PK of 
BIIB033 in subjects with RRMS or SPMS, multiple doses ranging from 0.3 to 100 mg/kg 
BIIB033 were administered to a total of 32 subjects.  There were no SAEs in the MAD study.  
The frequency of AEs was similar in BIIB033-treated subjects compared with placebo-treated 
subjects.  The most common AEs with an incidence of ≥5% reported by subjects receiving 
BIIB033 were headache and urinary tract infection (5 subjects [16%] each), upper respiratory 


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tract infection and MS relapse (3 subjects [9%] each), and postlumbar puncture headache 
(2 subjects [6%]).  
The completed Phase 2 Study 215ON201 was designed to assess the efficacy, safety, tolerability, 
and PK of BIIB033 in subjects with their first episode of AON.  In this study, the dose of 
100 mg/kg BIIB033 was well tolerated, and the overall incidence of AEs was the same in the 
placebo and BIIB033 groups (34 subjects [83%] in each group).  The most common AEs with an 
incidence of ≥10% reported by subjects receiving BIIB033 were nasopharyngitis (12 subjects 
[29%]), headache (11 subjects [27%]), fatigue (6 subjects [15%]), nausea (5 subjects [12%]), and 
paresthesia (4 subjects [10%]).  There were 7 of 82 subjects (9%) who experienced SAEs, 
5 subjects (12%) in the BIIB033 treatment group and 2 subjects (5%) in the placebo group.  In 
the BIIB033 treatment group, 3 subjects had SAEs that were considered related to study 
treatment by the Investigator:  2 subjects with hypersensitivity reactions occurring during study 
treatment infusions and 1 subject with asymptomatic increased aspartate aminotransferase, 
increased alanine aminotransferase, and liver disorder.  Two subjects in the BIIB033 treatment 
group experienced SAEs considered not related to study treatment.  These included 1 subject 
with MS relapse and 1 subject with optic neuritis.  All of the SAEs in the BIIB033 treatment 
group were reported as resolved.  No anti-BIIB033 antibodies were seen in Study 215ON201, 
except for 1 subject who tested positive at predose baseline. 
The reported events of hypersensitivity (serious and nonserious) in the clinical studies have 
occurred after the start of either the first or the second study treatment infusion in both Phase 1 
and 2 studies.  In all cases, the infusions were stopped, appropriate treatment was administered, 
and all events resolved. 
The Phase 2 Study, 215MS201, was designed to assess the efficacy, safety, tolerability, and PK 
of BIIB033 in subjects with relapsing forms of MS when used concurrently with Avonex and is 
currently ongoing.  In this study, the most common AEs with an incidence of ≥10% in the 
combined BIIB033 and placebo treatment groups are influenza like illness (175 subjects [42%]), 
MS relapse (123 subjects [29%]), headache (68 subjects [16%]), upper respiratory tract infection 
(51 subjects [12%]), urinary tract infection (46 subjects [11%]), pyrexia (44 subjects [11%]), and 
nasopharyngitis (40 subjects [10%]).  Fifty of 418 subjects enrolled (12%) reported SAEs as of 
07 May 2015.  SAEs that were reported in more than 1 subject included MS relapse (27 subjects 
[6%]), urinary tract infection (3 subjects [<1%]), and hypersensitivity (4 subjects [<1%]).  As 
this study is still ongoing, the treatment codes are blinded, and it is not known if the events 
occurred in subjects treated with BIIB033 or placebo. 
BIIB033 PK following a single dose (IV and SC) up to 100 mg/kg in healthy volunteers and 
2 repeated IV doses up to 100 mg/kg in subjects with MS was characterized in the SAD and 
MAD studies, respectively.  BIIB033 PK appears to be similar between healthy volunteers and 
subjects with MS.  In general, BIIB033 PK was linear with small volume of distribution at steady 
state, minimal target-mediated clearance, and an elimination half-life of approximately 2 to 
3 weeks.  As expected, the CSF/serum concentration ratio for BIIB033 in humans is estimated to 
be approximately 0.1%.  In the Phase 2 Study 215ON201, the preliminary PK results suggest that 


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the predicted BIIB033 pharmacological exposure at 100 mg/kg was achieved in subjects with 
AON, and BIIB033 PK appears to be similar to healthy adults and subjects with MS. 
Please refer to the BIIB033 IB for additional details and results on clinical studies. 
5.6. 
Study Rationale 
A biological effect of BIIB033 was shown in Study 215ON201 in subjects with AON.  In this 
study, subjects received 6 doses of 100 mg/kg BIIB033 or placebo administered via IV infusion 
every 4 weeks up to Week 20, with Follow-Up Visits at Weeks 24 and 32.  Efficacy results 
showed an improvement in mean change in full-field visual evoked potential (FF-VEP) latency 
values of the affected eye from the baseline of the fellow eye at Week 24 in the BIIB033 group 
compared with placebo in the intent-to-treat population (-3.48 [95% confidence interval (CI): 
-10.61, 3.65] msec, analysis of covariance [ANCOVA]).  The treatment effect was more 
pronounced in the per-protocol population (-7.55 [95% CI:  -15.12, 0.01] msec, ANCOVA).  The 
electrophysiologic differences between the treatment and placebo groups, first observed at 
Week 12 during the dosing period, persisted throughout the subsequent monthly dosing visits.   
The change in FF-VEP latency in the affected eye versus the baseline of the unaffected fellow 
eye by mixed model for repeated measures (MMRM) showed a greater treatment effect at 
Week 32 than at Week 24 for both the intent-to-treat (ITT) and per-protocol populations, despite 
subjects completing the dosing period at Week 20.  In the ITT population, an improvement of 
-6.06 msec over placebo was seen in the BIIB033 group at Week 32 by MMRM (p = 0.0711).  A 
significant improvement of -9.13 msec over placebo was seen in the BIIB033 group at Week 32 
in the per-protocol population by MMRM (p = 0.0112).   
Study 215ON201 also showed that all subjects, regardless of assigned treatment, recovered 
clinically to a large extend regardless of treatment assignment or severity of injury to the retina 
or the optic nerve; however, not all subjects demonstrated complete functional recovery upon 
electrophysiologic examination.  The rationale for the discrepancy between clinical recovery and 
electrophysiological improvement is unclear and requires further investigation.   
Given these data, the proposed follow-up study is necessary to assess the long-term 
electrophysiologic and clinical outcomes of this patient population with past randomized 
exposure to remyelinating therapy versus placebo, but also to explore potential mechanism(s) by 
which patients recover from previous AON.  This information will be critical in the ongoing 
clinical development of remyelinating therapies so that they can be optimally evaluated and 
utilized for maximal benefit.   
Please refer to the BIIB033 IB for additional details and results on Study 215ON201. 
5.7. 
Rationale for Dosing Regimen 
No study drug dosing is planned for this follow-up study. 


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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Primary Objective and Endpoint 
The primary objective of the study is to assess FF-VEP latency in subjects who were enrolled in 
Study 215ON201 2 years (+ 4 months) after the last study visit. 
The primary endpoint that is related to this objective is the change in FF-VEP latency of the 
affected eye as compared to the baseline of the fellow eye at 2 years (+ 4 months) after the last 
study visit assessment (Week 32) in Study 215ON201. 
6.2. 
Secondary Objectives and Endpoints 
The secondary objective is to assess clinical progression and severity of CNS demyelinating 
disease in subjects who were enrolled in Study 215ON201 2 years (+ 4 months) after the last 
study visit.  
The endpoints that relate to this objective are as follows: 
 Evaluate incidence of CDMS and time to diagnosis of CDMS. 
 Evaluate severity of CNS demyelinating disease with Expanded Disability Status 
Scale (EDSS) and multiple sclerosis functional composite (MSFC). 
 Evaluate change in disease activity from baseline with brain MRI with and without 
gadolinium (Gd).  MRI analysis will include the following: 
 Number of Gd-enhanced lesions 
 Volume of T2 lesions 


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7. 
STUDY DESIGN 
7.1. 
Study Overview 
This multicenter, follow-up study will determine the long-term electrophysiologic and clinical 
outcomes in subjects previously enrolled in Study 215ON201. 
One group is planned, with eligible subjects (previously enrolled in Study 215ON201) having 
been already administered at least 1 study treatment (BIIB033 100 mg/kg or placebo) by 
IV infusion once every 4 weeks for 20 weeks (a total of 6 doses).  Dosing was completed 2 years 
(+ 4 months) prior to enrollment in this follow-up study.  A maximum of 82 subjects (determined 
from the number of subjects who received at least 1 dose of BIIB033 or placebo in Study 
215ON201) will be included in this study.  There is no formal sample size calculation.  The 
number of subjects eligible for this study is determined by the number of subjects who 
participated in Study 215ON201. 
See Figure 1 for a schematic of the study design. 
7.2. 
Overall Study Duration  
The study period will consist of an approximately 1-day visit (with a +5-day window of the 
1-day visit) that is dependent on the scanner capabilities and equipment availability at each 
clinical site. 
7.2.1. 
Screening 
Subject eligibility for the study will be determined by the date of 2 years (+ 4 months) after the 
last study visit (Week 32) or projected Week 32 visit, if the subject did not complete all visits in 
Study 215ON201.  There is no screening visit in this study. 
7.2.2. 
Treatment 
No study drug dosing is planned for this study. 
7.2.3. 
Visit Schedule 
Each subject will have approximately 1 scheduled study visit (with a +5-day window of the 
1-day visit) that is dependent on the scanner capabilities and equipment availability at each 
clinical site. 
7.3. 
Study Stopping Rules 
Biogen will notify Investigators when the study is to be placed on hold, completed, or 
terminated. 


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


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8. 
SELECTION OF SUBJECTS 
8.1. 
Inclusion Criteria 
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at the time of Day 1 visit or at the timepoint specified in the individual eligibility criterion listed:   
1. Must have participated in Study 215ON201 and received at least 1 dose of BIIB033 or 
placebo, as per protocol, within 2 years (+ 4 months) from Day 1 of this study (2 years 
from Week 32 or projected Week 32 visit, if the subject did not complete all visits in 
Study 215ON201). 
2. 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.   
8.2. 
Exclusion Criteria 
Candidates will be excluded from study entry if any of the following exclusion criteria exist prior 
to enrolment, or at the timepoint specified in the individual criterion listed: 
1. Not previously enrolled in Study 215ON201. 
2. Inability to comply with study requirements. 
3. Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the 
subject unsuitable for enrollment. 
4. Subjects with recent kidney function, such as serum creatinine above upper limit of 
normal range, will not be allowed to receive administration of Gd but will otherwise be 
allowed to participate in the study, including MRI assessments not requiring the use of 
Gd. 
5. Female subjects must have had a recent pregnancy test and must not be breastfeeding 
prior to MRI assessments with Gd. 


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9. 
ENROLLMENT AND REGISTRATION 
9.1. 
Enrollment 
Subjects (or their legally authorized representative [e.g., parent or legal guardian], where 
applicable) must provide informed consent before any study-related tests are performed (see 
Section 15.3).  When a subject signs the informed consent form (ICF), that subject is considered 
to be enrolled 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 enrolment log. 
9.2. 
Registration of Subjects 
Subjects will be registered at 2 years (+ 4 months) after their last study visit (Week 32) or 
projected Week 32 visit, if the subjects did not complete all visits in Study 215ON201, and after 
the Investigator has verified that the subjects are eligible per criteria in Sections 8.1 and 8.2.   
Refer to the Study Reference Guide for details on registration. 
9.3. 
Blinding Procedures 
This is a follow-up study with no investigational product, therefore blinding is not applicable.  
As much as possible, the treatment disclosure for Study 215ON201 should not be shared with 
sites or patients until the end of this study to reduce the risk of bias on the follow on assessments 
based on knowledge of treatment.   
 
 


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10. 
WITHDRAWAL OF SUBJECTS FROM THE STUDY 
10.1. 
Withdrawal of Subjects From Study 
Subjects must be withdrawn from the study for any of the following reasons: 
 The subject withdraws consent.   
 The subject is unwilling or unable to comply with the protocol. 
 At the discretion of the Sponsor or Investigator for medical reasons or for 
noncompliance. 
The reason for the subject’s withdrawal from the study must be recorded in the subject’s case 
report form (CRF). 


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11. 
FOLLOW-UP ASSESSMENTS 
See Section 4 for the timing of all assessments. 
11.1. 
One-Day Visit Assessments 
This study will assess the electrophysiological function of the visual pathway using FF-VEP.  
The various electrophysiologic and imaging measurements will be made to assess feasibility of 
being utilized as potential clinical endpoints sensitive to remyelination therapy in multicenter 
clinical studies (Table 1).  Clinical progression and severity of disease will be assessed by the 
following: 
 Medical history, including date of diagnosis of CDMS 
 MS diagnosis 
 MS signs and symptoms 
 Concomitant therapy and procedures recording 
 Vital signs  
 Physical examination 
 EDSS 
 MSFC 
 
 
 
 
 FF-VEP 
 
 
 
 
 
 
 
 
 
 


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 
 
 
 
 SAEs related to study procedure(s) reporting 


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12. 
SAFETY ASSESSMENTS 
Refer to Section 4 for the timing of all safety assessments. 
12.1. 
Safety Assessments 
The following assessments will be performed to evaluate the safety profile related to study 
procedure(s): 
 Physical examinations 
 Vital sign measurements:  temperature, pulse rate, systolic and diastolic blood 
pressure, and respiratory rate  
 SAEs related to study procedure(s)  
12.2. 
Vital Signs 
The analysis of vital signs will focus on clinically relevant abnormalities.  The definitions of 
these clinically relevant abnormalities are shown in Table 2. 
Table 2: 
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs 
Vital Sign 
Criteria for Abnormalities 
Temperature 
>38°C  
Pulse 
>100 bpm 
<40 bpm  
Systolic Blood Pressure 
>160 mmHg  
<90 mmHg  
Diastolic Blood Pressure 
>100 mmHg  
<45 mmHg  
bpm = beats per minute. 


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13. 
SAFETY DEFINITIONS, CLASSIFICATIONS, RECORDING, 
REPORTING, AND RESPONSIBILITIES 
Throughout the course of the study, every effort must be made to remain alert to possible SAEs 
related to study procedure(s).  If an SAE 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 SAEs and medical emergencies. 
13.1. 
Definition 
13.1.1. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death. 
 In the view of the Investigator, places the subject at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred 
in a more severe form, might have caused death. 
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
 Results in persistent or significant disability/incapacity. 
 Results in a congenital anomaly/birth defect. 
An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above.  (Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or convulsions occurring at home that do not 
require an inpatient hospitalization.) 
13.2. 
Safety Classifications 
13.2.1. 
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 13.1.1. 
 The relationship of the event to the study procedure(s). 


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 The severity of the event as defined in Section 13.2.3. 
13.2.2. 
Relationship of Events to Study Procedure(s) 
The following definitions should be considered when evaluating the relationship of SAEs to the 
study procedure(s). 
Relationship of Event to Study Procedure(s) 
Not related 
An SAE will be considered “not related” to the study procedure(s) if there is not a 
reasonable possibility that the event has been caused by the study procedure(s).  Factors 
pointing toward this assessment include but are not limited to:  the lack of reasonable 
temporal relationship between study procedure(s) and the event, the presence of a 
biologically implausible relationship between the study procedure(s) and the SAE, or the 
presence of a more likely alternative explanation for the SAE. 
Related 
An SAE will be considered “related” to the study procedure(s) if there is a reasonable 
possibility that the event may have been caused by the study procedure(s).  Factors that 
point toward this assessment include but are not limited to:  a positive rechallenge, a 
reasonable temporal sequence between study procedure(s) and the event, a known 
response pattern of the study procedure(s), a biologically plausible relationship between 
the study procedure(s) and the SAE, or a lack of an alternative explanation for the SAE. 
 
13.2.3. 
Severity of Events 
The following definitions should be considered when evaluating the severity SAEs: 
Severity of Event 
Mild 
Symptoms barely noticeable to subject or does not make subject uncomfortable; does not 
influence performance or functioning; prescription drug not ordinarily needed for relief of 
symptoms but may be given because of personality of subject. 
Moderate 
Symptoms of a sufficient severity to make subject uncomfortable; performance of daily 
activity is influenced; subject is able to continue in study; treatment for symptoms may be 
needed. 
Severe 
Symptoms cause severe discomfort; symptoms cause incapacitation or significant impact 
on subject’s daily life; severity may cause cessation of study procedure(s); treatment for 
symptoms may be given and/or subject hospitalized. 
13.3. 
Monitoring and Recording Events 
13.3.1. 
Serious Adverse Events 
Any SAE experienced by a subject post ICF sign-off through end-of-study visit and considered 
by the Investigator to be related to study procedure(s) is to be recorded on an SAE form, 
regardless of the severity of the event.  Information on SAEs related to study procedure(s) must 


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be reported to 
 within 24 hours as described in Section 13.3.2.  
Follow-up information regarding an SAE also must be reported with 24 hours.  
Subjects will be followed for all SAEs until the event has resolved, stabilized, or returned to 
baseline status.   
13.3.2. 
Immediate Reporting of Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify 
 within 24 hours of the study site staff becoming aware 
of the SAE.  It is the Investigator’s responsibility to ensure that the SAE reporting information 
and procedures are used and followed appropriately. 
Reporting Information for SAEs 
Any SAE related to study procedure that occurs between post ICF sign-off through end-of-study 
visit must be reported to 
 within 24 hours of the study site staff 
becoming aware of the event.  
To report initial or follow-up information on an SAE, fax a completed SAE form; refer to the 
Study Reference Guide for complete contact information. 
13.3.2.1. Deaths 
Death is an outcome of an event.  The procedure-related event that resulted in death should be 
recorded on the appropriate CRF and reported as an SAE within 24 hours of the site becoming 
aware of the event.  The Investigator should make every effort to obtain and send death 
certificates and autopsy reports to 
.  The term death should be reported 
as an SAE only if the cause of death is not known and cannot be determined. 
13.3.3. 
Suspected Unexpected Serious Adverse Reactions 
Not applicable as no study treatment will be administered. 
13.3.4. 
Medical Emergency 
In a medical emergency requiring immediate attention, study site staff will apply appropriate 
medical intervention, according to current standards of care.  The Investigator (or designee) 
should contact the study’s Medical Director.  Refer to the Study Reference Guide’s Official 
Study Contact List for complete contact information. 
13.4. 
Safety Responsibilities 
13.4.1. 
The Investigator 
The Investigator’s responsibilities include the following: 


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 Monitor and record all SAEs that are deemed to be related to the study procedure(s). 
 Determine the relationship and severity of each event. 
 Determine the onset and resolution dates of each event. 
 Complete an SAE form for each procedure-related SAE and fax it to 
 
 within 24 hours of the study site staff becoming aware of the event. 
 Pursue SAE follow-up information actively and persistently until the event has 
resolved or become stable.  Follow-up information must be reported to 
 
 within 24 hours of the study site staff becoming aware of new 
information. 
 Ensure all SAE reports are supported by documentation in the subjects’ medical 
records. 
 Report SAEs to local ethics committees, as required by local law. 
13.4.2. 
Biogen 
Biogen’s responsibilities include the following: 
 Before study site activation and subject enrollment, the Clinical Monitor is 
responsible for reviewing with study site staff the definition of SAEs, as well as the 
instructions for monitoring, recording, and reporting procedure-related SAEs. 
 Biogen is to notify all appropriate regulatory authorities, central ethics committees, 
and Investigators of procedure-related SAEs, as required by local law, within required 
time frames. 


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14. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
The objectives of the study and the endpoints to be analyzed are listed in Section 6. 
14.1. 
Efficacy 
14.1.1. 
Analysis Population 
Analysis of efficacy endpoints will be based on all enrolled subjects who complete the 1-day 
assessments. 
14.1.2. 
General Methods of Analysis 
Unless stated otherwise, summary statistics will be presented by original treatment groups and 
overall.  For continuous endpoints, the summary statistics will generally include number of 
subjects enrolled, number of subjects evaluated, mean, standard deviation, median, and range.  
For categorical endpoints, the summary statistics will generally include number of subjects 
enrolled, number of subjects evaluated, and the percent of subjects in each category. 
14.1.2.1. Analysis of the Primary Endpoint 
The primary analysis will be on the change in FF-VEP latency of the affected eye as compared to 
the baseline (measured prior to dosing in Study 215201) of the fellow eye at 2 years (+ 4 months) 
after the last study visit assessment (Week 32) in Study 215ON201.  The ANCOVA model will 
be used to test the difference between the 2 original treatment groups from Study 215ON201, 
adjusting for the baseline of the unaffected fellow eye. 
14.1.2.2. Analysis of the Secondary Endpoints 
The secondary endpoints will include the time to diagnosis of CDMS, severity of disease 
evaluated by EDSS and MSFC, and brain MRI results.  Number and percentage of subjects with 
diagnosis of CDMS will be summarized, and descriptive statistics of time to diagnosis of CDMS 
will be presented.  EDSS, MSFC, and brain MRI outcomes will also be summarized using 
descriptive statistics. 


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14.2. 
Safety 
14.2.1. 
Analysis Population 
The safety population is defined as all enrolled subjects who complete the 1-day assessments. 
14.2.2. 
Methods of Analysis 
All SAEs, clinical laboratory abnormalities, vital sign measurements, and physical examination 
findings will be evaluated for safety. 
14.2.2.1. Serious Adverse Events 
SAEs will be coded using the Medical Dictionary for Regulatory Activities.  The incidence of 
clinical SAEs will be summarized by severity and by relationship to study procedure(s).  The 
summary tables will include incidence estimates for overall system organ class as well as for 
preferred terms within each system organ class. 
14.2.2.2. Vital Signs 
The analysis of vital signs will focus on clinically relevant abnormalities.  The definitions of 
these clinically relevant abnormalities are shown in Table 2.  
14.3. 
Interim Analyses 
An interim analysis will be performed when approximately 50% of potentially projected 
available subjects have been enrolled into the study to provide information to assist the 
interpretation and design of ongoing clinical development of CNS remyelinating therapies.  
Statistical analyses listed in Section 14.1 will be performed on primary, secondary, and 
 endpoints at the interim analysis. 
14.4. 
Sample Size Considerations 
The sample size is based on the number of subjects who participated in Study 215ON201 
(approximately 82) rather than statistical considerations.  The subjects eligible for this study 
must have participated in Study 215ON201.   


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15. 
ETHICAL REQUIREMENTS 
Biogen, 
, and the Investigator must comply with all instructions, regulations, and 
agreements in this protocol and applicable International Conference on Harmonisation (ICH) and 
Good Clinical Practice (GCP) guidelines and conduct the study according to local regulations. 
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines.  The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated. 
15.1. 
Declaration of Helsinki 
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki. 
15.2. 
Ethics Committee 
The Investigator must obtain ethics committee approval of the protocol, ICF, and other required 
study documents prior to starting the study.  Biogen will submit documents on behalf of the 
investigational sites in all countries where subjects are enrolled. 
If the Investigator makes any changes to the ICF, Biogen must approve the changes before the 
ICF is submitted to the ethics committee.  A copy of the approved ICF must be provided to 
Biogen.  After approval, the ICF must not be altered without the agreement of the relevant ethics 
committee and Biogen. 
It is the responsibility of the Investigators to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations. 
Biogen must receive a letter documenting ethics committee approval, which specifically 
identifies the protocol, protocol number, and ICF, prior to the initiation of the study.  Protocol 
amendments will be subject to the same requirements as the original protocol. 
A progress report must be submitted to the ethics committee at required intervals and not less 
than annually. 
At the completion or termination of the study, the investigational site must submit a close-out 
letter to the ethics committee and Biogen. 
15.3. 
Subject Information and Consent 
Prior to performing any study-related activities under this protocol, including study-related tests 
and assessments, written informed consent with the approved ICF must be obtained from the 


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subject or subject’s legally authorized representative (e.g., parent or legal guardian), as 
applicable, in accordance with local practice and regulations.   
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the subject must be explained to the subject (or the 
subject’s legally authorized representative).  The subject must be given sufficient time to 
consider whether to participate in the study. 
A copy of the signed and dated ICF must be given to the subject.  The signed and dated ICF will 
be retained with the study records.  Local regulations must be complied with in respect to the 
final disposition of the original (wet signature) and copies of the signed and dated ICFs. 
Confirmation of informed consent must also be documented in the subject’s medical record. 
15.4. 
Subject Data Protection 
Prior to any testing under this protocol, including assessments, candidates must also provide all 
authorizations required by local law (e.g., Protected Health Information authorization in North 
America). 
The subject will not be identified by name in the CRF or in any study reports, and these reports 
will be used for research purposes only.  Biogen, its partners and designees, ethics committees, 
and various government health agencies may inspect the records of this study.  Every effort will 
be made to keep the subject’s personal medical data confidential. 
15.5. 
Compensation for Injury 
Biogen maintains appropriate insurance coverage for clinical studies and will follow applicable 
local compensation laws. 
15.6. 
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. 
15.7. 
Registration of Study and Disclosure of Study Results 
Biogen will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations. 


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16. 
ADMINISTRATIVE PROCEDURES 
16.1. 
Study Site Initiation 
The Investigator must not enroll any subjects prior to completion of an on-site or remote study 
initiation visit, conducted by Biogen or designee.  This initiation visit will include a detailed 
review of the protocol and study procedures. 
16.2. 
Quality Assurance 
During and/or after completion of the study, quality assurance officers named by Biogen or the 
regulatory authorities may wish to perform onsite audits or inspections.  The Investigator will be 
expected to cooperate with any audit or inspection and to provide assistance and documentation 
(including source data) as requested. 
16.3. 
Monitoring of the Study 
No site may initiate the 1-day assessments until Biogen or its designee representatives have 
concluded protocol-specific training and approved assessment technitian(s). 
Biogen or its designee representatives may conduct on-site visits at the study facilities for the 
purpose of monitoring various aspects of the study.  The Investigator must agree to 
Sponsor-authorized personnel having direct access to subject (or associated) source files for the 
purpose of verifying entries made in the CRF and assist with their activities, if requested.  
Adequate space and time for monitoring visits should be made available by the Investigator or 
study staff.  The site must complete the CRFs in a timely manner and on an ongoing basis to 
allow regular review by the study team. 
During these visits, CRFs and supporting documentation related to the study will be reviewed 
and any discrepancies or omissions will be resolved.   
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure protocol adherence, quality of data, compliance with regulatory requirements, and 
continued adequacy of the investigational site and its facilities. 
16.4. 
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.  
16.5. 
Publications 
Details are included in the clinical study agreement for this study. 


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17. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION 
17.1. 
External Contract Organizations 
Biogen will be responsible for all administrative aspects of this study, including but not limited 
to, study initiation, monitoring, management of SAEs, and data management. 
17.1.1. 
Contract Research Organization  
, a contract research organization (CRO), will be responsible for administrative aspects 
of the study, including but not limited to, study initiation, monitoring, and management of SAE 
reports and data management.  Before subjects are enrolled at each study site, the CRO will 
review study responsibilities with the Investigators and other study site staff, as appropriate. 
17.1.2. 
Electronic Data Capture 
Subject information will be captured and managed by study sites on CRFs via an appropriate 
Web-based electronic remote data capture tool. 
17.1.3. 
Central Facility for Other Assessments 
A central facility has been selected by Biogen to be a central reader for 
, FF-VEP, and 
 for this study.  A separate central facility has been selected by Biogen to read and 
interpret all MRI results for this study. 
17.2. 
Changes to Final Study Protocol 
All protocol amendments must be submitted to the ethics committee and regulatory authorities if 
required by local law.  Protocol modifications that affect subject safety, the scope of the 
investigation, or the scientific quality of the study must be approved by the ethics committee 
before implementation of such modifications to the conduct of the study.  If required by local 
law, such modifications must also be approved by the appropriate regulatory agency prior to 
implementation. 
However, Biogen may, at any time, amend this protocol to eliminate an apparent immediate 
hazard to a subject.  In this case, the appropriate regulatory authorities will be notified 
subsequent to the modification. 
In the event of a protocol modification, the ICF may require similar modifications (see 
Section 15). 


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17.3. 
Ethics Committee Notification of Study Completion or Termination 
Where required, the regulatory authorities and ethics committees must be notified of completion 
or termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines. 
17.4. 
Retention of Study Data 
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local laws or regulations.  Prior to 
proceeding with destruction of records, the Investigator must notify Biogen in writing and 
receive written authorization from Biogen to destroy study records.  In addition, the Investigator 
must notify Biogen of any changes in the archival arrangements including but not limited to 
archival at an offsite facility or transfer of ownership if the Investigator leaves the site. 
17.5. 
Study Report Signatory 
Biogen will designate one of the participating Study Investigators as a signatory for the study 
report.  This determination will be made by several factors, including but not limited to, the 
Investigator's experience and reputation in the studied indication; the Investigator's contribution 
to the study in terms of design, management, and/or subject enrollment; or by other factors 
determined to be relevant by Biogen. 
Biogen will follow all applicable local regulations pertaining to study report signatories. 


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18. 
REFERENCES 
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Llorens F, Gil V, Iraola S, et al. Developmental analysis of Lingo-1/Lern1 protein expression in 
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Nat Neurosci. 2005;8(6):745-51. 
Mi S, Miller RH, Tang W, et al. Promotion of central nervous system remyelination by induced 
differentiation of oligodendrocyte precursor cells. Ann Neurol. 2009;65(3):304-15. 
Mi S, Sandrock A, Miller RH. LINGO-1 and its role in CNS repair. Int J Biochem Cell Biol. 
2008. 
Mowry EM, Loguidice MJ, Daniels AB, et al. Vision related quality of life in multiple sclerosis: 
correlation with new measures of low and high contrast letter acuity. J Neurol Neurosurg 
Psychiatry. 2009;80(7):767-72. 
Park JB, Yiu G, Kaneko S, et al. A TNF receptor family member, TROY, is a coreceptor with 
Nogo receptor in mediating the inhibitory activity of myelin inhibitors. Neuron. 2005;45(3):345-
51. 
Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 
Revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292-302. 
Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: 
guidelines for research protocols. Ann Neurol. 1983;13(3):227-31. 
Raz N, Dotan S, Benoliel T, et al. Sustained motion perception deficit following optic neuritis: 
Behavioral and cortical evidence. Neurology. 2011;76(24):2103-11. 
Runmarker B, Andersen O. Prognostic factors in a multiple sclerosis incidence cohort with 
twenty-five years of follow-up. Brain. 1993;116 ( Pt 1):117-34. 
Shao Z, Browning JL, Lee X, et al. TAJ/TROY, an orphan TNF receptor family member, binds 
Nogo-66 receptor 1 and regulates axonal regeneration. Neuron. 2005;45(3):353-9. 
Submacular Surgery Trials Research Group. Evaluation of minimum clinically meaningful 
changes in scores on the National Eye Institute Visual Function Questionnaire (NEI-VFQ) SST 
Report Number 19. Ophthalmic Epidemiol. 2007;14(4):205-15. 
Talman LS, Bisker ER, Sackel DJ, et al. Longitudinal study of vision and retinal nerve fiber 
layer thickness in multiple sclerosis. Ann Neurol. 2010;67(6):749-60. 


Protocol 215ON203 
Version 1.0 
Long-Term Assessment of Remyelinating Therapy 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
47 
 
Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a 
geographically based study. I. Clinical course and disability. Brain. 1989;112:133-146. 
 
 


Protocol 215ON203 
Version 1.0 
Long-Term Assessment of Remyelinating Therapy 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
48 
 
19. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL 
I have read the foregoing protocol, “A Multicenter, Follow-Up Study to Assess Long-Term 
Electrophysiologic and Clinical Outcomes in Subjects Previously Enrolled in Study 215ON201,” 
and agree to conduct the study according to the protocol and the applicable ICH guidelines and 
GCP regulations, and to inform all who assist me in the conduct of this study of their 
responsibilities and obligations. 
 
 
 
____________________________________________________ 
Investigator’s Signature 
 
 
 
Date 
 
 
____________________________________________________ 
Investigator’s Name (Print) 
 
 
 
____________________________________________________ 
Study Site (Print) 
 
 

SAP_000.pdf: 
A Multicenter, Follow-Up Study to Assess Long-Term 
Electrophysiologic and Clinical Outcomes in Subjects 
Protocol 215ON203/NCT02657915 Statistical Analysis Plan 
Study Phase: 2 
P1·oduct Studied: BIIB033 
Date of Protocol: 16 November 201S (vei-sion 3) 
Date of SAP: 02 Mar 2017 (version 2) 
Key words: (Follow-Up study, FF-YEP, ANCOVA, multiple sclerosis, adverse events) 
Approved By: 
, M.S .. 
_______ _ 
, Pb.D. 
oc 
 MD 
Date 
Date 
Date 
Date 
Co1J1Pli11.noo: The atugy described !11 lhis report was per.formed according lo lite priooiples of Qoml Clin!calPǺJ!.CUCe (000
Confidentiality Statem1mt 
TJic infonnalioll i11 this docume11I c1111tains hude secrets and com111C1.-cinl infommlion Illa! arc privileged or confidential and lllll)I nol be 
discloi:ed unless such disclosure is n:q11ircd by apptioablo law or reguJution. In any IIV81lt, p111u1s lo wl1om the infQl'll111tJQII m
disoloscd must be i11fori11cd thnt the infurmatlon is priYlleged or eonll.dcnllnl and may not be 1b1thct disclosed by lllOlll. T.hcsu 
restrietions on disclosmo wilt upply equally to ull future it1foru1atio11 supplied lo you wl1iel1 is indie:Ued as privileged or conlideutilll. 
215ON203 SAP Version 2.0 
Previously Enrolled in Study 21SON201  


A Multicenter, Follow-Up Study to Assess LongTerm 
Electrophysiologic and Clinical Outcomes in Subjects 
Previously Enrolled in Study 215ON201 
Protocol 215ON203 Statistical Analysis Plan 
Study Phase: 2 
Product Studied: BIIB033 
Date of Protocol: 16 l\ovember 2015 (version 3) 
Date of SAP: D3 Feb 2017 (version 2) 
Key words: (Follow-Up study, FF-VEP, ANCOVA, multiple sclerosis, adver!Se events) 
Approved By: 
, M.S .. 
 
. Ph.D. 
MD 
C'onfidstudlty Stlttemnt 
Date 
Date 
Date 
TI1c lntorm:itiotl in th1 r, doctl?'l"ICflt containƤ tiadc sccrƥts tmd (:im'Lmcn:.llll 1nforrmu.lon thut EU'C pri,ilt1!erl or c.onfid1:ntful ond m:i,y not he 
di-l'J"foƦ,etl unlƧƨ r.ud:i ill:.clOS'Jte is rc:qttircrl bƩ aƪplic!lhlt- law Qr rt-ƫ'Ul.ation. In :my e,·rnt, pe!Ƭl)ns. m \\'h-Om thtƭ i"\fortnƮtioll is 
dii:.cloƯ !l'IQư he: lnfom,cd thut tho: mibrmation iƱ privileged or confidmtfaJ .:ind m:,y nnl he fi1nhcr di.<.dus,;.-d by diem. I"hc<":.C. 
rƲƳƴtr1t;lion::. on disc!o!lure- wtll Ƶ'Pt.,Jy equally to .aJ1 tutu.rointi.mnution !ltipplied to ),Ou whiciJ. is indkatrd .ls. pth-ileged tPt" «.1.\nt1tlƶ!i:tl., 
:!15ON20:J SAP Version 1.0 


A Multicenter, Follow-Up Study to Assess LongTerm 
Electrophysiologic and Clinical Outcomes in Subjects 
Previously Enrolled in Study 215ON201 
Protocol 215ON203 Statistical Analysis Plan 
Study Phase: 2 
Product Studied: BIIB033 
Date of Protocol: 16 l\ovember 2015 (version 3) 
Date of SAP: D3 Feb 2017 (version 2) 
Key words: (Follow-Up study, FF-VEP, ANCOVA, multiple sclerosis, adver!Se events) 
Approved By: 
 
, M.S .. 
 
. Ph.D. 
,MD 
C'onfidstudlty Stlttemnt 
Date 
Date 
Date 
TI1c lntorm:itiotl in th1 r, doctl?'l"ICflt containƤ tiadc sccrƥts tmd (:im'Lmcn:.llll 1nforrmu.lon thut EU'C pri,ilt1!erl or c.onfid1:ntful ond m:i,y not he 
di-l'J"foƦ,etl unlƧƨ r.ud:i ill:.clOS'Jte is rc:qttircrl bƩ aƪplic!lhlt- law Qr rt-ƫ'Ul.ation. In :my e,·rnt, pe!Ƭl)ns. m \\'h-Om thtƭ i"\fortnƮtioll is 
dii:.cloƯ !l'IQư he: lnfom,cd thut tho: mibrmation iƱ privileged or confidmtfaJ .:ind m:,y nnl he fi1nhcr di.<.dus,;.-d by diem. I"hc<":.C. 
rƲƳƴtr1t;lion::. on disc!o!lure- wtll Ƶ'Pt.,Jy equally to .aJ1 tutu.rointi.mnution !ltipplied to ),Ou whiciJ. is indkatrd .ls. pth-ileged tPt" «.1.\nt1tlƶ!i:tl., 
:!15ON20:J SAP Version 1.0 


3 
215ON203 SAP Version 1.0 
TABLE OF CONTENTS 
1 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................. 5 
1.1 
Primary Objective and Endpoint ...................................................................................... 5 
1.2 
Secondary Objectives and Endpoints ............................................................................... 5 
 
 5 
2 
STUDY DESIGN ...................................................................................................................... 6 
2.1 
Study Overview ................................................................................................................ 6 
2.2 
Study Schematic ............................................................................................................... 7 
3 
STATISTICAL ANALYSIS METHODS ............................................................................... 10 
3.1 
General Considerations .................................................................................................. 10 
3.2 
Study Subjects ................................................................................................................ 11 
3.2.1 
Analysis population ................................................................................................. 11 
3.2.2 
Accounting of Subjects ............................................................................................ 11 
3.2.3 
Protocol Deviations ................................................................................................. 11 
3.2.4 
Demographics and Baseline Disease Characteristics .............................................. 11 
3.2.5 
Concomitant Medications and Non-drug Treatments .............................................. 12 
3.3 
Efficacy Analysis ........................................................................................................... 12 
3.3.1 
General consideration for efficacy analysis ............................................................. 12 
3.3.2 
Primary Efficacy Endpoint ...................................................................................... 12 
3.3.3 
Secondary Efficacy Endpoints ................................................................................. 13 
 
 15 
3.4 
Safety analysis ................................................................................................................ 20 
3.4.1 
General consideration for safety analysis ................................................................ 20 
3.4.2 
Clinical Adverse Events .......................................................................................... 20 
3.4.3 
Vital Sign Measurements ......................................................................................... 21 
3.4.4 
Physical Examination .............................................................................................. 22 
4 
INTERIM ANALYSES ........................................................................................................... 22 


4 
215ON203 SAP Version 1.0 
5 
SAMPLE SIZE DETERMINATION ...................................................................................... 22 
6 
REFERENCE ........................................................................................................................... 22 
7 
APPENDIX 1:  SELECTIVE EXAMPLE SAS CODES FOR THE STATISTICAL 
ANALYSIS IN SECTION 3.3.1 AND 3.3.3 ........................................................................... 24 
7.1 
ANCOVA ....................................................................................................................... 24 
7.2 
The SAS codes to check normality assumption ............................................................. 24 
7.3 
Wilcoxon signed-rank test .............................................................................................. 24 
7.4 
KM analysis ................................................................................................................... 24 
8 
APPENDIX 2: MULTIPLE SCLEROSIS FUNCTIONAL COMPOSITE (MSFC)[1] .......... 26 
 
 
 29 
 
 32 
 
 33 


5 
215ON203 SAP Version 1.0 
1 
STUDY OBJECTIVES AND ENDPOINTS 
1.1 
Primary Objective and Endpoint 
The primary objective of this study is to assess FF-VEP latency in subjects who were 
enrolled in Study 215ON201 2 years (+ 4 months) after the last study visit. 
The primary endpoint that is related to this objective is the change in FF-VEP latency of the 
affected eye as compared to the baseline of the fellow eye at 2 years (+ 4 months) after the 
last study visit assessment (Week 32) in Study 215ON201. 
1.2 
Secondary Objectives and Endpoints 
The secondary objective is to assess clinical progression and severity of central nervous 
system (CNS) demyelinating disease in subjects who were enrolled in Study 215ON201 
2 years (+ 4 months) after the last study visit. 
The endpoints that relate to this objective are as follows: 

Evaluate incidence of clinically definite multiple sclerosis (CDMS) and time to
diagnosis of CDMS.

Evaluate severity of  CNS demyelinating disease with Expanded Disability Status
Scale (EDSS), Symbol-Digit Modalities Test (SDMT), and multiple sclerosis
functional composite (MSFC). The MSFC includes the following:

Timed 25-Foot Walk (T25FW)

9-Hole Peg Test (9HPT) [dominant and nondominant hands]

(3-Second) Paced Auditory Serial Addition Test (PASAT)

Evaluate change in disease activity from baseline with brain magnetic resonance
imaging (MRI) with and without gadolinium (Gd).  MRI analysis will include the
following:

Number of Gd-enhanced lesions

Volume of T2 lesions


6 
215ON203 SAP Version 1.0 
2 
STUDY DESIGN 
2.1 
Study Overview 
This 
international 
multicenter, 
follow-up 
study 
will 
determine 
the 
long-term 
electrophysiologic and clinical outcomes in subjects previously enrolled in Study 215ON201. 
One group is planned, with eligible subjects (previously enrolled in Study 215ON201) 
having already been administered at least 1 study treatment (BIIB033 100 mg/kg or placebo) 
by IV infusion once every 4 weeks for 20 weeks (a total of 6 doses).   Dosing was completed 
2 years (+ 4 months) prior to enrollment in this follow-up study.  A maximum of 82 subjects 
(determined from the number of subjects who received at least 1 dose of BIIB033 or placebo 
in Study 215ON201) will be included in this study.  There is no formal sample size 
calculation.  The number of subjects eligible for this study is determined by the number of 
subjects who participated in Study 215ON201. 
See Figure 1 for a schematic of the study design. 


7 
215ON203 SAP Version 1.0 
Study Duration: 
The study period will consist of an approximately 1-day visit (with a +5-day window of the 
1-day visit) that is dependent on the scanner capabilities and equipment availability at each
clinical site.
2.2 
Study Schematic 
Figure 1: 
Study Design 
IP = investigational product; MRI= magnetic resonance imaging. 
Note:  All assessments should be performed on the same day where possible or within a + 5 day window of the 
1-day visit.


8 
215ON203 SAP Version 1.0 
Table 1: 
Schedule of Activities 
Tests and Assessments
1
Day 1
2: 
(2 Years + 4 Months After Week 32 Visit in Study 215ON201 or Projected Week 32 Visit 
if the Subject Did Not Complete All Visits) 
Informed Consent 
X 
Eligibility Criteria Check 
X 
Medical History
3
X 
Multiple Sclerosis Diagnosis 
X 
Multiple Sclerosis Signs and Symptoms 
X 
Concomitant Therapy and Procedures Recording 
X 
Vital Signs
4
X 
Physical Examination 
X 
Expanded Disability Status Scale
5
X 
Symbol-Digit Modalities Test 
X 
Multiple Sclerosis Functional Composite Including 

Timed 25-Foot Walk

9-Hole Peg Test (Dominant and Nondominant Hands)

(3-Second) Paced Auditory Serial Addition Test
X 
Full-Field Visual Evoked Potential7 
X 


9 
215ON203 SAP Version 1.0 
Tests and Assessments
1
Day 1
2: 
(2 Years + 4 Months After Week 32 Visit in Study 215ON201 or Projected Week 32 Visit 
if the Subject Did Not Complete All Visits) 
Adverse Event/Serious Adverse Event Recording
12
X 
; MRI = magnetic resonance imaging. 
1 All assessments should be performed on the same day and in the order listed, when possible (or within a + 5-day window of the 1-day visit). 
2 Completion of the Day 1 visit assessments constitutes the end-of-study visit. 
3 Medical history will be taken from after last study visit in Study 215ON201. 
4 Vital signs include temperature, systolic and diastolic blood pressure, pulse rate, body weight, and respiratory rate (after sitting for at least 5 minutes). 
5 Expanded Disability Status Scale should be performed by a study certified rater.  Where applicable, refer to study manual for instructions. 
 
 
 
7 Sites and technicians must be qualified and approved by the central reader to perform MRI, 
, full-field visual evoked 
potential, and 
. 
 
   
 
 
 
 
 
 
12 Adverse event/serious adverse event monitoring will be recorded after informed consent form sign-off through the end-of-study visit.  


10 
215ON203 SAP Version 1.0 
3 
STATISTICAL ANALYSIS METHODS 
3.1 
General Considerations 
Descriptive summary statistics will be presented for all study primary, secondary and 
 endpoints collected. 
Unless stated otherwise, summary statistics will be presented by original treatment groups 
and overall. For continuous endpoints, the summary statistics will generally include number 
of subjects enrolled, number of subjects evaluated, mean, standard deviation, median, and 
range (minimum, maximum). For categorical endpoints, the summary statistics will 
generally include number of subjects enrolled, number of subjects evaluated, and the percent 
of subjects in each category. 
Statistical testing for efficacy endpoints will be made between the BIIB033 group and the 
placebo group. There will be no multiple comparison adjustments. 
Unless stated otherwise, all statistical tests will be 2-sided with statistical significance level 
of 0.05.    
The statistical software, SAS®, will be used for all summaries and statistical analyses. 
Analysis population 
Intent-to-treat (ITT) population, per-protocol population, and safety population are defined 
as follows. 

Intent-to-Treat Population
The intent-to-treat population is defined as all randomized subjects who received at least 1 
dose of study treatment (BIIB033 or placebo) in 215ON201 study, and completed at least 
one of the 1-day assessments in this study. 

Per-protocol Population
The per-protocol population is defined as subjects from the ITT population who completed 
the 215ON201 study, did not miss more than one dose of BIIB033 or placebo, and did not 
receive MS modifying therapies during study 215ON201. These subjects were included in 
the per-protocol population of 215ON201 study. 

Safety population
The safety population is defined as all subjects who received at least 1 dose of study 
treatment in 215ON201 and completed at least one of  the 1-day assessments in this study. 
Baseline data 
Unless stated otherwise, baseline data are defined as the data collected prior to the time 
and/or on the date of first dose in 215ON201. If there are more than one value on or before 


11 
215ON203 SAP Version 1.0 
the date of first dose, the non-missing value closest to and prior to (including on) the date of 
first dose will be used as the baseline value. 
Treatment group 
No study drug dosing is planned for this follow-up study. The treatment group used in the 
descriptive summary and treatment comparison is determined by the prior treatment with the 
investigational drug in 215ON201. 

new in 215ON203

baseline T2 volume in 215ON201  (0 and >0)

EDSS  total score (>=median and < median)

EDSS FS visual score (>=median and < median)

RGCL thinning in the affected eye by week 4 (>=median and < median)
3.2 
Study Subjects 
3.2.1 Analysis population 
Unless stated otherwise, all study subjects data will be summarized by treatment groups and 
overall in the ITT population. 
3.2.2 Accounting of Subjects 
The summary of subjects disposition will include: subjects who completed the study; and 
subjects who withdrew from study early and the reasons for withdrawal. A listing of those 
subjects who withdrew from study and the associated reasons for withdrawal will be 
presented by treatment group. Number of subjects in each analysis population defined in 
Section 3.1 will also be summarized.  
3.2.3 Protocol Deviations 
Protocol deviations identified during site monitoring will be captured in a Protocol 
Deviation log and categorized as major or minor deviations by Biogen. Count and 
percentage of subjects with at least one major deviation will be summarized by category.  
3.2.4 Demographics and Baseline Disease Characteristics 
Demographic data, including age (in years), age category (in years; <18, 18-30, 31-40, 41-
50, and 51-55, >55), sex and race category, will be summarized using descriptive statistics.  
Demographic data will be also summarized in per-protocol population. 


12 
215ON203 SAP Version 1.0 
Medical history between last study visit Study 215ON201 and Day 1 is categorized into pre-
specified system organ categories. Number and percent of subjects for each category will be 
summarized.   
3.2.5 Concomitant Medications and Non-drug Treatments 
All concomitant medications will be coded using the World Health Organization (WHO) 
medication dictionary. A concomitant medication is any drug or substance administered 
between the time the subject has signed the ICF and the End of Study. A concomitant non-
drug treatment is any therapeutic interventions or diagnostic assessment performed between 
the time the subject has signed the ICF and the End of Study.  
The number and percent of subjects taking concomitant medication and non-drug treatments 
will be summarized by treatment group and overall.  
3.3 
Efficacy Analysis 
3.3.1 General consideration for efficacy analysis 
Analysis population 
All efficacy endpoints will be evaluated in the ITT and per-protocol population as defined in 
Section 3.1.  
The analyses performed in the per-protocol  population will be considered the primary 
analyses, and the analyses based on ITT population will be considered as sensitivity 
analyses. 
Analysis models 
Analysis of covariance (ANCOVA) model will be used as the primary inferential analysis 
approach to evaluate changes from the baseline measurement in 215ON201 to Day 1 of 
215ON203 in efficacy endpoints and to test the treatment differences between BIIB033 and 
placebo. ANCOVA model will include terms for the baseline value and treatment group. 
Based on Type III sum of squares, Least-squares (LS) adjusted mean of treatment 
difference, 95% confidence interval for the difference and the associated p-value will be 
presented.   
Since this is a follow up study, due to loss of follow up, if the distribution of the responses is 
markedly non-normal (eg., highly skewed or contains outliers), the normality assumption 
appears dramatically violated, the Wilcoxon rank-sum test will be used to compare the 
treatment difference of efficacy endpoints.  Normal probability plot, and QQ-plot with tests 
will be used to check normality assumption. 
3.3.2 Primary Efficacy Endpoint 
In order to be included in the statistical analyses of the FF-VEP data the subject had to have 
been evaluated using the same monitor type in both the 215ON201 and 215ON203 studies. 


13 
215ON203 SAP Version 1.0 
Subjects who were evaluated using different monitor types will have their FF-VEP data 
excluded from the statistical analyses. These data will appear in the subject listings. 
Latency as determined by FF-VEP 
P100 latency value from FF-VEP is the primary efficacy outcome and will be measured for 
affected and fellow eyes at Day 1.  
The actual value for affected eye, fellow eye and the difference between the two eyes at Day 
1 will be summarized using descriptive statistics by treatment group.  
Change in latency value at Day 1 for the affected eye in the current study from the baseline 
of fellow eye in RENEW will be analyzed using ANCOVA as mentioned in Section 3.3.1. 
The baseline of the fellow eye in RENEW will be used as the baseline covariate in above 
ANCOVA model. 
Sensitivity analysis 
Change in latency value at Day 1 for the affected eye in the current study from Week 32 of 
fellow eye in RENEW will be analyzed using ANCOVA as mentioned in Section 3.3.1. 
Week 32 of the fellow eye in RENEW will be used as the covariate in ANCOVA model. If 
Week 32 value is not available, then Week 24 value will be used to calculate the change in 
FF-VEP latency. 
Categorical Analyses on FF-VEP latency 
In addition, each subject’s latency values will be compared between baseline fellow eye in 
RENEW and affected eye at Day 1 in the current study. For subjects whose baseline 
affected eye data in RENEW are missing or more than 3% worse (higher) than baseline 
fellow eye, their affected eye data at Day 1 will be checked if they are within 10% of 
baseline fellow eye measurements in RENEW or worse than 10% (if the affected eye data 
are missing, they will be treated as worse than 10%). The 10% cutoff will be used to 
categorize latency delay as normal/mild (less or equal to 10%) or moderate/severe (>10%). 
Count and percent will be summarized by treatment and chi-squared test will be conducted 
for treatment comparison. 
3.3.3 Secondary Efficacy Endpoints 
The secondary endpoints will include the time to diagnosis of CDMS, severity of disease 
evaluated by EDSS, SDMT and MSFC, and brain MRI results.  Number and percentage of 
subjects with diagnosis of CDMS will be summarized, and descriptive statistics of time to 
diagnosis of CDMS will be presented. EDSS, SDMT, MSFC, and brain MRI outcomes will 
also be summarized using descriptive statistics. 
Clinically definite multiple sclerosis (CDMS) and time to diagnosis of CDMS 


14 
215ON203 SAP Version 1.0 
The number and percentage of subjects with diagnosis of CDMS will be displayed by 
treatment groups. The time to diagnosis of CDMS will be summarized using descriptive 
statistics . 
Time to confirmed MS is the time from the diagnosis of Acute optic neuritis (AON) to the 
confirmed MS date.  
Subjects who do not have a confirmed MS will be considered censored. The censor date for 
subjects is the time of the last study contact. The start date for calculation of day to censor is 
the date of diagnosis of AON in 215ON201. 
The proportion of subjects with a confirmed MS from the diagnosis of AON in 215ON201 
to  Day 1 in 215ON203, and the time to diagnosis of CDMS in 215ON203 from the 
diagnosis of AON in 215ON201 will be analyzed by the Kaplan-Meier (KM) product limit 
estimate. The KM estimate for the proportion of patients with MS and 10th percentile, 25th 
percentile and 50th percentiles of time to MS will be summarized by treatment group.  
EDSS, MSFC and SDMT 
For Expanded Disability Status Scale (EDSS), and its 7 functional system scores including 
Visual (Converted), Brainstem, Pyramidal, Cerebellar, Sensory, Bowel and Bladder 
(Converted), and Cerebral, each functional system score and EDSS total score will be 
summarized using descriptive statistics by treatment group. 
For multiple sclerosis functional composite (MSFC), MSFC z-score [1] for T25FW, 9HPT 
and PASAT-3 will be derived as in Appendix 2 and will be summarized using descriptive 
statistics by treatment group.  
The MSFC Z-score is calculated by creating Z-scores for each component of the MSFC, as 
explained below, and averaging them to create an overall composite score, i.e., 
MSFC Z-score = (Z25-foot-walk + Z9HPT + ZPASAT-3)/3, where Zj refers to Z-scores of 
component j. 
A Z-score represents the number of standard deviations a subject’s test result is higher (Z >0) 
or lower (Z <0) than the average test result (Z = 0) from the reference population. For this 
study,  the reference population will be the subjects from Biogen 999MS005 MS COG norm 
healthy volunteer study. 
For T25FW, 9HPT dominant hand, 9HPT non-dominant hand and PASAT-3, actual 
assessments as continuous variables will also be summarized using descriptive statistics by 
treatment group.  
For Symbol Digit Mobility Test (SDMT), the SDMT scores will be summarized using 
descriptive statistics by treatment group . 


15 
215ON203 SAP Version 1.0 
MS Signs and Symptoms 
MS signs and symptoms are listed in 9 classes including Vision Problems, Cognitive 
Impairment, Coordination/Balance Problems, Bladder Dysfunction, Bowel Dysfunction, 
Sexual Function Problems, General Signs and Symptoms, Sensory Disturbances, and Motor 
Disturbances. The unlisted signs and symptoms are recorded under “Other Signs and 
Symptoms” in case report form (CRF). 
Number and percentage of subjects having each listed MS signs and symptoms, and Other 
Signs and Symptoms will be displayed by treatment group.  
Disease Activity by Brain MRI Metrics  
Disease activity is measured by consensus Gd lesion count, and T2 lesion volume. 
The number of consensus GD-enhancing lesions and volume of T2 Lesions (in mL), and 
change from RENEW baseline of them at Day 1 in the current study will be summarized by 
treatment group.  
Change from baseline of the number of Gd-enhancing lesions at Day 1 will be compared 
between treatment groups using a Wilcoxon signed-rank test.  
Change from baseline of the volume of T2 lesions at Day 1 will be also compared between 
treatment groups using the Wilcoxon signed-rank test.  


16 
215ON203 SAP Version 1.0 


17 
215ON203 SAP Version 1.0 


18 
215ON203 SAP Version 1.0 


19 
215ON203 SAP Version 1.0 


20 
215ON203 SAP Version 1.0 
3.4 
Safety analysis 
3.4.1 General consideration for safety analysis 
Analysis population 
All safety endpoints will be evaluated in the safety population as defined in Section 3.1. 
Methods of Analysis 
All adverse events (AEs) and serious adverse events (SAEs), vital sign measurements, 
physical examination findings, will be evaluated for safety. Safety data will be summarized 
using descriptive statistics by treatment group and overall.  
3.4.2 Clinical Adverse Events 
For this study, any AE experienced by the subject after ICF sign-off through the end-of-
study visit is to be recorded on the CRF, regardless of the severity of the event or its 
relationship to the investigational drug (administered in Study 215ON201) or procedure(s) 
in this study. Any SAE experienced by the subject between the time the subject has signed 
the ICF and the End of Study Visit is to be recorded on an SAE Form, regardless of the 
severity of the event or its relationship to the investigational drug (administered in Study 
215ON201) or  procedure(s).   
All AEs will be coded using the MedDRA. The overall summary table of AEs will present 
the number of subjects with the following events for each treatment group and overall. A 
subject is counted only once in each category. 

AE;

AE with severity as “moderate” or “severe”;

AE with severity as “severe”;

investigational drug (administered in Study 215ON201) related AE

study procedure(s) related AE;

SAE;

AE leading to withdrawal from study.
The incidence of AEs will be summarized using the primary system organ class and 
preferred term. Preferred terms are presented by decreasing incidence in the total column 
within each system organ class. The incidence of AEs will also be summarized by event 
severity and by relationship to the investigational drug (administered in Study 215ON201) 
or study procedure(s) using system organ class and preferred term. Within each system 
organ class or/and preferred term, the same subject will be counted only once. If a subject 


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has more than one AE in the same system organ class or/and preferred term, the most severe 
AE will be reported. 
Additionally, the incidence of AEs will be summarized by using preferred term only, and 
preferred terms will be ordered by decreasing frequency of AEs in the BIIB033 100mg/kg 
column.  
The incidence of SAEs will also be summarized by primary system organ class and 
preferred term and treatment group as well.   
Listings of all AEs, SAEs, and AEs that led to study withdrawal will be presented. 
3.4.3 Vital Sign Measurements 
The analysis of vital signs will focus on the incidence of potentially clinically relevant 
abnormalities. The criteria for potentially clinically relevant abnormalities are given in 
Table 2.   
Table 2: Criteria to Determine Potentially Clinically Relevant Abnormalities in Vital 
Signs 
Vital Sign 
Criteria for Abnormalities 
Temperature 
>38°C
Pulse 
>100 beats per minute (bpm)
<40 bpm 
Systolic Blood Pressure 
>160 mmHg
<90 mmHg 
Diastolic Blood Pressure 
>100 mmHg
<45 mmHg 
A summary table for subjects with any potentially clinically relevant abnormalities will be 
provided. In the summary table, entries are numbers of subjects with an abnormality divided 
by number of subjects evaluated followed by corresponding percentages. Number evaluated 
is the number of subjects who had a baseline assessment and at least one post-baseline 
assessment for that vital sign.  
The count and percentage of subjects with weight change of greater than 7% from baseline 
at Day 1 will be summarized by treatment group. A subject listing of weight change of 
greater than 7% from baseline at Day 1 will be presented. 
For temperature, pulse, systolic blood pressure, diastolic blood pressure, and weight, actual 
values and changes from baseline will also be summarized using descriptive statistics by 
treatment group at day 1.  


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A subject listing will also be presented for subjects with any abnormalities in vital signs. In 
this listing, each subject’s complete vital sign values including the baseline values will be 
listed with abnormalities labeled. 
3.4.4 Physical Examination 
The result collected on CRF at Day 1 will be listed as performed or not performed, and 
abnormality will be reported as AE. 
4 
INTERIM ANALYSES 
An interim analysis will be performed when approximately 50% of potentially projected 
available subjects have been enrolled into the study to provide information to assist the 
interpretation and design of ongoing clinical development of CNS remyelinating therapies.   
The interim analyses will only include the following specified analyses: 

Demography as described in Section 3.2.4 including age, age category, sex and race
category

Analysis of latency as determined by FF-VEP as described in Section 3.3.2

Analysis of time to diagnosis of  CDMS as described in Section 3.3.3

Descriptive statistics of EDSS, T25FW, 9HPT (dominant/non-dominant), PASAT 3 and
SDMT



Correlation analysis between new assessments at Day 1 (EDSS, T25FW, 9HPT
(dominant/non-dominant), PASAT 3, SDMT, 
) and clinical and
electrophysiological recovery from baseline (FF-VEP, 
) at Day 1.
5 
SAMPLE SIZE DETERMINATION 
The sample size is based on the number of subjects who participated in Study 215ON201 
(approximately 82) rather than statistical considerations.  The subjects eligible for this study 
must have participated in Study 215ON201.   
6 
REFERENCE 
[1] Fischer, J., Jak, A.J.,  Kniker, J.E., Rudick, R.A. (2001). MSFC administrative and
scoring manual. 
(http://www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/
Brochures/10-2-3-31-MSFC_Manual_and_Forms.pdf) 


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[2] Mangione, C.M. (2000). The National Eye Institute 25-item visual function
questionnaire (VFQ-25): Version 2000. Scoring Manual. (Accessible at: 
www.nei.nih.gov/resources/visionfunction/manual_cm2000.pdf.) 
[3] Raphael, B. A., Galetta, K. M., Jacobs, D. A., Markowitz, C. E., Liu, G. T., Nano-
Schiavi, M. L., Galetta S. L., Maguire, M. G., Mangione, C. M., Globe, D. R., 
Balcer, L. J. (2006). Validation and test characteristics of a 10-item neuro-
ophthalmic supplement to the NEI-VFQ-25. American journal of 
ophthalmology, 142(6), 1026-1035. 
[4] Suner, I. J., Kokame, G. T., Yu, E., Ward, J., Dolan, C., Bressler, N. M. (2009).
Responsiveness of NEI VFQ-25 to changes in visual acuity in neovascular 
AMD: validation studies from two phase 3 clinical trials. Investigative 
ophthalmology & visual science, 50(8) 3629-3635.  


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7 
APPENDIX 1:  SELECTIVE EXAMPLE SAS CODES FOR THE 
STATISTICAL ANALYSIS IN SECTION 3.3.1 AND 3.3.3 


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8 
APPENDIX 2: MULTIPLE SCLEROSIS FUNCTIONAL COMPOSITE 
(MSFC)[1] 
There are 3 components in the MSFC (Fischer et al., 2001):  
(1) The average time from the 4 trials on the 9-hole peg test (HPT) (the 2 trials for each
hand are averaged, converted to the reciprocals of the mean times for each hand and then the 
2 reciprocals are averaged);  
(2) The average time of the 2 trials in Timed 25-Foot Walk;
(3) The number of correct answers on the Paced Auditory Serial Addition (PASAT) 3 test.
The MSFC Z-score is calculated by creating Z-scores for each component of the MSFC, as 
explained below, and averaging them to create an overall composite score, i.e., 
MSFC Z-score = (Z25-foot-walk + Z9HPT + ZPASAT-3)/3, where Zj refers to Z-scores of component 
j. 
A Z-score represents the number of standard deviations a subject’s test result is higher (Z 
>0) or lower (Z <0) than the average test result (Z = 0) from the reference population. For
this study,  the reference population will be the subjects from Biogen 999MS005 MS COG 
norm healthy volunteer study, and the overall scores are given in Table 3.  
Table 3: The overall scores of T25FW, 9HPT and PASAT 3  from Biogen 999MS005 
MS COG study 
T25FW 
1/9HPT 
PASAT-3 
mean 
4.2 
0.052 
45.6 
SD 
0.95 
0.0057 
11.05 
The Z-score for each component is defined as below: 
Timed 25-Foot Walk Z-score Calculation  
The Z-score is calculated as in the following formula: 
Z25-foot-walk =
)
(
)
(
)
2
/)
((
)1
(
2
1
reference
SD
reference
MEAN
t
t




, 


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where t1 and t2 are the time (in seconds) from the two trials, and the MEAN (reference) and 
SD (reference) are the mean and standard deviation of the averaged time from two trials for 
the reference population.  
If a subject is missing only one trial due to reasons other than MS related physical 
limitation, then the time from the non-missing trial will be used to calculate the Z-score. If 
both trials are missing due to reasons other than MS related physical limitation then the Z-
score is regarded as missing. 
If either trial is missing due to MS related physical limitation, then the subject will be given 
a Z-score -13.7 for T25FW.  
9HPT Z-score Calculation 
Z-score for the 9HPT is calculated as in the following formula:
Z9HPT =
)
(
)
(
)
2
/) 2
/)
(
1
 2
/)
(
1
((
22
21
12
11
reference
SD
reference
MEAN
t
t
t
t




, 
where t11, t12, t21, t22 are the time (in seconds) taken to complete for dominant hand trial 1, 
dominant hand trial 2, non-dominant hand trial 1, and non-dominant hand trial 2, 
respectively. The MEAN (reference) and SD (reference) are the mean and standard 
deviation of averaged reciprocals of time from two hands for the reference population. 
If one trial of either hand is missing due to reasons other than MS related physical 
limitation, then the time from the non-missing trial will be used to calculate the Z-score. If 
both trials of one hand are missing due to reasons other than MS related physical limitation, 
then the time from this hand is set as missing, and the non-missing hand will be used to 
calculate the Z-score. For example, if only one trial is performed per hand, then the Z-score 
is calculated as an average of the reciprocals of the two times; if both trials of the non-
dominant hand are missing, then the Z-score is calculated based on the reciprocal of the 
mean time from the dominant hand.  
If either trial from one hand is missing due to MS related physical limitation, then 777 
seconds are assigned to the disabled hand, and Z-score is calculated using the average of the 
inverse of each hand.  
PASAT-3 Z-score Calculation 


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For the PASAT-3, the z-score for each subject will be calculated by subtracting the 
reference population’s mean score from the subject’s PASAT-3 score and dividing by the 
SD of the reference population, i.e. 
ZPASAT-3 =
)
(
)
(
score
 
raw
 3 
PASAT
reference
SD
reference
MEAN

. 
If a subject is missing the PASAT-3 score due to MS disease limitations, the subject will be 
given a Z-score calculated using a raw score of 0. If missing score is due to other reasons, 
then the Z-score is regarded as missing. 


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