Clinical trial NCT03870763
Conditions: Multiple Sclerosis, Relapsing-Remitting
Keywords: Pediatric, Multiple Sclerosis
Sponsor: Biogen
Start date: 2019-03-19; Completion date: 2022-07-21
Enrollment: 11 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objective of the study is to evaluate the efficacy of dimethyl fumarate (Tecfidera) and peginterferon beta-1a (Plegridy), both compared with placebo, in pediatric participants with RRMS. The other objectives of this study are to evaluate the safety and tolerability of dimethyl fumarate and peginterferon beta-1a and to assess the effect of dimethyl fumarate and peginterferon beta-1a, both compared with placebo, on additional clinical and radiological measures of disease activity.

Detailed description:
Participants will be randomized in a 1:2:2 ratio to receive the double-blind study treatment (Dimethyl Fumarate, Peginterferon Beta-1a, and placebo). Participants experiencing a confirmed relapse or disability progression or high lesion burden on MRI will have the option to discontinue the blinded study treatment and switch to an alternative therapy or open-label BG00012.

Arms: arm 1: Participants will receive dimethyl fumarate 240 milligrams (mg) capsule twice daily (BID) orally and placebo subcutaneous (SC) injection every 2 weeks for up to 96 weeks (2 years). arm 2: Participants will receive peginterferon beta-1a 125 micrograms (µg) SC injection every 2 weeks and placebo capsule BID orally for up to 96 weeks (2 years). arm 3: Participants will receive placebo SC injection every 2 weeks and placebo capsule BID orally for up to 96 weeks (2 years)
Interventions: intervention 1: Dimethyl Fumarate intervention 2: Peginterferon Beta-1a intervention 3: Placebo
Intervention descriptions: intervention 1: Administered as specified in the treatment arm. intervention 2: Administered as specified in the treatment arm. intervention 3: Administered as specified in the treatment arm.

Protocol documents:
Prot_000.pdf: 




Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
3
TABLE OF CONTENTS
SPONSOR SIGNATURE PAGE ....................................................................................................2
TABLE OF CONTENTS.................................................................................................................3
1.
SPONSOR INFORMATION .....................................................................................10
2.
LIST OF ABBREVIATIONS.....................................................................................11
3.
SYNOPSIS .................................................................................................................13
4.
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR STUDY 
800MS301...................................................................................................................17
4.1.
Study Schematic .........................................................................................................17
4.2.
Schedule of Activities.................................................................................................18
4.3.
Additional Information ...............................................................................................23
4.3.1.
Administration of Study Treatment............................................................................23
4.3.2.
Blood Volumes...........................................................................................................23
4.3.3.
Site Personnel .............................................................................................................25
5.
INTRODUCTION......................................................................................................28
5.1.
Overview of Multiple Sclerosis..................................................................................28
5.2.
Current Therapies for Multiple Sclerosis ...................................................................28
5.3.
Profile of Previous Experience With BG00012 and BIIB017....................................29
5.3.1.
Nonclinical Experience With BG00012.....................................................................29
5.3.2.
Clinical Experience With BG00012 ...........................................................................29
5.3.3.
Nonclinical Experience With BIIB017.......................................................................31
5.3.4.
Clinical Experience With BIIB017.............................................................................31
5.4.
Study Rationale...........................................................................................................32
5.5.
Rationale for Dosing Regimen ...................................................................................33
5.5.1.
Rationale for Comparator/Reference Product or Placebo ..........................................34
6.
STUDY OBJECTIVES AND ENDPOINTS..............................................................35
6.1.
Primary Objective and Endpoint ................................................................................35
6.2.
Secondary Objectives and Endpoints .........................................................................35
6.3.
35
7.
STUDY DESIGN .......................................................................................................37
7.1.
Study Overview ..........................................................................................................37


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
4
7.2.
Study Specifics ...........................................................................................................38
7.2.1.
Relapses ......................................................................................................................38
7.2.2.
40
7.2.3.
MS Relapses, Treatment, and Alternative MS Therapy.............................................41
7.2.4.
Study Treatment Holding and/or Stopping Rules.......................................................41
7.3.
Overall Study Duration and Follow-Up .....................................................................42
7.3.1.
Screening ....................................................................................................................42
7.3.2.
Treatment....................................................................................................................42
7.3.3.
Follow-Up...................................................................................................................42
7.4.
Study Stopping Rules .................................................................................................42
7.5.
End of Study ...............................................................................................................43
8.
SELECTION OF SUBJECTS ....................................................................................44
8.1.
Inclusion Criteria ........................................................................................................44
8.2.
Exclusion Criteria.......................................................................................................44
9.
ENROLLMENT, REGISTRATION, AND RANDOMIZATION ............................49
9.1.
Screening and Enrollment...........................................................................................49
9.2.
Randomization and Registration of Subjects..............................................................49
9.3.
Blinding Procedures....................................................................................................49
10.
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY...........................................51
10.1.
Discontinuation of Study Treatment...........................................................................51
10.2.
Withdrawal of Subjects From Study...........................................................................52
11.
STUDY TREATMENT USE .....................................................................................53
11.1.
Regimen......................................................................................................................53
11.1.1.
BG00012.....................................................................................................................53
11.1.2.
BIIB017 ......................................................................................................................53
11.1.3.
Placebo........................................................................................................................53
11.2.
Modification of Dose and/or Treatment Schedule......................................................54
11.2.1.
Dose Reduction...........................................................................................................54
11.2.2.
Dosing Interruption for Abnormal Laboratory Values...............................................54
11.2.3.
Resumption of Study Treatment Dosing ....................................................................56
11.2.4.
Subsequent Development of Additional Laboratory Abnormalities ..........................57


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
5
11.2.5.
Abnormal Urinalyses That Require Additional Evaluation........................................57
11.2.6.
Treatment Schedule for Subjects With Abnormal Lymphocyte Count......................57
11.2.6.1.
Schedule for Subjects on Study Treatment or Alternative Therapy With 
Lymphocyte Count <LLN ..........................................................................................57
11.2.6.2.
Schedule for Subjects Who Complete, Temporarily Withhold, or 
Permanently Discontinue Study Treatment for any Reason and Have 
Lymphocyte Count <LLN ..........................................................................................58
11.3.
Precautions..................................................................................................................60
11.4.
Compliance.................................................................................................................60
11.5.
Concomitant Therapy and Procedures........................................................................60
11.5.1.
Concomitant Therapy .................................................................................................60
11.5.1.1.
Allowed Concomitant Therapy...................................................................................60
11.5.1.2.
Disallowed Concomitant Therapy..............................................................................60
11.5.2.
Concomitant Procedures.............................................................................................61
11.6.
Continuation of Treatment..........................................................................................61
12.
STUDY TREATMENT MANAGEMENT................................................................62
12.1.
BG00012.....................................................................................................................62
12.1.1.
BG00012 Preparation .................................................................................................62
12.1.2.
BG00012 Storage........................................................................................................63
12.1.3.
BG00012 Handling and Disposal...............................................................................63
12.1.4.
BG00012 Accountability............................................................................................63
12.2.
BIIB017 ......................................................................................................................63
12.2.1.
BIIB017 Preparation...................................................................................................63
12.2.2.
BIIB017 Storage.........................................................................................................64
12.2.3.
BIIB017 Handling and Disposal.................................................................................64
12.2.4.
BIIB017 Accountability..............................................................................................64
12.3.
Placebo........................................................................................................................64
12.4.
Additional Protocol-Designated Products ..................................................................65
13.
EFFICACY ASSESSMENTS ....................................................................................66
13.1.
Clinical Efficacy Assessments....................................................................................66
13.2.
Radiological Efficacy Assessments............................................................................66
13.3.
Additional Assessments..............................................................................................66
14.
SAFETY ASSESSMENTS ........................................................................................67


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
6
14.1.
Clinical Safety Assessments.......................................................................................67
14.2.
67
14.3.
68
15.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................69
15.1.
Definitions ..................................................................................................................69
15.1.1.
Adverse Event.............................................................................................................69
15.1.2.
Serious Adverse Event................................................................................................69
15.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments................70
15.2.
Safety Classifications..................................................................................................70
15.2.1.
Investigator Assessment of Events.............................................................................70
15.2.2.
Relationship of Events to Study Treatment................................................................71
15.2.3.
Severity of Events.......................................................................................................71
15.2.4.
Expectedness of Events ..............................................................................................71
15.3.
Monitoring and Recording Events..............................................................................71
15.3.1.
Adverse Events ...........................................................................................................71
15.3.2.
Serious Adverse Events..............................................................................................72
15.3.3.
Immediate Reporting of Serious Adverse Events.......................................................72
15.3.3.1.
Deaths .........................................................................................................................73
15.3.4.
Suspected Unexpected Serious Adverse Reactions....................................................73
15.4.
Procedures for Handling Special Situations ...............................................................74
15.4.1.
Pregnancy ...................................................................................................................74
15.4.2.
Overdose.....................................................................................................................74
15.4.3.
Medical Emergency....................................................................................................74
15.4.3.1.
Unblinding for Medical Emergency...........................................................................74
15.5.
Contraception Requirements ......................................................................................75
15.6.
Safety Responsibilities................................................................................................76
15.6.1.
The Investigator..........................................................................................................76
15.6.2.
Biogen.........................................................................................................................76
16.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........77
16.1.
Efficacy.......................................................................................................................77
16.1.1.
Analysis Population....................................................................................................77


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
7
16.1.2.
Methods of Analysis...................................................................................................77
16.1.2.1.
Analysis of the Primary Endpoint...............................................................................77
16.1.2.2.
Analysis of the Secondary Endpoints.........................................................................78
16.1.2.3.
79
16.2.
Pharmacokinetics........................................................................................................79
16.3.
Pharmacodynamics.....................................................................................................79
16.4.
79
16.5.
Safety..........................................................................................................................80
16.5.1.
Analysis Population....................................................................................................80
16.5.2.
Methods of Analysis...................................................................................................80
16.5.2.1.
Adverse Events ...........................................................................................................80
16.5.2.2.
80
16.5.2.3.
81
16.5.2.4.
81
16.5.2.5.
81
16.6.
81
16.6.1.
81
16.6.2.
81
16.7.
Interim Analyses.........................................................................................................82
16.8.
Sample Size Considerations .......................................................................................82
17.
ETHICAL REQUIREMENTS ...................................................................................83
17.1.
Declaration of Helsinki...............................................................................................83
17.2.
Ethics Committee........................................................................................................83
17.3.
Subject Information and Consent ...............................................................................83
17.4.
Subject Data Protection ..............................................................................................84
17.5.
Compensation for Injury.............................................................................................85
17.6.
Conflict of Interest......................................................................................................85
17.7.
Registration of Study and Disclosure of Study Results..............................................85
18.
ADMINISTRATIVE PROCEDURES.......................................................................86
18.1.
Study Site Initiation....................................................................................................86
18.2.
Quality Assurance.......................................................................................................86
18.3.
Monitoring of the Study..............................................................................................86


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
8
18.4.
Study Funding.............................................................................................................86
18.5.
Publications.................................................................................................................86
19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION........................87
19.1.
External Contract Organizations.................................................................................87
19.1.1.
Contract Research Organization.................................................................................87
19.1.2.
Interactive Response Technology...............................................................................87
19.1.3.
Electronic Data Capture..............................................................................................87
19.1.4.
Central Laboratories for Laboratory Assessments .....................................................87
19.1.5.
Central Facility for Other Assessments ......................................................................87
19.2.
Study Committees.......................................................................................................88
19.2.1.
Data Safety Monitoring Committee............................................................................88
19.2.2.
Steering (Advisory) Committee..................................................................................88
19.3.
Changes to Final Study Protocol ................................................................................88
19.4.
Ethics Committee Notification of Study Completion or Termination........................88
19.5.
Retention of Study Data..............................................................................................89
19.6.
Study Report Signatory...............................................................................................89
20.
REFERENCES ...........................................................................................................90
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL.........................................93
LIST OF TABLES
Table 1:
Study Activities and Assessments ..............................................................................18
Table 2:
Study Activities and Assessments (Unscheduled Visits) ...........................................21
Table 3:
Blood Volumes by Visit .............................................................................................24
Table 4:
Blood Volumes by Visit (Unscheduled Visits) ..........................................................24
Table 5:
Laboratory Criteria Requiring Withholding or Permanent Discontinuation of 
Study Treatment or Alternative Therapy with BG00012 or BIIB017........................54
Table 6:
Lymphocyte Count Criteria Requiring Permanent Discontinuation of Study 
Treatment or Alternative Therapy ..............................................................................58
Table 7:
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs ...................81


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
9
LIST OF FIGURES
Figure 1:
Study Design...............................................................................................................17
Figure 2:
Flow Diagram for Relapse Evaluation .......................................................................40
Figure 3:
Schedule for Subjects Who Complete, Temporarily Withhold, or 
Permanently Discontinue Study Treatment for Any Reason and Have a 
Lymphocyte Count <LLN ..........................................................................................59


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
10
1.
SPONSOR INFORMATION
Biogen is responsible for initiating and managing the study.
Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead, Berkshire 
SL6 4AY
United Kingdom
Biogen Australia PTY Ltd.
Suite 1, Level 3
123 Epping Road
North Ryde, NSW 2113
Australia
For urgent medical issues in which the study’s Medical Monitor should be contacted, please refer 
to the Study Reference Guide’s Official Study Contact List for complete contact information.
Biogen may transfer any or all of its study-related responsibilities to a contract research 
organization (CRO) and other third parties; however, Biogen retains overall accountability for 
these activities.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
11
2.
LIST OF ABBREVIATIONS 
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
BID
twice daily
BMI
body mass index
CI
confidence interval
CNS
central nervous system
CRF
case report form
CRO
contract research organization
DHA
Directions for Handling and Administration
DMF
dimethyl fumarate
DMT
disease-modifying therapy
DSMC
Data Safety Monitoring Committee 
ELISA
enzyme-linked immunosorbent assay
FLS
flu-like symptoms
GA
glatiramer acetate
GCP
Good Clinical Practice
Gd
gadolinium
GI
gastrointestinal
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Council for Harmonisation
IFN
interferon


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
12
ILM
Independent Laboratory Monitor
IM
intramuscular
IRT
interactive response technology
ITT
intent-to-treat 
IV
intravenous
IVMP
intravenous methylprednisolone
LAR
legally authorized representative
LLN
lower limit of normal
MMF
monomethyl fumarate
MRI
magnetic resonance imaging
MS
multiple sclerosis
NSAID
nonsteroidal anti-inflammatory drug
PD
pharmacodynamic
PEG
polyethylene glycol
PFS
prefilled syringe
PK
pharmacokinetic
PML
progressive multifocal leukoencephalopathy
RBC
red blood cell
RMS
relapsing multiple sclerosis
RRMS
relapsing-remitting multiple sclerosis
SABR
Safety and Benefit-Risk Management
SAE
serious adverse event
SC
subcutaneous
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamate pyruvate transaminase
SUSAR
suspected unexpected serious adverse reaction
TID
3 times daily
TTFR
time to first relapse
ULN
upper limit of normal
WBC
white blood cell


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
13
3.
SYNOPSIS
Protocol Number:
800MS301
Protocol Title:
A Randomized, Double-Blind, Double-Dummy, 
Placebo-Controlled, 3-Arm, Parallel-Group Study in 
Pediatric Subjects Aged 10 Through 17 Years to Evaluate 
the Efficacy and Safety of BG00012 and BIIB017 for the 
Treatment of Relapsing-Remitting Multiple Sclerosis
Version Number:
4 
Name of Study Treatment:
BG00012 (dimethyl fumarate; Tecfidera®); BIIB017 
(peginterferon beta-1a; Plegridy®)
Study Indication:
Relapsing-remitting multiple sclerosis (RRMS)
Study Rationale:
With limited availability of multiple sclerosis (MS) 
therapies for the pediatric population, there exists a 
significant need for safe, efficacious, and convenient 
treatment options.  Given the pathophysiological similarities 
between adult and pediatric MS, therapies effective for MS 
in adults may also be effective in the pediatric population. 
BG00012 and BIIB017 are approved therapies for MS in 
adults.
BG00012
In adult subjects with RRMS, BG00012 has demonstrated a 
significant effect on clinical endpoints of relapse and 
disability, as well as on magnetic resonance imaging (MRI) 
endpoints of MS disease activity in 2 large Phase 3 studies 
(Study 109MS301 and Study 109MS302).  The results from 
these 2 pivotal studies showed that BG00012 was well 
tolerated and has an acceptable safety profile.  The 
extension study of these pivotal studies, Study 109MS303, 
confirmed the longer-term efficacy and safety of BG00012.  
Given the demonstrated efficacy and acceptable safety 
profile of BG00012 in adult subjects, together with the oral 
dosing regimen, BG00012 may be a potential treatment 
option for the pediatric population.   
BIIB017
Interferon (IFN)-beta (β) therapies (Avonex®, Rebif®, 
Betaferon®, and Extavia®) have been shown to reduce 
relapse rates in adult subjects with RRMS with acceptable 


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
14
safety and tolerability.  The use of IFN-β in the pediatric MS 
population is well documented and appears to be well 
tolerated.
BIIB017, a polyethylene glycol (PEG) derivatized 
(PEGylated) form of IFN β-1a, has the same mechanism of 
action as non-PEGylated IFNs.  A pivotal Phase 3 study 
(Study 105MS301) showed that BIIB017 was efficacious 
and safe in the adult RRMS population.  The efficacy and 
safety of BIIB017 were confirmed in the extension study 
(Study 105MS302).  While it is difficult to compare across 
studies, it appears that the efficacy and safety in adult 
RRMS population are similar between non-PEGylated and 
PEGylated IFNs.  Given the previous experience of IFN use 
in the pediatric MS population and that BIIB017 has 
demonstrated similar safety profiles as non-PEGylated IFNs 
in the adult population, BIIB017 may be a potential 
treatment option for the pediatric population.  
This 3-arm, parallel group study is being conducted in the 
pediatric population to evaluate the efficacy and safety of 
the following:

BG00012 compared with placebo 
and 

BIIB017 compared with placebo
Phase of Development:
3
Study Objectives and 
Endpoints:
The primary objective of the study is to evaluate the efficacy 
of BG00012 and BIIB017, both compared with placebo, in 
pediatric subjects with RRMS.
The primary endpoint that relates to this objective is the 
time to first relapse (TTFR).
The secondary objectives and endpoints are as follows:

To evaluate the safety and tolerability of BG00012 
and BIIB017

Occurrence of adverse events (AEs) and serious 
adverse events (SAEs)

To assess the effect of BG00012 and BIIB017, both 
compared with placebo, on additional clinical and 
radiological measures of disease activity


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
15

Number of new or newly enlarging T2 
hyperintense lesions on brain MRI scans at 
Weeks 48 and 96

Number of gadolinium (Gd)-enhancing lesions at 
Baseline and at Weeks 48 and 96

Annualized relapse rate at Weeks 48 and 96
Additional objectives and endpoints are listed in Section 6.3.
Study Design:
This is a randomized, multicenter, double-blind, double-
dummy, placebo-controlled, 3-arm, parallel-group study.
Study Location:
This study will be conducted globally at approximately 
50 sites.
Number of Planned Subjects:
Approximately 260 subjects will be enrolled.
Study Population:
This study will be conducted in subjects aged 10 to 17 years, 
inclusive, with a diagnosis of RRMS as defined by the 
revised consensus definition for pediatric MS.
Detailed criteria are described in Section 8.
Treatment Groups:
Subjects will be randomized in a 1:2:2 ratio to the following 
3 treatment groups:

Treatment Group 1:  Approximately 52 subjects will 
receive BG00012 240 mg twice daily (BID) orally and 
placebo subcutaneous (SC) every 2 weeks for up to 96 
weeks (2 years).

Treatment Group 2:  Approximately 104 subjects will 
receive BIIB017 125 µg SC every 2 weeks and 
placebo BID orally for up to 96 weeks (2 years).

Treatment Group 3:  Approximately 104 subjects will 
receive placebo SC every 2 weeks and placebo BID 
orally for up to 96 weeks (2 years)
Titration
Subjects randomized to BG00012 will receive a starting 
dose of 120 mg BID orally for 7 days followed by the 
maintenance dose of 240 mg BID for the remainder of the 
study.  


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
16
Subjects randomized to BIIB017 will be titrated to the target 
dose of 125 µg SC:  63 µg on Day 1, 94 µg at Week 2, and 
125 µg at Week 4.  Once subjects reach the 125 µg target 
dose, they will continue on BIIB017 125 µg SC 
administered every 2 weeks for the remainder of the study.
Duration of Treatment and 
Follow-up:
Study duration for each subject will be approximately 
106 weeks: a 6-week Screening Period, a 96-week (2-year) 
Treatment Period, and a 4-week Post-Treatment Period.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
17
4.
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR 
STUDY 800MS301
4.1.
Study Schematic
The study design for Study 800MS301 is shown in Figure 1, and the study activities are shown in
Table 1 and Table 2.
Figure 1:
Study Design
Screening Visit
Within 6 weeks of Baseline
Baseline Visit (Day 1)
Randomized 1:2:2
Treatment (Tx) Period:  Double-Blind, Double-Dummy
On-Site or Phone Visits:  Weeks  2 & 6
     On-site Clinic Visits:  Weeks  4, 8, 12, 24, 36, 48, 60, 72, 84 & 96
                 Phone Visits:   Weeks 18, 30, 42, 54, 66, 78 & 90
Post-Treatment Visit
Week 100
Relapse or 
Progression
No Incident
Withdrawal
BG00012
BIIB017
PLACEBO
Clinic Visit within 4 Weeks

After start of open-label or alternative Tx

After last dose following a withdrawal
Treatment Options

Immediate or eventual withdrawal

Continue on study Tx to completion

Start open-label Tx with BG00012

Start alternative Tx












Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
23
4.3.
Additional Information
4.3.1.
Administration of Study Treatment
To ensure blinding across the 3 treatment groups, each subject will receive BG00012 or placebo 
capsules administered orally BID and BIIB017 or placebo injection administered SC every 
2 weeks.  Subjects can either swallow the capsules whole (preferred) or open the capsules and 
mix with food immediately prior to consumption.  If the subject is unable to self-administer the 
SC treatment, the parent will be allowed to administer the treatment.  
4.3.2.
Blood Volumes
Every effort will be made to collect the minimum blood volume needed per protocol assessment.  
The blood volumes required for this study do not exceed the recommended pediatric blood 
volume limits for sampling (i.e., volumes do not exceed 3% of the total blood volumes during a 
period of 4 weeks and volumes do not exceed 1% at any single visit [European Commission 
2008]).  For example, in a 30-kg child (the lowest possible weight permitted in this study), it was 
estimated that 1% of the total volume would be approximately 21 mL.  Children weighing more 
than 30 kg would have higher permitted amounts.  The total blood volumes drawn at each visit 
are provided in Table 3 and Table 4. 


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
24
Table 3:
Blood Volumes by Visit
Screening 
Visit
Randomized, Double-Blind, Double-Dummy, Placebo-Controlled Treatment Period
Post-
Treatment 
Visit
(Within 
6 Weeks of 
Baseline)
Baseline 
Visit 
(Day 1)
Wk 4 
±2 D
Wk 8 
±7 D
Wk 
12 
±7 D
Wk 
24 
±7 D
Wk 
36 
±7 D
Wk 
48 
±7 D
Wk 
60 
±7 D
Wk 
72 
±7 D
Wk 
84 
±7 D
Wk 
96 
±7 D
Wk 100 
±7 D
Blood draw 
volume (mL)
11.0
14.0
5.5 
14.0 
7.0
15.5 
7.0
15.5 
7.0
15.5 
7.0
15.5 
7.0
D = days; Wk = weeks
Table 4:
Blood Volumes by Visit (Unscheduled Visits)
Early Withdrawal Visit
Open-Label BG00012 
(Tecfidera)/Alternative Therapy Visit
(Within 4 Weeks after Switch if Next 
Study Visit not Within 4 Weeks)
Lymphocyte 
Follow-Up Visit
Unscheduled Relapse 
Assessment Visit
Blood draw 
volume (mL)
15.5
7.0
2.0
7.0






Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
27
The examining technician must remain blinded to AEs, concomitant medications, 
 
, MRI data, and any other data that have the potential of revealing the treatment assignment.  
To ensure consistency across sites, examining technicians must undergo a standardized training 
session prior to enrollment of subjects at their site.  All sites should attempt to maintain the same 
examining technician throughout the study.  If an examining technician has to be replaced, the 
new examining technician must undergo a training session.
The MRI technician will be responsible for performing brain MRI scans with and without Gd at 
all protocol-required timepoints.  Study-specific MRI scan procedures and protocols with and 
without Gd, which will be provided prior to study start, must be followed.  Subjects should be 
offered the use of topical anesthetics for venipuncture, and an intravenous (IV) line insertion 
must be performed for injection of Gd.
The pharmacist (or authorized designee) will be responsible for the storage, distribution, and site 
accountability of study treatment.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
28
5.
INTRODUCTION
BG00012 is a fumarate ester drug product formulation containing the active ingredient dimethyl 
fumarate (DMF), which is rapidly and completely metabolized to monomethyl fumarate (MMF).  
BIIB017 is a PEGylated form of IFN β-1a.  
BG00012 (as Tecfidera®) and BIIB017 (as Plegridy®) have been approved for the treatment of 
MS in adult populations in the United States, Canada, Australia, the European Union, and other 
countries.
5.1.
Overview of Multiple Sclerosis
MS is a chronic and neurodegenerative disease of the central nervous system (CNS) that is 
characterized by inflammation, cell-mediated demyelination, and oligodendrocyte and neuronal 
loss.  It is the most common demyelinating disorder of the CNS, affecting approximately 
2.5 million people worldwide.  The onset of MS typically occurs between the ages of 20 and 
40 years [O'Connor and Group 2002].  Although rare in the pediatric population (patients less 
than 18 years of age), approximately 2% to 5% of all MS cases have onset in childhood [Atzori 
2009; Chitnis 2009; Confavreux and Vukusic 2008; Ferreira 2008; Pohl 2007].  
Pathologically, MS is characterized by multifocal areas of demyelination with loss of 
oligodendrocytes and astroglial scarring.  Clinically, patients with MS exhibit a diverse range of 
neurological signs and symptoms attributed to white matter lesions that are disseminated in time 
and space; these signs and symptoms can occur in sudden attacks or can be insidious and 
progressive.  The majority of patients with MS present with a RRMS course, during which 
patients experience discrete episodes of neurological dysfunction (i.e., relapses) that can last 
several days to several weeks, and that occur intermittently over many years [Lublin and 
Reingold 1996].  Disease progression and advancing disability supervene in the majority of 
patients who start with a relapsing remitting course (secondary progression).  Disease 
progression can also begin insidiously from the onset of the disease (primary progression).
5.2.
Current Therapies for Multiple Sclerosis 
Therapies for MS include symptomatic treatments and disease-modifying therapies (DMTs).  
There are several DMTs that are currently approved or under review for use in patients with 
relapsing MS that differ in method of administration, convenience, efficacy, safety, and putative 
mechanism of action.  They include IFN-β products (Avonex®, Rebif®, 
Betaseron®/Betaferon®/Extavia®, and Plegridy®), glatiramer acetate (GA; Copaxone®), 
natalizumab (Tysabri®), alemtuzumab (Lemtrada®), fingolimod (Gilenya™), mitoxantrone 
(Novantrone®), teriflunomide (Aubagio®), ocrelizumab (Ocrevus®) siponimod (Mayzent®), 
cladribine (Mavenclad®) and dimethyl fumarate (Tecfidera®).
The most commonly used therapies in the pediatric population are IFN-β and GA [Waldman 
2011].  IFN-β and GA are first-line injectable therapies that have been available commercially 


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
29
for more than 15 years and have an established safety and efficacy profile.  The currently 
available IFN-β therapies and GA both require either intramuscular (IM) or SC injections, from 
as few as once every 2 weeks (PEGylated IFN β-1a SC) to once a week (IFN β-1a IM), to as 
many as 3 to 4 times a week (IFN β-1a SC, IFN β-1b SC) and 7 times a week (GA SC).  
Despite the availability of several therapies for the treatment of MS in adults, there remains an 
unmet need for safe and effective treatments for the pediatric population.  Currently, there are 
limited treatments that have been approved to treat MS in the pediatric population.  Current 
treatment options for pediatric MS are frequently adapted from therapeutic paradigms for adults, 
with dosing recommendations based solely on adult data and expert opinion, because there are 
no available data on pharmacological characterization for any of these DMTs in the pediatric 
population.
5.3.
Profile of Previous Experience With BG00012 and BIIB017
5.3.1.
Nonclinical Experience With BG00012
Nonclinical safety studies were performed to support the development of BG00012 for the 
treatment of MS.  CNS, respiratory, and cardiovascular safety studies demonstrated no drug-
related adverse effects on those systems, which is consistent with human data.  There were no 
findings of mutagenicity, fertility, and teratogenicity.  Repeat-dose toxicology studies were 
performed in rodents (mouse and rat) and nonrodents (dog and monkey).  The findings in the 
liver, forestomach, and testis were concluded to be of limited concern to human risk.  In the male 
rat juvenile toxicology study that specifically evaluated the reproductive organs, there were no 
toxicology findings.  Kidney findings seen in animals were not observed in humans.  In 2-year 
(life-time) carcinogenicity studies, renal tumors were attributed to a rodent-specific nephropathy.  
See the Investigator’s Brochure for detailed information on nonclinical studies.
5.3.2.
Clinical Experience With BG00012
The efficacy and safety of BG00012 are well established based on data from the clinical 
development program for BG00012 in adult subjects with MS.  Over 4,700 subjects with MS 
have received BG00012 in the clinical trial setting, accounting for approximately 
13,684 subject-years of exposure, as of 26 March 2019. 
In 2 pivotal Phase 3 placebo-controlled studies, BG00012 demonstrated robust efficacy in 
subjects with RRMS (Studies 109MS301 and 109MS302).  The results from these pivotal studies 
showed that 2 dosing regimens (240 mg BID and 240 mg 3 times daily [TID]) provided similar 
and consistent efficacy in reducing measures of relapse, delaying the accumulation of disability 
associated with MS, and resulted in improving MRI measures of MS disease activity.  Treatment 
with BG00012 for up to 2 years resulted in statistically significant and substantial reductions in 
the risk of relapse and in annualized relapse rate in both studies.  A robust treatment effect was 
evident within the initial 6 months of treatment and was sustained for up to 2 years of treatment.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
30
Overall, safety data from the clinical development program showed that BG00012 was well 
tolerated and has an acceptable safety profile.  The results from the 2 pivotal studies showed that 
both dosing regimens (240 mg BID and 240 mg TID) demonstrated similar and acceptable safety 
profiles in subjects with MS.  The most common AEs (incidence ≥5%) that also occurred at an 
incidence of ≥2% higher in subjects treated with BG00012 compared with placebo were flushing 
and hot flush, gastrointestinal (GI) events (diarrhea, nausea, abdominal pain upper, abdominal 
pain, vomiting, and dyspepsia), skin events (pruritus, rash, and erythema), nasopharyngitis, 
urinary tract infection, upper respiratory tract infection, albumin urine present, proteinuria, and 
microalbuminuria.  
In placebo-controlled studies, decreases in mean white blood cell (WBC) counts and lymphocyte 
counts were observed over the first year of treatment (approximately 10% and 30%, respectively) 
with both dose regimens of BG00012.  Mean WBC and lymphocyte counts then plateaued and 
remained stable, even during longer periods of observation of approximately 5.25 years.  
Analysis of the data did not show a clear correlation between infections, serious infections, and 
lymphocyte counts.  No increased risk of infection, serious infection, or opportunistic infection 
was observed in subjects treated with BG00012 in the placebo-controlled studies.  With 
open-label and marketed use of BG00012, progressive multifocal leukoencephalopathy (PML) 
has been observed in the setting of moderate to severe prolonged lymphopenia.  With open-label 
and marketed use of BG00012, there has been no other evidence of increased risk of infections, 
serious infections, or opportunistic infections.  
BG00012 was also associated with a small increase in the incidence of elevations of liver 
transaminases compared to placebo.  In the controlled studies, this increase was primarily due to 
differences that occurred within the first 6 months of treatment.  The majority of subjects with 
elevations had alanine transaminase (ALT) or aspartate transaminase (AST) levels <3 times the 
upper limit of normal (ULN).  No patients had elevations of ALT or AST ≥3 × ULN associated 
with an elevation in total bilirubin of >2 × ULN.  There were no cases of hepatic failure due to 
BG00012.  During extended treatment with BG00012, ALT and AST levels remained stable 
through 3.5 years of observation.  With marketed use of BG00012, liver function abnormalities 
(elevations in liver transaminases ≥3 × ULN with concomitant elevations in total bilirubin ≥2 × 
ULN) have been reported following BG00012 administration; these abnormalities resolved upon 
treatment discontinuation.  
Although the kidney was identified as a target organ of BG00012 toxicity in nonclinical studies, 
subjects treated with BG00012 in the clinical studies did not appear to have a higher risk of renal 
or urinary events.  Small increases in proteinuria were observed, but the increases did not appear 
to be clinically significant.  On laboratory evaluation, there were no clinically relevant changes 
in blood urea nitrogen, creatinine, electrolytes, calcium, phosphorus, parathyroid hormone, or 
1,25-dihydroxyvitamin D.  In the Phase 3 studies (Studies 109MS301 and 109MS302), there 
were no differences between placebo and BG00012 BID in the incidence of proteinuria on 2 
consecutive urinalyses (defined as trace or greater) or on findings of 3+ or 4+ protein, both of 
which are potential indicators of significant proteinuria and renal dysfunction.  In addition, there 
was no evidence of changes in β2-microglobulin and microalbumin, 2 more sensitive and 
specific markers of renal tubular dysfunction, over time, even during longer periods of 
observation of approximately 3.5 years.  


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
31
In the controlled studies, there was no increased incidence of malignancies in subjects who 
received BG00012 compared with placebo.  The types of malignancies observed and their 
incidence were within expected background rates.
5.3.3.
Nonclinical Experience With BIIB017
The nonclinical toxicology testing of BIIB017 has shown that BIIB017 is well tolerated and has 
identified effects consistent with the known nonclinical experience with type I IFNs.
See the Investigator’s Brochure for detailed information on nonclinical studies.
5.3.4.
Clinical Experience With BIIB017
The Phase 3 multicenter, randomized, double-blind, parallel-group, placebo-controlled clinical 
study (Study 105MS301) evaluated the efficacy and safety of BIIB017 125 µg SC administered 
every 2 or 4 weeks in subjects with relapsing MS (RMS).  In this study, 1512 subjects were 
dosed with either placebo or BIIB017.  
The efficacy results from the placebo-controlled phase (Year 1) of Study 105MS301 demonstrate 
that BIIB017 produced meaningful reductions in clinical and radiological measures of MS 
disease activity.  At Year 1, BIIB017 125 µg SC every 4 weeks and every 2 weeks had a 
statistically significant effect on the primary efficacy endpoint of annualized relapse rate and all 
secondary efficacy endpoints (proportion of subjects with relapse, number of new or newly 
enlarging T2 hyperintense lesions, and 12- and 24-week confirmed disability progression by 
EDSS) relative to placebo.  The effect sizes were consistently larger for the BIIB017 every 2 
weeks dose for all except for the risk of disability progression, which was similar for both doses.  
Efficacy was maintained through the second year of the study, especially in the BIIB017 every 2 
weeks group.  Statistically significant differences were observed in the BIIB017 125 µg SC 
every 2 weeks group compared with the BIIB017 125 µg SC every 4 weeks group for 2 years in 
relapse-related endpoints (reductions in annualized relapse rate and risk of relapse), the risk of 
24-week confirmed disability progression, and the number of lesions on MRI (reductions in 
Gd-enhancing, new or newly enlarging T2 hyperintense, and new T1 hypointense lesions).
Safety data demonstrated that BIIB017 was generally well tolerated and had a very similar and 
favorable safety profile when administered as either an every 2- or 4-week dose.  The safety 
profile of both BIIB017 treatment groups was consistent with the well-established safety profile 
of the IFN-β class of therapies currently approved for the treatment of patients with relapsing 
MS.    
Most AEs that were reported in BIIB017-treated subjects were nonserious in nature and mild or 
moderate in severity.  The most common adverse drug reactions (incidence ≥10%) in the 
BIIB017 every 2 weeks group were injection-site reactions (injection-site erythema, injection-
site pain, and injection-site pruritus), flu-like symptoms (FLSs; influenza-like illness, pyrexia, 
myalgia, chills, asthenia, and arthralgia), and headache.  Similar results were observed with the 
BIIB017 every 4 weeks group.  Influenza-like illness, injection-site erythema, pyrexia, and ALT 
increased were the most frequently reported AEs leading to investigational product 


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
32
discontinuation in BIIB017-treated subjects, and the incidence of each of these was ≤2% in each 
BIIB017 group.  The incidence of SAEs was low and similar across treatment groups.  
The incidence of hepatic disorders was low and consistent with the known hepatic AE profile of 
other IFN-β therapies.  There was a dose-dependent increase in ALT and AST levels from 
baseline, but the majority of these elevations were <3 × ULN.  Elevations of ALT and AST 
(>5 × ULN) were infrequently reported, and the incidence was balanced between the BIIB017 
and placebo groups.  Decreases in WBC counts (<3.0 × 109/L) were observed in a dose-related 
fashion in BIIB017-treated subjects and at a higher rate than in placebo-treated subjects.  Mean 
WBC counts remained within normal limits throughout the study, and the decreases in WBC 
counts were not associated with an increased risk of infections or serious infections.  
There was no increased risk of infection, serious infection, or opportunistic infection in the 
BIIB017-treated subjects as compared with placebo-treated subjects in Year 1 (the placebo-
controlled phase) of Study 105MS301, and BIIB017 treatment did not increase the risk of 
cardiovascular disorders, seizure events, depression and suicidal ideation, autoimmune disorders, 
or malignancy.  The safety results during the 2-year study period of Study 105MS301 were 
similar to those of Year 1 and demonstrated a similar safety profile for the BIIB017 every 4 
weeks and every 2 weeks groups.
5.4.
Study Rationale
With limited availability of MS therapies for the pediatric population, there exists a significant 
need for safe, efficacious, and convenient treatment options. Given the pathophysiological 
similarities between adult and pediatric MS [Chitnis 2013; Dale 2013; Hintzen and van Pelt 
2013], therapies effective for MS in adults may also be effective in the pediatric population.
BG00012 and BIIB017 are approved therapies for MS in adults.
BG00012
In adult subjects with RRMS, BG00012 has demonstrated a significant effect on clinical 
endpoints of relapses and disability, as well as on MRI endpoints of MS disease activity in 
2 large Phase 3 studies, Study 109MS301 and Study 109MS302.  The results from these 
2 pivotal studies showed that BG00012 was well tolerated and has an acceptable safety profile. 
The extension study of these pivotal studies, Study 109MS303, confirmed the longer-term 
efficacy and safety of BG00012.  Given the demonstrated efficacy and favorable safety profile of 
BG00012 in adult subjects, together with the oral dosing regimen, BG00012 may be a potential 
treatment option for the pediatric population.   
BIIB017
IFN-β therapies (Avonex, Rebif, Betaferon, and Extavia) are widely used injectable treatments 
and have been shown to reduce relapse rates in adults with RRMS.  Avonex and Betaferon have 
shown to attenuate disease progression.  Safety and tolerability of the IFN-β therapies have been 
well documented in several publications [Jacobs 2000; Johnson 1995; PRISMS Study Group 
2001; The IFNB Multiple Sclerosis Study Group 1993].  The use of IFN-β in pediatric patients is 
well documented and appears to be well tolerated [Adams 1999; Banwell 2006; Ghezzi 2005; 


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
33
Ghezzi 2009; Mikaeloff 2008; Mikaeloff 2001; Pohl 2005; Tenembaum and Segura 2006; 
Waubant 2001].  IFNs appear to be efficacious and safe in the pediatric population using the 
same doses as in the adult population.  
Like other biologics, BIIB017, a polyethylene glycol (PEG; PEGylated) form of IFN β-1a, is 
believed to be absorbed through the lymphatic system and by blood capillary absorption after SC 
or IM administration.  Given the molecular size of BIIB017 (~44 kDa), lymphatic absorption 
may dominate the bioavailability of BIIB017.  The absorption, distribution, metabolism, and 
excretion of BIIB017 is expected to be mechanistically similar between the targeted pediatric 
subjects (10 to 17 years old) and adults.  
BIIB017 has the same mechanism of action as non-PEGylated IFN-βs.  Phase 1 study results 
showed that BIIB017 administered at 125 µg SC achieved pharmacological effects that were 
both consistent with activation of the Type 1 IFN receptor and similar to or greater than those 
observed after single doses of Avonex (IFN β-1a IM) 30 µg.  A large pivotal Phase 3 study
(Study 105MS301) showed that BIIB017 was efficacious and safe in the adult RRMS 
population.  While it is difficult to compare across studies, it appears that the efficacy and safety 
in the adult RRMS population are similar between non-PEGylated IFN-β and PEGylated IFNs.  
Given the previous experience of IFN use in the pediatric MS population and that BIIB017 has 
demonstrated similar safety profiles as non-PEGylated IFNs in the adult population, BIIB017
may be a potential treatment option for the pediatric population.  
This 3-arm, parallel-group study is being conducted in the pediatric population to evaluate the 
efficacy and safety of the following:

BG00012 compared with placebo 
and 

BIIB017 compared with placebo
5.5.
Rationale for Dosing Regimen
BG00012 240 mg BID administered orally and BIIB017 125 µg administered SC every 2 weeks 
are the dosages chosen for this study.
BG00012
Biogen recently conducted Study 109MS202 (NCT02410200) to evaluate the 
pharmacokinetic/pharmacodynamic (PK/PD) of BG00012 in 22 subjects 10 to17 years of age 
with RRMS.  Subjects received BG00012 120 mg BID for the first week and 240 mg BID for the 
remainder of the 24-week duration of treatment.  The PK parameters in this study, as well as the 
neuroradiological efficacy and safety of BG00012, were consistent with those observed in adult 
MS patients.  These findings indicate that 240 mg BID is the appropriate dosage for the current 
study.
BIIB017
The BIIB017 dose regimen was chosen based on the positive benefit-risk profile demonstrated in 
the Phase 3 study (105MS301).  This dose is supported by a subgroup analysis, which 


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
34
demonstrated that AE incidence in BIIB017-treated subjects was not sensitive to body mass 
index (BMI), a surrogate for exposure.  This dose is further supported by results from modeling 
and simulation approaches.  While there were marginal to modest increases in pediatric 
compared with adult median area under the concentration-time curve and maximum observed 
plasma concentration, the simulated PK profiles of pediatric subjects largely overlapped those of 
adult subjects due to high PK variability.  Taken together, the findings indicate that 125 µg SC 
every 2 weeks is the appropriate dose for the current study.
5.5.1.
Rationale for Comparator/Reference Product or Placebo 
To date, there are few randomized, adequate, and well-controlled studies demonstrating that the 
agents available for treatment of MS in adults are safe and efficacious in pediatric patients.  A 
placebo control, therefore, is appropriate to evaluate the safety and efficacy of new therapies.  
Utilizing an active control in this setting presents challenges in interpreting the results against a 
therapy that has not been previously evaluated rigorously in the target population, as well as 
challenges in logistic feasibility because such studies require a much larger sample size.  To 
minimize any potential bias in the study conduct, a double-blind, double-dummy, 3-arm, parallel 
group, randomized design comparing BG00012 with placebo and BIIB017 with placebo was 
selected.  Furthermore, with careful considerations regarding the potential ethical concerns of 
such design in pediatric patients, TTFR was selected as the primary efficacy endpoint for this 
study, as recommended by the International Pediatric Multiple Sclerosis Study Group (IPMSSG) 
[Krupp 2013] to allow study subjects to receive an alternative therapy (at the discretion of the 
treating neurologist) if they experience a protocol-defined relapse or disability progression.






Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
37
7.
STUDY DESIGN
7.1.
Study Overview
This is a randomized, multicenter, double-blind, double-dummy, placebo-controlled, 3-arm, 
parallel-group study to evaluate the efficacy and safety of BG00012 and BIIB017 in pediatric 
subjects with RRMS.
Approximately 260 subjects, aged 10 to 17 years old, inclusive, with a diagnosis of RRMS as 
defined by the revised consensus definition for pediatric MS [Krupp 2013; Polman 2011] will be 
enrolled at approximately 50 sites globally.  Eligible subjects will be randomized within 6 weeks 
of screening.  At least 25% of subjects will be in the 10 to ≤14-year age group.  Subjects will be 
stratified by age (10 to ≤14 years of age and 15 to 17 years of age) and by site.  Subjects will be 
randomized (1:2:2) to treatment with BG00012, BIIB017, or placebo.  Clinic visits will occur at 
Day 1 and at Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, and 96.  Clinic visits at Weeks 2 and 6 are 
optional and, if not conducted, will occur by ‘phone.  Subjects will be contacted by ‘phone 
additionally at Weeks 18, 30, 42, 54, 66, 78, and 90.  Subjects randomized to BG00012 will 
receive a starting dose of 120 mg twice daily (BID) orally for 7 days followed by the 
maintenance dose of 240 mg BID orally.  Subjects randomized to BIIB017 will be titrated to the 
target dose of 125 µg:  63 µg on Day 1, 94 µg at Week 2, and 125 µg at Week 4.  Once subjects 
reach the 125 µg target dose, they will continue on BIIB017 125 µg subcutaneous (SC) 
administered every 2 weeks for the remainder of the study.  To ensure blinding across the 
3 treatment groups, each subject will receive BG00012 or placebo administered orally BID and 
BIIB017 or placebo administered SC every 2 weeks.
An Unscheduled Relapse Assessment Visit may occur as required to conduct neurological and
 evaluations within 72 hours of any new neurological symptoms that could indicate the 
onset of a clinical relapse.  Confirmed relapses may be treated at the discretion of the treating 
neurologist with intravenous methylprednisolone (IVMP) at any time from Baseline to Week 100 
and will not affect the subject’s eligibility to continue in the study. The primary endpoint of the 
study is the TTFR.  Therefore, subjects will be required to remain on assigned (blinded) study 
treatment until they experience their first protocol-defined relapse or disability progression.  
During the study, subjects who have a confirmed relapse or disability progression or high lesion 
burden on MRI at Week 48 (defined as ≥9 new/enlarged T2 lesions) will have the option of 
switching to an alternative therapy in accordance with local practices, or open-label BG00012 
(Tecfidera), at the discretion of the Investigator.  Subjects will discontinue blinded study 
treatment when they switch to an alternative therapy or open-label BG00012. Subjects who are 
switched to an alternative therapy or open-label BG00012 will remain in the study to complete 
the scheduled visits, along with any requisite safety monitoring.  Open-label BG00012 will only 
be provided until the subject completes or withdraws from the study or according to local 
regulatory requirements.




Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
39
detailed neurological examination and obtain an 
.  These new objective findings on 
neurological examination by the examining neurologist are required to determine whether a 
suspected protocol-defined relapse has occurred.  The examining neurologist’s findings will be 
provided to the treating neurologist via source documentation so he/she can evaluate treatment 
options.  Subjects may begin corticosteroid treatment of a confirmed relapse per protocol only 
after the examining neurologist has performed his/her examination and only after a 
Gd-enhancing MRI of the brain has been performed.  See Figure 2 for a flow diagram of relapse 
evaluation. 
If at any stage during relapse evaluation, i.e., the time of telephone contact, evaluation by the 
treating neurologist, and evaluation by the examining neurologist, the event is not determined to 
be a relapse, the specific reason for this determination must be recorded on the CRF. 






Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
42
7.3.
Overall Study Duration and Follow-Up
The study period will consist of Screening (up to 6 weeks), Treatment Period (up to 96 weeks), 
and Post-Treatment Period (4 weeks after the last dose of study treatment or alternative therapy).
Subjects who are allowed to resume study treatment following an interruption will restart dosing 
at a reduced dose and will be titrated to the maintenance dose.  
Subjects who withdraw prematurely will complete the Early Withdrawal Visit no later than 4 
weeks after taking their final dose of study treatment or alternative therapy.  Unscheduled 
Relapse Assessment Visit and Lymphocyte Follow-Up Visit will be performed as necessary.
7.3.1.
Screening
Subject eligibility for the study will be determined within 6 weeks prior to study entry.  The 
Screening Period begins on the day the subject signs the informed consent form (ICF).
7.3.2.
Treatment
Eligible subjects will report to the study site to receive study treatment at Baseline (Day 1) and at 
Weeks 4, 8, 12, 24, 36, 48, 60, 72, and 84.  Clinic visits at Weeks 2 and 6 are optional and, if not 
conducted, will occur by ‘phone.  Subjects will receive treatment for 96 weeks.  Subjects who 
switch to open-label BG00012 or an alternative therapy and who are assessed at an Open-Label 
BG00012/Alternative Therapy Visit will then follow the same schedule for assessments as 
subjects remaining on their original study treatment.
7.3.3.
Follow-Up
Subjects are to return to the study site for a follow-up visit at Week 100.  The final study visit 
will be at Week 100 or 4 weeks after the last dose of study treatment or alternative therapy. 
Subjects who withdraw prematurely from the study will complete the Early Withdrawal Visit no 
later than 4 weeks after taking their last dose of blinded study treatment, open-label BG00012 or 
alternative therapy.  Subjects who complete, temporarily withhold, or permanently discontinue 
study treatment for any reason and have a lymphocyte count <LLN will be followed every 4 
weeks for 24 weeks, then every 12 weeks (unless clinically indicated more often or at the 
Investigator’s discretion) until the lymphocyte count is ≥LLN, or for 48 weeks following 
treatment discontinuation, whichever occurs sooner, or until the subject is initiated on the 
appropriate MS treatment, according to local standard of care, following study 
withdrawal/completion.
7.4.
Study Stopping Rules
Biogen may terminate this study, at any time, after informing the Investigators.  Biogen will 
notify Investigators when the study is to be placed on hold, completed, or terminated.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
43
7.5.
End of Study
The end of study is last subject, last visit for final collection of data.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
44
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 randomization (Day 1) or at the timepoint specified in the individual eligibility 
criterion listed:  
1. Ability of a legally authorized representative (LAR; parent or legal guardian) 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.  Subjects will provide assent in addition to 
the LAR’s consent, as appropriate, per local regulations.
2. Aged 10 to 17 years old, inclusive, at the time of informed consent.  The minimum age 
can be older than 10 years as required by country-specific regulations and/or local ethics 
committees.
3. Must have a diagnosis of RRMS as defined by the revised consensus definition for 
pediatric MS [Krupp 2013; Polman 2011].
4. Must have an EDSS score between 0.0 and 5.0.
5. Must have a body weight of ≥30 kg; the minimum weight for inclusion in the study may 
be greater than 30 kg if required by country-specific regulations and/or local ethics 
committees.
6. Must have experienced ≥1 relapse in the 12 months prior to randomization (Day 1), or 
must have evidence of asymptomatic disease activity (Gd-positive lesions) seen on MRI 
in the 6 months prior to randomization (Day 1), or must have ≥2 relapses in the 
24 months prior to randomization (Day 1).  Relapse is defined as the occurrence of a 
clinical demyelination event regardless of whether the event is a first (initial) or 
subsequent (recurrent) demyelinating event.
7. Sexually active subjects of childbearing potential must practice effective contraception 
during the study and be willing and able to continue contraception for 3 months after 
their last dose of study treatment.  For further details of contraceptive requirements for 
this study, please refer to Section 15.5.
8.2.
Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
the time of randomization (Day 1) or at the timepoint specified in the individual criterion listed:


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
45
Medical history
1. Primary progressive, secondary progressive, or progressive RMS (as defined by [Lublin 
and Reingold 1996]).  These conditions require the presence of continuous clinical 
disease worsening over a period of at least 3 months.  Subjects with these conditions may 
also have superimposed relapses but are distinguished from relapsing subjects by the lack 
of clinically stable periods or clinical improvement.
2. Disorders mimicking MS, such as other demyelinating disorders (e.g., acute disseminated 
encephalomyelitis), systemic autoimmune disorders (e.g., Sjögren’s disease and lupus 
erythematosus), metabolic disorders (e.g., dystrophies), and infectious disorders.
3. History of severe allergic or anaphylactic reactions or known drug hypersensitivity. 
4. Known allergy to any component of DMF, fumaric acid esters, or BIIB017 formulation.
5. History of clinically significant cardiovascular, pulmonary, GI, hepatic, renal, 
endocrinologic, hematologic, immunologic, metabolic, dermatologic, growth, 
developmental, psychiatric (including depression), neurologic (other than MS), and/or 
other major disease and/or laboratory abnormality indicative thereof, that would preclude 
participation in a clinical study.
6. History of malignant disease, including solid tumors and hematologic malignancies, with 
the exception of basal cell and squamous cell carcinomas of the skin that have been 
completely excised and are considered cured.
7. History of seizure disorder or unexplained blackouts or history of a seizure within 3 
months prior to randomization (Day 1).
8. History of suicidal ideation within 3 months prior to randomization (Day 1) or an episode 
of severe depression within 3 months prior to randomization (Day 1).  Severe depression 
is defined as an episode of depression that requires hospitalization or is otherwise 
regarded as severe by the Investigator.
9. Clinically significant abnormal ECG values as determined by the Investigator.
10. History of human immunodeficiency virus (HIV) infection.  Note: HIV testing will be 
performed at Screening, only if required by local regulations.
11. Known history or positive test result for hepatitis C antibody, or current hepatitis B 
infection (defined as positive for hepatitis B surface antigen [HBsAg] and/or positive for 
hepatitis B core antibody [HBcAb]) at Screening.  Subjects with immunity to hepatitis B 
from either active vaccination (defined as negative HBsAg, positive hepatitis B surface 
antibody [HBsAb], and negative HBcAb) or from previous natural infection (defined as 
negative HBsAg, positive HBsAb immunoglobulin G, and positive HBcAb) are eligible 
to participate in the study (definitions are based on the Centers for Disease Control and 
Prevention [CDC] interpretation of the hepatitis B serology panel [CDC 2007]).


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
46
12. Abnormal screening blood tests exceeding any of the following limits defined below:

alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT) >2 
upper limit of normal (ULN), aspartate transaminase (AST)/serum glutamic 
oxaloacetic transaminase (SGOT) >2 ULN, gamma glutamyl transferase >2 ULN, 
or bilirubin >1.5 ULN

total WBC count <3700/mm3

absolute neutrophil count (ANC) of 1500/mm3

platelet count <150,000/mm3

absolute lymphocyte count ≤ LLN

eosinophils >0.7103/µL or >0.7 GI/L

hemoglobin <10 g/dL in female subjects or <11 g/dL in male subjects

serum creatinine >ULN 

prothrombin time or activated partial thromboplastin time >1.2 ULN
13. Proteinuria (1+ or greater) at Screening confirmed by a second urinalysis approximately 2 
weeks later or by a spot protein/creatinine ratio (with morning void) >0.2 mg/mg.  Note:  
Documented benign proteinuria is not exclusionary. 
OR 
Either of the following additional abnormal urine tests at Screening confirmed by a second 
urinalysis approximately 2 weeks later:

hematuria, without known etiology

glycosuria, without known etiology
14. Occurrence of an MS relapse within the 30 days prior to randomization (Day 1) and/or 
the subject has not stabilized from a previous relapse prior to randomization.
Treatment history
15. Any previous treatment with Fumaderm®, BG00012, or BIIB017.
16. History of hypersensitivity or intolerance to acetaminophen (paracetamol), ibuprofen, or 
naproxen that would preclude use of at least 1 of these during the study.  


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
47
17. Treatment with other agents to treat MS symptoms or underlying disease as specified 
below:

Prior treatment with any of the following:

total lymphoid radiation

cladribine

T-cell or T-cell receptor vaccine

any therapeutic monoclonal antibody (e.g., rituximab, natalizumab, or 
alemtuzumab)

Prior treatment with any of the following within 12 months prior to randomization 
(Day 1):

cyclophosphamide

mitoxantrone

Prior treatment with any of the following within 6 months prior to randomization 
(Day 1):

cyclosporine

fingolimod

plasma exchange or cytapheresis

IV immunoglobin

azathioprine

mycophenolate mofetil

methotrexate  

teriflunomide

laquinimod

Prior treatment with systemic corticosteroids, including agents that may act through 
the corticosteroid pathway (e.g., low-dose naltrexone) within 30 days prior to 
randomization (Day 1).


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
48

Prior treatment with GA, IFN, or 4-aminopyridine or related products (except 
subjects on a stable dose of controlled-release fampridine for at least 3 months) 
within 4 weeks prior to randomization (Day 1).

Prior treatment that might influence growth, including but not limited to 
methylphenidate hydrochloride, thyroid hormone, growth hormone, anabolic steroids, 
calcitonin, estrogens, progestins (with the exception of medication used for 
contraception), bisphosphonates, anticonvulsants, or phosphate-binding antacids.
18. Treatment with another investigational drug or approved therapy for investigational use 
within the 6 months prior to randomization (Day 1).
Miscellaneous
19. Female subjects who are pregnant, breastfeeding, or considering becoming pregnant 
while in the study.
20. History of drug or alcohol abuse (as determined by the Investigator) within 2 years prior 
to randomization (Day 1).  
21. Subjects for whom MRI is contraindicated (e.g., who have pacemakers, other 
contraindicated implanted metal devices, or embedded metals such as dental braces, 
tattoos, body piercings, etc.), or who are allergic to Gd, or have claustrophobia that 
cannot be medically managed.
22. Current enrollment in any other investigational drug study.
23. Previous randomization in this study.
24. Elective surgery performed within 2 weeks prior to randomization (Day 1).
25. Unwillingness or inability to comply with the study requirements.
26. Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the 
subject unsuitable for enrollment.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
49
9.
ENROLLMENT, REGISTRATION, AND RANDOMIZATION
9.1.
Screening and Enrollment
The subject’s LAR (e.g., parent or legal guardian, where applicable) must provide informed 
consent before any screening tests are performed (see Section 17.3).  When the ICF is signed, 
that subject is considered to be enrolled in the study.  Subjects who have a nonclinically 
significant out-of-range laboratory result may be rescreened 1 time only at the discretion of the 
Investigator.  Participating study sites are required to document all screened candidates initially 
considered for inclusion in this study.  If a subject is excluded from the study, the reasons for 
exclusion will be documented in the subject’s source documents and on the screening log.
9.2.
Randomization and Registration of Subjects 
Subjects will be registered and randomized at Baseline (Day 1), after all baseline and screening 
assessments have been completed and after the Investigator has verified that the subjects are 
eligible per criteria in Sections 8.1 and 8.2.  No subject may begin treatment prior to assignment 
of a unique identification number (registration) and randomization.  Any subject identification 
numbers that are assigned will not be reused even if the subject does not receive treatment.
Subjects will be randomized in a 1:2:2 ratio to receive BG00012:BIIB017:placebo.  Subjects will 
be stratified by age (10 to ≤14 years of age and 15 to 17 years of age) and by site.  
Refer to the Study Reference Guide for details on registration and randomization.
9.3.
Blinding Procedures
This is a randomized, double-blind, double-dummy, placebo-controlled study.
All study staff will be blinded to the subject treatment assignments.  To maintain the study blind, 
it is imperative that subject treatment assignments are not shared with the subjects, their families, 
or any member of the study team, either at the study site or at Biogen.
To ensure blinding across the 3 treatment groups, each subject will receive BG00012 or 
matching placebo administered orally BID and BIIB017 or matching placebo administered SC 
every 2 weeks.  Subjects must NOT take a dose of BG00012 or matching placebo within the 
4 hours prior to their scheduled appointment.  This should prevent any drug-induced symptoms 
from being observed by study personnel during the evaluation and prevent possible unblinding of 
study personnel.  When the subject has finished all evaluations and has left the clinic, the subject 
is to resume their dosing schedule. Whenever possible, study personnel (e.g., the treating nurse) 
should contact the subject the day before the scheduled appointment to remind the subject of 
these dosing restrictions.  Additionally, to reduce the likelihood that injection site reactions and 
FLS associated with BIIB017 could unblind subjects and/or study personnel, all subjects will be 
instructed to take acetaminophen, ibuprofen, or nonsteroidal anti-inflammatory drugs (NSAIDs) 


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
50
such as naproxen prior to each injection and for the 24 hours following each injection, for the 
first 24 weeks of the study.  After the first 24 weeks of the study, acetaminophen, ibuprofen, or 
other NSAID treatment may be discontinued at the discretion of the Investigator. 
White blood cell count (WBC) and differentials (including ANC and lymphocyte count) data that 
are obtained after the Screening Visit will not be sent to the sites and should not be reviewed by 
any site personnel, since these data can potentially compromise the blind of the study.  The WBC 
and differentials data will be reviewed by an Independent Laboratory Monitor (ILM).  Only 
laboratory abnormalities in WBC and differentials that meet the threshold limits in Table 5, as 
determined by the ILM, will be communicated to the sites.
At the end of the study (i.e., once the clinical study report is finalized), if unblinding will not 
jeopardize the results of ongoing related studies, Biogen will provide the randomization codes to 
Investigators, who then can inform subjects about the treatment received. 


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
51
10.
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY
10.1.
Discontinuation of Study Treatment
Unless otherwise indicated, a subject must permanently discontinue study treatment for any of 
the following reasons:

The subject becomes pregnant.  Study treatment must be discontinued immediately.  
Report the pregnancy according to the instructions in Section 15.4.1.

The subject experiences severe depression or suicidal ideation.  Severe depression is 
defined as an episode of depression that requires hospitalization or is otherwise regarded 
as severe by the Investigator.

The subject withdraws consent to continue study treatment.  

The subject experiences a medical emergency that necessitates permanent discontinuation 
of study treatment.

The subject experiences a medical emergency that necessitates unblinding of the 
subject’s treatment assignment.

The subject is unable to tolerate study treatment.

At the discretion of the Investigator, the subject discontinues study treatment due to 
medical reasons or for noncompliance.

The subject experiences a protocol-specified change in laboratory values that necessitates 
permanent discontinuation of treatment (Table 5).

The subject develops lymphocyte count <500/mm3 for more than 6 months (Table 6).

The subject experiences more than 1 deviation of the same laboratory parameter that 
meets the threshold limits defined in Table 5 at any time during the study. 

The subject experiences more than 2 deviations of different laboratory parameters that 
meet the threshold limits defined in Table 5 at any time during the study.  

The subject develops renal dysfunction based on a nephrologist’s evaluation.

The subject is diagnosed with PML.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
52
In the event of a subject experiencing a seizure or suspected seizure during the study, they should 
be managed as per local clinical guidelines/standard medical care.  The Investigator should 
re-evaluate whether the subject should continue in the study.
The reason for discontinuation of study treatment must be recorded in the subject’s case report 
form (CRF).
Subjects who discontinue study treatment or alternative therapy may remain in the study and 
continue protocol-required tests and assessments.  
If a subject switches to an alternative therapy, the study treatment must be permanently 
discontinued, and the subject cannot go back on that study treatment.
10.2.
Withdrawal of Subjects From Study
Subjects must be withdrawn from the study for any one of the following reasons:

The subject withdraws consent.  

The subject enrolls into another interventional clinical study in which an investigational 
treatment or approved therapy for investigational use is administered.

The subject is unwilling or unable to comply with the protocol.
The reason for the subject’s withdrawal from the study must be recorded in the subject’s CRF.
Subjects who withdraw prematurely will complete the Early Withdrawal Visit no later than 
4 weeks after taking their last dose of study treatment or alternative therapy.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
53
11.
STUDY TREATMENT USE
11.1.
Regimen
Refer to and follow the Directions for Handling and Administration (DHA).
Subjects are to contact the Investigator immediately if more than the prescribed dose is taken.  If 
a dose is missed, the dose should be taken as soon as possible.  If it is almost time for the next 
dose, the subject should skip the missed dose and go back to their regular dosing schedule.  
Doses should not be doubled to make up for missed doses.
11.1.1.
BG00012
BG00012 will be taken orally.  Subjects will take 1 capsule orally at a dose of 120 mg BID for 
the first 7 days and 2 capsules orally at a dose of 240 mg BID thereafter.  
Subjects will be instructed to swallow each BG00012 capsule whole and not chewed. The 
capsule and its contents are not to be crushed, divided, dissolved, sucked, or chewed since the 
enteric-coating of the microtablets in the capsule helps to prevent irritant effects on the stomach.  
If unable to swallow the capsule, the capsule may be opened and the contents mixed with food 
immediately prior to consumption.
11.1.2.
BIIB017
BIIB017 will be taken at a dose of 125 µg SC every 2 weeks for 96 weeks (2 years).
To mitigate FLS, all subjects randomized to receive BIIB017 treatment will be titrated to the 
target dose of 125 µg:  63 µg BIIB017 on Day 1, 94 µg at Week 2, and 125 µg at Week 4.  Once 
subjects reach the 125 µg target dose, they will continue on this dose for the remainder of the 
study.
11.1.3.
Placebo
Subjects will receive placebo using a regimen matching that for the BG00012 and BIIB017 
treatment groups, during the maintenance as well as titration periods.
To ensure blinding across the 3 treatment groups, each subject will receive BG00012 or 
matching placebo administered orally BID and BIIB017 or matching placebo administered SC 
every 2 weeks.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
54
11.2.
Modification of Dose and/or Treatment Schedule
11.2.1.
Dose Reduction
Dose reduction will be allowed only for subjects who are unable to tolerate BG00012 due to 
flushing and/or GI disturbances (dose reductions will not be allowed for abnormal laboratory 
values).  Subjects who do not tolerate BG00012 will reduce their dose by taking one 120 mg 
capsule BID for up to 4 weeks.  Within 4 weeks at the reduced dose, subjects will resume taking 
2 capsules BID.  If the subject is still unable to tolerate BG00012, the subject must discontinue 
BG00012 as described in Section 10.1.  Any subject who prematurely discontinues dosing with 
BG00012 may remain in the study and continue protocol-scheduled tests and assessments. 
11.2.2.
Dosing Interruption for Abnormal Laboratory Values
Blinded study treatment or alternative therapy with BG00012 or BIIB017 must be temporarily or 
permanently withheld when any of the following laboratory values meet the threshold limits 
defined in Table 5.  Laboratory abnormalities in WBC and differentials (including ANC and 
lymphocyte count) that meet the threshold limits in Table 5, as determined by the ILM, will be 
communicated to the sites. 
Table 5:
Laboratory Criteria Requiring Withholding or Permanent Discontinuation 
of Study Treatment or Alternative Therapy with BG00012 or BIIB017
Laboratory 
Parameter
Laboratory Result
Required Action
WBC
2000/mm3
The Investigator1 should repeat the test as soon as possible. If 
retest value confirms WBC count 2000/mm3 study treatment 
should be withheld and the test repeated approximately every 
2 weeks.  If the value remains 2000/mm3 ≥4 weeks after 
discontinuation of study treatment, the subject must 
permanently discontinue study treatment and the event must 
be recorded as an AE.
500/mm3
The Investigator1 should repeat the test as soon as possible, and 
if the retest confirms WBC 500/mm3, the Investigator will be 
informed of the laboratory value immediately.  Study treatment 
should be withheld and retesting will be performed as 
documented in the required action for WBC 2000/mm3.  
Medical evaluation should be conducted as appropriate and 
the event must be recorded as an AE.
ANC
750/mm3
The Investigator1 should repeat the test as soon as possible.  If 
the retest value confirms ANC <750/mm³, the study treatment 
should be withheld, and the test repeated approximately every 
2 weeks.  If the value remains <750/mm³ ≥4 weeks after 
discontinuation of study treatment, the subject must 
permanently discontinue study treatment and the event must 
be recorded as an AE.
100/mm3
The Investigator1 should repeat the test as soon as possible, and 
if the retest value confirms ANC <100/mm³, the Investigator will 
be informed of the laboratory value immediately.  Study 
treatment should be withheld and retesting will be performed as 


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
55
Laboratory 
Parameter
Laboratory Result
Required Action
documented in the required action for ANC <750/mm³.  Medical 
evaluation should be conducted as appropriate and the event 
must be recorded as an AE.
Platelets
75,000/mm3
The Investigator1 should repeat the test as soon as possible.  If 
the retest value confirms platelets <75,000/mm³, study treatment 
should be withheld and the test repeated approximately every 
2 weeks.  If the value remains <75,000/mm3 ≥4 weeks after
discontinuation of study treatment, the subject must 
permanently discontinue study treatment and the event must 
be recorded as an AE.
25,000/mm3
The Investigator1 should repeat the test as soon as possible, and 
if the retest value confirms platelets <25,000/mm³, study 
treatment should be withheld and retesting will be performed as 
documented in the required action for platelets <75,000/mm³.  
Medical evaluation should be conducted as appropriate and 
the event must be recorded as an AE.
Hemoglobin
8.5 g/dL
The Investigator1 should repeat the test as soon as possible.  If 
the retest value confirms hemoglobin <8.5 g/dL, study treatment 
should be withheld and the test repeated approximately every 
2 weeks.  If the value remains <8.5 g/dL ≥4 weeks after 
discontinuation of study treatment, the subject must 
permanently discontinue study treatment and the event must 
be recorded as an AE.
8.0 g/dL
The Investigator1 should repeat the test as soon as possible, and 
if the retest value confirms hemoglobin <8.0 g/dL, study 
treatment should be withheld and retesting will be performed as 
documented in the required action for hemoglobin <8.5 g/dL.  
Medical evaluation should be conducted as appropriate and 
the event must be recorded as an AE.
AST (SGOT) or ALT 
(SGPT)
>3 ULN
The Investigator1 should repeat the test as soon as possible.  If 
the retest value confirms ALT or AST > 3× ULN, study 
treatment should be withheld, and liver tests (ALT, AST, 
alkaline phosphatase, and total bilirubin) should be retested 
within 1 to 2 weeks.  If, on retesting, the ALT or AST remains 
>3 × ULN, the subject must permanently discontinue study 
treatment and the event must be recorded as an AE.
ALT or AST and total 
bilirubin
ALT or AST ≥3×
ULN and total 
bilirubin >2 × ULN in 
combination
The Investigator1 should repeat the test as soon as possible.  If 
the retest value confirms ALT or AST ≥3 × ULN and total 
bilirubin >2 × ULN in combination, the subject must 
permanently discontinue study treatment and the event must 
be recorded as an AE.
Creatinine
>1.2 ULN
The Investigator should repeat the test as soon as possible.  If the 
retest value confirms that creatinine is >1.2 ULN, the study 
treatment should be withheld and the test repeated approximately 
every 2 weeks.  If the value remains >1.2 ULN for 4 weeks 
after discontinuation of study treatment, then the subject must 
permanently discontinue study treatment, and the event must 
be recorded as an AE.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
56
Laboratory 
Parameter
Laboratory Result
Required Action
Urinalysis
Positive hematuria on 
microscopy
The Investigator should repeat the test as soon as possible.  If 
retest confirms microscopic hematuria without known etiology, 
the study treatment should be withheld and the test repeated 
approximately every 2 weeks, and urine cytology must be 
performed.  (Note: Urine cytology should be performed only 
once per episode of hematuria and does not have to be repeated).  
If hematuria persists for ≥4 weeks after discontinuation of study 
treatment or if cytology is positive, then the subject must 
permanently discontinue study treatment, and the event must 
be recorded as an AE.  Subjects should be referred to a 
nephrologist for further investigation.
AE = adverse event; ALT = alanine transaminase; ANC = absolute neutrophil count; AST = aspartate transaminase; 
SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase; ULN = upper 
limit of normal; WBC = white blood cell.
1WBC (including the differential) obtained after the Screening visit will not be sent to the sites and will not be 
reviewed by any site personnel, as these data could potentially compromise the blinding of the study.  All other 
laboratory data will be reviewed by the sites.  An Independent Laboratory Monitor (ILM) will regularly assess 
masked WBC counts and differentials (including ANC and lymphocyte count) in order to monitor subject safety, 
and may contact the sites to request additional information on an individual subject to confirm the safety of the 
subject or may request repeat blood testing.  The ILM will apply the above prespecified laboratory criteria 
pertaining to WBC, ANC, and lymphocyte count that will result in withholding or permanent discontinuation of 
study treatment, and will communicate these instructions to the sites.  In the setting of a medical emergency, as 
always, Investigators may perform local testing if needed for the care of the subject.
While dosing is withheld, subjects will continue tests and assessments according to the schedule 
defined in the protocol (and may also undergo additional assessments to evaluate the laboratory 
abnormality as per the Investigator’s standard practice).  In addition, subjects (whether dosing 
temporarily withheld or permanently discontinued) must have the abnormal laboratory result 
rechecked approximately every 2 weeks unless otherwise specified in the protocol, until 
resolution or stabilization of the laboratory value (rechecks will be run at the central laboratory).  
Depending on the severity and clinical significance of the abnormality, the Investigator may need 
to perform the retests more frequently.  
Subjects who have abnormal laboratory values as described in Table 5 that are sustained for 
more than 4 consecutive weeks must permanently discontinue dosing with study treatment or 
alternative therapy.
11.2.3.
Resumption of Study Treatment Dosing
Resumption of study treatment or alternative therapy is to be considered on a case-by-case basis 
and must be discussed with the Medical Monitor.  However, subjects who have abnormal 
laboratory values, as described in Table 5, that are sustained for more than 4 consecutive weeks 
must permanently discontinue dosing with study treatment or alternative therapy.  
Subjects with abnormal laboratory values, who are allowed to resume study treatment or 
alternative therapy dosing following an interruption, will restart dosing at a reduced dose and 


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
57
will be titrated to the maintenance dose.  Subjects randomized to BG00012 will receive a dose of 
120 mg BID orally for 7 days followed by the maintenance dose of 240 mg BID.  Subjects 
randomized to BIIB017 will be titrated to the target dose of 125 µg SC as follows:  63 µg on 
Day 1, 94 µg at Week 2, and 125 µg at Week 4. To ensure blinding across the 3 treatment 
groups, each subject will receive BG00012 or matching placebo administered orally BID and 
BIIB017 or matching placebo administered SC at the corresponding timepoints.
11.2.4.
Subsequent Development of Additional Laboratory Abnormalities 
Subjects who subsequently develop the same abnormal laboratory value at any other time during 
the study must permanently discontinue dosing with study treatment or alternative therapy, i.e., 
only 1 dosing interruption is allowed for each subject for the same laboratory abnormality.  
However, subjects who subsequently experience a different laboratory abnormality can have 
study treatment withheld again.  For example, if a subject had dosing temporarily withheld for an 
abnormal ALT, then resumed dosing after ALT returned to acceptable limits, and subsequently 
developed abnormal WBCs, the subject may have study treatment or alternative therapy withheld 
again.  However, only 2 dosing interruptions are allowed for each subject.  
Any subject who experiences abnormal laboratory results (that meet the criteria defined in 
Table 5 on a third occasion must permanently discontinue dosing for the remainder of the study.
11.2.5.
Abnormal Urinalyses That Require Additional Evaluation
Subjects who develop any of the following abnormal urine laboratory values must have the test 
repeated 2 weeks later:

urinary casts (other than hyaline casts)

glycosuria (trace or greater) in the setting of normal serum glucose
If the abnormality persists on retesting, the subject should be fully investigated for possible 
causes and referred for evaluation by a nephrologist if appropriate in the opinion of the 
Investigator.
Subjects who demonstrate 1+ or greater proteinuria on a urine dipstick (and do not have a 
documented history of prior benign proteinuria) should have a spot protein/creatinine ratio (on 
morning void).  If the spot protein/creatinine ratio is >0.2 mg/mg, the subject should be fully 
investigated for possible causes and referred to a nephrologist for evaluation if appropriate in the 
opinion of the Investigator.
11.2.6.
Treatment Schedule for Subjects With Abnormal Lymphocyte Count
11.2.6.1.
Schedule for Subjects on Study Treatment or Alternative Therapy With 
Lymphocyte Count <LLN
Subjects who are on study treatment and who have a lymphocyte count <LLN will be followed 
every 4 weeks until the lymphocyte count is ≥LLN.  


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
58
If subjects who are on study treatment have a lymphocyte count <500/mm3, the lymphocyte 
count should be closely monitored (at least every 4 weeks).  If lymphocyte count is <500/mm3 
for more than 6 months, study treatment must be permanently discontinued.  
Table 6:
Lymphocyte Count Criteria Requiring Permanent Discontinuation of Study 
Treatment or Alternative Therapy
Laboratory Parameter
Laboratory Result
Required Action
Lymphocyte Count
<500/mm3
The Investigator should repeat the test as soon as 
possible.  If retest confirms that the lymphocyte count 
is <500/mm3, the lymphocyte count should be closely 
monitored (at least every 4 weeks).  If the lymphocyte 
count is <500/mm3 for >24 weeks, study treatment or 
Tecfidera administered as alternative therapy must be 
permanently discontinued. 
11.2.6.2.
Schedule for Subjects Who Complete, Temporarily Withhold, or Permanently 
Discontinue Study Treatment for any Reason and Have Lymphocyte Count 
<LLN
Subjects who complete the 96-week Treatment Period and who have a lymphocyte count <LLN 
will be followed every 4 weeks for 24 weeks, then every 12 weeks (unless clinically indicated 
more often or at the Investigator’s discretion), until the lymphocyte count is ≥LLN, or for 
48 weeks following treatment discontinuation, whichever occurs sooner, or until the subject is 
initiated on the appropriate MS treatment, according to local standard of care, following study 
withdrawal/completion.  If the lymphocyte count does not recover after 48 weeks, the treating 
neurologist should contact the Medical Monitor.  
Subjects who temporarily withhold or permanently discontinue study treatment for any reason 
(see Section 11.2.2) and who have a lymphocyte count <LLN will continue protocol-required 
tests and assessments and also undergo lymphocyte follow-up every 4 weeks for 24 weeks, then 
every 12 weeks (unless clinically indicated more often or at the Investigator’s discretion), 
until the lymphocyte count is ≥LLN, or for 48 weeks following treatment discontinuation, 
whichever occurs sooner, or until the subject is initiated on the appropriate MS treatment, 
according to local standard of care, following study withdrawal/completion.  If the lymphocyte 
count does not recover after 48 weeks, the treating neurologist should contact the Medical 
Monitor.
See Figure 3 for a schedule for subjects who complete, temporarily withhold, or permanently 
discontinue study treatment for any reason and who have a lymphocyte count <LLN.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
59
Figure 3:
Schedule for Subjects Who Complete, Temporarily Withhold, or 
Permanently Discontinue Study Treatment for Any Reason and Have a 
Lymphocyte Count <LLN


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
60
11.3.
Precautions 
Not applicable.
11.4.
Compliance
Compliance with treatment dosing is to be monitored and recorded by site staff.  Compliance 
will be monitored by capsule count and syringe or auto-injector pen count conducted by study 
personnel at protocol-scheduled visits.
11.5.
Concomitant Therapy and Procedures
The use of concomitant therapies or procedures must be recorded on the subject’s CRF, 
according to instructions for CRF completion.  AEs related to administration of these therapies 
or procedures must be documented on the appropriate CRF.
11.5.1.
Concomitant Therapy
A concomitant therapy is any drug or substance administered between the subject’s Baseline and 
last study visit.
11.5.1.1.
Allowed Concomitant Therapy
Subjects should be instructed to contact their Investigators before taking any new medications, 
including nonprescription medications and herbal preparations.
Symptomatic therapy such as treatment for spasticity, depression, or fatigue, is not restricted but 
should be optimized as early as possible during screening to maintain consistent treatment for the 
duration of the study.
11.5.1.2.
Disallowed Concomitant Therapy
Concomitant treatment with any of the following is not allowed while receiving study treatment, 
unless approved by the Medical Monitor:

Any alternative drug treatments directed toward the treatment of MS such as chronic 
immunosuppressant therapy or other immunomodulatory treatments (including, but not 
limited to INF-β [with the exception of study-assigned BIIB017], IFN-α, GA, 
natalizumab, alemtuzumab, cyclophosphamide, methotrexate, azathioprine, 
mycophenolate mofetil, dimethyl fumarate, teriflunomide, 4-aminopyridine, fingolimod, 
or related products), with the exception of acute management of protocol-defined relapse 
(as described below).  

Any investigational product, including investigational symptomatic therapies for MS and 
investigational therapies for non-MS indications.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
61

Any systemic steroid therapy including, but not limited to, oral corticosteroids 
(e.g., prednisone) or periodic (e.g., monthly) treatment with IVMP, except for 
protocol-defined treatment of relapses as described in Section 7.2.3.  Steroids that are 
administered by nonsystemic routes (e.g., topical, inhaled) are allowed.

Total lymphoid radiation, cladribine, T-cell or T-cell receptor vaccination, any 
therapeutic monoclonal antibody, mitoxantrone, cyclosporine, IV immunoglobulin, 
plasmapheresis, or cytapheresis.
Subjects who receive any of these restricted medications without approval from the Medical 
Monitor will be required to permanently discontinue study treatment and will be withdrawn from 
the study as described in Section 10.2.
11.5.2.
Concomitant Procedures
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
the subject’s Baseline and last study visit. 
11.6.
Continuation of Treatment 
No further provisions are made for access to the study treatment.  If BG00012 and BIIB017 are 
proven to be beneficial, all regulatory requirements regarding post-study access will be met.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
62
12.
STUDY TREATMENT MANAGEMENT
Study site staff should follow the DHA for specific instructions on the handling, preparation, 
administration, and disposal of the study treatment.  The DHA supersedes all other references 
(e.g., protocol).
Study treatment must be dispensed only by a pharmacist or appropriately qualified staff.  Study 
treatment is to be dispensed only to subjects enrolled in this study. 
Study treatment kits will be identified by unique kit numbers on the clinical label. To ensure the 
appropriate treatment is provided to each subject, an interactive response technology (IRT) will 
be used to manage the dispensation of kits to subjects.  
12.1.
BG00012
BG00012 is a drug product formulated as enteric-coated microtablets in gelatin capsules (blue 
and white) for oral administration.  Each capsule contains 120 mg BG00012.
Excipients for the manufacturing of the enteric-coated microtablets include microcrystalline 
cellulose, croscarmellose sodium, talc, colloidal anhydrous silica (colloidal silicon dioxide), 
magnesium stearate, triethyl citrate, methacrylic acid-methyl methacrylate copolymer, 
methacrylic acid-ethyl acrylate copolymer, simethicone, sodium lauryl sulfate, and 
polysorbate 80.  Excipients for the manufacturing of the capsule shell include gelatin, titanium 
dioxide, and indigotin.
The contents of the study treatment label will be in accordance with all applicable regulatory 
requirements.  BG00012 should not be used after the expiration date unless a written notification 
of an expiration date extension is provided by Biogen.
12.1.1.
BG00012 Preparation
The individual preparing BG00012 should carefully review the instructions provided in the 
DHA.  
BG00012 will be provided as capsules.  Drug wallets will be provided for the BG00012 
treatment group to ensure that the appropriate treatment is provided to each subject.  Drug 
wallets will be supplied from an Interactive Voice and Web Response System (IXRS) during the 
study so that the appropriate wallets are correctly dispensed to the subjects at the required 
timepoints throughout the study.
If the packaging is damaged or if there is anything unusual about the appearance or attributes of 
the drug wallet or drug, it should not be used.  The drug wallet in question should be quarantined 
at the study site, and the problem should be immediately reported to Biogen.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
63
12.1.2.
BG00012 Storage
BG00012 is to be stored at room temperature (15C to 25C or 59F to 77F), in a secured, 
locked area with limited access.  For the most up-to-date storage requirements, follow the 
instructions provided in the DHA.
12.1.3.
BG00012 Handling and Disposal
The Investigator must return all used and unused drug wallets of BG00012 as instructed by 
Biogen unless approved for onsite destruction.
If any BG00012 supplies are to be destroyed at the study site, the institution or appropriate site 
personnel must obtain prior approval from Biogen by providing, in writing, the destruction 
policy or details of the method of destruction.  After such destruction, Biogen must be notified, 
in writing, of the details of the study treatment destroyed (e.g., lot or kit numbers and quantities), 
the date of destruction, and proof of destruction.
12.1.4.
BG00012 Accountability
The study site must maintain accurate records demonstrating dates and amount of study 
treatment received, to whom dispensed (subject-by-subject accounting), amount returned by the 
subject, and accounts of any study treatment accidentally or deliberately destroyed or lost.  
Unless otherwise notified, all drug wallets, both used and unused, must be saved for study 
treatment accountability.  At the end of the study, reconciliation must be made between the 
amount of BG00012 supplied, dispensed, and subsequently destroyed, lost, or returned to 
Biogen.  A written explanation must be provided for any discrepancies.
12.2.
BIIB017
BIIB017 is supplied as a liquid in an auto-injector pen to deliver 0.5 mL of 0.25 mg/mL (125 µg 
dose) of 20 kDa mPEG-O-2-methylpropionaldehyde-modified human IFN β-1a in 20 mM acetic 
acid/sodium acetate buffer pH 4.8, 150 mM arginine hydrochloride, and 0.005% polysorbate 20.   
BIIB017 is also supplied as a liquid in a prefilled-syringe (PFS) for titration dosing to deliver 
0.5 mL of 0.13 mg/mL (63 µg dose) or 0.19 mg/mL (94 µg dose) of 20 kDa 
mPEG-O-2-methylpropionaldehyde-modified human IFN β-1a in 20 mM acetic acid/sodium 
acetate buffer pH 4.8, 150 mM arginine hydrochloride, and 0.005% polysorbate 20.
The label will include conditions for storage, kit number, and other pertinent information in 
accordance with local regulations such as Sponsor, expiration date, and a caution statement.  
BIIB017 should not be used after the expiration date unless a written notification of an expiration 
date extension is provided by Biogen.
12.2.1.
BIIB017 Preparation
The individual preparing BIIB017 should carefully review the instructions provided in the DHA.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
64
If the packaging is damaged, or if there is anything unusual about the appearance or attributes of 
the syringe or auto-injector pen, it should not be used.  The syringe or auto-injector pen in 
question should be quarantined at the study site, and the problem should be immediately reported 
to Biogen. 
12.2.2.
BIIB017 Storage 
BIIB017 is to be stored at 2°C to 8°C (36°F to 46°F) in a temperature-monitored, secured, and 
locked refrigerator with limited access.  For the most up-to-date storage requirements, follow the 
instructions provided in the DHA.
12.2.3.
BIIB017 Handling and Disposal
The Investigator must return all used and unused syringes and auto-injector pens of BIIB017 as 
instructed by Biogen unless approved for onsite destruction.
If any BIIB017 supplies are to be destroyed at the study site, the institution or appropriate site 
personnel must obtain prior approval from Biogen, by providing, in writing, the destruction 
policy or details of the method of destruction.  After such destruction, Biogen must be notified, 
in writing, of the details of the study treatment destroyed (e.g., lot or kit numbers, quantities), the 
date of destruction, and proof of destruction.
12.2.4.
BIIB017 Accountability
The study site must maintain accurate records demonstrating dates and amount of study 
treatment received, to whom dispensed (subject-by-subject accounting), and accounts of any 
study treatment accidentally or deliberately destroyed or lost.  
Unless otherwise notified, all syringes and auto-injector pens, both used and unused, must be 
saved for study treatment accountability.  At the end of the study, reconciliation must be made 
between the amount of BIIB017 supplied, dispensed, and subsequently destroyed, lost, or 
returned to Biogen.  A written explanation must be provided for any discrepancies.
12.3.
Placebo
The matched placebo for BG00012 will be supplied as enteric-coated microtablets in gelatin 
capsules (blue and white) for oral administration.  DMF has been replaced in the placebo by 
lactose monohydrate to maintain the total weight.
Excipients for the manufacturing of the enteric-coated microtablets include microcrystalline 
cellulose, croscarmellose sodium, talc, colloidal anhydrous silica (colloidal silicon dioxide), 
magnesium stearate, triethyl citrate, methacrylic acid-methyl methacrylate copolymer, 
methacrylic acid-ethyl acrylate copolymer, simethicone, sodium lauryl sulfate, and 
polysorbate 80.  Excipients for the manufacturing of the capsule shell include gelatin, titanium 
dioxide, and indigotin.
Placebo is to be stored under the same conditions as those for BG00012.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
65
The matched diluent/placebo (20 mM acetic acid/sodium acetate pH 4.8, 150 mM arginine 
hydrochloride, and 0.005% polysorbate 20) for BIIB017 will be provided in a PFS, to deliver 
0.5 mL.
Placebo is to be stored under the same conditions as those for BIIB017.
12.4.
Additional Protocol-Designated Products
For the first 24 weeks of the study (starting at Baseline), all subjects will be instructed to take 
either acetaminophen (paracetamol) or ibuprofen prior to each injection and for the 24 hours 
following each injection at the recommended doses and frequencies per the local labels.  If a 
subject is allergic to or intolerant of acetaminophen or ibuprofen, other NSAIDs such as 
naproxen may be administered at the recommended dose and frequency per the local labels.  
After the first 24 weeks of the study, acetaminophen, ibuprofen, or other NSAID treatment may 
be discontinued at the discretion of the Investigator.
Subjects may receive additional doses of acetaminophen, ibuprofen, or naproxen, 24 hours after 
injection as necessary for relief of IFN-related FLS.  Sites should refer to the local labels for 
maximum daily dosages of these medications.  Subjects should be instructed to contact the site if 
they require additional medication beyond the maximum daily dosage per the local labels.
For current and updated US Label Dosing Guidelines refer to the Food and Drug Administration 
website (www.fda.gov). 


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
66
13.
EFFICACY ASSESSMENTS
See Section 4 for the timing of all assessments.
13.1.
Clinical Efficacy Assessments
The following clinical assessments will be performed to evaluate the efficacy of BG00012 and 
BIIB017:

Protocol-defined relapse 
13.2.
Radiological Efficacy Assessments
The following radiological efficacy assessments will be performed to evaluate the efficacy of 
BG00012 and BIIB017:

Brain MRI scans with and without Gd

total Gd-enhancing lesions

new or newly enlarging T2 hyperintense lesions


new or newly enlarging T1 hypointense lesions

13.3.
Additional Assessments






Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
69
15.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES
Throughout the course of the study, every effort must be made to remain alert to possible AEs.  
If an AE occurs, the first concern should be for the safety of the subject.  If necessary, 
appropriate medical intervention should be provided.
At the signing of the ICF, each subject or his/her LAR must be given the names and telephone 
numbers of study site staff for reporting AEs and medical emergencies.
15.1.
Definitions
15.1.1.
Adverse Event
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product.
Determination of whether an abnormal laboratory value meets the definition of an AE will be 
made by the Investigator.  Although abnormal laboratory values are typically not considered 
AEs, the following considerations may result in an abnormal laboratory value being considered 
an AE:

A laboratory test result that meets the criteria for an SAE

A laboratory test result that requires the subject to receive specific corrective therapy

A laboratory abnormality that the Investigator considers to be clinically significant
15.1.2.
Serious Adverse Event
An SAE is any untoward medical occurrence that at any dose:

Results in death

In the view of the Investigator, places the subject at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred in a 
more severe form, might have caused death

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
70

Results in a congenital anomaly/birth defect
An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above.  (Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or convulsions occurring at home that do not 
require an inpatient hospitalization.)
15.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized.  The study site must document all of the following:

The prescheduled or elective procedure or routinely scheduled treatment was scheduled 
(or was on a waiting list to be scheduled) prior to obtaining the subject’s consent to 
participate in the study.

The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the subject’s consent to participate in the study and the time of the 
procedure or treatment.

The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission.
o
If a subject is hospitalized due to local requirements for administration of the 
study treatment (i.e., BG00012 and BIIB017), the hospitalization should not 
be considered an SAE unless one of the requirements in Section 15.1.2 is met.
15.2.
Safety Classifications
15.2.1.
Investigator Assessment of Events
All events must be assessed to determine the following:

If the event meets the criteria for an SAE as defined in Section 15.1.2.

The relationship of the event to study treatment as defined in Section 15.2.2.

The severity of the event as defined in Section 15.2.3.




Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
72
15.3.2.
Serious Adverse Events
Any SAE experienced by the subject between the time of the signing of the ICF and 
Post-Treatment Visit is to be recorded on an SAE form, regardless of the severity of the event or 
its relationship to study treatment.  SAEs must be reported to Biogen Safety and Benefit-Risk 
Management (SABR) or designee within 24 hours as described in Section 15.3.3.  Follow-up 
information regarding an SAE also must be reported with 24 hours. 
Subjects will be followed for all SAEs until the Post-Treatment Visit.  Thereafter, the event 
should be reported to Biogen SABR or designee only if the Investigator considers the SAE to be 
related to study treatment.
Any SAE that is ongoing when the subject completes or discontinues the study will be followed 
by the Investigator until the event has resolved, stabilized, or returned to baseline status.
15.3.3.
Immediate Reporting of Serious Adverse Events
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify Biogen SABR or designee within 24 hours of the study site staff becoming aware 
of the SAE.  It is the Investigator’s responsibility to ensure that the SAE reporting information 
and procedures are used and followed appropriately.




Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
74
15.4.
Procedures for Handling Special Situations
15.4.1.
Pregnancy
Subjects should not become pregnant or impregnate their partners during the study and 
for 3 months after their last dose of study treatment.  If a female subject becomes pregnant, 
study treatment must be discontinued immediately.
The Investigator must report a pregnancy by faxing the appropriate form within 24 hours of the 
study site staff becoming aware of the pregnancy to
 (fax: see the Study 
Reference Manual; email: 
).  
The Investigator or study site staff must report the outcome of the pregnancy to 
 
. 
Congenital abnormalities and birth defects in the offspring of male or female subjects should be 
reported as an SAE if conception occurred during the study treatment period.
15.4.2.
Overdose
An overdose is any dose of study treatment administered to a subject or taken by a subject that 
exceeds the dose assigned to the subject according to the protocol.  Overdoses are not considered 
AEs and should not be recorded as an AE on the CRF; however, all overdoses must be recorded 
on an Overdose form and faxed to Biogen SABR or designee within 24 hours of the site 
becoming aware of the overdose.  An overdose must be reported to Biogen SABR or designee 
even if the overdose does not result in an AE.  If an overdose results in an AE, the AE must be 
recorded.  If an overdose results in an SAE, both the SAE and Overdose forms must be 
completed and faxed to Biogen SABR or designee.  All study treatment-related dosing 
information must be recorded on the dosing CRF.
15.4.3.
Medical Emergency
In a medical emergency requiring immediate attention, study site staff will apply appropriate 
medical intervention, according to current standards of care.  The Investigator (or designee) 
should contact the study’s Medical Monitor.  Refer to the Study Reference Guide’s Official 
Study Contact List for complete contact information.
15.4.3.1.
Unblinding for Medical Emergency
In a medical emergency when knowledge of the subject’s treatment assignment may influence 
the subject’s clinical care, the Investigator and, if applicable, designated personnel at Biogen 
may access the subject’s treatment assignment by IRT.  The Investigator must document the 
reasons for unblinding in the subject’s source documents.  The Investigator is strongly advised 
not to divulge the subject’s treatment assignment to any individual not directly involved in 
managing the medical emergency, nor to personnel involved with the analysis and conduct of the 
study.  The Investigator can contact Biogen or designee to discuss such situations.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
75
The Investigator must document the reasons for unblinding in the subject’s source documents.  
The Investigator is strongly advised not to divulge the subject’s treatment assignment to any 
individual not directly involved in managing the medical emergency or to personnel involved 
with the analysis and conduct of the study.
15.5.
Contraception Requirements
Sexually active subjects of reproductive potential must practice effective contraception during 
the study and for 3 months after their last dose of study treatment.  Investigators should advise 
subjects of the potential risks associated with pregnancy while taking BG00012 or BIIB017 and 
on the appropriate use of contraceptives (as defined below).
For the purposes of the study, effective contraception is defined as use of 1 or more of the 
following:
For females:

Established use of oral, injected, or implanted hormonal methods of contraception

Placement of an intrauterine device or intrauterine system

Barrier methods of contraception with use of a spermicide:  condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream suppository.  
The use of barrier contraceptives should always be supplemented with the use of a 
spermicide (where approved/available).

Female surgical sterilization (e.g., bilateral tubal ligation)
For males:

Effective male contraception includes the use of condoms with spermicide
In addition, male subjects must not donate sperm from the Baseline Visit (Day 1) to at least 90 
days after administration of the last dose of study treatment.
True abstinence, when this is consistent with the preferred and usual lifestyle of the subject, can 
be considered an acceptable method of contraception based on the evaluation of the Investigator 
who should also take into consideration the duration of the clinical trial.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not 
considered acceptable methods of contraception.
Pregnancy reporting is described in Section 15.4.1.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
76
15.6.
Safety Responsibilities
15.6.1.
The Investigator
The Investigator’s responsibilities include the following:

Monitor and record all AEs, including SAEs, regardless of the severity or relationship to 
study treatment.

Determine the seriousness, relationship, and severity of each event.

Determine the onset and resolution dates of each event.

Monitor and record all pregnancies and follow up on the outcome.

Complete an SAE form for each SAE and fax it to Biogen SABR or designee within 24 
hours of the study site staff becoming aware of the event.

Pursue SAE follow-up information actively and persistently.  Follow-up information 
must be reported to Biogen SABR or designee within 24 hours of the study site staff 
becoming aware of new information.

Ensure all AE and SAE reports are supported by documentation in the subjects’ medical 
records.

Pursue AE follow-up information, if possible, until the event has resolved or become 
stable.

Report SAEs to local ethics committees, as required by local law.
15.6.2.
Biogen 
Biogen’s responsibilities include the following:

Before study site activation and subject enrollment, the Clinical Monitor is responsible 
for reviewing with study site staff the definitions of AE and SAE, as well as the 
instructions for monitoring, recording, and reporting AEs and SAEs.

Biogen is to notify all appropriate regulatory authorities, central ethics committees, and 
Investigators of SAEs, as required by local law, within required time frames.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
77
16.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The objectives of the study and the endpoints to be analyzed are listed in Section 6.
The study is conducted to evaluate the efficacy and safety profiles of BG00012 and BIIB017, 
both compared with placebo, in pediatric subjects with RRMS.  Two separate sets of analyses 
will be performed for assessment of each active treatment.  One will include subjects assigned to 
BG00012 and placebo, and the other will include subjects assigned to BIIB017 and placebo. 
Unless noted otherwise, analysis methods described in this section would apply to both sets of 
analyses.
The stratification factor (age [10 to ≤14 years of age and 15 to 17 years of age]) will be included 
in relevant statistical models.
16.1.
Efficacy
16.1.1.
Analysis Population
The primary efficacy analysis will include subjects in the efficacy population, defined as those 
who are randomized and receive at least 1 dose of study treatment (BG00012, BIIB017, or 
placebo).  Subjects will be analyzed according to the treatment group to which they are 
randomized.
16.1.2.
Methods of Analysis
In general, summary statistics will be presented.  Continuous variables will be summarized using 
summary statistics (mean, standard deviation, median, minimum, and maximum) by treatment 
group, and categorical variables will be presented using frequency distributions by treatment 
group.
Baseline is defined as the closest nonmissing value prior to the first dose of study treatment, 
unless otherwise specified.
Statistical testing will be conducted at significance level of 0.05.
16.1.2.1.
Analysis of the Primary Endpoint
The primary endpoint of this study is TTFR.  Kaplan-Meier curves will be used to summarize the 
proportion of subjects achieving the primary endpoint over time.  A Cox proportional hazards 
model will be used to compare the BG00012 group and the placebo group and the BIIB017 
group and the placebo group.  The model will be stratified by baseline age group and will include 
covariates for treatment, baseline relapse rate, baseline age, presence of Gd-enhancing lesions at 
Baseline, and baseline 
.  Baseline relapse rate will be defined as the number of relapses 
over the 2 years prior to study entry, divided by 2.  The hazard ratio of BG00012 versus placebo 


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
78
and BIIB017 versus placebo and the 95% confidence interval (CI) will be derived from the 
model. 
Subjects who withdraw early without a relapse event for reasons unrelated to efficacy will be 
censored, and subjects who withdraw due to lack of efficacy will be considered as cases with an 
event at the time of withdrawal.  Subjects who elect to start an alternative therapy following a 
protocol-defined event of disability progression will also be considered as cases with an event at 
time of confirmed disability progression.  
16.1.2.2.
Analysis of the Secondary Endpoints
MRI:  Number of New or Newly Enlarging T2 Hyperintense Lesions at Weeks 48 and 96
The number of new or newly enlarging T2 hyperintense lesions will be summarized by treatment 
group and timepoint.  Comparison between BG00012 group and placebo group and between 
BIIB017 group and placebo group at each timepoint will be made using the negative binomial 
regression model.  The analysis model will be stratified by baseline age group and will include 
covariates for treatment and number of baseline T2 lesions.  The rate ratio of BG00012 versus 
placebo and BIIB017 versus placebo and the 95% CI will be derived from the model. 
Missing values for subjects who withdraw early will not be imputed.  The MRI scan reads after 
subjects elect to start an alternative therapy following an event of relapse or disability 
progression will not be included in the summary or analysis.  
MRI:  Number of Gd-Enhancing Lesions at Baseline and at Weeks 48 and 96
The number of Gd-enhancing lesions will be summarized by treatment group and timepoint.  
Comparison between BG00012 group and placebo group and between BIIB017 group and 
placebo group at each timepoint will be made using a negative binomial regression model.  The 
analysis model will be stratified by baseline age group and will include covariates for treatment 
and number of baseline Gd-enhancing lesions.  The rate ratio of BG00012 versus placebo and 
BIIB017 versus placebo, and the 95% CI will be derived from the model. 
Missing values for subjects who withdraw early will not be imputed.  The MRI scan reads after 
subjects elect to start an alternative therapy following an event of relapse or disability 
progression will not be included in the summary or analysis.  
Annualized Relapse Rate at Weeks 48 and 96
The number of relapses in each treatment group adjusted for the duration of study treatment 
before the start of alternative therapy will be annualized at Weeks 48 and 96.  At each timepoint, 
the number of relapses will be analyzed by a negative binomial regression model.  Logarithmic 
transformation of the time on study will be included as an independent variable in the model as 
the “offset” parameter.  The model will be stratified by baseline age group and will include 
covariates for treatment, baseline relapse rate, baseline age, and baseline 
.  Baseline relapse 
rate will be defined as the number of relapses over the 2 years prior to study entry, divided by 2.  
The adjusted relapse rate from the negative binomial regression analysis will be presented for 










Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
83
17.
ETHICAL REQUIREMENTS
Biogen, 
 and the Investigator must comply with all instructions, regulations, and 
agreements in this protocol and applicable International Council for Harmonisation (ICH) and 
Good Clinical Practice (GCP) guidelines and conduct the study according to local regulations.
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines.  The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated.
17.1.
Declaration of Helsinki
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki.
17.2.
Ethics Committee
The Investigator must obtain ethics committee approval of the protocol, ICF, and other required 
study documents prior to starting the study.  Biogen will submit documents on behalf of the 
investigational sites in countries other than the US.
If the Investigator makes any changes to the ICF, Biogen must approve the changes before the 
ICF is submitted to the ethics committee.  A copy of the approved ICF must be provided to 
Biogen.  After approval, the ICF must not be altered without the agreement of the relevant ethics 
committee and Biogen.
It is the responsibility of the Investigators to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations.
Biogen must receive a letter documenting ethics committee approval, which specifically 
identifies the protocol, protocol number, and ICF, prior to the initiation of the study.  Protocol 
amendments will be subject to the same requirements as the original protocol.
A progress report must be submitted to the ethics committee at required intervals and not less 
than annually.
At the completion or termination of the study, the investigational site must submit a close-out 
letter to the ethics committee and Biogen.
17.3.
Subject Information and Consent
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the 


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
84
subject’s LAR (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 and the 
subject’s LAR.  The subject must be given sufficient time to consider whether to participate in 
the study.
The subject and LAR will be informed that race, ethnicity, and month and year of birth will be 
collected during the study (unless the collection is not permitted by applicable law or not 
approved by the governing ethics committee), and that those data will be used during the conduct 
and analysis of the study.
In addition, subjects who have the capacity should provide their assent to participate in the study.  
The level of information provided to subjects should match their level of understanding as 
determined by the Investigator and in accordance with applicable regulations and guidelines.
A copy of the signed and dated ICF (and assent if applicable) must be given to the subject’s 
LAR.  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 and assent if applicable must also be documented in the 
subject’s medical record.
17.4.
Subject Data Protection
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by local law (e.g., Protected Health Information 
authorization in North America).
During the study, the subject’s race, ethnicity, and month and year of birth will be collected 
(unless the collection is not permitted by applicable law or not approved by the governing ethics 
committee).  Since it is not known whether the effects of the study treatment are influenced by 
race or ethnicity, this information will be of value in the analysis of safety.  The month and year 
of birth information is necessary to confirm study eligibility, to facilitate clinical assessments 
(such as 
, where permitted), to employ age-dependent laboratory reference 
intervals, and to conduct the planned statistical analysis.
The subject will not be identified by name in the CRF or in any study report, 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.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
85
17.5.
Compensation for Injury
Biogen maintains appropriate insurance coverage for clinical studies and will follow applicable 
local compensation laws.
17.6.
Conflict of Interest
The Investigators should address any potential conflicts of interest (e.g., financial interest in 
Biogen) with the subject before the subject makes a decision to participate in the study.
17.7.
Registration of Study and Disclosure of Study Results
Biogen will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
86
18.
ADMINISTRATIVE PROCEDURES
18.1.
Study Site Initiation
The Investigator must not screen any subjects prior to completion of a study initiation visit, 
conducted by Biogen or designee.  This initiation visit will include a detailed review of the 
protocol and study procedures.
18.2.
Quality Assurance
During and/or after completion of the study, quality assurance officers named by Biogen or the 
regulatory authorities may wish to perform onsite audits or inspections.  The Investigator will be 
expected to cooperate with any audit or inspection and to provide assistance and documentation 
(including source data) as requested.
18.3.
Monitoring of the Study
The Investigator must permit study-related monitoring by providing direct access to source data 
and to the subjects’ medical histories.
The Clinical Monitor will visit the Investigator at regular intervals during the study and after the 
study has completed, as appropriate.
During these visits, CRFs and supporting documentation related to the study will be reviewed 
and any discrepancies or omissions will be resolved.  
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure protocol adherence, quality of data, study treatment accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities.
18.4.
Study Funding
Biogen is the Sponsor of the study and is funding the study.  All financial details are provided in 
the separate contracts between the institution, Investigator, and Biogen.  
18.5.
Publications
Details are included in the clinical trial agreement for this study.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
87
19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION
19.1.
External Contract Organizations
Biogen will be responsible for the oversight of all administrative aspects of this study handled by 
the CRO 
, including but not limited to study initiation, monitoring, management of AEs, 
and data management.
19.1.1.
Contract Research Organization 
A CRO will be responsible for administrative aspects of the study including but not limited to 
study initiation, monitoring, medical support, and management of SAE reports and data 
management.  Before subjects are screened at each study site, the CRO will review study 
responsibilities with the Investigators and other study site staff, as appropriate.
19.1.2.
Interactive Response Technology
IRT will be used in this study.  Before subjects are screened or enrolled, the IRT vendor will 
provide each study site with the necessary training, a user manual, and access rights to the 
system.
19.1.3.
Electronic Data Capture
Subject information will be captured and managed by study sites on electronic CRFs by a 
Web-based electronic data capture tool supported by iMedidata Rave and configured by 
19.1.4.
Central Laboratories for Laboratory Assessments
A central laboratory has been selected by Biogen to analyze all safety laboratory samples 
collected for this study.
19.1.5.
Central Facility for Other Assessments
All of the MRI scans with and without Gd will be evaluated at a central MRI reading center.  All 
investigational sites will be required to send a test scan of a healthy volunteer or a subject with 
MS to the MRI reading center for evaluation in order to ensure that the site’s scanning 
techniques are appropriate.  This review will take place before the investigational site is 
permitted to enroll any subjects into the study.
MRI digital data should be sent by mail or via the network to a secure file transfer protocol 
(FTP) server.  Other methods of data transfer may be acceptable on a case-by-case basis (the 
Clinical Monitor will provide specific MRI data shipping instructions prior to the start of 
enrollment at each site).


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
88
Additional and more detailed MRI scans with and without Gd procedures and protocols are 
included in the study MRI manual.
19.2.
Study Committees
19.2.1.
Data Safety Monitoring Committee 
A Data Safety Monitoring Committee (DSMC) will be formed to review safety data and alert 
and/or make recommendations to the Advisory Committee about any existing or potential 
problems.  All SAEs will be forwarded to the DSMC as monthly cumulative SAE listings.  In 
addition, the DSMC will be able to access unblinded data as needed.
19.2.2.
Steering (Advisory) Committee 
A Steering (Advisory) Committee will be formed to provide scientific and medical direction for 
the study.  The Steering Committee will meet at regular intervals to monitor subject accrual and 
to discuss recruitment, external competitive environment and mitigation strategies.
Members of the Steering Committee will include the Medical Director, Clinical Trial Manager, 
and Project Statistician from Biogen (and/or their designees), and external experts.  Biogen will 
designate one of the external experts to be the Chairperson of the Steering Committee.
19.3.
Changes to Final Study Protocol
All protocol amendments must be submitted to the ethics committee and regulatory authorities if 
required by local law.  Protocol modifications that affect subject safety, the scope of the 
investigation, or the scientific quality of the study must be approved by the ethics committee 
before implementation of such modifications to the conduct of the study.  If required by local 
law, such modifications must also be approved by the appropriate regulatory agency prior to 
implementation.
However, Biogen may, at any time, amend this protocol to eliminate an apparent immediate 
hazard to a subject.  In this case, the appropriate regulatory authorities will be notified 
subsequent to the modification.
In the event of a protocol modification, the ICF may require similar modifications (see 
Section 17).
19.4.
Ethics Committee Notification of Study Completion or Termination
Where required, the regulatory authorities and ethics committees must be notified of completion 
or termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
89
19.5.
Retention of Study Data
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local laws or regulations.  Prior to 
proceeding with destruction of records, the Investigator must notify Biogen in writing and 
receive written authorization from Biogen to destroy study records.  In addition, the Investigator 
must notify Biogen of any changes in the archival arrangements including but not limited to 
archival at an offsite facility or transfer of ownership if the Investigator leaves the site.
19.6.
Study Report Signatory
Biogen will designate one of the participating Study Investigators as a signatory for the study 
report.  This determination will be made by several factors, including but not limited to, the 
Investigator's experience and reputation in the studied indication; the Investigator's contribution 
to the study in terms of design, management, and/or subject enrollment; or by other factors 
determined to be relevant by Biogen.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
90
20.
REFERENCES
Adams AB, Tyor WR, Holden KR. Interferon beta-1b and childhood multiple sclerosis. Pediatr 
Neurol. 1999;21(1):481-3.
Atzori M, Battistella P, Perini P, et al. Clinical and diagnostic aspects of multiple sclerosis and 
acute monophasic encephalomyelitis in pediatric patients: a single centre prospective study. Mult 
Scler. 2009;15(3):363-70.
Banwell B, Reder AT, Krupp L, et al. Safety and tolerability of interferon beta-1b in pediatric 
multiple sclerosis. Neurology. 2006;66(4):472-6.
CDC. Interpretation of the hepatitis B serology panel. [CDC, 2007; Appendix A]. 
http://www.cdc.gov/hepatitis/HBV/PDFs/SerologicChartv8.pdf.
Chitnis T. Paediatric MS is the same disease as adult MS: no. Mult Scler. 2013;19(10):1255-6.
Chitnis T, Arnold DL, Banwell B, et al. Trial of Fingolimod versus Interferon Beta-1a in 
Pediatric Multiple Sclerosis. N Engl J Med. 2018;379(11):1017-1027.
Chitnis T, Glanz B, Jaffin S, et al. Demographics of pediatric-onset multiple sclerosis in an MS 
center population from the Northeastern United States. Mult Scler. 2009;15(5):627-631.
Confavreux C, Vukusic S. The clinical epidemiology of multiple sclerosis. Neuroimaging Clin N 
Am. 2008;18(4):589-622, ix-x.
Dale RC. Paediatric MS is the same disease as adult MS: commentary. Mult Scler. 
2013;19(10):1259-60.
European Commission. Ethical considerations for clinical trials on medicinal products conducted 
with the paediatric population. 2008. p. 34.
Ferreira M, Machado M, Dantas M, et al. Pediatric multiple sclerosis: analysis of clinical and 
epidemiological aspects according to National MS Society Consensus 2007. Arq Neuropsiquiatr. 
2008;66(3B):665-670.
Ghezzi A. Childhood-juvenile multiple sclerosis: clinical characteristics and treatment. Expert 
Rev Neurother. 2005;5(3):403-11.
Ghezzi A, Amato M, Annovazzi P, et al. Long-term results of immunomodulatory treatment in 
children and adolescents with multiple sclerosis: the Italian experience. Neurol Sci. 
2009;30(3):193-199.
Hintzen RQ, van Pelt DE. Paediatric MS is the same disease as adult MS: yes. Mult Scler. 
2013;19(10):1257-8.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
91
Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during 
a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med. 
2000;343(13):898-904.
Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves 
disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-
blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 
1995;45(7):1268-76.
Krupp LB, Tardieu M, Amato MP, et al. International Pediatric Multiple Sclerosis Study Group 
criteria for pediatric multiple sclerosis and immune-mediated central nervous system 
demyelinating disorders: revisions to the 2007 definitions. Mult Scler. 2013;19(10):1261-7.
Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an 
international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical 
Trials of New Agents in Multiple Sclerosis. Neurology. 1996;46(4):907-911.
Mikaeloff Y, Caridade G, Tardieu M, et al. Effectiveness of early beta interferon on the first 
attack after confirmed multiple sclerosis: a comparative cohort study. Eur J Paediatr Neurol. 
2008;12(3):205-209.
Mikaeloff Y, Moreau T, Debouverie M, et al. Interferon-beta treatment in patients with 
childhood-onset multiple sclerosis. J Pediatr. 2001;139(3):443-6.
O'Connor P, Group CMSW. Key issues in the diagnosis and treatment of multiple sclerosis. An 
overview. Neurology. 2002;59(6 Suppl 3):S1-33.
Pohl D, Rostasy K, Gärtner J, et al. Treatment of early onset multiple sclerosis with 
subcutaneous interferon beta-1a. Neurology. 2005;64(5):888-890.
Pohl D, Waubant E, Banwell B, et al. Treatment of pediatric multiple sclerosis and variants. 
Neurology. 2007;68(16 Suppl 2):S54-65.
Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 
Revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292-302.
PRISMS Study Group. PRISMS-4: Long-term efficacy of interferon-beta-1a in relapsing MS. 
Neurology. 2001;56(12):1628-36.
Tenembaum S, Segura M. Interferon beta-1a treatment in childhood and juvenile-onset multiple 
sclerosis. Neurology. 2006;67(3):511-513.
The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting 
multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-
controlled trial. Neurology. 1993;43(4):655-61.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
92
Waldman AT, Gorman MP, Rensel MR, et al. Management of pediatric central nervous system 
demyelinating disorders: consensus of United States neurologists. J Child Neurol. 
2011;26(6):675-82.
Waubant E, Hietpas J, Stewart T, et al. Interferon beta-1a in children with multiple sclerosis is
well tolerated. Neuropediatrics. 2001;32(4):211-3.


Protocol 800MS301
Version 4 
Placebo-Controlled Study of the Efficacy and Safety of BG00012 and BIIB017 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
93
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “A Randomized, Double-Blind, Double-Dummy, 
Placebo-Controlled, 3-Arm, Parallel-Group Study in Pediatric Subjects Aged 10 Through
17 Years to Evaluate the Efficacy and Safety of BG00012 and BIIB017 for the Treatment of 
Relapsing-Remitting Multiple Sclerosis,” and agree to conduct the study according to the 
protocol and the applicable ICH guidelines and GCP regulations, and to inform all who assist me 
in the conduct of this study of their responsibilities and obligations.
____________________________________________________
Investigator’s Signature
Date
____________________________________________________
Investigator’s Name (Print)
____________________________________________________
Study Site (Print)


CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
1
Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead Berkshire
SL6 4AY
United Kingdom
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 800MS301
A Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, 3-Arm, Parallel-Group Study in 
Pediatric Subjects Aged 10 Through 17 Years to Evaluate the Efficacy and Safety of BG00012 and 
BIIB017 for the Treatment of Relapsing-Remitting Multiple Sclerosis
Version 3
Date:  09 August 2018
EUDRA CT Number: 2018-000516-22
Version 3 of the protocol has been prepared for this amendment, which supersedes Version 2.


Protocol 800MS301, Version 3
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
2
PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol 800MS301 is to clarify the level of detail and 
purpose of date-of-birth (DOB) information being collected for the subjects enrolled in the study.
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 17.4, Subject Data Protection
Now reads:
During the study, the subject’s’ race, and ethnicity, and full datemonth and year of birth will be 
collected, (unless the collection is not permitted by applicable law or not approved by the 
governing ethics committee).  These data will be used in the analysis of the safety profile of the 
study treatment.Since Iit is not unknown whether the effects of the study treatment are 
influenced by race or ethnicity, this information will be of value in the analysis of safety.  The 
month and year of birth information is necessary to confirm study eligibility, to facilitate 
clinical assessments (such as 
, where permitted), to employ age-dependent 
laboratory reference intervals, and to conduct the planned statistical analysis.
Rationale:  This study involves the treatment of pediatric subjects with relapsing-remitting 
multiple sclerosis between 10 and 17 years of age, inclusive, for up to 96 weeks.  The collection 
of full DOB information was determined to be inconsistent with standard Biogen practice and 
subject to restriction in many countries as a matter of personal privacy; however, the collection of 
both the month and year of birth is necessary to conduct and analyze the study properly.


Protocol 800MS301, Version 3
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
3
SUMMARY OF MAJOR CHANGES TO THE PROTOCOL
Changes to the protocol are presented chronologically.  New text is shown in bold type; deleted 
text is shown with a strikethrough.
Section 4.3.1, Administration of Study Treatment
Change:  The reference to “caregiver” was deleted.
Now reads:
To ensure blinding across the 3 treatment groups, each subject will receive BG00012 or placebo 
capsules administered orally BID and BIIB017 or placebo injection administered SC every 
2 weeks.  Subjects can either swallow the capsules whole (preferred) or open the capsules and 
mix with food immediately prior to consumption.  If the subject is unable to self-administer the 
SC treatment, the caregiver orparent will be allowed to administer the treatment.
Rationale:  The subject’s legally authorized representative (LAR; i.e., parent or legal guardian) 
has the authority and bears the responsibility for all decisions and actions regarding the subject’s 
participation in the study.  This includes compliance with the administration of study treatment, 
which is expected to be done by the subject or the parent.  Any caregiver who may be involved in 
facilitating management of the subject’s participation does so at the discretion of the LAR.
This change also affects Section 4.2, Schedule of Activities (Table 1:  Study Activities and 
Assessments, footnote 17); Section 7.2.1, Relapses; and Section 15, Safety Definitions, 
Recordings, Reporting, and Responsibilities.
Section 8.1, Inclusion Criteria
Change:  Criterion 1 was revised.
Now reads:
1. Ability of a legally authorized representative (LAR; parents or legal guardians) 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.  Subjects will provide assent in addition to the parent’s or 
guardian’s LAR’s consent, as appropriate, per local regulations.
Rationale:  The obligation of the LAR, not the subject, to provide written informed consent was 
clarified, given that the subjects participating in this study have not reached the age of majority at 
the time of enrollment.


Protocol 800MS301, Version 3
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
4
This change also affects Section 9.1, Screening and Enrollment; Section 15, Safety Definitions, 
Recording, Reporting, and Responsibilities; and Section 17.3, Subject Information and Consent.
Section 8.2, Exclusion Criteria
Change:  Criterion 17 was revised.
Now reads:
•
Prior treatment that might influence growth, including but not limited to methylphenidate 
hydrochloride, thyroid hormone, growth hormone, anabolic steroids, calcitonin, 
estrogens, progestins (with the exception of medication used for contraception), 
bisphosphonates, anticonvulsants, or phosphate-binding antacids.
Rationale:  The general exclusion of prior or concomitant treatment with progestins does not 
apply to subjects using oral contraceptives during the study.


Protocol 800MS301, Version 3
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
5
SUMMARY OF MINOR CHANGES TO THE PROTOCOL
The following minor changes were made to the protocol, as appropriate:

The version number and date were updated throughout the protocol.

The List of Abbreviations was updated.

Figures 1, 2, and 3 were completely revised to improve completeness and readability.

Table 1 was revised to clarify that the Week 2 and Week 4 contacts with the subject 
provide the option for a clinic visit or telephone call.

Table 2 was revised to move the Early Withdrawal Visit column from the leftmost to 
the rightmost position.


CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
1
Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead Berkshire
SL6 4AY
United Kingdom
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 800MS301
A Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, 3-Arm, Parallel-Group 
Study in Pediatric Subjects Aged 10 Through 17 Years to Evaluate the Efficacy and Safety of 
BG00012 and BIIB017 for the Treatment of Relapsing-Remitting Multiple Sclerosis
Version 2.0
Date:  15 June 2018
Version 2.0 of the protocol has been prepared for this amendment, which supersedes Version 1.0.


Protocol 800MS301, Version 2.0
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
2
PRIMARY REASON FOR AMENDMENT
The primary reasons for this amendment to Protocol 800MS301 are:
a) To exclude those subjects from further follow-up, who have a low lymphocyte count 
following study withdrawal/completion, should they be initiated on appropriate MS 
treatment, according to local standard of care.
b) Provision of open-label access to BG00012 (Tecfidera) for subjects who experience a 
confirmed relapse at any point during the study or who have a high lesion burden on 
magnetic resonance imaging (MRI) at Week 48 until the end of their scheduled 
participation in the study if this is considered suitable by the treating neurologist.
New text is shown in bold type; deleted text is shown with a strikethrough.
a)
Section 7.1, Study Overview
Now reads:
Subjects who complete, temporarily withhold, or permanently discontinue study treatment for 
any reason and have a lymphocyte count <lower limit of normal (LLN) will be followed at least 
every 4 weeks for 24 weeks, then every 12 weeks (unless clinically indicated more often or at the 
Investigator’s discretion) until the lymphocyte count is ≥LLN, or for 48 weeks following
treatment discontinuation, whichever is sooner, or until the subject is initiated on the 
appropriate MS treatment, according to local standard of care, following study 
withdrawal/completion.
Rationale:  The scientific purpose of monitoring lymphocyte count in subjects who have levels 
<LLN at the end of study completion or treatment interruption/discontinuation was to gain 
information on how long lymphocyte recovery takes after stopping BG00012.  Subjects who 
have a low lymphocyte count following study withdrawal/completion and then continue to 
receive BG00012 are being excluded from further follow-up because reconstitution of 
lymphocytes will not occur if a subject continues on BG00012.  In addition, if a subject is placed 
on BIIB017 or another disease-modifying therapy, it will not be possible to assess lymphocyte 
recovery time as the data will be confounded.  Hence, any affected subjects would have been 
exposed to unnecessary blood tests without any scientific knowledge being gained.
This change also affects Section 4.2, Schedule of Activities, Table 2; Section 7.3.3, Follow-Up; 
and Section 11.2.6.2, Schedule for Subjects Who Complete, Temporarily Withhold, or 
Permanently Discontinue Study Treatment for Any Reason and Have a Lymphocyte Count 
<LLN.


Protocol 800MS301, Version 2.0
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
3
b)
Section 7.1, Study Overview
Now reads:
If a confirmed relapse or disability progression occurs, the subject will be eligible to receive appropriate 
alternative therapy, along with any requisite safety monitoring, at the discretion of the treating neurologist 
and will be allowed to remain in the study.  Investigators can choose to offer alternative DMTs 
according to local standard of care. 
During the study, subjects who have a confirmed relapse or disability progression or a high 
lesion burden on MRI at Week 48 (defined as ≥9 new/enlarged T2 lesions) will have the 
option of switching to an alternative therapy in accordance with local practices, or open-
label BG00012 (Tecfidera), at the discretion of the Investigator.  Subjects will discontinue 
blinded study treatment when they switch to an alternative therapy or open-label 
BG00012. Subjects who are switched to an alternative therapy or open-label BG00012 will 
remain in the study to complete the scheduled visits, along with any requisite safety 
monitoring.  Open-label BG00012 will only be provided until the subject completes or 
withdraws from the study or according to local regulatory requirements.
If a subject receives open-label BG00012 or an alternative therapy, they should be assessed at 
the Open-Label BG00012/Alternative Therapy Visit within 24 weeks of switching.
Section 7.2.3, MS Relapses, Treatment, and Alternative MS Therapy
Now reads:
During the study, sSubjects who have a confirmed relapse or disability progression or high 
lesion burden on MRI at Week 48 (defined as ≥9 new/enlarged T2 lesions) will have the 
option of switching to an alternative therapy in accordance with local practices, or open-label 
BG00012, at the discretion of the Investigator.  Subjects will discontinue blinded study 
treatment when they switch to an alternative therapy or open-label BG00012due to a relapse or 
disability,. Subjects who are switched to an alternative therapy or open-label BG00012 
willbut can remain in the study to complete the scheduled visits, along with any requisite safety 
monitoring.  Open-label BG00012 will only be provided until the subject completes or 
withdraws from the study or according to local regulatory requirements.
Rationale:  Patients will be allowed to receive open-label BG00012 (Tecfidera) following a 
confirmed relapse or disability progression or who have a high lesion burden on MRI at Week 48 
and if they continue in the study for the continued monitoring of safety and efficacy. Where 
Investigators think it is more appropriate, subjects may switch to alternative therapies and are 
allowed to remain in the study. The rationale for providing BG00012 is that it has an established 
safety and efficacy profile in the adult population and is relatively easy to administer, not 
requiring SC injections in the pediatric population.  Furthermore, subjects will not be unblinded,
thus, it is preferable to continue subjects on open-label therapy with the treatment demonstrated 
to have higher efficacy than interferons in the adult population.


Protocol 800MS301, Version 2.0
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
4
This change also affects Section 4.1, Study Schematic, Figure 1; Section 4.2, Schedule of 
Activities, Table 2; Section 7.2.1, Relapses; Section 7.2.2, Definition of Disability Progression; 
Section 7.3.2, Treatment; and Section 7.3.3, Follow-Up.




Protocol 800MS301, Version 2.0
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
6
Section 4.3.2, Blood Volumes
Change:  The blood volumes have been amended as follows.
Table 3: Blood Volumes by Visit
Screening 
Visit
Randomized, Double-Blind, Double-Dummy, Placebo-Controlled Treatment Period
Post-
Treatment  
Visit
Week
(Within 
6 Weeks 
of 
Baseline)
Baseline 
Visit 
(Day 1)
Wk 4 
±2 D
Wk 
8
±7 D
Wk 
12 
±7 D
Wk 
24
±7 D
Wk 36
±7 D
Wk 
48
±7 D
Wk 
60
±7 D
Wk  
72 
±7 D
Wk 
84 
±7 D
Wk 
96 
±7 D
Wk 100 
±7 D
Blood 
draw 
volume 
(mL)
11.08.0
14.07.0
5.5
8.0
14.0
6.0
7.0
15.5
7.0
7.06.0
15.5
7.0
7.06.0
15.5
8.0
7.0 
6.0
15.5
7.0
7.05.0
Table 4: Blood Volumes by Visit (Unscheduled Visits)
Early Withdrawal 
Visit
Open-Label 
BG00012/Alternative 
Therapy Visit
(Within 4 Weeks after Switch
if next Study Visit not Within 
4 Weeks)
Lymphocyte Follow-Up
Visit
Unscheduled Relapse 
Assessment Visit
Blood draw 
volume (mL)
15.56.0
7.06.0
2.01.2
7.05.0
Rationale:  This change was made because of an original error in the protocol.
Section 7.1, Study Overview
Change:  Text has been amended to make clinic visits at Weeks 2 and 6 optional, if patients 
need assistance with their injections.
Now reads:
Clinic visits will occur at Day 1 and at Weeks 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, 84, and 96.  
Clinic visits at Weeks 2 and 6 are optional and, if not conducted, will occur by ‘phone.
Rationale:  This change was made to reduce the burden of additional clinic visits when not 
absolutely required.


Protocol 800MS301, Version 2.0
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
7
Section 7.3.2, Treatment
Change:  Text has been amended to make clinic visits at Weeks 2 and 6 optional, if patients 
need assistance with their injections and to include additional visits for patients switching to 
open-label BG00012.
Now reads:
Eligible subjects will report to the study site to receive study treatment at Baseline (Day 1) and at 
Weeks 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, and 84.  Clinic visits at Weeks 2 and 6 are optional 
and, if not conducted, will occur by ‘phone.  Subjects will receive treatment for 96 weeks.  
Subjects who switch to open-label BG00012 or an alternative therapy and who are assessed at 
an Open-Label BG00012/Alternative Therapy Visit will then follow the same schedule for 
assessments as subjects remaining on their original study treatment.
Rationale:  This change was made to reduce the burden of additional clinic visits when not 
absolutely required.
Section 8.1, Inclusion Criteria 
Change:  The text of Inclusion Criterion #6 has been amended to describe the options for the 
relevant conditions and to include the definition of relapse.
Now reads:
6. Must have experienced ≥1 relapse in the 12 months prior to randomization (Day 1), 
or must have evidence of asymptomatic disease activity (Gd-positive lesions) seen 
on MRI in the 6 months prior to randomization (Day 1), or must have ≥2 relapses 
in the 24 months prior to randomization (Day 1).  Relapse is defined as the 
occurrence of a clinical demyelination event regardless of whether the event is a 
first (initial) or subsequent (recurrent) demyelinating event.
Rationale:  This change clarifies that subjects who do not meet the relapse criteria (a or b) may 
still be eligible for the study if they show evidence of gadolinium (Gd)-enhancing lesions of the 
brain (c).
Section 19.2.2, Steering (Advisory) Committee 
Change:  A new section has been inserted to detail the purpose and composition of a Steering 
Committee for study oversight.
Now reads:
A Steering (Advisory) Committee will be formed to provide scientific and medical direction 
for the study.  The Steering Committee will meet at regular intervals to monitor subject 
accrual and to discuss recruitment, external competitive environment, and mitigation 
strategies.


Protocol 800MS301, Version 2.0
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
8
Members of the Steering Committee will include the Medical Director, Clinical Trial 
Manager, and Project Statistician from Biogen (and/or their designees), and external 
experts.  Biogen will designate one of the external experts to be the Chairperson of the 
Steering Committee.
Rationale:  This change is required to confirm with the accompanying reference in Section 
19.2.1, Data Safety Monitoring Committee, to provide suitable oversight and direction for the 
study.




Protocol 800MS301, Version 2.0
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
10

Section 4.2, Schedule of Activities, Tables 1 and 3 have been amended to extend the 
time window for clinic visits at Week 8 onward to ±7 days rather than ±5 days to ease 
the burden on parents and subjects and allow for greater flexibility in scheduling.

Section 4.2, Schedule of Activities, Table 2, footnote 1 has been deleted as this is not 
applicable.  Now reads:  1Tests and assessments must be completed prior to study treatment 
administration and/or distribution unless otherwise specified.

Section 4.2, Schedule of Activities, Table 2 has been amended to delete the row 
referencing dispensing of treatment, as this does not take place at unscheduled visits.

Section 4.3.3, Site Personnel has been amended because, in some countries, EDSS-
certified raters are not necessarily neurologists.  Now reads:  Both the treating 
neurologist and the examining neurologist must have a minimum of 2 years of 
neurology specialty training and be able to make at least a 1 year commitment to the 
study.  …  The examining neurologist or EDSS-certified rater will be responsible 
for the following:

Section 7.2.3, MS Relapses, Treatment, and Alternative MS Therapy, has been 
further amended to clarify that open-label BG00012 will only be provided until study 
completion or withdrawal.  Now reads:  Subjects will have the option of switching to 
an alternative therapy in accordance with local practices at the discretion of the 
Investigator or open-label BG00012.  Subjects will discontinue study treatment 
when they switch to an alternative therapy or open-label BG00012 due to a relapse 
or disability (including high MRI disease activity at Week 48 [defined as ≥9 
new/enlarged T2 lesions]). Subjects who are switched to alternative therapy are 
allowed to but can remain in the study to complete the scheduled visits.  Open-label 
BG00012 will only be provided until the subject completes or withdraws from 
the study or according to local regulatory requirements.

Section 8.1, Inclusion Criteria:  Inclusion Criterion #2 has been amended to allow for 
country-specific requirements relating to the minimum age.  Now reads:  Aged 10 to 
17 years old, inclusive, at the time of informed consent.  The minimum age can be 
older than 10 years as required by country-specific regulations and/or local 
ethics committees.

Section 8.2, Exclusion Criteria:  Exclusion Criterion #2 has been amended to remove 
the reference to historical disorders mimicking MS, as only current disorders are 
considered to be of an exclusionary nature.  Now reads:  History of dDisorders 
mimicking MS, such as other demyelinating disorders (e.g., acute disseminated 
encephalomyelitis), systemic autoimmune disorders (e.g., Sjögren’s disease and lupus 
erythematosus), metabolic disorders (e.g., dystrophies), and infectious disorders.

Section 8.2, Exclusion Criteria: Exclusion Criterion #8 has been amended to clarify 
the definition of severe depression.  Now reads:  History of suicidal ideation within 3 


Protocol 800MS301, Version 2.0
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
11
months prior to randomization (Day 1) or an episode of severe depression within 3 
months prior to randomization (Day 1).  Severe depression is defined as an episode of 
depression that requires hospitalization or is otherwise regarded as severe by at the 
discretion of the Investigator.

A typographical error has been corrected in Section 8.2, Exclusion Criteria: 
Exclusion Criterion #20, which now reads:  History of drug or alcohol abuse (as 
determineddefined by the Investigator) within 2 years prior to randomization (Day 
1).

Section 8.2, Exclusion Criteria: Exclusion Criterion #23 has been amended to allow 
for the re-screening of subjects.  Now reads:  Previous randomizationparticipation
in this study.

Section 9.2, Randomization and Registration of Subjects has been amended to include 
details regarding stratification, which were previously missing.  Now reads:  Subjects 
will be randomized in a 1:2:2 ratio to receive BG00012:BIIB017:placebo.  Subjects 
will be stratified by age (10 to ≤14 years of age and 15 to 17 years of age) and by 
site.

Section 9.3, Blinding Procedures:  Additional text inserted to allow for the disclosure 
of treatment assignments at the conclusion of the study.  Now reads:  At the end of 
the study (i.e., once the clinical study report is finalized), if unblinding will not 
jeopardize the results of ongoing related studies, Biogen will provide the 
randomization codes to Investigators, who then can inform their subjects about 
the treatment received.

Section 10.1, Discontinuation of Study Treatment has been amended to clarify the 
definition of severe depression.  Now reads:  Severe depression is defined as an 
episode of depression that requires hospitalization or is otherwise regarded as 
severe by at the discretion of the Investigator.

Section 10.1, Discontinuation of Study Treatment has been amended to provide 
guidance in the event of a seizure or suspected seizure.  Now reads:  In the event of 
a subject experiencing a seizure or suspected seizure during the study, they 
should be managed as per local clinical guidelines/standard medical care.  The 
Investigator should re-evaluate whether the subject should continue in the study.

Section 11.2.3, Resumption of Study Treatment Dosing has been amended to provide 
clarification regarding the resumption of study treatment whilst maintaining study 
blinding.  Now reads: Subjects randomized to BG00012 will receive a dose of 
120 mg BID orally for 7 days followed by the maintenance dose of 240 mg BID.  
Subjects randomized to BIIB017 will be titrated to the target dose of 125 µg SC as 
follows:  63 µg on Day 1, 94 µg at Week 2, and 125 µg at Week 4. To ensure 
blinding across the 3 treatment groups, each subject will receive BG00012 or 




Protocol 800MS301, Version 2.0
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
13

Section 16.1.2.2, Analysis of the Secondary Endpoints (MRI:  Number of 
Gd-Enhancing Lesions at Baseline and at Weeks 48 and 96) has been amended to 
include provisions for stratification and now reads:  Comparison between BG00012 
group and placebo group and between BIIB017 group and placebo group at each 
timepoint will be made using a negative binomialmultiple logistic regression model.  
The analysis model will be stratified by baseline age group and will include 
covariatesa term for treatment and for the number of baseline Gd-enhancing lesions.  
The rateodds ratio of BG00012 versus placebo and BIIB017 versus placebo, and the 
95% CI will be derived from the model.

Section 16.1.2.2, Analysis of the Secondary Endpoints (Annualized Relapse Rate at 
Weeks 48 and 96) has been amended to include provisions for stratification and now 
reads:  The model will be stratified by baseline age group and will include 
covariatesa term for treatment, and will be adjusted for baseline relapse rate, baseline 
age, and baseline 
.

Section 16.5.1, Analysis Population has been amended to provide further clarification 
regarding the safety analysis population.  Now reads:  The safety population is 
defined as all subjects who receive at least 1 dose of study treatment.  Subjects will 
be analyzed based on the actual treatment received.
The primary safety analyses of AEs,
 will be 
performed based on the safety population during the period from the first dose of 
blinded treatment to the end of the blinded treatment, whether or not subjects 
have been on an alternative therapy following an event of protocol defined relapse or 
disability progression.  In general, safety data collected after subjects elect to start 
open-label BG00012 or an alternative therapy will be excluded from these primary 
summary analyses.  However, supportive analyses on all safety data, including those 
collected during the period of treatment with open-label BG00012 or alternative 
therapies, will be providedreported in subject listings.

Section 16.8, Sample Size Considerations has been amended as there was an initial 
error in the study protocol.  Now reads:  Assuming that 59.6% of subjects in the 
placebo group will have their first relapse during the 2-year period, the study will 
have at least 80% power to detect a 50% and 39% reduction compared with placebo 
in the risk of relapse in the BG00012 and BIIB017 arms, respectively, when a total of 
148156 events (first relapses) have accrued.

Section 17.4, Subject Data Protection has been amended to explicitly state that race, 
ethnicity, and date of birth will be obtained, where allowed for by local regulations.  
Now reads:  During the study, subjects’ race and ethnicity and full date of birth 
will be collected, unless the collection is not permitted by applicable law or not 
approved by the governing ethics committee.  These data will be used in the 
analysis of the safety profile of the study treatment.  It is unknown whether the 
effects of the study treatment are influenced by race or ethnicity.


Protocol 800MS301, Version 2.0
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
14

Typographical errors and formatting were corrected.

SAP_001.pdf: 
S T A TI S TI C A L A N A L Y SI S P L A N  
Versi o n N o. : 1. 0  
D ate : 4  Ma y  2 0 2 2  
 A ut h or : 
, P h. D. 
St u d y Title : A Ra n d o mize d, D o u ble -Bli n d, D o u ble -D u m m y, Place b o -C o ntr olle d, 3 -Ar m, 
Parallel Gr o u p St u d y i n Pe diatric S u bjects A ge d 1 0 T hr o u g h 1 7 Years t o E val uate t he Efficac y 
a n d Safet y of B G 0 0 0 1 2 a n d BII B 0 1 7 f or t he Treat me nt of Rela psi n g -Re mitti n g M ulti ple 
Scler osis  
N a me of St u d y Tre at me nt : B G 0 0 0 1 2 ( di met h yl f u marate; Tecfi dera ® ); BII B 0 1 7 ( pe gi nterfer o n -1a; 
Ple gri d y ® ) 
Pr ot oc ol N o .: 8 0 0 M S 3 0 1 / N C T 0 3 8 7 0 7 6 3 
St u d y P h ase : 3  
C o nfi de nti al I nf or m ati o n  
T he i nf or m ati o n c o nt ai ne d i n t his St atistic al A n alysis Pl a n ( S A P) is c o nfi de nti al a n d m ay n ot be 
re pr o d uce d or ot her wise disse mi n ate d wit h o ut t he a p pr ov al of Bi o ge n, I nc.  




Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y ) a n d BII B 0 1 7 (Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 3  
 
 
 
V E R SI O N HI S T O R Y  
 
S A P Versi o n  
D ate  
Pri m ar y  R e as o n s f or 
A me n d me nt  
0 . 1 ( Sta ble S A P) 
1 4 -M A Y -2 0 2 1    
N/ A  
1. 0  ( Fi nal S A P)  
0 3 -M A Y -2 0 2 2    
N/ A  
 
 
 


Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y ) a n d BII B 0 1 7 (Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 4  
 
 
 
T A B L E O F C O N T E N T S  
 
S T A TI S TI C AL A N AL Y SI S PL A N  ......................................................................................................................... 1  
A P P R O V AL  ..................................................................................................................................................... 2  
V E R SI O N HI S T O R Y  ......................................................................................................................................... 3  
T A BL E O F C O N T E N T S  ..................................................................................................................................... 4  
LI S T O F A B B R E VI A TI O N S ............................................................................................................................... 6  
1.  
I ntr o d ucti o n .......................................................................................................................................... 7  
2.  
St u dy Ov ervi e w  ..................................................................................................................................... 8  
2. 1.    
St u d y O bjecti ves a n d E n d p oi nts  ............................................................................................ 8  
2. 2.    
St u d y Desi g n  ............................................................................................................................ 9  
2. 3.    
S a m ple Size C o nsi der ati o ns  ................................................................................................. 1 1  
2. 4.    
St u d y st o p pi n g r ules .............................................................................................................. 1 2  
3.  
E arly t er mi n ati o n of st u dy d u e t o s p o ns or’s d ecisi o n  ........................................................................ 1 2  
4.  
C h a n g es fr o m t h e pr ot oc ol -d efi n e d st atistic al a n alysis pl a n  .............................................................. 1 2  
5.  
D efi niti o ns  ........................................................................................................................................... 1 3  
5. 1.    
D ates a n d P oi nts of Refere nce  .............................................................................................. 1 4  
5. 2.    
St u d y Tre at me nt  ................................................................................................................... 1 8  
5. 3.    
St u d y Peri o ds  ......................................................................................................................... 1 8  
5. 4.    
Str atific ati o n F act ors a n d S u b gr o u p V ari a bles  ................................................................. 1 9  
5. 4. 1.    
Str atific ati o n F act ors  ........................................................................................................... 1 9  
5. 4. 2.    
S u b gr o u p V ari a bl es  ............................................................................................................. 1 9  
5. 5.    
A n al ysis P o p ul ati o ns  ............................................................................................................. 1 9  
6.  
List of Pl a n n e d St u dy A n al ys es ............................................................................................................ 1 9  
6. 1.    
I nteri m A n al ysis .................................................................................................................... 1 9  
6. 2.    
Pri m ar y A n al ysis  ................................................................................................................... 2 0  
6. 3.    
Fi n al A n al ysis  ........................................................................................................................ 2 0  
7.  
St atistic al M et h o ds f or Pl a n n e d A n al ys es  ........................................................................................... 2 0  
7. 1.    
Ge ner al Pri nci ples  ................................................................................................................. 2 0  
7. 2.    
P artici p a nt Acc o u nt a bilit y  ................................................................................................... 2 2  


Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y ) a n d BII B 0 1 7 (Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 5  
 
 
7. 3.    
De m o gr a p hic a n d B aseli ne C h a r acteristics ........................................................................ 2 2  
7. 4.    
Pr ot oc ol De vi ati o ns  ............................................................................................................... 2 2  
7. 5.    
St u d y Tre at me nt E x p os ure a n d C o nc o mit a nt Me dic ati o ns  .............................................. 2 2  
7. 5. 1.    
Pri m ar y Effic acy E n d p oi nt  ................................................................................................... 2 3  
7. 5. 2.    
S ec o n d ar y Effic ac y E n d p oi nts  ............................................................................................. 2 3  
7. 5. 3.  
 2 3  
7. 6.    
S afet y E n d p oi nts  ................................................................................................................... 2 3  
7. 6. 1 A dv ers e Ev e nts  ........................................................................................................................... 2 3  
7. 7.    
P h ar m ac o ki netic ( P K) E n d p oi nts  ........................................................................................ 2 5  
7. 8.    
P h ar m ac o d y n a mic ( P D) E n d p oi nts  ..................................................................................... 2 5  
7. 9.  
2 5  
7. 1 0.    
A nti ge nicit y/I m m u n o ge nicit y E n d p oi nts  ............................................................................ 2 5  
7. 1 1.    
Ot her A n al yses  ...................................................................................................................... 2 5  
7. 1 2.    
St atistic al C o nsi der ati o ns f or I nteri m A n al ysis  ................................................................. 2 5  
8.  
S u m m ary of C h a n g es fr o m t h e Pr evi o us V ersi o n of t h e S A P  .............................................................. 2 5  
9.  
R e f er e nc es .......................................................................................................................................... 2 6  
A P P E N DI C E S  ................................................................................................................................................ 2 7  
 
 
 


Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y ) a n d BII B 0 1 7 (Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 6  
 
 
 
LI S T O F A B B R E VI A TI O N S  
A b bre vi ati o n  
Defi niti o n  
A E  
a d verse e ve nt 
A L T  
ala ni ne a mi n otra nsferase  
a P T T  
acti vate d partial t hr o m b o plasti n ti me  
A S T  
as partate a mi n otra nsferase  
BI D  
t wice dail y  
B P M  
beats per mi n ute  
 
 
 
 
C R F  
case re p ort f or m  
D M F  
di met h yl f u marate  
 
 
 
 
G d  
ga d oli ni u m  
H Bc A b  
he patitis B c ore a nti b o d y  
H Bs A b  
he patitis B s urface a nti b o d y  
HI V  
h u ma n i m m u n o deficie nc y vir us  
I C F 
i nf or me d c o nse nt f or m 
 
I T T 
i nte nt-t o-treat  
I V 
i ntra ve n o us 
I V M P 
i ntra ve n o us met h yl pre d nis ol o ne 
L A R  
le gall y a ut h orize d re prese ntati ve  
L L N  
l o wer li mit of n or mal 


Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y ) a n d BII B 0 1 7 (Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 7  
 
 
A b bre vi ati o n  
Defi niti o n  
M RI  
ma g netic res o na nce i ma gi n g  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Affairs  
M S  
m ulti ple scler osis  
N S AI D  
n o nster oi dal a nti -i nfla m mat or y dr u g 
P D  
p har mac o d y na mic  
 
 
P E G  
p ol yet h yle ne gl yc ol  
P K  
p har mac o ki netic  
P R O  
Patie nt -re p orte d O utc o me 
 
 
R R M S  
rela psi n g-re mitti n g m ulti ple scler osis 
S A E  
seri o us a d verse e ve nt 
S C  
s u bc uta ne o us 
 
 
T T F R  
ti me t o first rela pse 
W H O  
W orl d Healt h Or ga nizati o n  
 
1.  I ntr o d ucti o n 
T his  S A P is ass ociate d wit h t he B L A S T st u d y ( 8 0 0 M S 3 0 1) of BII B 9 1 7 ( Tecfi dera) a n d 
B G 0 0 0 1 2 ( Ple gri d y ). It is base d o n versi o n 4 of t h e st u d y pr ot oc ol, date d 0 6-N O V -2 0 2 0. T his is 
t he fi nal S A P f or t he st u d y a n d is i nte n de d t o o utli ne t he basic pla n ne d a nal yses at t he ti me of its 
writi n g.  
 
T he B L A S T st u d y was  a ra n d o mize d m ultice nter d o u ble -bli n d a n d d o u b le-d u m m y place b o -
c o ntr olle d t hree ar m parallel gr o u p st u d y t o e val uate t he effi cac y a n d safet y of B G 0 0 0 1 2 a n d 
BII B 0 1 7 i n pe diatri c s u bjects wit h Rela psi n g -Re mitti n g M ulti ple Scler osis ( R R M S).  


Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y ) a n d BII B 0 1 7 (Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 8  
 
 
2.  St u d y O ver vie w  
T his was  a ra n d o mize d, m ultice nter, d o u ble -bli n d, d o u ble -d u m m y, place b o -c o ntr olle d, 3 -ar m, 
parallel -gr o u p st u d y t o e val uate t he efficac y a n d s afet y of B G 0 0 0 1 2 a n d BII B 0 1 7 i n pe diatri c 
s u bjects wit h R R M S. 
U nless state d ot her wise bel o w, t he ter m s u m m ar y st atistics refers t o t he c o m p utati o n of t he 
mea n, sta n dar d de viati o n, me dia n , mi ni m u m, a n d ma xi m u m. 
2. 1.  St u d y O bjecti ves a n d E n d p oi nts  
St u d y Pri m ar y O bjecti ve  
T he pri mar y o bjecti ve of t his st u d y was  t o e val uate t he efficac y of B G 0 0 0 1 2 a n d BII B 0 1 7, 
b ot h c o m pare d wit h place b o, i n pe diatric s u bjects wit h R R M S.  
St u d y Pri m ar y E n d p oi nt  
T he pri mar y e n d p oi nt rel ate d t o t his o bjecti ve was  t he Ti me-t o-First  Rela pse ( T T F R).   
St u d y Sec o n d ar y O bjecti ve s 
T he sec o n d ar y o bjecti ves of t his st u d y we re as f oll o ws: 
•  T o e val uate t he safet y a n d t olera bilit y of B G 0 0 0 1 2 a n d BII B 0 1 7.  
•  T o assess t he effect of B G 0 0 0 1 2 a n d BII B 0 1 7 , b ot h c o m pare d t o place b o , o n 
a d diti o nal cli nical a n d ra di ol o gical meas ures of disease acti vit y.  
St u d y Sec o n d ar y S afet y  E n d p oi nts  
Occ urre nce of a d v erse e v e nts  ( A Es) a n d s eri o us a d verse e ve nts ( S A Es). N u m ber of ne w or 
ne wl y e nlar gi n g T 2 h y p eri nte nse lesi o ns o n brai n M RI sca ns at Wee ks 4 8 a n d 9 6 . 
N u m ber of G d -e n ha n ci n g lesi o ns at Baseli ne a n d at Wee ks 4 8 a n d 9 6 . 
A n n ualize d rela pse rate at Wee ks 4 8 a n d 9 6 . 
A d diti o n al O bjecti ves a n d E n d p oi nts   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y ) a n d BII B 0 1 7 (Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. 2.  St u d y Desi g n  
T his was  a ra n d o mize d , m ultice nter , d o u ble -bli n d,  a n d d o u ble-d u m m y place b o -c o ntr olle d 
t hree ar m parallel gr o u p st u d y t o e val uate t he effi cac y a n d safet y of B G 0 0 0 1 2 a n d BII B 0 1 7 i n 
pe diatric s u bjects wit h R R M S.  
A p pr o xi matel y 2 6 0 s u bj ects a g e d 1 0 t o 1 7 years (i ncl usi ve) wit h a dia g n osis of R R M S as 
defi ne d b y t he re vise d c o nse ns us defi niti o n f or pe diatric M S  ( Kr u p p L B, 2 0 1 3), ( P ol ma n C H, 
2 0 1 1)   were t o  be e nr olle d at a p pr o xi matel y 5 0 sites gl o ball y. Eli gi ble s u bjects were  
ra n d o mize d wit hi n 6 wee ks of scree ni n g. At least 2 5 % of s u bj ects were t o  be n o m ore t ha n 1 4 
years of a ge. S u bjects were  stratifie d b y a ge ( 1 0 t o <  1 4 years of a ge a n d 1 5 t o 1 7 years of  a ge) 
a n d b y site. S u bjects were ra n d o mize d i n a 1: 2: 2 rati o t o treat me nt wit h place b o, B G 0 0 0 1 2, 
BII B 0 1 7, res pecti vel y. See t he St u d y Acti vities sc he d ule bel o w f or details o n st u d y visits. 
Visits i n Wee k 2 a n d Wee k 6 were c o n d ucte d  i n-pers o n ( o pti o nal) or tele p h o nic. S u bjects 
ra n d o mize d t o B G 0 0 0 1 2 recei v ed  a starti n g d ose of 1 2 0 m g BI D orall y (t wice dail y) f or 7 da ys 
f oll o we d b y a mai nte na n ce d ose of 2 4 0 m g BI D orall y. S u bjects ra n d o mize d t o BII B 0 1 7 wer e 
titrate d t o t he tar get d ose of 1 2 5 m g: 6 3 m g o n Da y 1, 9 4 m g at Wee k 2, a n d 1 2 5 m g at Wee k 
4. O nce s u bjects reac h e d t he 1 2 5 m g tar get d ose, t hey  c o nti n ued  wit h  BII B 0 1 7 1 2 5 m g 
s u bc uta ne o usl y ( S C) a d mi nistere d e ver y t w o wee ks f or t he re mai n der of t he st u d y. T o e ns ure 
bli n di n g acr oss t he treat me nt gr o u ps all s u bjects recei v e d  B G 0 0 0 1 2 (or pl ace b o ) a d mi nistere d 
orall y BI D a n d BII B 0 1 7 (or place b o ) a d mi nistere d S C e ver y t w o wee ks.  
A n U nsc he d ule d Rela pse Visit occ ur re d as re q uire d t o c o n d uct ne ur ol o gical a n d    
 
e val uati o ns wit hi n 7 2 h o urs of a n y ne w ne ur ol o gi cal s y m pt o ms t hat c o ul d i n dicate t he o nset 
of a cli nical rela pse. C o nfir me d rela pses were  treate d at t he treati n g ne ur ol o gist’s discreti o n 
wit h i ntra ve n o us met h yl pre d nis ol o ne (I V M P) at a n y ti me fr o m B aseli ne t o Wee k 1 0 0. S uc h 
treat me nt di d  n ot affect t he s u bject’s eli gi bilit y t o c o nti n ue i n t he st u d y. T he pri mar y e n d p oi nt 
of t he st u d y was  t he T T F R: t heref ore, s u bjects were  re q uire d t o re mai n o n t h e assi g ne d bli n de d 
treat me nt u ntil t he y e x perie nce t heir first pr ot oc ol-defi ne d rela pse or disa bilit y pr o gressi o n.  
D uri n g t he st u d y, s u bjects w h o ha d  a c o nfir me d rela pse or disa bilit y pr o gressi o n or hi g h lesi o n 
b ur de n o n M RI at Wee k 4 8 ( defi ne d as ≥9 ne w/e nlar ge d T 2 lesi o ns) ha d  t he o pti o n of s witc hi n g 
t o a n alter nati ve t hera p y i n acc or da nce wit h l ocal practices, or o pe n-la bel B G 0 0 0 1 2 
( Tecfi dera), at t h e discreti o n of t he I n vesti gat or. S u bjects disc o ntin ue d  bli n de d st u d y treat me nt 
w he n t he y s witc h t o a n alter nati ve t hera p y or o pe n -la bel B G 0 0 0 1 2. S u bjects w h o we re 


Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y ) a n d BII B 0 1 7 (Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 1 0  
 
 
s witc he d t o a n alter nati ve t hera p y or o pe n-l a bel B G 0 0 0 1 2 re mai ne d i n t he st u d y t o c o m plete 
t he sc he d ule d visits, al o n g wit h a n y re q uisite safety m o nit ori n g.   
If a s u bject recei ved  o pe n -la bel B G 0 0 0 1 2 or a n alter nati ve t hera p y, t he y were t o  be assesse d 
at t he O pe n -La bel B G 0 0 0 1 2/ Alter nati ve T hera p y Visit wit hi n 4 wee ks of s witc hi n g.  
I n a d diti o n t o cli nical m o nit ori n g f or rela pses, effi cac y e val uatio ns i ncl u de d  assess me nts of 
brai n M RIs wit h G d e n ha nce me nt at Baseli ne a n d Wee ks  4 8 a n d 9 6; 
 
.  Safet y was e val uate d 
b y t he occ urre nce of A Es a n d S A Es as well as c ha n ges i n 
 
. 
S u bjects w h o wit h dr ew were t o  c o m plet e t he Earl y Wit h dra wal V isit n o later t ha n 4 wee ks 
after t he l ast d ose of st u d y treat me nt or alter nati ve t hera p y.  
S u bjects w h ose l y m p h oc yte c o u nt decrease d  t o less t ha n t he l o wer li mit of n or mal ( L L N) w hile 
o n st u d y treat me nt w ere f oll o we d at least e ver y 4 wee ks u ntil t he l y m p h ocyte c o u nt reac he d 
L L N.  S u bjects w h o c o m plete d , te m p oraril y wit h hel d, or per ma ne ntl y disc o nti n ued  st u d y 
treat me nt f or a n y reas o n a n d had  a l y m p h oc yte c o u nt < L L N w ere t o be f oll o we d e ver y 4 wee ks 
f or 2 4 wee ks, t he n e v er y 1 2 wee ks ( u nless cli nic all y i n dic ate d m ore ofte n or at t he 
I n vesti g at or’s discreti o n) u ntil t he l y m p h oc yte c o u nt was at least L L N, or f or 4 8 wee ks 
f oll o wi n g treat me nt disc o nti n uati o n, w hic he ver occ urre d s o o ner, or u ntil t he s u bject wa s 
i nitiate d o n t he a p pr o priate M S treat me nt, acc or di n g t o l ocal sta n dar d of care, f oll o wi n g st u d y 
wit h dra wal/c o m pleti o n.  
See  
 bel o w f or a sc he m atic of t he st u d y desi g n. 
 
 


Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y ) a n d BII B 0 1 7 (Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 1 1  
 
 
2. 3.  S a m ple Size  C o nsi der ati o n s  
T he pri mar y e n d p oi nt of t his st u d y wa s T T F R. I n t he P hase 3 a d ult st u d y of B G 0 0 0 1 2 ( St u d y 
1 0 9 M S 3 0 1) wit h t he sa me e n d p oi nt, t he re d ucti o n i n t he ris k of rel a pse o ver 2 years w hile 
recei vi n g B G 0 0 0 1 2 2 4 0 m g BI D c o m pare d wit h place b o was esti mate d t o be 5 0 %. I n t he P hase 3 
a d ult st u d y of BII B 0 1 7 ( St u d y 1 0 5 M S 3 0 1) wit h t he sa me e n d p oi nt, t he re d ucti o n i n t he ris k of 
Scree ni n g Visit
Wit hi n 6 w ee ks of Bas eli ne
B aseli ne Visit ( D a y 1)
Ran d o mize d 1: 2: 2
T re at m e nt ( T x ) P eri o d:  D o u bl e- Bli n d, D o u bl e- D u m m y
O n - Site or P h o n e Visits:  Wee ks  2 &  6
     O n -site Cli nic Visits:  Wee ks  4, 8 , 1 2 , 2 4 , 3 6 , 4 8 , 6 0 , 7 2 , 8 4 &  9 6
                 P h o ne Visits:   Wee ks 1 8 , 3 0 , 4 2 , 5 4 , 6 6 , 7 8 &  9 0
P ost- T re at m e nt Visit
Wee k 1 0 0
R el a pse or 
Pr o gr essi o n
N o I nci de nt
Wit h dr a wal
B G 0 0 0 1 2
BII B 0 1 7
P L A C E B O
Cli ni c Visit wit hi n 4 Wee ks
• 
Aft er start of o pe n-la bel or alter nati ve T x
• 
Aft er last d ose f oll o wi n g a wit h dra wal
T re at m e nt O pti o ns
• 
I m m e diate or e ve nt ual wit h dra w al
• 
C o nti n ue o n st u d y T x t o c o m pleti o n
• 
Start o pe n-la bel T x wit h B G 0 0 0 1 2
• 
Start altern ati v e T x
Fi g ure 1 :    
St u dy Desi g n  


Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y ) a n d BII B 0 1 7 (Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 1 2  
 
 
rela pse o ver 1 year (t he place b o-c o ntr olle d peri o d of t his trial) w hile recei vi n g BII B 0 1 7 1 2 5 µ g 
e ver y 2 wee ks c o m pare d wit h place b o was esti mate d t o be 3 9 %.  Base d o n t h e P A R A DI G M S st u d y 
f or fi n g oli m o d vs. I nterfer o n -1a ( C hit nis, et al., 2 0 1 8), a n d c o nsiste nt wit h t he u n dersta n di n g of 
pe diatric M S, a hi g her rela pse rate was o bs er ve d i n pe diatric patie nts c o m p are d t o a d ults.  T his is 
s u p p orte d b y i nter nal Bi o ge n Tecfi dera trial data o n y o u n ger a d ult patie nts. Base d o n t he 
pr o p orti o n of s u bjects rela psed  (6 1. 2 % ) i n t he I nt erfer o n -1 a  ar m, a n d t h e o bser ve d efficac y i n 
D E FI N E , C O N FI R M  (N C T 0 0 4 2 0 2 1 2 , st u dies 1 0 9 M S 3 0 1 a n d 1 0 9 M S 3 0 2 ), a n d P L E G RI D Y 
( N C T 0 0 9 0 6 3 9 9, A D V A N C E st u d y 1 0 5 M S3 0 1 ), we c o nser vati vel y ass u m e d  t hat 7 5 % of s u bjects 
i n t he place b o gr o u p wo ul d  ha ve  ha d  t heir first rel a pse d uri n g t he 2-year peri o d . T he st u d y w o ul d 
ha ve  ha d  at least 8 0 % p o wer t o detect a 5 0 % a n d 3 9 % re d ucti o n c o m p are d wit h place b o i n t he ris k 
of rela pse i n t he B G 0 0 0 1 2 a n d BII B 0 1 7 ar ms, res pecti vel y, w he n a t otal of 1 5 3 e ve nts (first 
rela pses) were  e x pecte d t o be accr ue d . T he t y pe I err or of eac h c o m p aris o n w as c o ntr olle d at 0. 0 5.  
T his 3 -ar m st u d y w as t o be c o n d uct e d i n a pe diatric M S p o p ulati o n t o e val uate t he efficac y a n d 
safet y of B G 0 0 0 1 2 a n d BII B 0 1 7, eac h c o m pare d wit h t he sa me place b o ar m.  T he sa me g oals c o ul d 
ha ve bee n  ac hie ve d i n 2 se parat e place b o -c o ntr oll e d st u dies.  H o we ver, t he 3 -ar m platf or m desi g n 
w o ul d  all o w fe wer s u bj ects e x p ose d t o place b o.  Wit h 2 c o m paris o ns t o be ma de s e paratel y 
bet wee n differe nt acti ve treat me nts a n d place b o ( B G 0 0 0 1 2 vs. place b o a n d BII B 0 1 7 vs. place b o), 
as i n t w o se parate st u dies, m ulti plicit y a dj ust me nt w ere u n necessar y. Ta ki n g i nt o t he acc o u nt a 2 -
year disc o nti n uati o n rate of 1 5 %, t he st u d y pla n ne d  t o ra n d o mize a p pr o xi matel y 2 6 0 s u bjects 
(a p pr o xi matel y 5 2 s u bjects ra n d o mize d t o B G 0 0 0 1 2, 1 04 s u bjects ra n d o mize d t o BII B 0 1 7, a n d 
1 0 4 s u bjects ra n d o mize d t o place b o).  T he disc o nti n uati o n rate was  m o nit ore d t hr o u g h o ut t he 
st u d y, a n d disc o nti n ue d s u bjects were pl a n ne d t o be  re place d b y ne w s u bjects t o ac hie ve 8 0 % 
p o wer.  
2. 4.  S t u d y st o p pi n g r ules  
T he st u d y pr ot oc ol all o we d Bi o ge n t o ter mi nate t he st u d y at a n y  ti me, after i nf or mi n g t he 
I n v esti gat ors. Bi o ge n was re q uire d t o n otif y t he I n vesti gat ors w he n t h e st u d y stat us was 
c ha n ge d, i ncl u di n g st u d y h ol ds, st u d y c o m pleti o n, a n d st u d y ter mi nati o n.  
3.  E arl y ter mi n ati o n of st u d y d ue t o s p o ns or’s decisi o n  
T he B L A S T st u d y was p ut o n h ol d i n 2 0 2 1 d ue t o l o w recr uit me nt. Aft er n otificati o n of all 
i ntereste d parties (i n vesti gat ors, I R Bs, et hics c o m mittees, a n d re g ulat or y a ge ncies), B L A S T was 
ca ncele d b y Bi o ge n wit h t he c o nse nt of t he F D A. At t he ti me t he st u d y was p ut o n h ol d , 1 6 
s u bjects ha d bee n s cree n e d a n d 1 1 s u bjects ha d bee n e nr olle d.  
4.  C h a n ges fr o m t he pr ot oc ol -defi ne d st atistic al a n al ysis pl a n  
D ue t o t he li mite d n u m ber of s u bjects e nr olle d a n d earl y cl os ure of t he st u d y, t he data o btai ne d  
fr o m t his st u d y are n ot s ufficie nt t o s u p p ort t he ori gi nal st u d y o bjecti ves a n d t he a nal yses 
o utli ne d i n t he pr ot oc ol . T he pr ot oc ol s tatistical a nal ysis pla n was a dj uste d as reflecte d i n t his 
d oc u me nt t o s u m marize t he baseli ne c haracteristics a n d safet y d ata . S u m mar y ta bles of t he 
baseli ne disease a n d de m o gra p hic c h aracteristics  will  be pr o vi de d  b y treat me nt gr o u p ; a d verse 
e ve nts, 
 als o will be descri pti vel y e val uate d: s u m maries b y 
act ual treat me nt recei ve d  will be ta b ulate d, wit h listi n g pr o vi de d i nstea d w he n t he data are 


Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y ) a n d BII B 0 1 7 (Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 1 3  
 
 
li mite d. Dr u g efficac y a n d patie nt -re p orte d o utc o me ( P R O) data will n ot be s u m marize d b ut  will 
be pr o vi de d i n listi n gs.  
 
5.  Defi niti o ns  
B aseli ne  V al ue : t he last n o n -missi n g o bser vati o n pri or t o recei vi n g st u d y treat me nt o n or bef ore 
St u d y Da y 1.  
 
 
 
 
  
E nr oll me nt : S u bjects will be e nr olle d i n t he st u d y o n t he date t he I C F is si g ne d b y t he s u bject’s 
le gall y a ut h orize d re pres e ntati ve ( L A R).  
 
 
 
  
Rel a pse : A rela pse is defi ne d as ne w or rec urre nt ne ur ol o gic s y m pt o ms n ot ass ociate d wit h fe ver 
or i nfecti o n, lasti n g at least 2 4 h o urs, a n d acc o m pa nie d b y ne w o bjecti ve ne ur ol o gical fi n di n gs 
u p o n e xa mi nati o n b y t he e xa mi ni n g ne ur ol o gist. If a s u bject e x perie nces ne w ne ur ol o gic  
s y m pt o ms, t he s u bject ( or pare nt) m ust c o nt act t he treati n g n urse or p h ysici a n as s o o n as p ossi ble 
wit hi n 4 8 h o urs of t he o nset of s y m pt o ms. A n A E s h o ul d be rec or de d.  
St u d y D a y : St u d y Da y 1 is t he da y of t he first d os e of st u d y treat me nt. (It is t he Baseli ne Da y i n 
m ost circ u msta nces. If a necessar y meas ure me nt is missi n g o n St u d y Da y 1, t he baseli ne val ue is 
t he last n o n -missi n g  o bser vati o n pri or t o recei vi n g t he st u d y treat me nt o n St u d y Da y 1. ) 
F or dates after St u d y Da y 1  
St u d y Da y = ( Dat e of ass ess me nt) –  ( Dat e of St u d y Da y 1) + 1. 
F or dates pri or t o St u d y Da y 1  
St u d y Da y = ( Dat e of Assess me nt) –  ( Dat e of St u d y Da y 1). 
F or a d v erse e ve nts  
O nset St u d y Da y = ( Date of A E or w ors e ni n g A E) –  ( Date of St u d y Da y 1) + 1 
F or Ti me o n St u d y  
St u d y D urati o n = ( E n d of St u d y Date) –  ( Dat e of St u d y Da y 1) + 1 


Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y ) a n d BII B 0 1 7 (Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 1 4  
 
 
F or Ti me o n Treat me nt  
Treat me nt D urati o n = ( Date of last d ose per C R F) –  ( Date of St u d y Da y 1) + 1. 
 
 
 
Tre at me nt E mer ge nt :  
A treat me nt e mer ge nt A E  is defi ne d as a n y A E  t hat eit her occ urs or w ors e ns i n se verit y after t he 
first d ose of st u d y treat me nt. If treat me nt e mer ge nce ca n n ot be deter mi ne d d ue t o i nc o m plete or 
partial start a n d/ or e n d dates, t he e ve nt will be c o nsi dere d treat me nt e mer ge nt.  
 
5. 1.  D ates a n d P oi nts of Refere nce  
Assess me nt    
E n d p oi nt(s)    
St u d y Visit  
T ar get D a y ( Visit 
Wi n d o w)  
A E, S A E 
m o nit ori n g  
Safet y  
C o nti n u o us fr o m 
e nr oll me nt  
N/ A  


Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y ) a n d BII B 0 1 7 (Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 1 5  
 
 
Assess me nt    
E n d p oi nt(s)    
St u d y Visit  
T ar get D a y ( Visit 
Wi n d o w)  
Brai n M RI +  G d 
c o ntrast a ge nt.  
Sec o n dar y Efficac y  
Baseli ne  
Wee k 4 8  
Wee k 9 6  
St u d y Da y 1  ( 1- 1)  
Da y 3 3 7 ( 3 3 0 - 3 4 4)  
Da y 6 7 3 ( 6 6 6 - 6 8 0)  
C o nc o mita nt 
Me dicati o n 
M o nit ori n g  
Safet y  
C o nti n u o us fr o m 
e nr oll me nt.  
N/ A  


Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y ) a n d BII B 0 1 7 (Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 1 6  
 
 
Assess me nt    
E n d p oi nt(s)    
St u d y Visit  
T ar get D a y ( Visit 
Wi n d o w)  


Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y ) a n d BII B 0 1 7 (Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 1 7  
 
 
Assess me nt    
E n d p oi nt(s)    
St u d y Visit  
T ar get D a y ( Visit 
Wi n d o w)  
 
 


Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y ) a n d BII B 0 1 7 (Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 1 8  
 
 
Assess me nt    
E n d p oi nt(s)    
St u d y Visit  
T ar get D a y ( Visit 
Wi n d o w)  
 
5. 2.  St u d y T re at me nt  
T his st u d y wa s a d o u ble-bli n de d, d o u ble -d u m m y, place b o -c o ntr olle d trial. T o mai ntai n t he 
bli n d all s u bjects recei ve d  a place b o f or t he treat me nt t he y are n ot assi g ne d.  
B G 0 0 0 1 2  (Tecfi dera ) was t o  be ta ke n orall y at a d ose of 1 2 0 m g BI D f or t h e first 7 da ys ( 1 
ca ps ule dail y), a n d at 2 4 0 m g BI D t hereafter ( 2 ca ps ules dail y). T he B G 0 0 0 1 2 treat me nt 
gr o u p will recei v e a place b o i njecti o n of BII B 0 1 7  ve hicle e ver y t w o wee ks.  
BII B 0 1 7  (Ple gri d y ) was t o  be  a d mi nistere d S C at a d ose of 1 2 5 g e ver y t w o wee ks f or 9 6 
wee ks. BII B 0 1 2 s u bjects will be titrate d t o t he tar get d ose o n t he f oll o wi n g sc he d ule: 6 3 g 
BII B 0 1 7 o n Da y 1, 9 4 g at Wee k 2, a n d 1 2 5 g e ver y ot her wee k t hereafter f or t he d urati o n 
of t he trial. BII B 0 1 7  s u bjects will recei ve dail y place b o ca ps ule(s) o n t he sa me sc he d ule as 
B G 0 0 0 1 2 s u bject s. 
Pl ace b o  s u bjects were t o  recei v e a S C i njecti o n of t he BII B 0 17  ve hicle e ver y 2 wee ks a n d 
dail y place b o ca ps ule s acc or di n g t o t he titrati o n re gi me n f or t he B G 0 0 0 1 2 gr o u p. 
5. 3.  St u d y P eri o ds  
T his is a si n gle peri o d st u d y, wit h n o f oll o w -u p  peri o d . Scree ni n g t o o k place u p t o 6 wee ks 
pri or t o St u d y Da y 1. S u bjects were  e nr olle d i n t he st u d y after t he i nf or me d c o nse nt was  
si g ne d b y t heir L A R. 


Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y ) a n d BII B 0 1 7 (Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 1 9  
 
 
5. 4.  Str atific ati o n F act ors a n d S u b gr o u p  V ari a bles  
5. 4. 1.  S tr atific ati o n F a ct ors  
T he st u d y was  stratifie d o n a ge a n d site. A ge was  t he s u bject a ge at Baseli ne  ( St u d y Da y 
1).  
•  A ge  
o  Baseli ne a ge 1 0 t o less t ha n or e q ual t o 1 4 years  
o  Baseli ne a ge greater t ha n 1 4 years.  
•  Site — a p pr o xi matel y 5 0 sites will be use d w orl d -wi de . 
Recr uit me nt w as use d t o e ns ure t hat at least 2 5 % of s u bjects we re i n t he 1 0 t o less t ha n or 
e q ual t o 1 4 years a ge gr o u p.  All a nal yses t hat fit a statistical m o del w ere t o  i ncl u de t he 
a ge stratificati o n. A nal ys es w ere n ot  t o be stratifie d b y site.  
5. 4. 2.  S u b gr o u p V ari a bles  
N o s u b gr o u p a nal yses are pla n ne d f or t his st u d y.  
5. 5.  A n al ysis P o p ul ati o ns  
T he pr ot oc ol defi n e s t w o a nal ysis p o p ulati o ns . 
S afet y P o p ul ati o n  
T he S afet y p o p ulati o n  is defi ne d as all s u bjects w h o recei v e d at least 1 d os e of st u d y 
treat me nt. S u bjects will be a nal yze d acc or di n g t o t he  treat me nt recei v e d. 
T he pri mar y safet y a nal ysis of A Es, 
 will be perf or me d 
o n t he safet y p o p ulati o n  d uri n g t he peri o d fr o m t h e first d ose of bli n de d treat me nt t o t he e n d 
of bli n de d treat me nt.  
I T T P o p ul ati o n 
T he I nte nt-t o-Treat ( I T T) P o p ulati o n  is defi ne d as all s u bjects w h o are ra n d o mize d a n d 
recei v e at least 1 d ose of st u d y treat me nt ( B G 0 0 0 1 2, BII B 0 1 7, or pl ace b o). S u bjects will be 
a nal yze d acc or di n g t o t he treat me nt gr o u p t o w hi c h t he y are ra n d o mize d.     
 
6.  L ist of Pl a n ne d St u d y A n al yses  
As n ote d a b o ve, B L A S T was ter mi nate d earl y d ue t o t he se verel y li mite d s u bject e nr oll me nt a n d 
pr o gress i n t he st u d y. As a res ult, t he data c ollecte d are i ns uffi cie nt t o s u p p ort t he ori gi nal st u d y 
o bjecti ves. T he pr ot oc ol st u d y pla n is c ha n ge d as reflecte d i n t his d oc u me nt t o briefl y s u m marize 
t he baseli ne c h aracteristics a n d safet y data b y treat me nt gr o u p a n d o verall. T he data s u m maries 
are des cri pti ve i n nat ure : c o m paris o n a m o n g t he st u d y treat me nt gr o u ps is i na p pr o priate. Dr u g 
efficac y a n d P R O data will n ot be s u m marize d b ut will be pr o vi de d i n listi n gs.  
6. 1.  I nteri m A n al ysis 
N o i nteri m a nal ysis wa s pla n ne d f or t his st u d y. 


Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y ) a n d BII B 0 1 7 (Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 2 0  
 
 
6. 2.  Pri m ar y A n al ysis  
T he pri mar y a n al ysis will be perf or me d after t he data base is l oc ke d. T he pri mar y a nal ysis 
will c o nsist of t w o  parts: S u bject s u m maries  a n d Safet y A nal ysis . T he S u bj ect s u m maries 
will pr o vi de a c o m plete listi n g of all c ollecte d  dat a f or eac h s u bject. T he S afet y A nal ysis will 
c o nsist of A E s u m maries, 
. 
6. 3.  Fi n al A n al ysis   
T he pri mar y a n al ysis is t he fi nal pla n ne d a nal ysis. T he B L A S T  st u d y d oes n ot e n visi o n a n y 
l o n g-ter m f oll o w-u p of s u bjects: t he data bas e will be c o m plete at l oc k f oll o wi n g t he site 
cl ose-o ut visits.  
7.  St atistic al Met h o ds f or Pl a n ne d A n al yses  
7. 1.  Ge ner al P ri nci ples  
T he o nl y pla n ne d a n al ysis f or t his st u d y is  t he fi nal re p ort. T his st u d y desi g n is str uct ure d t o 
mi ni mize s u bject e x p os ure t o place b o, a n d beca us e eac h acti ve ar m f u ncti o n s as a disti nct 
st u d y, m ulti plicit y a dj ust me nts are u n necessar y. 
T his is a d o u ble -bli n d, d o u ble -d u m m y st u d y. T he bli n d ma y be br o ke n i n case of a m e dical 
e mer ge n c y if t he treati n g p h ysicia n nee ds t o k n o w t he assi g ne d treat me nt.  O nce u n bli n de d, 
t he s u bject will n o l o n ger recei v e st u d y treat me nt. T he i n vesti gat or m ust d oc u me nt t he ca us e 
f or t he u n bli n di n g i n t he s o urce d oc u m e nts a nd ma ke eff orts t o a v oi d u n bli n di n g ot her st u d y 
pers o n nel, li miti n g treat me nt i nf or mati o n t o t h ose i n v ol ve d i n t he me dical e mer ge nc y.  
S u bjects will be i nstr ucte d n ot t o ta ke a d ose of st u d y dr u g wit hi n 4 h o urs of a cli nic visit t o 
pre ve nt dr u g -i n d u ce d s y m pto ms fr o m bei n g o bser ve d b y st u d y pers o n nel a n d ris k t heir 
u n bli n di n g. After t he fi nal cli nical st u d y re p ort  is c o m plete d, Bi o ge n will i nf or m t he cli nical 
i n vesti gat ors w h o ma y i nf or m s u bjects a b o ut t he treat me nt t he y recei ve d, if t his d oes n ot 
je o par dize on g oi n g relate d st u dies.  
Ot her wise, all bli n di n g will re mai n i n place u ntil t he data bas e is l oc ke d.  
S u m mar y statistics  f or q ua ntitati ve varia bles will c o nsist of t he mea n, sta n dar d de viati o n, 
n u m ber of n o n -missi n g o bser vati o ns, mi ni m u m, t he me dia n , a n d t he m a xi m u m. All 
q ua ntitati ve data will be s u m marize d wit h t hese st atistics classifie d b y treat me nt ar m a n d 
visit u nless ot her wise n ote d bel o w. S u m mar y statistics f or cate g orical data will c o nsist of t he 
fre q ue n c y c o u nt a n d t h e perce nt a ge wit h res pect t o a stu d y -rele va nt base ( us uall y t he n u m ber 
of s u bjects at -ris k). 
A m o n g t he de m o gra p hic data, a ge, baseli ne hei g ht, a n d baseli ne wei g ht will be s u m marize d 
as q ua ntitati ve varia bles. Race, et h nicit y, se x, a n d 
 will be s u m marize d as 
cate g orical varia bl es. N o gra p hics are pla n ne d f or t he de m o gra p hic data.  
Missi n g dates will be ha n dle d as s h o w n i n Ta ble 1  bel o w.  
 
 


Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y ) a n d BII B 0 1 7 (Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 2 1  
 
 
 
T a ble 1 . D ate i m p ut ati o n r ules f or A E a n d C o nc o mit a nt Me dic ati o n.  
    
Missi n g    
C o n diti o n  
I m p ute d V al ue 
Start date ( A E, 
c o nc o mita nt 
me dicati o n)  
Da y    
T he e ve nt starte d i n t he 
sa me year a n d m o nt h as 
St u d y Da y 1 ( or treat me nt 
peri o d start date)  
St u d y Da y 1 ( or 
treat me nt peri o d start 
date)  
Ot her wise  
0 1  
Da y a n d 
m o nt h  
T he e ve nt starte d i n t he 
sa me year as St u d y Da y 1 
( or treat me nt p eri o d start 
date)  
St u d y Da y 1 ( or 
treat me nt peri o d start 
date)  
Ot her wise  
0 1J A N  
  
C o m pletel y missi n g ( missi n g da y, m o nt h, 
a n d year)  
N o i m p utati o n will be 
perf or me d  
St o p date ( A E, 
c o nc o mita nt 
me dicati o n)  
Da y    
T he e ve nt st o p pe d i n t he 
sa me year a n d m o nt h as t he 
E n d of St u d y date  
T he E n d of St u d y date 
or t he a nal ysis data 
c ut-off dat e  
Ot her wise  
T he last da y of t he 
m o nt h  
Da y a n d 
m o nt h  
T he e ve nt st o p pe d i n t he 
sa me year as t he E n d of 
St u d y date  
T he E n d of St u d y date 
or t he a nal ysis data 
c ut-off dat e  
Ot her wise  
3 1 D E C  
  
C o m pletel y missi n g ( missi n g da y, m o nt h, 
a n d year)  
N o i m p utati o n will be 
perf or me d  
 
F or all ot her sit uati o ns if date i m p utati o n is a p pr o priate t he i m p utati o n r ules are:  
If t he da y is missi n g, defa ult t o t he 1 5 t h of t he m o nt h.  
If m o nt h a n d da y are missi n g, defa ult t o J ul y 1 of t he year. 
If t he year is missi n g, d o n ot i m p ute a date. 
F or all hist orical dat es, if t he i m p utati o n met h o d yiel ds a date after St u d y Da y 1, i m p ute 
St u d y Da y –  2 . 
All a nal yses will be pr o gra m me d i n S A S ® Versi o n 9. 4 or later.  


Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y ) a n d BII B 0 1 7 (Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 2 2  
 
 
7. 2.   P artici p a nt A cc o u nt a bilit y  
T he n u m ber of s u bjects e nr olle d, t he n u m ber ra n d o mize d w h o recei ve d at least o ne d ose of 
st u d y dr u g, t he n u m ber disc o nti n ui n g pri or t o Wee k 9 6 a n d t he reas o n f or wit h dra wal will be 
s u m marize d b y treat me nt assi g ne d a n d o verall. 
A detaile d listi n g of s u bject stat us, i ncl u di n g scree n fail ures will be create d. T his listi n g will 
s h o w i nf or me d c o nse nt d ate, fi nal st u d y stat us, St u d y Da y 1, a n d c o m pleti o n or wit h dra wal 
date , a n d f or wit h drawals, t he reas o n f or wit h dra wal . F or scree n fail ures, t h e pri mar y reas o n 
f or scree n fail ure will be s h o w n. 
7. 3.   De m o gr a p hic a n d B aseli ne C h ar acteristics  
T he Safet y A n al ysis Set ’s de m o gra p hic c haracteristics will s u m marize a ge (i n years, 
tr u ncate d t o t he year of a ge at baseli ne)  as a q ua ntitati ve varia ble  b y treat me nt ar m a n d 
o verall,  a n d as c o u nts a n d perce nt b y treat me nt ar m a n d o verall, f or  t h e f oll o wi n g cate g ories: 
1 0 t o < 1 4 , a n d 14  t o < 1 8 years.  
Se x will be s u m marize d as c o u nts a n d perce nt f or eac h treat me nt ar m a n d o verall. 
Et h nicit y ( Lati n o/ N ot Lati n o/ N ot re p orte d d ue t o c o nfi de ntialit y re g ulati o ns) will be 
s u m marize d as c o u nts a n d perce nt f or eac h treat me nt ar m a n d o verall.  
Race will be s u m marize d b y c o u nts a n d perce nt a ge i nt o A merica n I n dia n or Alas ka Nati ve, 
Asia n, Blac k or Africa n A merica n , Nati ve Ha waiia n or ot her Pacifi c Isla n der, W hite, N ot 
re p orte d d u e t o c o nfi de ntialit y re g ulati o ns, a n d Ot her. Ot her val ues will be liste d b ut n ot 
f urt her cate g ori ze d. Baseli ne hei g ht (c m) a n d wei g ht ( k g) will  be prese nt e d wit h s u m mar y 
statistics b y treat me nt gr o u p a n d o verall. 
S u m maries of baseli ne disease c h aracteristics ( M S disease hist or y , e. g., ti me si nce t he first 
M S s y m pt o m, ti me si nce M S dia g n osis, t he n u m ber of rela pses i n t he past 1 2 m o n , 2  years, 
t he ti mi n g of t he last rela pse pri or t o e nr oll me nt a n d t he   
) will be p rese nt e d b y 
treat me nt gr o u p f or t he I T T P o p ulati o n. M e dical hist or y a n d M S Treat me nt h ist or y will be 
als o s u m marize d. 
7. 4.  Pr ot oc ol D e vi ati o ns  
Maj or a n d mi n or pr ot oc ol de viati o ns i de ntifie d i n t he st u d y will be liste d.   
7. 5.  S t u d y T re at me nt E x p os ure  a n d C o nc o mit a nt Me dic ati o ns  
D urati o n  of st u d y treat m e nt a n d ti me o n st u d y will be s u m marize d b y treat me nt recei v e d f or 
t he Safet y P o p ulati o n. C o m plia nce u ntil t he last d ose will  als o be s u m marize d b y treat me nt 
recei v e d f or t he Safet y P o p ulati o n. 
T he n u m ber of d os es ta ke n will be c o m p ute d per visit as  
 
D oses ta ke n = D oses dis pe nse d –  D oses ret ur ne d.  
 
T he n u m ber of d os es ta ke n will be liste d b y visit . C o m plia nce will be c o m p ute d per s u bject 
as 


Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y ) a n d BII B 0 1 7 (Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 2 3  
 
 
 
C o m plia nce = ( D oses Ta ke n –  D oses E x pecte d)/ D oses E x pecte d.  
 
See   Secti o n 5  f or t he defi niti o ns of treat me nt d urati o n a n d ti me o n st u d y.  
A C o nc o mita nt t hera p y wa s defi ne d as a n y t hera p y t hat was ta ke n o n or after t he da y of t he 
first d ose of st u d y dr u g. T his i ncl u des t hera pies t hat start pri or t o t he i nitiati o n of t he first 
d osi n g if t heir use c o nti n ues o n or after t he dat e of t he first d ose. All c o nc o mita nt me dicati o ns 
were  c o d e d usi n g t he W orl d Healt h Or ga nizati o n ( W H O) me dicati o n dicti o nar y ( Se pte m ber 
2 0 2 1 ). All c o n c o mita nt n o n -dr u g t hera pies were  c o de d usi n g t h e  Me dical Dicti o nar y f or 
Re g ulat or y Affairs  (Me d D R A ) Versi o n 2 4. 1 . 
N u m bers a n d p erce nta ges of s u bjects ta ki n g c o nc o mita nt me dicati o ns a n d n o n -dr u g t hera pies 
will be s u m marize d b y treat me nt gr o u p . 
E ffic ac y E n d p oi nts  
All efficac y data will be liste d f or t he I T T P o p ulati o n b y treat me nt gr o u p a n d, f or eac h 
s u bject, b y visit a n d /or  date.  N o statistical s u m maries will be pr o vi de d.  Listi n gs will be 
pr o vi de d f or:  
•  R ela pse data  
•  M RI para meters ( t he n u m ber of ne w or ne wl y e nlar gi n g T 2 h y peri nte nse l esi o ns  
c o m pare d t o t he pri or visit , t otal n u m ber of G d -e n ha nci n g lesi o ns, 
 
, 
 
, a n d 
  
 
 
 
 
 
 
7. 5. 1.  Pri m ar y Effic ac y E n d p oi nt  
Beca use t he n u m b er of s u bjects is li mite d, n o a nal yses of t he T T F R will be pr o vi de d.  
7. 5. 2.  S ec o n d ar y E ffic ac y E n d p oi nts  
Beca use t he n u m b er of s u bjects is li mite d, n o a nal yses of t he sec o n dar y efficac y 
e n d p oi nts will be pr o vi de d.  
 
 
 
 
7. 6.  S afet y E n d p oi nts  
 7. 6 . 1 A d verse E ve nts  
All treat me nt -e mer ge nt A Es  will be i ncl u de d i n t he e val uati o n of safet y. A Es  were  c o de d 
usi n g t he Me d D R A versi o n 2 4. 1 . T he i nci de nce of treat me nt -e mer ge nt A E a n d S A E will 
be s u m marize d b y s yste m or ga n class ( S O C) a n d preferre d t er m ( P T) f or eac h treat me nt 


Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y ) a n d BII B 0 1 7 (Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 2 4  
 
 
a n d o verall.  A n o verall s u m mar y of A E will be create d. T he o verall A E s u m mar y will 
i ncl u de t he i nci de nce of t he f oll o wi n g treat me nt -e mer ge nt A Es:  
 
•  N u m ber of s u bjects wit h a n e ve nt  
•  N u m ber o f s u bjects wit h a m o derate or se vere e ve nt 
•  N u m ber of s u bjects wit h a se vere e ve nt  
•  N u m ber of s u bjects wit h a relate d e ve nt  
•  N u m ber of s u bjects wit h a seri o us e ve nt  
•  N u m ber of s u bjects w h o disc o nti n ue d st u d y treat me nt d ue t o a n e ve nt  
•  N u m ber of s u bjects w h o wit h dre w fr o m t he st u d y d ue t o a n e ve nt  
 
All A E s will be liste d, i ncl u di n g t heir treat me nt e mer ge nt stat us.  A E s a n d S A Es will be 
classifie d b y se verit y ( mil d, m o derate, or se vere) a n d relate d ness  (relate d or n ot relate d) 
t o treat me nt b y t he i n vesti gat or a n d i ncl u de d i n t he listi n g of all A E s. T his listi n g will 
als o incl u de fla gs s h o wi n g A E s t hat res ulte d i n disc o nti n uati o n of t he st u d y dr u g , A E s 
t hat res ulte d i n wit h dra wal fr o m t he st u d y , seri o us A Es, a n d A Es t hat le d t o d ose 
re d ucti o n or i nterr u pti o n . I n a d diti o n, a listi n g of deat hs ( bla n k pa ge if n o ne) will be 
pr o vi de d.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 


Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y ) a n d BII B 0 1 7 (Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 2 5  
 
 
 
 
 
 
 
 
 
 
 
 
7. 7.   P h ar m ac o ki netic ( P K) E n d p oi nts  
N/ A  
7. 8.  P h ar m ac o d y n a mic ( P D) E n d p oi nts  
N/ A  
  
 
 
7. 1 0.  A nti ge nicit y/ Im m u n o ge nicit y E n d p oi nts  
I m m u n o ge nicit y dat a will be liste d f or t he Safet y P o p ulati o n b y treat me nt recei ve d a n d, f or 
eac h p atie nt,  b y visit . 
7. 1 1.  Ot her A n al yses  
N/ A  
7. 1 2.  St atistic al C o nsi der ati o ns f or Interi m A n al ysis  
N/ A  
8.  S u m m ar y of C h a n ges fr o m t he Pre vi o us Versi o n of t he S A P 
N/ A  


Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y ) a n d BII B 0 1 7 (Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 2 6  
 
 
9.  Refere nces  
C hit nis, T., Ar n ol d, D., B a n w ell, B., Br uc k, W., G h ezzi, A., Gi ov a n n o ni, G., . . . W oli ns k y, J. ( 2 0 1 8). Tri al of 
Fi n g oli m o d v ers us I nt erf er o n B et a -1 a i n P e di atric M ulti pl e Scl er osis. N e w E n gl a n d J o ur n al of 
M e dici n e , 3 7 9: 1 0 1 7-1 0 2 7.  
Kr u p p L B, T. M. ( 2 0 1 3). I nt er n ati o n al P e di atric M ulti pl e Scl er osis St u dy Gr o u p crit eri a f or p e di atric 
m ulti pl e scl er osis a n d i m m u n e -m e di at e d c e ntr al n erv o us syst e m d e my eli n ati n g dis or d ers: 
r evisi o ns t o t h e 2 0 0 7 d efi niti o ns. M ult Scl er. , 1 9( 1 0): 1 2 6 1-7.  
P ol m a n C H, R. S. ( 2 0 1 1). Di a g n ostic crit eri a f or m ulti pl e scl er osis: 2 0 1 0 R evisi o ns t o t h e Mc D o n al d 
crit eri a. A n n N e ur ol. , 6 9( 2): 2 9 2-3 0 2.  
 
 






Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y) a n d BII B 0 1 7 ( Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 2 9  
 
 
M RI = ma g netic res o na nce i ma gi n g; 
; P T =  pr ot hr o m bi n ti me; 
; S A E = seri o us a d verse e ve nt; 
 
; W k =  wee k.  
1 Tests a n d assess me nts m ust b e c o m plete d pri or t o st u d y treat me nt a d mi nistrati o n a n d/ or distri b uti o n u nless ot her wise s pecifie d.  
2 Writte n i nf or me d c o nse nt fr o m t he s u bject’s pare nts or le gal g uar dia ns a n d asse nt fr o m t h e s u bject, if a p pr o priate, m ust be o btai ne d pri or t o perf or mi n g a n y st u d y -relate d pr oce d ures. 
3 Hei g ht s h o ul d be meas ure d usi n g sta di o metr y a n d rec or de d t o t he nearest 1 0
t h of a ce nti meter.  
 
 
 
 
 
 
 
 
 
 
 
 
9 HI V testi n g will be perf or me d at Scree ni n g, o nl y if re q uire d b y l ocal re g ulati o ns.  
1 0 F or se x uall y acti ve fe males of c hil d beari n g p ote ntial.   
1 1All uri ne pre g na nc y testi n g will be perf or me d at t he site.  Res ults m ust b e k n o w n pri or t o dis pe nsi n g st u d y treat me nt.  
 
 
1 3 M RI m ust n ot be perf or me d wit hi n 3 0 da ys of recei vi n g a c o urse of ster oi ds.   
1 4M RI m ust be perf or me d wit hi n 1 4 da ys pri or t o first d ose or o n Da y 1 ( Baseli ne Visit) a n d at Wee k 4 8 ± 1 4  da ys, a n d at Wee k 9 6 ± 1 4 da ys.  
1 5 O n t he visits w he n s u bc uta ne o us i njecti o n is a d mi nistere d at t he cli nic, a nti b o d y sa m ples are t o be c ollecte d bef ore d osi n g.  
1 7S u bjects are t o self -a d mi nister ( or pare nt is t o a d mi nister) S C i njecti o n i n t he cli nic fr o m Baseli ne t hr o u g h Wee k 6.   
1 8F or t he first 2 4 wee ks of t he st u d y, all s u bjects will be i nstr ucte d t o ta ke aceta mi n o p he n ( paraceta m ol), i b u pr ofe n, or ot her n o nster oi dal a nti -i nfla m mat or y dr u gs ( N S AI Ds)  s uc h as 
na pr o xe n pri or t o eac h i njecti o n a n d f or t he 2 4 h o urs f oll o wi n g eac h i njecti o n at t he rec o m me n de d d ose a n d fre q ue nc y per t he l ocal la bels. After t he first 2 4 wee ks of t he st u d y, 
aceta mi n o p he n, i b u pr ofe n, or ot her N S AI D treat me nt ma y  be disc o nti n ue d at t he discreti o n of t he I n vesti gat or.  
 
 
 




Pr o d uct:  B G 0 0 0 1 2 ( Ple gri d y) a n d BII B 0 1 7 ( Tecfi dera ) 
St u d y : 8 0 0 M S 3 0 1  
St atistic al A n al ysis Pl a n  
Versi o n:  1. 0  
 
 
Pa ge 3 1  
 
 
A E = a d verse e ve nt; E C G = electr ocar di o gra m; 
; S A E = seri o us 
a d verse e ve nt; 
; W k = wee k. 
1 T he Earl y Wit h dra wal V isit s h o ul d be c o n d ucte d n o later t ha n 4 wee ks after t he s u bject’s last d ose of st u d y treat me nt or alter nati ve t hera p y.  
2T he O pe n -La bel B G 0 0 0 1 2/ Alter nati ve T hera p y Visit i ncl u des assess me nts t o be perf or me d f or s u bjects w h o eit her s witc h t o o pe n -la bel B G 0 00 1 2 or alter nati ve t hera p y, or 
disc o nti n ue alter nati ve t hera p y.  S u bjects will res u me pr ot oc ol visits a n d assess me nts as detaile d i n  Pr ot oc ol Ta ble 1  w hile o n B G 0 0 0 1 2/alter nati ve t hera p y.  
3S u bjects w h o c o m plete, te m p oraril y wit h h ol d, or per ma ne ntl y disc o nti n ue st u d y treat me nt f or a n y reas o n a n d ha ve a l y m p h oc yte c o u nt < L L N will be f oll o we d e ver y 4  wee ks f or 
2 4  wee ks, t he n e ver y 1 2 wee ks ( u nless cli nic all y i n dic ate d m ore ofte n or at t he I n vesti g at or’s discreti o n ) u ntil t he l y m p h oc yte c o u nt is ≥L L N, or f or 4 8  wee ks f oll o wi n g treat me nt 
disc o nti n uati o n, w hic he ver occ urs s o o ner, or u ntil t he s u bject is i nitiate d o n t he a p pr o priate M S treat me nt, acc or di n g t o l oc al sta n dar d of care, f oll o wi n g st u d y wit h dra wal/c o m pleti o n.  
4 Hei g ht s h o ul d be meas ure d usi n g sta di o metr y a n d rec or de d t o t he nearest 1 0
t h of a ce nti meter.  
 
 
 
  
 
 
 
 
8F or se x uall y acti ve fe males of c hil d beari n g p ote ntial. All uri ne pre g na nc y testi n g will be perf or me d at t he site.  Res ults m ust be k n o w n pri or t o dis pe nsi n g st u d y treat me nt.  
9Uri ne c yt ol o g y m ust be perf or me d if micr osc o pic he mat uria of u n k n o w n eti ol o g y is prese nt at t he Earl y Wit h dra wal Visit.   
1 0A brai n M RI sca n will be perf or me d u nless assesse d i n t he last 3 0 da ys.  E xce pt w he n c o n d ucte d as part of  rela pse assess me nt, M RIs m ust n ot be perf or me d wit hi n 3 0 da ys of 
recei vi n g a c o urse of ster oi ds.