Conditions: Relapsing-Remitting Multiple Sclerosis Multiple Sclerosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1501
Healthy volunteers: no

Brief summary:
The primary objective of the study is to assess the safety and tolerability of long-term treatment with BIIB019 (Daclizumab High Yield Process; DAC HYP) monotherapy in participants with relapsing remitting multiple sclerosis (RRMS) who completed Study 205MS301 (NCT01064401), Study 205MS203 (NCT01051349) or Study 205MS302 (NCT01462318).

Secondary objectives of this study in this study population are as follows:

To describe MS-related outcomes, including MS relapse, disability progression, MS lesion formation, and participant-reported impact of MS, following long-term treatment with DAC HYP To assess the long-term immunogenicity of DAC HYP administered by prefilled syringe (PFS) To assess the safety, tolerability, and efficacy of switching to DAC HYP in participants previously on long-term treatment with interferon β-1a (Avonex) in Study 205MS301(NCT01064401).

Detailed description:
Enrollment will include up to 1600 Participants, this includes approximately 1200 Participants who completed Study 205MS301 (NCT01064401). Additionally, approximately 400 Participants from the other BIIB019 extension studies 205MS203 (NCT01051349) and 205MS302 (NCT01462318) will be eligible to enter Study 205MS303 at Week 144 of Study 205MS303 \[Study 205MS301 (NCT01064401), study 205MS203 (NCT01051349) and study 205MS302 (NCT01462318) have been referred to as parent studies in the protocol\]. All Participants will receive the same dose of DAC HYP as received in the parent studies; i.e., 150 mg by an SC injection every 4 weeks.

Arms:
arm 1: BIIB019 150 mg subcutaneous (SC) every 4 weeks

Interventions: intervention 1: BIIB019 (Daclizumab)
Intervention descriptions: intervention 1: Participants will receive open-label treatment with BIIB019 150 mg subcutaneous injection every 4 weeks for up to 5 years.

Protocol document:
Prot_000.pdf: 




Protocol 205MS303
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TABLE OF CONTENTS
SPONSOR SIGNATURE PAGE ....................................................................................................2
1.
SPONSOR INFORMATION .......................................................................................9
2.
LIST OF ABBREVIATIONS.....................................................................................10
3.
SYNOPSIS .................................................................................................................12
4.
STUDY SCHEMATIC AND SCHEDULE OF EVENTS TABLES FOR 
STUDY 205MS303 ....................................................................................................17
4.1.
Study Schematic .........................................................................................................17
4.2.
Schedule of Events .....................................................................................................19
5.
INTRODUCTION......................................................................................................34
5.1.
Profile of Previous Experience with Daclizumab in MS............................................34
5.2.
Study Rationale...........................................................................................................36
5.3.
Rationale for Dose and Schedule Selection................................................................36
6.
STUDY OBJECTIVES AND ENDPOINTS..............................................................38
6.1.
Objectives ...................................................................................................................38
6.1.1.
Primary Objective.......................................................................................................38
6.1.2.
Secondary Objectives .................................................................................................38
6.1.3.
Exploratory Objective.................................................................................................38
6.2.
Endpoints....................................................................................................................38
6.2.1.
Primary Endpoints ......................................................................................................38
6.2.2.
Secondary Endpoints ..................................................................................................38
7.
STUDY DESIGN .......................................................................................................40
7.1.
Study Overview ..........................................................................................................40
7.2.
Overall Study Duration and Follow-Up .....................................................................40
7.2.1.
Baseline/Entry Visit Assessments ..............................................................................40
7.2.2.
Treatment....................................................................................................................40
7.2.3.
Post-Treatment Long-Term Follow-Up......................................................................41
7.3.
Study Stopping Rules .................................................................................................41
7.4.
End of Study ...............................................................................................................41
8.
SELECTION OF SUBJECTS ....................................................................................42
8.1.
Inclusion Criteria ........................................................................................................42
8.2.
Exclusion Criteria.......................................................................................................42




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12.2.
Pharmacokinetic Assessments....................................................................................60
12.3.
.................................................................................60
12.4.
..............................................................................................60
13.
SAFETY ASSESSMENTS ........................................................................................61
13.1.
Clinical Safety Assessments.......................................................................................61
13.2.
Laboratory Safety Assessments..................................................................................61
13.3.
Study-Specific Safety Assessments............................................................................62
14.
SCHEDULE OF EVENTS.........................................................................................63
14.1.
Overview.....................................................................................................................63
14.2.
Site Personnel .............................................................................................................64
14.3.
Subject Management ..................................................................................................66
14.4.
Special Instructions for Tests and Assessments .........................................................66
14.4.1.
Rescreening.................................................................................................................66
14.4.2.
Pregnancy Testing ......................................................................................................66
14.4.3.
Liver Function Test Assessments Prior to DAC HYP Dosing...................................66
14.4.4.
Other Assessments......................................................................................................67
14.5.
Definition of MS Relapse and Disability Progression................................................68
14.5.1.
MS Relapse.................................................................................................................68
14.5.2.
Disability Progression.................................................................................................68
14.6.
Management of MS Relapse.......................................................................................68
14.7.
Cutaneous Events........................................................................................................69
14.8.
Unscheduled Hepatic Assessment Visit .....................................................................69
14.9.
Lymphadenopathy and Lymphadenitis Events...........................................................69
14.10.
Post-Treatment Safety Follow-Up Visit Schedule for All Subjects...........................70
15.
SAFETY DEFINITIONS, MONITORING, AND REPORTING .............................71
15.1.
Definitions ..................................................................................................................71
15.1.1.
Serious Pretreatment Event.........................................................................................71
15.1.2.
Adverse Event.............................................................................................................71
15.1.3.
Serious Adverse Event................................................................................................71
15.2.
Monitoring and Recording Events..............................................................................72
15.2.1.
Serious Pretreatment Events.......................................................................................72
15.2.2.
Adverse Events ...........................................................................................................72


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15.2.3.
Serious Adverse Events..............................................................................................72
15.2.4.
All Events ...................................................................................................................72
15.2.5.
Immediate Reporting of Serious Adverse Events.......................................................72
15.2.5.1.
Deaths .........................................................................................................................73
15.3.
Safety Classifications..................................................................................................73
15.3.1.
Relationship of Events to Study Treatment................................................................73
15.3.2.
Severity of Events.......................................................................................................74
15.3.3.
Expectedness of Events ..............................................................................................74
15.4.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments................74
15.5.
Procedures for Handling Special Situations ...............................................................75
15.5.1.
Overdose.....................................................................................................................75
15.5.2.
Medical Emergency....................................................................................................75
15.5.3.
Contraception Requirements ......................................................................................75
15.5.4.
Pregnancy ...................................................................................................................76
15.5.5.
Regulatory Reporting..................................................................................................76
15.6.
Investigator Responsibilities.......................................................................................76
15.7.
Biogen Responsibilities ..............................................................................................77
16.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........78
16.1.
Description of Objectives ...........................................................................................78
16.2.
Description of Endpoints............................................................................................78
16.3.
Demography and Baseline Disease Characteristics....................................................78
16.4.
Safety and Efficacy.....................................................................................................78
16.4.1.
Analysis Population....................................................................................................78
16.4.2.
General Methods of Analysis .....................................................................................78
16.4.3.
Primary Endpoints Analysis .......................................................................................79
16.4.4.
Other Safety Endpoint Analyses.................................................................................79
16.4.5.
Efficacy Endpoints Analyses......................................................................................80
16.5.
Interim Analyses.........................................................................................................81
16.6.
Sample Size Considerations .......................................................................................81
17.
ETHICAL REQUIREMENTS ...................................................................................82
17.1.
Declaration of Helsinki...............................................................................................82
17.2.
Ethics Committee........................................................................................................82


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17.3.
Subject Information and Consent ...............................................................................82
17.4.
Subject Data Protection ..............................................................................................83
17.5.
Compensation for Injury.............................................................................................83
17.6.
Conflict of Interest......................................................................................................83
17.7.
Registration of Study and Disclosure of Study Results..............................................83
18.
ADMINISTRATIVE PROCEDURES.......................................................................84
18.1.
Study Site Initiation....................................................................................................84
18.2.
Quality Assurance.......................................................................................................84
18.3.
Monitoring of the Study..............................................................................................84
18.4.
Study Funding.............................................................................................................84
18.5.
Publications.................................................................................................................84
19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION........................85
19.1.
External Contract Organizations.................................................................................85
19.1.1.
Contract Research Organization.................................................................................85
19.1.2.
Electronic or Remote Data Capture............................................................................85
19.1.3.
Central Laboratories for Laboratory Assessments .....................................................85
19.1.4.
Central Facility for Independent Assessment of Biopsy Samples..............................85
19.1.5.
Central Facility for Other Assessments ......................................................................85
19.2.
Study Committees.......................................................................................................86
19.2.1.
Advisory Committee...................................................................................................86
19.2.2.
Internal Safety Monitoring Committee.......................................................................86
19.3.
Changes to Final Study Protocol ................................................................................86
19.4.
Ethics Committee Notification of Study Completion or Termination........................86
19.5.
Retention of Study Data..............................................................................................86
19.6.
Study Report Signatory...............................................................................................87
20.
REFERENCES ...........................................................................................................88
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL.........................................89
LIST OF TABLES
Table 1:
Schedule of Activities:  Baseline Through Week 84 for Subjects Enrolling 
From Study 205MS301 Into Study 205MS303..........................................................19


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Table 2:
Schedule of Activities:  Week 96 through Week 144 for Subjects Enrolling 
From Study 205MS301 Into Study 205MS303..........................................................22
Table 3:
Schedule of Activities:  Entry Visit (Week 144) for Subjects Enrolling From 
Study 205MS203 or Study 205MS302 Into Study 205MS303 ..................................24
Table 4:
Schedule of Activities:  Week 156 through Week 240 (End of Treatment) for 
Subjects Enrolling From Study 205MS301, Study 205MS203, or 
Study 205MS302 Into Study 205MS303....................................................................26
Table 5:
Schedule of Activities:  Post-Treatment Safety Follow-Up .......................................29
Table 6:
Schedule of Activities:  Unscheduled Assessments ...................................................30
Table 7:
Schedule of Activities:  Autoinjector Use by Subjects at Selected Sites ...................32
Table 8:
Summary of Management of Subjects With Elevated Liver Function Tests .............53
Table 9:  
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs ...................80
LIST OF FIGURES
Figure 1:
Study Design...............................................................................................................18
Figure 2:
Flowchart for Management of Subjects With Cutaneous AEs...................................55


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


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2.
LIST OF ABBREVIATIONS
ADAs
anti-drug antibodies
AE
adverse event
ALT
alanine aminotransferase
ARR
annualized relapse rate 
AST
aspartate aminotransferase
AUDIT-C
Alcohol Use Disorders Identification Test - Consumption 
Questionnaire
BDI-II
Beck Depression Inventory, Second Edition
bpm
beats per minute
BUN
blood urea nitrogen
CRF
case report form
CRO
contract research organization
DAC HYP
Daclizumab High Yield Process
DHA
Directions for Handling and Administration
EDSS
Expanded Disability Status Scale
EQ-5D
European Quality of Life, 5-dimensions
EQ-VAS
European Quality of Life, visual analog scale
FDA
Food and Drug Administration
GCP
Good Clinical Practice
Gd
gadolinium
GGT
gamma-glutamyltransferase
HIV
human immunodeficiency virus
HRPQ
Health Related Productivity Questionnaire
HRU
health resource utilization
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IFN
interferon
IL-2
interleukin-2
IM
intramuscular 
ITT
intent-to-treat
IV
intravenous
IVIg
intravenous immunoglobulin
IVMP
intravenous methylprednisolone
LFT
liver function test
MRI
magnetic resonance imaging
MS
multiple sclerosis
MSFC
Multiple Sclerosis Functional Composite
MSIS-29
Multiple Sclerosis Impact Scale-29
NAbs
neutralizing antibodies
NK
natural killer cells
PASAT 3
3-Second Paced Auditory Serial Addition Test


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PFS
prefilled syringe
PHI
protected health information
PK
pharmacokinetic(s)
RRMS
relapsing-remitting multiple sclerosis
SABR
Safety and Benefit-Risk Management
SAE
serious adverse event
SC
subcutaneous
SDMT
Symbol Digit Modalities Test
SGOT
serum glutamic oxaloacetic transaminase; see AST
SGPT
serum glutamic pyruvic transaminase; see ALT
SNP
single nucleotide polymorphism
SUSAR
suspected unexpected serious adverse reaction
T1
MRI hypointense designation
T2
MRI hyperintense designation
T4
thyroxine
ULN
upper limit of normal
US
United States
VAS
visual analog scale


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3.
SYNOPSIS
This is a brief summary.  For details refer to the body of the protocol.
Protocol Number:
205MS303
Protocol Title:
A Multicenter, Open-Label, Extension Study to Evaluate the 
Long-Term Safety and Efficacy of BIIB019, Daclizumab High
Yield Process (DAC HYP), Monotherapy in Subjects With 
Multiple Sclerosis Who Have Completed Study 205MS301
Version Number:
4
Name of Study Treatment:
Daclizumab High Yield Process (DAC HYP)
Study Indication:
Relapsing-Remitting Multiple Sclerosis (RRMS)
Phase of Development:
3
Rationale for the Study:
To evaluate the long-term safety, efficacy, and 
immunogenicity of DAC HYP in subjects with multiple 
sclerosis (MS) who have completed Study 205MS301
(DECIDE), Study 205MS203 (SELECTED), or 
Study 205MS302 (OBSERVE).
Study Objectives and 
Endpoints:
Objectives
Primary: 
The primary objective of the study is to assess the safety and 
tolerability of long-term treatment with DAC HYP 
monotherapy in subjects who completed Study 205MS301, 
Study 205MS203, or Study 205MS302.
Secondary:
Secondary objectives of this study in this study population 
are as follows:

To describe MS-related outcomes, including MS 
relapse, disability progression, MS lesion 
formation, and patient-reported impact of MS, 
following long-term treatment with DAC HYP

To assess the long-term immunogenicity of 
DAC HYP administered by prefilled syringe 
(PFS)

To assess the safety, tolerability, and efficacy of 




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
Change in quality of life as assessed by the 
European Quality of Life, 5 dimensions (EQ-5D)
and European Quality of Life, visual analog scale
(EQ-VAS)  

Change in direct health resource utilization 
(HRU; hospitalizations, emergency room visits, 
and unscheduled neurologist visits)

Change in treatment satisfaction as assessed by 
the subject 

Change in subject productivity as assessed by the 
Health Related Productivity Questionnaire 
(HRPQ)

Changes in clinical laboratory assessments 
(hematology and blood chemistry)

Local tolerability as assessed by subject-reported 
injection site pain (visual analog scale [VAS]) 
and clinician injection site assessments

Incidence of anti-drug antibodies to DAC HYP 
over time

Incidence of neutralizing antibodies to DAC HYP 
over time
Study Design:
Multicenter, open-label, long-term extension study
Rationale for Dose and 
Schedule Selection:
The DAC HYP dose and schedule were used in the pivotal 
Phase 3 205MS301 study and will be the treatment regimen 
used in the commercial setting.  The same DAC HYP dose 
and schedule were used in Study 205MS203 and 
Study 205MS302.
Study Location:
Global
Number of Planned Subjects:
Approximately 1600 subjects.  This includes approximately 
1200 subjects who completed Study 205MS301. 
Additionally, approximately 400 subjects from the other 
ongoing DAC HYP extension studies (Study 205MS203 and 
Study 203MS302) will be eligible to enter Study 205MS303 
at Week 144 of Study 205MS303. 
Study Population:
This study will be conducted in subjects with MS currently 
participating in Study 205MS301 who have completed either 
the Week 144 Visit or the End of Study Visit (Week 96) of 




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(AUDIT-C); and AE and concomitant medication monitoring 
will be performed in this study.  Additional comprehensive 
hepatic testing will be required for subjects who permanently 
discontinue study treatment due to elevated liver function 
tests.
Subject Reported 
Assessments:
Subject assessment of MSIS-29, EQ-5D quality of life 
questionnaire (the EQ-5D descriptive system and the 
respondent’s self-rated health on a vertical visual analog 
scale [EQ-VAS]), Treatment Satisfaction Questionnaire for 
Medication (before the first use of a PFS and at multiple 
timepoints during the study), Treatment Satisfaction Survey 
at selected sites (before the first and last use of an 
autoinjector), HRU, and HRPQ.
Statistical Methods:
Analyses will generally be descriptive in nature and will 
focus on data collected during Study 205MS303 only.  
Efficacy endpoints will be summarized for all subjects using 
descriptive statistics.  For relevant efficacy analyses, the data 
may be summarized for subjects by previous treatment group 
(Avonex® or DAC HYP 150 mg). The adjusted ARR and 
number of new or newly enlarging T2 lesions will be 
estimated using a negative binomial regression model.  The 
proportion of subjects with sustained progression and the 
proportion with a relapse will be estimated from the Kaplan-
Meier curve.  The incidence of AEs and changes in clinical 
laboratory assessments will also be summarized.   An 
analysis by 3- or 6-month intervals may also be performed.  
Summary statistics for other safety, efficacy, and 
pharmacokinetic (PK) endpoints will be presented.
Sample Size Determination: 
There is no formal sample size calculation for this study.  
The number of subjects in this study is determined by the 
number of subjects who completed Study 205MS301, 
Study 205MS203, or Study 205MS302, and enrolled in 
Study 205MS303.
Study Stopping Rules:
Biogen may terminate this study, after informing 
Investigators, at any time.  Investigators will be notified by 
Biogen or designee if the study is placed on hold, completed, 
or closed.


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4.
STUDY SCHEMATIC AND SCHEDULE OF EVENTS TABLES 
FOR STUDY 205MS303
A schematic of the study design is provided in Section 4.1.
The tabulated schedule of events for this study is provided in Section 4.2.
4.1.
Study Schematic
Figure 1 shows the design of Study 205MS301 and its open-label extension, Study 205MS303, 
in which subjects from Study 205MS203 and 205MS302 enter at Week 144.


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Figure 1:
Study Design










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1On dosing days, all tests and assessments (other than Treatment Satisfaction Questionnaire for Medication) must be completed prior to administration of study 
treatment. 
2Week 144 (start of Year 4) of Study 205MS303 will be the timepoint at which subjects from Study 205MS203 (SELECTED) and Study 205MS302 
(OBSERVE) enter Study 205MS303 (see Table 3 for the assessments at Week 144 in these subjects).
3ALT/SGPT, AST/SGOT, alkaline phosphatase, total bilirubin, and GGT only.
4If local LFTs have been used to determine whether dosing should continue or be suspended at the time of a scheduled clinic visit, LFTs must also be performed 
at the central laboratory at the time of the scheduled clinic visit (Note:  Scheduled clinic visits occur every 4 weeks during the first 12 weeks of the study and 
every 12 weeks thereafter.)
5Pregnancy test results must be negative prior to dosing.
6MRI scan can be performed up to 4 days prior to the visit.
7When possible, subjects should be evaluated by the same neurologist assigned to them in the parent study. 
8Prior to the first administration of either SDMT or PASAT 3, a practice SDMT and PASAT 3 should be performed at that visit prior to the test that is scored.
9This test will be performed beginning in Week 144 and every 24 weeks thereafter.  Data will be collected only from subjects enrolled from Study 205MS301.
10Before a monthly dose of DAC HYP is given, LFT results from a prior test performed within the previous 32 days must be reviewed by the Study Neurologist
or their backup. 
11A window of 4 days applies to DAC HYP dose even if it is done at home.




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Protocol Compliance and DAC HYP 
Accountability
X
1When possible, subjects should be evaluated by the same Study Neurologist assigned to them in the parent studies. 
2Week 144 (start of Year 4) of Study 205MS303 will be the timepoint at which subjects from Study 205MS203 and Study 205MS302 enter Study 205MS303. 
Entry Visit must take place within 6 months of the last DAC HYP dose in the parent studies (i.e., Study 205MS203 or Study 205MS302). 
3ALT/SGPT, AST/SGOT, alkaline phosphatase, total bilirubin, and GGT only.
5Pregnancy test results must be negative prior to dosing.
6Before a monthly dose of DAC HYP is given at the clinic, LFT results from a prior test performed within the previous 32 days must be reviewed by the Study 
Neurologist or their backup.  
Note:  MRI assessment will not be done at the Week 144/Entry Visit for Study 205MS303.






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3 If local LFTs have been used to determine whether dosing should continue or be suspended at the time of a scheduled clinic visit, LFTs must also be performed 
at the central laboratory at the time of the scheduled clinic visit (Note:  Scheduled clinic visits occur every 12 weeks.).
 
5 Pregnancy test results must be negative prior to dosing.
6 MRI scan can be performed up to 4 days prior to the visit.
7 MRI assessment is optional for the Early Termination visit.
8 When possible, subjects should be evaluated by the same neurologist assigned to them in the parent studies. 
9 Performed only for subjects originally enrolled from Study 205MS301.
10Before a monthly dose of DAC HYP is given, LFT results from a prior test performed within the previous 32 days must be reviewed by the Study Neurologist
or their backup.
11A window of ±4 days applies to DAC HYP dose even if it is done at home.






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9Performed by the Study Neurologist or their back-up within 72 hours of a suspected relapse. 
10 Refer to Section 11.7.3 for information on when to perform these assessments.




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3The procedure for taking this measurement is provided in the Study Reference Manual.
4Injection Site Assessment to be completed as soon as possible but within 10 minutes after the injection at Visit 1.
5VAS to be completed as soon as possible after the injection is administered but no later than 10-30 minutes post-injection.
6If the subject withdraws from the study or reverts to PFS use prior to receiving all 6 autoinjector doses, the subject should complete the Treatment Satisfaction 
Survey and the Patient Usability Survey provided for the Autoinjector 6 dosing day before returning to PFS or receiving alternative MS disease modifying 
therapy.


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5.
INTRODUCTION
5.1.
Profile of Previous Experience with Daclizumab in MS
Background
DAC HYP is a humanized monoclonal IgG1 antibody specific for CD25 (α subunit of the 
IL-2 receptor).  CD25 is expressed at low levels on resting T cells but is rapidly upregulated after 
T-cell activation, enabling high-affinity IL-2 signal transduction.  The primary hypothesis for 
using DAC HYP to treat MS is to selectively inhibit activated T cells.  
Anti-CD25 antibodies have multiple in vitro effects that suggest DAC HYP may directly 
decrease T-cell activation and proliferation.  These include inhibition of IL-2 dependent 
lymphocyte proliferation, disruption of both IL-2 dependent and independent pathways of 
IFN-gamma production, and interference in CD28-dependent CD40 ligand expression.  In vivo, 
daclizumab has been confirmed to cause expansion of CD56bright NK cells.  This expansion has 
also been shown to correlate with MRI-defined therapeutic response of daclizumab in MS.  
CD56bright NK cells are believed to have an immunoregulatory function, and they have been 
shown to kill activated T cells through a contact-dependent mechanism.  Therefore, selective 
inhibition of activated T cells with DAC HYP may occur through both direct and indirect 
mechanisms [Bielekova 2009; Bielekova 2004].  
Clinical Experience With Daclizumab in Multiple Sclerosis
Initial clinical studies of daclizumab in MS were conducted with material manufactured by F.  
Hoffmann-La Roche, Ltd. (Roche) at their facilities in Nutley, New Jersey (DAC Nutley)
[Bielekova 2004; Rose 2003; Rose 2004], and in Penzberg, Germany (DAC Penzberg) [Wynn 
2010].  Study 205MS301 is conducted with DAC HYP, which is produced using a different 
manufacturing process than the previous versions of daclizumab.  DAC HYP has characteristics 
that are similar to DAC Nutley and DAC Penzberg, although certain differences in 
physicochemical and biological characteristics have been observed (refer to the Investigator’s 
Brochure for details).  
Study 205MS201
Study 205MS201 (SELECT) was a double-blind, placebo-controlled study to evaluate the safety 
and efficacy of DAC HYP in subjects with RRMS that randomized 621 subjects in a 1:1:1 ratio 
to receive placebo, 150 mg DAC HYP, or 300 mg DAC HYP SC every 4 weeks over a 52-week 
treatment period.  Among subjects randomized to DAC HYP (150 mg, 300 mg) versus placebo, 
there was a significantly lower annualized relapse rate (ARR; 0.21, 0.23 versus 0.46; p < 0.001), 
a higher proportion of relapse-free subjects (81%, 80% versus 64%; p < 0.001), and a trend 
towards improvement in the MSIS-29 physical score (p = 0.128 for DAC HYP 300 mg versus 
placebo; p < 0.001 for DAC HYP 150 mg versus placebo).  There were significant reductions in 
the mean number of new or newly enlarging T2 lesions at 1 year (2.4, 1.7 versus 8.1) and in the 
mean number of new Gd+ lesions between Weeks 8 and 24 in a monthly MRI substudy 
(n = 307) (1.5, 1.0 versus 4.8) in the DAC HYP 150 mg and 300 mg groups versus placebo 
(p < 0.001 for all comparisons).  The risk of 3-month sustained disability progression at 1 year, a 


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tertiary study endpoint, was reduced by 57% (p = 0.021) in the DAC HYP 150 mg group and by 
43% (p = 0.091) in the DAC HYP 300 mg group.  
Analysis of safety data from Study 205MS201 showed that, overall, DAC HYP was well 
tolerated in this patient population.  The most frequently reported (≥10%) adverse events (AEs)
for subjects treated with DAC HYP, excluding MS relapse, were nasopharyngitis (14%), and 
headache and upper respiratory tract infection (10% each).  In Study 205MS201, serious adverse 
events (SAEs) including MS relapses occurred in 26% of placebo-treated subjects and in 16% of 
subjects treated with DAC HYP.  Excluding MS relapses, SAEs occurred in 6% of the placebo 
group, in 7% of the DAC HYP 150 mg group, and in 9% of the DAC HYP 300 mg group.  
One DAC HYP-treated subject died due to ischemic colitis following a complicated course of 
events.  Adverse events observed more frequently in DAC HYP-treated patients included an 
increase in serious infections (2%), serious cutaneous events (1%), and elevations in LFTs 
(ALT/AST) >5the upper limit of normal (ULN) (4%).
Upon completion of the 12-month treatment period in Study 205MS201, subjects were eligible to 
complete up to an additional 12 months of treatment with DAC HYP in a double-blind extension 
study (Study 205MS202 [SELECTION]), which was completed in 2012.  Study 205MS202 also 
assessed the effects of DAC HYP washout in some subjects who were actively treated in 
Study 205MS201.  Subjects completing Study 205MS202 continued long-term therapy with 
open-label DAC HYP in extension Study 205MS203 (SELECTED), which evaluated long-term 
safety and efficacy of DAC HYP monotherapy for up to an additional 144 weeks.
Study 205MS301
Study 205MS301 (DECIDE), a double-blind, randomized, parallel-group, active-controlled study 
testing the superiority of DAC HYP monotherapy compared to Avonex® (IFN -1a) in 
preventing MS relapse, was initiated in May 2010; 1841 subjects with RRMS have been enrolled 
and randomized in a 1:1 ratio to receive 150 mg DAC HYP given SC every 4 weeks, or Avonex 
30 mcg given IM once weekly over a 96- to 144-week treatment period. The primary endpoint 
was the annualized relapse rate.  In this study, DAC HYP demonstrated statistically and 
clinically meaningful superiority to IFN β-1a, on validated clinical, radiographic, and patient-
reported MS outcome measures.  DAC HYP reduced the annualized relapse rate by 45% 
(p<0.0001) compared to IFN β-1a.  DAC HYP’s treatment effect on relapses was also evidenced 
by a 41% reduction in the risk of relapse in subjects in the DAC HYP group compared to the 
IFN β-1a group (p<0.0001).  A reduction in the proportion of subjects relapsing was observed as 
early as 24 weeks after the initiation of treatment and persisted throughout the end of the study.  
The risk of 12-week confirmed disability progression was reduced by 16% in the DAC HYP 
group compared with the IFN β-1a group, a result that was not statistically significant 
(p=0.1575) in the primary analysis.  In the pre-specified analysis of 24-week confirmed 
progression, disability progression was reduced by 27% (p=0.0332) in the DAC HYP group 
compared with the IFN β-1a group.  Overall, the results of the 12-week and 24-week confirmed 
progression analyses were consistent with each other and supported a clinically meaningful 
effect of DAC HYP in preventing confirmed disability progression compared with IFN β-1a.  
DAC HYP reduced the number of new or newly enlarging T2 lesions at Week 96 by 54.4% 
(p<0.0001) compared to IFN β-1a.  The magnitude of the treatment effect was consistent with 
the results seen on the primary endpoint of annualized relapse rate.  The tertiary MRI endpoints 


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of T2, T1, and Gd-enhancing lesion count and volume were also consistent with the effect on 
new or enlarging T2 lesions and provide important confirmation of DAC HYP’s ability to reduce 
focal and destructive areas of brain inflammation in RRMS patients.  The treatment effect of 
DAC HYP on new or enlarging T2 lesions and other MRI endpoints was detectable by Week 24 
(p<0.0001) and was sustained through to the Week 96 and Week 144 MRI at a similar 
magnitude.  
In Study 205MS301, the safety profile of DAC HYP was characterized by an increased 
incidence of elevations of serum transaminases and serious hepatic events, cutaneous events,
infections, and gastrointestinal events.  The overall incidence of AEs was balanced across the 
2 treatment groups (91% IFN β-1a vs. 91% DAC HYP).  The majority of subjects with AEs had 
events that were mild to moderate in severity.  The incidence of subjects with AEs that were 
considered severe was 14% in the DAC HYP group and 12% in the IFN β-1a group.  AEs 
reported more frequently in the DAC HYP group than in the IFN β-1a group included 
nasopharyngitis, upper respiratory tract infections, influenza, oropharyngeal pain, rash, and 
lymphadenopathy, whereas influenza-like illness, pyrexia, chills, and hypertension were reported 
more frequently in the IFN β-1a group.
There was a higher incidence of SAEs in the DAC HYP group (24%) compared with the 
IFN β-1a group (21%).  Excluding MS relapse, SAEs were reported in 10% of the IFN β-1a 
group and in 15% of the DAC HYP group.  Five deaths were reported in the study (4 subjects in 
the IFN β-1a group, 1 subject in the DAC HYP group).  None of the deaths were considered by 
the Investigators to be related to study treatment.  While safety events were more common in the 
DAC HYP-treated subjects compared with IFN β-1a-treated subjects, the types of events were 
generally manageable with standard medical care, monitoring, and treatment discontinuation, as 
appropriate for the event.  Overall, the results of the study support a positive benefit/risk profile 
for DAC HYP.
The PK and immunogenicity of DAC HYP 150 mg SC administered every 4 weeks using a 
prefilled syringe (PFS) were investigated in 26 subjects in Study 205MS302 (OBSERVE), a
single-arm, open-label study that enrolled a total of 113 subjects with RRMS.
Refer to the Investigator’s Brochure for additional details.
5.2.
Study Rationale
This study will evaluate the long-term safety, efficacy, and immunogenicity of DAC HYP in 
subjects with MS who have completed Study 205MS301, Study 205MS203, or 
Study 205MS302. In addition, this study will assess the safety, tolerability, and efficacy of 
switching to DAC HYP in subjects previously on long-term treatment with interferon β-1a in 
Study 205MS301.
5.3.
Rationale for Dose and Schedule Selection
The existing scientific and clinical experience with DAC HYP supports its further investigation 
in the management of MS.  The DAC HYP dose and schedule in this protocol were used in the 
pivotal Phase 3 Study 205MS301 and will be the treatment regimen used in the commercial 


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setting.  The same DAC HYP dose and schedule were used in Study 205MS203 and 
Study 205MS302.
A single-use, disposable PFS will be provided to simplify the injection process and thereby 
reduce the burden of administering a long-term therapy such as DAC HYP in the clinic or at 
home. At the Sponsor’s discretion, single-use autoinjectors containing PFS may be used to 
administer DAC HYP in 75-100 subjects from Study 205MS303 at selected sites. Autoinjectors 
will be dispensed to each participating subject for use on up to 6 consecutive scheduled dosing 
days.




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
Change in EDSS score

Change in Symbol Digit Modalities Test (SDMT) score

Change in 3-Second Paced Auditory Serial Addition Test (PASAT 3) score

Proportion of subjects who are free from disease activity.

Change in Multiple Sclerosis Impact Scale-29 (MSIS-29) physical and psychological 
scores 

Change in quality of life as assessed by the European Quality of Life, 5 dimensions 
(EQ-5D and EQ-VAS)  

Change in direct health resource utilization (HRU; hospitalizations, emergency room 
visits, and unscheduled neurologist visits) 

Change in treatment satisfaction as assessed by the subject

Change in subject productivity as assessed by the Health Related Productivity 
Questionnaire (HRPQ)

Changes in clinical laboratory assessments (hematology and blood chemistry)

Local tolerability as assessed by subject-reported injection site pain (VAS) and 
clinician injection site assessments

Incidence of anti-drug antibodies (ADAs) to DAC HYP over time

Incidence of neutralizing antibodies (NAbs) to DAC HYP over time


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7.
STUDY DESIGN
7.1.
Study Overview
The design of Study 205MS303 is provided in Figure 1.  Approximately 1600 subjects will 
enroll in this study.  This includes approximately 1200 subjects who completed Study 
205MS301.  Additionally, approximately 400 subjects from the other DAC HYP extension 
studies (205MS203 [SELECTED] and 203MS302 [OBSERVE]) will be eligible to enter 
Study 205MS303 at Week 144 of Study 205MS303 (Study 205MS301, Study 205MS203, and 
Study 205MS302 have been referred to as parent studies in the protocol).
All subjects will receive the same dose of DAC HYP as received in the parent studies; 
i.e., 150 mg by an SC injection every 4 weeks.  The duration of DAC HYP treatment is up to 
approximately 5 years, or until availability of commercial product (whichever is sooner).
7.2.
Overall Study Duration and Follow-Up
The study period will consist of Baseline/Entry Visit assessments, treatment (for up to 
approximately 5 years), and post-treatment safety follow-up visits (from approximately 4 to 
24 weeks after the last dose of DAC HYP).
7.2.1.
Baseline/Entry Visit Assessments
Subjects Entering From Study 205MS301
Tests/assessments performed at the subject’s last visit in Study 205MS301 and within 28 days of 
the subject’s first dose of DAC HYP (Week 0) in Study 205MS303 may be used as the baseline 
for Study 205MS303; if final Study 205MS301 tests/assessments are not performed within the 
28-day window, they must be repeated upon entry into Study 205MS303 and before the first 
dose of DAC HYP is administered. 
Subjects Entering From Study 205MS203 or Study 205MS302
The Week 144 Visit of Study 205MS303 will be the Entry Visit for subjects enrolled from 
Study 205MS203 or Study 205MS302.  Any test/assessment done at the subject’s last visit in 
parent studies and within 28 days of the subject’s first dose in Study 205MS303 will be used as 
the baseline and does not need to be repeated at entry into Study 205MS303; tests/assessments 
performed >28 days before the Entry Visit must be repeated at the Entry Visit.  Central LFT 
testing is mandatory at the Entry Visit.
7.2.2.
Treatment
Subjects from Study 205MS301 continuing in Study 205MS303 will receive DAC HYP 
treatment for up to approximately 5 years, or until availability of commercial product (whichever 
is sooner), under this protocol.  Subjects from Study 205MS203 and Study 205MS302 entering 
Study 205MS303 at Week 144 will have DAC HYP treatment for up to approximately 2 years, 
or until availability of commercial product (whichever is sooner), under this protocol.


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At the Sponsor’s discretion, 75-100 subjects from Study 205MS303 at selected sites may dose 
with DAC HYP using a single-use autoinjector that contains a PFS on 6 consecutive scheduled 
dosing days (Table 7).
Eligible subjects will have clinic visits scheduled every 4 weeks for up to Week 12 in this study, 
followed by clinic visits scheduled every 12 weeks. 
Subjects who are dosing at home must be instructed to not administer their monthly dose 
of DAC HYP until the study site has contacted them to authorize dosing (after the Study
Neurologist or their backup has reviewed LFT results obtained during the previous 32 days).  
Subjects need to record the date and time of dosing in their diary if they are dosing at home.
A window of ±4 days applies to scheduled visits and home dosing.
7.2.3.
Post-Treatment Long-Term Follow-Up
In addition to the End of Treatment Visit (Week 240), which occurs 4 weeks (±4 days) after the 
subject’s last dose of DAC HYP, subjects are to return to the study site for follow-up visits at 8, 
12, 16, 20, and 24 weeks (±10 days) after the last dose of DAC HYP.
7.3.
Study Stopping Rules
Biogen may terminate this study, after informing Investigators, at any time.  Investigators will be 
notified by Biogen or designee if the study is placed on hold, completed, or closed.
7.4.
End of Study
The End of Study is last subject, last visit for final collection of data.


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8.
SELECTION OF SUBJECTS
8.1.
Inclusion Criteria
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at the 205MS303 Baseline/Entry Visit or at the timepoint specified in the individual eligibility 
criterion listed (Note:  Week 0/Day 1 is the Baseline Visit in Study 205MS303 for 205MS301 
subjects.  Week 144 is the Entry Visit in Study 205MS303 for 205MS203 and 205MS302 
subjects): 
1. Ability to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use protected health information (PHI) in 
accordance with national and local subject privacy regulations.  
2. Must be a subject currently participating in Study 205MS301 who has completed either 
the Week 144 Visit or the End of Study Visit (Week 96) of Study 205MS301 OR subject 
currently participating in Study 205MS203 or Study 205MS302.
3. Women of childbearing potential must practice effective contraception during the study 
and be willing and able to continue contraception for 4 months after their last dose of 
study treatment.
8.2.
Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
the Study 205MS303 Baseline/Entry Visit or at the timepoint specified in the individual criterion 
listed (Note:  Week 0/Day 1 is the Baseline Visit in Study 205MS303 for 205MS301 subjects. 
Week 144 is the Entry Visit in Study 205MS303 for 205MS203 and 205MS302 subjects):
Medical History
1. Any subject who permanently discontinued study treatment in Study 205MS301, 
Study 205MS203, or Study 205MS302 prior to the end of the study treatment period, or 
had an early termination in those studies OR any subject who has completed all the safety 
follow-up visits after Week 144 of Study 205MS303 per the original protocol. 
Note:  Subjects for whom dosing was temporarily suspended in Study 205MS301, 
Study 205MS203, or Study 205MS302 are not excluded from participation in this 
extension study if the criteria for resuming DAC HYP treatment under the parent study
protocol have been met at the time of enrollment into Study 205MS303.  
2. Any significant change in the subject’s medical history that would preclude 
administration of DAC HYP, including laboratory tests or a current clinically significant 
condition that, in the opinion of the Investigator, would have excluded the subject’s 
participation in Study 205MS301, Study 205MS203, or Study 205MS302.  The 
Investigator must re-review the subject’s medical fitness for participation and consider 
any factors that would preclude treatment in Study 205MS303, including:  


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
History of any significant cardiac, endocrine, hematological, hepatic, immunologic, 
metabolic, urologic, pulmonary, gastrointestinal, dermatologic, psychiatric, renal, 
neurological (other than MS), and/or other major disease (e.g., malignancy) that 
would preclude administration of DAC HYP.

Clinically significant laboratory abnormalities (hematology and blood chemistry) 
from the most recently available test in the parent study, as determined by the 
Investigator.  Laboratory findings mandating discontinuation of study treatment as 
defined in parent study protocol are exclusionary.
3. Other medical reasons that, in the opinion of the Investigator and/or Biogen, make the 
subject unsuitable for enrollment.  
Treatment History
4. Treatment with any prohibited concomitant medication during the parent study, as 
described in Section 11.5 of this protocol.
Note:  Subjects who start an approved, open-label IFN β preparation after completion of 
dosing in Study 205MS301 are not excluded, but IFN β treatment must be discontinued 
before the first dose of DAC HYP in Study 205MS303 is given.  
Miscellaneous
5. Female subjects who are currently pregnant or breastfeeding, or considering becoming 
pregnant while in the study.
6. History of drug or alcohol abuse (as defined by the Investigator) at any time after the start 
of Study 205MS303 or any of the parent studies.
7. Unwillingness or inability to comply with the requirements of the protocol, including the 
presence of any condition (physical, mental, or social) that is likely to affect the subject’s 
ability to comply with the protocol.


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9.
ENROLLMENT AND REGISTRATION PROCEDURES
9.1.
Enrollment and Screening
Subjects must be consented before any procedures are performed.  At the time of consent, the 
subject will be enrolled into the study.  If a subject is excluded from the study, the reasons for 
exclusion will be documented in the subject’s source documents and on the enrollment log. Any 
test/assessment done at the subject’s last visit in the parent studies and within 28 days of the 
subject’s first dose in Study 205MS303 will be used as the baseline for Study 205MS303 and 
does not need to be repeated at entry into Study 205MS303 (Note:  Central LFT testing is 
mandatory at the Week 144 Entry Visit for subjects rolling over from Study 205MS203 and 
Study 205MS302 into Study 205MS303).  Testing required at the Baseline/Entry Visit that is 
done outside the 28-day window must be repeated upon entry into 205MS303.  
9.2.
Registration of Subjects
Subjects should be registered in the study after the Investigator has verified that they are eligible 
per the criteria in Section 8.1 and Section 8.2 and all baseline assessments have been performed.  
No subject may begin treatment prior to enrollment and registration. 
As confirmation, the Investigator will be provided with written verification of the subject’s 
registration by mail or fax.  
Refer to the Study Reference Manual for details on registration.


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10.
STUDY TREATMENT MANAGEMENT
Study treatment (PFS or autoinjectors) must be stored in a secure location.  Accountability for 
study treatment is the responsibility of the Investigator.  Study treatment must only be dispensed 
by a Pharmacist or medically qualified staff, and stored in a secure, monitored, locked location in 
accordance with the conditions specified in current prescribing information or the Directions for 
Handling and Administration (DHA) included in the Study Reference Manual.
Study treatment is to be dispensed only to subjects enrolled in this study.  Once treatment is 
dispensed to a subject, it can only be used by that subject.
10.1.
DAC HYP
Prefilled Syringe 
DAC HYP is supplied as a liquid in a 1-mL BD-staked PFS with a 29 gauge × ½ inch needle, 
comprising 150 mg/mL DAC HYP plus excipient materials (sodium succinate, sodium chloride, 
and polysorbate 80).  At a minimum, the study treatment label will include a study reference 
code, drug identifier, quantity of dosage units, lot number, and other pertinent information in 
accordance with local law.  Depending on country requirements, the Investigator’s name may 
also appear on the label.  DAC HYP must not be used after the expiration date unless a written 
notification of an expiration date extension is provided by Biogen.
Autoinjector 
The DAC HYP PFS is assembled inside a single-use, disposable autoinjector device.  
The autoinjector label will include the DAC HYP product code “BIIB019,” conditions for 
storage, Sponsor, and a caution statement.  Depending on country requirements, the 
Investigator’s name may also appear on the label.  DAC HYP must not be used after the 
expiration date unless a written notification of an expiration date extension is provided by 
Biogen.
10.2.
DAC HYP Preparation
Each DAC HYP PFS or autoinjector contains only one dose and is intended for SINGLE USE 
INJECTION ONLY.  Any drug that remains in the PFS after injection must not be used for 
another dose or another subject. 
After Week 12, subjects may choose to administer their DAC HYP dose at home, either by 
administering the injection themselves or by a designated caregiver. The subject or designated 
caregiver will be trained by clinic staff on the correct PFS injection technique prior to initiating 
at-home DAC HYP dosing.
Autoinjectors may be provided to selected sites and will be supplied injection-ready.  Study 
personnel or subjects at these sites do not need to insert the PFS into the device. Study site 
personnel will receive appropriate autoinjector training from a Sponsor-designated trainer prior 
to initiation of autoinjector use.


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10.3.
DAC HYP Accountability
The study site must maintain accurate records demonstrating dates and amount of study 
treatment received, to whom dispensed (subject-by-subject accounting), any amount returned by 
subject, and accounts of any study treatment accidentally or deliberately destroyed.  
Unless otherwise notified, all PFS and autoinjectors, both used and unused, must be saved for 
study treatment accountability.  At the end of the study, a final reconciliation must be made 
between the amount of study treatment supplied, dispensed, and subsequently destroyed or 
returned to Biogen. 
A written explanation will be provided for any discrepancies.  After reconciliation, the 
Investigator must destroy or return to Biogen all unused study treatment PFS and autoinjectors as 
instructed by Biogen.
If any study treatment supplies are to be destroyed at the site, the Principal Investigator(s) must 
obtain prior approval by Biogen.  The Principal Investigator(s) must notify Biogen, in writing, of 
the method, date, and location of destruction.  


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11.
TREATMENT OF SUBJECTS
Biogen will provide DAC HYP (PFS or autoinjectors) to all study sites.
Refer to Section 10 (Study Treatment Management) for specifics on the preparation, storage, 
handling, disposal, and accountability of study treatment.
11.1.
Study Treatment Schedule and Administration
All subjects will receive one DAC HYP 150 mg SC injection every 4 weeks.  
DAC HYP will be administered by clinic staff at the monthly visits for the first 12 weeks of this 
study.  After Week 12, administration of DAC HYP may occur in the clinic or at home (by the 
subject or by a designated caregiver) depending on subject preference.  The subject or designated 
caregiver will be trained by clinic staff on the correct injection technique prior to initiating 
at-home DAC HYP dosing.  Subjects who are dosing at home must be instructed to not 
administer their monthly dose of DAC HYP until the study site has contacted them to 
authorize dosing.  A window of ±4 days applies to home dosing.
Before a monthly dose of DAC HYP is given, LFT results from a prior test performed within the 
previous 32 days must be reviewed by the Study Neurologist or their backup. Study personnel 
should promptly inform the subject whether the monthly dose of DAC HYP should be 
administered or whether study treatment is to be withheld based on the dosing criteria defined in 
Section 11.7.2.  Study personnel will document this communication with the subject.  Subjects 
should administer DAC HYP as soon as permission has been given as per the dosing schedule.  
Subjects need to record the date and time of dosing in their diary if they are dosing at home.
11.2.
Placebo or Reference Product Agents
Not applicable.
11.3.
Treatment Precautions
Anaphylactic-like and hypersensitivity reactions following administration of proteins such as 
DAC HYP can occur.  DAC HYP will be administered in the clinic under observation by 
qualified medical personnel for the first 12 weeks of this study.  Subjects will be educated by the 
Study Neurologist or their back-up on the signs and symptoms of hypersensitivity reactions and 
instructed to contact the site if they experience any acute or delayed reactions post injection.  
11.4.
Treatment Compliance
Compliance with treatment dosing is to be monitored and recorded by study site staff.
After Week 12, subjects who choose to administer their DAC HYP dose at home will record 
treatment in a dosing diary.  The diary will be reviewed periodically by study site staff and the 
Clinical Monitor throughout the study.  Subjects who choose at-home administration will return 
used PFS or autoinjectors to the clinic at their scheduled clinic visits.  


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11.5.
Concomitant Therapy
A concomitant therapy is any drug or substance administered from the Baseline/Entry Visit until 
completion of the study. A concomitant procedure is defined as any therapeutic intervention 
(e.g., surgery/biopsy, physical therapy) or diagnostic assessment (e.g., blood gas measurement, 
bacterial cultures) performed from the time the subject is enrolled in the study until the subject’s 
final clinic visit.
11.5.1.
Concomitant Therapies That are Prohibited
Concomitant treatment with any of the following is not allowed during the study, unless 
approved by the Biogen Medical Director(s) or the Advisory Committee, or as otherwise 
described in this protocol:

Any alternative disease modifying MS drug treatment such as chronic 
immunosuppressant therapy or other immunomodulatory treatments (including, but 
not limited to:  IFN-β, IFN-α, glatiramer acetate, cyclophosphamide, methotrexate, 
mycophenolate mofetil, mitoxantrone, cyclosporine, azathioprine, or related 
products).

Any investigational product, including investigational symptomatic therapies for MS 
and investigational therapies for non-MS indications.

Any monoclonal antibodies other than DAC HYP.

Intravenous immunoglobulin (IVIg), plasmapheresis or cytapheresis, total lymphoid 
irradiation, or T-cell or T-cell receptor vaccination.

Any systemic steroid therapy including, but not limited to, oral corticosteroids 
(e.g., prednisone) or periodic (e.g., monthly) treatment with IV methylprednisolone 
(IVMP), except for protocol-defined treatment of relapses as described in
Section 14.6 or for limited, acute treatment of general medical conditions as per the 
discretion of Study Neurologist.  Steroids that are administered by non-systemic 
routes (e.g., topical, inhaled) are allowed.

Antineoplastic or chemotherapeutic agents, including, but not limited to, 
cyclophosphamide, methotrexate, azathioprine, cladribine, cytarabine, or flutamide.

Valproic acid, carbamazepine, lamotrigine, or phenytoin.  Subjects who have been 
taking 1 of these medications at a stable dose for at least 6 consecutive months may 
continue to receive the medication and may continue study treatment under this 
protocol.  However, if any of these medications must be initiated or dose escalated, 
study treatment must be permanently discontinued as described in Section 11.8.  
Subjects who have been treated with any of these medications (which have not been
approved by the Biogen Medical Director[s]) for fewer than 6 consecutive months, or 
who take more than 1 of these medications, or who have had dose escalations within 
the past 6 months must do 1 of the following:


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
Discontinue the medication (any agent used for <6 consecutive months must be 
discontinued).  Subjects may use an alternative medication allowed by the 
protocol, if needed.

Subjects taking more than 1 agent must reduce to 1 agent (any agent that is 
continued must have been taken for at least 6 consecutive months).

In the case of dose escalation, revert to a previous dose that had been used for at 
least 6 months.

Permanently discontinue study treatment.

Isoniazid, propylthiouracil, or nimesulide.  Subjects who currently take any of these 
medications must either change to an alternative medication allowed by the protocol 
or permanently discontinue study treatment.  
Subjects who receive any of these restricted medications may be required to permanently 
discontinue study treatment as outlined in Section 11.8.  Subjects who permanently discontinue 
study treatment will be allowed to receive IVMP as treatment for MS relapse while they are 
participating in the study, as described in Section 11.8.
11.5.2.
Concomitant Therapies That Require Precaution 
Caution should be used when administering drugs of known hepatotoxic potential, including 
non-prescription products, concomitantly with DAC HYP.  Patients should be observed for signs 
and symptoms of hepatic dysfunction, particularly when DAC HYP is used concomitantly with 
other potentially hepatotoxic medicinal products.  Use of the following medications is strongly 
discouraged during the study:

Herbal or dietary supplements. 

Agents that have established risks of hepatotoxicity or serious rash according to 
labeling information (examples include, but are not limited to, 
amoxicillin/clavulanate, clarithromycin, ketoconazole, minocycline, nitrofurantoin, 
trimethoprim/sulfamethoxazole, diclofenac, sulfasalazine, amiodarone, methyldopa, 
nefazodone, halothane, and tizanidine).  Alternatives to these therapies should be used 
whenever possible.
Symptomatic therapy, such as treatment for spasticity, depression, or fatigue is not restricted, but 
should be optimized as early as possible in an attempt to maintain consistent treatment for the 
duration of the study. Symptomatic therapies for spasticity that have established risks of 
hepatotoxicity are strongly discouraged for use during the study.  Initiation of Fampridine-SR 
after enrollment is permitted, including when it is used in the acute management of protocol-
defined relapse (as described in Section 14.6).
11.5.3.
Concomitant Therapy Guidelines
Subjects should be instructed not to start taking any new medications, including non-prescribed 
medications, unless they have received permission from the Investigator.  The use of live 
vaccines in humans concurrently treated with daclizumab has not been explored; therefore live 
vaccines should not be administered to MS subjects who are being treated with DAC HYP.


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The use of concomitant therapies or procedures defined in this section must be recorded on the 
subject’s case report form (CRF), according to instructions for CRF completion (Note: 
concomitant therapies in the parent study that continued at Study 205MS303 entry must be 
recorded on the CRF).  AEs related to administration of these therapies or procedures must be 
documented on the appropriate CRF.  For subjects who prematurely discontinue study treatment,
all concomitant medications should be recorded throughout the remainder of the subject’s 
participation in the study.
11.6.
Continuation of Treatment 
No further provisions are made for access to the study treatment.  If DAC HYP is proven to be 
beneficial, all regulatory requirements regarding poststudy access will be met.
11.7.
Treatment Schedule Modifications
Subjects who experience a significant change in their medical status (e.g., neurological 
worsening/suspected MS relapse, possible injection-site reaction, infection, cutaneous AE, fever, 
abdominal pain, persistent diarrhea, jaundice, nausea, vomiting, pruritus) must contact the Study
Neurologist as soon as possible and no more than 48 hours after symptom onset.  The subject 
should then be evaluated by the Study Neurologist within no more than 72 hours for physical and 
neurological assessments and further treatment recommendations if appropriate.  These subjects 
should not administer additional DAC HYP until they have been evaluated by the Study
Neurologist or their backup.
Unscheduled PK/
 Visit (Table 6) can be performed in subjects who have evidence of 
significant changes in their medical conditions (as assessed by the Investigator).  This visit must 
be approved by the Biogen Medical Director in advance.
Additional treatment considerations for specific events are described below.
11.7.1.
Infections
Subjects who have evidence of a clinically significant infection will be instructed to notify the 
Study Neurologist or their backup within 48 hours of onset, and scheduled dosing of DAC HYP 
may be withheld.  If the subject’s infection resolves within 2 weeks of the scheduled DAC HYP 
dose, the subject may receive the previously scheduled dose of DAC HYP at that time.  If the 
infection has not resolved within the 2 weeks, dosing of DAC HYP will remain suspended, and 
the subject will miss dosing until the infection is resolved.  
11.7.2.
Elevated Liver Function Tests
Before a monthly dose of DAC HYP is given, LFT results from a prior test (performed within 
the previous 32 days) must be reviewed by the Study Neurologist or their backup, and must be 
within the protocol-required limits shown below (LFT procedures are described in 
Section 14.4.3).
If a subject develops clinical signs or symptoms suggestive of hepatic dysfunction 
(e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark 


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urine), promptly measure serum transaminases and interrupt or discontinue treatment with DAC 
HYP, as appropriate.
Table 8 summarizes how subjects with elevated LFTs will be managed during the study.
11.7.2.1.
ALT/SGPT or AST/SGOT >3 to ≤5×ULN
In subjects with alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) or 
aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) >3 to
≤5ULN and total bilirubin ≤2×ULN, the following should be performed:

Study treatment must be temporarily suspended.

LFT elevation should be confirmed as soon as possible but no later than 1 week by a 
repeat test performed at the central laboratory.

Tests are repeated weekly until both ALT/SGPT and AST/SGOT are <2×ULN.

After a temporary suspension, dosing of DAC HYP may be resumed when 
ALT/SGPT and AST/SGOT are <2×ULN provided that the criteria for permanent 
discontinuation have not been met (see Section 11.8).
In subjects with ALT/SGPT or AST/SGOT >3 to ≤5×ULN and total bilirubin >2×ULN, the 
following should be performed:

Study treatment must be withheld.

LFT elevation should be confirmed as soon as possible but no later than 1 week by a 
repeat test performed at the central laboratory.

If the elevation is confirmed on repeat testing, study treatment must be permanently
discontinued.  Otherwise, follow the guidelines in Section 11.7.2.4.
In addition to these conditions, study treatment must be temporarily suspended and managed per 
the guidelines in Section 11.7.2.4 if a subject develops any other clinically significant hepatic 
condition in the opinion of the Investigator, including jaundice.
11.7.2.2.
ALT/SGPT or AST/SGOT >5×ULN
In subjects with an ALT/SGPT or AST/SGOT >5ULN, regardless of total bilirubin level, the 
following should be performed:

Study treatment must be withheld.

LFT elevation should be confirmed as soon as possible but no later than 1 week by a 
repeat test performed at the central laboratory.

If the elevation of >5ULN is confirmed on repeat testing, study treatment must be 
permanently discontinued.  Otherwise, follow the guidelines in Section 11.7.2.4.
11.7.2.3.
Second Temporary Suspension Due to Elevated LFTs
If a subject has treatment suspended for an LFT elevation and has also had a prior treatment 
suspension for an LFT elevation during DAC HYP use, DAC HYP must be permanently 


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discontinued unless an alternative explanation for the LFT elevation unrelated to DAC HYP use 
is clearly identified by the Investigator.
11.7.2.4.
Management Guidelines Following Temporary Suspension or Permanent 
Discontinuation
All subjects with elevated LFTs (ALT/SGPT or AST/SGOT >3×ULN) should be managed per 
the guidelines below.

Study treatment must be temporarily suspended and LFT elevation should be 
confirmed as soon as possible but no later than 1 week by a repeat test performed at 
the central laboratory. In cases where LFTs cannot be performed via the central 
laboratory, repeat LFT results from a local laboratory can be used for confirmation.

After a temporary suspension, dosing of DAC HYP may be resumed when 
ALT/SGPT and AST/SGOT are <2×ULN provided that the criteria for permanent 
discontinuation have not been met (see Section 11.8).

For subjects that have had DAC HYP treatment suspended for >8 weeks due to 
elevated LFTs, Investigators should consider whether subjects should permanently 
discontinue treatment with DAC HYP in order to allow treatment with another 
disease-modifying therapy and minimize the risk of return of MS disease activity.  
Such decisions are at the discretion of the Investigators and their assessment of risks 
and benefits.

All subsequent testing after a temporary treatment suspension or permanent 
discontinuation is required to be performed centrally at least weekly until the LFT 
elevation is <2×ULN. 

Monitoring of LFT elevations will occur for up to 6 months after the last DAC HYP 
dose has been administered.  If after 6 months the LFT remains elevated at ≥2×ULN, 
the Investigator or health care professional should continue to monitor the LFT as 
clinically appropriate; any relevant follow-up data should be reported to the Sponsor 
as a spontaneous report.

A careful review of all concomitant medications must be documented.  The 
Investigator should consider discontinuation of all potential hepatotoxic medications.  
All recently started or non-essential concomitant medications should be suspended 
until the LFT elevation is <2×ULN.

An Unscheduled Hepatic Assessment Visit as soon as possible but within 1 week
should be performed in the event of permanent discontinuation due to elevated LFTs
(see Table 6).

Subjects should be referred to a hepatic specialist if medically indicated.  In 
consultation with the hepatic specialist, a full evaluation of alternative causes of liver 
injury should be performed.  Additional hepatic studies should be performed 
according to local standard of care.  The central laboratory may be utilized for 
additional hepatic testing per Investigator request.  If testing for viral hepatitis is 
negative, LFT elevations are not improving, DAC HYP is suspected as the cause of 


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the LFT elevation, and there are no known contraindications for corticosteroids, then, 
in continued consultation with the hepatic specialist, empiric treatment with systemic 
corticosteroids should be considered.  
Table 8:
Summary of Management of Subjects With Elevated Liver Function Tests
Total Bilirubin
Serum Transaminases
ALT/SGPT or 
AST/SGOT
>3 to ≤5×ULN
ALT/SGPT or 
AST/SGOT
>5×ULN
Second Temporary 
Suspension Due to 
Elevated ALT/SGPT or 
AST/SGOT
≤2×ULN
Temporarily suspend
dosing1
Weekly LFT until both 
ALT/SGPT and 
AST/SGOT are <2×ULN
Withhold dosing2
Repeat test as soon as 
possible but no later than 
1 week after the elevation
If confirmed, permanently 
discontinue study 
treatment.  Otherwise, 
follow the guidelines in 
Section 11.7.2.4.
Withhold dosing2
Repeat test as soon as 
possible but no later than 
1 week after the elevation
If confirmed, permanently 
discontinue study 
treatment.  Otherwise, 
follow the guidelines in 
Section 11.7.2.4.
>2×ULN
Withhold dosing2
Repeat test as soon as 
possible but no later than 
1 week after the elevation
If confirmed, permanently 
discontinue study 
treatment.  Otherwise, 
follow the guidelines in 
Section 11.7.2.4.
As above
As above
ALT = alanine aminotransferase; AST = aspartate aminotransferase; LFT = liver function test; SGOT = serum 
glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase; ULN = upper limit of normal.
1 Subjects should be managed according to the following guidelines:  LFT elevation should be confirmed as soon as 
possible but no later than 1 week; LFT is required to be performed at least weekly until the LFT elevation is 
<2×ULN; dosing of DAC HYP may be resumed when ALT/SGPT, AST/SGOT, and bilirubin are <2×ULN,
provided that the criteria for permanent discontinuation have not been met; a careful review of all concomitant 
medications must be documented; and if treatment is permanently discontinued, subjects should be referred to a 
hepatic specialist if medically indicated.
2 Subjects should be managed according to the following guidelines:  LFT elevation should be confirmed as soon as 
possible but no later than 1 week; LFT is required to be performed at least weekly until the LFT elevation is 
<2×ULN; an Unscheduled Hepatic Assessment Visit is performed as soon as possible but within 1 week of the 
elevation; a careful review of all concomitant medications must be documented; and if treatment is permanently 
discontinued, subjects should be referred to a hepatic specialist if medically indicated.
11.7.3.
Cutaneous Events
Subjects participating in Study 205MS303 who develop a mild or moderate cutaneous AE that is 
not associated with more than 1 systemic symptom or sign do not need to be evaluated by the 
Study Dermatologist; the Study Neurologist can complete the Unscheduled Dermatology 


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Assessment Visit as soon as possible.  In such cases, the Study Neurologist should complete the 
Physician’s Global Assessment Scale form.  Any subject participating in Study 205MS303 who 
develops a mild or moderate cutaneous AE that is associated with more than 1 systemic 
symptom or sign, a severe cutaneous AE (with or without systemic symptoms or signs), or a 
serious cutaneous AE (with or without systemic symptoms or signs) needs to be evaluated by the 
Study Dermatologist at an Unscheduled Dermatology Assessment Visit as soon as possible.
Systemic symptoms associated with a mild or moderate cutaneous AE that would require 
evaluation by a dermatologist may include, but are not limited to, fever, hematological 
abnormalities, abnormalities of internal organs (as may be detected by renal and liver function 
tests), and lymphadenopathy.
If the Study Neurologist sees the subject prior to the Study Dermatologist, the Study Neurologist
should, if possible, assess the cutaneous AE prior to the subject seeing the Study Dermatologist. 
The information from the assessment by the Study Neurologist will be captured in addition to the 
information from the assessment by the Study Dermatologist. If the cutaneous AE is assessed by 
the Study Dermatologist as a mild or moderate cutaneous AE not associated with more than 
1 systemic symptom or sign, any follow-up visits can be conducted by the Study Neurologist.
A flowchart is presented in Figure 2 to summarize how these subjects will be managed during 
the study.


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Figure 2:
Flowchart for Management of Subjects With Cutaneous AEs
AE = adverse event; PGA = Physician’s Global Assessment.
Photographs can be taken by the Study Neurologist or designee at these visits for mild or
moderate cutaneous AEs that are associated with more than 1 systemic symptom or sign, severe
cutaneous AEs (with or without systemic symptoms or signs), or serious cutaneous AEs (with or 
without systemic symptoms or signs) if they have not been taken by the Study Dermatologist
(see Section 4.2).  The subjects will be asked for their consent to having their dermatological 
photographs used for educational purposes, if required.  
Skin biopsy must be performed in subjects with severe or serious cutaneous AEs (with or 
without systemic symptoms or signs) at the Unscheduled Dermatology Assessment Visit, unless 
medically contraindicated.


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Skin biopsies from study subjects with severe or serious cutaneous AEs (with or without 
systemic symptoms or signs) will be sent to a centralized laboratory for evaluation.  Results of 
the skin biopsy will be provided back to the Study Dermatologist as soon as possible with a copy 
sent to the sponsor.  Skin biopsy may also be locally evaluated per the discretion of the Study 
Dermatologist.
If the cutaneous AE is suspected to be an allergic or hypersensitivity reaction to study treatment, 
study treatment must be suspended until consultation with the Study Dermatologist. Under the 
consultation of the Study Dermatologist, the subject should also withhold all other non-essential 
medications, including protocol-required medications (as appropriate), and non-prescription 
drugs and supplements, at least until the cutaneous event has resolved.  The decision to 
permanently discontinue study treatment should be made by the Investigator in consultation with 
the Study Dermatologist.  If an allergic or hypersensitivity reaction to study treatment is 
confirmed, study treatment must be permanently discontinued.  
11.7.4.
Gastrointestinal Events of Inflammatory Colitis
For any subject participating in Study 205MS303 who develops symptoms of inflammatory 
colitis (e.g., persistent diarrhea and abdominal cramps, blood in the stool, and fever), treatment 
with DAC HYP should be stopped and the subject should be referred to a specialist.  Some 
subjects with mild colitis who require DAC HYP therapy may be able to continue the study 
treatment if the benefit-risk profile is considered positive per Investigator's assessment and the 
subject's informed decision.
11.7.5.
Lymphadenopathy or Lymphadenitis Events
Any subject participating in Study 205MS303 who develops clinically significant 
lymphadenopathy or lymphadenitis should be referred to a specialist.  Additional diagnostic 
tests, such as imaging, blood tests, and/or biopsy, should be performed according to the local 
standard of care.  
When diagnostic tests are performed, the results may be requested for internal safety review and, 
when available, biopsy materials will be sent to a centralized laboratory for evaluation.  The 
results of the central laboratory biopsy report will be provided back to the Study Neurologist as 
soon as possible, with a copy sent to the Sponsor.  
Study treatment may continue or be resumed after a temporary suspension in cases of 
uncomplicated lymphadenopathy if the benefit-risk profile is considered positive per the 
Investigator’s assessment and the subject’s informed decision. Subjects who discontinued study 
treatment for any reason while presenting with ongoing lymphadenopathy or lymphadenitis 
should be followed until the lymphadenopathy or lymphadenitis has stabilized or resolved or the 
study has terminated, whichever comes first.


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11.8.
Discontinuation of Study Treatment
A subject must permanently discontinue DAC HYP 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 15.5.4.

The subject experiences a hypersensitivity or suspected allergic reaction 
(e.g., anaphylaxis and anaphylactoid reactions) to study treatment.

The subject develops a chronic viral infection (e.g., hepatitis C, HIV).

The subject develops elevated LFTs that meet any of the following criteria:

ALT/SGPT or AST/SGOT >5ULN that is confirmed by a repeat test performed 
within 1 week

ALT/SGPT or AST/SGOT >3ULN with concomitant elevation of total bilirubin 
>2ULN that is confirmed by a repeat test performed within 1 week

If a subject has treatment suspended for an LFT elevation and has also had a prior 
treatment suspension for an LFT elevation during DAC HYP use, DAC HYP 
must be permanently discontinued unless an alternative explanation for the LFT 
elevation unrelated to DAC HYP use is clearly identified by the Investigator.

The subject experiences a cutaneous AE, which the Investigator (in consultation with 
the Study Dermatologist) considers to be a generalized allergic or hypersensitivity 
reaction to study treatment (see Section 11.7.3). 

The subject experiences inflammatory colitis, except in subjects with mild colitis who 
require DAC HYP therapy and have a positive benefit-risk profile per Investigator's 
assessment and the subject's informed decision (see Section 11.7.4).

The subject requires treatment with any of the disallowed concomitant medications, 
unless approval is given by the Biogen Medical Director(s) or Advisory Committee.  
Note:  IVMP for treatment of a protocol-defined relapse is allowed as detailed in the 
protocol (see Section 11.5).  Treatment with valproic acid, carbamazepine, 
lamotrigine, or phenytoin is only allowed under the conditions detailed in the 
protocol.  

The subject experiences a medical emergency that necessitates permanent 
discontinuation of treatment.  

The subject desires to discontinue treatment under this protocol.  

At the discretion of the Investigator for medical reasons or for non-compliance.   

Upon confirmatory tests 1 month apart, the subject’s hematology results are as 
follows in the absence of an identified reversible cause by the Investigator 
(e.g., infection):  

white blood cell count is <2500 cells/L, or 

lymphocyte count is <800 cells/L, or 


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
platelet count is <75,000 cells/L  
Subjects who meet the above criteria must have study treatment withheld until 
hematology retest results are available.  

The subject experiences severe depression and/or suicidal ideation.  Severe 
depression is defined as any episode that requires hospitalization, or at the discretion 
of the Investigator.
Subjects who permanently discontinue DAC HYP treatment should complete all post-treatment
safety follow-up evaluations (see Section 14.10).
Subjects who permanently discontinue study treatment may be treated with alternative approved 
MS therapies according to local practices, and should remain in the study and complete safety 
follow-up evaluations as described in Section 4.2 and Section 13. However, subjects who desire 
to discontinue participation in this study or are unwilling or unable to comply with the protocol 
should be withdrawn from the study and complete an Early Termination Visit.  As noted in
Table 6 (Footnote 3) and Section 11.9, subjects terminating treatment with an ongoing cutaneous 
AE require an Unscheduled Dermatology Assessment Visit prior to leaving the study if the 
subject has not had such a visit in the 4 weeks±4 days prior to leaving the study.  If the event is, 
at the time of termination, a mild or moderate cutaneous AE that is associated with more than 
1 systemic symptom or sign, a severe cutaneous AE (with or without systemic symptoms or 
signs), or a serious cutaneous AE (with or without systemic symptoms or signs), then the 
assessment should be performed by the Study Dermatologist.  If the event is considered mild or 
moderate and is not associated with more than 1 systemic symptom or sign, then the assessment 
can be performed by the Study Neurologist or the Study Dermatologist.
The reason(s) for discontinuation of treatment must be recorded in the subject’s CRF.
11.9.
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 is unwilling or unable to comply with the protocol.  

At the discretion of the Investigator for medical reasons.
Subjects who withdraw from the study should complete the End of Treatment Visit assessments 
as described in Section 14.10 (subjects should be encouraged to complete all other post-treatment
safety follow-up visits).  The reason for the subject’s withdrawal from the study must be 
recorded in the subject’s CRF.  
For subjects with an ongoing mild or moderate cutaneous AE that is associated with more than 
1 systemic symptom or sign, severe cutaneous AE (with or without systemic symptoms or signs), 
or serious cutaneous AE (with or without systemic symptoms or signs), the Study Dermatologist
should perform an Unscheduled Dermatology Assessment Visit if this visit has not been 
performed in the 4 weeks±4 days prior to leaving the study (see Section 11.7.3). If the event is 
considered mild or moderate and is not associated with more than 1 systemic symptom or sign, 
then the assessment can be performed by the Study Neurologist or the Study Dermatologist.


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12.
EFFICACY, DAC HYP CONCENTRATION, AND
ASSESSMENTS
12.1.
Clinical Efficacy Assessments
The following clinical tests/assessments will be performed to assess the efficacy of DAC HYP:

Relapse Assessment: Subjects who suspect they are experiencing new symptoms or 
worsening symptoms need to contact the Study Neurologist within 48 hours of the 
onset of the symptoms.  

Refer also to Section 14.6 Unscheduled Relapse Assessment Visit for additional 
details.  

EDSS [Kurtzke 1983]:  Review of EDSS procedures will be performed prior to study 
start as necessary for training purposes.  

MSFC [Fischer 1999]:  Timed 25-Foot Walk, 9HPT with both upper extremities, and 
PASAT 3  

SDMT:  Data will be collected only from subjects enrolled from Study 205MS301, 
and test performance data will be collected beginning in Week 144 and every 
24 weeks thereafter.

PASAT 3:  This test will be performed separately from the MSFC beginning in
Week 144 and every 24 weeks thereafter.  Data will be collected only from subjects 
enrolled from Study 205MS301.

Brain MRI scan with and without Gd (T2 hyperintense lesions, T1 hypointense 
lesions, Gd+ lesions, brain atrophy).

Subjects will complete the following questionnaires at various timepoints specified in 
Section 4.2:  

EQ-5D quality of life questionnaire (the EQ-5D descriptive system and the 
EQ-VAS)  

MSIS-29 (29-item physical and psychological assessment)  

HRU (hospitalizations, emergency room visits, and unscheduled neurologist 
visits)  

Treatment Satisfaction Questionnaire for Medication (with PFS use) or Treatment 
Satisfaction Survey (with autoinjector use)  

HRPQ (productivity questionnaire)  
Refer to Section 4.2 for the timing of assessments.  




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13.
SAFETY ASSESSMENTS
13.1.
Clinical Safety Assessments
The following clinical assessments will be performed to determine the safety profile of 
DAC HYP:

Medical history

Physical and neurological examination 

Vital sign measurements:  temperature, pulse rate, systolic and diastolic blood 
pressure, and respiratory rate (subjects must remain in the same body position quietly 
for 5 minutes prior to having their pulse and blood pressure taken)

Weight

Concomitant therapy and procedure recording

AE and SAE recording

Beck Depression Inventory, Second Edition (BDI-II)

Immunogenicity assessments

Alcohol Use Disorders Identification Test - Consumption Questionnaire (AUDIT-C)
See Section 4.2 for the timing of assessments.
13.2.
Laboratory Safety Assessments
The following laboratory tests will be performed to assess the safety profile of DAC HYP:

Hematology:  hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, red blood cell count, white 
blood cell count (with differential), and platelet count

Blood chemistry:  sodium, potassium, chloride, total bilirubin, alkaline phosphatase, 
ALT/SGPT AST/SGOT, lactate dehydrogenase, gamma glutamyl transferase, blood 
urea nitrogen (BUN), creatinine, and bicarbonate

Comprehensive hepatic panel (only required for subjects who permanently 
discontinue dosing due to elevated LFTs as defined in Section 11.7.2).  Testing will 
include screening for the following: 

hepatitis A, B, C, and E 

other viral infections:  Epstein-Barr virus (EBV), cytomegalovirus (CMV), human 
herpes virus 6 (HHV-6), varicella zoster virus (VZV), herpes simplex virus 
(HSV), and Parvovirus B19

gamma-globulins, including IgG levels


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
autoantibodies:  antinuclear antibody (ANA), anti-smooth muscle antibody
(anti-SM), anti-liver/kidney microsome-1 antibody (anti-LKM1), 
antimitochondrial antibody (AMA), and anti-soluble liver antigen (SLA) 
Additional testing may be performed based on results of the above testing or the 
subject’s clinical history.  Additional hepatic assessments should be performed 
according to local standard of care.  

Thyroid function panel, including TSH and T4

Urinalysis:  protein, blood, glucose, ketones, nitrite, leukocytes, pH, specific gravity 
by dipstick and microscopy

Urine pregnancy testing 

Skin biopsy (only required for subjects who experience cutaneous AEs reported as 
serious or severe as defined in Section 11.7.3)
Refer to Section 4.2 for the timing of assessments.
13.3.
Study-Specific Safety Assessments
Blood serum collection for binding and neutralizing anti-drug antibody testing will be 
performed.  Note:  When necessary, samples drawn for one purpose (e.g., immunogenicity) may 
be used to meet another protocol-defined objective (e.g., DAC HYP concentration assessment).


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14.
SCHEDULE OF EVENTS
14.1.
Overview
A written, signed Informed Consent Form (ICF) and all authorizations required by local law 
(e.g., Protected Health Information [PHI] in North America) must be obtained prior to 
performing any tests or assessments under this protocol.
For subjects entering from Study 205MS301, tests/assessments performed at the subject’s last 
visit in Study 205MS301 and within 28 days of the subject’s first dose of DAC HYP (Week 0) in 
Study 205MS303 may be used as baseline data for Study 205MS303; if final Study 205MS301 
tests/assessments are not performed within the 28-day window, they must be repeated upon entry 
into Study 205MS303 and before the first dose of DAC HYP is administered.
Week 144 Visit of Study 205MS303 will be the Entry Visit for subjects enrolled from 
Study 205MS203 or Study 205MS302.  Any test/assessment done at the subject’s last visit in 
parent studies and within 28 days of the subject’s first dose in Study 205MS303 will be used as 
the baseline and does not need to be repeated at entry into Study 205MS303; test/assessments 
performed >28 days before the Entry Visit must be repeated at the Entry Visit. Central LFT 
testing is mandatory at Entry Visit.
Clinic visits will occur once every 4 weeks for the first 12 weeks, then every 12 weeks thereafter. 
On a dosing day, all tests and assessments must be performed prior to DAC HYP administration.  
When DAC HYP administration and MRI evaluation are required at the same visit, the MRI scan 
should be performed prior to DAC HYP administration (Note:  MRI scan can be performed up to 
4 days prior to the visit).
Before a monthly dose of DAC HYP is given, LFT results (ALT/SGPT, AST/SGOT, alkaline 
phosphatase, total bilirubin, and GGT only) from prior testing performed within the previous 
32 days must be reviewed by the Study Neurologist or their backup, and must be within the 
protocol-required limits.
After Week 12, subjects will have the option of administering DAC HYP at home following 
Investigator review of monthly pre-dose LFT results.  Subjects who are not able to administer 
their own dose or prefer not to administer their own dose of DAC HYP will be given the option 
to choose another individual (caregiver) to administer their treatment at home or to have their 
treatment administered by staff at the study site.
Follow-up visits will take place at 4 (End of Treatment Visit), 8, 12, 16, 20, and 24 weeks after 
each subject’s last dose of DAC HYP. Unscheduled Relapse Assessment Visits (if necessary) 
should be scheduled within 72 hours of the onset of any new neurological symptoms that may 
indicate neurological worsening or possible clinical relapse. Unscheduled Hepatic Assessment 
Visits (if necessary) should be scheduled as soon as possible (but within 1 week) following 
discontinuation of study treatment due to elevated LFTs.  Unscheduled Dermatology Assessment 
Visits will be performed as per Section 11.7.3.  


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Unscheduled PK/
 Visits should be scheduled as soon as possible following significant 
changes in subjects’ medical conditions, as assessed by the Investigator.  This visit must be 
approved by the Biogen Medical Director in advance.
14.2.
Site Personnel
For each subject, the Principal Investigator will designate the following study site personnel:

A primary Study Neurologist and backup neurologist

A primary and backup Nurse (or Study Coordinator)

A primary and backup Examining Technician

An MRI Technician

A Pharmacist (or authorized designee)

A Study Dermatologist
The Study Neurologist must have a minimum of 2 years of neurology specialty training and 
anticipate at least a 3-year commitment to the study, or be approved by the study Advisory 
Committee. The Study Neurologists may designate another neurologist at the center who meets 
the same qualifications to perform the EDSS assessments and other neurologic assessment 
during the trial. Whenever possible, the EDSS and other neurologic assessments should be 
performed by the same examiner who performed these assessments in the parent study.  
The primary Study Neurologist will be responsible for:

Management of the routine neurological care of the subject

Assessment (including assignment of causality) and treatment of AEs and MS 
relapses

Obtaining an EDSS score based on a detailed neurological examination at the 
scheduled timepoints required in the protocol, and at every Unscheduled Relapse 
Assessment Visit

Review of selected hematology and all blood chemistry results from the central 
laboratory

Assessment of LFT results, as detailed in Section 11.7.2

Monitoring and follow-up of any abnormal hepatic tests

Referral of subjects to a dermatologist if that subject experiences a mild or moderate 
cutaneous AE that is associated with more than 1 systemic symptom or sign, a severe 
cutaneous AE (with or without systemic symptoms or signs), or a serious cutaneous 
AE (with or without systemic symptoms or signs) as described in Section 11.7.3

Performing Dermatology Assessments and Physician Global Assessment Scale in 
subjects with mild or moderate cutaneous AEs (not associated with more than 
1 systemic symptom or sign), as detailed in Section 11.7.3


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
Assessment of injection sites, as detailed in Table 7
Hematology and blood chemistry data will be sent to the investigational sites to aid in 
management of the subject.  
The primary Nurse or Study Coordinator will be responsible for:

Assisting the Study Neurologist in subject management, including the treatment of 
AEs, the treatment and assessment of disease relapses, and the recording of AEs and 
concomitant medications

Monitoring the EDSS scores and informing the Study Neurologist if a subject 
experiences at least a 1.0-point increase on the EDSS from a baseline EDSS ≥1.0 that 
is sustained for 24 weeks, or at least a 1.5-point increase on the EDSS from a baseline 
EDSS <1.0 that is sustained for 24 weeks

Administering the patient-reported questionnaires (BDI-II, MSIS-29, EQ-5D), HRU,
and subject assessment of injection pain (VAS)

Collection of blood samples and obtaining vital signs

Study treatment administration/dispensation/accountability
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.  It is not necessary for the 
Examining Technician to be a healthcare professional as long as he/she is qualified, in the 
opinion of the Principal Investigator, to administer the MSFC (Note:  MSFC was administered in 
this study only until Week 48;  therefore, the role of the Examining Technician ended after that).
The MRI Technician will be responsible for:

Performing a brain MRI scan with and without Gd at all protocol-required timepoints.  
Study-specific MRI scan procedures and protocols, which will be provided prior to 
study start, must be followed.
The Pharmacist (or authorized designee) will be responsible for:

Storage, distribution, and accountability of study treatment.
The Study Dermatologist will be responsible for:

Performing Cutaneous Assessments and Physician Global Assessment Scale in 
subjects with a mild or moderate cutaneous AE that is associated with more than 
1 systemic symptom or sign, a severe cutaneous AE (with or without systemic 
symptoms or signs), or a serious cutaneous AE (with or without systemic symptoms 
or signs), as detailed in Section 11.7.3

Documenting cutaneous events, as per the protocol.  

Taking photograph(s) of the affected body areas, as required.

Performing a skin biopsy, as required.


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
Evaluating, treating, and managing mild or moderate cutaneous AEs that are 
associated with more than 1 systemic symptom or sign, severe cutaneous AEs (with 
or without systemic symptoms or signs), or serious cutaneous AEs (with or without 
systemic symptoms or signs), as described in Section 11.7.3.
14.3.
Subject Management
The following restrictions apply to all subjects enrolled into this study:

Subjects must follow the restrictions for concomitant medications and procedures 
described in Section 11.5.

Contraception requirements are to be followed as described in Section 15.5.3.

Whenever possible, a subject should undergo protocol-required tests and assessments 
at the same time of day throughout the study.

Subjects should not donate blood until 4 months after their last dose of DAC HYP.

Subjects should not receive live or live-attenuated vaccines during DAC HYP 
treatment or for at least 6 months after treatment with DAC HYP.
14.4.
Special Instructions for Tests and Assessments
Note:  Information about the tests and assessments to be performed in this study is also provided 
in Section 12 and Section 13, and in the Study Reference Manual.
14.4.1.
Rescreening
Subjects who are not eligible for participation at baseline due to a temporary condition 
(e.g., acute infection) are allowed to be rescreened once the condition has resolved, provided 
they are rescreened and enrolled within 6 months of completing Study 205MS301, 
Study 205MS203, or Study 205MS302.
14.4.2.
Pregnancy Testing

Pregnancy testing is only required for women of childbearing potential.  A urine 
pregnancy test is to be performed at the Baseline/Entry Visit and at other timepoints 
designated in Section 4.2 Schedule of Events.  Study treatment will be immediately
discontinued if the subject has a positive pregnancy test at any time during the study.

Results from all urine pregnancy tests must be reviewed by the study site prior to dosing 
and must be negative.
14.4.3.
Liver Function Test Assessments Prior to DAC HYP Dosing
Before a monthly dose of DAC HYP is given, LFT results from prior testing performed within 
the previous 32 days must be reviewed by the Study Neurologist or their backup, and must be 
within protocol-required limits as described in Section 11.7.2.
LFTs can be performed as follows:  


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
Samples for LFTs must be drawn prior to administration of the monthly DAC HYP 
dose.  These samples may be tested either locally inside or outside of the clinic 
(e.g., at a local laboratory or by visiting nurses) or at the central laboratory at the 
discretion of the Investigator and the results can then be used to determine whether 
dosing should continue or be suspended at the monthly dosing timepoint (see 
Section 11.1).

If local LFTs have been used to determine whether dosing should continue or be 
suspended at the time of a scheduled clinic visit, LFTs must also be performed at the 
central laboratory at the time of the scheduled clinic visit (Note:  Scheduled clinic 
visits occur every 4 weeks during the first 12 weeks of the study and every 12 weeks 
thereafter).

If the subject is administering DAC HYP injections at home, site personnel must 
contact the subject after review of prior LFT results performed within the previous 
32 days to authorize the monthly injection, or if LFT results warrant, to instruct the 
subject to withhold their injection.  

LFTs following a treatment suspension must be performed through the central 
laboratory until the LFT abnormality is <2×ULN. In cases where LFTs cannot be 
performed via central laboratory, repeat LFT results from local laboratory can be used 
for confirmation.
14.4.4.
Other Assessments

Vital signs include systolic and diastolic blood pressure, pulse, and body temperature, 
and should be measured pre-dose. The subject must rest quietly for 5 minutes prior to 
blood pressure and pulse measurements.  Weight will be collected at Baseline/Entry 
Visit and at the time of first autoinjector use at selected sites.

The MSIS-29 must be administered prior to the subject’s visit with the Study
Neurologist.  

Subject assessment of injection pain using a VAS should be completed as soon as 
possible after the injection is administered but no later than 10 to 30 minutes 
post-injection.

The first 4 DAC HYP injections (i.e., Weeks 0 through 12) must be given in the 
clinic.  The first of these injections must be given by study personnel.  At subsequent 
visits, subjects and/or caregivers will be instructed on DAC HYP self-administration 
and may administer their scheduled dose under staff supervision.  After the subject 
completes the required in-clinic injections (i.e., after Week 12), DAC HYP may be 
dispensed to subjects for at-home administration if the subject chooses.  If necessary, 
drug dispensation may occur at monthly intervals.  

Additional visits to assess elevated LFTs, cutaneous events, or PK/
 markers may 
be required as described in Section 11.7.


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14.5.
Definition of MS Relapse and Disability Progression
14.5.1.
MS Relapse
Relapses are defined as new or recurrent neurological symptoms not associated with fever or 
infection, lasting at least 24 hours, and accompanied by new objective neurological findings 
upon examination by the Study Neurologist* or their backup.  The subject must have objective 
signs on the examination confirming the event.  
*When possible subjects should be evaluated by the same neurologist assigned to them in the 
parent study.  
New or recurrent neurologic symptoms that evolve gradually over months should be considered 
disability progression, not an acute relapse.  New or recurrent neurological symptoms that occur 
less than 30 days following the onset of a protocol-defined relapse should be considered part of 
the same relapse.  Management of MS relapse is described in Section 14.6.
14.5.2.
Disability Progression
Disability progression can only be confirmed from the EDSS scores obtained according to the 
protocol-defined schedule of assessments at regular visits, and is defined as one of the following:

at least a 1.0-point increase on the EDSS from a baseline EDSS ≥1.0 that is sustained 
for 24 weeks, or 

at least a 1.5-point increase on the EDSS from a baseline EDSS <1.0 that is sustained 
for 24 weeks 
14.6.
Management of MS Relapse
Subjects who experience new or worsening neurological symptoms must contact the Nurse or 
Study Neurologist or their backup within 48 hours after the onset of symptoms.  A standardized 
Suspected Relapse Questionnaire will be completed to determine the necessity of an 
Unscheduled Relapse Assessment Visit.
If required, the subject will then be evaluated in person by the Study Neurologist not more than 
72 hours after the onset of the symptoms.  At the Unscheduled Relapse Assessment Visit, the 
Study Neurologist is to perform a relapse assessment and obtain an EDSS score.  New objective 
findings on neurological examination performed by the Study Neurologist* are required to 
determine if a suspected protocol-defined relapse has occurred. Treatment of an acute relapse 
event with intravenous methylprednisolone (IVMP) [or equivalent] may proceed at the discretion 
of the Study Neurologist after the examination and will not affect the subject’s eligibility to 
continue in the study.
*When possible subjects should be evaluated by the same neurologist assigned to them in the 
parent study.  
Subjects who prematurely discontinue study treatment should complete safety follow-up 
evaluations (see Section 4.2 and Section 13).  


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Subjects who permanently discontinue DAC HYP treatment should complete the visit schedule 
described in Section 11.8.  
14.7.
Cutaneous Events
Subjects who experience a mild or moderate cutaneous AE that is associated with more than 
1 systemic symptom or sign, a severe cutaneous AE (with or without systemic symptoms or 
signs), or a serious cutaneous AE (with or without systemic symptoms or signs) must be referred 
to and evaluated and managed by the Study Dermatologist as per Section 11.7.3.  An 
Unscheduled Dermatology Assessment Visit will be performed, at which time a photograph will 
be taken, whenever a subject experiences a mild or moderate cutaneous AE that is associated 
with more than 1 systemic symptom or sign, a severe cutaneous AE (with or without systemic 
symptoms or signs), or a serious cutaneous AE (with or without systemic symptoms or signs), 
per Table 6.  Subjects who develop a mild or moderate cutaneous AE that is not associated with 
more than 1 systemic symptom or sign do not need to be evaluated by the Study Dermatologist; 
the Study Neurologist can complete the Unscheduled Dermatology Assessment Visit as soon as 
possible.
If a generalized allergic or hypersensitivity reaction to study treatment is confirmed, study 
treatment must be permanently discontinued as per Section 11.8.  
14.8.
Unscheduled Hepatic Assessment Visit
The following tests/assessments will be performed as soon as possible (but within 1 week) after 
discontinuation of study treatment for subjects who are required to discontinue dosing due to 
elevated LFTs as described in Table 6 and Section 11.8.

Physical examination and vital signs 

Comprehensive hepatic panel

Recording of concomitant therapy

Monitor and record AE/SAEs

Protocol compliance and DAC HYP accountability

LFTs (ALT/SGPT, AST/SGOT, alkaline phosphatase, total bilirubin, and GGT only)
14.9.
Lymphadenopathy and Lymphadenitis Events
Subjects who experience a clinically significant event of lymphadenopathy or lymphadenitis 
should be referred to a specialist as per Section 11.7.5.
Interruption or discontinuation of DAC HYP treatment due to events of lymphadenopathy or 
lymphadenitis is a clinical decision that should take the overall benefit-risk assessment of 
therapy into consideration.  Subjects who discontinued study treatment for any reason while 
presenting with ongoing lymphadenopathy or lymphadenitis should be followed until the 
lymphadenopathy or lymphadenitis has stabilized or resolved or the study has terminated, 
whichever comes first.


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14.10.
Post-Treatment Safety Follow-Up Visit Schedule for All Subjects 
All subjects should complete the following schedule of safety follow-up visits after their last 
dose of DAC HYP:

End of Treatment Visit (i.e., the assessments required at Week 240).  For subjects 
who prematurely discontinue study treatment before Week 240, these assessments 
should be performed 4 weeks (±4 days) after the subject’s last dose of DAC HYP.   

Post-treatment safety follow-up visits at 8, 12, 16, 20, and 24 weeks after the 
subject’s last dose.  The details of these visits are shown in Table 5.
Note:  Subjects who complete Week 144 of DAC HYP treatment in Study 205MS303 and are in 
the safety follow-up period per the original protocol, will have the option to restart DAC HYP 
treatment from Week 156 Visit in Study 205MS303 (see Table 4) as long as they meet the 
eligibility criteria (Section 8). 


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15.
SAFETY DEFINITIONS, MONITORING, AND REPORTING
Throughout the course of the study, every effort must be made to remain alert to possible AEs.  
If an AE occurs, the first concern should be for the safety of the subject.  If necessary, 
appropriate medical intervention should be provided.
At the signing of the ICF, each subject must be given the names and telephone numbers of study 
site staff for reporting AEs and medical emergencies.
15.1.
Definitions
15.1.1.
Serious Pretreatment Event
A serious pretreatment event is any event that meets the criteria for SAE reporting (as defined in 
Section 15.1.3) and occurs after the subject signs the ICF, but before administration of study 
treatment.
15.1.2.
Adverse Event
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product.
15.1.3.
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, or

results in a congenital anomaly/birth defect.
An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or convulsions occurring at home that do not 
require an inpatient hospitalization.


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15.2.
Monitoring and Recording Events
15.2.1.
Serious Pretreatment Events
A serious pretreatment event experienced by the subject after signing and dating the ICF but 
before administration of study treatment is to be recorded on the SAE Form and faxed to the 
contract research organization (CRO) within 24 hours of the study site staff becoming aware of 
the event (see Section 15.2.5).
15.2.2.
Adverse Events
Any AE experienced by the subject between the time of signing the ICF and subject’s final visit 
is to be recorded on the CRF, regardless of the severity of the event or its relationship to study 
treatment.
15.2.3.
Serious Adverse Events
Any SAE experienced by the subject between the time of the first dose of study treatment and 
subject’s final 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 the CRO.
Any SAE ongoing when the subject completes the study or discontinues from the study will be 
followed by the Investigator until the event has resolved, stabilized, or returned to baseline 
status.
Subjects will be followed for all SAEs until the subject’s final visit.  Thereafter, the event should 
only be recorded if the Investigator considers it related to study treatment.
15.2.4.
All Events
All events must be assessed to determine the following:

If the event meets the criteria for an SAE as defined in Section 15.1.3.

The relationship of the event to study treatment as defined in Section 15.3.1.

The severity of the event as defined in Section 15.3.2.
15.2.5.
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 the CRO 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.






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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.
15.5.
Procedures for Handling Special Situations
15.5.1.
Overdose
An overdose is any dose of study treatment given to a subject or taken by a subject that exceeds 
the dose described in the protocol.  Overdoses are not considered AEs; however, all overdoses 
should be recorded on an Overdose Form and faxed to the CRO within 24 hours.  An overdose 
should be reported even if it does not result in an AE.  Overdoses do not need to be recorded in 
the CRF; dosing information is recorded on a CRF.
15.5.2.
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 CRO Medical Monitor at one of the following phone numbers:
North America (USA and Canada):  
Latin America: 
Europe and Asia Pacific: 
15.5.3.
Contraception Requirements
All women of childbearing potential must practice effective contraception during the study and 
be willing and able to continue contraception for 4 months after their last dose of study 
treatment.
For the purposes of this study, women of childbearing potential are defined as all women 
physiologically capable of becoming pregnant, UNLESS they meet one of the following 
conditions:

Postmenopausal:  12 months of natural (spontaneous) amenorrhea or 6 weeks after 
surgical bilateral oophorectomy with or without hysterectomy

Posthysterectomy
For the purposes of the study, effective contraception is defined as follows:
For females:

Using 1 or more of the following acceptable methods of contraception:  surgical 
sterilization (e.g., bilateral tubal ligation), intrauterine contraception/device, hormonal 
contraception, or any 2 barrier methods (a combination of male or female condom with 
spermicide; diaphragm, sponge, cervical cap)


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
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, post-ovulation 
methods) and withdrawal are not considered acceptable methods of contraception.
15.5.4.
Pregnancy
Subjects should not become pregnant during the study.  If a female subject becomes 
pregnant, study treatment must be discontinued immediately.
The Investigator must report the pregnancy by faxing the appropriate form to Pharmacovigilance 
at the CRO within 24 hours of the study site staff becoming aware of the pregnancy (refer to 
Section 15.2.5 for reporting information). The Investigator or study site staff must report the 
outcome of the pregnancy to Pharmacovigilance at the CRO.
Please note that congenital abnormalities/birth defects in the offspring of male or female subjects 
should be reported when conception occurred during the study treatment period.
15.5.5.
Regulatory Reporting
Suspected Unexpected Serious Adverse Reactions (SUSARs) are SAEs that are unexpected and 
judged by the Investigator or the Sponsor to be related to the study treatment administered.
Biogen Safety and Benefit-Risk Management (SABR) will report SUSARs to the appropriate 
regulatory authorities and Investigators as required, according to local law.
15.6.
Investigator Responsibilities
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 of the pregnancy.

Complete an SAE form for each serious event and fax it to the CRO 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 the CRO within 24 hours of the study site staff becoming aware 
of new information.

Complete an Adverse Event of Special Interest form for each transaminase elevation, 
hepatic event, and cutaneous event as described in the protocol and fax it to the CRO 
as soon as possible following the study site staff becoming aware of the event.

Ensure all AE and SAE reports are supported by documentation in the subjects’ 
medical records.


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
Report SAEs to local ethics committees, as required by local law.
15.7.
Biogen Responsibilities
Biogen’s responsibilities include the following:

Before study site activation and subject enrollment, the Clinical Monitor or designee
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.


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16.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
16.1.
Description of Objectives
See Section 6.1, Objectives.
16.2.
Description of Endpoints
See Section 6.2, Endpoints.
16.3.
Demography and Baseline Disease Characteristics
Demographic data collected at baseline will be summarized (i.e., age, gender, ethnicity, and 
weight).  Medical history and baseline characteristic data (e.g., EDSS, number of relapses in the 
previous study, MRI endpoints) will also be summarized.
16.4.
Safety and Efficacy
16.4.1.
Analysis Population
Study 205MS303 Safety Population
The safety population will include all subjects who received at least 1 dose of DAC HYP in 
Study 205MS303.  All safety analyses will be completed on the safety population.
Study 205MS303 Intent-to-Treat Population
The intent-to-treat (ITT) population will include all subjects who received at least 1 dose of DAC 
HYP in Study 205MS303.  This population will be utilized for the efficacy analyses.  
Study 205MS301 and Study205MS303 Intent-to-Treat population
This population will include all subjects randomized to DAC HYP or Avonex in 
Study 205MS301 and received at least one dose of DAC HYP in Study 205MS303.
16.4.2.
General Methods of Analysis
Summary statistics will be presented.  For continuous endpoints, summary statistics will 
generally include the number of subjects with data, mean, standard deviation, median, and range.  
Categorical endpoints will include the number of subjects with data and the percentage in each 
category.
Analyses will generally be descriptive in nature and will focus on data collected during 
Study 205MS303 only.  However, for relevant efficacy analyses, the data may be summarized by 
previous treatment group (Avonex or DAC HYP).  Also, statistical comparisons may be made 
between efficacy in Study 205MS301 and efficacy in Study 205MS303 among subjects 
previously randomized to Avonex in Study 205MS301.
All statistical tests will be 2-sided with an overall Type I error of 5%.  Adjustments for multiple 
comparisons will not be considered.


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16.4.3.
Primary Endpoints Analysis
Clinical Adverse Events
AEs will be coded using the Medical Dictionary for Regulatory Activities. All treatment-
emergent events will be included in the evaluation of safety.  Treatment emergent includes any 
event that either occurs or worsens in severity after the onset of study treatment.  Overall 
incidence of treatment-emergent events will be summarized; in addition, summaries by severity 
and by relationship to study treatment will be provided.  The summary tables will include 
incidence estimates for the overall system organ class as well as for preferred terms within each 
system organ class.  In order to assess whether the incidence of events changes over time, the 
incidence of key events may also be summarized by time period (e.g., 6-month time intervals).  
16.4.4.
Other Safety Endpoint Analyses
Unless otherwise specified, the baseline measurement for safety assessments such as laboratory 
values and vital signs was the measurement acquired on the day of the first receipt of DAC HYP.  
The first receipt of dosing of DAC HYP could be either Study 205MS303 (for subjects who 
received Avonex in Study 205MS301) or the parent studies (i.e., Study 205MS301, 
Study 205MS203, or Study 205MS302) for all other subjects.
Laboratory Data
Changes in laboratory values will be summarized using shift tables.  Shift tables will include 
hematology, LFTs, kidney function tests, electrolytes, and other blood chemistry tests.  Shifts 
will be presented from baseline of DAC HYP treatment (the last measurement acquired before or 
on the day of the first receipt of DAC HYP, e.g., Study 205MS303 baseline for subjects 
randomized to Avonex in Study 205MS301 and Study 205MS301 baseline for subjects 
randomized to DAC HYP 150 mg in Study 205MS301).  Summaries of worst post-baseline 
laboratory values by clinically relevant categories may also be presented for selected parameters 
of interest by treatment group.  For example, for LFT (alkaline phosphatase, ALT, AST, GGT,
and total bilirubin), categories may be defined based on cutoff values relative to the ULN.
Vital Signs
Vital signs collected will be examined to determine the incidence of clinically relevant 
abnormalities.  These abnormalities are described in Table 9.  For the purpose of the shifts from 
baseline, the baseline evaluation at the start of DAC HYP treatment will be used.
For each vital sign, the number of subjects evaluated and the number and percentage of subjects 
with the defined abnormality at any time post dosing will be presented by treatment group.  


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Table 9:  
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs
Vital Sign
Criteria for Abnormalities
Temperature 
>38°C or an increase from baseline of ≥1°C
Pulse
>120 beats per minute (bpm) or an increase from baseline of 
20 bpm
<50 bpm or a decrease from baseline of >20 bpm
Systolic Blood Pressure
>180 mmHg or an increase from baseline of >40 mmHg
<90 mmHg or a decrease from baseline of >30 mmHg
Diastolic Blood Pressure
>105 mmHg or an increase from baseline of >30 mmHg
<50 mmHg or a decrease from baseline of >20 mmHg
Physical Examination
The physical examination findings will be summarized.
16.4.5.
Efficacy Endpoints Analyses
Annualized Relapse Rate
Relapses will be summarized over the follow-up period in Study 205MS303.  For subjects in 
Study 205MS301 and Study 205MS303 ITT population, relapses may be summarized over the 
combined study period (Studies 205MS301 and 205MS303).  
A negative binomial regression model will be used to estimate the adjusted ARR.  
Proportion of Subjects with a Relapse
The proportion of subjects relapsed will be estimated using a Kaplan-Meier curve.  
Disability Progression  
Sustained disability progression is defined as at least a 1.0 point increase on the EDSS from 
baseline EDSS 1.0 that is sustained for 24 weeks, or at least a 1.5 point increase on the EDSS 
from baseline EDSS <1.0 that is sustained for 24 weeks.  The proportion of subjects with 
progression will be summarized using a Kaplan-Meier curve.  In addition, summary statistics for 
EDSS and for the change from baseline in EDSS will be presented by visit, and for subjects who 
participated in Study 205MS301, by previous treatment group.
MSFC
Changes in the MSFC z-score will be summarized by study visit, and for subjects who 
participated in Study 205MS301, by previous treatment group. For subjects in Study 205MS301 
and Study 205MS303 ITT population, MSFC z-score may be summarized over the combined 
study period (Studies 205MS301 and 205MS303).  Details on the calculations of the z-score for 
each component will be described in the statistical analysis plan.
SDMT
Changes in the SDMT scores will be summarized by study visit and by previous treatment group 
in Study 205MS301.  Change in the SDMT scores over the combined study period 
(Studies 205MS301 and 205MS303) will be calculated using the Study 205MS301 baseline visit 


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as baseline. Change in the SDMT score over the Study 205MS303 study period will be 
calculated using the last SDMT measurement in Study 205MS301 as baseline.
PASAT 3
Changes in the PASAT 3 scores will be summarized by study visit and by previous treatment 
group in Study 205MS301.  Change in the PASAT 3 scores over the combined study period 
(Studies 205MS301 and 205MS303) will be calculated using the Study 205MS301 baseline visit 
as baseline. Change in the PASAT 3 score over the Study 205MS303 study period will be 
calculated using the Week 0/baseline visit as baseline. 
MRI Endpoints
MRI endpoints will be summarized with descriptive statistics both as a continuous variable and 
categorically.  Over time summaries and summaries by previous treatment group (Avonex or 
DAC HYP 150 mg) may also be provided.  A negative binomial regression model will be used 
for the analysis of new or newly enlarging T2 lesions. The change in volume of lesions will be 
analyzed using an analysis of covariance.  
Quality of Life Outcomes
Actual scores and change from baseline in quality of life endpoints will be summarized by visit. 
Pharmacokinetics
The population for DAC HYP concentration analyses will include all subjects who received at 
least 1 dose of study medication and who have at least 1 sample available for analysis. 
Serum concentration levels will be summarized with descriptive statistics by visit.  
Antigenicity/Immunogenicity Data
Immunogenicity (i.e., ADAs to DAC HYP) will be assessed on subjects.  Positive samples will 
be further tested for NAbs to DAC HYP using a specific NAb assay.  Results will be tabulated 
by time period and overall.
16.5.
Interim Analyses
No formal interim analyses are planned for this study.  However, analyses may be performed 
prior to the end of the study at the discretion of the Sponsor. 
16.6.
Sample Size Considerations
There is no formal sample size calculation.  The number of subjects in this study is determined 
by the number of subjects who completed Study 205MS301, Study 205MS203, or
Study 205MS302.


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17.
ETHICAL REQUIREMENTS
Biogen and the Investigator must comply with all instructions, regulations, and agreements in 
this protocol and applicable International Council for Harmonisation (ICH) and Good Clinical 
Practice (GCP) guidelines and conduct the study according to local regulations.
17.1.
Declaration of Helsinki
The Investigator and Biogen must adhere to the principles set forth by the Declaration of 
Helsinki dated October 2008.
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. The Sponsor may submit documents on behalf of 
the study sites in countries other than the US as applicable. 
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 Principal Investigator(s) to ensure that all aspects of institutional 
review are conducted in accordance with current governmental 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 study site must submit a close-out letter to the 
ethics committee and Biogen.
17.3.
Subject Information and Consent
Prior to performing any study-related activities under this protocol, including Baseline/Entry 
Visit tests and assessments, written informed consent with the approved ICF must be obtained 
from the subject or subject’s legally authorized representative, as applicable, in accordance with 
local practice and regulations.  Written informed consent must be obtained from all subjects 
participating in a clinical study conducted by Biogen.
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.  The subject 
must be given sufficient time to consider whether to participate in the study.
A copy of the ICF, signed and dated by the subject, must be given to the subject.  Confirmation 
of a subject’s informed consent must also be documented in the subject’s medical record prior to 
any testing under this protocol, including Baseline/Entry Visit tests and assessments.


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Each consent form should contain an authorization allowing the Principal Investigator(s) and 
Biogen to use and disclose PHI (i.e., subject-identifiable health information) in compliance with 
local law.
The signed consent form will be retained with the study records.
17.4.
Subject Data Protection
Prior to any testing under this protocol, including Baseline/Entry Visit tests and assessments, 
candidates must also provide all authorizations required by local law (e.g., PHI authorization in 
North America).
The subject will not be identified by name in the CRF or in any study reports and these reports 
will be used for research purposes only. Biogen, its partner(s) and designee(s), ethics 
committees, and various government health agencies may inspect the records of this study.  
Every effort will be made to keep the subject’s personal medical data confidential.
17.5.
Compensation for Injury
Biogen maintains appropriate insurance coverage for clinical trials 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 the 
Sponsor) with the subject before the subject makes a decision to participate in the study.
17.7.
Registration of Study and Disclosure of Study Results
Biogen will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations.


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18.
ADMINISTRATIVE PROCEDURES
18.1.
Study Site Initiation
The Investigator must not enroll 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 on-site audits.  The Investigator will be expected to 
cooperate with any audit and to provide assistance and documentation (including source data) as 
requested.
18.3.
Monitoring of the Study
The Principal Investigator(s) must permit study-related monitoring by providing direct access to 
source data and to the subjects’ medical histories.
The Clinical Monitor(s) will visit the Investigator(s) at regular intervals during the course of 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.  
The 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 study site and its facilities.
18.4.
Study Funding
Biogen is the Sponsor of the study and is funding the study.  All financial details are provided in 
the separate contract(s) between the institution, Investigator, and Biogen.
18.5.
Publications
Details are included in the clinical trial agreement for this study.


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19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION
Biogen will be responsible for all administrative aspects of this study including, but not limited 
to, study initiation, monitoring, management of AEs, and data management.
19.1.
External Contract Organizations
19.1.1.
Contract Research Organization 
The CRO will be responsible for administrative aspects of the study including, but not limited to, 
study initiation, monitoring, and management of SAE reports. 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.
Electronic or Remote Data Capture
Subject information will be captured and managed by study sites on electronic CRFs via a 
remote data capturing system.
19.1.3.
Central Laboratories for Laboratory Assessments
A central laboratory has been selected by Biogen to analyze all hematology, blood chemistry, 
and urine samples collected for this study.
If local LFTs have been used to determine whether dosing should continue or be suspended at 
the time of a scheduled clinic visit, LFTs must also be performed at the central laboratory at the 
time of the scheduled clinic visit (Note:  Scheduled clinic visits occur every 4 weeks during the 
first 12 weeks of the study and every 12 weeks thereafter).     
19.1.4.
Central Facility for Independent Assessment of Biopsy Samples
A central laboratory service has been selected by Biogen to coordinate the collection and 
distribution of biopsy samples.  A central assessor has been selected to subsequently analyze skin 
biopsies or lymph node biopsies (as applicable).
19.1.5.
Central Facility for Other Assessments
MRI Reading Center
All scheduled MRI scans with and without Gd will be evaluated at a central MRI reading center.  
All study sites will be required to send a test scan 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 study site is permitted to enroll any subjects into the study.
Original MRI images are to be sent to the MRI Reading Center for review (MRI shipping 
instructions will be provided prior to the start of enrollment at each site).  
Additional and more detailed MRI scans with and without Gd procedures and instructions are 
included in the study MRI manual (to be provided under separate cover prior to start of the 
study).


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19.2.
Study Committees
19.2.1.
Advisory Committee
The Advisory Committee from parent Study 205MS301 will oversee the administrative progress 
and provide scientific and medical direction for this study while Study 205MS301 is ongoing. 
Advisory Committee will monitor subject accrual and compliance with the protocol at individual 
study sites.  The Advisory Committee will determine whether the study should be stopped or 
amended for reasons other than safety.
Members of the Advisory Committee will include the Medical Director, Clinical Trial Manager, 
and Project Statistician from Biogen (and/or their designees), and participating Investigators.  
Biogen will designate one of the participating Investigators to be the Chairperson of the 
Advisory Committee.
19.2.2.
Internal Safety Monitoring Committee
An internal Safety Monitoring Committee will be formed to review interim safety data on an 
ongoing basis. Investigational sites will be notified of any relevant safety findings that may 
jeopardize subject safety.
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 subject consent form may require similar 
modifications (see Section 17.2 and Section 17.3).
19.4.
Ethics Committee Notification of Study Completion or Termination
Where required, the Health Authorities and ethics committees must be notified of completion or 
termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines.
19.5.
Retention of Study Data
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local 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 


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must notify Biogen of any changes in the archival arrangements including, but not limited to, 
archival at an off-site 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.
Biogen will follow all applicable local regulations pertaining to study report signatories.


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20.
REFERENCES
Bielekova B, Howard T, Packer AN, et al. Effect of anti-CD25 antibody daclizumab in the 
inhibition of inflammation and stabilization of disease progression in multiple sclerosis. Arch 
Neurol. 2009;66(4):483-9.
Bielekova B, Richert N, Howard T, et al. Humanized anti-CD25 (daclizumab) inhibits disease 
activity in multiple sclerosis patients failing to respond to interferon beta. Proc Natl Acad Sci U 
S A. 2004;101(23):8705-8.
Fischer JS, LaRocca NG, Miller DM, et al. Recent developments in the assessment of quality of 
life in multiple sclerosis (MS). Mult Scler. 1999;5(4):251-9.
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status 
scale (EDSS). Neurology. 1983;33(11):1444-52. Epub 1983/11/01.
Rose JW. Treatment of Multiple Sclerosis with a Humanized Monoclonal Antibody Specific for 
IL-2 Receptor Chain. Neurology. 2003;60(Suppl 1):A478-9.
Rose JW, Watt HE, White AT, et al. Treatment of multiple sclerosis with an anti-interleukin-2 
receptor monoclonal antibody. Ann Neurol. 2004;56(6):864-7.
Wynn D, Kaufman M, Montalban X, et al. Daclizumab in active relapsing multiple sclerosis 
(CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with 
interferon beta. Lancet Neurol. 2010;9(4):381-90.


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21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “A Multicenter, Open-Label, Extension Study to Evaluate the 
Long-Term Safety and Efficacy of BIIB019, Daclizumab High Yield Process (DAC HYP),
Monotherapy in Subjects With Multiple Sclerosis Who Have Completed Study 205MS301” and 
agree to conduct the study according to the protocol and the applicable ICH guidelines and GCP 
regulations, and to inform all who assist me in the conduct of this study of their responsibilities 
and obligations.
____________________________________________________
Investigator’s Signature
Date
____________________________________________________
Investigator’s Name (Print)
____________________________________________________
Study Site (Print)


CONFIDENTIAL
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Biogen MA Inc.
1
Biogen MA Inc.
250 Binney Street
Cambridge, MA 02142
United States
PROTOCOL NUMBER:
205MS303
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead Berkshire
SL6 4AY
United Kingdom
PHASE OF DEVELOPMENT:
3
PROTOCOL TITLE:  A Multicenter, Open-Label, Extension Study to Evaluate the 
Long-Term Safety and Efficacy of BIIB019, Daclizumab High Yield Process (DAC HYP),
Monotherapy in Subjects With Multiple Sclerosis Who Have Completed Study 205MS301 
EUDRA CT NO:
2012-003176-39
DATE:
06 March 2017
Version 4
FINAL




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TABLE OF CONTENTS
SPONSOR SIGNATURE PAGE ....................................................................................................2
1.
SPONSOR INFORMATION .......................................................................................9
2.
LIST OF ABBREVIATIONS.....................................................................................10
3.
SYNOPSIS .................................................................................................................12
4.
STUDY SCHEMATIC AND SCHEDULE OF EVENTS TABLES FOR 
STUDY 205MS303 ....................................................................................................18
4.1.
Study Schematic .........................................................................................................18
4.2.
Schedule of Events .....................................................................................................20
5.
INTRODUCTION......................................................................................................35
5.1.
Profile of Previous Experience with Daclizumab in MS............................................35
5.2.
Study Rationale...........................................................................................................37
5.3.
Rationale for Dose and Schedule Selection................................................................37
6.
STUDY OBJECTIVES AND ENDPOINTS..............................................................39
6.1.
Objectives ...................................................................................................................39
6.1.1.
Primary Objective.......................................................................................................39
6.1.2.
Secondary Objectives .................................................................................................39
6.1.3.
Exploratory Objective.................................................................................................39
6.2.
Endpoints....................................................................................................................39
6.2.1.
Primary Endpoints ......................................................................................................39
6.2.2.
Secondary Endpoints ..................................................................................................39
7.
STUDY DESIGN .......................................................................................................41
7.1.
Study Overview ..........................................................................................................41
7.2.
Overall Study Duration and Follow-Up .....................................................................41
7.2.1.
Baseline/Entry Visit Assessments ..............................................................................41
7.2.2.
Treatment....................................................................................................................41
7.2.3.
Post-Treatment Long-Term Follow-Up......................................................................42
7.3.
Study Stopping Rules .................................................................................................42
7.4.
End of Study ...............................................................................................................42
8.
SELECTION OF SUBJECTS ....................................................................................43
8.1.
Inclusion Criteria ........................................................................................................43


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8.2.
Exclusion Criteria.......................................................................................................43
9.
ENROLLMENT AND REGISTRATION PROCEDURES ......................................45
9.1.
Enrollment and Screening...........................................................................................45
9.2.
Registration of Subjects..............................................................................................45
10.
STUDY TREATMENT MANAGEMENT................................................................46
10.1.
DAC HYP...................................................................................................................46
10.2.
DAC HYP Preparation ...............................................................................................46
10.3.
DAC HYP Accountability..........................................................................................47
11.
TREATMENT OF SUBJECTS..................................................................................48
11.1.
Study Treatment Schedule and Administration..........................................................48
11.2.
Placebo or Reference Product Agents ........................................................................48
11.3.
Treatment Precautions ................................................................................................48
11.4.
Treatment Compliance................................................................................................48
11.5.
Concomitant Therapy .................................................................................................49
11.6.
Continuation of Treatment..........................................................................................50
11.7.
Treatment Schedule Modifications.............................................................................51
11.7.1.
Infections ....................................................................................................................51
11.7.2.
Elevated Liver Function Tests....................................................................................51
11.7.3.
Cutaneous Events........................................................................................................53
11.7.4.
Gastrointestinal Events of Inflammatory Colitis ........................................................55
11.7.5.
Lymphadenopathy or Lymphadenitis Events .............................................................55
11.8.
Discontinuation of Study Treatment...........................................................................56
11.9.
Withdrawal of Subjects From Study...........................................................................58
12.
EFFICACY, DAC HYP CONCENTRATION, AND 
 ASSESSMENTS..............................................................59
12.1.
Clinical Efficacy Assessments....................................................................................59
12.2.
Pharmacokinetic Assessments....................................................................................60
12.3.
.................................................................................60
12.4.
..............................................................................................60
13.
SAFETY ASSESSMENTS ........................................................................................61
13.1.
Clinical Safety Assessments.......................................................................................61
13.2.
Laboratory Safety Assessments..................................................................................61


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13.3.
Study-Specific Safety Assessments............................................................................62
14.
SCHEDULE OF EVENTS.........................................................................................63
14.1.
Overview.....................................................................................................................63
14.2.
Site Personnel .............................................................................................................64
14.3.
Subject Management ..................................................................................................66
14.4.
Special Instructions for Tests and Assessments .........................................................66
14.4.1.
Rescreening.................................................................................................................66
14.4.2.
Pregnancy Testing ......................................................................................................66
14.4.3.
Liver Function Test Assessments Prior to DAC HYP Dosing...................................66
14.4.4.
Other Assessments......................................................................................................67
14.5.
Definition of MS Relapse and Disability Progression................................................68
14.5.1.
MS Relapse.................................................................................................................68
14.5.2.
Disability Progression.................................................................................................68
14.6.
Management of MS Relapse.......................................................................................68
14.7.
Cutaneous Events........................................................................................................69
14.8.
Unscheduled Hepatic Assessment Visit .....................................................................69
14.9.
Lymphadenopathy and Lymphadenitis Events...........................................................69
14.10.
Post-Treatment Safety Follow-Up Visit Schedule for All Subjects...........................70
15.
SAFETY DEFINITIONS, MONITORING, AND REPORTING .............................71
15.1.
Definitions ..................................................................................................................71
15.1.1.
Serious Pretreatment Event.........................................................................................71
15.1.2.
Adverse Event.............................................................................................................71
15.1.3.
Serious Adverse Event................................................................................................71
15.2.
Monitoring and Recording Events..............................................................................72
15.2.1.
Serious Pretreatment Events.......................................................................................72
15.2.2.
Adverse Events ...........................................................................................................72
15.2.3.
Serious Adverse Events..............................................................................................72
15.2.4.
All Events ...................................................................................................................72
15.2.5.
Immediate Reporting of Serious Adverse Events.......................................................72
15.2.5.1.
Deaths .........................................................................................................................73
15.3.
Safety Classifications..................................................................................................73


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15.3.1.
Relationship of Events to Study Treatment................................................................73
15.3.2.
Severity of Events.......................................................................................................74
15.3.3.
Expectedness of Events ..............................................................................................74
15.4.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments................74
15.5.
Procedures for Handling Special Situations ...............................................................75
15.5.1.
Overdose.....................................................................................................................75
15.5.2.
Medical Emergency....................................................................................................75
15.5.3.
Contraception Requirements ......................................................................................75
15.5.4.
Pregnancy ...................................................................................................................76
15.5.5.
Regulatory Reporting..................................................................................................76
15.6.
Investigator Responsibilities.......................................................................................76
15.7.
Biogen Responsibilities ..............................................................................................77
16.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........78
16.1.
Description of Objectives ...........................................................................................78
16.2.
Description of Endpoints............................................................................................78
16.3.
Demography and Baseline Disease Characteristics....................................................78
16.4.
Safety and Efficacy.....................................................................................................78
16.4.1.
Analysis Population....................................................................................................78
16.4.2.
General Methods of Analysis .....................................................................................78
16.4.3.
Primary Endpoints Analysis .......................................................................................79
16.4.4.
Other Safety Endpoint Analyses.................................................................................79
16.4.5.
Efficacy Endpoints Analyses......................................................................................80
16.5.
Interim Analyses.........................................................................................................81
16.6.
Sample Size Considerations .......................................................................................81
17.
ETHICAL REQUIREMENTS ...................................................................................82
17.1.
Declaration of Helsinki...............................................................................................82
17.2.
Ethics Committee........................................................................................................82
17.3.
Subject Information and Consent ...............................................................................82
17.4.
Subject Data Protection ..............................................................................................83
17.5.
Compensation for Injury.............................................................................................83
17.6.
Conflict of Interest......................................................................................................83


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17.7.
Registration of Study and Disclosure of Study Results..............................................83
18.
ADMINISTRATIVE PROCEDURES.......................................................................84
18.1.
Study Site Initiation....................................................................................................84
18.2.
Quality Assurance.......................................................................................................84
18.3.
Monitoring of the Study..............................................................................................84
18.4.
Study Funding.............................................................................................................84
18.5.
Publications.................................................................................................................84
19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION........................85
19.1.
External Contract Organizations.................................................................................85
19.1.1.
Contract Research Organization.................................................................................85
19.1.2.
Electronic or Remote Data Capture............................................................................85
19.1.3.
Central Laboratories for Laboratory Assessments .....................................................85
19.1.4.
Central Facility for Independent Assessment of Biopsy Samples..............................85
19.1.5.
Central Facility for Other Assessments ......................................................................85
19.2.
Study Committees.......................................................................................................86
19.2.1.
Advisory Committee...................................................................................................86
19.2.2.
Internal Safety Monitoring Committee.......................................................................86
19.3.
Changes to Final Study Protocol ................................................................................86
19.4.
Ethics Committee Notification of Study Completion or Termination........................86
19.5.
Retention of Study Data..............................................................................................86
19.6.
Study Report Signatory...............................................................................................87
20.
REFERENCES ...........................................................................................................88
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL.........................................89
LIST OF TABLES
Table 1:
Schedule of Activities:  Baseline Through Week 84 for Subjects Enrolling 
From Study 205MS301 Into Study 205MS303..........................................................20
Table 2:
Schedule of Activities:  Week 96 through Week 144 for Subjects Enrolling 
From Study 205MS301 Into Study 205MS303..........................................................23
Table 3:
Schedule of Activities:  Entry Visit (Week 144) for Subjects Enrolling From 
Study 205MS203 or Study 205MS302 Into Study 205MS303 ..................................25


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Table 4:
Schedule of Activities:  Week 156 through Week 240 (End of Treatment) for 
Subjects Enrolling From Study 205MS301, Study 205MS203, or 
Study 205MS302 Into Study 205MS303....................................................................27
Table 5:
Schedule of Activities:  Post-Treatment Safety Follow-Up .......................................30
Table 6:
Schedule of Activities:  Unscheduled Assessments ...................................................31
Table 7:
Schedule of Activities:  Autoinjector Use by Subjects at Selected Sites ...................33
Table 8:  
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs ...................80
LIST OF FIGURES
Figure 1:
Study Design...............................................................................................................19
Figure 2:
Flowchart for Management of Subjects With Cutaneous AEs...................................54


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


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2.
LIST OF ABBREVIATIONS
ADAs
anti-drug antibodies
AE
adverse event
ALT
alanine aminotransferase
ARR
annualized relapse rate 
AST
aspartate aminotransferase
AUDIT-C
Alcohol Use Disorders Identification Test - Consumption 
Questionnaire
BDI-II
Beck Depression Inventory, Second Edition
bpm
beats per minute
BUN
blood urea nitrogen
CRF
case report form
CRO
contract research organization
DAC HYP
Daclizumab High Yield Process
DHA
Directions for Handling and Administration
EDSS
Expanded Disability Status Scale
EQ-5D
European Quality of Life, 5-dimensions
EQ-VAS
European Quality of Life, visual analog scale
FDA
Food and Drug Administration
GCP
Good Clinical Practice
Gd
gadolinium
GGT
gamma-glutamyltransferase
HIV
human immunodeficiency virus
HRPQ
Health Related Productivity Questionnaire
HRU
health resource utilization
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IFN
interferon
IL-2
interleukin-2
IM
intramuscular 
ITT
intent-to-treat
IV
intravenous
IVIg
intravenous immunoglobulin
IVMP
intravenous methylprednisolone
LFT
liver function test
MRI
magnetic resonance imaging
MS
multiple sclerosis
MSFC
Multiple Sclerosis Functional Composite
MSIS-29
Multiple Sclerosis Impact Scale-29
NAbs
neutralizing antibodies
NK
natural killer cells


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PASAT 3
3-Second Paced Auditory Serial Addition Test
PFS
prefilled syringe
PHI
protected health information
PK
pharmacokinetic(s)
RRMS
relapsing-remitting multiple sclerosis
SABR
Safety and Benefit-Risk Management
SAE
serious adverse event
SC
subcutaneous
SDMT
Symbol Digit Modalities Test
SGOT
serum glutamic oxaloacetic transaminase; see AST
SGPT
serum glutamic pyruvic transaminase; see ALT
SNP
single nucleotide polymorphism
SUSAR
suspected unexpected serious adverse reaction
T1
MRI hypointense designation
T2
MRI hyperintense designation
T4
thyroxine
ULN
upper limit of normal
US
United States
VAS
visual analog scale


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3.
SYNOPSIS
This is a brief summary.  For details refer to the body of the protocol.
Protocol Number:
205MS303
Protocol Title:
A Multicenter, Open-Label, Extension Study to Evaluate the 
Long-Term Safety and Efficacy of BIIB019, Daclizumab High
Yield Process (DAC HYP), Monotherapy in Subjects With 
Multiple Sclerosis Who Have Completed Study 205MS301
Version Number:
4
Name of Study Treatment:
Daclizumab High Yield Process (DAC HYP)
Study Indication:
Relapsing-Remitting Multiple Sclerosis (RRMS)
Phase of Development:
3
Rationale for the Study:
To evaluate the long-term safety, efficacy, and 
immunogenicity of DAC HYP in subjects with multiple 
sclerosis (MS) who have completed Study 205MS301
(DECIDE), Study 205MS203 (SELECTED), or 
Study 205MS302 (OBSERVE).
Study Objectives and 
Endpoints:
Objectives
Primary: 
The primary objective of the study is to assess the safety and 
tolerability of long-term treatment with DAC HYP 
monotherapy in subjects who completed Study 205MS301, 
Study 205MS203, or Study 205MS302.
Secondary:
Secondary objectives of this study in this study population 
are as follows:

To describe MS-related outcomes, including MS 
relapse, disability progression, MS lesion 
formation, and patient-reported impact of MS, 
following long-term treatment with DAC HYP

To assess the long-term immunogenicity of 
DAC HYP administered by prefilled syringe 
(PFS)




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
Change in Multiple Sclerosis Impact Scale-29 
(MSIS-29) physical and psychological scores 

Change in quality of life as assessed by the 
European Quality of Life, 5 dimensions (EQ-5D)
and European Quality of Life, visual analog scale
(EQ-VAS)  

Change in direct health resource utilization 
(HRU; hospitalizations, emergency room visits, 
and unscheduled neurologist visits)

Change in treatment satisfaction as assessed by 
the subject 

Change in subject productivity as assessed by the 
Health Related Productivity Questionnaire 
(HRPQ)

Changes in clinical laboratory assessments 
(hematology and blood chemistry)

Local tolerability as assessed by subject-reported 
injection site pain (visual analog scale [VAS])
and clinician injection site assessments

Incidence of anti-drug antibodies to DAC HYP 
over time

Incidence of neutralizing antibodies to DAC HYP 
over time
Study Design:
Multicenter, open-label, long-term extension study
Rationale for Dose and 
Schedule Selection:
The DAC HYP dose and schedule were used in the pivotal 
Phase 3 205MS301 study and will be the treatment regimen 
used in the commercial setting.  The same DAC HYP dose 
and schedule were used in Study 205MS203 and 
Study 205MS302.
Study Location:
Global
Number of Planned Subjects:
Approximately 1600 subjects.  This includes approximately 
1200 subjects who completed Study 205MS301. 
Additionally, approximately 400 subjects from the other 
ongoing DAC HYP extension studies (Study 205MS203 and 
Study 203MS302) will be eligible to enter Study 205MS303 
at Week 144 of Study 205MS303. 




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thyroid function panel [including thyroid-stimulating 
hormone and T4], urinalysis); urine pregnancy testing; Beck 
Depression Inventory, Second Edition; immunogenicity 
assessments; Alcohol Use Disorders Identification Test -
Consumption Questionnaire (AUDIT-C); and AE and 
concomitant medication monitoring will be performed in this 
study.  Additional comprehensive hepatic testing will be 
required for subjects who permanently discontinue study 
treatment due to elevated liver function tests.
Subject Reported 
Assessments:
Subject assessment of MSIS-29, EQ-5D quality of life 
questionnaire (the EQ-5D descriptive system and the 
respondent’s self-rated health on a vertical visual analog 
scale [EQ-VAS]), Treatment Satisfaction Questionnaire for 
Medication (before the first use of a PFS and at multiple 
timepoints during the study), Treatment Satisfaction Survey 
at selected sites (before the first and last use of an 
autoinjector), HRU, and HRPQ.
Statistical Methods:
Analyses will generally be descriptive in nature and will 
focus on data collected during Study 205MS303 only.  
Efficacy endpoints will be summarized for all subjects using 
descriptive statistics.  For relevant efficacy analyses, the data 
may be summarized for subjects by previous treatment group 
(Avonex® or DAC HYP 150 mg). The adjusted ARR and 
number of new or newly enlarging T2 lesions will be 
estimated using a negative binomial regression model.  The 
proportion of subjects with sustained progression and the 
proportion with a relapse will be estimated from the Kaplan-
Meier curve.  The incidence of AEs and changes in clinical 
laboratory assessments will also be summarized.   An 
analysis by 3- or 6-month intervals may also be performed.  
Summary statistics for other safety, efficacy, and 
pharmacokinetic (PK) endpoints will be presented.
Sample Size Determination: 
There is no formal sample size calculation for this study.  
The number of subjects in this study is determined by the 
number of subjects who completed Study 205MS301, 
Study 205MS203, or Study 205MS302, and enrolled in 
Study 205MS303.


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Study Stopping Rules:
Biogen may terminate this study, after informing 
Investigators, at any time.  Investigators will be notified by 
Biogen or designee if the study is placed on hold, completed, 
or closed.


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4.
STUDY SCHEMATIC AND SCHEDULE OF EVENTS TABLES 
FOR STUDY 205MS303
A schematic of the study design is provided in Section 4.1.
The tabulated schedule of events for this study is provided in Section 4.2.
4.1.
Study Schematic
Figure 1 shows the design of Study 205MS301 and its open-label extension, Study 205MS303, 
in which subjects from Study 205MS203 and 205MS302 enter at Week 144.


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Figure 1:
Study Design














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Concomitant Therapy and AEs
X
Protocol Compliance and DAC HYP 
Accountability
X
1When possible, subjects should be evaluated by the same Study Neurologist assigned to them in the parent studies. 
2Week 144 (start of Year 4) of Study 205MS303 will be the timepoint at which subjects from Study 205MS203 and Study 205MS302 enter Study 205MS303. 
Entry Visit must take place within 6 months of the last DAC HYP dose in the parent studies (i.e., Study 205MS203 or Study 205MS302). 
3ALT/SGPT, AST/SGOT, alkaline phosphatase, total bilirubin, and GGT only.
5Pregnancy test results must be negative prior to dosing.
6Before a monthly dose of DAC HYP is given at the clinic, LFT results from a prior test performed within the previous 32 days must be reviewed by the Study 
Neurologist or their backup.  
Note:  MRI assessment will not be done at the Week 144/Entry Visit for Study 205MS303.






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1 For subjects who prematurely discontinue dosing, the End of Treatment (Early Termination) Visit should be performed 28 ± 4 days following the subject’s last 
dose of study treatment.
2 ALT/SGPT, AST/SGOT, alkaline phosphatase, total bilirubin, and GGT only.
3 If local LFTs have been used to determine whether dosing should continue or be suspended at the time of a scheduled clinic visit, LFTs must also be performed 
at the central laboratory at the time of the scheduled clinic visit (Note:  Scheduled clinic visits occur every 12 weeks.).
 
5 Pregnancy test results must be negative prior to dosing.
6 MRI scan can be performed up to 4 days prior to the visit.
7 MRI assessment is not necessary for the Early Termination visit.
8 When possible, subjects should be evaluated by the same neurologist assigned to them in the parent studies. 
9 Performed only for subjects originally enrolled from Study 205MS301.
10Before a monthly dose of DAC HYP is given, LFT results from a prior test performed within the previous 32 days must be reviewed by the Study Neurologist
or their backup.
11A window of ±4 days applies to DAC HYP dose even if it is done at home.






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9Performed by the Study Neurologist or their back-up within 72 hours of a suspected relapse.  
10 Refer to Section 11.7.3 for information on when to perform these assessments.




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2Subjects must provide written informed consent for autoinjector use prior to first DAC HYP dose by autoinjector.
3The procedure for taking this measurement is provided in the Study Reference Manual.
4Injection Site Assessment to be completed as soon as possible but within 10 minutes after the injection at Visit 1.
5VAS to be completed as soon as possible after the injection is administered, but no later than 10-30 minutes post-injection.
6If the subject withdraws from the study or reverts to PFS use prior to receiving all 6 autoinjector doses, the subject should complete the Treatment Satisfaction 
Survey and the Patient Usability Survey provided for the Autoinjector 6 dosing day before returning to PFS or receiving alternative MS disease modifying 
therapy.


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5.
INTRODUCTION
5.1.
Profile of Previous Experience with Daclizumab in MS
Background
DAC HYP is a humanized monoclonal IgG1 antibody specific for CD25 (α subunit of the 
IL-2 receptor).  CD25 is expressed at low levels on resting T cells but is rapidly upregulated after 
T-cell activation, enabling high-affinity IL-2 signal transduction.  The primary hypothesis for 
using DAC HYP to treat MS is to selectively inhibit activated T cells.  
Anti-CD25 antibodies have multiple in vitro effects that suggest DAC HYP may directly 
decrease T-cell activation and proliferation.  These include inhibition of IL-2 dependent 
lymphocyte proliferation, disruption of both IL-2 dependent and independent pathways of 
IFN-gamma production, and interference in CD28-dependent CD40 ligand expression.  In vivo, 
daclizumab has been confirmed to cause expansion of CD56bright NK cells.  This expansion has 
also been shown to correlate with MRI-defined therapeutic response of daclizumab in MS.  
CD56bright NK cells are believed to have an immunoregulatory function, and they have been 
shown to kill activated T cells through a contact-dependent mechanism.  Therefore, selective 
inhibition of activated T cells with DAC HYP may occur through both direct and indirect 
mechanisms [Bielekova 2009; Bielekova 2004].  
Clinical Experience With Daclizumab in Multiple Sclerosis
Initial clinical studies of daclizumab in MS were conducted with material manufactured by 
F. Hoffmann-La Roche, Ltd. (Roche) at their facilities in Nutley, New Jersey (DAC Nutley)
[Bielekova 2004; Rose 2003; Rose 2004], and in Penzberg, Germany (DAC Penzberg) [Wynn 
2010].  Study 205MS301 is conducted with DAC HYP, which is produced using a different 
manufacturing process than the previous versions of daclizumab.  DAC HYP has characteristics 
that are similar to DAC Nutley and DAC Penzberg, although certain differences in 
physicochemical and biological characteristics have been observed (refer to the Investigator’s 
Brochure for details).  
Study 205MS201
Study 205MS201 (SELECT) was a double-blind, placebo-controlled study to evaluate the safety 
and efficacy of DAC HYP in subjects with RRMS that randomized 621 subjects in a 1:1:1 ratio 
to receive placebo, 150 mg DAC HYP, or 300 mg DAC HYP SC every 4 weeks over a 52-week 
treatment period.  Among subjects randomized to DAC HYP (150 mg, 300 mg) versus placebo, 
there was a significantly lower annualized relapse rate (ARR; 0.21, 0.23 versus 0.46; p < 0.001), 
a higher proportion of relapse-free subjects (81%, 80% versus 64%; p < 0.001), and a trend 
towards improvement in the MSIS-29 physical score (p = 0.128 for DAC HYP 300 mg versus 
placebo; p < 0.001 for DAC HYP 150 mg versus placebo).  There were significant reductions in 
the mean number of new or newly enlarging T2 lesions at 1 year (2.4, 1.7 versus 8.1) and in the 
mean number of new Gd+ lesions between Weeks 8 and 24 in a monthly MRI substudy 
(n = 307) (1.5, 1.0 versus 4.8) in the DAC HYP 150 mg and 300 mg groups versus placebo 


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(p < 0.001 for all comparisons).  The risk of 3-month sustained disability progression at 1 year, a 
tertiary study endpoint, was reduced by 57% (p = 0.021) in the DAC HYP 150 mg group and by 
43% (p = 0.091) in the DAC HYP 300 mg group.  
Analysis of safety data from Study 205MS201 showed that, overall, DAC HYP was well 
tolerated in this patient population.  The most frequently reported (≥10%) adverse events (AEs)
for subjects treated with DAC HYP, excluding MS relapse, were nasopharyngitis (14%), and 
headache and upper respiratory tract infection (10% each).  In Study 205MS201, serious adverse 
events (SAEs) including MS relapses occurred in 26% of placebo-treated subjects and in 16% of 
subjects treated with DAC HYP.  Excluding MS relapses, SAEs occurred in 6% of the placebo 
group, in 7% of the DAC HYP 150 mg group, and in 9% of the DAC HYP 300 mg group.  
One DAC HYP-treated subject died due to ischemic colitis following a complicated course of 
events.  Adverse events observed more frequently in DAC HYP-treated patients included an 
increase in serious infections (2%), serious cutaneous events (1%), and elevations in LFTs 
(ALT/AST) >5ULN (4%).
Upon completion of the 12-month treatment period in Study 205MS201, subjects were eligible to 
complete up to an additional 12 months of treatment with DAC HYP in a double-blind extension 
study (Study 205MS202 [SELECTION]), which was completed in 2012.  Study 205MS202 also 
assessed the effects of DAC HYP washout in some subjects who were actively treated in 
Study 205MS201.  Subjects completing Study 205MS202 continued long-term therapy with 
open-label DAC HYP in extension Study 205MS203 (SELECTED), which evaluated long-term 
safety and efficacy of DAC HYP monotherapy for up to an additional 144 weeks.
Study 205MS301
Study 205MS301 (DECIDE), a double-blind, randomized, parallel-group, active-controlled study 
testing the superiority of DAC HYP monotherapy compared to Avonex® (IFN -1a) in 
preventing MS relapse, was initiated in May 2010; 1841 subjects with RRMS have been enrolled 
and randomized in a 1:1 ratio to receive 150 mg DAC HYP given SC every 4 weeks, or Avonex 
30 mcg given IM once weekly over a 96- to 144-week treatment period. The primary endpoint 
was the annualized relapse rate.  In this study, DAC HYP demonstrated statistically and 
clinically meaningful superiority to IFN β-1a, on validated clinical, radiographic, and patient-
reported MS outcome measures.  DAC HYP reduced the annualized relapse rate by 45% 
(p<0.0001) compared to IFN β-1a.  DAC HYP’s treatment effect on relapses was also evidenced 
by a 41% reduction in the risk of relapse in subjects in the DAC HYP group compared to the 
IFN β-1a group (p<0.0001).  A reduction in the proportion of subjects relapsing was observed as 
early as 24 weeks after the initiation of treatment and persisted throughout the end of the study.  
The risk of 12-week confirmed disability progression was reduced by 16% in the DAC HYP 
group compared with the IFN β-1a group, a result that was not statistically significant 
(p=0.1575) in the primary analysis.  In the pre-specified analysis of 24-week confirmed 
progression, disability progression was reduced by 27% (p=0.0332) in the DAC HYP group 
compared with the IFN β-1a group.  Overall, the results of the 12-week and 24-week confirmed 
progression analyses were consistent with each other and supported a clinically meaningful 
effect of DAC HYP in preventing confirmed disability progression compared with IFN β-1a.  
DAC HYP reduced the number of new or newly enlarging T2 lesions at Week 96 by 54.4% 
(p<0.0001) compared to IFN β-1a.  The magnitude of the treatment effect was consistent with 


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the results seen on the primary endpoint of annualized relapse rate.  The tertiary MRI endpoints 
of T2, T1, and Gd-enhancing lesion count and volume were also consistent with the effect on 
new or enlarging T2 lesions and provide important confirmation of DAC HYP’s ability to reduce 
focal and destructive areas of brain inflammation in RRMS patients.  The treatment effect of 
DAC HYP on new or enlarging T2 lesions and other MRI endpoints was detectable by Week 24 
(p<0.0001) and was sustained through to the Week 96 and Week 144 MRI at a similar 
magnitude.  
In Study 205MS301, the safety profile of DAC HYP was characterized by an increased 
incidence of elevations of serum transaminases and serious hepatic events, cutaneous events,
infections, and gastrointestinal events.  The overall incidence of AEs was balanced across the 
2 treatment groups (91% IFN β-1a vs. 91% DAC HYP).  The majority of subjects with AEs had 
events that were mild to moderate in severity.  The incidence of subjects with AEs that were 
considered severe was 14% in the DAC HYP group and 12% in the IFN β-1a group.  AEs 
reported more frequently in the DAC HYP group than in the IFN β-1a group included 
nasopharyngitis, upper respiratory tract infections, influenza, oropharyngeal pain, rash, and 
lymphadenopathy, whereas influenza-like illness, pyrexia, chills, and hypertension were reported 
more frequently in the IFN β-1a group.
There was a higher incidence of SAEs in the DAC HYP group (24%) compared with the 
IFN β-1a group (21%).  Excluding MS relapse, SAEs were reported in 10% of the IFN β-1a 
group and in 15% of the DAC HYP group.  Five deaths were reported in the study (4 subjects in 
the IFN β-1a group, 1 subject in the DAC HYP group).  None of the deaths were considered by 
the Investigators to be related to study treatment.  While safety events were more common in the 
DAC HYP-treated subjects compared with IFN β-1a-treated subjects, the types of events were 
generally manageable with standard medical care, monitoring, and treatment discontinuation, as 
appropriate for the event.  Overall, the results of the study support a positive benefit/risk profile 
for DAC HYP.
The PK and immunogenicity of DAC HYP 150 mg SC administered every 4 weeks using a 
prefilled syringe (PFS) were investigated in 26 subjects in Study 205MS302 (OBSERVE), a
single-arm, open-label study that enrolled a total of 113 subjects with RRMS.
Refer to the Investigator’s Brochure for additional details.
5.2.
Study Rationale
This study will evaluate the long-term safety, efficacy, and immunogenicity of DAC HYP in 
subjects with MS who have completed Study 205MS301, Study 205MS203, or 
Study 205MS302. In addition, this study will assess the safety, tolerability, and efficacy of 
switching to DAC HYP in subjects previously on long-term treatment with interferon β-1a in 
Study 205MS301.
5.3.
Rationale for Dose and Schedule Selection
The existing scientific and clinical experience with DAC HYP supports its further investigation 
in the management of MS.  The DAC HYP dose and schedule in this protocol were used in the 
pivotal Phase 3 Study 205MS301 and will be the treatment regimen used in the commercial 


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setting.  The same DAC HYP dose and schedule were used in Study 205MS203 and 
Study 205MS302.
A single-use, disposable PFS will be provided to simplify the injection process and thereby 
reduce the burden of administering a long-term therapy such as DAC HYP in the clinic or at 
home. At the Sponsor’s discretion, single-use autoinjectors containing PFS may be used to 
administer DAC HYP in 75-100 subjects from Study 205MS303 at selected sites. Autoinjectors 
will be dispensed to each participating subject for use on up to 6 consecutive scheduled dosing 
days.




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
Change in EDSS score

Change in Symbol Digit Modalities Test (SDMT) score

Change in 3-Second Paced Auditory Serial Addition Test (PASAT 3) score

Proportion of subjects who are free from disease activity.

Change in Multiple Sclerosis Impact Scale-29 (MSIS-29) physical and psychological 
scores 

Change in quality of life as assessed by the European Quality of Life, 5 dimensions 
(EQ-5D and EQ-VAS)  

Change in direct health resource utilization (HRU; hospitalizations, emergency room 
visits, and unscheduled neurologist visits) 

Change in treatment satisfaction as assessed by the subject

Change in subject productivity as assessed by the Health Related Productivity 
Questionnaire (HRPQ)

Changes in clinical laboratory assessments (hematology and blood chemistry)

Local tolerability as assessed by subject-reported injection site pain (VAS) and 
clinician injection site assessments

Incidence of anti-drug antibodies (ADAs) to DAC HYP over time

Incidence of neutralizing antibodies (NAbs) to DAC HYP over time


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7.
STUDY DESIGN
7.1.
Study Overview
The design of Study 205MS303 is provided in Figure 1.  Approximately 1600 subjects will 
enroll in this study.  This includes approximately 1200 subjects who completed Study 
205MS301.  Additionally, approximately 400 subjects from the other DAC HYP extension 
studies (205MS203 [SELECTED] and 203MS302 [OBSERVE]) will be eligible to enter 
Study 205MS303 at Week 144 of Study 205MS303 (Study 205MS301, Study 205MS203, and 
Study 205MS302 have been referred to as parent studies in the protocol).
All subjects will receive the same dose of DAC HYP as received in the parent studies; 
i.e., 150 mg by an SC injection every 4 weeks.  The duration of DAC HYP treatment is up to 
approximately 5 years, or until availability of commercial product (whichever is sooner).
7.2.
Overall Study Duration and Follow-Up
The study period will consist of Baseline/Entry Visit assessments, treatment (for up to 
approximately 5 years), and post-treatment safety follow-up visits (from approximately 4 to 
24 weeks after the last dose of DAC HYP).
7.2.1.
Baseline/Entry Visit Assessments
Subjects Entering From Study 205MS301
Tests/assessments performed at the subject’s last visit in Study 205MS301 and within 28 days of 
the subject’s first dose of DAC HYP (Week 0) in Study 205MS303 may be used as the baseline 
for Study 205MS303; if final Study 205MS301 tests/assessments are not performed within the 
28-day window, they must be repeated upon entry into Study 205MS303 and before the first 
dose of DAC HYP is administered. 
Subjects Entering From Study 205MS203 or Study 205MS302
The Week 144 Visit of Study 205MS303 will be the Entry Visit for subjects enrolled from 
Study 205MS203 or Study 205MS302.  Any test/assessment done at the subject’s last visit in 
parent studies and within 28 days of the subject’s first dose in Study 205MS303 will be used as 
the baseline and does not need to be repeated at entry into Study 205MS303; tests/assessments 
performed >28 days before the Entry Visit must be repeated at the Entry Visit.  Central LFT 
testing is mandatory at the Entry Visit.
7.2.2.
Treatment
Subjects from Study 205MS301 continuing in Study 205MS303 will receive DAC HYP 
treatment for up to approximately 5 years, or until availability of commercial product (whichever 
is sooner), under this protocol.  Subjects from Study 205MS203 and Study 205MS302 entering 
Study 205MS303 at Week 144 will have DAC HYP treatment for up to approximately 2 years, 
or until availability of commercial product (whichever is sooner), under this protocol.


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At the Sponsor’s discretion, 75-100 subjects from Study 205MS303 at selected sites may dose 
with DAC HYP using a single-use autoinjector that contains a PFS on 6 consecutive scheduled 
dosing days (Table 7).
Eligible subjects will have clinic visits scheduled every 4 weeks for up to Week 12 in this study, 
followed by clinic visits scheduled every 12 weeks. 
Subjects who are dosing at home must be instructed to not administer their monthly dose 
of DAC HYP until the study site has contacted them to authorize dosing (after the Study
Neurologist or their backup has reviewed LFT results obtained during the previous 32 days).  
Subjects need to record the date and time of dosing in their diary if they are dosing at home.
A window of ±4 days applies to scheduled visits and home dosing.
7.2.3.
Post-Treatment Long-Term Follow-Up
Subjects are to return to the study site for follow-up visits at 8, 12, 16, and 24 weeks (±10 days) 
after the last dose of DAC HYP.
7.3.
Study Stopping Rules
Biogen may terminate this study, after informing Investigators, at any time.  Investigators will be 
notified by Biogen or designee if the study is placed on hold, completed, or closed.
7.4.
End of Study
The End of Study is last subject, last visit for final collection of data.


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8.
SELECTION OF SUBJECTS
8.1.
Inclusion Criteria
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at the 205MS303 Baseline/Entry Visit or at the timepoint specified in the individual eligibility 
criterion listed (Note:  Week 0/Day 1 is the Baseline Visit in Study 205MS303 for 205MS301 
subjects.  Week 144 is the Entry Visit in Study 205MS303 for 205MS203 and 205MS302 
subjects): 
1. Ability to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use protected health information (PHI) in 
accordance with national and local subject privacy regulations.  
2. Must be a subject currently participating in Study 205MS301 who has completed either 
the Week 144 Visit or the End of Study Visit (Week 96) of Study 205MS301 OR subject 
currently participating in Study 205MS203 or Study 205MS302.
3. Women of childbearing potential must practice effective contraception during the study 
and be willing and able to continue contraception for 4 months after their last dose of 
study treatment.
8.2.
Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
the Study 205MS303 Baseline/Entry Visit or at the timepoint specified in the individual criterion 
listed (Note:  Week 0/Day 1 is the Baseline Visit in Study 205MS303 for 205MS301 subjects. 
Week 144 is the Entry Visit in Study 205MS303 for 205MS203 and 205MS302 subjects):
Medical History
1. Any subject who permanently discontinued study treatment in Study 205MS301, 
Study 205MS203, or Study 205MS302 prior to the end of the study treatment period, or 
had an early termination in those studies OR any subject who has completed all the safety 
follow-up visits after Week 144 of Study 205MS303 per the original protocol. 
Note: Subjects for whom dosing was temporarily suspended in Study 205MS301, 
Study 205MS203, or Study 205MS302 are not excluded from participation in this 
extension study if the criteria for resuming DAC HYP treatment under the parent study
protocol have been met at the time of enrollment into Study 205MS303.  
2. Any significant change in the subject’s medical history that would preclude 
administration of DAC HYP, including laboratory tests or a current clinically significant 
condition that, in the opinion of the Investigator, would have excluded the subject’s 
participation in Study 205MS301, Study 205MS203, or Study 205MS302.  The 
Investigator must re-review the subject’s medical fitness for participation and consider 
any factors that would preclude treatment in Study 205MS303, including:  


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
History of any significant cardiac, endocrine, hematological, hepatic, immunologic, 
metabolic, urologic, pulmonary, gastrointestinal, dermatologic, psychiatric, renal, 
neurological (other than MS), and/or other major disease (e.g., malignancy) that 
would preclude administration of DAC HYP.

Clinically significant laboratory abnormalities (hematology and blood chemistry) 
from the most recently available test in the parent study, as determined by the 
Investigator.  Laboratory findings mandating discontinuation of study treatment as 
defined in parent study protocol are exclusionary.
3. Other medical reasons that, in the opinion of the Investigator and/or Biogen, make the 
subject unsuitable for enrollment.  
Treatment History
4. Treatment with any prohibited concomitant medication during the parent study, as 
described in Section 11.5 of this protocol.
Note:  Subjects who start an approved, open-label IFN β preparation after completion of 
dosing in Study 205MS301 are not excluded, but IFN β treatment must be discontinued 
before the first dose of DAC HYP in Study 205MS303 is given.  
Miscellaneous
5. Female subjects who are currently pregnant or breastfeeding, or considering becoming 
pregnant while in the study.
6. History of drug or alcohol abuse (as defined by the Investigator) at any time after the start 
of Study 205MS303 or any of the parent studies.
7. Unwillingness or inability to comply with the requirements of the protocol, including the 
presence of any condition (physical, mental, or social) that is likely to affect the subject’s 
ability to comply with the protocol.


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9.
ENROLLMENT AND REGISTRATION PROCEDURES
9.1.
Enrollment and Screening
Subjects must be consented before any procedures are performed.  At the time of consent, the 
subject will be enrolled into the study.  If a subject is excluded from the study, the reasons for 
exclusion will be documented in the subject’s source documents and on the enrollment log. Any 
test/assessment done at the subject’s last visit in the parent studies and within 28 days of the 
subject’s first dose in Study 205MS303 will be used as the baseline for Study 205MS303 and 
does not need to be repeated at entry into Study 205MS303 (Note:  Central LFT testing is 
mandatory at the Week 144 Entry Visit for subjects rolling over from Study 205MS203 and 
Study 205MS302 into Study 205MS303).  Testing required at the Baseline/Entry Visit that is 
done outside the 28-day window must be repeated upon entry into 205MS303.  
9.2.
Registration of Subjects
Subjects should be registered in the study after the Investigator has verified that they are eligible 
per the criteria in Section 8.1 and Section 8.2 and all baseline assessments have been performed.  
No subject may begin treatment prior to enrollment and registration. 
As confirmation, the Investigator will be provided with written verification of the subject’s 
registration by mail or fax.  
Refer to the Study Reference Manual for details on registration.


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10.
STUDY TREATMENT MANAGEMENT
Study treatment (PFS or autoinjectors) must be stored in a secure location.  Accountability for 
study treatment is the responsibility of the Investigator.  Study treatment must only be dispensed 
by a Pharmacist or medically qualified staff, and stored in a secure, monitored, locked location in 
accordance with the conditions specified in current prescribing information or the Directions for 
Handling and Administration (DHA) included in the Study Reference Manual.
Study treatment is to be dispensed only to subjects enrolled in this study.  Once treatment is 
dispensed to a subject, it can only be used by that subject.
10.1.
DAC HYP
Prefilled Syringe 
DAC HYP is supplied as a liquid in a 1-mL BD-staked PFS with a 29 gauge × ½ inch needle, 
comprising 150 mg/mL DAC HYP plus excipient materials (sodium succinate, sodium chloride, 
and polysorbate 80).  At a minimum, the study treatment label will include a study reference 
code, drug identifier, quantity of dosage units, lot number, and other pertinent information in 
accordance with local law.  Depending on country requirements, the Investigator’s name may 
also appear on the label.  DAC HYP must not be used after the expiration date unless a written 
notification of an expiration date extension is provided by Biogen.
Autoinjector 
The DAC HYP PFS is assembled inside a single-use, disposable autoinjector device.  
The autoinjector label will include the DAC HYP product code “BIIB019,” conditions for 
storage, Sponsor, and a caution statement.  Depending on country requirements, the 
Investigator’s name may also appear on the label.  DAC HYP must not be used after the 
expiration date unless a written notification of an expiration date extension is provided by 
Biogen.
10.2.
DAC HYP Preparation
Each DAC HYP PFS or autoinjector contains only one dose and is intended for SINGLE USE 
INJECTION ONLY.  Any drug that remains in the PFS after injection must not be used for 
another dose or another subject. 
After Week 12, subjects may choose to administer their DAC HYP dose at home, either by 
administering the injection themselves or by a designated caregiver. The subject or designated 
caregiver will be trained by clinic staff on the correct PFS injection technique prior to initiating 
at-home DAC HYP dosing.
Autoinjectors may be provided to selected sites and will be supplied injection-ready.  Study 
personnel or subjects at these sites do not need to insert the PFS into the device. Study site 
personnel will receive appropriate autoinjector training from a Sponsor-designated trainer prior 
to initiation of autoinjector use.


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10.3.
DAC HYP Accountability
The study site must maintain accurate records demonstrating dates and amount of study 
treatment received, to whom dispensed (subject-by-subject accounting), any amount returned by 
subject, and accounts of any study treatment accidentally or deliberately destroyed.  
Unless otherwise notified, all PFS and autoinjectors, both used and unused, must be saved for 
study treatment accountability.  At the end of the study, a final reconciliation must be made
between the amount of study treatment supplied, dispensed, and subsequently destroyed or 
returned to Biogen. 
A written explanation will be provided for any discrepancies.  After reconciliation, the 
Investigator must destroy or return to Biogen all unused study treatment PFS and autoinjectors as 
instructed by Biogen.
If any study treatment supplies are to be destroyed at the site, the Principal Investigator(s) must 
obtain prior approval by Biogen.  The Principal Investigator(s) must notify Biogen, in writing, of 
the method, date, and location of destruction.  


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11.
TREATMENT OF SUBJECTS
Biogen will provide DAC HYP (PFS or autoinjectors) to all study sites.
Refer to Section 10 (Study Treatment Management) for specifics on the preparation, storage, 
handling, disposal, and accountability of study treatment.
11.1.
Study Treatment Schedule and Administration
All subjects will receive one DAC HYP 150 mg SC injection every 4 weeks.  
DAC HYP will be administered by clinic staff at the monthly visits for the first 12 weeks of this 
study.  After Week 12, administration of DAC HYP may occur in the clinic or at home (by the 
subject or by a designated caregiver) depending on subject preference.  The subject or designated 
caregiver will be trained by clinic staff on the correct injection technique prior to initiating 
at-home DAC HYP dosing.  Subjects who are dosing at home must be instructed to not 
administer their monthly dose of DAC HYP until the study site has contacted them to 
authorize dosing.  A window of ±4 days applies to home dosing.
Before a monthly dose of DAC HYP is given, LFT results from a prior test performed within the 
previous 32 days must be reviewed by the Study Neurologist or their backup. Study personnel 
should promptly inform the subject whether the monthly dose of DAC HYP should be 
administered or whether study treatment is to be withheld based on the dosing criteria defined in 
Section 11.7.2.  Study personnel will document this communication with the subject.  Subjects 
should administer DAC HYP as soon as permission has been given as per the dosing schedule.  
Subjects need to record the date and time of dosing in their diary if they are dosing at home.
11.2.
Placebo or Reference Product Agents
Not applicable.
11.3.
Treatment Precautions
Anaphylactic-like and hypersensitivity reactions following administration of proteins such as 
DAC HYP can occur.  DAC HYP will be administered in the clinic under observation by 
qualified medical personnel for the first 12 weeks of this study.  Subjects will be educated by the 
Study Neurologist or their back-up on the signs and symptoms of hypersensitivity reactions and 
instructed to contact the site if they experience any acute or delayed reactions post injection.  
11.4.
Treatment Compliance
Compliance with treatment dosing is to be monitored and recorded by study site staff.
After Week 12, subjects who choose to administer their DAC HYP dose at home will record 
treatment in a dosing diary.  The diary will be reviewed periodically by study site staff and the 
Clinical Monitor throughout the study.  Subjects who choose at-home administration will return 
used PFS or autoinjectors to the clinic at their scheduled clinic visits.  


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11.5.
Concomitant Therapy
A concomitant therapy is any drug or substance administered from the Baseline/Entry Visit until 
completion of the study. A concomitant procedure is defined as any therapeutic intervention 
(e.g., surgery/biopsy, physical therapy) or diagnostic assessment (e.g., blood gas measurement, 
bacterial cultures) performed from the time the subject is enrolled in the study until the subject’s 
final clinic visit.
Concomitant treatment with any of the following is not allowed during the study, unless 
approved by the Biogen Medical Director(s) or the Advisory Committee, or as otherwise 
described in this protocol:

Any alternative disease modifying MS drug treatment such as chronic 
immunosuppressant therapy or other immunomodulatory treatments (including, but 
not limited to:  IFN-β, IFN-α, glatiramer acetate, cyclophosphamide, methotrexate, 
mycophenolate mofetil, mitoxantrone, cyclosporine, azathioprine, or related 
products).

Any investigational product, including investigational symptomatic therapies for MS 
and investigational therapies for non-MS indications.

Any monoclonal antibodies other than DAC HYP.

Intravenous immunoglobulin (IVIg), plasmapheresis or cytapheresis, total lymphoid 
irradiation, or T-cell or T-cell receptor vaccination.

Any systemic steroid therapy including, but not limited to, oral corticosteroids 
(e.g., prednisone) or periodic (e.g., monthly) treatment with IV methylprednisolone 
(IVMP), except for protocol-defined treatment of relapses as described in
Section 14.6 or for limited, acute treatment of general medical conditions as per the 
discretion of Study Neurologist.  Steroids that are administered by non-systemic 
routes (e.g., topical, inhaled) are allowed.

Antineoplastic or chemotherapeutic agents, including, but not limited to, 
cyclophosphamide, methotrexate, azathioprine, cladribine, cytarabine, or flutamide.

Valproic acid, carbamazepine, lamotrigine, or phenytoin.  Subjects who have been 
taking 1 of these medications at a stable dose for at least 6 consecutive months may 
continue to receive the medication and may continue study treatment under this 
protocol.  However, if any of these medications must be initiated or dose escalated, 
study treatment must be permanently discontinued as described in Section 11.8.  
Subjects who have been treated with any of these medications (which have not been
approved by the Biogen Medical Director[s]) for fewer than 6 consecutive months, or 
who take more than 1 of these medications, or who have had dose escalations within 
the past 6 months must do 1 of the following:

Discontinue the medication (any agent used for <6 consecutive months must be 
discontinued).  Subjects may use an alternative medication allowed by the 
protocol, if needed.


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
Subjects taking more than 1 agent must reduce to 1 agent (any agent that is 
continued must have been taken for at least 6 consecutive months).

In the case of dose escalation, revert to a previous dose that had been used for at 
least 6 months.

Permanently discontinue study treatment.

Isoniazid, propylthiouracil, or nimesulide.  Subjects who currently take any of these 
medications must either change to an alternative medication allowed by the protocol 
or permanently discontinue study treatment.  
Subjects who receive any of these restricted medications may be required to permanently 
discontinue study treatment as outlined in Section 11.8.  Subjects who permanently discontinue 
study treatment will be allowed to receive IVMP as treatment for MS relapse while they are 
participating in the study, as described in Section 11.8.
Use of the following medications is strongly discouraged during the study:

Herbal or dietary supplements. 

Agents that have established risks of hepatotoxicity or serious rash according to 
labeling information (examples include, but are not limited to, 
amoxicillin/clavulanate, clarithromycin, ketoconazole, minocycline, nitrofurantoin, 
trimethoprim/sulfamethoxazole, diclofenac, sulfasalazine, amiodarone, methyldopa, 
nefazodone, and halothane).  Alternatives to these therapies should be used whenever 
possible.
Symptomatic therapy, such as treatment for spasticity, depression, or fatigue is not restricted, but 
should be optimized as early as possible in an attempt to maintain consistent treatment for the 
duration of the study. Initiation of Fampridine-SR after enrollment is permitted, including when 
it is used in the acute management of protocol-defined relapse (as described in Section 14.6).
Subjects should be instructed not to start taking any new medications, including non-prescribed 
medications, unless they have received permission from the Investigator.  The use of live 
vaccines in humans concurrently treated with daclizumab has not been explored; therefore live 
vaccines should not be administered to MS subjects who are being treated with DAC HYP.
The use of concomitant therapies or procedures defined in this section must be recorded on the 
subject’s case report form (CRF), according to instructions for CRF completion (Note: 
concomitant therapies in the parent study that continued at Study 205MS303 entry must be 
recorded on the CRF).  AEs related to administration of these therapies or procedures must be 
documented on the appropriate CRF.  For subjects who prematurely discontinue study treatment, 
all concomitant medications should be recorded throughout the remainder of the subject’s 
participation in the study.
11.6.
Continuation of Treatment 
No further provisions are made for access to the study treatment.  If DAC HYP is proven to be 
beneficial, all regulatory requirements regarding poststudy access will be met.


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11.7.
Treatment Schedule Modifications
Subjects who experience a significant change in their medical status (e.g., neurological 
worsening/suspected MS relapse, possible injection-site reaction, infection, cutaneous AE, fever, 
abdominal pain, persistent diarrhea, jaundice, nausea, vomiting, pruritus) must contact the Study
Neurologist as soon as possible and no more than 48 hours after symptom onset.  The subject 
should then be evaluated by the Study Neurologist within no more than 72 hours for physical and 
neurological assessments and further treatment recommendations if appropriate.  These subjects 
should not administer additional DAC HYP until they have been evaluated by the Study
Neurologist or their backup.
Unscheduled PK/
 Visit (Table 6) can be performed in subjects who have evidence of 
significant changes in their medical conditions (as assessed by the Investigator).  This visit must 
be approved by the Biogen Medical Director in advance.
Additional treatment considerations for specific events are described below.
11.7.1.
Infections
Subjects who have evidence of a clinically significant infection will be instructed to notify the 
Study Neurologist or their backup within 48 hours of onset, and scheduled dosing of DAC HYP 
may be withheld.  If the subject’s infection resolves within 2 weeks of the scheduled DAC HYP 
dose, the subject may receive the previously scheduled dose of DAC HYP at that time.  If the 
infection has not resolved within the 2 weeks, dosing of DAC HYP will remain suspended, and 
the subject will miss dosing until the infection is resolved.  
11.7.2.
Elevated Liver Function Tests
Before a monthly dose of DAC HYP is given, LFT results from a prior test (performed within 
the previous 32 days) must be reviewed by the Study Neurologist or their backup, and must be 
within the protocol-required limits shown below (LFT procedures are described in Section 
14.4.3).
Study treatment must be temporarily suspended if a subject develops any of the following: 

ALT/SGPT or AST/SGOT >3ULN  

any other clinically significant hepatic condition in the opinion of the Investigator 
including jaundice
Note:  For subjects who present with jaundice, an LFT must be performed as soon as possible.
After a suspension, dosing of DAC HYP may be resumed when ALT/SGPT and AST/SGOT are 
<2×ULN provided that the criteria for permanent discontinuation have not been met (see 
Section 11.8).
Study treatment must be permanently discontinued if a subject develops any of the following:

ALT/SGPT or AST/SGOT elevation >8×ULN that is confirmed by a repeat test 
(preferably within 24 hours)

ALT/SGPT or AST/SGOT >5×ULN for more than 2 weeks


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
ALT/SGPT or AST/SGOT >3×ULN with concomitant elevation of total bilirubin 
>2×ULN 

If a subject has treatment suspended for an LFT elevation and has also had a prior 
treatment suspension for an LFT elevation during DAC HYP use, DAC HYP must be 
permanently discontinued unless an alternative explanation for the LFT elevation 
unrelated to DAC HYP use is clearly identified by the Investigator.
All subjects with elevated LFTs (ALT/SGPT or AST/SGOT >3×ULN) should be managed per 
the guidelines below.

Study treatment must be temporarily suspended and LFT elevation should be confirmed
as soon as possible but no later than a week by a repeat test performed at the central 
laboratory. In cases where LFTs cannot be performed via the central laboratory, repeat 
LFT results from local laboratory can be used for confirmation. 

All subsequent testing after a treatment suspension or discontinuation is required to be 
performed centrally at least weekly until the LFT elevation has resolved. 

In subjects with treatment suspension or discontinuation, DAC HYP treatment may 
resume if a laboratory error is documented upon repeat testing OR when ALT/SGPT and 
AST/SGOT are <2×ULN provided that the criteria for permanent discontinuation have 
not been met (see Section 11.8).

A careful review of all concomitant medications must be documented.  The Investigator 
should consider discontinuation of all potential hepatotoxic medications.  All recently 
started or non-essential concomitant medications should be suspended until the LFT
elevation has resolved.

An Unscheduled Hepatic Assessment Visit as soon as possible but within 7 days should 
be performed in the event of permanent discontinuation due to elevated LFTs (see
Table 6).

Subjects should be referred to a hepatic specialist if medically indicated.

The LFT elevation that led to treatment discontinuation should continue to be monitored 
until LFT elevation has resolved.

For subjects with initial ALT/SGPT or AST/SGOT >3×ULN and concomitant 
elevation of total bilirubin >2ULN: 
o
Permanently discontinue DAC HYP and monitor until the LFT elevation has 
resolved.  

For subjects with initial ALT/SGPT or AST/SGOT >5×ULN but 8×ULN: 
o
Suspend dosing and confirm as soon as possible but no later than a week. 
o
For subjects with ALT/SGPT or AST/SGOT >5×ULN for more than 2 weeks:

Permanently discontinue DAC HYP and monitor until the LFT elevation
has resolved.


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
For subjects with ALT/SGPT or AST/SGOT >8×ULN:
o
Suspend dosing and confirm by a repeat test (preferably within 24 hours).  

If AST/SGOT >8×ULN in repeat test:  Permanently discontinue
DAC HYP and monitor until the LFT elevation has resolved. 

For subjects with ALT/SGPT or AST/SGOT >10×ULN not resolving for more than 
2 weeks:
o
In consultation with the hepatic specialist, a full evaluation of alternative causes 
of liver injury should be performed, and if testing for viral hepatitis is negative, 
LFT elevations are not improving, DAC HYP is suspected as the cause of the 
LFT elevation, and there are no known contraindications for corticosteroids, then, 
in continued consultation with the hepatic specialist, empiric treatment with 
systemic corticosteroids should be considered.
11.7.3.
Cutaneous Events
Subjects participating in Study 205MS303 who develop a mild or moderate cutaneous AE that is 
not associated with 1 or more systemic symptoms or signs do not need to be evaluated by the 
Study Dermatologist; the Study Neurologist can complete the Unscheduled Dermatology 
Assessment Visit as soon as possible.  In such cases, the Study Neurologist should complete the 
Physician’s Global Assessment Scale form.  Any subject participating in Study 205MS303 who 
develops a mild or moderate cutaneous AE that is associated with more than 1 systemic 
symptom or sign, a severe cutaneous AE (with or without systemic symptoms or signs), or a 
serious cutaneous AE (with or without systemic symptoms or signs) needs to be evaluated by the 
Study Dermatologist at an Unscheduled Dermatology Assessment Visit as soon as possible.
Systemic symptoms associated with a mild or moderate cutaneous AE that would require 
evaluation by a dermatologist may include, but are not limited to, fever, hematological 
abnormalities, abnormalities of internal organs (as may be detected by renal and liver function 
tests), and lymphadenopathy.
If the Study Neurologist sees the subject prior to the Study Dermatologist, the Study Neurologist
should, if possible, assess the cutaneous AE prior to the subject seeing the Study Dermatologist. 
The information from the assessment by the Study Neurologist will be captured in addition to the 
information from the assessment by the Study Dermatologist. If the cutaneous AE is assessed by 
the Study Dermatologist as a mild or moderate cutaneous AE not associated with 1 or more 
systemic symptoms or signs, any follow-up visits can be conducted by the Study Neurologist.
A flowchart is presented in Figure 2 to summarize how these subjects will be managed during 
the study.


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Figure 2:
Flowchart for Management of Subjects With Cutaneous AEs
AE = adverse event; PGA = Physician’s Global Assessment.
Photographs can be taken by the Study Neurologist or designee at these visits for mild or
moderate cutaneous AEs that are associated with more than 1 systemic symptom or sign, severe
cutaneous AEs (with or without systemic symptoms or signs), or serious cutaneous AEs (with or 
without systemic symptoms or signs) if they have not been taken by the Study Dermatologist
(see Section 4.2).  The subjects will be asked for their consent to having their dermatological 
photographs used for educational purposes, if required.  


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Skin biopsy must be performed in subjects with severe or serious cutaneous AEs (with or 
without systemic symptoms or signs) at the Unscheduled Dermatology Assessment Visit, unless 
medically contraindicated.
Skin biopsies from study subjects with severe or serious cutaneous AEs (with or without 
systemic symptoms or signs) will be sent to a centralized laboratory for evaluation.  Results of 
the skin biopsy will be provided back to the Study Dermatologist as soon as possible with a copy 
sent to the sponsor.  Skin biopsy may also be locally evaluated per the discretion of the Study 
Dermatologist.
If the cutaneous AE is suspected to be an allergic or hypersensitivity reaction to study treatment, 
study treatment must be suspended until consultation with the Study Dermatologist. Under the 
consultation of the Study Dermatologist, the subject should also withhold all other non-essential 
medications, including protocol-required medications (as appropriate), and non-prescription 
drugs and supplements, at least until the cutaneous event has resolved.  The decision to 
permanently discontinue study treatment should be made by the Investigator in consultation with 
the Study Dermatologist.  If an allergic or hypersensitivity reaction to study treatment is 
confirmed, study treatment must be permanently discontinued.  
11.7.4.
Gastrointestinal Events of Inflammatory Colitis
For any subject participating in Study 205MS303 who develops symptoms of inflammatory 
colitis (e.g., persistent diarrhea and abdominal cramps, blood in the stool, and fever), treatment 
with DAC HYP should be stopped and the subject should be referred to a specialist.  Some 
subjects with mild colitis who require DAC HYP therapy may be able to continue the study 
treatment if the benefit-risk profile is considered positive per Investigator's assessment and the 
subject's informed decision.
11.7.5.
Lymphadenopathy or Lymphadenitis Events
Any subject participating in Study 205MS303 who develops clinically significant 
lymphadenopathy or lymphadenitis should be referred to a specialist.  Additional diagnostic 
tests, such as imaging, blood tests, and/or biopsy, should be performed according to the local 
standard of care.  
When diagnostic tests are performed, the results may be requested for internal safety review and, 
when available, biopsy materials will be sent to a centralized laboratory for evaluation.  The 
results of the central laboratory biopsy report will be provided back to the Study Neurologist as 
soon as possible, with a copy sent to the Sponsor.  
Study treatment may continue or be resumed after a temporary suspension in cases of 
uncomplicated lymphadenopathy if the benefit-risk profile is considered positive per the 
Investigator’s assessment and the subject’s informed decision. Subjects who discontinued study 
treatment for any reason while presenting with ongoing lymphadenopathy or lymphadenitis 
should be followed until the lymphadenopathy or lymphadenitis has stabilized or resolved or the 
study has terminated, whichever comes first.


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11.8.
Discontinuation of Study Treatment
A subject must permanently discontinue DAC HYP 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 15.5.4.

The subject experiences a hypersensitivity or suspected allergic reaction 
(e.g., anaphylaxis and anaphylactoid reactions) to study treatment.

The subject develops a chronic viral infection (e.g., hepatitis C, HIV).

The subject develops elevated LFTs that meet any of the following criteria:

The subject develops an ALT/SGPT or AST/SGOT elevation >8ULN that is 
confirmed by a repeat test (preferably within 24 hours).  This requires immediate
discontinuation of DAC HYP, and treatment may not resume unless a laboratory 
error is documented upon repeat testing. 

ALT/SGPT or AST/SGOT >5ULN for more than 2 weeks

ALT/SGPT or AST/SGOT >3ULN with concomitant elevation of total bilirubin 
>2ULN at any time unless a laboratory error is documented upon repeat testing

If a subject has treatment suspended for an LFT elevation and has also had a prior 
treatment suspension for an LFT elevation during DAC HYP use, DAC HYP 
must be permanently discontinued unless an alternative explanation for the LFT 
elevation unrelated to DAC HYP use is clearly identified by the Investigator.

The LFT abnormality that led to treatment discontinuation should continue to be 
monitored until resolution is documented.  An Unscheduled Hepatic Assessment 
Visit is needed in the event of permanent discontinuation due to elevated LFTs 
(see Section 11.7.2).
In addition, a careful review of all concomitant medications must be documented.  
The Investigator should consider discontinuation of all potential hepatotoxic 
medications.  The subject should be referred to a physician with expertise in the 
diagnosis and treatment of liver disease, and additional hepatic studies should be 
performed according to local standard of care.  The central laboratory may be 
utilized for additional hepatic testing per Investigator request.  

The subject experiences a cutaneous AE, which the Investigator (in consultation with 
the Study Dermatologist) considers to be a generalized allergic or hypersensitivity 
reaction to study treatment (see Section 11.7.3). 

The subject experiences inflammatory colitis, except in subjects with mild colitis who 
require DAC HYP therapy and have a positive benefit-risk profile per Investigator's 
assessment and the subject's informed decision (see Section 11.7.4).

The subject requires treatment with any of the disallowed concomitant medications, 
unless approval is given by the Biogen Medical Director(s) or Advisory Committee.  
Note:  IVMP for treatment of a protocol-defined relapse is allowed as detailed in the 


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protocol (see Section 11.5).  Treatment with valproic acid, carbamazepine, 
lamotrigine, or phenytoin is only allowed under the conditions detailed in the 
protocol.  

The subject experiences a medical emergency that necessitates permanent 
discontinuation of treatment.  

The subject desires to discontinue treatment under this protocol.  

At the discretion of the Investigator for medical reasons or for non-compliance.   

Upon confirmatory tests 1 month apart, the subject’s hematology results are as 
follows in the absence of an identified reversible cause by the Investigator 
(e.g., infection):  

white blood cell count is <2500 cells/L, or 

lymphocyte count is <800 cells/L, or 

platelet count is <75,000 cells/L  
Subjects who meet the above criteria must have study treatment withheld until 
hematology retest results are available.  

The subject experiences severe depression and/or suicidal ideation.  Severe 
depression is defined as any episode that requires hospitalization, or at the discretion 
of the Investigator.
Subjects who permanently discontinue DAC HYP treatment should complete all post-treatment
safety follow-up evaluations (see Section 13.3).
Subjects who permanently discontinue study treatment may be treated with alternative approved 
MS therapies according to local practices, and should remain in the study and complete safety 
follow-up evaluations as described in Section 4.2 and Section 13. However, subjects who desire 
to discontinue participation in this study or are unwilling or unable to comply with the protocol 
should be withdrawn from the study and complete an Early Termination Visit.  As noted in
Table 6 (Footnote 3) and Section 11.9, subjects terminating treatment with an ongoing cutaneous 
AE require an Unscheduled Dermatology Assessment Visit prior to leaving the study if the 
subject has not had such a visit in the 4 weeks±4 days prior to leaving the study.  If the event is, 
at the time of termination, a mild or moderate cutaneous AE that is associated with more than 
1 systemic symptom or sign, a severe cutaneous AE (with or without systemic symptoms or 
signs), or a serious cutaneous AE (with or without systemic symptoms or signs), then the 
assessment should be performed by the Study Dermatologist.  If the event is considered mild or 
moderate and is not associated with 1 or more systemic symptoms or signs, then the assessment 
can be performed by the Study Neurologist or the Study Dermatologist.
The reason(s) for discontinuation of treatment must be recorded in the subject’s CRF.


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11.9.
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 is unwilling or unable to comply with the protocol.  

At the discretion of the Investigator for medical reasons.
Subjects who withdraw from the study should complete the End of Treatment Visit assessments 
as described in Section 14.9 (subjects should be encouraged to complete all other post-treatment
safety follow-up visits).  The reason for the subject’s withdrawal from the study must be 
recorded in the subject’s CRF.  
For subjects with an ongoing mild or moderate cutaneous AE that is associated with more than 
1 systemic symptom or sign, severe cutaneous AE (with or without systemic symptoms or signs), 
or serious cutaneous AE (with or without systemic symptoms or signs), the Study Dermatologist
should perform an Unscheduled Dermatology Assessment Visit if this visit has not been 
performed in the 4 weeks±4 days prior to leaving the study (see Section 11.7.3). If the event is 
considered mild or moderate and is not associated with 1 or more systemic symptoms or signs, 
then the assessment can be performed by the Study Neurologist or the Study Dermatologist.


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12.
EFFICACY, DAC HYP CONCENTRATION, AND
ASSESSMENTS
12.1.
Clinical Efficacy Assessments
The following clinical tests/assessments will be performed to assess the efficacy of DAC HYP:

Relapse Assessment: Subjects who suspect they are experiencing new symptoms or 
worsening symptoms need to contact the Study Neurologist within 48 hours of the 
onset of the symptoms.  

Refer also to Section 14.6 Unscheduled Relapse Assessment Visit for additional 
details.  

EDSS [Kurtzke 1983]:  Review of EDSS procedures will be performed prior to study 
start as necessary for training purposes.  

MSFC [Fischer 1999]:  Timed 25-Foot Walk, 9HPT with both upper extremities, and 
PASAT 3  

SDMT:  Data will be collected only from subjects enrolled from Study 205MS301, 
and test performance data will be collected beginning in Week 144 and every 
24 weeks thereafter.

PASAT 3:  This test will be performed separately from the MSFC beginning in
Week 144 and every 24 weeks thereafter.  Data will be collected only from subjects 
enrolled from Study 205MS301.

Brain MRI scan with and without Gd (T2 hyperintense lesions, T1 hypointense 
lesions, Gd+ lesions, brain atrophy).

Subjects will complete the following questionnaires at various timepoints specified in 
Section 4.2:  

EQ-5D quality of life questionnaire (the EQ-5D descriptive system and the 
EQ-VAS)  

MSIS-29 (29-item physical and psychological assessment)  

HRU (hospitalizations, emergency room visits, and unscheduled neurologist 
visits)  

Treatment Satisfaction Questionnaire for Medication (with PFS use) or Treatment 
Satisfaction Survey (with autoinjector use)  

HRPQ (productivity questionnaire)  
Refer to Section 4.2 for the timing of assessments.  




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13.
SAFETY ASSESSMENTS
13.1.
Clinical Safety Assessments
The following clinical assessments will be performed to determine the safety profile of 
DAC HYP:

Medical history

Physical and neurological examination 

Vital sign measurements:  temperature, pulse rate, systolic and diastolic blood 
pressure, and respiratory rate (subjects must remain in the same body position quietly 
for 5 minutes prior to having their pulse and blood pressure taken)

Weight

Concomitant therapy and procedure recording

AE and SAE recording

Beck Depression Inventory, Second Edition (BDI-II)

Immunogenicity assessments

Alcohol Use Disorders Identification Test - Consumption Questionnaire (AUDIT-C)
See Section 4.2 for the timing of assessments.
13.2.
Laboratory Safety Assessments
The following laboratory tests will be performed to assess the safety profile of DAC HYP:

Hematology:  hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, red blood cell count, white 
blood cell count (with differential), and platelet count

Blood chemistry:  sodium, potassium, chloride, total bilirubin, alkaline phosphatase, 
ALT/SGPT AST/SGOT, lactate dehydrogenase, gamma glutamyl transferase, blood 
urea nitrogen (BUN), creatinine, and bicarbonate

Comprehensive hepatic panel (only required for subjects who permanently 
discontinue dosing due to elevated LFTs as defined in Section 11.7.2).  Testing will 
include screening for the following: 

hepatitis A, B, C, and E 

other viral infections:  Epstein-Barr virus (EBV), cytomegalovirus (CMV), human 
herpes virus 6 (HHV-6), varicella zoster virus (VZV), herpes simplex virus 
(HSV), and Parvovirus B19

gamma-globulins, including IgG levels


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
autoantibodies:  antinuclear antibody (ANA), anti-smooth muscle antibody 
(anti-SM), anti-liver/kidney microsome-1 antibody (anti-LKM1), 
antimitochondrial antibody (AMA), and anti-soluble liver antigen (SLA) 
Additional testing may be performed based on results of the above testing or the 
subject’s clinical history.  Additional hepatic assessments should be performed 
according to local standard of care.  

Thyroid function panel, including TSH and T4

Urinalysis:  protein, blood, glucose, ketones, nitrite, leukocytes, pH, specific gravity 
by dipstick and microscopy

Urine pregnancy testing 

Skin biopsy (only required for subjects who experience cutaneous AEs reported as 
serious or severe as defined in Section 11.7.3)
Refer to Section 4.2 for the timing of assessments.
13.3.
Study-Specific Safety Assessments
Blood serum collection for binding and neutralizing anti-drug antibody testing will be 
performed.  Note:  When necessary, samples drawn for one purpose (e.g., immunogenicity) may 
be used to meet another protocol-defined objective (e.g., DAC HYP concentration assessment).


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14.
SCHEDULE OF EVENTS
14.1.
Overview
A written, signed Informed Consent Form (ICF) and all authorizations required by local law 
(e.g., Protected Health Information [PHI] in North America) must be obtained prior to 
performing any tests or assessments under this protocol.
For subjects entering from Study 205MS301, tests/assessments performed at the subject’s last 
visit in Study 205MS301 and within 28 days of the subject’s first dose of DAC HYP (Week 0) in 
Study 205MS303 may be used as baseline data for Study 205MS303; if final Study 205MS301 
tests/assessments are not performed within the 28-day window, they must be repeated upon entry 
into Study 205MS303 and before the first dose of DAC HYP is administered.
Week 144 Visit of Study 205MS303 will be the Entry Visit for subjects enrolled from 
Study 205MS203 or Study 205MS302.  Any test/assessment done at the subject’s last visit in 
parent studies and within 28 days of the subject’s first dose in Study 205MS303 will be used as 
the baseline and does not need to be repeated at entry into Study 205MS303; test/assessments 
performed >28 days before the Entry Visit must be repeated at the Entry Visit. Central LFT 
testing is mandatory at Entry Visit.
Clinic visits will occur once every 4 weeks for the first 12 weeks, then every 12 weeks thereafter. 
On a dosing day, all tests and assessments must be performed prior to DAC HYP administration.  
When DAC HYP administration and MRI evaluation are required at the same visit, the MRI scan 
should be performed prior to DAC HYP administration (Note:  MRI scan can be performed up to 
4 days prior to the visit).
Before a monthly dose of DAC HYP is given, LFT results (ALT/SGPT, AST/SGOT, alkaline 
phosphatase, total bilirubin, and GGT only) from prior testing performed within the previous 
32 days must be reviewed by the Study Neurologist or their backup, and must be within the 
protocol-required limits.
After Week 12, subjects will have the option of administering DAC HYP at home following 
Investigator review of monthly pre-dose LFT results.  Subjects who are not able to administer 
their own dose or prefer not to administer their own dose of DAC HYP will be given the option 
to choose another individual (caregiver) to administer their treatment at home or to have their 
treatment administered by staff at the study site.
Follow-up visits will take place at 8, 12, 16, and 24 weeks after each subject’s last dose of DAC 
HYP. Unscheduled Relapse Assessment Visits (if necessary) should be scheduled within 
72 hours of the onset of any new neurological symptoms that may indicate neurological 
worsening or possible clinical relapse. Unscheduled Hepatic Assessment Visits (if necessary) 
should be scheduled as soon as possible (but within 1 week) following discontinuation of study 
treatment due to elevated LFTs.  Unscheduled Dermatology Assessment Visits will be performed 
as per Section 11.7.3.  


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Unscheduled PK/
 Visits should be scheduled as soon as possible following significant 
changes in subjects’ medical conditions, as assessed by the Investigator.  This visit must be 
approved by the Biogen Medical Director in advance.
14.2.
Site Personnel
For each subject, the Principal Investigator will designate the following study site personnel:

A primary Study Neurologist and backup neurologist

A primary and backup Nurse (or Study Coordinator)

A primary and backup Examining Technician

An MRI Technician

A Pharmacist (or authorized designee)

A Study Dermatologist
The Study Neurologist must have a minimum of 2 years of neurology specialty training and 
anticipate at least a 3-year commitment to the study, or be approved by the study Advisory 
Committee. The Study Neurologists may designate another neurologist at the center who meets 
the same qualifications to perform the EDSS assessments and other neurologic assessment 
during the trial. Whenever possible, the EDSS and other neurologic assessments should be 
performed by the same examiner who performed these assessments in the parent study.  
The primary Study Neurologist will be responsible for:

Management of the routine neurological care of the subject

Assessment (including assignment of causality) and treatment of AEs and MS 
relapses

Obtaining an EDSS score based on a detailed neurological examination at the 
scheduled timepoints required in the protocol, and at every Unscheduled Relapse 
Assessment Visit

Review of selected hematology and all blood chemistry results from the central 
laboratory

Assessment of LFT results, as detailed in Section 11.7.2

Monitoring and follow-up of any abnormal hepatic tests

Referral of subjects to a dermatologist if that subject experiences a mild or moderate 
cutaneous AE that is associated with more than 1 systemic symptoms or signs, a 
severe cutaneous AE (with or without systemic symptoms or signs), or a serious 
cutaneous AE (with or without systemic symptoms or signs) as described in 
Section 11.7.3

Performing Dermatology Assessments and Physician Global Assessment Scale in 
subjects with mild or moderate cutaneous AEs (not associated with 1 or more 
systemic symptoms or signs), as detailed in Section 11.7.3


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
Assessment of injection sites, as detailed in Table 7
Hematology and blood chemistry data will be sent to the investigational sites to aid in 
management of the subject.  
The primary Nurse or Study Coordinator will be responsible for:

Assisting the Study Neurologist in subject management, including the treatment of 
AEs, the treatment and assessment of disease relapses, and the recording of AEs and 
concomitant medications

Monitoring the EDSS scores and informing the Study Neurologist if a subject 
experiences at least a 1.0-point increase on the EDSS from a baseline EDSS ≥1.0 that 
is sustained for 24 weeks, or at least a 1.5-point increase on the EDSS from a baseline 
EDSS <1.0 that is sustained for 24 weeks

Administering the patient-reported questionnaires (BDI-II, MSIS-29, EQ-5D), HRU,
and subject assessment of injection pain (VAS)

Collection of blood samples and obtaining vital signs

Study treatment administration/dispensation/accountability
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.  It is not necessary for the 
Examining Technician to be a healthcare professional as long as he/she is qualified, in the 
opinion of the Principal Investigator, to administer the MSFC (Note:  MSFC was administered in 
this study only until Week 48;  therefore, the role of the Examining Technician ended after that).
The MRI Technician will be responsible for:

Performing a brain MRI scan with and without Gd at all protocol-required timepoints.  
Study-specific MRI scan procedures and protocols, which will be provided prior to 
study start, must be followed.
The Pharmacist (or authorized designee) will be responsible for:

Storage, distribution, and accountability of study treatment.
The Study Dermatologist will be responsible for:

Performing Cutaneous Assessments and Physician Global Assessment Scale in 
subjects with a mild or moderate cutaneous AE that is associated with more than 
1 systemic symptoms or signs, a severe cutaneous AE (with or without systemic 
symptoms or signs), or a serious cutaneous AE (with or without systemic symptoms 
or signs), as detailed in Section 11.7.3

Documenting cutaneous events, as per the protocol.  

Taking photograph(s) of the affected body areas, as required.

Performing a skin biopsy, as required.


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
Evaluating, treating, and managing mild or moderate cutaneous AEs that are 
associated with more than 1 systemic symptoms or signs, severe cutaneous AEs (with 
or without systemic symptoms or signs), or serious cutaneous AEs (with or without 
systemic symptoms or signs), as described in Section 11.7.3.
14.3.
Subject Management
The following restrictions apply to all subjects enrolled into this study:

Subjects must follow the restrictions for concomitant medications and procedures 
described in Section 11.5.

Contraception requirements are to be followed as described in Section 15.5.3.

Whenever possible, a subject should undergo protocol-required tests and assessments 
at the same time of day throughout the study.

Subjects should not donate blood until 4 months after their last dose of DAC HYP.

Subjects should not receive live or live-attenuated vaccines during DAC HYP 
treatment or for at least 6 months after treatment with DAC HYP.
14.4.
Special Instructions for Tests and Assessments
Note:  Information about the tests and assessments to be performed in this study is also provided 
in Section 12 and Section 13, and in the Study Reference Manual.
14.4.1.
Rescreening
Subjects who are not eligible for participation at baseline due to a temporary condition 
(e.g., acute infection) are allowed to be rescreened once the condition has resolved, provided 
they are rescreened and enrolled within 6 months of completing Study 205MS301, 
Study 205MS203, or Study 205MS302.
14.4.2.
Pregnancy Testing

Pregnancy testing is only required for women of childbearing potential.  A urine 
pregnancy test is to be performed at the Baseline/Entry Visit and at other timepoints 
designated in Section 4.2 Schedule of Events.  Study treatment will be immediately
discontinued if the subject has a positive pregnancy test at any time during the study.

Results from all urine pregnancy tests must be reviewed by the study site prior to dosing 
and must be negative.  
14.4.3.
Liver Function Test Assessments Prior to DAC HYP Dosing
Before a monthly dose of DAC HYP is given, LFT results from prior testing performed within 
the previous 32 days must be reviewed by the Study Neurologist or their backup, and must be 
within protocol-required limits as described in Section 11.7.2. 
LFTs can be performed as follows:  


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
Samples for LFTs must be drawn prior to administration of the monthly DAC HYP 
dose.  These samples may be tested either locally inside or outside of the clinic 
(e.g., at a local laboratory or by visiting nurses) or at the central laboratory at the 
discretion of the Investigator and the results can then be used to determine whether 
dosing should continue or be suspended at the monthly dosing timepoint (see 
Section 11.1).

If local LFTs have been used to determine whether dosing should continue or be 
suspended at the time of a scheduled clinic visit, LFTs must also be performed at the 
central laboratory at the time of the scheduled clinic visit (Note:  Scheduled clinic 
visits occur every 4 weeks during the first 12 weeks of the study and every 12 weeks 
thereafter).    

If the subject is administering DAC HYP injections at home, site personnel must 
contact the subject after review of prior LFT results performed within the previous 
32 days to authorize the monthly injection, or if LFT results warrant, to instruct the 
subject to withhold their injection.  

LFTs following a treatment suspension must be performed through the central 
laboratory until the LFT abnormality has resolved. In cases where LFTs cannot be 
performed via central laboratory, repeat LFT results from local laboratory can be used 
for confirmation.
14.4.4.
Other Assessments

Vital signs include systolic and diastolic blood pressure, pulse, and body temperature, 
and should be measured pre-dose. The subject must rest quietly for 5 minutes prior to 
blood pressure and pulse measurements.  Weight will be collected at Baseline/Entry 
Visit and at the time of first autoinjector use at selected sites.

The MSIS-29 must be administered prior to the subject’s visit with the Study
Neurologist.  

Subject assessment of injection pain using a VAS should be completed as soon as 
possible after the injection is administered, but no later than 10 to 30 minutes 
post-injection.

The first 4 DAC HYP injections (i.e., Weeks 0 through 12) must be given in the 
clinic.  The first of these injections must be given by study personnel. At subsequent 
visits, subjects and/or caregivers will be instructed on DAC HYP self-administration 
and may administer their scheduled dose under staff supervision.  After the subject 
completes the required in-clinic injections (i.e., after Week 12), DAC HYP may be 
dispensed to subjects for at-home administration if the subject chooses.  If necessary, 
drug dispensation may occur at monthly intervals.  

Additional visits to assess elevated LFTs, cutaneous events, or PK/
 markers may 
be required as described in Section 11.7.


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14.5.
Definition of MS Relapse and Disability Progression
14.5.1.
MS Relapse
Relapses are defined as new or recurrent neurological symptoms not associated with fever or 
infection, lasting at least 24 hours, and accompanied by new objective neurological findings 
upon examination by the Study Neurologist* or their backup.  The subject must have objective 
signs on the examination confirming the event.  
*When possible subjects should be evaluated by the same neurologist assigned to them in the 
parent study.  
New or recurrent neurologic symptoms that evolve gradually over months should be considered 
disability progression, not an acute relapse.  New or recurrent neurological symptoms that occur 
less than 30 days following the onset of a protocol-defined relapse should be considered part of 
the same relapse.  Management of MS relapse is described in Section 14.6.
14.5.2.
Disability Progression
Disability progression can only be confirmed from the EDSS scores obtained according to the 
protocol-defined schedule of assessments at regular visits, and is defined as one of the following:

at least a 1.0-point increase on the EDSS from a baseline EDSS ≥1.0 that is sustained 
for 24 weeks, or 

at least a 1.5-point increase on the EDSS from a baseline EDSS <1.0 that is sustained 
for 24 weeks 
14.6.
Management of MS Relapse
Subjects who experience new or worsening neurological symptoms must contact the Nurse or 
Study Neurologist or their backup within 48 hours after the onset of symptoms.  A standardized 
Suspected Relapse Questionnaire will be completed to determine the necessity of an 
Unscheduled Relapse Assessment Visit.
If required, the subject will then be evaluated in person by the Study Neurologist not more than 
72 hours after the onset of the symptoms.  At the Unscheduled Relapse Assessment Visit, the 
Study Neurologist is to perform a relapse assessment and obtain an EDSS score.  New objective 
findings on neurological examination performed by the Study Neurologist* are required to 
determine if a suspected protocol-defined relapse has occurred. Treatment of an acute relapse 
event with intravenous methylprednisolone (IVMP) [or equivalent] may proceed at the discretion 
of the Study Neurologist after the examination and will not affect the subject’s eligibility to 
continue in the study.
*When possible subjects should be evaluated by the same neurologist assigned to them in the 
parent study.  
Subjects who prematurely discontinue study treatment should complete safety follow-up 
evaluations (see Section 4.2 and Section 13).  


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Subjects who permanently discontinue DAC HYP treatment should complete the visit schedule 
described in Section 11.8.  
14.7.
Cutaneous Events
Subjects who experience a mild or moderate cutaneous AE that is associated with more than 
1 systemic symptoms or signs, a severe cutaneous AE (with or without systemic symptoms or 
signs), or a serious cutaneous AE (with or without systemic symptoms or signs) must be referred 
to and evaluated and managed by the Study Dermatologist as per Section 11.7.3.  An 
Unscheduled Dermatology Assessment Visit will be performed, at which time a photograph will 
be taken, whenever a subject experiences a mild or moderate cutaneous AE that is associated 
with more than 1 systemic symptoms or signs, a severe cutaneous AE (with or without systemic 
symptoms or signs), or a serious cutaneous AE (with or without systemic symptoms or signs), 
per Table 6.  Subjects who develop a mild or moderate cutaneous AE that is not associated with 
1 or more systemic symptoms or signs do not need to be evaluated by the Study Dermatologist; 
the Study Neurologist can complete the Unscheduled Dermatology Assessment Visit as soon as 
possible.
If a generalized allergic or hypersensitivity reaction to study treatment is confirmed, study 
treatment must be permanently discontinued as per Section 11.8.  
14.8.
Unscheduled Hepatic Assessment Visit
The following tests/assessments will be performed as soon as possible (but within 7 days) after 
discontinuation of study treatment for subjects who are required to discontinue dosing due to 
elevated LFTs as described in Table 6 and Section 11.8.

Physical examination and vital signs 

Comprehensive hepatic panel

Recording of concomitant therapy

Monitor and record AE/SAEs

Protocol compliance and DAC HYP accountability

LFTs (ALT/SGPT, AST/SGOT, alkaline phosphatase, total bilirubin, and GGT only)
14.9.
Lymphadenopathy and Lymphadenitis Events
Subjects who experience a clinically significant event of lymphadenopathy or lymphadenitis 
should be referred to a specialist as per Section 11.7.5.
Interruption or discontinuation of DAC HYP treatment due to events of lymphadenopathy or 
lymphadenitis is a clinical decision that should take the overall benefit-risk assessment of 
therapy into consideration.  Subjects who discontinued study treatment for any reason while 
presenting with ongoing lymphadenopathy or lymphadenitis should be followed until the 
lymphadenopathy or lymphadenitis has stabilized or resolved or the study has terminated, 
whichever comes first.


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14.10.
Post-Treatment Safety Follow-Up Visit Schedule for All Subjects 
All subjects should complete the following schedule of safety follow-up visits after their last 
dose of DAC HYP:

End of Treatment Visit (i.e., the assessments required at Week 240).  For subjects 
who prematurely discontinue study treatment before Week 240, these assessments 
should be performed 4 weeks (±4 days) after the subject’s last dose of DAC HYP.   

Post-treatment safety follow-up visits at 8, 12, 16, and 24 weeks after the subject’s 
last dose.  The details of these visits are shown in Table 5.
Note:  Subjects who complete Week 144 of DAC HYP treatment in Study 205MS303 and are in 
the safety follow-up period per the original protocol, will have the option to restart DAC HYP 
treatment from Week 156 Visit in Study 205MS303 (see Table 4) as long as they meet the 
eligibility criteria (Section 8). 


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15.
SAFETY DEFINITIONS, MONITORING, AND REPORTING
Throughout the course of the study, every effort must be made to remain alert to possible AEs.  
If an AE occurs, the first concern should be for the safety of the subject.  If necessary, 
appropriate medical intervention should be provided.
At the signing of the ICF, each subject must be given the names and telephone numbers of study 
site staff for reporting AEs and medical emergencies.
15.1.
Definitions
15.1.1.
Serious Pretreatment Event
A serious pretreatment event is any event that meets the criteria for SAE reporting (as defined in 
Section 15.1.3) and occurs after the subject signs the ICF, but before administration of study 
treatment.
15.1.2.
Adverse Event
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product.
15.1.3.
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, or

results in a congenital anomaly/birth defect.
An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or convulsions occurring at home that do not 
require an inpatient hospitalization.


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15.2.
Monitoring and Recording Events
15.2.1.
Serious Pretreatment Events
A serious pretreatment event experienced by the subject after signing and dating the ICF but 
before administration of study treatment is to be recorded on the SAE Form and faxed to the 
contract research organization (CRO) within 24 hours of the study site staff becoming aware of 
the event (see Section 15.2.5).
15.2.2.
Adverse Events
Any AE experienced by the subject between the time of signing the ICF and subject’s final visit 
is to be recorded on the CRF, regardless of the severity of the event or its relationship to study 
treatment.
15.2.3.
Serious Adverse Events
Any SAE experienced by the subject between the time of the first dose of study treatment and 
subject’s final 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 the CRO.
Any SAE ongoing when the subject completes the study or discontinues from the study will be 
followed by the Investigator until the event has resolved, stabilized, or returned to baseline 
status.
Subjects will be followed for all SAEs until the subject’s final visit.  Thereafter, the event should 
only be recorded if the Investigator considers it related to study treatment.
15.2.4.
All Events
All events must be assessed to determine the following:

If the event meets the criteria for an SAE as defined in Section 15.1.3.

The relationship of the event to study treatment as defined in Section 15.3.1.

The severity of the event as defined in Section 15.3.2.
15.2.5.
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 the CRO 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.






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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.
15.5.
Procedures for Handling Special Situations
15.5.1.
Overdose
An overdose is any dose of study treatment given to a subject or taken by a subject that exceeds 
the dose described in the protocol.  Overdoses are not considered AEs; however, all overdoses 
should be recorded on an Overdose Form and faxed to the CRO within 24 hours.  An overdose 
should be reported even if it does not result in an AE.  Overdoses do not need to be recorded in 
the CRF; dosing information is recorded on a CRF.
15.5.2.
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 CRO Medical Monitor at one of the following phone numbers:
North America (USA and Canada):  
Latin America: 
Europe and Asia Pacific: 
15.5.3.
Contraception Requirements
All women of childbearing potential must practice effective contraception during the study and 
be willing and able to continue contraception for 4 months after their last dose of study 
treatment.
For the purposes of this study, women of childbearing potential are defined as all women 
physiologically capable of becoming pregnant, UNLESS they meet one of the following 
conditions:

Postmenopausal:  12 months of natural (spontaneous) amenorrhea or 6 weeks after 
surgical bilateral oophorectomy with or without hysterectomy

Posthysterectomy
For the purposes of the study, effective contraception is defined as follows:
For females:

Using 1 or more of the following acceptable methods of contraception:  surgical 
sterilization (e.g., bilateral tubal ligation), intrauterine contraception/device, hormonal 
contraception, or any 2 barrier methods (a combination of male or female condom with 
spermicide; diaphragm, sponge, cervical cap)


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
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, post-ovulation 
methods) and withdrawal are not considered acceptable methods of contraception.
15.5.4.
Pregnancy
Subjects should not become pregnant during the study.  If a female subject becomes 
pregnant, study treatment must be discontinued immediately.
The Investigator must report the pregnancy by faxing the appropriate form to Pharmacovigilance 
at the CRO within 24 hours of the study site staff becoming aware of the pregnancy (refer to 
Section 15.2.5 for reporting information). The Investigator or study site staff must report the 
outcome of the pregnancy to Pharmacovigilance at the CRO.
Please note that congenital abnormalities/birth defects in the offspring of male or female subjects 
should be reported when conception occurred during the study treatment period.
15.5.5.
Regulatory Reporting
Suspected Unexpected Serious Adverse Reactions (SUSARs) are SAEs that are unexpected and 
judged by the Investigator or the Sponsor to be related to the study treatment administered.
Biogen Safety and Benefit-Risk Management (SABR) will report SUSARs to the appropriate 
regulatory authorities and Investigators as required, according to local law.
15.6.
Investigator Responsibilities
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 of the pregnancy.

Complete an SAE form for each serious event and fax it to the CRO 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 the CRO within 24 hours of the study site staff becoming aware 
of new information.

Complete an Adverse Event of Special Interest form for each transaminase elevation, 
hepatic event, and cutaneous event as described in the protocol and fax it to the CRO 
as soon as possible following the study site staff becoming aware of the event.

Ensure all AE and SAE reports are supported by documentation in the subjects’ 
medical records.


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
Report SAEs to local ethics committees, as required by local law.
15.7.
Biogen Responsibilities
Biogen’s responsibilities include the following:

Before study site activation and subject enrollment, the Clinical Monitor or designee
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.


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16.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
16.1.
Description of Objectives
See Section 6.1, Objectives.
16.2.
Description of Endpoints
See Section 6.2, Endpoints.
16.3.
Demography and Baseline Disease Characteristics
Demographic data collected at baseline will be summarized (i.e., age, gender, ethnicity, and 
weight).  Medical history and baseline characteristic data (e.g., EDSS, number of relapses in the 
previous study, MRI endpoints) will also be summarized.
16.4.
Safety and Efficacy
16.4.1.
Analysis Population
Study 205MS303 Safety Population
The safety population will include all subjects who received at least 1 dose of DAC HYP in 
Study 205MS303.  All safety analyses will be completed on the safety population.
Study 205MS303 Intent-to-Treat Population
The intent-to-treat (ITT) population will include all subjects who received at least 1 dose of DAC 
HYP in Study 205MS303.  This population will be utilized for the efficacy analyses.  
Study 205MS301 and Study205MS303 Intent-to-Treat population
This population will include all subjects randomized to DAC HYP or Avonex in 
Study 205MS301 and received at least one dose of DAC HYP in Study 205MS303.
16.4.2.
General Methods of Analysis
Summary statistics will be presented.  For continuous endpoints, summary statistics will 
generally include the number of subjects with data, mean, standard deviation, median, and range.  
Categorical endpoints will include the number of subjects with data and the percentage in each 
category.
Analyses will generally be descriptive in nature and will focus on data collected during 
Study 205MS303 only.  However, for relevant efficacy analyses, the data may be summarized by 
previous treatment group (Avonex or DAC HYP).  Also, statistical comparisons may be made 
between efficacy in Study 205MS301 and efficacy in Study 205MS303 among subjects 
previously randomized to Avonex in Study 205MS301.
All statistical tests will be 2-sided with an overall Type I error of 5%.  Adjustments for multiple 
comparisons will not be considered.


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16.4.3.
Primary Endpoints Analysis
Clinical Adverse Events
AEs will be coded using the Medical Dictionary for Regulatory Activities. All treatment-
emergent events will be included in the evaluation of safety.  Treatment emergent includes any 
event that either occurs or worsens in severity after the onset of study treatment.  Overall 
incidence of treatment-emergent events will be summarized; in addition, summaries by severity 
and by relationship to study treatment will be provided.  The summary tables will include 
incidence estimates for the overall system organ class as well as for preferred terms within each 
system organ class.  In order to assess whether the incidence of events changes over time, the 
incidence of key events may also be summarized by time period (e.g., 6-month time intervals).  
16.4.4.
Other Safety Endpoint Analyses
Unless otherwise specified, the baseline measurement for safety assessments such as laboratory 
values and vital signs was the measurement acquired on the day of the first receipt of DAC HYP.  
The first receipt of dosing of DAC HYP could be either Study 205MS303 (for subjects who 
received Avonex in Study 205MS301) or the parent studies (i.e., Study 205MS301, 
Study 205MS203, or Study 205MS302) for all other subjects.
Laboratory Data
Changes in laboratory values will be summarized using shift tables.  Shift tables will include 
hematology, LFTs, kidney function tests, electrolytes, and other blood chemistry tests.  Shifts 
will be presented from baseline of DAC HYP treatment (the last measurement acquired before or 
on the day of the first receipt of DAC HYP, e.g., Study 205MS303 baseline for subjects 
randomized to Avonex in Study 205MS301 and Study 205MS301 baseline for subjects 
randomized to DAC HYP 150 mg in Study 205MS301).  Summaries of worst post-baseline 
laboratory values by clinically relevant categories may also be presented for selected parameters 
of interest by treatment group.  For example, for LFT (alkaline phosphatase, ALT, AST, GGT,
and total bilirubin), categories may be defined based on cutoff values relative to the ULN.
Vital Signs
Vital signs collected will be examined to determine the incidence of clinically relevant 
abnormalities.  These abnormalities are described in Table 8.  For the purpose of the shifts from 
baseline, the baseline evaluation at the start of DAC HYP treatment will be used.
For each vital sign, the number of subjects evaluated and the number and percentage of subjects 
with the defined abnormality at any time post dosing will be presented by treatment group.  


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Table 8:  
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs
Vital Sign
Criteria for Abnormalities
Temperature 
>38°C or an increase from baseline of ≥1°C
Pulse
>120 beats per minute (bpm) or an increase from baseline of 
20 bpm
<50 bpm or a decrease from baseline of >20 bpm
Systolic Blood Pressure
>180 mmHg or an increase from baseline of >40 mmHg
<90 mmHg or a decrease from baseline of >30 mmHg
Diastolic Blood Pressure
>105 mmHg or an increase from baseline of >30 mmHg
<50 mmHg or a decrease from baseline of >20 mmHg
Physical Examination
The physical examination findings will be summarized.
16.4.5.
Efficacy Endpoints Analyses
Annualized Relapse Rate
Relapses will be summarized over the follow-up period in Study 205MS303.  For subjects in 
Study 205MS301 and Study 205MS303 ITT population, relapses may be summarized over the 
combined study period (Studies 205MS301 and 205MS303).  
A negative binomial regression model will be used to estimate the adjusted ARR.  
Proportion of Subjects with a Relapse
The proportion of subjects relapsed will be estimated using a Kaplan-Meier curve.  
Disability Progression  
Sustained disability progression is defined as at least a 1.0 point increase on the EDSS from 
baseline EDSS 1.0 that is sustained for 24 weeks, or at least a 1.5 point increase on the EDSS 
from baseline EDSS <1.0 that is sustained for 24 weeks.  The proportion of subjects with 
progression will be summarized using a Kaplan-Meier curve.  In addition, summary statistics for 
EDSS and for the change from baseline in EDSS will be presented by visit, and for subjects who 
participated in Study 205MS301, by previous treatment group.
MSFC
Changes in the MSFC z-score will be summarized by study visit, and for subjects who 
participated in Study 205MS301, by previous treatment group. For subjects in Study 205MS301 
and Study 205MS303 ITT population, MSFC z-score may be summarized over the combined 
study period (Studies 205MS301 and 205MS303).  Details on the calculations of the z-score for 
each component will be described in the statistical analysis plan.
SDMT
Changes in the SDMT scores will be summarized by study visit and by previous treatment group 
in Study 205MS301.  Change in the SDMT scores over the combined study period 
(Studies 205MS301 and 205MS303) will be calculated using the Study 205MS301 baseline visit 


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as baseline. Change in the SDMT score over the Study 205MS303 study period will be 
calculated using the last SDMT measurement in Study 205MS301 as baseline.
PASAT 3
Changes in the PASAT 3 scores will be summarized by study visit and by previous treatment 
group in Study 205MS301.  Change in the PASAT 3 scores over the combined study period 
(Studies 205MS301 and 205MS303) will be calculated using the Study 205MS301 baseline visit 
as baseline. Change in the PASAT 3 score over the Study 205MS303 study period will be 
calculated using the Week 0/baseline visit as baseline. 
MRI Endpoints
MRI endpoints will be summarized with descriptive statistics both as a continuous variable and 
categorically.  Over time summaries and summaries by previous treatment group (Avonex or 
DAC HYP 150 mg) may also be provided.  A negative binomial regression model will be used 
for the analysis of new or newly enlarging T2 lesions. The change in volume of lesions will be 
analyzed using an analysis of covariance.  
Quality of Life Outcomes
Actual scores and change from baseline in quality of life endpoints will be summarized by visit. 
Pharmacokinetics
The population for DAC HYP concentration analyses will include all subjects who received at 
least 1 dose of study medication and who have at least 1 sample available for analysis. 
Serum concentration levels will be summarized with descriptive statistics by visit.  
Antigenicity/Immunogenicity Data
Immunogenicity (i.e., ADAs to DAC HYP) will be assessed on subjects.  Positive samples will 
be further tested for NAbs to DAC HYP using a specific NAb assay.  Results will be tabulated 
by time period and overall.
16.5.
Interim Analyses
No formal interim analyses are planned for this study.  However, analyses may be performed 
prior to the end of the study at the discretion of the Sponsor. 
16.6.
Sample Size Considerations
There is no formal sample size calculation.  The number of subjects in this study is determined 
by the number of subjects who completed Study 205MS301, Study 205MS203, or
Study 205MS302.


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17.
ETHICAL REQUIREMENTS
Biogen and the Investigator must comply with all instructions, regulations, and agreements in 
this protocol and applicable International Council for Harmonisation (ICH) and Good Clinical 
Practice (GCP) guidelines and conduct the study according to local regulations.
17.1.
Declaration of Helsinki
The Investigator and Biogen must adhere to the principles set forth by the Declaration of 
Helsinki dated October 2008.
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. The Sponsor may submit documents on behalf of the 
study sites in countries other than the US as applicable. 
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 Principal Investigator(s) to ensure that all aspects of institutional 
review are conducted in accordance with current governmental 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 study site must submit a close-out letter to the 
ethics committee and Biogen.
17.3.
Subject Information and Consent
Prior to performing any study-related activities under this protocol, including Baseline/Entry 
Visit tests and assessments, written informed consent with the approved ICF must be obtained 
from the subject or subject’s legally authorized representative, as applicable, in accordance with 
local practice and regulations.  Written informed consent must be obtained from all subjects 
participating in a clinical study conducted by Biogen.
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.  The subject 
must be given sufficient time to consider whether to participate in the study.
A copy of the ICF, signed and dated by the subject, must be given to the subject.  Confirmation 
of a subject’s informed consent must also be documented in the subject’s medical record prior to 
any testing under this protocol, including Baseline/Entry Visit tests and assessments.


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Each consent form should contain an authorization allowing the Principal Investigator(s) and 
Biogen to use and disclose PHI (i.e., subject-identifiable health information) in compliance with 
local law.
The signed consent form will be retained with the study records.
17.4.
Subject Data Protection
Prior to any testing under this protocol, including Baseline/Entry Visit tests and assessments, 
candidates must also provide all authorizations required by local law (e.g., PHI authorization in 
North America).
The subject will not be identified by name in the CRF or in any study reports and these reports 
will be used for research purposes only. Biogen, its partner(s) and designee(s), ethics 
committees, and various government health agencies may inspect the records of this study.  
Every effort will be made to keep the subject’s personal medical data confidential.
17.5.
Compensation for Injury
Biogen maintains appropriate insurance coverage for clinical trials 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 the 
Sponsor) with the subject before the subject makes a decision to participate in the study.
17.7.
Registration of Study and Disclosure of Study Results
Biogen will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations.


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18.
ADMINISTRATIVE PROCEDURES
18.1.
Study Site Initiation
The Investigator must not enroll 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 on-site audits.  The Investigator will be expected to 
cooperate with any audit and to provide assistance and documentation (including source data) as 
requested.
18.3.
Monitoring of the Study
The Principal Investigator(s) must permit study-related monitoring by providing direct access to 
source data and to the subjects’ medical histories.
The Clinical Monitor(s) will visit the Investigator(s) at regular intervals during the course of 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.  
The 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 study site and its facilities.
18.4.
Study Funding
Biogen is the Sponsor of the study and is funding the study.  All financial details are provided in 
the separate contract(s) between the institution, Investigator, and Biogen.
18.5.
Publications
Details are included in the clinical trial agreement for this study.


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19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION
Biogen will be responsible for all administrative aspects of this study including, but not limited 
to, study initiation, monitoring, management of AEs, and data management.
19.1.
External Contract Organizations
19.1.1.
Contract Research Organization 
The CRO will be responsible for administrative aspects of the study including, but not limited to, 
study initiation, monitoring, and management of SAE reports. 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.
Electronic or Remote Data Capture
Subject information will be captured and managed by study sites on electronic CRFs via a 
remote data capturing system.
19.1.3.
Central Laboratories for Laboratory Assessments
A central laboratory has been selected by Biogen to analyze all hematology, blood chemistry, 
and urine samples collected for this study.
If local LFTs have been used to determine whether dosing should continue or be suspended at 
the time of a scheduled clinic visit, LFTs must also be performed at the central laboratory at the 
time of the scheduled clinic visit (Note:  Scheduled clinic visits occur every 4 weeks during the 
first 12 weeks of the study and every 12 weeks thereafter).     
19.1.4.
Central Facility for Independent Assessment of Biopsy Samples
A central laboratory service has been selected by Biogen to coordinate the collection and 
distribution of biopsy samples.  A central assessor has been selected to subsequently analyze skin 
biopsies or lymph node biopsies (as applicable).
19.1.5.
Central Facility for Other Assessments
MRI Reading Center
All scheduled MRI scans with and without Gd will be evaluated at a central MRI reading center.  
All study sites will be required to send a test scan 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 study site is permitted to enroll any subjects into the study.
Original MRI images are to be sent to the MRI Reading Center for review (MRI shipping 
instructions will be provided prior to the start of enrollment at each site).  
Additional and more detailed MRI scans with and without Gd procedures and instructions are 
included in the study MRI manual (to be provided under separate cover prior to start of the 
study).


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19.2.
Study Committees
19.2.1.
Advisory Committee
The Advisory Committee from parent Study 205MS301 will oversee the administrative progress 
and provide scientific and medical direction for this study while Study 205MS301 is ongoing. 
Advisory Committee will monitor subject accrual and compliance with the protocol at individual 
study sites.  The Advisory Committee will determine whether the study should be stopped or 
amended for reasons other than safety.
Members of the Advisory Committee will include the Medical Director, Clinical Trial Manager, 
and Project Statistician from Biogen (and/or their designees), and participating Investigators.  
Biogen will designate one of the participating Investigators to be the Chairperson of the 
Advisory Committee.
19.2.2.
Internal Safety Monitoring Committee
An internal Safety Monitoring Committee will be formed to review interim safety data on an 
ongoing basis. Investigational sites will be notified of any relevant safety findings that may 
jeopardize subject safety.
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 subject consent form may require similar 
modifications (see Section 17.2 and Section 17.3).
19.4.
Ethics Committee Notification of Study Completion or Termination
Where required, the Health Authorities and ethics committees must be notified of completion or 
termination of this study, and sent a copy of the study synopsis in accordance with necessary
timelines.
19.5.
Retention of Study Data
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local 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 


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must notify Biogen of any changes in the archival arrangements including, but not limited to, 
archival at an off-site 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.
Biogen will follow all applicable local regulations pertaining to study report signatories.


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20.
REFERENCES
Bielekova B, Howard T, Packer AN, et al. Effect of anti-CD25 antibody daclizumab in the 
inhibition of inflammation and stabilization of disease progression in multiple sclerosis. Arch 
Neurol. 2009;66(4):483-9.
Bielekova B, Richert N, Howard T, et al. Humanized anti-CD25 (daclizumab) inhibits disease 
activity in multiple sclerosis patients failing to respond to interferon beta. Proc Natl Acad Sci U 
S A. 2004;101(23):8705-8.
Fischer JS, LaRocca NG, Miller DM, et al. Recent developments in the assessment of quality of 
life in multiple sclerosis (MS). Mult Scler. 1999;5(4):251-9.
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status 
scale (EDSS). Neurology. 1983;33(11):1444-52. Epub 1983/11/01.
Rose JW. Treatment of Multiple Sclerosis with a Humanized Monoclonal Antibody Specific for 
IL-2 Receptor Chain. Neurology. 2003;60(Suppl 1):A478-9.
Rose JW, Watt HE, White AT, et al. Treatment of multiple sclerosis with an anti-interleukin-2 
receptor monoclonal antibody. Ann Neurol. 2004;56(6):864-7.
Wynn D, Kaufman M, Montalban X, et al. Daclizumab in active relapsing multiple sclerosis 
(CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with 
interferon beta. Lancet Neurol. 2010;9(4):381-90.


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21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “A Multicenter, Open-Label, Extension Study to Evaluate the 
Long-Term Safety and Efficacy of BIIB019, Daclizumab High Yield Process (DAC HYP),
Monotherapy in Subjects With Multiple Sclerosis Who Have Completed Study 205MS301” and 
agree to conduct the study according to the protocol and the applicable ICH guidelines and GCP 
regulations, and to inform all who assist me in the conduct of this study of their responsibilities 
and obligations.
____________________________________________________
Investigator’s Signature
Date
____________________________________________________
Investigator’s Name (Print)
____________________________________________________
Study Site (Print)


CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
1
Biogen MA Inc.
250 Binney Street
Cambridge, MA 02142
United States
PROTOCOL NUMBER:
205MS303
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead Berkshire
SL6 4AY
United Kingdom
PHASE OF DEVELOPMENT:
3
PROTOCOL TITLE:  A Multicenter, Open-Label, Extension Study to Evaluate the 
Long-Term Safety and Efficacy of BIIB019, Daclizumab High Yield Process (DAC HYP),
Monotherapy in Subjects With Multiple Sclerosis Who Have Completed Study 205MS301 
EUDRA CT NO:
2012-003176-39
DATE:
29 January 2016
Version 3
Final
Supersedes previous Version 2 dated 01 April 2015.


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TABLE OF CONTENTS
1.
SPONSOR INFORMATION .......................................................................................8
2.
LIST OF ABBREVIATIONS.......................................................................................9
3.
SYNOPSIS .................................................................................................................11
4.
STUDY SCHEMATIC AND SCHEDULE OF EVENTS TABLES FOR 
STUDY 205MS303 ....................................................................................................17
4.1.
Study Schematic .........................................................................................................17
4.2.
Schedule of Events .....................................................................................................19
5.
INTRODUCTION......................................................................................................33
5.1.
Profile of Previous Experience with Daclizumab in MS............................................33
5.2.
Study Rationale...........................................................................................................35
5.3.
Rationale for Dose and Schedule Selection................................................................35
6.
STUDY OBJECTIVES AND ENDPOINTS..............................................................37
6.1.
Objectives ...................................................................................................................37
6.1.1.
Primary Objective.......................................................................................................37
6.1.2.
Secondary Objectives .................................................................................................37
6.1.3.
Exploratory Objective.................................................................................................37
6.2.
Endpoints....................................................................................................................37
6.2.1.
Primary Endpoints ......................................................................................................37
6.2.2.
Secondary Endpoints ..................................................................................................37
7.
STUDY DESIGN .......................................................................................................39
7.1.
Study Overview ..........................................................................................................39
7.2.
Overall Study Duration and Follow-Up .....................................................................39
7.2.1.
Baseline/Entry Visit Assessments ..............................................................................39
7.2.2.
Treatment....................................................................................................................39
7.2.3.
Post-Treatment Long-Term Follow-Up......................................................................40
7.3.
Study Stopping Rules .................................................................................................40
7.4.
End of Study ...............................................................................................................40
8.
SELECTION OF SUBJECTS ....................................................................................41
8.1.
Inclusion Criteria ........................................................................................................41
8.2.
Exclusion Criteria.......................................................................................................41


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9.
ENROLLMENT AND REGISTRATION PROCEDURES ......................................43
9.1.
Enrollment and Screening...........................................................................................43
9.2.
Registration of Subjects..............................................................................................43
10.
STUDY TREATMENT MANAGEMENT................................................................44
10.1.
DAC HYP...................................................................................................................44
10.2.
DAC HYP Preparation ...............................................................................................44
10.3.
DAC HYP Accountability..........................................................................................45
11.
TREATMENT OF SUBJECTS..................................................................................46
11.1.
Study Treatment Schedule and Administration..........................................................46
11.2.
Placebo or Reference Product Agents ........................................................................46
11.3.
Treatment Precautions ................................................................................................46
11.4.
Treatment Compliance................................................................................................46
11.5.
Concomitant Therapy .................................................................................................47
11.6.
Continuation of Treatment..........................................................................................48
11.7.
Treatment Schedule Modifications.............................................................................49
11.7.1.
Infections ....................................................................................................................49
11.7.2.
Elevated Liver Function Tests....................................................................................49
11.7.3.
Cutaneous Events........................................................................................................51
11.7.4.
Gastrointestinal Events of Inflammatory Colitis ........................................................53
11.7.5.
Lymphadenopathy or Lymphadenitis Events .............................................................53
11.8.
Discontinuation of Study Treatment...........................................................................53
11.9.
Withdrawal of Subjects From Study...........................................................................55
12.
EFFICACY,  DAC HYP CONCENTRATION, AND 
 ASSESSMENTS..............................................................56
12.1.
Clinical Efficacy Assessments....................................................................................56
12.2.
Pharmacokinetic Assessments....................................................................................57
12.3.
.................................................................................57
12.4.
..............................................................................................57
13.
SAFETY ASSESSMENTS ........................................................................................58
13.1.
Clinical Safety Assessments.......................................................................................58
13.2.
Laboratory Safety Assessments..................................................................................58
13.3.
Study-Specific Safety Assessments............................................................................59


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14.
SCHEDULE OF EVENTS.........................................................................................60
14.1.
Overview.....................................................................................................................60
14.2.
Site Personnel .............................................................................................................61
14.3.
Subject Management ..................................................................................................63
14.4.
Special Instructions for Tests and Assessments .........................................................63
14.4.1.
Rescreening.................................................................................................................63
14.4.2.
Pregnancy Testing ......................................................................................................63
14.4.3.
Liver Function Test Assessments Prior to DAC HYP Dosing...................................63
14.4.4.
Other Assessments......................................................................................................64
14.5.
Definition of MS Relapse and Disability Progression................................................64
14.5.1.
MS Relapse.................................................................................................................64
14.5.2.
Disability Progression.................................................................................................65
14.6.
Management of MS Relapse.......................................................................................65
14.7.
Cutaneous Events........................................................................................................65
14.8.
Unscheduled Hepatic Assessment Visit .....................................................................66
14.9.
Lymphadenopathy and Lymphadenitis Events...........................................................66
14.10.
Post-Treatment Safety Follow-Up Visit Schedule for All Subjects...........................66
15.
SAFETY DEFINITIONS, MONITORING, AND REPORTING .............................67
15.1.
Definitions ..................................................................................................................67
15.1.1.
Serious Pretreatment Event.........................................................................................67
15.1.2.
Adverse Event.............................................................................................................67
15.1.3.
Serious Adverse Event................................................................................................67
15.2.
Monitoring and Recording Events..............................................................................68
15.2.1.
Serious Pretreatment Events.......................................................................................68
15.2.2.
Adverse Events ...........................................................................................................68
15.2.3.
Serious Adverse Events ..............................................................................................68
15.2.4.
All Events ...................................................................................................................68
15.2.5.
Immediate Reporting of Serious Adverse Events.......................................................68
15.2.5.1.
Deaths .........................................................................................................................69
15.3.
Safety Classifications..................................................................................................69
15.3.1.
Relationship of Events to Study Treatment................................................................69


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15.3.2.
Severity of Events.......................................................................................................70
15.3.3.
Expectedness of Events ..............................................................................................70
15.4.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments................70
15.5.
Procedures for Handling Special Situations ...............................................................71
15.5.1.
Overdose.....................................................................................................................71
15.5.2.
Medical Emergency....................................................................................................71
15.5.3.
Contraception Requirements ......................................................................................71
15.5.4.
Pregnancy ...................................................................................................................72
15.5.5.
Regulatory Reporting..................................................................................................72
15.6.
Investigator Responsibilities.......................................................................................72
15.7.
Biogen Responsibilities ..............................................................................................73
16.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........74
16.1.
Description of Objectives ...........................................................................................74
16.2.
Description of Endpoints............................................................................................74
16.3.
Demography and Baseline Disease Characteristics....................................................74
16.4.
Safety and Efficacy.....................................................................................................74
16.4.1.
Analysis Population....................................................................................................74
16.4.2.
General Methods of Analysis .....................................................................................74
16.4.3.
Primary Endpoints Analysis .......................................................................................75
16.4.4.
Other Safety Endpoint Analyses.................................................................................75
16.4.5.
Efficacy Endpoints Analyses......................................................................................76
16.5.
Interim Analyses.........................................................................................................77
16.6.
Sample Size Considerations .......................................................................................77
17.
ETHICAL REQUIREMENTS ...................................................................................78
17.1.
Declaration of Helsinki...............................................................................................78
17.2.
Ethics Committee........................................................................................................78
17.3.
Subject Information and Consent ...............................................................................78
17.4.
Subject Data Protection ..............................................................................................79
17.5.
Compensation for Injury.............................................................................................79
17.6.
Conflict of Interest......................................................................................................79
17.7.
Registration of Study and Disclosure of Study Results..............................................79


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18.
ADMINISTRATIVE PROCEDURES.......................................................................80
18.1.
Study Site Initiation....................................................................................................80
18.2.
Quality Assurance.......................................................................................................80
18.3.
Monitoring of the Study..............................................................................................80
18.4.
Study Funding.............................................................................................................80
18.5.
Publications.................................................................................................................80
19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION........................81
19.1.
External Contract Organizations.................................................................................81
19.1.1.
Contract Research Organization.................................................................................81
19.1.2.
Electronic or Remote Data Capture............................................................................81
19.1.3.
Central Laboratories for Laboratory Assessments .....................................................81
19.1.4.
Central Facility for Independent Assessment of Biopsy Samples..............................81
19.1.5.
Central Facility for Other Assessments ......................................................................81
19.2.
Study Committees.......................................................................................................82
19.2.1.
Advisory Committee...................................................................................................82
19.2.2.
Internal Safety Monitoring Committee.......................................................................82
19.3.
Changes to Final Study Protocol ................................................................................82
19.4.
Ethics Committee Notification of Study Completion or Termination........................82
19.5.
Retention of Study Data..............................................................................................82
19.6.
Study Report Signatory...............................................................................................83
20.
REFERENCES ...........................................................................................................84
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL.........................................85
LIST OF TABLES
Table 1:
Schedule of Activities:  Baseline Through Week 84 for Subjects Enrolling 
From Study 205MS301 Into Study 205MS303..........................................................19
Table 2:
Schedule of Activities:  Week 96 through Week 144 for Subjects Enrolling 
From Study 205MS301 Into Study 205MS303..........................................................22
Table 3:
Schedule of Activities:  Entry Visit (Week 144) for Subjects Enrolling From 
Study 205MS203 or Study 205MS302 Into Study 205MS303 ..................................24
Table 4:
Schedule of Activities:  Week 156 through Week 240 (End of Treatment) for 
Subjects Enrolling From Study 205MS301, Study 205MS203, or 
Study 205MS302 Into Study 205MS303....................................................................26


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Table 5:
Schedule of Activities:  Post-Treatment Safety Follow-Up .......................................29
Table 6:
Schedule of Activities:  Unscheduled Assessments ...................................................30
Table 7:
Schedule of Activities:  Autoinjector Use by Subjects at Selected Sites ...................31
Table 8:  
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs ...................76
LIST OF FIGURES
Figure 1:
Study Design...............................................................................................................18
Figure 2:
Flowchart for Management of Subjects With Clinically Significant 
Cutaneous Events........................................................................................................52


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


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2.
LIST OF ABBREVIATIONS
ADAs
anti-drug antibodies
AE
adverse event
ALT
alanine aminotransferase
ARR
annualized relapse rate 
AST
aspartate aminotransferase
AUDIT-C
Alcohol Use Disorders Identification Test - Consumption 
Questionnaire
BDI-II
Beck Depression Inventory, Second Edition
bpm
beats per minute
BUN
blood urea nitrogen
CRF
case report form
CRO
contract research organization
DAC HYP
Daclizumab High Yield Process
DHA
Directions for Handling and Administration
EDSS
Expanded Disability Status Scale
EQ-5D
European Quality of Life, 5-dimensions
EQ-VAS
European Quality of Life, visual analog scale
FDA
Food and Drug Administration
GCP
Good Clinical Practice
Gd
gadolinium
GGT
gamma-glutamyltransferase
HIV
human immunodeficiency virus
HRPQ
Health Related Productivity Questionnaire
HRU
health resource utilization
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IFN
interferon
IL-2
interleukin-2
IM
intramuscular 
ITT
intent-to-treat
IV
intravenous
IVIg
intravenous immunoglobulin
IVMP
intravenous methylprednisolone
LFT
liver function test
MRI
magnetic resonance imaging
MS
multiple sclerosis
MSFC
Multiple Sclerosis Functional Composite
MSIS-29
Multiple Sclerosis Impact Scale-29
NAbs
neutralizing antibodies
NK
natural killer cells


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PASAT 3
3-Second Paced Auditory Serial Addition Test
PFS
prefilled syringe
PHI
protected health information
PK
pharmacokinetic(s)
RRMS
relapsing-remitting multiple sclerosis
SABR
Safety and Benefit-Risk Management
SAE
serious adverse event
SC
subcutaneous
SDMT
Symbol Digit Modalities Test
SGOT
serum glutamic oxaloacetic transaminase; see AST
SGPT
serum glutamic pyruvic transaminase; see ALT
SNP
single nucleotide polymorphism
SUSAR
suspected unexpected serious adverse reaction
T1
MRI hypointense designation
T2
MRI hyperintense designation
T4
thyroxine
ULN
upper limit of normal
US
United States
VAS
visual analog scale


Protocol 205MS303
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Long-Term Extension Study to Evaluate the Safety and Efficacy of DAC HYP
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11
3.
SYNOPSIS
This is a brief summary.  For details refer to the body of the protocol.
Protocol Number:
205MS303
Protocol Title:
A Multicenter, Open-Label, Extension Study to Evaluate the 
Long-Term Safety and Efficacy of BIIB019, Daclizumab High
Yield Process (DAC HYP), Monotherapy in Subjects With 
Multiple Sclerosis Who Have Completed Study 205MS301
Version Number:
3
Name of Study Treatment:
Daclizumab High Yield Process (DAC HYP)
Study Indication:
Relapsing-Remitting Multiple Sclerosis (RRMS)
Phase of Development:
3
Rationale for the Study:
To evaluate the long-term safety, efficacy, and 
immunogenicity of DAC HYP in subjects with multiple 
sclerosis (MS) who have completed Study 205MS301
(DECIDE), Study 205MS203 (SELECTED), or 
Study 205MS302 (OBSERVE).
Study Objectives and 
Endpoints:
Objectives
Primary: 
The primary objective of the study is to assess the safety and 
tolerability of long-term treatment with DAC HYP 
monotherapy in subjects who completed Study 205MS301, 
Study 205MS203, or Study 205MS302.
Secondary:
Secondary objectives of this study in this study population 
are as follows:

To describe MS-related outcomes, including MS 
relapse, disability progression, MS lesion 
formation, and patient-reported impact of MS, 
following long-term treatment with DAC HYP

To assess the long-term immunogenicity of 
DAC HYP administered by prefilled syringe 
(PFS)




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
Change in Multiple Sclerosis Impact Scale-29 
(MSIS-29) physical and psychological scores 

Change in quality of life as assessed by the 
European Quality of Life, 5 dimensions (EQ-5D)
and European Quality of Life, visual analog scale
(EQ-VAS)  

Change in direct health resource utilization 
(HRU; hospitalizations, emergency room visits, 
and unscheduled neurologist visits)

Change in treatment satisfaction as assessed by 
the subject 

Change in subject productivity as assessed by the 
Health Related Productivity Questionnaire 
(HRPQ)

Changes in clinical laboratory assessments 
(hematology and blood chemistry)

Local tolerability as assessed by subject-reported 
injection site pain (visual analog scale [VAS]) 
and clinician injection site assessments

Incidence of anti-drug antibodies to DAC HYP 
over time

Incidence of neutralizing antibodies to DAC HYP 
over time
Study Design:
Multicenter, open-label, long-term extension study
Rationale for Dose and 
Schedule Selection:
The DAC HYP dose and schedule were used in the pivotal 
Phase 3 205MS301 study and will be the treatment regimen 
used in the commercial setting.  The same DAC HYP dose 
and schedule were used in Study 205MS203 and 
Study 205MS302.
Study Location:
Global
Number of Planned Subjects:
Approximately 1600 subjects.  This includes approximately 
1200 subjects who completed Study 205MS301. 
Additionally, approximately 400 subjects from the other 
ongoing DAC HYP extension studies (Study 205MS203 and 
Study 203MS302) will be eligible to enter Study 205MS303 
at Week 144 of Study 205MS303. 




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thyroid function panel [including thyroid-stimulating 
hormone and T4], urinalysis); urine pregnancy testing; Beck 
Depression Inventory, Second Edition; immunogenicity 
assessments; Alcohol Use Disorders Identification Test -
Consumption Questionnaire (AUDIT-C); and AE and 
concomitant medication monitoring will be performed in this 
study.  Additional comprehensive hepatic testing will be 
required for subjects who permanently discontinue study 
treatment due to elevated liver function tests.
Subject Reported 
Assessments:
Subject assessment of MSIS-29, EQ-5D quality of life 
questionnaire (the EQ-5D descriptive system and the 
respondent’s self-rated health on a vertical visual analog 
scale [EQ-VAS]), Treatment Satisfaction Questionnaire for 
Medication (before the first use of a PFS and at multiple 
timepoints during the study), Treatment Satisfaction Survey 
at selected sites (before the first and last use of an 
autoinjector), HRU, and HRPQ.
Statistical Methods:
Analyses will generally be descriptive in nature and will 
focus on data collected during Study 205MS303 only.  
Efficacy endpoints will be summarized for all subjects using 
descriptive statistics.  For relevant efficacy analyses, the data 
may be summarized for subjects by previous treatment group 
(Avonex® or DAC HYP 150 mg). The adjusted ARR and 
number of new or newly enlarging T2 lesions will be 
estimated using a negative binomial regression model.  The 
proportion of subjects with sustained progression and the 
proportion with a relapse will be estimated from the Kaplan-
Meier curve.  The incidence of AEs and changes in clinical 
laboratory assessments will also be summarized.   An 
analysis by 3- or 6-month intervals may also be performed.  
Summary statistics for other safety, efficacy, and 
pharmacokinetic (PK) endpoints will be presented.
Sample Size Determination: 
There is no formal sample size calculation for this study.  
The number of subjects in this study is determined by the 
number of subjects who completed Study 205MS301, 
Study 205MS203, or Study 205MS302, and enrolled in 
Study 205MS303.


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Study Stopping Rules:
Biogen may terminate this study, after informing 
Investigators, at any time.  Investigators will be notified by 
Biogen or designee if the study is placed on hold, completed, 
or closed.


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4.
STUDY SCHEMATIC AND SCHEDULE OF EVENTS TABLES 
FOR STUDY 205MS303
A schematic of the study design is provided in Section 4.1.
The tabulated schedule of events for this study is provided in Section 4.2.
4.1.
Study Schematic
Figure 1 shows the design of Study 205MS301 and its open-label extension, Study 205MS303, 
in which subjects from Study 205MS203 and 205MS302 enter at Week 144.


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Figure 1:
Study Design














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Concomitant Therapy and AEs
X
Protocol Compliance and DAC HYP 
Accountability
X
1When possible, subjects should be evaluated by the same Study Neurologist assigned to them in the parent studies. 
2Week 144 (start of Year 4) of Study 205MS303 will be the timepoint at which subjects from Study 205MS203 and Study 205MS302 enter Study 205MS303. 
Entry Visit must take place within 6 months of the last DAC HYP dose in the parent studies (i.e., Study 205MS203 or Study 205MS302). 
3ALT/SGPT, AST/SGOT, alkaline phosphatase, total bilirubin, and GGT only.
Pregnancy test results must be negative prior to dosing.
6Before a monthly dose of DAC HYP is given at the clinic, LFT results from a prior test performed within the previous 28(+4) days must be reviewed by the 
Study Neurologist or their backup.  






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6When possible, subjects should be evaluated by the same neurologist assigned to them in the parent studies. 
7Performed only for subjects originally enrolled from Study 205MS301.
8Before a monthly dose of DAC HYP is given, LFT results from a prior test performed within the previous 28(+4) days must be reviewed by the Study 
Neurologist or their backup.
9A window of 4 days applies to DAC HYP dose even if it is done at home.








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2Subjects must provide written informed consent for autoinjector use prior to first DAC HYP dose by autoinjector.
3The procedure for taking this measurement is provided in the Study Reference Manual.
4Injection Site Assessment to be completed as soon as possible but within 10 minutes after the injection at Visit 1.
5VAS to be completed as soon as possible after the injection is administered, but no later than 10-30 minutes post-injection.
6If the subject withdraws from the study or reverts to PFS use prior to receiving all 6 autoinjector doses, the subject should complete the Treatment Satisfaction 
Survey and the Patient Usability Survey provided for the Autoinjector 6 dosing day before returning to PFS or receiving alternative MS disease modifying 
therapy.


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5.
INTRODUCTION
5.1.
Profile of Previous Experience with Daclizumab in MS
Background
DAC HYP is a humanized monoclonal IgG1 antibody specific for CD25 (α subunit of the 
IL-2 receptor).  CD25 is expressed at low levels on resting T cells but is rapidly upregulated after 
T-cell activation, enabling high-affinity IL-2 signal transduction.  The primary hypothesis for 
using DAC HYP to treat MS is to selectively inhibit activated T cells.  
Anti-CD25 antibodies have multiple in vitro effects that suggest DAC HYP may directly 
decrease T-cell activation and proliferation.  These include inhibition of IL-2 dependent 
lymphocyte proliferation, disruption of both IL-2 dependent and independent pathways of 
IFN-gamma production, and interference in CD28-dependent CD40 ligand expression.  In vivo, 
daclizumab has been confirmed to cause expansion of CD56bright NK cells.  This expansion has 
also been shown to correlate with MRI-defined therapeutic response of daclizumab in MS.  
CD56bright NK cells are believed to have an immunoregulatory function, and they have been 
shown to kill activated T cells through a contact-dependent mechanism.  Therefore, selective 
inhibition of activated T cells with DAC HYP may occur through both direct and indirect 
mechanisms [Bielekova 2009; Bielekova 2004].  
Clinical Experience With Daclizumab in Multiple Sclerosis
Initial clinical studies of daclizumab in MS were conducted with material manufactured by 
F. Hoffmann-La Roche, Ltd. (Roche) at their facilities in Nutley, New Jersey (DAC Nutley)
[Bielekova 2004; Rose 2003; Rose 2004], and in Penzberg, Germany (DAC Penzberg) [Wynn 
2010].  Study 205MS301 is conducted with DAC HYP, which is produced using a different 
manufacturing process than the previous versions of daclizumab.  DAC HYP has characteristics 
that are similar to DAC Nutley and DAC Penzberg, although certain differences in 
physicochemical and biological characteristics have been observed (refer to the Investigator’s 
Brochure for details).  
Study 205MS201
Study 205MS201 (SELECT) was a double-blind, placebo-controlled study to evaluate the safety 
and efficacy of DAC HYP in subjects with RRMS that randomized 621 subjects in a 1:1:1 ratio 
to receive placebo, 150 mg DAC HYP, or 300 mg DAC HYP SC every 4 weeks over a 52-week 
treatment period.  Among subjects randomized to DAC HYP (150 mg, 300 mg) versus placebo, 
there was a significantly lower annualized relapse rate (ARR; 0.21, 0.23 versus 0.46; p < 0.001), 
a higher proportion of relapse-free subjects (81%, 80% versus 64%; p < 0.001), and a trend 
towards improvement in the MSIS-29 physical score (p = 0.128 for DAC HYP 300 mg versus 
placebo; p < 0.001 for DAC HYP 150 mg versus placebo).  There were significant reductions in 
the mean number of new or newly enlarging T2 lesions at 1 year (2.4, 1.7 versus 8.1) and in the 
mean number of new Gd+ lesions between Weeks 8 and 24 in a monthly MRI substudy 
(n = 307) (1.5, 1.0 versus 4.8) in the DAC HYP 150 mg and 300 mg groups versus placebo 


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(p < 0.001 for all comparisons).  The risk of 3-month sustained disability progression at 1 year, a 
tertiary study endpoint, was reduced by 57% (p = 0.021) in the DAC HYP 150 mg group and by 
43% (p = 0.091) in the DAC HYP 300 mg group.  
Analysis of safety data from Study 205MS201 showed that, overall, DAC HYP was well 
tolerated in this patient population.  The most frequently reported (≥10%) AEs for subjects 
treated with DAC HYP, excluding MS relapse, were nasopharyngitis (14%), and headache and 
upper respiratory tract infection (10% each).  In Study 205MS201, serious adverse events 
(SAEs) including MS relapses occurred in 26% of placebo-treated subjects and in 16% of 
subjects treated with DAC HYP.  Excluding MS relapses, SAEs occurred in 6% of the placebo 
group, in 7% of the DAC HYP 150 mg group, and in 9% of the DAC HYP 300 mg group.  
One DAC HYP-treated subject died due to ischemic colitis following a complicated course of 
events.  Adverse events observed more frequently in DAC HYP-treated patients included an 
increase in serious infections (2%), serious cutaneous events (1%), and elevations in LFTs 
(ALT/AST) >5ULN (4%).
Upon completion of the 12-month treatment period in Study 205MS201, subjects were eligible to 
complete up to an additional 12 months of treatment with DAC HYP in a double-blind extension 
study (Study 205MS202 [SELECTION]), which was completed in 2012.  Study 205MS202 also 
assessed the effects of DAC HYP washout in some subjects who were actively treated in 
Study 205MS201.  Subjects completing Study 205MS202 continued long-term therapy with 
open-label DAC HYP in extension Study 205MS203 (SELECTED), which evaluated long-term 
safety and efficacy of DAC HYP monotherapy for up to an additional 144 weeks.
Study 205MS301
Study 205MS301 (DECIDE), a double-blind, randomized, parallel-group, active-controlled study 
testing the superiority of DAC HYP monotherapy compared to Avonex® (IFN -1a) in 
preventing MS relapse, was initiated in May 2010; 1841 subjects with RRMS have been enrolled 
and randomized in a 1:1 ratio to receive 150 mg DAC HYP given SC every 4 weeks, or Avonex 
30 mcg given IM once weekly over a 96- to 144-week treatment period. The primary endpoint 
was the annualized relapse rate.  In this study, DAC HYP demonstrated statistically and 
clinically meaningful superiority to IFN β-1a, on validated clinical, radiographic, and patient-
reported MS outcome measures.  DAC HYP reduced the annualized relapse rate by 45% 
(p<0.0001) compared to IFN β-1a.  DAC HYP’s treatment effect on relapses was also evidenced 
by a 41% reduction in the risk of relapse in subjects in the DAC HYP group compared to the 
IFN β-1a group (p<0.0001).  A reduction in the proportion of subjects relapsing was observed as 
early as 24 weeks after the initiation of treatment and persisted throughout the end of the study.  
The risk of 12-week confirmed disability progression was reduced by 16% in the DAC HYP 
group compared with the IFN β-1a group, a result that was not statistically significant 
(p=0.1575) in the primary analysis.  In the pre-specified analysis of 24-week confirmed 
progression, disability progression was reduced by 27% (p=0.0332) in the DAC HYP group 
compared with the IFN β-1a group.  Overall, the results of the 12-week and 24-week confirmed 
progression analyses were consistent with each other and supported a clinically meaningful 
effect of DAC HYP in preventing confirmed disability progression compared with IFN β-1a.  
DAC HYP reduced the number of new or newly enlarging T2 lesions at Week 96 by 54.4% 
(p<0.0001) compared to IFN β-1a.  The magnitude of the treatment effect was consistent with 


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the results seen on the primary endpoint of annualized relapse rate.  The tertiary MRI endpoints 
of T2, T1, and Gd-enhancing lesion count and volume were also consistent with the effect on 
new or enlarging T2 lesions and provide important confirmation of DAC HYP’s ability to reduce 
focal and destructive areas of brain inflammation in RRMS patients.  The treatment effect of 
DAC HYP on new or enlarging T2 lesions and other MRI endpoints was detectable by Week 24 
(p<0.0001) and was sustained through to the Week 96 and Week 144 MRI at a similar 
magnitude.  
In Study 205MS301, the safety profile of DAC HYP was characterized by an increased 
incidence of elevations of serum transaminases and serious hepatic events, cutaneous events,
infections, and gastrointestinal events.  The overall incidence of AEs was balanced across the 
2 treatment groups (91% IFN β-1a vs. 91% DAC HYP).  The majority of subjects with AEs had 
events that were mild to moderate in severity.  The incidence of subjects with AEs that were 
considered severe was 14% in the DAC HYP group and 12% in the IFN β-1a group.  AEs 
reported more frequently in the DAC HYP group than in the IFN β-1a group included 
nasopharyngitis, upper respiratory tract infections, influenza, oropharyngeal pain, rash, and 
lymphadenopathy, whereas influenza-like illness, pyrexia, chills, and hypertension were reported 
more frequently in the IFN β-1a group.
There was a higher incidence of SAEs in the DAC HYP group (24%) compared with the 
IFN β-1a group (21%).  Excluding MS relapse, SAEs were reported in 10% of the IFN β-1a 
group and in 15% of the DAC HYP group.  Five deaths were reported in the study (4 subjects in 
the IFN β-1a group, 1 subject in the DAC HYP group).  None of the deaths were considered by 
the Investigators to be related to study treatment.  While safety events were more common in the 
DAC HYP-treated subjects compared with IFN β-1a-treated subjects, the types of events were 
generally manageable with standard medical care, monitoring, and treatment discontinuation, as 
appropriate for the event.  Overall, the results of the study support a positive benefit/risk profile 
for DAC HYP.
The PK and immunogenicity of DAC HYP 150 mg SC administered every 4 weeks using a 
prefilled syringe (PFS) were investigated in 26 subjects in Study 205MS302 (OBSERVE), a
single-arm, open-label study that enrolled a total of 113 subjects with RRMS.
Refer to the Investigator’s Brochure for additional details.
5.2.
Study Rationale
This study will evaluate the long-term safety, efficacy, and immunogenicity of DAC HYP in 
subjects with MS who have completed Study 205MS301, Study 205MS203, or 
Study 205MS302. In addition, this study will assess the safety, tolerability, and efficacy of 
switching to DAC HYP in subjects previously on long-term treatment with interferon β-1a in 
Study 205MS301.
5.3.
Rationale for Dose and Schedule Selection
The existing scientific and clinical experience with DAC HYP supports its further investigation 
in the management of MS.  The DAC HYP dose and schedule in this protocol were used in the 
pivotal Phase 3 Study 205MS301 and will be the treatment regimen used in the commercial 


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setting.  The same DAC HYP dose and schedule were used in Study 205MS203 and 
Study 205MS302.
A single-use, disposable PFS will be provided to simplify the injection process and thereby 
reduce the burden of administering a long-term therapy such as DAC HYP in the clinic or at 
home. At the Sponsor’s discretion, single-use autoinjectors containing PFS may be used to 
administer DAC HYP in 75-100 subjects from Study 205MS303 at selected sites. Autoinjectors 
will be dispensed to each participating subject for use on up to 6 consecutive scheduled dosing 
days.




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
Change in EDSS score

Change in Symbol Digit Modalities Test (SDMT) score

Change in 3-Second Paced Auditory Serial Addition Test (PASAT 3) score

Proportion of subjects who are free from disease activity.

Change in Multiple Sclerosis Impact Scale-29 (MSIS-29) physical and psychological 
scores 

Change in quality of life as assessed by the European Quality of Life, 5 dimensions 
(EQ-5D and EQ-VAS)  

Change in direct health resource utilization (HRU; hospitalizations, emergency room 
visits, and unscheduled neurologist visits) 

Change in treatment satisfaction as assessed by the subject

Change in subject productivity as assessed by the Health Related Productivity 
Questionnaire (HRPQ)

Changes in clinical laboratory assessments (hematology and blood chemistry)

Local tolerability as assessed by subject-reported injection site pain (VAS) and 
clinician injection site assessments

Incidence of anti-drug antibodies (ADAs) to DAC HYP over time

Incidence of neutralizing antibodies (NAbs) to DAC HYP over time


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7.
STUDY DESIGN
7.1.
Study Overview
The design of Study 205MS303 is provided in Figure 1.  Approximately 1600 subjects will 
enroll in this study.  This includes approximately 1200 subjects who completed Study 
205MS301.  Additionally, approximately 400 subjects from the other DAC HYP extension 
studies (205MS203 [SELECTED] and 203MS302 [OBSERVE]) will be eligible to enter 
Study 205MS303 at Week 144 of Study 205MS303 (Study 205MS301, Study 205MS203, and 
Study 205MS302 have been referred to as parent studies in the protocol).
All subjects will receive the same dose of DAC HYP as received in the parent studies; 
i.e., 150 mg by an SC injection every 4 weeks.  The duration of DAC HYP treatment is up to 
approximately 5 years, or until availability of commercial product (whichever is sooner).
7.2.
Overall Study Duration and Follow-Up
The study period will consist of Baseline/Entry Visit assessments, treatment (for up to 
approximately 5 years), and post-treatment safety follow-up visits (from approximately 4 to 
24 weeks after the last dose of DAC HYP).
7.2.1.
Baseline/Entry Visit Assessments
Subjects Entering From Study 205MS301
Tests/assessments performed at the subject’s last visit in Study 205MS301 and within 28 days of 
the subject’s first dose of DAC HYP (Week 0) in Study 205MS303 may be used as the baseline 
for Study 205MS303; if final Study 205MS301 tests/assessments are not performed within the 
28-day window, they must be repeated upon entry into Study 205MS303 and before the first 
dose of DAC HYP is administered. 
Subjects Entering From Study 205MS203 or Study 205MS302
The Week 144 Visit of Study 205MS303 will be the Entry Visit for subjects enrolled from 
Study 205MS203 or Study 205MS302.  Any test/assessment done at the subject’s last visit in 
parent studies and within 28 days of the subject’s first dose in Study 205MS303 will be used as 
the baseline and does not need to be repeated at entry into Study 205MS303; tests/assessments 
performed >28 days before the Entry Visit must be repeated at the Entry Visit.  Central LFT 
testing is mandatory at the Entry Visit.
7.2.2.
Treatment
Subjects from Study 205MS301 continuing in Study 205MS303 will receive DAC HYP 
treatment for up to approximately 5 years, or until availability of commercial product (whichever 
is sooner), under this protocol.  Subjects from Study 205MS203 and Study 205MS302 entering 
Study 205MS303 at Week 144 will have DAC HYP treatment for up to approximately 2 years, 
or until availability of commercial product (whichever is sooner), under this protocol.


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At the Sponsor’s discretion, 75-100 subjects from Study 205MS303 at selected sites may dose 
with DAC HYP using a single-use autoinjector that contains a PFS on 6 consecutive scheduled 
dosing days (Table 7).
Eligible subjects will have clinic visits scheduled every 4 weeks for up to Week 12 in this study, 
followed by clinic visits scheduled every 12 weeks. 
Subjects who are dosing at home must be instructed to not administer their monthly dose 
of DAC HYP until the study site has contacted them to authorize dosing (after the Study
Neurologist or their backup has reviewed LFT results obtained during the previous 28[+4] days).  
Subjects need to record the date and time of dosing in their diary if they are dosing at home.
A window of ±4 days applies to scheduled visits and home dosing.
7.2.3.
Post-Treatment Long-Term Follow-Up
Subjects are to return to the study site for follow-up visits at 8, 12, 16, and 24 weeks (±10 days) 
after the last dose of DAC HYP.
7.3.
Study Stopping Rules
Biogen may terminate this study, after informing Investigators, at any time.  Investigators will be 
notified by Biogen or designee if the study is placed on hold, completed, or closed.
7.4.
End of Study
The End of Study is last subject, last visit for final collection of data.


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8.
SELECTION OF SUBJECTS
8.1.
Inclusion Criteria
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at the 205MS303 Baseline/Entry Visit or at the timepoint specified in the individual eligibility 
criterion listed (Note:  Week 0/Day 1 is the Baseline Visit in Study 205MS303 for 205MS301 
subjects.  Week 144 is the Entry Visit in Study 205MS303 for 205MS203 and 205MS302 
subjects): 
1. Ability to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use protected health information (PHI) in 
accordance with national and local subject privacy regulations.  
2. Must be a subject currently participating in Study 205MS301 who has completed either 
the Week 144 Visit or the End of Study Visit (Week 96) of Study 205MS301 OR subject 
currently participating in Study 205MS203 or Study 205MS302.
3. Women of childbearing potential must practice effective contraception during the study 
and be willing and able to continue contraception for 4 months after their last dose of 
study treatment.
8.2.
Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
the Study 205MS303 Baseline/Entry Visit or at the timepoint specified in the individual criterion 
listed (Note:  Week 0/Day 1 is the Baseline Visit in Study 205MS303 for 205MS301 subjects. 
Week 144 is the Entry Visit in Study 205MS303 for 205MS203 and 205MS302 subjects):
Medical History
1. Any subject who permanently discontinued study treatment in Study 205MS301, 
Study 205MS203, or Study 205MS302 prior to the end of the study treatment period, or 
had an early termination in those studies OR any subject who has completed all the safety 
follow-up visits after Week 144 of Study 205MS303 per the original protocol. 
Note:  Subjects for whom dosing was temporarily suspended in Study 205MS301, 
Study 205MS203, or Study 205MS302 are not excluded from participation in this 
extension study if the criteria for resuming DAC HYP treatment under the parent study
protocol have been met at the time of enrollment into Study 205MS303.  
2. Any significant change in the subject’s medical history that would preclude 
administration of DAC HYP, including laboratory tests or a current clinically significant 
condition that, in the opinion of the Investigator, would have excluded the subject’s 
participation in Study 205MS301, Study 205MS203, or Study 205MS302.  The 
Investigator must re-review the subject’s medical fitness for participation and consider 
any factors that would preclude treatment in Study 205MS303, including:  


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
History of any significant cardiac, endocrine, hematological, hepatic, immunologic, 
metabolic, urologic, pulmonary, gastrointestinal, dermatologic, psychiatric, renal, 
neurological (other than MS), and/or other major disease (e.g., malignancy) that 
would preclude administration of DAC HYP.

Clinically significant laboratory abnormalities (hematology and blood chemistry) 
from the most recently available test in the parent study, as determined by the 
Investigator.  Laboratory findings mandating discontinuation of study treatment as 
defined in parent study protocol are exclusionary.
3. Other medical reasons that, in the opinion of the Investigator and/or Biogen, make the 
subject unsuitable for enrollment.  
Treatment History
4. Treatment with any prohibited concomitant medication during the parent study, as 
described in Section 11.5 of this protocol.
Note:  Subjects who start an approved, open-label IFN β preparation after completion of 
dosing in Study 205MS301 are not excluded, but IFN β treatment must be discontinued 
before the first dose of DAC HYP in Study 205MS303 is given.  
Miscellaneous
5. Female subjects who are currently pregnant or breastfeeding, or considering becoming 
pregnant while in the study.
6. History of drug or alcohol abuse (as defined by the Investigator) at any time after the start 
of Study 205MS303 or any of the parent studies.
7. Unwillingness or inability to comply with the requirements of the protocol, including the 
presence of any condition (physical, mental, or social) that is likely to affect the subject’s 
ability to comply with the protocol.


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9.
ENROLLMENT AND REGISTRATION PROCEDURES
9.1.
Enrollment and Screening
Subjects must be consented before any procedures are performed.  At the time of consent, the 
subject will be enrolled into the study.  If a subject is excluded from the study, the reasons for 
exclusion will be documented in the subject’s source documents and on the enrollment log. Any 
test/assessment done at the subject’s last visit in the parent studies and within 28 days of the 
subject’s first dose in Study 205MS303 will be used as the baseline for Study 205MS303 and 
does not need to be repeated at entry into Study 205MS303 (Note:  Central LFT testing is 
mandatory at the Week 144 Entry Visit for subjects rolling over from Study 205MS203 and 
Study 205MS302 into Study 205MS303).  Testing required at the Baseline/Entry Visit that is 
done outside the 28-day window must be repeated upon entry into 205MS303.  
9.2.
Registration of Subjects
Subjects should be registered in the study after the Investigator has verified that they are eligible 
per the criteria in Section 8.1 and Section 8.2 and all baseline assessments have been performed. 
No subject may begin treatment prior to enrollment and registration. 
As confirmation, the Investigator will be provided with written verification of the subject’s 
registration by mail or fax.  
Refer to the Study Reference Manual for details on registration.


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10.
STUDY TREATMENT MANAGEMENT
Study treatment (PFS or autoinjectors) must be stored in a secure location.  Accountability for 
study treatment is the responsibility of the Investigator.  Study treatment must only be dispensed 
by a Pharmacist or medically qualified staff, and stored in a secure, monitored, locked location in 
accordance with the conditions specified in current prescribing information or the Directions for 
Handling and Administration (DHA) included in the Study Reference Manual.
Study treatment is to be dispensed only to subjects enrolled in this study.  Once treatment is 
dispensed to a subject, it can only be used by that subject.
10.1.
DAC HYP
Prefilled Syringe 
DAC HYP is supplied as a liquid in a 1-mL BD-staked PFS with a 29 gauge × ½ inch needle, 
comprising 150 mg/mL DAC HYP plus excipient materials (sodium succinate, sodium chloride, 
and polysorbate 80).  At a minimum, the study treatment label will include a study reference 
code, drug identifier, quantity of dosage units, lot number, and other pertinent information in 
accordance with local law.  Depending on country requirements, the Investigator’s name may 
also appear on the label.  DAC HYP must not be used after the expiration date unless a written 
notification of an expiration date extension is provided by Biogen.
Autoinjector 
The DAC HYP PFS is assembled inside a single-use, disposable autoinjector device.  
The autoinjector label will include the DAC HYP product code “BIIB019,” conditions for 
storage, Sponsor, and a caution statement.  Depending on country requirements, the 
Investigator’s name may also appear on the label.  DAC HYP must not be used after the 
expiration date unless a written notification of an expiration date extension is provided by 
Biogen.
10.2.
DAC HYP Preparation
Each DAC HYP PFS or autoinjector contains only one dose and is intended for SINGLE USE 
INJECTION ONLY.  Any drug that remains in the PFS after injection must not be used for 
another dose or another subject. 
After Week 12, subjects may choose to administer their DAC HYP dose at home, either by 
administering the injection themselves or by a designated caregiver. The subject or designated 
caregiver will be trained by clinic staff on the correct PFS injection technique prior to initiating 
at-home DAC HYP dosing.
Autoinjectors may be provided to selected sites and will be supplied injection-ready.  Study 
personnel or subjects at these sites do not need to insert the PFS into the device. Study site 
personnel will receive appropriate autoinjector training from a Sponsor-designated trainer prior 
to initiation of autoinjector use.


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10.3.
DAC HYP Accountability
The study site must maintain accurate records demonstrating dates and amount of study 
treatment received, to whom dispensed (subject-by-subject accounting), any amount returned by 
subject, and accounts of any study treatment accidentally or deliberately destroyed.  
Unless otherwise notified, all PFS and autoinjectors, both used and unused, must be saved for 
study treatment accountability.  At the end of the study, a final reconciliation must be made 
between the amount of study treatment supplied, dispensed, and subsequently destroyed or 
returned to Biogen. 
A written explanation will be provided for any discrepancies.  After reconciliation, the 
Investigator must destroy or return to Biogen all unused study treatment PFS and autoinjectors as 
instructed by Biogen.
If any study treatment supplies are to be destroyed at the site, the Principal Investigator(s) must 
obtain prior approval by Biogen.  The Principal Investigator(s) must notify Biogen, in writing, of 
the method, date, and location of destruction.  


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11.
TREATMENT OF SUBJECTS
Biogen will provide DAC HYP (PFS or autoinjectors) to all study sites.
Refer to Section 10 (Study Treatment Management) for specifics on the preparation, storage, 
handling, disposal, and accountability of study treatment.
11.1.
Study Treatment Schedule and Administration
All subjects will receive one DAC HYP 150 mg SC injection every 4 weeks.  
DAC HYP will be administered by clinic staff at the monthly visits for the first 12 weeks of this 
study.  After Week 12, administration of DAC HYP may occur in the clinic or at home (by the 
subject or by a designated caregiver) depending on subject preference.  The subject or designated 
caregiver will be trained by clinic staff on the correct injection technique prior to initiating 
at-home DAC HYP dosing.  Subjects who are dosing at home must be instructed to not 
administer their monthly dose of DAC HYP until the study site has contacted them to 
authorize dosing.  A window of ±4 days applies to home dosing.
Before a monthly dose of DAC HYP is given, LFT results from a prior test performed within the 
previous 28(+4) days must be reviewed by the Study Neurologist or their backup. Study 
personnel should promptly inform the subject whether the monthly dose of DAC HYP should be 
administered or whether study treatment is to be withheld based on the dosing criteria defined in 
Section 11.7.2.  Study personnel will document this communication with the subject. Subjects 
should administer DAC HYP as soon as permission has been given as per the dosing schedule.  
Subjects need to record the date and time of dosing in their diary if they are dosing at home.
11.2.
Placebo or Reference Product Agents
Not applicable.
11.3.
Treatment Precautions
Anaphylactic-like and hypersensitivity reactions following administration of proteins such as 
DAC HYP can occur.  DAC HYP will be administered in the clinic under observation by 
qualified medical personnel for the first 12 weeks of this study.  Subjects will be educated by the 
Study Neurologist or their back-up on the signs and symptoms of hypersensitivity reactions and 
instructed to contact the site if they experience any acute or delayed reactions post injection.  
11.4.
Treatment Compliance
Compliance with treatment dosing is to be monitored and recorded by study site staff.
After Week 12, subjects who choose to administer their DAC HYP dose at home will record 
treatment in a dosing diary.  The diary will be reviewed periodically by study site staff and the 
Clinical Monitor throughout the study.  Subjects who choose at-home administration will return 
used PFS or autoinjectors to the clinic at their scheduled clinic visits.  


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11.5.
Concomitant Therapy
A concomitant therapy is any drug or substance administered from the Baseline/Entry Visit until 
completion of the study. A concomitant procedure is defined as any therapeutic intervention 
(e.g., surgery/biopsy, physical therapy) or diagnostic assessment (e.g., blood gas measurement, 
bacterial cultures) performed from the time the subject is enrolled in the study until the subject’s 
final clinic visit.
Concomitant treatment with any of the following is not allowed during the study, unless 
approved by the Biogen Medical Director(s) or the Advisory Committee, or as otherwise 
described in this protocol:

Any alternative disease modifying MS drug treatment such as chronic 
immunosuppressant therapy or other immunomodulatory treatments (including, but 
not limited to:  IFN-β, IFN-α, glatiramer acetate, cyclophosphamide, methotrexate, 
mycophenolate mofetil, mitoxantrone, cyclosporine, azathioprine, or related 
products).

Any investigational product, including investigational symptomatic therapies for MS 
and investigational therapies for non-MS indications.

Any monoclonal antibodies other than DAC HYP.

Intravenous immunoglobulin (IVIg), plasmapheresis or cytapheresis, total lymphoid 
irradiation, or T-cell or T-cell receptor vaccination.

Any systemic steroid therapy including, but not limited to, oral corticosteroids 
(e.g., prednisone) or periodic (e.g., monthly) treatment with IV methylprednisolone 
(IVMP), except for protocol-defined treatment of relapses as described in
Section 14.6 or for limited, acute treatment of general medical conditions as per the 
discretion of Study Neurologist.  Steroids that are administered by non-systemic 
routes (e.g., topical, inhaled) are allowed.

Antineoplastic or chemotherapeutic agents, including, but not limited to, 
cyclophosphamide, methotrexate, azathioprine, cladribine, cytarabine, or flutamide.

Valproic acid, carbamazepine, lamotrigine, or phenytoin.  Subjects who have been 
taking 1 of these medications at a stable dose for at least 6 consecutive months may 
continue to receive the medication and may continue study treatment under this 
protocol.  However, if any of these medications must be initiated or dose escalated, 
study treatment must be permanently discontinued as described in Section 11.8.  
Subjects who have been treated with any of these medications (which have not been
approved by the Biogen Medical Director[s]) for fewer than 6 consecutive months, or 
who take more than 1 of these medications, or who have had dose escalations within 
the past 6 months must do 1 of the following:

Discontinue the medication (any agent used for <6 consecutive months must be 
discontinued).  Subjects may use an alternative medication allowed by the 
protocol, if needed.


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
Subjects taking more than 1 agent must reduce to 1 agent (any agent that is 
continued must have been taken for at least 6 consecutive months).

In the case of dose escalation, revert to a previous dose that had been used for at 
least 6 months.

Permanently discontinue study treatment.

Isoniazid, propylthiouracil, or nimesulide.  Subjects who currently take any of these 
medications must either change to an alternative medication allowed by the protocol 
or permanently discontinue study treatment.  
Subjects who receive any of these restricted medications may be required to permanently 
discontinue study treatment as outlined in Section 11.8.  Subjects who permanently discontinue 
study treatment will be allowed to receive IVMP as treatment for MS relapse while they are 
participating in the study, as described in Section 11.8.
Use of the following medications is strongly discouraged during the study:

Herbal or dietary supplements. 

Agents that have established risks of hepatotoxicity or serious rash according to 
labeling information (examples include, but are not limited to, 
amoxicillin/clavulanate, clarithromycin, ketoconazole, minocycline, nitrofurantoin, 
trimethoprim/sulfamethoxazole, diclofenac, sulfasalazine, amiodarone, methyldopa, 
nefazodone, and halothane).  Alternatives to these therapies should be used whenever 
possible.
Symptomatic therapy, such as treatment for spasticity, depression, or fatigue is not restricted, but 
should be optimized as early as possible in an attempt to maintain consistent treatment for the 
duration of the study. Initiation of Fampridine-SR after enrollment is permitted, including when 
it is used in the acute management of protocol-defined relapse (as described in Section 14.6).
Subjects should be instructed not to start taking any new medications, including non-prescribed 
medications, unless they have received permission from the Investigator.  The use of live 
vaccines in humans concurrently treated with daclizumab has not been explored; therefore live 
vaccines should not be administered to MS subjects who are being treated with DAC HYP.
The use of concomitant therapies or procedures defined in this section must be recorded on the 
subject’s case report form (CRF), according to instructions for CRF completion (Note: 
concomitant therapies in the parent study that continued at Study 205MS303 entry must be 
recorded on the CRF).  AEs related to administration of these therapies or procedures must be 
documented on the appropriate CRF.  For subjects who prematurely discontinue study treatment, 
all concomitant medications should be recorded throughout the remainder of the subject’s 
participation in the study.
11.6.
Continuation of Treatment 
No further provisions are made for access to the study treatment.  If DAC HYP is proven to be 
beneficial, all regulatory requirements regarding poststudy access will be met.


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11.7.
Treatment Schedule Modifications
Subjects who experience a significant change in their medical status (e.g., neurological 
worsening/suspected MS relapse, possible injection-site reaction, infection, cutaneous event,
fever, abdominal pain, persistent diarrhea, jaundice, nausea, vomiting, pruritus) must contact the 
Study Neurologist as soon as possible and no more than 48 hours after symptom onset.  The 
subject should then be evaluated by the Study Neurologist within no more than 72 hours for 
physical and neurological assessments and further treatment recommendations if appropriate.  
These subjects should not administer additional DAC HYP until they have been evaluated by the 
Study Neurologist or their backup.
Unscheduled PK/
 Visit (Table 6) can be performed in subjects who have evidence of 
significant changes in their medical conditions (as assessed by the Investigator).  This visit must 
be approved by the Biogen Medical Director in advance.
Additional treatment considerations for specific events are described below.
11.7.1.
Infections
Subjects who have evidence of a clinically significant infection will be instructed to notify the 
Study Neurologist or their backup within 48 hours of onset, and scheduled dosing of DAC HYP 
may be withheld.  If the subject’s infection resolves within 2 weeks of the scheduled DAC HYP 
dose, the subject may receive the previously scheduled dose of DAC HYP at that time.  If the 
infection has not resolved within the 2 weeks, dosing of DAC HYP will remain suspended, and 
the subject will miss dosing until the infection is resolved.  
11.7.2.
Elevated Liver Function Tests
Before a monthly dose of DAC HYP is given, LFT results from a prior test (performed within 
28[+4] days) must be reviewed by the Study Neurologist or their backup, and must be within the 
protocol-required limits shown below (LFT procedures are described in Section 14.4.3).
Study treatment must be temporarily suspended if a subject develops any of the following: 

ALT/SGPT or AST/SGOT >3ULN  

any other clinically significant hepatic condition in the opinion of the Investigator 
including jaundice
Note:  For subjects who present with jaundice, an LFT must be performed as soon as possible.
After a suspension, dosing of DAC HYP may be resumed when ALT/SGPT and AST/SGOT are 
<2×ULN provided that the criteria for permanent discontinuation have not been met (see 
Section 11.8).
Study treatment must be permanently discontinued if a subject develops any of the following:

ALT/SGPT or AST/SGOT elevation >8×ULN that is confirmed by a repeat test 
(preferably within 24 hours)

ALT/SGPT or AST/SGOT >5×ULN for more than 2 weeks


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
ALT/SGPT or AST/SGOT >3×ULN with concomitant elevation of total bilirubin 
>2×ULN 

If a subject has treatment suspended for an LFT elevation and has also had a prior 
treatment suspension for an LFT elevation during DAC HYP use, DAC HYP must be 
permanently discontinued unless an alternative explanation for the LFT elevation 
unrelated to DAC HYP use is clearly identified by the Investigator.
All subjects with elevated LFTs (ALT/SGPT or AST/SGOT >3×ULN) should be managed per 
the guidelines below.

Study treatment must be temporarily suspended and LFT elevation should be confirmed
as soon as possible but no later than a week by a repeat test performed at the central 
laboratory. In cases where LFTs cannot be performed via the central laboratory, repeat 
LFT results from local laboratory can be used for confirmation. 

All subsequent testing after a treatment suspension or discontinuation is required to be 
performed centrally at least weekly until the LFT elevation has resolved. 

In subjects with treatment suspension or discontinuation, DAC HYP treatment may 
resume if a laboratory error is documented upon repeat testing OR when ALT/SGPT and 
AST/SGOT are <2×ULN provided that the criteria for permanent discontinuation have 
not been met (see Section 11.8).

A careful review of all concomitant medications must be documented.  The Investigator 
should consider discontinuation of all potential hepatotoxic medications.  All recently 
started or non-essential concomitant medications should be suspended until the LFT 
elevation has resolved.

An Unscheduled Hepatic Assessment Visit as soon as possible but within 7 days should 
be performed in the event of permanent discontinuation due to elevated LFTs (see
Table 6).

Subjects should be referred to a hepatic specialist if medically indicated.

The LFT elevation that led to treatment discontinuation should continue to be monitored 
until LFT elevation has resolved.

For subjects with initial ALT/SGPT or AST/SGOT >3×ULN and concomitant 
elevation of total bilirubin >2ULN: 
o
Permanently discontinue DAC HYP and monitor until the LFT elevation has 
resolved.  

For subjects with initial ALT/SGPT or AST/SGOT >5×ULN but 8×ULN: 
o
Suspend dosing and confirm as soon as possible but no later than a week. 
o
For subjects with ALT/SGPT or AST/SGOT >5×ULN for more than 2 weeks:

Permanently discontinue DAC HYP and monitor until the LFT elevation
has resolved.


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
For subjects with ALT/SGPT or AST/SGOT >8×ULN:
o
Suspend dosing and confirm by a repeat test (preferably within 24 hours).  

If AST/SGOT >8×ULN in repeat test:  Permanently discontinue
DAC HYP and monitor until the LFT elevation has resolved. 

For subjects with ALT/SGPT or AST/SGOT >10×ULN not resolving for more than 
2 weeks:
o
In consultation with the hepatic specialist, a full evaluation of alternative causes 
of liver injury should be performed, and if testing for viral hepatitis is negative, 
LFT elevations are not improving, DAC HYP is suspected as the cause of the 
LFT elevation, and there are no known contraindications for corticosteroids, then, 
in continued consultation with the hepatic specialist, empiric treatment with 
systemic corticosteroids should be considered.
11.7.3.
Cutaneous Events
Any subject participating in Study 205MS303 who develops a clinically significant cutaneous 
event (e.g., rash, dermatitis, eczema, acne, folliculitis) should be evaluated by the Study 
Dermatologist at an Unscheduled Dermatology Assessment Visit as soon as possible (see
Table 6).
A flowchart is presented in Figure 2 to summarize how these subjects will be managed during 
the study.


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Figure 2:
Flowchart for Management of Subjects With Clinically Significant 
Cutaneous Events
In addition to this, when the Study Neurologist and Study Dermatologist evaluate a subject with a 
clinically significant cutaneous AE (either at an unscheduled or scheduled clinical visit), they
should also perform the Physician Global Assessment Scale as well as standard AE reporting.  
Photographs should also be taken by the Study Neurologist or designee at these visits for severe 
or serious cutaneous AEs if they have not been taken by the Study Dermatologist (see 
Section 4.2).  The subjects will be asked for their consent to having their dermatological 
photographs used for educational purposes, if required.  
Skin biopsy must be performed in subjects with cutaneous SAEs at the Unscheduled 
Dermatology Assessment Visit, unless medically contraindicated.
Skin biopsies from study subjects will be sent to a centralized laboratory for evaluation.  Results 
of the skin biopsy will be provided back to the Study Dermatologist as soon as possible with a 
copy sent to the sponsor.  Skin biopsy may also be locally evaluated per the discretion of the 
Study Dermatologist.


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For subjects with a severe or serious cutaneous event, DAC HYP must be withheld until the 
cutaneous event has resolved.  Under the consultation of the Study Dermatologist, the subject 
should also withhold all other non-essential medications, including protocol-required 
medications (as appropriate), and non-prescription drugs and supplements, at least until the 
cutaneous event has resolved.  The decision to permanently discontinue study treatment should 
be made by the Investigator in consultation with the Study Dermatologist.  If an allergic or 
hypersensitivity reaction to study treatment is suspected, study treatment must be permanently 
discontinued.  
11.7.4.
Gastrointestinal Events of Inflammatory Colitis
For any subject participating in Study 205MS303 who develops symptoms of inflammatory 
colitis (e.g., persistent diarrhea and abdominal cramps, blood in the stool, and fever), treatment 
with DAC HYP should be stopped and the subject should be referred to a specialist.  Some 
subjects with mild colitis who require DAC HYP therapy may be able to continue the study 
treatment if the benefit-risk profile is considered positive per Investigator's assessment and the 
subject's informed decision.
11.7.5.
Lymphadenopathy or Lymphadenitis Events
Any subject participating in Study 205MS303 who develops clinically significant 
lymphadenopathy or lymphadenitis should be referred to a specialist.  Additional diagnostic 
tests, such as imaging, blood tests, and/or biopsy, should be performed according to the local 
standard of care.  
When diagnostic tests are performed, the results may be requested for internal safety review and, 
when available, biopsy materials will be sent to a centralized laboratory for evaluation.  The 
results of the central laboratory biopsy report will be provided back to the Study Neurologist as 
soon as possible, with a copy sent to the Sponsor.  
Study treatment may continue or be resumed after a temporary suspension in cases of 
uncomplicated lymphadenopathy if the benefit-risk profile is considered positive per the 
Investigator’s assessment and the subject’s informed decision. Subjects who discontinued study 
treatment for any reason while presenting with ongoing lymphadenopathy or lymphadenitis 
should be followed until the lymphadenopathy or lymphadenitis has stabilized or resolved or the 
study has terminated, whichever comes first.
11.8.
Discontinuation of Study Treatment
A subject must permanently discontinue DAC HYP 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 15.5.4.

The subject experiences a hypersensitivity or suspected allergic reaction 
(e.g., anaphylaxis and anaphylactoid reactions) to study treatment.

The subject develops a chronic viral infection (e.g., hepatitis C, HIV).

The subject develops elevated LFTs that meet any of the following criteria:


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
The subject develops an ALT/SGPT or AST/SGOT elevation >8ULN that is 
confirmed by a repeat test (preferably within 24 hours).  This requires immediate
discontinuation of DAC HYP, and treatment may not resume unless a laboratory 
error is documented upon repeat testing. 

ALT/SGPT or AST/SGOT >5ULN for more than 2 weeks

ALT/SGPT or AST/SGOT >3ULN with concomitant elevation of total bilirubin 
>2ULN at any time unless a laboratory error is documented upon repeat testing

If a subject has treatment suspended for an LFT elevation and has also had a prior 
treatment suspension for an LFT elevation during DAC HYP use, DAC HYP 
must be permanently discontinued unless an alternative explanation for the LFT 
elevation unrelated to DAC HYP use is clearly identified by the Investigator.

The LFT abnormality that led to treatment discontinuation should continue to be 
monitored until resolution is documented.  An Unscheduled Hepatic Assessment 
Visit is needed in the event of permanent discontinuation due to elevated LFTs 
(see Section 11.7.2).
In addition, a careful review of all concomitant medications must be documented.  
The Investigator should consider discontinuation of all potential hepatotoxic 
medications.  The subject should be referred to a physician with expertise in the 
diagnosis and treatment of liver disease, and additional hepatic studies should be 
performed according to local standard of care.  The central laboratory may be 
utilized for additional hepatic testing per Investigator request.  

The subject experiences a clinically significant cutaneous event, which the 
Investigator (in consultation with the Study Dermatologist) considers to be a 
generalized allergic or hypersensitivity reaction to study treatment (see 
Section 11.7.3). 

The subject experiences inflammatory colitis, except in subjects with mild colitis who 
require DAC HYP therapy and have a positive benefit-risk profile per Investigator's 
assessment and the subject's informed decision (see Section 11.7.4).

The subject requires treatment with any of the disallowed concomitant medications, 
unless approval is given by the Biogen Medical Director(s) or Advisory Committee.  
Note:  IVMP for treatment of a protocol-defined relapse is allowed as detailed in the 
protocol (see Section 11.5).  Treatment with valproic acid, carbamazepine, 
lamotrigine, or phenytoin is only allowed under the conditions detailed in the 
protocol.  

The subject experiences a medical emergency that necessitates permanent 
discontinuation of treatment.  

The subject desires to discontinue treatment under this protocol.  

At the discretion of the Investigator for medical reasons or for non-compliance.   


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
Upon confirmatory tests 1 month apart, the subject’s hematology results are as 
follows in the absence of an identified reversible cause by the Investigator 
(e.g., infection):  

white blood cell count is <2500 cells/L, or 

lymphocyte count is <800 cells/L, or 

platelet count is <75,000 cells/L  
Subjects who meet the above criteria must have study treatment withheld until 
hematology retest results are available.  

The subject experiences severe depression and/or suicidal ideation.  Severe 
depression is defined as any episode that requires hospitalization, or at the discretion 
of the Investigator.
Subjects who permanently discontinue DAC HYP treatment should complete all post-treatment
safety follow-up evaluations (see Section 13.3).
Subjects who permanently discontinue study treatment may be treated with alternative approved 
MS therapies according to local practices, and should remain in the study and complete safety 
follow-up evaluations as described in Section 4.2 and Section 13. However, subjects who desire 
to discontinue participation in this study or are unwilling or unable to comply with the protocol 
should be withdrawn from the study and complete an Early Termination Visit.  As noted in
Table 6 (Footnote 3) and Section 11.9, subjects terminating treatment with an ongoing clinically 
significant cutaneous event require an Unscheduled Dermatology Assessment Visit with the 
Study Dermatologist prior to leaving the study if a visit with the Study Dermatologist has not 
been completed in the 4 weeks±4 days prior to leaving the study.
The reason(s) for discontinuation of treatment must be recorded in the subject’s CRF.
11.9.
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 is unwilling or unable to comply with the protocol.  

At the discretion of the Investigator for medical reasons.
Subjects who withdraw from the study should complete the End of Treatment Visit assessments 
as described in Section 14.9 (subjects should be encouraged to complete all other post-treatment
safety follow-up visits).  The reason for the subject’s withdrawal from the study must be 
recorded in the subject’s CRF.  
For subjects with an ongoing clinically significant cutaneous AE, the Study Dermatologist
should perform an Unscheduled Dermatology Assessment Visit, if this visit has not been 
performed in the 4 weeks±4 days prior to leaving the study (see Section 11.7.3).


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12.
EFFICACY,  DAC HYP CONCENTRATION, AND
ASSESSMENTS
12.1.
Clinical Efficacy Assessments
The following clinical tests/assessments will be performed to assess the efficacy of DAC HYP:

Relapse Assessment: Subjects who suspect they are experiencing new symptoms or 
worsening symptoms need to contact the Study Neurologist within 48 hours of the 
onset of the symptoms.  

Refer also to Section 14.6 Unscheduled Relapse Assessment Visit for additional 
details.  

EDSS [Kurtzke 1983]:  Review of EDSS procedures will be performed prior to study 
start as necessary for training purposes.  

MSFC [Fischer 1999]:  Timed 25-Foot Walk, 9HPT with both upper extremities, and 
PASAT 3  

SDMT:  Data will be collected only from subjects enrolled from Study 205MS301, 
and test performance data will be collected beginning in Week 144 and every 
24 weeks thereafter.

PASAT 3:  This test will be performed separately from the MSFC beginning in
Week 144 and every 24 weeks thereafter.  Data will be collected only from subjects 
enrolled from Study 205MS301.

Brain MRI scan with and without Gd (T2 hyperintense lesions, T1 hypointense 
lesions, Gd+ lesions, brain atrophy).

Subjects will complete the following questionnaires at various timepoints specified in 
Section 4.2:  

EQ-5D quality of life questionnaire (the EQ-5D descriptive system and the 
EQ-VAS)  

MSIS-29 (29-item physical and psychological assessment)  

HRU (hospitalizations, emergency room visits, and unscheduled neurologist 
visits)  

Treatment Satisfaction Questionnaire for Medication (with PFS use) or Treatment 
Satisfaction Survey (with autoinjector use)  

HRPQ (productivity questionnaire)  
Refer to Section 4.2 for the timing of assessments.  




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13.
SAFETY ASSESSMENTS
13.1.
Clinical Safety Assessments
The following clinical assessments will be performed to determine the safety profile of 
DAC HYP:

Medical history

Physical and neurological examination 

Vital sign measurements:  temperature, pulse rate, systolic and diastolic blood 
pressure, and respiratory rate (subjects must remain in the same body position quietly 
for 5 minutes prior to having their pulse and blood pressure taken)

Weight

Concomitant therapy and procedure recording

AE and SAE recording

Beck Depression Inventory, Second Edition (BDI-II)

Immunogenicity assessments

Alcohol Use Disorders Identification Test - Consumption Questionnaire (AUDIT-C)
See Section 4.2 for the timing of assessments.
13.2.
Laboratory Safety Assessments
The following laboratory tests will be performed to assess the safety profile of DAC HYP:

Hematology:  hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, red blood cell count, white 
blood cell count (with differential), and platelet count

Blood chemistry:  sodium, potassium, chloride, total bilirubin, alkaline phosphatase, 
ALT/SGPT AST/SGOT, lactate dehydrogenase, gamma glutamyl transferase, blood 
urea nitrogen (BUN), creatinine, and bicarbonate

Comprehensive hepatic panel (only required for subjects who permanently 
discontinue dosing due to elevated LFTs as defined in Section 11.7.2).  Testing will 
include screening for the following: 

hepatitis A, B, C, and E 

other viral infections:  Epstein-Barr virus (EBV), cytomegalovirus (CMV), human 
herpes virus 6 (HHV-6), varicella zoster virus (VZV), herpes simplex virus 
(HSV), and Parvovirus B19

gamma-globulins, including IgG levels


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
autoantibodies:  antinuclear antibody (ANA), anti-smooth muscle antibody 
(anti-SM), anti-liver/kidney microsome-1 antibody (anti-LKM1), 
antimitochondrial antibody (AMA), and anti-soluble liver antigen (SLA) 
Additional testing may be performed based on results of the above testing or the 
subject’s clinical history.  Additional hepatic assessments should be performed 
according to local standard of care.  

Thyroid function panel, including TSH and T4

Urinalysis:  protein, blood, glucose, ketones, nitrite, leukocytes, pH, specific gravity 
by dipstick and microscopy

Urine pregnancy testing 

Skin biopsy (only required for subjects who experience cutaneous events reported as 
serious or severe as defined in Section 11.7.3)
Refer to Section 4.2 for the timing of assessments.
13.3.
Study-Specific Safety Assessments
Blood serum collection for binding and neutralizing anti-drug antibody testing will be 
performed.  Note:  When necessary, samples drawn for one purpose (e.g., immunogenicity) may 
be used to meet another protocol-defined objective (e.g., DAC HYP concentration assessment).


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14.
SCHEDULE OF EVENTS
14.1.
Overview
A written, signed Informed Consent Form (ICF) and all authorizations required by local law 
(e.g., Protected Health Information [PHI] in North America) must be obtained prior to 
performing any tests or assessments under this protocol.
For subjects entering from Study 205MS301, tests/assessments performed at the subject’s last 
visit in Study 205MS301 and within 28 days of the subject’s first dose of DAC HYP (Week 0) in 
Study 205MS303 may be used as baseline data for Study 205MS303; if final Study 205MS301 
tests/assessments are not performed within the 28-day window, they must be repeated upon entry 
into Study 205MS303 and before the first dose of DAC HYP is administered.
Week 144 Visit of Study 205MS303 will be the Entry Visit for subjects enrolled from 
Study 205MS203 or Study 205MS302.  Any test/assessment done at the subject’s last visit in 
parent studies and within 28 days of the subject’s first dose in Study 205MS303 will be used as 
the baseline and does not need to be repeated at entry into Study 205MS303; test/assessments 
performed >28 days before the Entry Visit must be repeated at the Entry Visit. Central LFT 
testing is mandatory at Entry Visit.
Clinic visits will occur once every 4 weeks for the first 12 weeks, then every 12 weeks thereafter. 
On a dosing day, all tests and assessments must be performed prior to DAC HYP administration.  
When DAC HYP administration and MRI evaluation are required at the same visit, the MRI scan 
should be performed prior to DAC HYP administration (Note:  MRI scan can be performed up to 
4 days prior to the visit).
Before a monthly dose of DAC HYP is given, LFT results (ALT/SGPT, AST/SGOT, alkaline 
phosphatase, total bilirubin, and GGT only) from prior testing performed within 28(+4) days 
must be reviewed by the Study Neurologist or their backup, and must be within the 
protocol-required limits.
After Week 12, subjects will have the option of administering DAC HYP at home following 
Investigator review of monthly pre-dose LFT results.  Subjects who are not able to administer 
their own dose or prefer not to administer their own dose of DAC HYP will be given the option 
to choose another individual (caregiver) to administer their treatment at home or to have their 
treatment administered by staff at the study site.
Follow-up visits will take place at 8, 12, 16, and 24 weeks after each subject’s last dose of DAC 
HYP. Unscheduled Relapse Assessment Visits (if necessary) should be scheduled within 
72 hours of the onset of any new neurological symptoms that may indicate neurological 
worsening or possible clinical relapse. Unscheduled Hepatic Assessment Visits (if necessary) 
should be scheduled as soon as possible (but within 1 week) following discontinuation of study 
treatment due to elevated LFTs.  Unscheduled Dermatology Assessment Visits will be performed 
as per Section 11.7.3.  


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Unscheduled PK/
 Visits should be scheduled as soon as possible following significant 
changes in subjects’ medical conditions, as assessed by the Investigator.  This visit must be 
approved by the Biogen Medical Director in advance.
14.2.
Site Personnel
For each subject, the Principal Investigator will designate the following study site personnel:

A primary Study Neurologist and backup neurologist

A primary and backup Nurse (or Study Coordinator)

A primary and backup Examining Technician

An MRI Technician

A Pharmacist (or authorized designee)

A Study Dermatologist
The Study Neurologist must have a minimum of 2 years of neurology specialty training and 
anticipate at least a 3-year commitment to the study, or be approved by the study Advisory 
Committee. The Study Neurologists may designate another neurologist at the center who meets 
the same qualifications to perform the EDSS assessments and other neurologic assessment 
during the trial. Whenever possible, the EDSS and other neurologic assessments should be 
performed by the same examiner who performed these assessments in the parent study.  
The primary Study Neurologist will be responsible for:

Management of the routine neurological care of the subject

Assessment (including assignment of causality) and treatment of AEs and MS 
relapses

Obtaining an EDSS score based on a detailed neurological examination at the 
scheduled timepoints required in the protocol, and at every Unscheduled Relapse 
Assessment Visit

Review of selected hematology and all blood chemistry results from the central 
laboratory

Assessment of LFT results, as detailed in Section 11.7.2

Monitoring and follow-up of any abnormal hepatic tests

Performing Physician Global Assessment Scale in subjects with clinically significant 
cutaneous event, as detailed in Section 11.7.3

Assessment of injection sites, as detailed in Table 7

Referral of subjects to a dermatologist if that subject experiences a cutaneous event as 
described in Section 14.7
Hematology and blood chemistry data will be sent to the investigational sites to aid in 
management of the subject.  


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The primary Nurse or Study Coordinator will be responsible for:

Assisting the Study Neurologist in subject management, including the treatment of 
AEs, the treatment and assessment of disease relapses, and the recording of AEs and 
concomitant medications

Monitoring the EDSS scores and informing the Study Neurologist if a subject 
experiences at least a 1.0-point increase on the EDSS from a baseline EDSS ≥1.0 that 
is sustained for 24 weeks, or at least a 1.5-point increase on the EDSS from a baseline 
EDSS <1.0 that is sustained for 24 weeks

Administering the patient-reported questionnaires (BDI-II, MSIS-29, EQ-5D), HRU,
and subject assessment of injection pain (VAS)

Collection of blood samples and obtaining vital signs

Study treatment administration/dispensation/accountability
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.  It is not necessary for the 
Examining Technician to be a healthcare professional as long as he/she is qualified, in the 
opinion of the Principal Investigator, to administer the MSFC (Note:  MSFC was administered in 
this study only until Week 48;  therefore, the role of the Examining Technician ended after that).
The MRI Technician will be responsible for:

Performing a brain MRI scan with and without Gd at all protocol-required timepoints.  
Study-specific MRI scan procedures and protocols, which will be provided prior to 
study start, must be followed.
The Pharmacist (or authorized designee) will be responsible for:

Storage, distribution, and accountability of study treatment.
The Study Dermatologist will be responsible for:

Documenting cutaneous events, as per the protocol.  

Taking photograph(s) of the affected body areas, as required.

Performing a skin biopsy, as required.

Evaluating, treating, and managing clinically significant cutaneous events as 
described in Section 11.7.3.

Performing Physician Global Assessment Scale in subjects with clinically significant 
cutaneous event, as detailed in Section 11.7.3


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14.3.
Subject Management
The following restrictions apply to all subjects enrolled into this study:

Subjects must follow the restrictions for concomitant medications and procedures 
described in Section 11.5.

Contraception requirements are to be followed as described in Section 15.5.3.

Whenever possible, a subject should undergo protocol-required tests and assessments 
at the same time of day throughout the study.

Subjects should not donate blood until 4 months after their last dose of DAC HYP.

Subjects should not receive live or live-attenuated vaccines during DAC HYP 
treatment or for at least 6 months after treatment with DAC HYP.
14.4.
Special Instructions for Tests and Assessments
Note:  Information about the tests and assessments to be performed in this study is also provided 
in Section 12 and Section 13, and in the Study Reference Manual.
14.4.1.
Rescreening
Subjects who are not eligible for participation at baseline due to a temporary condition 
(e.g., acute infection) are allowed to be rescreened once the condition has resolved, provided 
they are rescreened and enrolled within 6 months of completing Study 205MS301, 
Study 205MS203, or Study 205MS302.
14.4.2.
Pregnancy Testing

Pregnancy testing is only required for women of childbearing potential.  A urine 
pregnancy test is to be performed at the Baseline/Entry Visit and at other timepoints 
designated in Section 4.2 Schedule of Events.  Study treatment will be immediately
discontinued if the subject has a positive pregnancy test at any time during the study.

Results from all urine pregnancy tests must be reviewed by the study site prior to dosing 
and must be negative.  
14.4.3.
Liver Function Test Assessments Prior to DAC HYP Dosing
Before a monthly dose of DAC HYP is given, LFT results from prior testing performed within 
the previous 28(+4) days must be reviewed by the Study Neurologist or their backup, and must 
be within protocol-required limits as described in Section 11.7.2. 
LFTs can be performed as follows:  

Samples for LFTs must be drawn prior to administration of the monthly DAC HYP 
dose.  These samples may be tested either locally inside or outside of the clinic 
(e.g., at a local laboratory or by visiting nurses) or at the central laboratory at the 
discretion of the Investigator and the results can then be used to determine whether 


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dosing should continue or be suspended at the monthly dosing timepoint (see 
Section 11.1).

If local LFTs have been used to determine whether dosing should continue or be 
suspended at the time of a scheduled clinic visit, LFTs must also be performed at the 
central laboratory at the time of the scheduled clinic visit (Note:  Scheduled clinic 
visits occur every 4 weeks during the first 12 weeks of the study and every 12 weeks 
thereafter).    

If the subject is administering DAC HYP injections at home, site personnel must 
contact the subject after review of prior LFT results performed within 28(+4) days) to 
authorize the monthly injection, or if LFT results warrant, to instruct the subject to 
withhold their injection.  

LFTs following a treatment suspension must be performed through the central 
laboratory until the LFT abnormality has resolved. In cases where LFTs cannot be 
performed via central laboratory, repeat LFT results from local laboratory can be used 
for confirmation.
14.4.4.
Other Assessments

Vital signs include systolic and diastolic blood pressure, pulse, and body temperature, 
and should be measured pre-dose. The subject must rest quietly for 5 minutes prior to 
blood pressure and pulse measurements.  Weight will be collected at Baseline/Entry 
Visit and at the time of first autoinjector use at selected sites.

The MSIS-29 must be administered prior to the subject’s visit with the Study
Neurologist.  

Subject assessment of injection pain using a VAS should be completed as soon as 
possible after the injection is administered, but no later than 10 to 30 minutes 
post-injection.

The first 4 DAC HYP injections (i.e., Weeks 0 through 12) must be given in the 
clinic.  The first of these injections must be given by study personnel.  At subsequent 
visits, subjects and/or caregivers will be instructed on DAC HYP self-administration 
and may administer their scheduled dose under staff supervision.  After the subject 
completes the required in-clinic injections (i.e., after Week 12), DAC HYP may be 
dispensed to subjects for at-home administration if the subject chooses.  If necessary, 
drug dispensation may occur at monthly intervals.  

Additional visits to assess elevated LFTs, cutaneous events, or PK/
 may 
be required as described in Section 11.7.
14.5.
Definition of MS Relapse and Disability Progression
14.5.1.
MS Relapse
Relapses are defined as new or recurrent neurological symptoms not associated with fever or 
infection, lasting at least 24 hours, and accompanied by new objective neurological findings 


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upon examination by the Study Neurologist* or their backup.  The subject must have objective 
signs on the examination confirming the event.  
*When possible subjects should be evaluated by the same neurologist assigned to them in the 
parent study.  
New or recurrent neurologic symptoms that evolve gradually over months should be considered 
disability progression, not an acute relapse.  New or recurrent neurological symptoms that occur 
less than 30 days following the onset of a protocol-defined relapse should be considered part of 
the same relapse.  Management of MS relapse is described in Section 14.6.
14.5.2.
Disability Progression
Disability progression can only be confirmed from the EDSS scores obtained according to the 
protocol-defined schedule of assessments at regular visits, and is defined as one of the following:

at least a 1.0-point increase on the EDSS from a baseline EDSS ≥1.0 that is sustained 
for 24 weeks, or 

at least a 1.5-point increase on the EDSS from a baseline EDSS <1.0 that is sustained 
for 24 weeks 
14.6.
Management of MS Relapse
Subjects who experience new or worsening neurological symptoms must contact the Nurse or 
Study Neurologist or their backup within 48 hours after the onset of symptoms.  A standardized 
Suspected Relapse Questionnaire will be completed to determine the necessity of an 
Unscheduled Relapse Assessment Visit.
If required, the subject will then be evaluated in person by the Study Neurologist not more than 
72 hours after the onset of the symptoms.  At the Unscheduled Relapse Assessment Visit, the 
Study Neurologist is to perform a relapse assessment and obtain an EDSS score.  New objective 
findings on neurological examination performed by the Study Neurologist* are required to 
determine if a suspected protocol-defined relapse has occurred. Treatment of an acute relapse 
event with intravenous methylprednisolone (IVMP) [or equivalent] may proceed at the discretion 
of the Study Neurologist after the examination and will not affect the subject’s eligibility to 
continue in the study.
*When possible subjects should be evaluated by the same neurologist assigned to them in the 
parent study.  
Subjects who prematurely discontinue study treatment should complete safety follow-up 
evaluations (see Section 4.2 and Section 13).  
Subjects who permanently discontinue DAC HYP treatment should complete the visit schedule 
described in Section 11.8.  
14.7.
Cutaneous Events
Subjects who experience a clinically significant cutaneous event (e.g., rash, dermatitis, eczema, 
acne, folliculitis) must be referred to and evaluated and managed by the Study Dermatologist as 


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per Section 11.7.3.  An Unscheduled Dermatology Assessment Visit will be performed per
Table 6.
If a generalized allergic or hypersensitivity reaction to study treatment is suspected, study 
treatment must be permanently discontinued as per Section 11.8.  
14.8.
Unscheduled Hepatic Assessment Visit
The following tests/assessments will be performed as soon as possible (but within 7 days) after 
discontinuation of study treatment for subjects who are required to discontinue dosing due to 
elevated LFTs as described in Table 6 and Section 11.8.

Physical examination and vital signs 

Comprehensive hepatic panel

Recording of concomitant therapy

Monitor and record AE/SAEs

Protocol compliance and DAC HYP accountability

LFTs (ALT/SGPT, AST/SGOT, alkaline phosphatase, total bilirubin, and GGT only)
14.9.
Lymphadenopathy and Lymphadenitis Events
Subjects who experience a clinically significant event of lymphadenopathy or lymphadenitis 
should be referred to a specialist as per Section 11.7.5.
Interruption or discontinuation of DAC HYP treatment due to events of lymphadenopathy or 
lymphadenitis is a clinical decision that should take the overall benefit-risk assessment of 
therapy into consideration.  Subjects who discontinued study treatment for any reason while 
presenting with ongoing lymphadenopathy or lymphadenitis should be followed until the 
lymphadenopathy or lymphadenitis has stabilized or resolved or the study has terminated, 
whichever comes first.
14.10.
Post-Treatment Safety Follow-Up Visit Schedule for All Subjects 
All subjects should complete the following schedule of safety follow-up visits after their last 
dose of DAC HYP:

End of Treatment Visit (i.e., the assessments required at Week 240).  For subjects 
who prematurely discontinue study treatment before Week 240, these assessments 
should be performed 4 weeks (±4 days) after the subject’s last dose of DAC HYP.   

Post-treatment safety follow-up visits at 8, 12, 16, and 24 weeks after the subject’s 
last dose.  The details of these visits are shown in Table 5.
Note:  Subjects who complete Week 144 of DAC HYP treatment in Study 205MS303 and are in 
the safety follow-up period per the original protocol, will have the option to restart DAC HYP 
treatment from Week 156 Visit in Study 205MS303 (see Table 4) as long as they meet the 
inclusion/exclusion criteria (Section 8). 


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15.
SAFETY DEFINITIONS, MONITORING, AND REPORTING
Throughout the course of the study, every effort must be made to remain alert to possible AEs.  
If an AE occurs, the first concern should be for the safety of the subject.  If necessary, 
appropriate medical intervention should be provided.
At the signing of the ICF, each subject must be given the names and telephone numbers of study 
site staff for reporting AEs and medical emergencies.
15.1.
Definitions
15.1.1.
Serious Pretreatment Event
A serious pretreatment event is any event that meets the criteria for SAE reporting (as defined in 
Section 15.1.3) and occurs after the subject signs the ICF, but before administration of study 
treatment.
15.1.2.
Adverse Event
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product.
15.1.3.
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, or

results in a congenital anomaly/birth defect.
An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or convulsions occurring at home that do not 
require an inpatient hospitalization.


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15.2.
Monitoring and Recording Events
15.2.1.
Serious Pretreatment Events
A serious pretreatment event experienced by the subject after signing and dating the ICF but 
before administration of study treatment is to be recorded on the SAE Form and faxed to the 
contract research organization (CRO) within 24 hours of the study site staff becoming aware of 
the event (see Section 15.2.5).
15.2.2.
Adverse Events
Any AE experienced by the subject between the time of signing the ICF and subject’s final visit 
is to be recorded on the CRF, regardless of the severity of the event or its relationship to study 
treatment.
15.2.3.
Serious Adverse Events
Any SAE experienced by the subject between the time of the first dose of study treatment and 
subject’s final 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 the CRO.
Any SAE ongoing when the subject completes the study or discontinues from the study will be 
followed by the Investigator until the event has resolved, stabilized, or returned to baseline 
status.
Subjects will be followed for all SAEs until the subject’s final visit.  Thereafter, the event should 
only be recorded if the Investigator considers it related to study treatment.
15.2.4.
All Events
All events must be assessed to determine the following:

If the event meets the criteria for an SAE as defined in Section 15.1.3.

The relationship of the event to study treatment as defined in Section 15.3.1.

The severity of the event as defined in Section 15.3.2.
15.2.5.
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 the CRO 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.






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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.
15.5.
Procedures for Handling Special Situations
15.5.1.
Overdose
An overdose is any dose of study treatment given to a subject or taken by a subject that exceeds 
the dose described in the protocol.  Overdoses are not considered AEs; however, all overdoses 
should be recorded on an Overdose Form and faxed to the CRO within 24 hours.  An overdose 
should be reported even if it does not result in an AE.  Overdoses do not need to be recorded in 
the CRF; dosing information is recorded on a CRF.
15.5.2.
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 CRO Medical Monitor at one of the following phone numbers:
North America (USA and Canada):  
Latin America: 
Europe and Asia Pacific: 
15.5.3.
Contraception Requirements
All women of childbearing potential must practice effective contraception during the study and 
be willing and able to continue contraception for 4 months after their last dose of study 
treatment.
For the purposes of this study, women of childbearing potential are defined as all women 
physiologically capable of becoming pregnant, UNLESS they meet one of the following 
conditions:

Postmenopausal:  12 months of natural (spontaneous) amenorrhea or 6 weeks after 
surgical bilateral oophorectomy with or without hysterectomy

Posthysterectomy
For the purposes of the study, effective contraception is defined as follows:
For females:

Using 1 or more of the following acceptable methods of contraception:  surgical 
sterilization (e.g., bilateral tubal ligation), intrauterine contraception/device, hormonal 
contraception, or any 2 barrier methods (a combination of male or female condom with 
spermicide; diaphragm, sponge, cervical cap)


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
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, post-ovulation 
methods) and withdrawal are not considered acceptable methods of contraception.
15.5.4.
Pregnancy
Subjects should not become pregnant during the study.  If a female subject becomes 
pregnant, study treatment must be discontinued immediately.
The Investigator must report the pregnancy by faxing the appropriate form to Pharmacovigilance 
at the CRO within 24 hours of the study site staff becoming aware of the pregnancy (refer to 
Section 15.2.5 for reporting information). The Investigator or study site staff must report the 
outcome of the pregnancy to Pharmacovigilance at the CRO.
Please note that congenital abnormalities/birth defects in the offspring of male or female subjects 
should be reported when conception occurred during the study treatment period.
15.5.5.
Regulatory Reporting
Suspected Unexpected Serious Adverse Reactions (SUSARs) are SAEs that are unexpected and 
judged by the Investigator or the Sponsor to be related to the study treatment administered.
Biogen Safety and Benefit-Risk Management (SABR) will report SUSARs to the appropriate 
regulatory authorities and Investigators as required, according to local law.
15.6.
Investigator Responsibilities
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 of the pregnancy.

Complete an SAE form for each serious event and fax it to the CRO 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 the CRO within 24 hours of the study site staff becoming aware 
of new information.

Complete an Adverse Event of Special Interest form for each transaminase elevation, 
hepatic event, and cutaneous event as described in the protocol and fax it to the CRO 
as soon as possible following the study site staff becoming aware of the event.

Ensure all AE and SAE reports are supported by documentation in the subjects’ 
medical records.


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
Report SAEs to local ethics committees, as required by local law.
15.7.
Biogen Responsibilities
Biogen’s responsibilities include the following:

Before study site activation and subject enrollment, the Clinical Monitor or designee
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.


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16.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
16.1.
Description of Objectives
See Section 6.1, Objectives.
16.2.
Description of Endpoints
See Section 6.2, Endpoints.
16.3.
Demography and Baseline Disease Characteristics
Demographic data collected at baseline will be summarized (i.e., age, gender, ethnicity, and 
weight).  Medical history and baseline characteristic data (e.g., EDSS, number of relapses in the 
previous study, MRI endpoints) will also be summarized.
16.4.
Safety and Efficacy
16.4.1.
Analysis Population
Study 205MS303 Safety Population
The safety population will include all subjects who received at least 1 dose of DAC HYP in 
Study 205MS303.  All safety analyses will be completed on the safety population.
Study 205MS303 Intent-to-Treat Population
The intent-to-treat (ITT) population will include all subjects who received at least 1 dose of DAC 
HYP in Study 205MS303.  This population will be utilized for the efficacy analyses.  
Study 205MS301 and Study205MS303 Intent-to-Treat population
This population will include all subjects randomized to DAC HYP or Avonex in 
Study 205MS301 and received at least one dose of DAC HYP in Study 205MS303.
16.4.2.
General Methods of Analysis
Summary statistics will be presented.  For continuous endpoints, summary statistics will 
generally include the number of subjects with data, mean, standard deviation, median, and range.  
Categorical endpoints will include the number of subjects with data and the percentage in each 
category.
Analyses will generally be descriptive in nature and will focus on data collected during 
Study 205MS303 only.  However, for relevant efficacy analyses, the data may be summarized by 
previous treatment group (Avonex or DAC HYP).  Also, statistical comparisons may be made 
between efficacy in Study 205MS301 and efficacy in Study 205MS303 among subjects 
previously randomized to Avonex in Study 205MS301.
All statistical tests will be 2-sided with an overall Type I error of 5%.  Adjustments for multiple 
comparisons will not be considered.


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16.4.3.
Primary Endpoints Analysis
Clinical Adverse Events
AEs will be coded using the Medical Dictionary for Regulatory Activities. All treatment-
emergent events will be included in the evaluation of safety.  Treatment emergent includes any 
event that either occurs or worsens in severity after the onset of study treatment.  Overall 
incidence of treatment-emergent events will be summarized; in addition, summaries by severity 
and by relationship to study treatment will be provided.  The summary tables will include 
incidence estimates for the overall system organ class as well as for preferred terms within each 
system organ class.  In order to assess whether the incidence of events changes over time, the 
incidence of key events may also be summarized by time period (e.g., 6-month time intervals).  
16.4.4.
Other Safety Endpoint Analyses
Unless otherwise specified, the baseline measurement for safety assessments such as laboratory 
values and vital signs was the measurement acquired on the day of the first receipt of DAC HYP.  
The first receipt of dosing of DAC HYP could be either Study 205MS303 (for subjects who 
received Avonex in Study 205MS301) or the parent studies (i.e., Study 205MS301, 
Study 205MS203, or Study 205MS302) for all other subjects.
Laboratory Data
Changes in laboratory values will be summarized using shift tables.  Shift tables will include 
hematology, LFTs, kidney function tests, electrolytes, and other blood chemistry tests.  Shifts 
will be presented from baseline of DAC HYP treatment (the last measurement acquired before or 
on the day of the first receipt of DAC HYP, e.g., Study 205MS303 baseline for subjects 
randomized to Avonex in Study 205MS301 and Study 205MS301 baseline for subjects 
randomized to DAC HYP 150 mg in Study 205MS301).  Summaries of worst post-baseline 
laboratory values by clinically relevant categories may also be presented for selected parameters 
of interest by treatment group.  For example, for LFT (alkaline phosphatase, ALT, AST, GGT,
and total bilirubin), categories may be defined based on cutoff values relative to the ULN.
Vital Signs
Vital signs collected will be examined to determine the incidence of clinically relevant 
abnormalities.  These abnormalities are described in Table 8.  For the purpose of the shifts from 
baseline, the baseline evaluation at the start of DAC HYP treatment will be used.
For each vital sign, the number of subjects evaluated and the number and percentage of subjects 
with the defined abnormality at any time post dosing will be presented by treatment group.  


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Table 8:  
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs
Vital Sign
Criteria for Abnormalities
Temperature 
>38°C or an increase from baseline of ≥1°C
Pulse
>120 beats per minute (bpm) or an increase from baseline of 
20 bpm
<50 bpm or a decrease from baseline of >20 bpm
Systolic Blood Pressure
>180 mmHg or an increase from baseline of >40 mmHg
<90 mmHg or a decrease from baseline of >30 mmHg
Diastolic Blood Pressure
>105 mmHg or an increase from baseline of >30 mmHg
<50 mmHg or a decrease from baseline of >20 mmHg
Physical Examination
The physical examination findings will be summarized.
16.4.5.
Efficacy Endpoints Analyses
Annualized Relapse Rate
Relapses will be summarized over the follow-up period in Study 205MS303.  For subjects in 
Study 205MS301 and Study 205MS303 ITT population, relapses may be summarized over the 
combined study period (Studies 205MS301 and 205MS303).  
A negative binomial regression model will be used to estimate the adjusted ARR.  
Proportion of Subjects with a Relapse
The proportion of subjects relapsed will be estimated using a Kaplan-Meier curve.  
Disability Progression  
Sustained disability progression is defined as at least a 1.0 point increase on the EDSS from 
baseline EDSS 1.0 that is sustained for 24 weeks, or at least a 1.5 point increase on the EDSS 
from baseline EDSS <1.0 that is sustained for 24 weeks.  The proportion of subjects with 
progression will be summarized using a Kaplan-Meier curve.  In addition, summary statistics for 
EDSS and for the change from baseline in EDSS will be presented by visit, and for subjects who 
participated in Study 205MS301, by previous treatment group.
MSFC
Changes in the MSFC z-score will be summarized by study visit, and for subjects who 
participated in Study 205MS301, by previous treatment group. For subjects in Study 205MS301 
and Study 205MS303 ITT population, MSFC z-score may be summarized over the combined 
study period (Studies 205MS301 and 205MS303).  Details on the calculations of the z-score for 
each component will be described in the statistical analysis plan.
SDMT
Changes in the SDMT scores will be summarized by study visit and by previous treatment group 
in Study 205MS301.  Change in the SDMT scores over the combined study period 
(Studies 205MS301 and 205MS303) will be calculated using the Study 205MS301 baseline visit 


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as baseline. Change in the SDMT score over the Study 205MS303 study period will be 
calculated using the last SDMT measurement in Study 205MS301 as baseline.
PASAT 3
Changes in the PASAT 3 scores will be summarized by study visit and by previous treatment 
group in Study 205MS301.  Change in the PASAT 3 scores over the combined study period 
(Studies 205MS301 and 205MS303) will be calculated using the Study 205MS301 baseline visit 
as baseline. Change in the PASAT 3 score over the Study 205MS303 study period will be 
calculated using the Week 0/baseline visit as baseline. 
MRI Endpoints
MRI endpoints will be summarized with descriptive statistics both as a continuous variable and 
categorically.  Over time summaries and summaries by previous treatment group (Avonex or 
DAC HYP 150 mg) may also be provided.  A negative binomial regression model will be used 
for the analysis of new or newly enlarging T2 lesions. The change in volume of lesions will be 
analyzed using an analysis of covariance.  
Quality of Life Outcomes
Actual scores and change from baseline in quality of life endpoints will be summarized by visit. 
Pharmacokinetics
The population for DAC HYP concentration analyses will include all subjects who received at 
least 1 dose of study medication and who have at least 1 sample available for analysis. 
Serum concentration levels will be summarized with descriptive statistics by visit.  
Antigenicity/Immunogenicity Data
Immunogenicity (i.e., ADAs to DAC HYP) will be assessed on subjects.  Positive samples will 
be further tested for neutralizing  antibodies to DAC HYP using a specific NAb assay.  Results 
will be tabulated by time period and overall.
16.5.
Interim Analyses
No formal interim analyses are planned for this study.  However, analyses may be performed 
prior to the end of the study at the discretion of the Sponsor. 
16.6.
Sample Size Considerations
There is no formal sample size calculation.  The number of subjects in this study is determined 
by the number of subjects who completed Study 205MS301, Study 205MS203, or
Study 205MS302.


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17.
ETHICAL REQUIREMENTS
Biogen and the Investigator must comply with all instructions, regulations, and agreements in 
this protocol and applicable International Council for Harmonisation (ICH) and Good Clinical 
Practice (GCP) guidelines and conduct the study according to local regulations.
17.1.
Declaration of Helsinki
The Investigator and Biogen must adhere to the principles set forth by the Declaration of 
Helsinki dated October 2008.
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. The Sponsor may submit documents on behalf of the 
study sites in countries other than the US as applicable. 
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 Principal Investigator(s) to ensure that all aspects of institutional 
review are conducted in accordance with current governmental 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 study site must submit a close-out letter to the 
ethics committee and Biogen.
17.3.
Subject Information and Consent
Prior to performing any study-related activities under this protocol, including Baseline/Entry 
Visit tests and assessments, written informed consent with the approved ICF must be obtained 
from the subject or subject’s legally authorized representative, as applicable, in accordance with 
local practice and regulations.  Written informed consent must be obtained from all subjects 
participating in a clinical study conducted by Biogen.
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.  The subject 
must be given sufficient time to consider whether to participate in the study.
A copy of the ICF, signed and dated by the subject, must be given to the subject.  Confirmation 
of a subject’s informed consent must also be documented in the subject’s medical record prior to 
any testing under this protocol, including Baseline/Entry Visit tests and assessments.


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Each consent form should contain an authorization allowing the Principal Investigator(s) and 
Biogen to use and disclose PHI (i.e., subject-identifiable health information) in compliance with
local law.
The signed consent form will be retained with the study records.
17.4.
Subject Data Protection
Prior to any testing under this protocol, including Baseline/Entry Visit tests and assessments, 
candidates must also provide all authorizations required by local law (e.g., PHI authorization in 
North America).
The subject will not be identified by name in the CRF or in any study reports and these reports 
will be used for research purposes only. Biogen, its partner(s) and designee(s), ethics 
committees, and various government health agencies may inspect the records of this study.  
Every effort will be made to keep the subject’s personal medical data confidential.
17.5.
Compensation for Injury
Biogen maintains appropriate insurance coverage for clinical trials 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 the 
Sponsor) with the subject before the subject makes a decision to participate in the study.
17.7.
Registration of Study and Disclosure of Study Results
Biogen will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations.


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18.
ADMINISTRATIVE PROCEDURES
18.1.
Study Site Initiation
The Investigator must not enroll 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 on-site audits.  The Investigator will be expected to 
cooperate with any audit and to provide assistance and documentation (including source data) as 
requested.
18.3.
Monitoring of the Study
The Principal Investigator(s) must permit study-related monitoring by providing direct access to 
source data and to the subjects’ medical histories.
The Clinical Monitor(s) will visit the Investigator(s) at regular intervals during the course of 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.  
The 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 study site and its facilities.
18.4.
Study Funding
Biogen is the Sponsor of the study and is funding the study.  All financial details are provided in 
the separate contract(s) between the institution, Investigator, and Biogen.
18.5.
Publications
Details are included in the clinical trial agreement for this study.


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19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION
Biogen will be responsible for all administrative aspects of this study including, but not limited 
to, study initiation, monitoring, management of AEs, and data management.
19.1.
External Contract Organizations
19.1.1.
Contract Research Organization 
The CRO will be responsible for administrative aspects of the study including, but not limited to, 
study initiation, monitoring, and management of SAE reports. 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.
Electronic or Remote Data Capture
Subject information will be captured and managed by study sites on electronic CRFs via a 
remote data capturing system.
19.1.3.
Central Laboratories for Laboratory Assessments
A central laboratory has been selected by Biogen to analyze all hematology, blood chemistry, 
and urine samples collected for this study.
If local LFTs have been used to determine whether dosing should continue or be suspended at 
the time of a scheduled clinic visit, LFTs must also be performed at the central laboratory at the 
time of the scheduled clinic visit (Note:  Scheduled clinic visits occur every 4 weeks during the 
first 12 weeks of the study and every 12 weeks thereafter).     
19.1.4.
Central Facility for Independent Assessment of Biopsy Samples
A central laboratory service has been selected by Biogen to coordinate the collection and 
distribution of biopsy samples.  A central assessor has been selected to subsequently analyze skin 
biopsies or lymph node biopsies (as applicable).
19.1.5.
Central Facility for Other Assessments
MRI Reading Center
All scheduled MRI scans with and without Gd will be evaluated at a central MRI reading center.  
All study sites will be required to send a test scan 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 study site is permitted to enroll any subjects into the study.
Original MRI images are to be sent to the MRI Reading Center for review (MRI shipping 
instructions will be provided prior to the start of enrollment at each site).  
Additional and more detailed MRI scans with and without Gd procedures and instructions are 
included in the study MRI manual (to be provided under separate cover prior to start of the 
study).


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19.2.
Study Committees
19.2.1.
Advisory Committee
The Advisory Committee from parent Study 205MS301 will oversee the administrative progress 
and provide scientific and medical direction for this study while Study 205MS301 is ongoing. 
Advisory Committee will monitor subject accrual and compliance with the protocol at individual 
study sites.  The Advisory Committee will determine whether the study should be stopped or 
amended for reasons other than safety.
Members of the Advisory Committee will include the Medical Director, Clinical Trial Manager, 
and Project Statistician from Biogen (and/or their designees), and participating Investigators.  
Biogen will designate one of the participating Investigators to be the Chairperson of the 
Advisory Committee.
19.2.2.
Internal Safety Monitoring Committee
An internal Safety Monitoring Committee will be formed to review interim safety data on an 
ongoing basis. Investigational sites will be notified of any relevant safety findings that may 
jeopardize subject safety.
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 subject consent form may require similar 
modifications (see Section 17.2 and Section 17.3).
19.4.
Ethics Committee Notification of Study Completion or Termination
Where required, the Health Authorities and ethics committees must be notified of completion or 
termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines.
19.5.
Retention of Study Data
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local 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 


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must notify Biogen of any changes in the archival arrangements including, but not limited to, 
archival at an off-site 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.
Biogen will follow all applicable local regulations pertaining to study report signatories.


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20.
REFERENCES
Bielekova B, Howard T, Packer AN, et al. Effect of anti-CD25 antibody daclizumab in the 
inhibition of inflammation and stabilization of disease progression in multiple sclerosis. Arch 
Neurol. 2009;66(4):483-9.
Bielekova B, Richert N, Howard T, et al. Humanized anti-CD25 (daclizumab) inhibits disease 
activity in multiple sclerosis patients failing to respond to interferon beta. Proc Natl Acad Sci U 
S A. 2004;101(23):8705-8.
Fischer JS, LaRocca NG, Miller DM, et al. Recent developments in the assessment of quality of 
life in multiple sclerosis (MS). Mult Scler. 1999;5(4):251-9.
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status 
scale (EDSS). Neurology. 1983;33(11):1444-52. Epub 1983/11/01.
Rose JW. Treatment of Multiple Sclerosis with a Humanized Monoclonal Antibody Specific for 
IL-2 Receptor Chain. Neurology. 2003;60(Suppl 1):A478-9.
Rose JW, Watt HE, White AT, et al. Treatment of multiple sclerosis with an anti-interleukin-2 
receptor monoclonal antibody. Ann Neurol. 2004;56(6):864-7.
Wynn D, Kaufman M, Montalban X, et al. Daclizumab in active relapsing multiple sclerosis 
(CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with 
interferon beta. Lancet Neurol. 2010;9(4):381-90.


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21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “A Multicenter, Open-Label, Extension Study to Evaluate the 
Long-Term Safety and Efficacy of BIIB019, Daclizumab High Yield Process (DAC HYP),
Monotherapy in Subjects With Multiple Sclerosis Who Have Completed Study 205MS301” and 
agree to conduct the study according to the protocol and the applicable ICH guidelines and GCP 
regulations, and to inform all who assist me in the conduct of this study of their responsibilities 
and obligations.
____________________________________________________
Investigator’s Signature
Date
____________________________________________________
Investigator’s Name (Print)
____________________________________________________
Study Site (Print)


Signature Page
Document Name: 205MS303 Protocol V3 Final 29Jan16
Document Title: A Multicenter, Open-Label, Extension Study to Evaluate the Long
Term Safety and Efficacy of BIIB019, Daclizumab High Yield Process (DAC HYP),
Monotherapy in Subjects With Multiple Sclerosis Who Have Completed Study
205MS301
Signed by
Role
Date / Time (UTC)
Signing as Approver
02/01/2016 02:13:45




CONFIDENTIAL 
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Biogen Idec MA Inc. 
1 
 
 
 
 
 
 
 
Biogen Idec MA Inc. 
14 Cambridge Center 
Cambridge, MA 02142, USA 
 
PROTOCOL NUMBER: 
205MS303 
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead Berkshire 
SL6 4AY 
United Kingdom 
 
PHASE OF DEVELOPMENT: 
3 
 
 
PROTOCOL TITLE:  A Multicenter, Open-Label, Extension Study to Evaluate the 
Long-Term Safety and Efficacy of BIIB019, Daclizumab High Yield Process (DAC HYP), 
Monotherapy in Subjects With Multiple Sclerosis Who Have Completed Study 205MS301  
 
 
EUDRA CT NO: 
 
2012-003176-39 
 
 
DATE: 
01 April 2015  
Version 2 
FINAL  
 
Supersedes previous Version 1 dated 28 September 2012. 




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TABLE OF CONTENTS 
1. 
SPONSOR INFORMATION .......................................................................................9 
2. 
LIST OF ABBREVIATIONS.....................................................................................10 
3. 
SYNOPSIS .................................................................................................................12 
4. 
STUDY SCHEMATIC AND SCHEDULE OF EVENTS TABLES FOR 
STUDY 205MS303 ....................................................................................................17 
4.1. 
Study Schematic .........................................................................................................17 
4.2. 
Schedule of Events .....................................................................................................19 
5. 
INTRODUCTION ......................................................................................................34 
5.1. 
Profile of Previous Experience with Daclizumab in MS ............................................34 
5.2. 
Study Rationale ...........................................................................................................36 
5.3. 
Rationale for Dose and Schedule Selection ................................................................36 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................38 
6.1. 
Objectives ...................................................................................................................38 
6.1.1. 
Primary Objective .......................................................................................................38 
6.1.2. 
Secondary Objectives .................................................................................................38 
6.1.3. 
Exploratory Objective .................................................................................................38 
6.2. 
Endpoints ....................................................................................................................38 
6.2.1. 
Primary Endpoints ......................................................................................................38 
6.2.2. 
Secondary Endpoints ..................................................................................................38 
7. 
STUDY DESIGN .......................................................................................................40 
7.1. 
Study Overview ..........................................................................................................40 
7.2. 
Overall Study Duration and Follow-Up .....................................................................40 
7.2.1. 
Baseline/Entry Visit Assessments ..............................................................................40 
7.2.2. 
Treatment ....................................................................................................................40 
7.2.3. 
Post-Treatment Long-Term Follow-Up ......................................................................41 
7.3. 
Study Stopping Rules .................................................................................................41 
7.4. 
End of Study ...............................................................................................................41 
8. 
SELECTION OF SUBJECTS ....................................................................................42 
8.1. 
Inclusion Criteria ........................................................................................................42 
8.2. 
Exclusion Criteria .......................................................................................................42 


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9. 
ENROLLMENT AND REGISTRATION PROCEDURES ......................................44 
9.1. 
Enrollment and Screening ...........................................................................................44 
9.2. 
Registration of Subjects ..............................................................................................44 
10. 
STUDY TREATMENT MANAGEMENT ................................................................45 
10.1. 
DAC HYP ...................................................................................................................45 
10.2. 
DAC HYP Preparation ...............................................................................................45 
10.3. 
DAC HYP Accountability ..........................................................................................46 
11. 
TREATMENT OF SUBJECTS ..................................................................................47 
11.1. 
Study Treatment Schedule and Administration ..........................................................47 
11.2. 
Placebo or Reference Product Agents ........................................................................47 
11.3. 
Treatment Precautions ................................................................................................47 
11.4. 
Treatment Compliance ................................................................................................47 
11.5. 
Concomitant Therapy .................................................................................................48 
11.6. 
Continuation of Treatment ..........................................................................................50 
11.7. 
Treatment Schedule Modifications .............................................................................50 
11.7.1. 
Infections ....................................................................................................................50 
11.7.2. 
Elevated Liver Function Tests ....................................................................................50 
11.7.3. 
Cutaneous Events ........................................................................................................52 
11.7.4. 
Gastrointestinal Events of Inflammatory Colitis ........................................................54 
11.8. 
Discontinuation of Study Treatment ...........................................................................54 
11.9. 
Withdrawal of Subjects From Study ...........................................................................56 
12. 
EFFICACY,  DAC HYP CONCENTRATION, AND 
 ASSESSMENTS ..............................................................57 
12.1. 
Clinical Efficacy Assessments ....................................................................................57 
12.2. 
Pharmacokinetic Assessments ....................................................................................57 
12.3. 
 .................................................................................58 
12.4. 
 ..............................................................................................58 
13. 
SAFETY ASSESSMENTS ........................................................................................59 
13.1. 
Clinical Safety Assessments .......................................................................................59 
13.2. 
Laboratory Safety Assessments ..................................................................................59 
13.3. 
Study-Specific Safety Assessments ............................................................................60 
14. 
SCHEDULE OF EVENTS .........................................................................................61 


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14.1. 
Overview .....................................................................................................................61 
14.2. 
Site Personnel .............................................................................................................62 
14.3. 
Subject Management ..................................................................................................63 
14.4. 
Special Instructions for Tests and Assessments .........................................................64 
14.4.1. 
Rescreening .................................................................................................................64 
14.4.2. 
Pregnancy Testing ......................................................................................................64 
14.4.3. 
Liver Function Test Assessments Prior to DAC HYP Dosing ...................................64 
14.4.4. 
Other Assessments ......................................................................................................65 
14.5. 
Definition of MS Relapse and Disability Progression ................................................66 
14.5.1. 
MS Relapse .................................................................................................................66 
14.5.2. 
Disability Progression .................................................................................................66 
14.6. 
Management of MS Relapse .......................................................................................66 
14.7. 
Cutaneous Events ........................................................................................................67 
14.8. 
Unscheduled Hepatic Assessment Visit .....................................................................67 
14.9. 
Post-Treatment Safety Follow-Up Visit Schedule for All Subjects ...........................67 
15. 
SAFETY DEFINITIONS, MONITORING, AND REPORTING .............................68 
15.1. 
Definitions ..................................................................................................................68 
15.1.1. 
Serious Pretreatment Event .........................................................................................68 
15.1.2. 
Adverse Event .............................................................................................................68 
15.1.3. 
Serious Adverse Event ................................................................................................68 
15.2. 
Monitoring and Recording Events ..............................................................................69 
15.2.1. 
Serious Pretreatment Events .......................................................................................69 
15.2.2. 
Adverse Events ...........................................................................................................69 
15.2.3. 
Serious Adverse Events ..............................................................................................69 
15.2.4. 
All Events ...................................................................................................................69 
15.2.5. 
Immediate Reporting of Serious Adverse Events .......................................................69 
15.2.5.1. 
Deaths .........................................................................................................................70 
15.3. 
Safety Classifications ..................................................................................................70 
15.3.1. 
Relationship of Events to Study Treatment ................................................................70 
15.3.2. 
Severity of Events .......................................................................................................71 
15.3.3. 
Expectedness of Events ..............................................................................................71 


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15.4. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................71 
15.5. 
Procedures for Handling Special Situations ...............................................................72 
15.5.1. 
Overdose .....................................................................................................................72 
15.5.2. 
Medical Emergency ....................................................................................................72 
15.5.3. 
Contraception Requirements ......................................................................................72 
15.5.4. 
Pregnancy ...................................................................................................................73 
15.5.5. 
Regulatory Reporting ..................................................................................................73 
15.6. 
Investigator Responsibilities .......................................................................................73 
15.7. 
Biogen Idec Responsibilities ......................................................................................74 
16. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ...........75 
16.1. 
Description of Objectives ...........................................................................................75 
16.2. 
Description of Endpoints ............................................................................................75 
16.3. 
Demography and Baseline Disease Characteristics ....................................................75 
16.4. 
Safety and Efficacy .....................................................................................................75 
16.4.1. 
Analysis Population ....................................................................................................75 
16.4.2. 
General Methods of Analysis .....................................................................................75 
16.4.3. 
Primary Endpoints Analysis .......................................................................................76 
16.4.4. 
Other Safety Endpoint Analyses .................................................................................76 
16.4.5. 
Efficacy Endpoints Analyses ......................................................................................77 
16.5. 
Interim Analyses .........................................................................................................78 
16.6. 
Sample Size Considerations .......................................................................................78 
17. 
ETHICAL REQUIREMENTS ...................................................................................79 
17.1. 
Declaration of Helsinki ...............................................................................................79 
17.2. 
Ethics Committee ........................................................................................................79 
17.3. 
Subject Information and Consent ...............................................................................79 
17.4. 
Subject Data Protection ..............................................................................................80 
17.5. 
Compensation for Injury .............................................................................................80 
17.6. 
Conflict of Interest ......................................................................................................80 
17.7. 
Registration of Study and Disclosure of Study Results ..............................................80 
18. 
ADMINISTRATIVE PROCEDURES .......................................................................81 
18.1. 
Study Site Initiation ....................................................................................................81 


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18.2. 
Quality Assurance .......................................................................................................81 
18.3. 
Monitoring of the Study..............................................................................................81 
18.4. 
Study Funding .............................................................................................................81 
18.5. 
Publications .................................................................................................................81 
19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION ........................82 
19.1. 
External Contract Organizations .................................................................................82 
19.1.1. 
Contract Research Organization .................................................................................82 
19.1.2. 
Electronic or Remote Data Capture ............................................................................82 
19.1.3. 
Central Laboratories for Laboratory Assessments .....................................................82 
19.1.4. 
Central Facility for Biopsy Assessments ....................................................................82 
19.1.5. 
Central Facility for Other Assessments ......................................................................82 
19.2. 
Study Committees .......................................................................................................83 
19.2.1. 
Advisory Committee ...................................................................................................83 
19.2.2. 
Internal Safety Monitoring Committee .......................................................................83 
19.3. 
Changes to Final Study Protocol ................................................................................83 
19.4. 
Ethics Committee Notification of Study Completion or Termination ........................83 
19.5. 
Retention of Study Data ..............................................................................................83 
19.6. 
Study Report Signatory...............................................................................................84 
20. 
REFERENCES ...........................................................................................................85 
21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL .........................................86 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities:  Baseline Through Week 84 for Subjects Enrolling 
From Study 205MS301 Into Study 205MS303 ..........................................................19 
Table 2: 
Schedule of Activities:  Week 96 through Week 144 for Subjects Enrolling 
From Study 205MS301 Into Study 205MS303 ..........................................................22 
Table 3: 
Schedule of Activities:  Entry Visit (Week 144) for Subjects Enrolling From 
Study 205MS203 or Study 205MS302 Into Study 205MS303 ..................................24 
Table 4: 
Schedule of Activities:  Week 156 through Week 240 (End of Treatment) for 
Subjects Enrolling From Study 205MS301, Study 205MS203, or 
Study 205MS302 Into Study 205MS303 ....................................................................26 
Table 5: 
Schedule of Activities:  Post-Treatment Safety Follow-Up .......................................29 
Table 6: 
Schedule of Activities:  Unscheduled Assessments ...................................................30 


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Table 7: 
Schedule of Activities:  Autoinjector Use by Subjects at Selected Sites ...................32 
Table 8:   Criteria to Determine Clinically Relevant Abnormalities in Vital Signs ...................77 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................18 
Figure 2: 
Flowchart for Management of Subjects With Clinically Significant 
Cutaneous Events ........................................................................................................53 


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1. 
SPONSOR INFORMATION 
 
Biogen Idec MA Inc. 
14 Cambridge Center 
Cambridge, MA  02142 
USA 
 
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead, Berkshire  
SL6 4AY 
United Kingdom 
Biogen Idec Australia Pty Ltd 
Suite 1, Level 5 
123 Epping Road 
North Ryde, NSW 2113 
Australia 
 
For urgent medical issues in which the study’s Medical Director should be contacted, please 
refer to the Study Reference Guide’s Official Study Contact List for complete contact 
information. 
 
Biogen Idec may transfer any or all of its study-related responsibilities to a contract research 
organization (CRO) and other third parties; however, Biogen Idec retains overall accountability 
for these activities. 


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2. 
LIST OF ABBREVIATIONS 
ADAs 
anti-drug antibodies 
AE 
adverse event 
AESI 
Adverse Event of Special Interest 
ALT 
alanine aminotransferase 
ARR 
annualized relapse rate  
AST 
aspartate aminotransferase 
AUDIT-C 
Alcohol Use Disorders Identification Test - Consumption 
Questionnaire 
BDI-II 
Beck Depression Inventory, Second Edition 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
CRF 
case report form 
CRO 
contract research organization 
DAC HYP 
Daclizumab High Yield Process 
DHA 
Directions for Handling and Administration 
EDSS 
Expanded Disability Status Scale 
EQ-5D 
European Quality of Life, 5-dimensions 
EQ-VAS 
European Quality of Life, visual analog scale 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
Gd 
gadolinium 
GGT 
gamma-glutamyltransferase 
HIV 
human immunodeficiency virus 
HRPQ 
Health Related Productivity Questionnaire 
HRU 
health resource utilization 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IFN 
interferon 
IL-2 
interleukin-2 
IM 
intramuscular  
ITT 
intent-to-treat 
IV 
intravenous 
IVIg 
intravenous immunoglobulin 
IVMP 
intravenous methylprednisolone 
LFT 
liver function test 
MRI 
magnetic resonance imaging 
MS 
multiple sclerosis 
MSFC 
Multiple Sclerosis Functional Composite 
MSIS-29 
Multiple Sclerosis Impact Scale-29 
NAbs 
neutralizing antibodies 


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NK 
natural killer cells 
PASAT 3 
3 Second Paced Auditory Serial Addition Test 
 
 
PFS 
prefilled syringe 
PHI 
protected health information 
PK 
pharmacokinetic(s) 
 
 
RDC 
remote data capture 
RRMS 
relapsing-remitting multiple sclerosis 
SABR 
Safety and Benefit-Risk Management 
SAE 
serious adverse event 
SC 
subcutaneous 
SGOT 
serum glutamic oxaloacetic transaminase; see AST 
SGPT 
serum glutamic pyruvic transaminase; see ALT 
SNP 
single nucleotide polymorphism 
SUSAR 
suspected unexpected serious adverse reaction 
T1 
MRI hypointense designation 
T2 
MRI hyperintense designation 
T4 
thyroxine 
ULN 
upper limit of normal 
US 
United States 
VAS 
visual analog scale 


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3. 
SYNOPSIS 
This is a brief summary.  For details refer to the body of the protocol. 
Protocol Number: 
205MS303 
Protocol Title: 
A Multicenter, Open-Label, Extension Study to Evaluate the 
Long-Term Safety and Efficacy of BIIB019, Daclizumab High
Yield Process (DAC HYP), Monotherapy in Subjects With 
Multiple Sclerosis Who Have Completed Study 205MS301 
Version Number: 
2 
Name of Study Treatment: 
Daclizumab High Yield Process (DAC HYP) 
Study Indication: 
Relapsing-Remitting Multiple Sclerosis (RRMS) 
Phase of Development: 
3 
Rationale for the Study: 
To evaluate the long-term safety, efficacy, and 
immunogenicity of DAC HYP in subjects with multiple 
sclerosis (MS) who have completed Study 205MS301 
(DECIDE), Study 205MS203 (SELECTED), or 
Study 205MS302 (OBSERVE). 
Study Objectives and 
Endpoints: 
Objectives 
Primary:  
The primary objective of the study is to assess the safety and 
tolerability of long-term treatment with DAC HYP 
monotherapy in subjects who completed Study 205MS301, 
Study 205MS203, or Study 205MS302. 
Secondary: 
Secondary objectives of this study in this study population 
are as follows: 
 To describe MS-related outcomes, including MS 
relapse, disability progression, MS lesion 
formation, and patient-reported impact of MS, 
following long-term treatment with DAC HYP 
 To assess the long-term immunogenicity of DAC 
HYP administered by prefilled syringe (PFS) 
 To assess the safety, tolerability, and efficacy of 


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switching to DAC HYP in subjects previously on 
long-term treatment with Avonex® in 
Study 205MS301 
Exploratory: 
 
 
 
 
 
Endpoints  
Primary:  
 Incidence of adverse events (AEs) and serious 
AEs (SAEs)  
Secondary: 
 Relapse outcomes:  annualized relapse rate 
(ARR), and proportion of subjects who relapse 
 Sustained disability progression defined by at 
least a 1.0-point increase on the Expanded 
Disability Status Scale (EDSS) score from a 
baseline EDSS ≥1.0 that is sustained for 
24 weeks, or at least a 1.5-point increase on the 
EDSS from a baseline EDSS <1.0 that is 
sustained for 24 weeks.  
 Magnetic resonance imaging (MRI) outcomes:  
total number and volume of new or newly 
enlarging T2 hyperintense lesions, gadolinium-
enhancing (Gd+) lesions, T1 hypointense lesions, 
and brain volume change on brain MRI. 
 Change in Multiple Sclerosis Functional 
Composite (MSFC) score 
 Change in EDSS score 
 Proportion of subjects who are free from disease 
activity. 
 Change in Multiple Sclerosis Impact Scale-29 
(MSIS-29) physical and psychological scores  
 Change in quality of life as assessed by the 
European Quality of Life, 5 dimensions (EQ-5D 
and European Quality of Life, visual analog scale 


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[EQ-VAS])   
 Change in direct health resource utilization 
(HRU; hospitalizations, emergency room visits, 
and unscheduled neurologist visits)  
 Change in treatment satisfaction as assessed by 
the subject  
 Change in subject productivity as assessed by the 
Health Related Productivity Questionnaire 
(HRPQ) 
 Changes in clinical laboratory assessments 
(hematology and blood chemistry) 
 Local tolerability as assessed by subject-reported 
injection site pain (visual analog scale [VAS]) 
and clinician injection site assessments 
 Incidence of anti-drug antibodies to DAC HYP 
over time 
 Incidence of neutralizing antibodies to DAC HYP 
over time  
Study Design: 
Multicenter, open-label, long-term extension study 
Rationale for Dose and 
Schedule Selection: 
The DAC HYP dose and schedule were used in the pivotal 
Phase 3 205MS301 study, and will be the treatment regimen 
used in the commercial setting.  The same DAC HYP dose 
and schedule were used in Study 205MS203 and 
Study 205MS302. 
Study Location: 
Global 
Number of Planned Subjects: 
Approximately 1600 subjects.  This includes approximately 
1200 subjects who completed Study 205MS301.  
Additionally, approximately 400 subjects from the other 
ongoing DAC HYP extension studies (Study 205MS203 and 
Study 203MS302) will be eligible to enter Study 205MS303 
at Week 144 of Study 205MS303.  
Study Population: 
This study will be conducted in subjects with MS currently 
participating in Study 205MS301 who have completed either 
the Week 144 Visit or the End of Study Visit (Week 96) of 
Study 205MS301, OR subjects with MS currently 
participating in Study 205MS203 or Study 205MS302.  


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Treatment Groups: 
This is a single-arm study.  All subjects will receive 
open-label treatment with DAC HYP 150 mg by a 
subcutaneous injection using the PFS every 4 weeks. 
Depending on availability and local regulations, some 
subjects may dose with DAC HYP using a single-use 
autoinjector that contains a PFS. 
Duration of Treatment and 
Follow-up: 
Subjects will participate in this study for up to approximately 
5 years, or until availability of commercial product 
(whichever is sooner), and in accordance with applicable 
laws and regulations. All subjects should complete safety 
follow-up evaluations at 8, 12, 16, and 24 weeks after the 
subject’s last dose of DAC HYP. 
Criteria for Evaluation:  
 
Efficacy: 
Clinical relapse assessments, EDSS, MSFC (Timed 25-Foot 
Walk, Nine-Hole Peg Test with both upper extremities, 
PASAT 3), and brain MRI scan with and without Gd (T2 
hyperintense lesions, T1 hypointense lesions, Gd+ lesions, 
brain atrophy). 
Pharmacokinetics: 
Blood serum will be collected at selected timepoints 
throughout the study to determine DAC HYP serum 
concentrations in order to monitor the drug trough level and 
 
 
   
: 
 
 
 
 
 
   
Safety: 
Physical and neurological exams, vital signs, clinical 
laboratory assessments (hematology, blood chemistry, 
thyroid function panel [including thyroid stimulating 
hormone and T4], urinalysis), urine pregnancy testing, Beck 
Depression Inventory, Second Edition, immunogenicity 
assessments, Alcohol Use Disorders Identification Test - 
Consumption Questionnaire (AUDIT-C), and AE and 
concomitant medication monitoring will be performed in this 


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study.  Additional comprehensive hepatic testing will be 
required for subjects who permanently discontinue study 
treatment due to elevated liver function tests. 
Subject Reported 
Assessments: 
Subject assessment of MSIS-29, EQ-5D quality of life 
questionnaire (the EQ-5D descriptive system and the 
respondent’s self-rated health on a vertical visual analog 
scale [EQ-VAS]), Treatment Satisfaction Questionnaire for 
Medication (before the first use of a PFS and at multiple 
timepoints during the study), Treatment Satisfaction Survey 
at selected sites (before the first and last use of an 
autoinjector), HRU, and HRPQ. 
Statistical Methods: 
 
Analyses will generally be descriptive in nature and will 
focus on data collected during Study 205MS303 only.  
Efficacy endpoints will be summarized for all subjects using 
descriptive statistics.  For relevant efficacy analyses, the data 
may be summarized for subjects by previous treatment group 
(Avonex® or DAC HYP 150 mg). The adjusted ARR and 
number of new or newly enlarging T2 lesions will be 
estimated using a negative binomial regression model.  The 
proportion of subjects with sustained progression and the 
proportion with a relapse will be estimated from the Kaplan-
Meier curve.  The incidence of AEs and changes in clinical 
laboratory assessments will also be summarized.   An 
analysis by 3- or 6-month intervals may also be performed.  
Summary statistics for other safety, efficacy, and 
pharmacokinetic (PK) endpoints will be presented. 
Sample Size Determination:  
There is no formal sample size calculation for this study.  
The number of subjects in this study is determined by the 
number of subjects who completed Study 205MS301, 
Study 205MS203, or Study 205MS302, and enrolled in 
Study 205MS303. 
Study Stopping Rules: 
Biogen Idec may terminate this study, after informing 
Investigators, at any time.  Investigators will be notified by 
Biogen Idec or designee if the study is placed on hold, 
completed, or closed. 


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4. 
STUDY SCHEMATIC AND SCHEDULE OF EVENTS TABLES 
FOR STUDY 205MS303 
A schematic of the study design is provided in Section 4.1.  
The tabulated schedule of events for this study is provided in Section 4.2.  
4.1. 
Study Schematic 
Figure 1 shows the design of Study 205MS301 and its open-label extension, Study 205MS303, 
in which subjects from Study 205MS203 and 205MS302 enter at Week 144. 
 
 


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Figure 1: 
Study Design 
 






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3Baseline Visit must take place within 6 months of completing Study 205MS301. Any test/assessment done at the subject’s last visit in Study 205MS301 and 
within 28 days of the subject’s first dose in Study 205MS303 may be used as the baseline and does not need to be repeated at entry into Study 205MS303; for 
subjects who enroll in Study 205MS303 >28 days after their final Study 205MS301 visit, tests and assessments must be repeated at the Baseline Visit. 
4ALT/SGPT, AST/SGOT, alkaline phosphatase, total bilirubin, and GGT only. 
5If local LFTs have been used to determine whether dosing should continue or be suspended at the time of a scheduled clinic visit, LFTs must also be performed 
at the central laboratory at the time of the scheduled clinic visit (Note:  Scheduled clinic visits occur every 4 weeks during the first 12 weeks of the study and 
every 12 weeks thereafter).   
6
7Subjects who did not consent to 
 collection in 205MS301 will be re-approached for this consent upon entry into Study 205MS303.  A separate informed 
consent form may be used for 
 sample collection.  Samples for 
 may be collected after the Baseline Visit, if necessary. 
8Pregnancy test results must be negative prior to dosing. 
9MSIS-29 to be administered prior to seeing the Study Neurologist.  
10To be performed after the DAC HYP injection at this visit. 
11MRI scan can be performed up to 4 days prior to the visit. 
12Before a monthly dose of DAC HYP is given, LFT results from a prior test performed within the previous 28(+4) days must be reviewed by the Study 
Neurologist or their backup. 
13A window of 4 days applies to DAC HYP dose even if it is done at home. 
14At the Week 4, 8, and 12 Visits, subjects will be instructed on DAC HYP self-administration and may administer their scheduled dose under staff supervision. 
After Week 12, DAC HYP may be dispensed to subjects for at-home administration if the subject chooses.




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1On dosing days, all tests and assessments (other than Treatment Satisfaction Questionnaire for Medication) must be completed prior to administration of study 
treatment.  
2Week 144 (start of Year 4) of Study 205MS303 will be the timepoint at which subjects from Study 205MS203 (SELECTED) and Study 205MS302 
(OBSERVE) enter Study 205MS303 (see Table 3 for the assessments at Week 144 in these subjects).  
3ALT/SGPT, AST/SGOT, alkaline phosphatase, total bilirubin, and GGT only. 
4If local LFTs have been used to determine whether dosing should continue or be suspended at the time of a scheduled clinic visit, LFTs must also be performed 
at the central laboratory at the time of the scheduled clinic visit (Note:  Scheduled clinic visits occur every 4 weeks during the first 12 weeks of the study and 
every 12 weeks thereafter.)5Pregnancy test results must be negative prior to dosing. 
6MRI scan can be performed up to 4 days prior to the visit. 
7When possible, subjects should be evaluated by the same neurologist assigned to them in the parent study.  
8Before a monthly dose of DAC HYP is given, LFT results from a prior test performed within the previous 28(+4) days must be reviewed by the Study 
Neurologist or their backup.  
9A window of 4 days applies to DAC HYP dose even if it is done at home. 
 




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Concomitant Therapy and AEs 
X 
Protocol Compliance and DAC HYP 
Accountability 
X 
1When possible, subjects should be evaluated by the same Study Neurologist assigned to them in the parent studies.  
2Week 144 (start of Year 4) of Study 205MS303 will be the timepoint at which subjects from Study 205MS203 and Study 205MS302 enter Study 205MS303. 
Entry Visit must take place within 6 months of the last DAC HYP dose in the parent studies (i.e., Study 205MS203 or Study 205MS302).   
3ALT/SGPT, AST/SGOT, alkaline phosphatase, total bilirubin, and GGT only.  
5Pregnancy test results must be negative prior to dosing. 
6Before a monthly dose of DAC HYP is given at the clinic, LFT results from a prior test performed within the previous 28(+4) days must be reviewed by the 
Study Neurologist or their backup.   
 
 






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7Before a monthly dose of DAC HYP is given, LFT results from a prior test performed within the previous 28(+4) days must be reviewed by the Study 
Neurologist or their backup. 
8A window of 4 days applies to DAC HYP dose even if it is done at home. 






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8Whole blood samples will be collected for potential determination of DAC HYP serum concentrations 
 
 
9Performed by the Study Neurologist or their back-up within 72 hours of a suspected relapse.   
10 Refer to Section 11.7.3 for information on when to perform these assessments. 
 




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2Subjects must provide written informed consent for autoinjector use prior to first DAC HYP dose by autoinjector. 
3The procedure for taking this measurement is provided in the Study Reference Manual. 
4Injection Site Assessment to be completed as soon as possible but within 10 minutes after the injection at Visit 1. 
5VAS to be completed as soon as possible after the injection is administered, but no later than 10-30 minutes post-injection. 
6If the subject withdraws from the study or reverts to PFS use prior to receiving all 6 autoinjector doses, the subject should complete the Treatment Satisfaction 
Survey and the Patient Usability Survey provided for the Autoinjector 6 dosing day before returning to PFS or receiving alternative MS disease modifying 
therapy. 


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5. 
INTRODUCTION  
5.1. 
Profile of Previous Experience with Daclizumab in MS 
Background 
DAC HYP is a humanized monoclonal IgG1 antibody specific for CD25 (α subunit of the IL-2 
receptor).  CD25 is expressed at low levels on resting T cells but is rapidly upregulated after T-
cell activation, enabling high-affinity IL-2 signal transduction.  The primary hypothesis for using 
DAC HYP to treat MS is to selectively inhibit activated T cells.   
Anti-CD25 antibodies have multiple in vitro effects that suggest DAC HYP may directly 
decrease T-cell activation and proliferation.  These include inhibition of IL-2 dependent 
lymphocyte proliferation, disruption of both IL-2 dependent and independent pathways of 
IFN-gamma production, and interference in CD28-dependent CD40 ligand expression.  In vivo, 
daclizumab has been confirmed to cause expansion of CD56bright NK cells.  This expansion has 
also been shown to correlate with MRI-defined therapeutic response of daclizumab in MS.  
CD56bright NK cells are believed to have an immunoregulatory function, and they have been 
shown to kill activated T cells through a contact-dependent mechanism.  Therefore, selective 
inhibition of activated T cells with DAC HYP may occur through both direct and indirect 
mechanisms [Bielekova 2009; Bielekova 2004].   
Clinical Experience With Daclizumab in Multiple Sclerosis 
Initial clinical studies of daclizumab in MS were conducted with material manufactured by 
F. Hoffmann-La Roche, Ltd. (Roche) at their facilities in Nutley, New Jersey (DAC Nutley) 
[Bielekova 2004; Rose 2003; Rose 2004], and in Penzberg, Germany (DAC Penzberg) [Wynn 
2010].  Study 205MS301 is conducted with DAC HYP, which is produced using a different 
manufacturing process than the previous versions of daclizumab.  DAC HYP has characteristics 
that are similar to DAC Nutley and DAC Penzberg, although certain differences in 
physicochemical and biological characteristics have been observed (refer to the Investigator’s 
Brochure for details).   
Study 205MS201 
Study 205MS201 (SELECT) was a double-blind, placebo-controlled study to evaluate the safety 
and efficacy of DAC HYP in subjects with RRMS that randomized 621 subjects in a 1:1:1 ratio 
to receive placebo, 150 mg DAC HYP, or 300 mg DAC HYP SC every 4 weeks over a 52-week 
treatment period.  Among subjects randomized to DAC HYP (150 mg, 300 mg) versus placebo, 
there was a significantly lower annualized relapse rate (ARR; 0.21, 0.23 versus 0.46; p < 0.001), 
a higher proportion of relapse-free subjects (81%, 80% versus 64%; p < 0.001), and a trend 
towards improvement in the MSIS-29 physical score (p = 0.128 for DAC HYP 300 mg versus 
placebo; p < 0.001 for DAC HYP 150 mg versus placebo).  There were significant reductions in 
the mean number of new or newly enlarging T2 lesions at 1 year (2.4, 1.7 versus 8.1) and in the 
mean number of new Gd+ lesions between Weeks 8 and 24 in a monthly MRI substudy 
(n = 307) (1.5, 1.0 versus 4.8) in the DAC HYP 150 mg and 300 mg groups versus placebo (p < 


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0.001 for all comparisons).  The risk of 3-month sustained disability progression at 1 year, a 
tertiary study endpoint, was reduced by 57% (p = 0.021) in the DAC HYP 150 mg group and by 
43% (p = 0.091) in the DAC HYP 300 mg group.   
Analysis of safety data from Study 205MS201 showed that, overall, DAC HYP was well 
tolerated in this patient population.  The most frequently reported (≥10%) AEs for subjects 
treated with DAC HYP, excluding MS relapse, were nasopharyngitis (14%), and headache and 
upper respiratory tract infection (10% each).  In Study 205MS201, serious adverse events 
(SAEs) including MS relapses occurred in 26% of placebo-treated subjects and in 16% of 
subjects treated with DAC HYP.  Excluding MS relapses, SAEs occurred in 6% of the placebo 
group, in 7% of the DAC HYP 150 mg group, and in 9% of the DAC HYP 300 mg group.  One 
DAC HYP-treated subject died due to ischemic colitis following a complicated course of events.  
Adverse events observed more frequently in DAC HYP-treated patients included an increase in 
serious infections (2%), serious cutaneous events (1%), and elevations in liver function tests 
(ALT/AST) >5 ULN (4%). 
Upon completion of the 12-month treatment period in Study 205MS201, subjects were eligible to 
complete up to an additional 12 months of treatment with DAC HYP in a double-blind extension 
study (Study 205MS202 [SELECTION]), which was completed in 2012.  Study 205MS202 also 
assessed the effects of DAC HYP washout in some subjects who were actively treated in Study 
205MS201.  Subjects completing Study 205MS202 continued long-term therapy with open-label 
DAC HYP in extension Study 205MS203 (SELECTED), which evaluated long-term safety and 
efficacy of DAC HYP monotherapy for up to an additional 144 weeks.  
Study 205MS301 
Study 205MS301 (DECIDE), a double-blind, randomized, parallel-group, active-controlled study 
testing the superiority of DAC HYP monotherapy compared to Avonex® (IFN -1a) in 
preventing MS relapse, was initiated in May 2010; 1841 subjects with RRMS have been enrolled 
and randomized in a 1:1 ratio to receive 150 mg DAC HYP given SC every 4 weeks, or Avonex 
30 mcg given IM once weekly over a 96- to 144-week treatment period.  The primary endpoint 
was the annualized relapse rate.  In this study, DAC HYP demonstrated statistically and 
clinically meaningful superiority to IFN β-1a, on validated clinical, radiographic, and patient-
reported MS outcome measures.  DAC HYP reduced the annualized relapse rate by 45% 
(p<0.0001) compared to IFN β-1a.  DAC HYP’s treatment effect on relapses was also evidenced 
by a 41% reduction in the risk of relapse in subjects in the DAC HYP group compared to the IFN 
β-1a group (p<0.0001).  A reduction in the proportion of subjects relapsing was observed as 
early as 24 weeks after the initiation of treatment and persisted throughout the end of the study.  
The risk of 12-week confirmed disability progression was reduced by 16% in the DAC HYP 
group compared with the IFN β-1a group, a result that was not statistically significant 
(p=0.1575) in the primary analysis.  In the pre-specified analysis of 24-week confirmed 
progression, disability progression was reduced by 27% (p=0.0332) in the DAC HYP group 
compared with the IFN β-1a group.  Overall, the results of the 12-week and 24-week confirmed 
progression analyses were consistent with each other and supported a clinically meaningful 
effect of DAC HYP in preventing confirmed disability progression compared with IFN β-1a.  
DAC HYP reduced the number of new or newly enlarging T2 lesions at Week 96 by 54.4% 
(p<0.0001) compared to IFN β-1a.  The magnitude of the treatment effect was consistent with 


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the results seen on the primary endpoint of annualized relapse rate.  The tertiary MRI endpoints 
of T2, T1, and Gd-enhancing lesion count and volume were also consistent with the effect on 
new or enlarging T2 lesions and provide important confirmation of DAC HYP’s ability to reduce 
focal and destructive areas of brain inflammation in RRMS patients.  The treatment effect of 
DAC HYP on new or enlarging T2 lesions and other MRI endpoints was detectable by Week 24 
(p<0.0001) and was sustained through to the Week 96 and Week 144 MRI at a similar 
magnitude.   
In Study 205MS301, the safety profile of DAC HYP was characterized by an increased 
incidence of elevations of serum transaminases and serious hepatic events, cutaneous events, 
infections, and gastrointestinal events.  The overall incidence of AEs was balanced across the 2 
treatment groups (91% IFN β-1a vs. 91% DAC HYP).  The majority of subjects with AEs had 
events that were mild to moderate in severity.  The incidence of subjects with AEs that were 
considered severe was 14% in the DAC HYP group and 12% in the IFN β-1a group.  AEs 
reported more frequently in the DAC HYP group than in the IFN β-1a group included 
nasopharyngitis, upper respiratory tract infections, influenza, oropharyngeal pain, rash, and 
lymphadenopathy, whereas influenza-like illness, pyrexia, chills, and hypertension were reported 
more frequently in the IFN β-1a group. 
There was a higher incidence of SAEs in the DAC HYP group (24%) compared with the 
IFN β-1a group (21%).  Excluding MS relapse, SAEs were reported in 10% of the IFN β-1a 
group and in 15% of the DAC HYP group.  Five deaths were reported in the study (4 subjects in 
the IFN β-1a group, 1 subject in the DAC HYP group).  None of the deaths were considered by 
the Investigators to be related to study treatment.  While safety events were more common in the 
DAC HYP-treated subjects compared with IFN β-1a-treated subjects, the types of events were 
generally manageable with standard medical care, monitoring, and treatment discontinuation, as 
appropriate for the event.  Overall, the results of the study support a positive benefit/risk profile 
for DAC HYP. 
The PK and immunogenicity of DAC HYP 150 mg SC administered every 4 weeks using a 
prefilled syringe (PFS) were investigated in 26 subjects in Study 205MS302 (OBSERVE), a 
single-arm, open-label study that enrolled a total of 113 subjects with RRMS. 
Refer to the Investigator’s Brochure for additional details.  
5.2. 
Study Rationale 
This study will evaluate the long-term safety, efficacy, and immunogenicity of DAC HYP in 
subjects with MS who have completed Study 205MS301, Study 205MS203, or 
Study 205MS302.  In addition, this study will assess the safety, tolerability, and efficacy of 
switching to DAC HYP in subjects previously on long-term treatment with interferon β-1a in 
Study 205MS301. 
5.3. 
Rationale for Dose and Schedule Selection 
The existing scientific and clinical experience with DAC HYP supports its further investigation 
in the management of MS.  The DAC HYP dose and schedule in this protocol were used in the 
pivotal Phase 3 Study 205MS301, and will be the treatment regimen used in the commercial 


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setting.  The same DAC HYP dose and schedule were used in Study 205MS203 and 
Study 205MS302. 
A single-use, disposable PFS will be provided to simplify the injection process and thereby 
reduce the burden of administering a long-term therapy such as DAC HYP in the clinic or at 
home.  At the Sponsor’s discretion, single-use autoinjectors containing PFS may be used to 
administer DAC HYP in 75-100 subjects from Study 205MS303 at selected sites.  Autoinjectors 
will be dispensed to each participating subject for use on up to 6 consecutive scheduled dosing 
days. 


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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Objectives  
6.1.1. 
Primary Objective 
The primary objective of the study is to assess the safety and tolerability of long-term treatment 
with DAC HYP monotherapy in subjects who completed Study 205MS301, Study 205MS203, or 
Study 205MS302. 
6.1.2. 
Secondary Objectives 
Secondary objectives of this study in this study population are as follows: 
 To describe MS-related outcomes, including MS relapse, disability progression, MS 
lesion formation, and patient-reported impact of MS, following long-term treatment 
with DAC HYP 
 To assess the long-term immunogenicity of DAC HYP administered by PFS  
 To assess the safety, tolerability, and efficacy of switching to DAC HYP in subjects 
previously on long-term treatment with interferon β-1a in Study 205MS301 
6.1.3. 
Exploratory Objective 
 
 
 
6.2. 
Endpoints 
6.2.1. 
Primary Endpoints 
 Incidence of AEs and SAEs 
6.2.2. 
Secondary Endpoints 
 Relapse outcomes:  annualized relapse rate (ARR), and proportion of subjects who 
relapse 
 Sustained disability progression defined by at least a 1.0-point increase on the 
Expanded Disability Status Scale (EDSS) score from a baseline EDSS ≥1.0 that is 
sustained for 24 weeks, or at least a 1.5-point increase on the EDSS from a baseline 
EDSS <1.0 that is sustained for 24 weeks  
 Magnetic Resonance Imaging (MRI) outcomes:  total number and volume of new or 
newly enlarging T2 hyperintense lesions, Gd-enhancing lesions, T1 hypointense 
lesions, and brain volume change on brain MRI  
 Change in Multiple Sclerosis Functional Composite (MSFC) score 


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 Change in EDSS score 
 Proportion of subjects who are free from disease activity. 
 Change in Multiple Sclerosis Impact Scale-29 (MSIS-29) physical and psychological 
scores  
 Change in quality of life as assessed by the European Quality of Life, 5 dimensions 
(EQ-5D and EQ-VAS)   
 Change in direct health resource utilization (HRU; hospitalizations, emergency room 
visits, and unscheduled neurologist visits)  
 Change in treatment satisfaction as assessed by the subject 
 Change in subject productivity as assessed by the Health Related Productivity 
Questionnaire (HRPQ) 
 Changes in clinical laboratory assessments (hematology and blood chemistry) 
 Local tolerability as assessed by subject-reported injection site pain (VAS) and 
clinician injection site assessments 
 Incidence of anti-drug antibodies (ADAs) to DAC HYP over time 
 Incidence of neutralizing antibodies (NAbs) to DAC HYP over time 
 


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7. 
STUDY DESIGN 
7.1. 
Study Overview 
The design of Study 205MS303 is provided in Figure 1.  Approximately 1600 subjects will 
enroll in this study.  This includes approximately 1200 subjects who completed Study 
205MS301.  Additionally, approximately 400 subjects from the other DAC HYP extension 
studies (205MS203 [SELECTED] and 203MS302 [OBSERVE]) will be eligible to enter Study 
205MS303 at Week 144 of Study 205MS303 (Study 205MS301, Study 205MS203, and 
Study 205MS302 have been referred to as parent studies in the protocol). 
All subjects will receive the same dose of DAC HYP as received in the parent studies; i.e., 
150 mg by an SC injection every 4 weeks.  The duration of DAC HYP treatment is up to 
approximately 5 years, or until availability of commercial product (whichever is sooner). 
7.2. 
Overall Study Duration and Follow-Up 
The study period will consist of Baseline/Entry Visit assessments, treatment (for up to 
approximately 5 years), and post-treatment safety follow-up visits (from approximately 4 to 24 
weeks after the last dose of DAC HYP). 
7.2.1. 
Baseline/Entry Visit Assessments 
Subjects Entering From Study 205MS301 
Tests/assessments performed at the subject’s last visit in Study 205MS301 and within 28 days of 
the subject’s first dose of DAC HYP (Week 0) in Study 205MS303 may be used as the baseline 
for Study 205MS303; if final Study 205MS301 tests/assessments are not performed within the 
28-day window, they must be repeated upon entry into Study 205MS303 and before the first 
dose of DAC HYP is administered.  
Subjects Entering From Study 205MS203 or Study 205MS302 
The Week 144 Visit of Study 205MS303 will be the Entry Visit for subjects enrolled from 
Study 205MS203 or Study 205MS302.  Any test/assessment done at the subject’s last visit in 
parent studies and within 28 days of the subject’s first dose in Study 205MS303 will be used as 
the baseline and does not need to be repeated at entry into Study 205MS303; tests/assessments 
performed >28 days before the Entry Visit must be repeated at the Entry Visit.  Central LFT 
testing is mandatory at the Entry Visit. 
7.2.2. 
Treatment 
Subjects from Study 205MS301 continuing in Study 205MS303 will receive DAC HYP 
treatment for up to approximately 5 years, or until availability of commercial product (whichever 
is sooner), under this protocol.  Subjects from Study 205MS203 and Study 205MS302 entering 
Study 205MS303 at Week 144 will have DAC HYP treatment for up to approximately 2 years, 
or until availability of commercial product (whichever is sooner), under this protocol. 


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At the Sponsor’s discretion, 75-100 subjects from Study 205MS303 at selected sites may dose 
with DAC HYP using a single-use autoinjector that contains a PFS on 6 consecutive scheduled 
dosing days (Table 7). 
Eligible subjects will have clinic visits scheduled every 4 weeks for up to Week 12 in this study, 
followed by clinic visits scheduled every 12 weeks.  
Subjects who are dosing at home must be instructed to not administer their monthly dose 
of DAC HYP until the study site has contacted them to authorize dosing (after the Study 
Neurologist or their backup has reviewed LFT results obtained during the previous 28(+4) days).  
Subjects need to record the date and time of dosing in their diary if they are dosing at home. 
A window of ±4 days applies to scheduled visits and home dosing. 
7.2.3. 
Post-Treatment Long-Term Follow-Up 
Subjects are to return to the study site for follow-up visits at 8, 12, 16, and 24 weeks (±10 days) 
after the last dose of DAC HYP. 
7.3. 
Study Stopping Rules 
Biogen Idec may terminate this study, after informing Investigators, at any time.  Investigators 
will be notified by Biogen Idec or designee if the study is placed on hold, completed, or closed. 
7.4. 
End of Study 
The End of Study is last subject, last visit for final collection of data. 


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8. 
SELECTION OF SUBJECTS 
8.1. 
Inclusion Criteria  
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at the 205MS303 Baseline/Entry Visit or at the timepoint specified in the individual eligibility 
criterion listed (Note:  Week 0/Day 1 is the Baseline Visit in Study 205MS303 for 205MS301 
subjects.  Week 144 is the Entry Visit in Study 205MS303 for 205MS203 and 205MS302 
subjects):  
1. Ability to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use protected health information (PHI) in 
accordance with national and local subject privacy regulations.   
2. Must be a subject currently participating in Study 205MS301 who has completed either 
the Week 144 Visit or the End of Study Visit (Week 96) of Study 205MS301 OR subject 
currently participating in Study 205MS203 or Study 205MS302. 
3. Women of childbearing potential must practice effective contraception during the study 
and be willing and able to continue contraception for 4 months after their last dose of 
study treatment. 
8.2. 
Exclusion Criteria 
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
the Study 205MS303 Baseline/Entry Visit or at the timepoint specified in the individual criterion 
listed (Note:  Week 0/Day 1 is the Baseline Visit in Study 205MS303 for 205MS301 subjects.  
Week 144 is the Entry Visit in Study 205MS303 for 205MS203 and 205MS302 subjects): 
Medical History 
1. Any subject who permanently discontinued study treatment in Study 205MS301, 
Study 205MS203, or Study 205MS302 prior to the end of the study treatment period, or 
had an early termination in those studies OR any subject who has completed all the safety 
follow-up visits after Week 144 of Study 205MS303 per the original protocol.   
Note:  Subjects for whom dosing was temporarily suspended in Study 205MS301, 
Study 205MS203, or Study 205MS302 are not excluded from participation in this 
extension study if the criteria for resuming DAC HYP treatment under the parent study 
protocol have been met at the time of enrollment into Study 205MS303.   
2. Any significant change in the subject’s medical history that would preclude 
administration of DAC HYP, including laboratory tests or a current clinically significant 
condition that, in the opinion of the Investigator, would have excluded the subject’s 
participation in Study 205MS301, Study 205MS203, or Study 205MS302.  The 
Investigator must re-review the subject’s medical fitness for participation and consider 
any factors that would preclude treatment in Study 205MS303, including:   


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 History of any significant cardiac, endocrine, hematological, hepatic, immunologic, 
metabolic, urologic, pulmonary, gastrointestinal, dermatologic, psychiatric, renal, 
neurological (other than MS), and/or other major disease (e.g., malignancy) that 
would preclude administration of DAC HYP. 
 Clinically significant laboratory abnormalities (hematology and blood chemistry) 
from the most recently available test in the parent study, as determined by the 
Investigator.  Laboratory findings mandating discontinuation of study treatment as 
defined in parent study protocol are exclusionary. 
3. Other medical reasons that, in the opinion of the Investigator and/or Biogen Idec, make 
the subject unsuitable for enrollment.   
Treatment History 
4. Treatment with any prohibited concomitant medication during the parent study. 
Note:  Subjects who start an approved, open-label IFN β preparation after completion of 
dosing in Study 205MS301 are not excluded, but IFN β treatment must be discontinued 
before the first dose of DAC HYP in Study 205MS303 is given.   
Miscellaneous 
5. Female subjects who are currently pregnant or breastfeeding, or considering becoming 
pregnant while in the study. 
6. History of drug or alcohol abuse (as defined by the Investigator) at any time after the start 
of Study 205MS303 or any of the parent studies. 
7. Unwillingness or inability to comply with the requirements of the protocol, including the 
presence of any condition (physical, mental, or social) that is likely to affect the subject’s 
ability to comply with the protocol. 


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9. 
ENROLLMENT AND REGISTRATION PROCEDURES 
9.1. 
Enrollment and Screening 
Subjects must be consented before any procedures are performed.  At the time of consent, the 
subject will be enrolled into the study.   If a subject is excluded from the study, the reasons for 
exclusion will be documented in the subject’s source documents and on the enrollment log.  Any 
test/assessment done at the subject’s last visit in the parent studies and within 28 days of the 
subject’s first dose in Study 205MS303 will be used as the baseline for Study 205MS303 and 
does not need to be repeated at entry into Study 205MS303 (Note:  Central LFT testing is 
mandatory at the Week 144 Entry Visit for subjects rolling over from Study 205MS203 and 
Study 205MS302 into Study 205MS303).  Testing required at the Baseline/Entry Visit that is 
done outside the 28-day window must be repeated upon entry into 205MS303.   
9.2. 
Registration of Subjects 
Subjects should be registered in the study after the Investigator has verified that they are eligible 
per the criteria in Section 8.1 and Section 8.2 and all baseline assessments have been performed.  
No subject may begin treatment prior to enrollment and registration.   
As confirmation, the Investigator will be provided with written verification of the subject’s 
registration by mail or fax.   
Refer to the Study Reference Manual for details on registration. 
 


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10. 
STUDY TREATMENT MANAGEMENT 
Study treatment (PFS or autoinjectors) must be stored in a secure location.  Accountability for 
study treatment is the responsibility of the Investigator.  Study treatment must only be dispensed 
by a Pharmacist or medically qualified staff, and stored in a secure, monitored, locked location in 
accordance with the conditions specified in current prescribing information or the Directions for 
Handling and Administration (DHA) included in the Study Reference Manual. 
Study treatment is to be dispensed only to subjects enrolled in this study.  Once treatment is 
dispensed to a subject, it can only be used by that subject. 
10.1. 
DAC HYP 
Prefilled Syringe  
DAC HYP is supplied as a liquid in a 1-mL BD-staked PFS with a 29 gauge × ½ inch needle, 
comprising 150 mg/mL DAC HYP plus excipient materials (sodium succinate, sodium chloride, 
and polysorbate 80).  At a minimum, the study treatment label will include a study reference 
code, drug identifier, quantity of dosage units, lot number, and other pertinent information in 
accordance with local law.  Depending on country requirements, the Investigator’s name may 
also appear on the label.  DAC HYP must not be used after the expiration date unless a written 
notification of an expiration date extension is provided by Biogen Idec. 
Autoinjector  
The DAC HYP PFS is assembled inside a single-use, disposable autoinjector device.   
The autoinjector label will include the DAC HYP product code “BIIB019,” conditions for 
storage, Sponsor, and a caution statement.  Depending on country requirements, the 
Investigator’s name may also appear on the label.  DAC HYP must not be used after the 
expiration date unless a written notification of an expiration date extension is provided by 
Biogen Idec. 
10.2. 
DAC HYP Preparation 
Each DAC HYP PFS or autoinjector contains only one dose and is intended for SINGLE USE 
INJECTION ONLY.  Any drug that remains in the PFS after injection must not be used for 
another dose or another subject.  
After Week 12, subjects may choose to administer their DAC HYP dose at home, either by 
administering the injection themselves or by a designated caregiver.  The subject or designated 
caregiver will be trained by clinic staff on the correct PFS injection technique prior to initiating 
at-home DAC HYP dosing. 
Autoinjectors may be provided to selected sites and will be supplied injection-ready.  Study 
personnel or subjects at these sites do not need to insert the PFS into the device.  Study site 
personnel will receive appropriate autoinjector training from a Sponsor-designated trainer prior 
to initiation of autoinjector use. 


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10.3. 
DAC HYP Accountability 
The study site must maintain accurate records demonstrating dates and amount of study 
treatment received, to whom dispensed (subject-by-subject accounting), any amount returned by 
subject, and accounts of any study treatment accidentally or deliberately destroyed.   
Unless otherwise notified, all PFS and autoinjectors, both used and unused, must be saved for 
study treatment accountability.  At the end of the study, a final reconciliation must be made 
between the amount of study treatment supplied, dispensed, and subsequently destroyed or 
returned to Biogen Idec.  
A written explanation will be provided for any discrepancies.  After reconciliation, the 
Investigator must destroy or return to Biogen Idec all unused study treatment PFS and 
autoinjectors as instructed by Biogen Idec. 
If any study treatment supplies are to be destroyed at the site, the Principal Investigator(s) must 
obtain prior approval by Biogen Idec.  The Principal Investigator(s) must notify Biogen Idec, in 
writing, of the method, date, and location of destruction.   


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11. 
TREATMENT OF SUBJECTS 
Biogen Idec will provide DAC HYP (PFS or autoinjectors) to all study sites. 
Refer to Section 10 (Study Treatment Management) for specifics on the preparation, storage, 
handling, disposal, and accountability of study treatment. 
11.1. 
Study Treatment Schedule and Administration 
All subjects will receive one DAC HYP 150 mg SC injection every 4 weeks.   
DAC HYP will be administered by clinic staff at the monthly visits for the first 12 weeks of this 
study.  After Week 12, administration of DAC HYP may occur in the clinic or at home (by the 
subject or by a designated caregiver) depending on subject preference.  The subject or designated 
caregiver will be trained by clinic staff on the correct injection technique prior to initiating at-
home DAC HYP dosing.  Subjects who are dosing at home must be instructed to not 
administer their monthly dose of DAC HYP until the study site has contacted them to 
authorize dosing.  A window of ±4 days applies to home dosing. 
Before a monthly dose of DAC HYP is given, LFT results from a prior test performed within the 
previous 28(+4) days must be reviewed by the Study Neurologist or their backup.  Study 
personnel should promptly inform the subject whether the monthly dose of DAC HYP should be 
administered or whether study treatment is to be withheld based on the dosing criteria defined in 
Section 11.7.2.  Study personnel will document this communication with the subject.  Subjects 
should administer DAC HYP as soon as permission has been given as per the dosing schedule.  
Subjects need to record the date and time of dosing in their diary if they are dosing at home. 
11.2. 
Placebo or Reference Product Agents 
Not applicable. 
11.3. 
Treatment Precautions 
Anaphylactic-like and hypersensitivity reactions following administration of proteins such as 
DAC HYP can occur.  DAC HYP will be administered in the clinic under observation by 
qualified medical personnel for the first 12 weeks of this study.  Subjects will be educated by the 
Study Neurologist or their back-up on the signs and symptoms of hypersensitivity reactions and 
instructed to contact the site if they experience any acute or delayed reactions post injection.   
11.4. 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded by study site staff. 
After Week 12, subjects who choose to administer their DAC HYP dose at home will record 
treatment in a dosing diary.  The diary will be reviewed periodically by study site staff and the 
Clinical Monitor throughout the study.  Subjects who choose at-home administration will return 
used PFS or autoinjectors to the clinic at their scheduled clinic visits.   


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11.5. 
Concomitant Therapy 
A concomitant therapy is any drug or substance administered from the Baseline/Entry Visit until 
completion of the study. A concomitant procedure is defined as any therapeutic intervention 
(e.g., surgery/biopsy, physical therapy) or diagnostic assessment (e.g., blood gas measurement, 
bacterial cultures) performed from the time the subject is enrolled in the study until the subject’s 
final clinic visit. 
Concomitant treatment with any of the following is not allowed during the study, unless 
approved by the Biogen Idec Medical Director(s) or the Advisory Committee, or as otherwise 
described in this protocol: 
 Any alternative disease modifying MS drug treatment such as chronic 
immunosuppressant therapy or other immunomodulatory treatments (including, but 
not limited to:  IFN-β, IFN-α, glatiramer acetate, cyclophosphamide, methotrexate, 
mycophenolate mofetil, mitoxantrone, cyclosporine, azathioprine, 4-aminopyridine or 
related products), except for subjects who were on a stable dose of commercially 
available Fampridine-SR prior to study enrollment. Initiation of Fampridine-SR after 
enrollment is not permitted, with the exception of acute management of protocol-
defined relapse (as described in Section 14.6). 
 Any investigational product, including investigational symptomatic therapies for MS 
and investigational therapies for non-MS indications. 
 Any monoclonal antibodies other than DAC HYP. 
 Intravenous immunoglobulin (IVIg), plasmapheresis or cytapheresis, total lymphoid 
irradiation, or T-cell or T-cell receptor vaccination. 
 Any systemic steroid therapy including, but not limited to, oral corticosteroids (e.g., 
prednisone) or periodic (e.g., monthly) treatment with IV methylprednisolone 
(IVMP), except for protocol-defined treatment of relapses as described in 
Section 14.6 or for limited, acute treatment of general medical conditions as per the 
discretion of Study Neurologist.  Steroids that are administered by non-systemic 
routes (e.g., topical, inhaled) are allowed. 
 Antineoplastic or chemotherapeutic agents, including, but not limited to, 
cyclophosphamide, methotrexate, azathioprine, cladribine, cytarabine, or flutamide. 
 Valproic acid, carbamazepine, lamotrigine, or phenytoin.  Subjects who have been 
taking 1 of these medications at a stable dose for at least 6 consecutive months may 
continue to receive the medication and may continue study treatment under this 
protocol.  However, if any of these medications must be initiated or dose escalated, 
study treatment must be permanently discontinued as described in Section 11.8.   
Subjects who have been treated with any of these medications for fewer than 
6 consecutive months, or who take more than 1 of these medications, or who have 
had dose escalations within the past 6 months must do 1 of the following: 


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 Discontinue the medication (any agent used for <6 consecutive months must be 
discontinued).  Subjects may use an alternative medication allowed by the 
protocol, if needed. 
 Subjects taking more than 1 agent must reduce to 1 agent (any agent that is 
continued must have been taken for at least 6 consecutive months). 
 In the case of dose escalation, revert to a previous dose that had been used for at 
least 6 months. 
 Permanently discontinue study treatment. 
 Isoniazid, propylthiouracil, or nimesulide.  Subjects who currently take any of these 
medications must either change to an alternative medication allowed by the protocol 
or permanently discontinue study treatment.   
Subjects who receive any of these restricted medications may be required to permanently 
discontinue study treatment as outlined in Section 11.8.  Subjects who permanently discontinue 
study treatment will be allowed to receive IVMP as treatment for MS relapse while they are 
participating in the study, as described in Section 11.8. 
Use of the following medications is strongly discouraged during the study: 
 Herbal or dietary supplements.  
 Agents that have established risks of hepatotoxicity or serious rash according to 
labeling information (examples include, but are not limited to, 
amoxicillin/clavulanate, clarithromycin, ketoconazole, minocycline, nitrofurantoin, 
trimethoprim/sulfamethoxazole, diclofenac, sulfasalazine, amiodarone, methyldopa, 
nefazodone, and halothane).  Alternatives to these therapies should be used whenever 
possible. 
Symptomatic therapy, such as treatment for spasticity, depression, or fatigue is not restricted, but 
should be optimized as early as possible in an attempt to maintain consistent treatment for the 
duration of the study.  
Subjects should be instructed not to start taking any new medications, including non-prescribed 
medications, unless they have received permission from the Investigator.  The use of live 
vaccines in humans concurrently treated with daclizumab has not been explored; therefore live 
vaccines should not be administered to MS subjects who are being treated with DAC HYP. 
The use of concomitant therapies or procedures defined in this section must be recorded on the 
subject’s case report form (CRF), according to instructions for CRF completion (Note: 
concomitant therapies in the parent study that continued at Study 205MS303 entry must be 
recorded on the CRF).  AEs related to administration of these therapies or procedures must be 
documented on the appropriate CRF.  For subjects who prematurely discontinue study treatment, 
all concomitant medications should be recorded throughout the remainder of the subject’s 
participation in the study.  


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11.6. 
Continuation of Treatment  
No further provisions are made for access to the study treatment.  If DAC HYP is proven to be 
beneficial, all regulatory requirements regarding poststudy access will be met. 
11.7. 
Treatment Schedule Modifications 
Subjects who experience a significant change in their medical status (e.g., neurological 
worsening/suspected MS relapse, possible injection-site reaction, infection, cutaneous event, 
fever, abdominal pain, persistent diarrhea, jaundice, nausea, vomiting, pruritus) must contact the 
Study Neurologist as soon as possible and no more than 48 hours after symptom onset.  The 
subject should then be evaluated by the Study Neurologist within no more than 72 hours for 
physical and neurological assessments and further treatment recommendations if appropriate.  
These subjects should not administer additional DAC HYP until they have been evaluated by the 
Study Neurologist or their backup. 
Unscheduled PK/
 Visit (Table 6) can be performed in subjects who have evidence of 
significant changes in their medical conditions (as assessed by the Investigator).  This visit must 
be approved by the Biogen Idec Medical Director in advance. 
Additional treatment considerations for specific events are described below. 
11.7.1. 
Infections 
Subjects who have evidence of a clinically significant infection will be instructed to notify the 
Study Neurologist or their backup within 48 hours of onset, and scheduled dosing of DAC HYP 
may be withheld.  If the subject’s infection resolves within 2 weeks of the scheduled DAC HYP 
dose, the subject may receive the previously scheduled dose of DAC HYP at that time.  If the 
infection has not resolved within the 2 weeks, dosing of DAC HYP will remain suspended, and 
the subject will miss dosing until the infection is resolved.   
11.7.2. 
Elevated Liver Function Tests 
Before a monthly dose of DAC HYP is given, LFT results from a prior test (performed within 
28[+4] days) must be reviewed by the Study Neurologist or their backup, and must be within the 
protocol-required limits shown below (LFT procedures are described in Section 14.4.3).  
Study treatment must be temporarily suspended if a subject develops any of the following:  
 ALT/SGPT or AST/SGOT >3ULN   
 any other clinically significant hepatic condition in the opinion of the Investigator 
including jaundice  
Note:  For subjects who present with jaundice, an LFT must be performed as soon as possible. 
After a suspension, dosing of DAC HYP may be resumed when ALT/SGPT and AST/SGOT are 
<2×ULN provided that the criteria for permanent discontinuation have not been met (see 
Section 11.8). 
Study treatment must be permanently discontinued if a subject develops any of the following: 


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 ALT/SGPT or AST/SGOT elevation >8×ULN that is confirmed by a repeat test 
(preferably within 24 hours) 
 ALT/SGPT or AST/SGOT >5×ULN for more than 2 weeks 
 ALT/SGPT or AST/SGOT >3×ULN with concomitant elevation of total bilirubin 
>2×ULN  
 Subjects who previously had study treatment suspended for LFT elevations during the 
past 12 months (including the parent studies) and then resumed dosing, now meet the 
criteria for LFT elevations that require a new suspension of study treatment 
All subjects with elevated LFTs (ALT/SGPT or AST/SGOT >3×ULN) should be managed per 
the guidelines below. 
 Study treatment must be temporarily suspended and LFT elevation should be confirmed 
as soon as possible but no later than a week by a repeat test performed at the central 
laboratory.  In cases where LFTs cannot be performed via the central laboratory, repeat 
LFT results from local laboratory can be used for confirmation.  
 All subsequent testing after a treatment suspension or discontinuation is required to be 
performed centrally at least weekly until the LFT elevation has resolved.  
 In subjects with treatment suspension or discontinuation, DAC HYP treatment may 
resume if a laboratory error is documented upon repeat testing OR when ALT/SGPT and 
AST/SGOT are <2×ULN provided that the criteria for permanent discontinuation have 
not been met (see Section 11.8). 
 DAC HYP treatment should be permanently discontinued in subjects who previously had 
study treatment suspended for another LFT elevation during the past 12 months 
(including the parent studies) and then resumed dosing, and now meet the LFT elevation 
criteria that require a new suspension of study treatment. 
 A careful review of all concomitant medications must be documented.  The Investigator 
should consider discontinuation of all potential hepatotoxic medications.  All recently 
started or non-essential concomitant medications should be suspended until the LFT 
elevation has resolved. 
 An Unscheduled Hepatic Assessment Visit as soon as possible but within 7 days should 
be performed in the event of permanent discontinuation due to elevated LFTs (see 
Table 6) 
 Subjects should be referred to a hepatic specialist if medically indicated. 
 The LFT elevation that led to treatment discontinuation should continue to be monitored 
until LFT elevation has resolved. 
 For subjects with initial ALT/SGPT or AST/SGOT >3×ULN and concomitant 
elevation of total bilirubin >2ULN:  
o Permanently discontinue DAC HYP and monitor until the LFT elevation has 
resolved.   


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 For subjects with initial ALT/SGPT or AST/SGOT >5×ULN but 8×ULN:  
o Suspend dosing and confirm as soon as possible but no later than a week.  
o For subjects with ALT/SGPT or AST/SGOT >5×ULN for more than 2 weeks: 
 Permanently discontinue DAC HYP and monitor until the LFT elevation 
has resolved. 
 For subjects with ALT/SGPT or AST/SGOT >8×ULN: 
o Suspend dosing and confirm by a repeat test (preferably within 24 hours).   
 If AST/SGOT >8×ULN in repeat test:  Permanently discontinue 
DAC HYP and monitor until the LFT elevation has resolved.  
 For subjects with ALT/SGPT or AST/SGOT >10×ULN not resolving for more than 
2 weeks: 
o In consultation with the hepatic specialist, a full evaluation of alternative causes 
of liver injury should be performed, and if testing for viral hepatitis is negative, 
LFT elevations are not improving, DAC HYP is suspected as the cause of the 
LFT elevation, and there are no known contraindications for corticosteroids, then, 
in continued consultation with the hepatic specialist, empiric treatment with 
systemic corticosteroids should be considered. 
11.7.3. 
Cutaneous Events 
Any subject participating in Study 205MS303 who develops a clinically significant cutaneous 
event (e.g., rash, dermatitis, eczema, acne, folliculitis) should be evaluated by the Study 
Dermatologist at an Unscheduled Dermatology Assessment Visit as soon as possible (see 
Table 6). 
A flowchart is presented in Figure 2 to summarize how these subjects will be managed during 
the study. 


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Figure 2: 
Flowchart for Management of Subjects With Clinically Significant 
Cutaneous Events 
 
 
In addition to this, when the Study Neurologist evaluates a subject with a clinically significant 
cutaneous AE (either at an unscheduled or scheduled clinical visit), he or she should also 
perform the Physician Global Assessment Scale as well as standard AE reporting.  Photographs 
should also be taken by the Study Neurologist or designee at these visits for severe or serious 
cutaneous AEs if they have not been taken by the Study Dermatologist (see Section 4.2). 
Skin biopsy must be performed in subjects with cutaneous SAEs at the Unscheduled 
Dermatology Assessment Visit, unless medically contraindicated. 
Skin biopsies from study subjects will be sent to a centralized laboratory for evaluation.  Results 
of the biopsy will be provided back to the Study Dermatologist as soon as possible with a copy 
sent to the sponsor.  Skin biopsy may also be locally evaluated per the discretion of the Study 
Dermatologist. 
For subjects with a severe or serious cutaneous event, DAC HYP must be withheld until the 
cutaneous event has resolved.  Under the consultation of the Study Dermatologist, the subject 
should also withhold all other non-essential medications, including protocol-required 


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medications (as appropriate), and non-prescription drugs and supplements, at least until the 
cutaneous event has resolved.  The decision to permanently discontinue study treatment should 
be made by the Investigator in consultation with the Study Dermatologist.  If an allergic or 
hypersensitivity reaction to study treatment is suspected, study treatment must be permanently 
discontinued.   
11.7.4. 
Gastrointestinal Events of Inflammatory Colitis 
For any subject participating in Study 205MS303 who develops symptoms of inflammatory 
colitis (e.g., persistent diarrhea and abdominal cramps, blood in the stool, and fever), treatment 
with DAC HYP should be stopped and the subject should be referred to a specialist.  Some 
subjects with mild colitis who require DAC HYP therapy may be able to continue the study 
treatment if the benefit-risk profile is considered positive per Investigator's assessment and the 
subject's informed decision. 
11.8. 
Discontinuation of Study Treatment 
A subject must permanently discontinue DAC HYP 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 15.5.4. 
 The subject experiences a hypersensitivity or suspected allergic reaction (e.g. 
anaphylaxis and anaphylactoid reactions) to study treatment. 
 The subject develops a chronic viral infection (e.g., hepatitis C, HIV). 
 The subject develops elevated LFTs that meet any of the following criteria: 
 The subject develops an ALT/SGPT or AST/SGOT elevation >8ULN that is 
confirmed by a repeat test (preferably within 24 hours).  This requires immediate 
discontinuation of DAC HYP, and treatment may not resume unless a laboratory 
error is documented upon repeat testing.  
 ALT/SGPT or AST/SGOT >5ULN for more than 2 weeks 
 ALT/SGPT or AST/SGOT >3ULN with concomitant elevation of total bilirubin 
>2ULN at any time unless a laboratory error is documented upon repeat testing 
 Subjects who previously had study treatment suspended for LFT elevation during 
the past 12 months (including the parent studies) and then resumed dosing, and 
now meet the LFT abnormalities that require a new suspension of study treatment. 
The LFT abnormality that led to treatment discontinuation should continue to be 
monitored until resolution is documented.  An Unscheduled Hepatic Assessment 
Visit is needed in the event of permanent discontinuation due to elevated LFTs 
(see Section 11.7.2). 
In addition, a careful review of all concomitant medications must be documented.  
The Investigator should consider discontinuation of all potential hepatotoxic 
medications.  The subject should be referred to a physician with expertise in the 
diagnosis and treatment of liver disease, and additional hepatic studies should be 


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performed according to local standard of care.  The central laboratory may be 
utilized for additional hepatic testing per Investigator request.   
 The subject experiences a clinically significant cutaneous event, which the 
Investigator (in consultation with the Study Dermatologist) considers to be a 
generalized allergic or hypersensitivity reaction to study treatment (see 
Section 11.7.3).  
 The subject experiences inflammatory colitis, except in subjects with mild colitis who 
require DAC HYP therapy and have a positive benefit-risk profile per Investigator's 
assessment and the subject's informed decision (see Section 11.7.4). 
 The subject requires treatment with any of the disallowed concomitant medications, 
unless approval is given by the Biogen Idec Medical Director(s) or Advisory 
Committee.  Note:  IVMP for treatment of a protocol-defined relapse is allowed as 
detailed in the protocol (see Section 11.5).  Treatment with valproic acid, 
carbamazepine, lamotrigine, or phenytoin is only allowed under the conditions 
detailed in the protocol.   
 The subject experiences a medical emergency that necessitates permanent 
discontinuation of treatment.   
 The subject desires to discontinue treatment under this protocol.   
 At the discretion of the Investigator for medical reasons or for non-compliance.    
 Upon confirmatory tests 1 month apart, the subject’s hematology results are as 
follows in the absence of an identified reversible cause by the Investigator (e.g., 
infection):   
 white blood cell count is <2500 cells/L, or   
 lymphocyte count is <800 cells/L, or   
 platelet count is <75,000 cells/L   
Subjects who meet the above criteria must have study treatment withheld until 
hematology retest results are available.   
 The subject experiences severe depression.  Severe depression is defined as any 
episode that requires hospitalization, or at the discretion of the Investigator. 
Subjects who permanently discontinue DAC HYP treatment should complete all post-treatment 
safety follow-up evaluations (see Section 13.3). 
Subjects who permanently discontinue study treatment may be treated with alternative approved 
MS therapies according to local practices, and should remain in the study and complete safety 
follow-up evaluations as described in Section 4.2 and Section 13. However, subjects who desire 
to discontinue participation in this study or are unwilling or unable to comply with the protocol 
should be withdrawn from the study and complete an Early Termination Visit.  As noted in 
Table 6 (Footnote 3) and Section 11.9, subjects terminating treatment with an ongoing clinically 
significant cutaneous event require an Unscheduled Dermatology Assessment Visit with the 


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Study Dermatologist prior to leaving the study if a visit with the Study Dermatologist has not 
been completed in the 4 weeks±4 days prior to leaving the study. 
The reason(s) for discontinuation of treatment must be recorded in the subject’s CRF.  
11.9. 
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 is unwilling or unable to comply with the protocol.   
 At the discretion of the Investigator for medical reasons.   
Subjects who withdraw from the study should complete the End of Treatment Visit assessments 
as described in Section 14.9 (subjects should be encouraged to complete all other post-treatment 
safety follow-up visits).  The reason for the subject’s withdrawal from the study must be 
recorded in the subject’s CRF.   
For subjects with an ongoing clinically significant cutaneous AE, the Study Dermatologist 
should perform an Unscheduled Dermatology Assessment Visit, if this visit has not been 
performed in the 4 weeks±4 days prior to leaving the study (see Section 11.7.3). 


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12. 
EFFICACY,  DAC HYP CONCENTRATION, AND 
ASSESSMENTS 
12.1. 
Clinical Efficacy Assessments 
The following clinical tests/assessments will be performed to assess the efficacy of DAC HYP: 
 Relapse Assessment:  Subjects who suspect they are experiencing new symptoms or 
worsening symptoms need to contact the Study Neurologist within 48 hours of the 
onset of the symptoms.   
 Refer also to Section 14.6 Unscheduled Relapse Assessment Visit for additional 
details.   
 EDSS [Kurtzke 1983]:  Review of EDSS procedures will be performed prior to study 
start as necessary for training purposes.   
 MSFC [Fischer 1999]:  Timed 25-Foot Walk, 9HPT with both upper extremities and 
PASAT 3   
 Brain MRI scan with and without Gd (T2 hyperintense lesions, T1 hypointense 
lesions, Gd+ lesions, brain atrophy).   
 Subjects will complete the following questionnaires at various timepoints specified in 
Section 4.2:   
 EQ-5D quality of life questionnaire (the EQ-5D descriptive system and the EQ-
VAS)   
 MSIS-29 (29-item physical and psychological assessment)   
 HRU (hospitalizations, emergency room visits, and unscheduled neurologist 
visits)   
 Treatment Satisfaction Questionnaire for Medication (with PFS use) or Treatment 
Satisfaction Survey (with autoinjector use)   
 HRPQ (productivity questionnaire)   
Refer to Section 4.2 for the timing of assessments.   
12.2. 
Pharmacokinetic Assessments 
Blood samples will be collected at selected timepoints throughout the study to determine DAC 
HYP serum concentrations in order to monitor the drug trough level and 
 
 
 
Unscheduled PK/
 Visits  
Whole blood samples will be collected at Unscheduled PK
 Visits for potential determination 
of DAC HYP serum concentrations in subjects with significant changes in their medical 


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conditions, as assessed by the Investigator.  This visit must be approved by the Biogen Idec 
Medical Director in advance. 
Refer to Section 4.2 for the timing of sample collection. 
12.3. 
 
 
 
 
 
 
 
 
 PK/
  
 PK/
 
 
  
 
12.4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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13. 
SAFETY ASSESSMENTS 
13.1. 
Clinical Safety Assessments 
The following clinical assessments will be performed to determine the safety profile of 
DAC HYP: 
 Medical history 
 Physical and neurological examination  
 Vital sign measurements:  temperature, pulse rate, systolic and diastolic blood 
pressure, and respiratory rate (subjects must remain in the same body position quietly 
for 5 minutes prior to having their pulse and blood pressure taken)  
 Weight  
 Concomitant therapy and procedure recording  
 AE and SAE recording  
 Beck Depression Inventory, Second Edition (BDI-II)  
 Immunogenicity assessments  
 Alcohol Use Disorders Identification Test - Consumption Questionnaire (AUDIT-C)  
See Section 4.2 for the timing of assessments.  
13.2. 
Laboratory Safety Assessments 
The following laboratory tests will be performed to assess the safety profile of DAC HYP: 
 Hematology:  hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, red blood cell count, white 
blood cell count (with differential), and platelet count 
 Blood chemistry:  sodium, potassium, chloride, total bilirubin, alkaline phosphatase, 
ALT/SGPT AST/SGOT, lactate dehydrogenase, gamma glutamyl transferase, blood 
urea nitrogen (BUN), creatinine, and bicarbonate 
 Comprehensive hepatic panel (only required for subjects who permanently 
discontinue dosing due to elevated liver function tests as defined in Section 11.7.2).  
Testing will include screening for the following:  
 hepatitis A, B, C, and E  
 other viral infections:  Epstein-Barr virus (EBV), cytomegalovirus (CMV), human 
herpes virus 6 (HHV-6), varicella zoster virus (VZV), herpes simplex virus 
(HSV), and Parvovirus B19 
 gamma-globulins, including IgG levels 


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 autoantibodies:  antinuclear antibody (ANA), anti-smooth muscle antibody 
(anti-SM), anti-liver/kidney microsome-1 antibody (anti-LKM1), 
antimitochondrial antibody (AMA), and anti-soluble liver antigen (SLA)  
Additional testing may be performed based on results of the above testing or the 
subject’s clinical history.  Additional hepatic assessments should be performed 
according to local standard of care.   
 Thyroid function panel, including TSH and T4  
 Urinalysis:  protein, blood, glucose, ketones, nitrite, leukocytes, pH, specific gravity 
by dipstick and microscopy  
 Urine pregnancy testing  
Refer to Section 4.2 for the timing of assessments. 
13.3. 
Study-Specific Safety Assessments 
Blood serum collection for binding and neutralizing anti-drug antibody testing will be 
performed.  Note:  When necessary, samples drawn for one purpose (e.g., immunogenicity) may 
be used to meet another protocol-defined objective (e.g., DAC HYP concentration assessment). 
 


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14. 
SCHEDULE OF EVENTS 
14.1. 
Overview 
A written, signed Informed Consent Form (ICF) and all authorizations required by local law 
(e.g., Protected Health Information [PHI] in North America) must be obtained prior to 
performing any tests or assessments under this protocol. 
For subjects entering from Study 205MS301, tests/assessments performed at the subject’s last 
visit in Study 205MS301 and within 28 days of the subject’s first dose of DAC HYP (Week 0) in 
Study 205MS303 may be used as baseline data for Study 205MS303; if final Study 205MS301 
tests/assessments are not performed within the 28-day window, they must be repeated upon entry 
into Study 205MS303 and before the first dose of DAC HYP is administered. 
Week 144 Visit of Study 205MS303 will be the Entry Visit for subjects enrolled from 
Study 205MS203 or Study 205MS302.  Any test/assessment done at the subject’s last visit in 
parent studies and within 28 days of the subject’s first dose in Study 205MS303 will be used as 
the baseline and does not need to be repeated at entry into Study 205MS303; test/assessments 
performed >28 days before the Entry Visit must be repeated at the Entry Visit.  Central LFT 
testing is mandatory at Entry Visit. 
Clinic visits will occur once every 4 weeks for the first 12 weeks, then every 12 weeks thereafter.   
On a dosing day, all tests and assessments must be performed prior to DAC HYP administration.  
When DAC HYP administration and MRI evaluation are required at the same visit, the MRI scan 
should be performed prior to DAC HYP administration (Note:  MRI scan can be performed up to 
4 days prior to the visit). 
Before a monthly dose of DAC HYP is given, LFT results (ALT/SGPT, AST/SGOT, alkaline 
phosphatase, total bilirubin, and GGT only) from prior testing performed within 28(+4) days 
must be reviewed by the Study Neurologist or their backup, and must be within the 
protocol-required limits. 
After Week 12, subjects will have the option of administering DAC HYP at home following 
Investigator review of monthly pre-dose LFT results.  Subjects who are not able to administer 
their own dose or prefer not to administer their own dose of DAC HYP will be given the option 
to choose another individual (caregiver) to administer their treatment at home or to have their 
treatment administered by staff at the study site. 
Follow-up visits will take place at 8, 12, 16, and 24 weeks after each subject’s last dose of DAC 
HYP.  Unscheduled Relapse Assessment Visits (if necessary) should be scheduled within 
72 hours of the onset of any new neurological symptoms that may indicate neurological 
worsening or possible clinical relapse.  Unscheduled Hepatic Assessment Visits (if necessary) 
should be scheduled as soon as possible (but within 1 week) following discontinuation of study 
treatment due to elevated LFTs.  Unscheduled Dermatology Assessment Visits will be performed 
as per Section 11.7.3.   


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Unscheduled PK/
 Visits should be scheduled as soon as possible following significant 
changes in subjects’ medical conditions, as assessed by the Investigator.  This visit must be 
approved by the Biogen Idec Medical Director in advance. 
14.2. 
Site Personnel 
For each subject, the Principal Investigator will designate the following study site personnel: 
 A primary Study Neurologist and backup neurologist 
 A primary and backup Nurse (or Study Coordinator) 
 A primary and backup Examining Technician 
 An MRI Technician 
 A Pharmacist (or authorized designee) 
 A Study Dermatologist 
 
The Study  Neurologist must have a minimum of 2 years of neurology specialty training and 
anticipate at least a 3-year commitment to the study, or be approved by the study Advisory 
Committee.  The Study Neurologists may designate another neurologist at the center who meets 
the same qualifications to perform the EDSS assessments and other neurologic assessment 
during the trial.  Whenever possible, the EDSS and other neurologic assessments should be 
performed by the same examiner who performed these assessments in the parent study.   
The primary Study Neurologist will be responsible for: 
 Management of the routine neurological care of the subject 
 Assessment (including assignment of causality) and treatment of AEs and MS 
relapses 
 Obtaining an EDSS score based on a detailed neurological examination at the 
scheduled timepoints required in the protocol, and at every Unscheduled Relapse 
Assessment Visit 
 Review of selected hematology and all blood chemistry results from the central 
laboratory 
 Assessment of LFT results, as detailed in Section 11.7.2  
 Monitoring and follow-up of any abnormal hepatic tests 
 Performing Physician Global Assessment Scale in subjects with clinically significant 
cutaneous event, as detailed in Section 11.7.3 
 Assessment of injection sites, as detailed in Table 7  
 Referral of subjects to a dermatologist if that subject experiences a cutaneous event as 
described in Section 14.7 


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Hematology and blood chemistry data will be sent to the investigational sites to aid in 
management of the subject.   
The primary Nurse or Study Coordinator will be responsible for: 
 Assisting the Study Neurologist in subject management, including the treatment of 
AEs, the treatment and assessment of disease relapses, and the recording of AEs and 
concomitant medications 
 Monitoring the EDSS scores and informing the Study Neurologist if a subject 
experiences at least a 1.0-point increase on the EDSS from a baseline EDSS ≥1.0 that 
is sustained for 24 weeks, or at least a 1.5-point increase on the EDSS from a baseline 
EDSS <1.0 that is sustained for 24 weeks 
 Administering the patient-reported questionnaires (BDI-II, MSIS-29, EQ-5D), HRU, 
and subject assessment of injection pain (VAS) 
 Collection of blood samples and obtaining vital signs 
 Study treatment administration/dispensation/accountability 
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.  It is not necessary for the 
Examining Technician to be a healthcare professional as long as he/she is qualified, in the 
opinion of the Principal Investigator, to administer the MSFC (Note:  MSFC was administered in 
this study only until Week 48;  therefore, the role of the Examining Technician ended after that). 
The MRI Technician will be responsible for: 
 Performing a brain MRI scan with and without Gd at all protocol-required timepoints.  
Study-specific MRI scan procedures and protocols, which will be provided prior to 
study start, must be followed. 
The Pharmacist (or authorized designee) will be responsible for: 
 Storage, distribution, and accountability of study treatment. 
The Study Dermatologist will be responsible for: 
 Documenting cutaneous events, as per the protocol.   
 Taking photograph(s) of the affected body areas, as required.  
 Performing a skin biopsy, as required. 
 Evaluating, treating, and managing clinically significant cutaneous events as 
described in Section 11.7.3.  
14.3. 
Subject Management 
The following restrictions apply to all subjects enrolled into this study: 


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 Subjects must follow the restrictions for concomitant medications and procedures 
described in Section 11.5.  
 Contraception requirements are to be followed as described in Section 15.5.3.  
 Whenever possible, a subject should undergo protocol-required tests and assessments 
at the same time of day throughout the study.  
 Subjects should not donate blood until 4 months after their last dose of DAC HYP.  
 Subjects should not receive live or live-attenuated vaccines during DAC HYP 
treatment or for at least 6 months after treatment with DAC HYP.  
14.4. 
Special Instructions for Tests and Assessments 
Note:  Information about the tests and assessments to be performed in this study is also provided 
in Section 12 and Section 13, and in the Study Reference Manual. 
14.4.1. 
Rescreening 
Subjects who are not eligible for participation at baseline due to a temporary condition (e.g., 
acute infection) are allowed to be rescreened once the condition has resolved, provided they are 
rescreened and enrolled within 6 months of completing Study 205MS301, Study 205MS203, or 
Study 205MS302. 
14.4.2. 
Pregnancy Testing 
 Pregnancy testing is only required for women of childbearing potential.  A urine 
pregnancy test is to be performed at the Baseline/Entry Visit and at other timepoints 
designated in Section 4.2 Schedule of Events.  Study treatment will be immediately 
discontinued if the subject has a positive pregnancy test at any time during the study. 
 Results from all urine pregnancy tests must be reviewed by the study site prior to dosing 
and must be negative.   
14.4.3. 
Liver Function Test Assessments Prior to DAC HYP Dosing 
Before a monthly dose of DAC HYP is given, LFT results from prior testing performed within 
the previous 28(+4) days must be reviewed by the Study Neurologist or their backup, and must 
be within protocol-required limits as described in Section 11.7.2.   
LFTs can be performed as follows:   
 Samples for LFTs must be drawn prior to administration of the monthly DAC HYP 
dose.  These samples may be tested either locally inside or outside of the clinic (e.g., 
at a local laboratory or by visiting nurses) or at the central laboratory at the discretion 
of the Investigator and the results can then be used to determine whether dosing 
should continue or be suspended at the monthly dosing timepoint (see Section 11.1). 
 If local LFTs have been used to determine whether dosing should continue or be 
suspended at the time of a scheduled clinic visit, LFTs must also be performed at the 
central laboratory at the time of the scheduled clinic visit (Note:  Scheduled clinic 


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visits occur every 4 weeks during the first 12 weeks of the study and every 12 weeks 
thereafter).     
 If the subject is administering DAC HYP injections at home, site personnel must 
contact the subject after review of prior LFT results performed within 28(+4) days) to 
authorize the monthly injection, or if LFT results warrant, to instruct the subject to 
withhold their injection.   
 LFTs following a treatment suspension must be performed through the central 
laboratory until the LFT abnormality has resolved.  In cases where LFTs cannot be 
performed via central laboratory, repeat LFT results from local laboratory can be used 
for confirmation. 
14.4.4. 
Other Assessments 
 Vital signs include systolic and diastolic blood pressure, pulse, and body temperature, 
and should be measured pre-dose. The subject must rest quietly for 5 minutes prior to 
blood pressure and pulse measurements.  Weight will be collected at Baseline/Entry 
Visit and at the time of first autoinjector use at selected sites. 
 The MSIS-29 must be administered prior to the subject’s visit with the Study 
Neurologist.   
 Subject assessment of injection pain using a VAS should be completed as soon as 
possible after the injection is administered, but no later than 10 to 30 minutes post-
injection.   
 The first 4 DAC HYP injections (i.e., Weeks 0 through 12) must be given in the 
clinic.  The first of these injections must be given by study personnel.  At subsequent 
visits, subjects and/or caregivers will be instructed on DAC HYP self-administration 
and may administer their scheduled dose under staff supervision.  After the subject 
completes the required in-clinic injections (i.e., after Week 12), DAC HYP may be 
dispensed to subjects for at-home administration if the subject chooses.  If necessary, 
drug dispensation may occur at monthly intervals.   
 Additional visits to assess elevated LFTs, cutaneous events, or PK/
may 
be required as described in Section 11.7. 


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14.5. 
Definition of MS Relapse and Disability Progression 
14.5.1. 
MS Relapse 
Relapses are defined as new or recurrent neurological symptoms not associated with fever or 
infection, lasting at least 24 hours, and accompanied by new objective neurological findings 
upon examination by the Study Neurologist* or their backup.  The subject must have objective 
signs on the examination confirming the event.   
*When possible subjects should be evaluated by the same neurologist assigned to them in the 
parent study.   
New or recurrent neurologic symptoms that evolve gradually over months should be considered 
disability progression, not an acute relapse.  New or recurrent neurological symptoms that occur 
less than 30 days following the onset of a protocol-defined relapse should be considered part of 
the same relapse.  Management of MS relapse is described in Section 14.6. 
14.5.2. 
Disability Progression 
Disability progression can only be confirmed from the EDSS scores obtained according to the 
protocol-defined schedule of assessments at regular visits, and is defined as one of the following: 
 at least a 1.0-point increase on the EDSS from a baseline EDSS ≥1.0 that is sustained 
for 24 weeks, or  
 at least a 1.5-point increase on the EDSS from a baseline EDSS <1.0 that is sustained 
for 24 weeks  
14.6. 
Management of MS Relapse 
Subjects who experience new or worsening neurological symptoms must contact the Nurse or 
Study Neurologist or their backup within 48 hours after the onset of symptoms.  A standardized 
Suspected Relapse Questionnaire will be completed to determine the necessity of an 
Unscheduled Relapse Assessment Visit. 
If required, the subject will then be evaluated in person by the Study Neurologist not more than 
72 hours after the onset of the symptoms.  At the Unscheduled Relapse Assessment Visit, the 
Study Neurologist is to perform a relapse assessment and obtain an EDSS score.  New objective 
findings on neurological examination performed by the Study Neurologist* are required to 
determine if a suspected protocol-defined relapse has occurred. Treatment of an acute relapse 
event with intravenous methylprednisolone (IVMP) [or equivalent] may proceed at the discretion 
of the Study Neurologist after the examination and will not affect the subject’s eligibility to 
continue in the study. 
 *When possible subjects should be evaluated by the same neurologist assigned to them in the 
parent study.   
Subjects who prematurely discontinue study treatment should complete safety follow-up 
evaluations (see Section 4.2 and Section 13).   


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Subjects who permanently discontinue DAC HYP treatment should complete the visit schedule 
described in Section 11.8.   
14.7. 
Cutaneous Events 
Subjects who experience a clinically significant cutaneous event (e.g., rash, dermatitis, eczema, 
acne, folliculitis) must be referred to and evaluated and managed by the Study Dermatologist as 
per Section 11.7.3.  An Unscheduled Dermatology Assessment Visit will be performed per 
Table 6. 
If a generalized allergic or hypersensitivity reaction to study treatment is suspected, study 
treatment must be permanently discontinued as per Section 11.8.   
14.8. 
Unscheduled Hepatic Assessment Visit 
The following tests/assessments will be performed as soon as possible (but within 7 days) after 
discontinuation of study treatment for subjects who are required to discontinue dosing due to 
elevated LFTs as described in Table 6 and Section 11.8. 
 Physical examination and vital signs  
 Comprehensive hepatic panel 
 Recording of concomitant therapy 
 Monitor and record AE/SAEs 
 Protocol compliance and DAC HYP accountability 
 Liver function tests (ALT/SGPT, AST/SGOT, alkaline phosphatase, total bilirubin, 
and GGT only) 
14.9. 
Post-Treatment Safety Follow-Up Visit Schedule for All Subjects  
All subjects should complete the following schedule of safety follow-up visits after their last 
dose of DAC HYP: 
 End of Treatment Visit (i.e., the assessments required at Week 240).  For subjects 
who prematurely discontinue study treatment before Week 240, these assessments 
should be performed 4 weeks (±4 days) after the subject’s last dose of DAC HYP.    
 Post-treatment safety follow-up visits at 8, 12, 16, and 24 weeks after the subject’s 
last dose.  The details of these visits are shown in Table 5. 
Note:  Subjects who complete Week 144 of DAC HYP treatment in Study 205MS303 and are in 
the safety follow-up period per the original protocol, will have the option to restart DAC HYP 
treatment from Week 156 Visit in Study 205MS303 (see Table 4) as long as they meet the 
inclusion/exclusion criteria (Section 8).  


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15. 
SAFETY DEFINITIONS, MONITORING, AND REPORTING 
Throughout the course of the study, every effort must be made to remain alert to possible AEs.  
If an AE occurs, the first concern should be for the safety of the subject.  If necessary, 
appropriate medical intervention should be provided. 
At the signing of the ICF, each subject must be given the names and telephone numbers of study 
site staff for reporting AEs and medical emergencies. 
15.1. 
Definitions 
15.1.1. 
Serious Pretreatment Event 
A serious pretreatment event is any event that meets the criteria for SAE reporting (as defined in 
Section 15.1.3) and occurs after the subject signs the ICF, but before administration of study 
treatment. 
15.1.2. 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
15.1.3. 
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, or 
 results in a congenital anomaly/birth defect. 
An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or convulsions occurring at home that do not 
require an inpatient hospitalization. 


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15.2. 
Monitoring and Recording Events 
15.2.1. 
Serious Pretreatment Events 
A serious pretreatment event experienced by the subject after signing and dating the ICF, but 
before administration of study treatment is to be recorded on the SAE Form and faxed to the 
contract research organization (CRO), 
 within 
24 hours of the study site staff becoming aware of the event (see Section 15.2.5).  
15.2.2. 
Adverse Events 
Any AE experienced by the subject between the time of signing the ICF and subject’s final visit 
is to be recorded on the CRF, regardless of the severity of the event or its relationship to study 
treatment. 
15.2.3. 
Serious Adverse Events 
Any SAE experienced by the subject between the time of the first dose of study treatment and 
subject’s final 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 
. 
Any SAE ongoing when the subject completes the study or discontinues from the study will be 
followed by the Investigator until the event has resolved, stabilized, or returned to baseline 
status. 
Subjects will be followed for all SAEs until the subject’s final visit.  Thereafter, the event should 
only be recorded if the Investigator considers it related to study treatment. 
15.2.4. 
All Events 
All events must be assessed to determine the following: 
 If the event meets the criteria for an SAE as defined in Section 15.1.3. 
 The relationship of the event to study treatment as defined in Section 15.3.1. 
 The severity of the event as defined in Section 15.3.2. 
15.2.5. 
Immediate Reporting of Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify 
 within 24 hours of the study site staff becoming aware of the SAE.  It is the 
Investigator’s responsibility to ensure that the SAE reporting information and procedures are 
used and followed appropriately. 
 
 






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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. 
15.5. 
Procedures for Handling Special Situations 
15.5.1. 
Overdose 
An overdose is any dose of study treatment given to a subject or taken by a subject that exceeds 
the dose described in the protocol.  Overdoses are not considered AEs; however, all overdoses 
should be recorded on an Overdose Form and faxed to 
within 24 hours.  An overdose 
should be reported even if it does not result in an AE.  Overdoses do not need to be recorded in 
the CRF; dosing information is recorded on a CRF. 
15.5.2. 
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 
Medical Monitor at one of the following phone numbers: 
North America (USA and Canada):  
 
Latin America: 
Europe and Asia Pacific: 
15.5.3. 
Contraception Requirements 
All women of childbearing potential must practice effective contraception during the study and 
be willing and able to continue contraception for 4 months after their last dose of study 
treatment. 
For the purposes of this study, women of childbearing potential are defined as all women 
physiologically capable of becoming pregnant, UNLESS they meet one of the following 
conditions: 
 Postmenopausal:  12 months of natural (spontaneous) amenorrhea or 6 weeks after 
surgical bilateral oophorectomy with or without hysterectomy 
 Posthysterectomy 
For the purposes of the study, effective contraception is defined as follows: 
For females: 
 Using 1 or more of the following acceptable methods of contraception:  surgical 
sterilization (e.g., bilateral tubal ligation), intrauterine contraception/device, hormonal 
contraception, or any 2 barrier methods (a combination of male or female condom with 
spermicide; diaphragm, sponge, cervical cap) 


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 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, post-ovulation 
methods) and withdrawal are not considered acceptable methods of contraception. 
15.5.4. 
Pregnancy 
Subjects should not become pregnant during the study.  If a female subject becomes 
pregnant, study treatment must be discontinued immediately. 
The Investigator must report the pregnancy by faxing the appropriate form to 
 
Pharmacovigilance within 24 hours of the study site staff becoming aware of the pregnancy 
(refer to Section 15.2.5 for reporting information).  The Investigator or study site staff must 
report the outcome of the pregnancy to 
 Pharmacovigilance. 
Please note that congenital abnormalities/birth defects in the offspring of male or female subjects 
should be reported when conception occurred during the study treatment period. 
15.5.5. 
Regulatory Reporting 
Suspected Unexpected Serious Adverse Reactions (SUSARs) are SAEs that are unexpected and 
judged by the Investigator or the Sponsor to be related to the study treatment administered. 
Biogen Idec Safety and Benefit-Risk Management (SABR) will report SUSARs to the 
appropriate regulatory authorities and Investigators as required, according to local law. 
15.6. 
Investigator Responsibilities 
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 of the pregnancy. 
 Complete an SAE form for each serious event and fax it to 
within 24 hours of 
the study site staff becoming aware of the event. 
 Pursue SAE follow-up information actively and persistently.  Follow-up information 
must be reported to 
 within 24 hours of the study site staff becoming aware of 
new information. 
 Complete an Adverse Event of Special Interest form for each transaminase elevation, 
hepatic event, and cutaneous event as described in the protocol and fax it to 
 as 
soon as possible following the study site staff becoming aware of the event. 
 Ensure all AE and SAE reports are supported by documentation in the subjects’ 
medical records. 


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 Report SAEs to local ethics committees, as required by local law. 
15.7. 
Biogen Idec Responsibilities 
Biogen Idec’s responsibilities include the following: 
 Before study site activation and subject enrollment, the Clinical Monitor or designee 
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 Idec is to notify all appropriate regulatory authorities, central ethics 
committees, and Investigators of SAEs, as required by local law, within required time 
frames. 


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16. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
16.1. 
Description of Objectives 
See Section 6.1, Objectives. 
16.2. 
Description of Endpoints 
See Section 6.2, Endpoints. 
16.3. 
Demography and Baseline Disease Characteristics 
Demographic data collected at baseline will be summarized (i.e., age, gender, ethnicity, and 
weight).  Medical history and baseline characteristic data (e.g., EDSS, number of relapses in the 
previous study, MRI endpoints) will also be summarized. 
16.4. 
Safety and Efficacy 
16.4.1. 
Analysis Population 
Study 205MS303 Safety Population 
The safety population will include all subjects who received at least 1 dose of DAC HYP in 
Study 205MS303.  All safety analyses will be completed on the safety population. 
Study 205MS303 Intent-to-Treat Population 
The intent-to-treat (ITT) population will include all subjects who received at least 1 dose of DAC 
HYP in Study 205MS303.  This population will be utilized for the efficacy analyses.   
Study 205MS301 and Study205MS303 Intent-to-Treat population 
This population will include all subjects randomized to DAC HYP or Avonex in 
Study 205MS301 and received at least one dose of DAC HYP in Study 205MS303. 
16.4.2. 
General Methods of Analysis 
Summary statistics will be presented.  For continuous endpoints, summary statistics will 
generally include the number of subjects with data, mean, standard deviation, median, and range.  
Categorical endpoints will include the number of subjects with data and the percentage in each 
category. 
Analyses will generally be descriptive in nature and will focus on data collected during 
Study 205MS303 only.  However, for relevant efficacy analyses, the data may be summarized by 
previous treatment group (Avonex or DAC HYP).  Also, statistical comparisons may be made 
between efficacy in Study 205MS301 and efficacy in Study 205MS303 among subjects 
previously randomized to Avonex in Study 205MS301. 
All statistical tests will be 2-sided with an overall Type I error of 5%.  Adjustments for multiple 
comparisons will not be considered. 


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16.4.3. 
Primary Endpoints Analysis 
Clinical Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities. All treatment-
emergent events will be included in the evaluation of safety.  Treatment emergent includes any 
event that either occurs or worsens in severity after the onset of study treatment.  Overall 
incidence of treatment-emergent events will be summarized; in addition, summaries by severity 
and by relationship to study treatment will be provided.  The summary tables will include 
incidence estimates for the overall system organ class as well as for preferred terms within each 
system organ class.  In order to assess whether the incidence of events changes over time, the 
incidence of key events may also be summarized by time period (e.g., 6-month time intervals).   
16.4.4. 
Other Safety Endpoint Analyses 
Unless otherwise specified, the baseline measurement for safety assessments such as laboratory 
values and vital signs was the measurement acquired on the day of the first receipt of DAC HYP.  
The first receipt of dosing of DAC HYP could be either Study 205MS303 (for subjects who 
received Avonex in Study 205MS301) or the parent studies (i.e., Study 205MS301, 
Study 205MS203, or Study 205MS302) for all other subjects. 
Laboratory Data 
Changes in laboratory values will be summarized using shift tables.  Shift tables will include 
hematology,  LFTs, kidney function tests, electrolytes, and other blood chemistry tests.  Shifts 
will be presented from baseline of DAC HYP treatment (the last measurement acquired before or 
on the day of the first receipt of DAC HYP, e.g., Study 205MS303 baseline for subjects 
randomized to Avonex in Study 205MS301 and Study 205MS301 baseline for subjects 
randomized to DAC HYP 150 mg in Study 205MS301).  Summaries of worst post-baseline 
laboratory values by clinically relevant categories may also be presented for selected parameters 
of interest by treatment group.  For example, for LFT (alkaline phosphatase, ALT, AST, GGT, 
and total bilirubin), categories may be defined based on cutoff values relative to the ULN. 
Vital Signs 
Vital signs collected will be examined to determine the incidence of clinically relevant 
abnormalities.  These abnormalities are described in Table 8.  For the purpose of the shifts from 
baseline, the baseline evaluation at the start of DAC HYP treatment will be used. 
For each vital sign, the number of subjects evaluated and the number and percentage of subjects 
with the defined abnormality at any time post dosing will be presented by treatment group.   


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Table 8:   
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs 
Vital Sign 
Criteria for Abnormalities 
Temperature  
>38°C or an increase from baseline of ≥1°C 
Pulse 
>120 beats per minute (bpm) or an increase from baseline of 
20 bpm 
<50 bpm or a decrease from baseline of >20 bpm 
Systolic Blood Pressure 
>180 mmHg or an increase from baseline of >40 mmHg 
<90 mmHg or a decrease from baseline of >30 mmHg 
Diastolic Blood Pressure 
>105 mmHg or an increase from baseline of >30 mmHg 
<50 mmHg or a decrease from baseline of >20 mmHg 
Physical Examination 
The physical examination findings will be summarized. 
16.4.5. 
Efficacy Endpoints Analyses 
Annualized Relapse Rate 
Relapses will be summarized over the follow-up period in Study 205MS303.  For subjects in 
Study 205MS301 and Study 205MS303 ITT population, relapses may be summarized over the 
combined study period (Studies 205MS301 and 205MS303).   
A negative binomial regression model will be used to estimate the adjusted ARR.   
Proportion of Subjects with a Relapse 
The proportion of subjects relapsed will be estimated using a Kaplan-Meier curve.   
Disability Progression   
Sustained disability progression is defined as at least a 1.0 point increase on the EDSS from 
baseline EDSS 1.0 that is sustained for 24 weeks, or at least a 1.5 point increase on the EDSS 
from baseline EDSS <1.0 that is sustained for 24 weeks.  The proportion of subjects with 
progression will be summarized using a Kaplan-Meier curve.  In addition, summary statistics for 
EDSS and for the change from baseline in EDSS will be presented by visit, and for subjects who 
participated in Study 205MS301, by previous treatment group.   
MSFC 
Changes in the MSFC z-score will be summarized by study visit, and for subjects who 
participated in Study 205MS301, by previous treatment group.  For subjects in Study 205MS301 
and Study 205MS303 ITT population, MSFC z-score may be summarized over the combined 
study period (Studies 205MS301 and 205MS303).  Details on the calculations of the z-score for 
each component will be described in the statistical analysis plan. 
MRI Endpoints 
MRI endpoints will be summarized with descriptive statistics both as a continuous variable and 
categorically.  Over time summaries and summaries by previous treatment group (Avonex or 
DAC HYP 150 mg) may also be provided.  A negative binomial regression model will be used 


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for the analysis of new or newly enlarging T2 lesions.  The change in volume of lesions will be 
analyzed using an analysis of covariance.   
Quality of Life Outcomes 
Actual scores and change from baseline in quality of life endpoints will be summarized by visit.  
Pharmacokinetics 
The population for DAC HYP concentration analyses will include all subjects who received at 
least 1 dose of study medication and who have at least 1 sample available for analysis.  
Serum concentration levels will be summarized with descriptive statistics by visit.   
Antigenicity/Immunogenicity Data 
Immunogenicity (i.e., ADAs to DAC HYP) will be assessed on subjects.  Positive samples will 
be further tested for neutralizing  antibodies to DAC HYP using a specific NAb assay.  Results 
will be tabulated by time period and overall. 
16.5. 
Interim Analyses 
No formal interim analyses are planned for this study.  However, analyses may be performed 
prior to the end of the study at the discretion of the Sponsor.  
16.6. 
Sample Size Considerations 
There is no formal sample size calculation.  The number of subjects in this study is determined 
by the number of subjects who completed Study 205MS301, Study 205MS203, or 
Study 205MS302. 
 


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17. 
ETHICAL REQUIREMENTS 
Biogen Idec and the Investigator must comply with all instructions, regulations, and agreements 
in this protocol and applicable International Conference on Harmonisation (ICH) and Good 
Clinical Practice (GCP) guidelines and conduct the study according to local regulations. 
17.1. 
Declaration of Helsinki 
The Investigator and Biogen Idec must adhere to the principles set forth by the Declaration of 
Helsinki dated October 2008. 
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. The Sponsor may submit documents on behalf of the 
study sites in countries other than the US as applicable.  
If the Investigator makes any changes to the ICF, Biogen Idec must approve the changes before 
the ICF is submitted to the ethics committee.  A copy of the approved ICF must be provided to 
Biogen Idec.  After approval, the ICF must not be altered without the agreement of the relevant 
ethics committee and Biogen Idec. 
It is the responsibility of the Principal Investigator(s) to ensure that all aspects of institutional 
review are conducted in accordance with current governmental regulations. 
Biogen Idec 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 study site must submit a close-out letter to the 
ethics committee and Biogen Idec. 
17.3. 
Subject Information and Consent 
Prior to performing any study-related activities under this protocol, including Baseline/Entry 
Visit tests and assessments, written informed consent with the approved ICF must be obtained 
from the subject or subject’s legally authorized representative, as applicable, in accordance with 
local practice and regulations.  Written informed consent must be obtained from all subjects 
participating in a clinical study conducted by Biogen Idec. 
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.  The subject 
must be given sufficient time to consider whether to participate in the study. 
A copy of the ICF, signed and dated by the subject, must be given to the subject.  Confirmation 
of a subject’s informed consent must also be documented in the subject’s medical record prior to 
any testing under this protocol, including Baseline/Entry Visit tests and assessments. 


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Each consent form should contain an authorization allowing the Principal Investigator(s) and 
Biogen Idec to use and disclose PHI (i.e., subject-identifiable health information) in compliance 
with local law. 
The signed consent form will be retained with the study records. 
17.4. 
Subject Data Protection 
Prior to any testing under this protocol, including Baseline/Entry Visit tests and assessments, 
candidates must also provide all authorizations required by local law (e.g., PHI authorization in 
North America). 
The subject will not be identified by name in the CRF or in any study reports and these reports 
will be used for research purposes only.  Biogen Idec, its partner(s) and designee(s), ethics 
committees, and various government health agencies may inspect the records of this study.  
Every effort will be made to keep the subject’s personal medical data confidential. 
17.5. 
Compensation for Injury 
Biogen Idec maintains appropriate insurance coverage for clinical trials 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 the 
Sponsor) 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 Idec will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations. 


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18. 
ADMINISTRATIVE PROCEDURES 
18.1. 
Study Site Initiation 
The Investigator must not enroll any subjects prior to completion of a study initiation visit, 
conducted by Biogen Idec 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 Idec or 
the regulatory authorities may wish to perform on-site audits.  The Investigator will be expected 
to cooperate with any audit and to provide assistance and documentation (including source data) 
as requested. 
18.3. 
Monitoring of the Study 
The Principal Investigator(s) must permit study-related monitoring by providing direct access to 
source data and to the subjects’ medical histories. 
The Clinical Monitor(s) will visit the Investigator(s) at regular intervals during the course of 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.   
The 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 study site and its facilities. 
18.4. 
Study Funding 
Biogen Idec is the Sponsor of the study and is funding the study.  All financial details are 
provided in the separate contract(s) between the institution, Investigator, and Biogen Idec. 
18.5. 
Publications 
Details are included in the clinical trial agreement for this study. 
 


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19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION 
Biogen Idec will be responsible for all administrative aspects of this study including, but not 
limited to, study initiation, monitoring, management of AEs, and data management. 
19.1. 
External Contract Organizations 
19.1.1. 
Contract Research Organization  
 will be responsible for administrative aspects of the study including, but not limited to, 
study initiation, monitoring, and management of SAE reports. Before subjects are screened at 
each study site, 
 will review study responsibilities with the Investigators and other study site 
staff, as appropriate. 
19.1.2. 
Electronic or Remote Data Capture 
Subject information will be captured and managed by study sites on electronic CRFs via a 
remote data capture (RDC) developed and supported by 
 and 
configured by Biogen Idec. 
19.1.3. 
Central Laboratories for Laboratory Assessments 
 has been selected by Biogen Idec to analyze all hematology, blood 
chemistry, and urine samples collected for this study. 
If local LFTs have been used to determine whether dosing should continue or be suspended at 
the time of a scheduled clinic visit, LFTs must also be performed at the central laboratory at the 
time of the scheduled clinic visit (Note:  Scheduled clinic visits occur every 4 weeks during the 
first 12 weeks of the study and every 12 weeks thereafter).      
19.1.4. 
Central Facility for Biopsy Assessments 
 has been has been selected by Biogen Idec to analyze skin 
biopsy samples collected for this study. 
19.1.5. 
Central Facility for Other Assessments 
MRI Reading Center 
All scheduled MRI scans with and without Gd will be evaluated at a central MRI reading center.  
All study sites will be required to send a test scan 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 study site is permitted to enroll any subjects into the study. 
Original MRI images are to be sent to the MRI Reading Center for review (MRI shipping 
instructions will be provided prior to the start of enrollment at each site).   
Additional and more detailed MRI scans with and without Gd procedures and instructions are 
included in the study MRI manual (to be provided under separate cover prior to start of the 
study). 


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19.2. 
Study Committees 
19.2.1. 
Advisory Committee 
The Advisory Committee from parent Study 205MS301 will oversee the administrative progress 
and provide scientific and medical direction for this study while Study 205MS301 is ongoing. 
Advisory Committee will monitor subject accrual and compliance with the protocol at individual 
study sites.  The Advisory Committee will determine whether the study should be stopped or 
amended for reasons other than safety. 
Members of the Advisory Committee will include the Medical Director, Clinical Trial Manager, 
and Project Statistician from Biogen Idec (and/or their designees), and participating 
Investigators.  Biogen Idec will designate one of the participating Investigators to be the 
Chairperson of the Advisory Committee. 
19.2.2. 
Internal Safety Monitoring Committee 
An internal Safety Monitoring Committee  will be formed to review interim safety data on an 
ongoing basis.  Investigational sites will be notified of any relevant safety findings that may 
jeopardize subject safety. 
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 Idec 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 subject consent form may require similar 
modifications (see Section 17.2 and Section 17.3). 
19.4. 
Ethics Committee Notification of Study Completion or Termination 
Where required, the Health Authorities and ethics committees must be notified of completion or 
termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines. 
19.5. 
Retention of Study Data 
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local laws or regulations.  Prior to 
proceeding with destruction of records, the Investigator must notify Biogen Idec in writing and 


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receive written authorization from Biogen Idec to destroy study records.  In addition, the 
Investigator must notify Biogen Idec of any changes in the archival arrangements including, but 
not limited to, archival at an off-site facility or transfer of ownership if the Investigator leaves the 
site. 
19.6. 
Study Report Signatory 
Biogen Idec 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 Idec. 
Biogen Idec will follow all applicable local regulations pertaining to study report signatories.  
 


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20. 
REFERENCES 
 
Bielekova B, Howard T, Packer AN, et al. Effect of anti-CD25 antibody daclizumab in the 
inhibition of inflammation and stabilization of disease progression in multiple sclerosis. Arch 
Neurol. 2009;66(4):483-9. 
Bielekova B, Richert N, Howard T, et al. Humanized anti-CD25 (daclizumab) inhibits disease 
activity in multiple sclerosis patients failing to respond to interferon beta. Proc Natl Acad Sci U 
S A. 2004;101(23):8705-8. 
Fischer JS, LaRocca NG, Miller DM, et al. Recent developments in the assessment of quality of 
life in multiple sclerosis (MS). Mult Scler. 1999;5(4):251-9. 
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status 
scale (EDSS). Neurology. 1983;33(11):1444-52. Epub 1983/11/01. 
Rose JW. Treatment of Multiple Sclerosis with a Humanized Monoclonal Antibody Specific for 
IL-2 Receptor Chain. Neurology. 2003;60(Suppl 1):A478-9. 
Rose JW, Watt HE, White AT, et al. Treatment of multiple sclerosis with an anti-interleukin-2 
receptor monoclonal antibody. Ann Neurol. 2004;56(6):864-7. 
Wynn D, Kaufman M, Montalban X, et al. Daclizumab in active relapsing multiple sclerosis 
(CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with 
interferon beta. Lancet Neurol. 2010;9(4):381-90. 
 
 
 


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21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL 
I have read the foregoing protocol, “A Multicenter, Open-Label, Extension Study to Evaluate the 
Long term Safety and Efficacy of BIIB019, Daclizumab High Yield Process (DAC HYP), 
Monotherapy in Subjects With Multiple Sclerosis Who Have Completed Study 205MS301” and 
agree to conduct the study according to the protocol and the applicable ICH guidelines and GCP 
regulations, and to inform all who assist me in the conduct of this study of their responsibilities 
and obligations. 
 
 
 
____________________________________________________ 
Investigator’s Signature 
 
 
 
Date 
 
 
____________________________________________________ 
Investigator’s Name (Print) 
 
 
____________________________________________________ 
Study Site (Print) 


CONFIDENTIAL 
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1 
Biogen Idec MA Inc. 
14 Cambridge Center 
Cambridge, MA 02142, USA 
PROTOCOL NUMBER: 
205MS303
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead Berkshire 
SL6 4AY 
United Kingdom 
PHASE OF DEVELOPMENT: 
3 
PROTOCOL TITLE:  A Multicenter, Open-Label, Extension Study to Evaluate the 
Long-Term Safety and Efficacy of BIIB019, Daclizumab High Yield Process (DAC HYP), 
Monotherapy in Subjects With Multiple Sclerosis Who Have Completed Study 205MS301  
EUDRA CT NO: 
2012-003176-39
DATE: 
28 September 2012 
Version 1 
Final  






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TABLE OF CONTENTS 
1. 
SPONSOR INFORMATION .....................................................................................10 
2. 
LIST OF ABBREVIATIONS.....................................................................................11 
3. 
SYNOPSIS .................................................................................................................13 
4. 
STUDY SCHEMATIC AND SCHEDULE OF EVENTS TABLES FOR 
STUDY 205MS303 ....................................................................................................18 
4.1. 
Study Schematic .........................................................................................................18 
4.2. 
Schedule of Events .....................................................................................................19 
5. 
INTRODUCTION ......................................................................................................26 
5.1. 
Profile of Previous Experience with Daclizumab in MS ............................................26 
5.2. 
Study Rationale ...........................................................................................................27 
5.3. 
Rationale for Dose and Schedule Selection ................................................................28 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................29 
6.1. 
Objectives ...................................................................................................................29 
6.1.1. 
Primary Objective .......................................................................................................29 
6.1.2. 
Secondary Objectives .................................................................................................29 
6.2. 
Endpoints ....................................................................................................................29 
6.2.1. 
Primary Endpoints ......................................................................................................29 
6.2.2. 
Secondary Endpoints ..................................................................................................29 
7. 
STUDY DESIGN .......................................................................................................31 
7.1. 
Study Overview ..........................................................................................................31 
7.2. 
Overall Study Duration and Follow-Up .....................................................................31 
7.2.1. 
Baseline Assessments .................................................................................................31 
7.2.2. 
Treatment ....................................................................................................................31 
7.2.3. 
Post-Treatment Long-Term Follow-Up ......................................................................32 
7.3. 
Study Stopping Rules .................................................................................................32 
7.4. 
End of Study ...............................................................................................................32 
8. 
SELECTION OF SUBJECTS ....................................................................................33 
8.1. 
Inclusion Criteria ........................................................................................................33 
8.2. 
Exclusion Criteria .......................................................................................................33 
9. 
ENROLLMENT AND REGISTRATION PROCEDURES ......................................35 


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9.1. 
Enrollment and Screening ...........................................................................................35 
9.2. 
Registration of Subjects ..............................................................................................35 
10. 
STUDY TREATMENT MANAGEMENT ................................................................36 
10.1. 
DAC HYP ...................................................................................................................36 
10.2. 
DAC HYP Preparation ...............................................................................................36 
10.3. 
DAC HYP Accountability ..........................................................................................37 
11. 
TREATMENT OF SUBJECTS ..................................................................................38 
11.1. 
Study Treatment Schedule and Administration ..........................................................38 
11.2. 
Placebo or Reference Product Agents ........................................................................38 
11.3. 
Treatment Precautions ................................................................................................38 
11.4. 
Treatment Compliance ................................................................................................38 
11.5. 
Concomitant Therapy .................................................................................................39 
11.6. 
Continuation of Treatment ..........................................................................................41 
11.7. 
Treatment Schedule Modifications .............................................................................41 
11.7.1. 
Infections ....................................................................................................................41 
11.7.2. 
Elevated Liver Function Tests ....................................................................................41 
11.8. 
Discontinuation of Study Treatment ...........................................................................42 
11.9. 
Withdrawal of Subjects From Study ...........................................................................44 
12. 
EFFICACY,  DAC HYP CONCENTRATION, AND 
PHARMACODYNAMIC ASSESSMENTS ..............................................................45 
12.1. 
Clinical Efficacy Assessments ....................................................................................45 
12.2. 
Pharmacokinetic Assessments ....................................................................................45 
12.3. 
Pharmacodynamic Assessments .................................................................................45 
12.4. 
 ..............................................................................................46 
13. 
SAFETY ASSESSMENTS ........................................................................................47 
13.1. 
Clinical Safety Assessments .......................................................................................47 
13.2. 
Laboratory Safety Assessments ..................................................................................47 
13.3. 
Study-Specific Safety Assessments ............................................................................48 
14. 
SCHEDULE OF EVENTS .........................................................................................49 
14.1. 
Overview .....................................................................................................................49 
14.2. 
Site Personnel .............................................................................................................49 
14.3. 
Subject Management ..................................................................................................52 


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14.4. 
Special Instructions for Tests and Assessments .........................................................52 
14.4.1. 
Rescreening .................................................................................................................52 
14.4.2. 
Pregnancy Testing ......................................................................................................52 
14.4.3. 
Monthly Liver Function Test Assessments Prior to DAC HYP Dosing ....................52 
14.4.4. 
Other Assessments ......................................................................................................53 
14.5. 
Definition of MS Relapse and Disability Progression ................................................54 
14.5.1. 
MS Relapse .................................................................................................................54 
14.5.2. 
Disability Progression .................................................................................................54 
14.6. 
Management of MS Relapse .......................................................................................54 
14.7. 
Cutaneous Events ........................................................................................................55 
14.8. 
Unscheduled Hepatic Assessment Visit .....................................................................55 
14.9. 
Post-Treatment Safety Follow-Up Visit Schedule for All Subjects ...........................55 
15. 
SAFETY DEFINITIONS, MONITORING, AND REPORTING .............................56 
15.1. 
Definitions ..................................................................................................................56 
15.1.1. 
Serious Pretreatment Event .........................................................................................56 
15.1.2. 
Adverse Event .............................................................................................................56 
15.1.3. 
Serious Adverse Event ................................................................................................56 
15.2. 
Monitoring and Recording Events ..............................................................................57 
15.2.1. 
Serious Pretreatment Events .......................................................................................57 
15.2.2. 
Adverse Events ...........................................................................................................57 
15.2.3. 
Serious Adverse Events ..............................................................................................57 
15.2.4. 
All Events ...................................................................................................................57 
15.2.5. 
Immediate Reporting of Serious Adverse Events .......................................................57 
15.2.5.1. 
Deaths .........................................................................................................................58 
15.3. 
Safety Classifications ..................................................................................................58 
15.3.1. 
Relationship of Events to Study Treatment ................................................................58 
15.3.2. 
Severity of Events .......................................................................................................59 
15.3.3. 
Expectedness of Events ..............................................................................................59 
15.4. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................59 
15.5. 
Procedures for Handling Special Situations ...............................................................60 
15.5.1. 
Overdose .....................................................................................................................60 


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15.5.2. 
Medical Emergency ....................................................................................................60 
15.5.3. 
Contraception Requirements ......................................................................................60 
15.5.4. 
Pregnancy ...................................................................................................................61 
15.5.5. 
Regulatory Reporting ..................................................................................................61 
15.6. 
Investigator Responsibilities .......................................................................................61 
15.7. 
Biogen Idec Responsibilities ......................................................................................62 
16. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ...........63 
16.1. 
Description of Objectives ...........................................................................................63 
16.2. 
Description of Endpoints ............................................................................................63 
16.3. 
Demography and Baseline Disease Characteristics ....................................................63 
16.4. 
Safety and Efficacy .....................................................................................................63 
16.4.1. 
Analysis Population ....................................................................................................63 
16.4.2. 
General Methods of Analysis .....................................................................................63 
16.4.3. 
Primary Endpoints Analysis .......................................................................................64 
16.4.4. 
Other Safety Endpoint Analyses .................................................................................64 
16.4.5. 
Efficacy Endpoints Analyses ......................................................................................65 
16.5. 
Interim Analyses .........................................................................................................66 
16.6. 
Sample Size Considerations .......................................................................................66 
17. 
ETHICAL REQUIREMENTS ...................................................................................67 
17.1. 
Declaration of Helsinki ...............................................................................................67 
17.2. 
Ethics Committee ........................................................................................................67 
17.3. 
Subject Information and Consent ...............................................................................67 
17.4. 
Subject Data Protection ..............................................................................................68 
17.5. 
Compensation for Injury .............................................................................................68 
17.6. 
Conflict of Interest ......................................................................................................68 
17.7. 
Registration of Study and Disclosure of Study Results ..............................................68 
18. 
ADMINISTRATIVE PROCEDURES .......................................................................69 
18.1. 
Study Site Initiation ....................................................................................................69 
18.2. 
Quality Assurance .......................................................................................................69 
18.3. 
Monitoring of the Study..............................................................................................69 
18.4. 
Study Funding .............................................................................................................69 


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18.5. 
Publications .................................................................................................................69 
19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION ........................70 
19.1. 
External Contract Organizations .................................................................................70 
19.1.1. 
Contract Research Organization .................................................................................70 
19.1.2. 
Electronic or Remote Data Capture ............................................................................70 
19.1.3. 
Central Laboratories for Laboratory Assessments .....................................................70 
19.1.4. 
Central Facility for Other Assessments ......................................................................70 
19.2. 
Study Committees .......................................................................................................71 
19.2.1. 
Advisory Committee ...................................................................................................71 
19.2.2. 
Safety Monitoring Committee ....................................................................................71 
19.3. 
Changes to Final Study Protocol ................................................................................71 
19.4. 
Ethics Committee Notification of Study Completion or Termination ........................71 
19.5. 
Retention of Study Data ..............................................................................................71 
19.6. 
Study Report Signatory...............................................................................................72 
20. 
REFERENCES ...........................................................................................................73 
21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL .........................................74 
22. 
APPENDIX 1: GUIDELINES FOR MANAGEMENT OF CUTANEOUS 
EVENTS FOR SUBJECTS PARTICIPATING IN BIOGEN IDEC 
CLINICAL STUDIES OF DAC HYP ........................................................................75 
22.1. 
Background .................................................................................................................75 
22.2. 
General Management of Cutaneous Events ................................................................75 
22.3. 
Evaluation and Management of Diffuse Cutaneous Eruptions/Rash .........................76 
22.3.1. 
Evaluation of Diffuse Cutaneous Eruptions/Rash ......................................................76 
22.3.2. 
Management of Diffuse Cutaneous Eruption/Rash ....................................................77 
22.4. 
Examples of Diffuse Maculopapular Eruptions/Rash in DAC HYP Clinical 
Studies.........................................................................................................................78 
22.5. 
Treatment Algorithm for Subjects Presenting with Diffuse Cutaneous 
Eruption/Rash .............................................................................................................80 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities:  Baseline Through Week 84 ..................................................19 
Table 2: 
Schedule of Activities:  Week 96 through Week 144 (End of Treatment) .................22 


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Table 3: 
Schedule of Activities:  Post-Treatment Safety Follow-Up and Unscheduled 
Assessments ................................................................................................................24 
Table 4: 
Schedule of Activities:  Autoinjector Use by Subjects at Selected Sites ...................25 
Table 5:   Criteria to Determine Clinically Relevant Abnormalities in Vital Signs ...................64 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................18 




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2. 
LIST OF ABBREVIATIONS 
9HPT 
Nine-Hole Peg Test 
ADAbs 
anti-DAC HYP binding antibodies 
AE 
adverse event 
ALT 
alanine aminotransferase 
ARR 
annualized relapse rate  
AST 
aspartate aminotransferase 
AUDIT-C 
Alcohol Use Disorders Identification Test - Consumption 
Questionnaire 
BDI-II 
Beck Depression Inventory, Second Edition 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
CRF 
case report form 
CRO 
contract research organization 
DAC HYP 
Daclizumab High Yield Process 
DHA 
Directions for Handling and Administration 
EDSS 
Expanded Disability Status Scale 
EQ-5D 
European Quality of Life, 5-dimensions 
EQ-VAS 
European Quality of Life, visual analog scale 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
Gd 
gadolinium 
GGT 
gamma-glutamyltransferase 
HIV 
human immunodeficiency virus 
HRPQ 
Health Related Productivity Questionnaire 
HRU 
healthcare resource utilization 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IL-2 
interleukin-2 
IFN 
interferon 
IM 
intramuscular  
ITT 
intent-to-treat 
IV 
intravenous 
IVIg 
intravenous immunoglobulin 
IVMP 
intravenous methylprednisolone 
LFT 
liver function test 
MRI 
magnetic resonance imaging 
MS 
multiple sclerosis 
MSFC 
Multiple Sclerosis Functional Composite 
MSIS-29 
Multiple Sclerosis Impact Scale-29 
NAbs 
anti-DAC HYP neutralizing antibodies 


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NK 
natural killer cells 
PASAT 3 
 
3 Second Paced Auditory Serial Addition Test 
PD 
pharmacodynamic(s) 
PFS 
prefilled syringe 
PHI 
protected health information 
PK 
pharmacokinetic(s) 
 
 
RDC 
remote data capture 
RRMS 
relapsing-remitting multiple sclerosis 
SABR 
Safety and Benefit-Risk Management 
SAE 
serious adverse event 
SC 
Subcutaneous 
SGPT 
serum glutamic pyruvic transaminase; see ALT 
SGOT 
serum glutamic oxaloacetic transaminase; see AST 
SMC 
Safety Monitoring Committee 
SNP 
single nucleotide polymorphism 
SUSAR 
suspected unexpected serious adverse reaction 
T1 
MRI hypointense designation 
T2 
MRI hyperintense designation 
T4 
thyroxine 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
VAS 
visual analog scale 


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3. 
SYNOPSIS 
This is a brief summary.  For details refer to the body of the protocol. 
Protocol Number: 
205MS303 
Protocol Title: 
A Multicenter, Open-Label, Extension Study to Evaluate the 
Long-Term Safety and Efficacy of BIIB019, Daclizumab High
Yield Process (DAC HYP), Monotherapy in Subjects With 
Multiple Sclerosis Who Have Completed Study 205MS301 
Version Number: 
1 
Name of Study Treatment: 
Daclizumab High Yield Process (DAC HYP) 
Study Indication: 
Relapsing-Remitting Multiple Sclerosis (RRMS) 
Phase of Development: 
3 
Rationale for the Study: 
This study will provide subjects who complete Phase 3 
Study 205MS301 with the opportunity to receive open-label 
DAC HYP monotherapy prior to local product marketing 
approval for evaluation of long-term safety, efficacy, and 
immunogenicity of DAC HYP in subjects with RRMS. 
Study Objectives and 
Endpoints: 
Objectives 
Primary:    
The primary objective of the study is to assess the safety and 
tolerability of long-term treatment with DAC HYP 
monotherapy in subjects who completed Study 205MS301. 
Secondary: 
Secondary objectives of this study in this study population 
are as follows: 
 To assess the long-term immunogenicity of DAC 
HYP administered by prefilled syringe (PFS) 
 To describe MS-related outcomes, including MS 
relapse, disability progression, MS lesion 
formation, and patient-reported impact of MS, 
following long-term treatment with DAC HYP 
 To assess the safety, tolerability, and efficacy of 
switching to DAC HYP in subjects previously on 


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long-term treatment with interferon β-1a in 
Study 205MS301 
 To evaluate pharmacodynamic (PD) parameters 
that may be associated with treatment response 
Endpoints  
Primary:  
 Incidence of adverse events (AEs) and serious 
adverse events (SAEs)  
Secondary: 
 Shifts in clinical laboratory assessments 
(hematology and blood chemistry) 
 Incidence of depression as assessed by the Beck 
Depression Inventory, Second Edition (BDI-II)   
 Incidence of anti-DAC HYP binding antibodies 
(ADAbs) over time 
 Incidence of anti-DAC HYP neutralizing 
antibodies (NAbs) over time 
 Relapse outcomes:  annualized relapse rate 
(ARR), and proportion of subjects who relapse 
 Sustained disability progression defined by at 
least a 1.0-point increase on the Expanded 
Disability Status Scale (EDSS) score from a 
baseline EDSS ≥1.0 that is sustained for 12 
weeks, or at least a 1.5-point increase on the 
EDSS from a baseline EDSS <1.0 that is 
sustained for 12 weeks 
 Magnetic resonance imaging (MRI) outcomes:  
total number and volume of new or newly 
enlarging T2 hyperintense lesions, gadolinium 
(Gd)-enhancing lesions, T1 hypointense lesions, 
and brain atrophy on brain MRI (Note:  The 
decision to collect and analyze brain atrophy data 
will be made after the analysis of Study 
205MS301 is complete.  Brain atrophy analysis 
may be omitted.) 
 Change in Multiple Sclerosis Functional 
Composite (MSFC) score 


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 Change in EDSS score 
 Proportion of subjects who are free from disease 
activity. 
 Proportion of subjects with sustained 
improvement in disability as defined by the 
number of subjects with baseline EDSS of at least 
2.0 who experience ≥1.0 decrease in EDSS that is 
sustained for 24 weeks. 
 Change in Multiple Sclerosis Impact Scale-29 
(MSIS-29) physical and psychological scores  
 Change in quality of life as assessed by the 
European Quality of Life, 5 dimensions (EQ-5D 
and EQ-VAS)   
 Change in direct health resource utilization 
(HRU; hospitalizations, emergency room visits, 
and unscheduled neurologist visits)  
 Change in treatment satisfaction as assessed by 
the subject  
 Change in subject productivity as assessed by the 
Health Related Productivity Questionnaire 
(HRPQ)  
Study Design: 
Multicenter, open-label, long-term extension study 
Rationale for Dose and 
Schedule Selection: 
The DAC HYP dose and schedule were used in the Phase 3 
205MS301 (DECIDE) study, and will be the treatment 
regimen used in the commercial setting. 
Study Location: 
Global (approximately 261 study sites participating in 
205MS301) 
Number of Planned Subjects: 
Up to 1841 subjects may be treated in the study 
Study Population: 
This study will be conducted in subjects with RRMS who 
have completed Study 205MS301. 
Treatment Groups: 
This is a single-arm study.  All subjects will receive 
open-label treatment with DAC HYP 150 mg by an 
SC injection using the PFS every 4 weeks for up to 
approximately 3 years, or until availability of commercial 
product (whichever is sooner), and in accordance with 




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treatment due to elevated liver function tests (LFTs). 
Subject Reported 
Assessments: 
Subject assessment of 29-item Multiple Sclerosis Impact 
Scale (MSIS-29), EQ-5D quality of life questionnaire (the 
EQ-5D descriptive system and the respondent’s self-rated 
health on a vertical visual analog scale [EQ-VAS]), 
Treatment Satisfaction Questionnaire for Medication (before 
the first use of a PFS and at multiple timepoints during the 
study), Treatment Satisfaction Survey at selected sites 
(before the first and last use of an autoinjector), HRU, and 
HRPQ. 
Statistical Methods: 
 
Efficacy endpoints will be summarized by previous treatment 
group (Avonex® or DAC HYP 150 mg during Study 
205MS301), all subjects (DAC HYP 150 mg during the 3-
year extension study), and the combined 5- to 6-year follow-
up period (Study 205MS301 and the 3-year extension study) 
using descriptive statistics.  The adjusted ARR and number 
of new or newly enlarging T2 lesions will be estimated using 
a negative binomial regression model.  The proportion of 
subjects with sustained progression and the proportion with a 
relapse will be estimated from the Kaplan-Meier curve.  The 
incidence of AEs and shifts in clinical laboratory 
assessments will also be summarized by treatment group 
during similar time periods.   An analysis by 3- or 6-month 
intervals may also be performed.  Summary statistics for 
other safety, efficacy, pharmacokinetic (PK), and PD 
endpoints will be presented. 
Sample Size Determination:  
There is no formal sample size calculation for this study.  
The number of subjects in this study is determined by the 
number of subjects who participate in Study 205MS301. 
Study Stopping Rules: 
Until the analysis of Study 205MS301 is complete, an 
independent Safety Monitoring Committee (SMC) will make 
recommendations for the continuation of Study 205MS303 
based on a review of safety data from this study and from 
other ongoing studies of DAC HYP in subjects with MS 
conducted by the Sponsor.  Thereafter, the independent SMC 
will no longer monitor Study 205MS303 and the decision to 
continue the study will be made by the Sponsor. 


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4. 
STUDY SCHEMATIC AND SCHEDULE OF EVENTS TABLES 
FOR STUDY 205MS303 
A schematic of the study design is provided in Section 4.1.  
The tabulated schedule of events for this study is provided in Section 4.2.  
4.1. 
Study Schematic 
 
Figure 1 shows the design of Study 205MS301 and its open-label extension, Study 205MS303. 
 
Figure 1: 
Study Design 
 
 
 






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9 EQ-5D including both the questionnaire and the VAS components. 
10 MSIS-29 to be administered prior to seeing the Treating Neurologist.  
11 To be performed after the DAC HYP injection at this visit. 
12 If a subject experiences at least a 1.0-point increase on the EDSS from a baseline EDSS ≥1.0 or a 1.5-point increase on the EDSS from a baseline EDSS <1.0 , 
then the EDSS must be repeated within 12 weeks to determine whether protocol-defined disability progression has occurred. 
13 At the Week 4, 8, and 12 Visits, subjects will be instructed on DAC HYP self-administration and may administer their scheduled dose under staff supervision. 
After Week 12, DAC HYP may be dispensed to subjects for at-home administration if the subject chooses. 
 








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Table 4: 
Schedule of Activities:  Autoinjector Use by Subjects at Selected Sites  
Note:   At the Sponsor’s discretion, approximately 75-100 eligible subjects at selected sites may begin using autoinjectors on any 
regularly scheduled dosing day, after they have received at least 6 consecutive monthly doses of DAC HYP by PFS in 
Study 205MS303.  Six consecutive DAC HYP injections will be administered by the subject.  Doses 1 and 4 will be supervised during 
clinic visits, all other doses can be given at home or the clinic.  Following the use of autoinjectors, subjects should resume 
administration of DAC HYP using the PFS. 
Note:  Subjects are to continue the visit schedule and evaluations listed in Table 1 while they are using autoinjectors. 
Tests and Assessments 
Autoinjector 11 
Autoinjector 2  
Autoinjector 3 
Autoinjector 41 
Autoinjector 5 
Autoinjector 6 
Pre-
Dose 
Post-
Dose 
Minutes/Hours/Weeks After First Autoinjection 
4 weeks  
±4 days 
8 weeks  
±4 days 
12 weeks 
±4 days 
16 weeks  
±4 days 
20 weeks 
±4 days 
Informed Consent 
X2 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
Waist Circumference3 
X 
 
 
 
 
 
 
Abdominal Fold Thickness3 
X 
 
 
 
 
 
 
DAC HYP Administration  
 
X 
X 
X 
X 
X 
X 
Injection Site Assessment  
 
X 
 
 
X 
 
 
Subject Assessment of Injection Pain (VAS) 
 
X4 
 
 
X 
 
 
Observer Report 
 
X 
 
 
X 
 
 
Treatment Satisfaction Survey5 
X 
 
 
 
 
 
X6 
DAC HYP Concentration Assessment 
X 
 
 
 
X7 
 
 
Anti-Drug Antibody Sample 
X 
 
 
 
X 
 
 
1 To be administered during a scheduled clinic visit. 
2  Subjects must provide written informed consent for autoinjector use prior to first DAC HYP dose by autoinjector. 
3 The procedure for taking this measurement is provided in the Study Reference Manual. 
4 VAS to be completed as soon as possible but within 10 minutes after the injection. 
5 If the subject withdraws from the study or reverts to PFS use prior to receiving all 6 autoinjector doses, the subject should complete the Treatment Satisfaction 
Survey provided for the Autoinjector 6 dosing day. 
6 To be administered immediately prior to dosing. 
7 Blood sample should be collected pre-dose.


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5. 
INTRODUCTION  
5.1. 
Profile of Previous Experience with Daclizumab in MS 
Background 
DAC HYP is a humanized monoclonal IgG1 antibody specific for CD25 (α subunit of the IL-2 
receptor).  CD25 is expressed at low levels on resting T cells but is rapidly upregulated after T-
cell activation, enabling high-affinity IL-2 signal transduction.  The primary hypothesis for using 
DAC HYP to treat MS is to selectively inhibit activated T cells.   
Anti-CD25 antibodies have multiple in vitro effects that suggest DAC HYP may directly 
decrease T-cell activation and proliferation.  These include inhibition of IL-2 dependent 
lymphocyte proliferation, disruption of both IL-2 dependent and independent pathways of 
IFN-gamma production, and interference in CD28-dependent CD40 ligand expression.  In vivo, 
daclizumab has been confirmed to cause expansion of CD56bright NK cells.  This expansion has 
also been shown to correlate with MRI-defined therapeutic response of daclizumab in MS.  
CD56bright NK cells are believed to have an immunoregulatory function, and they have been 
shown to kill activated T cells through a contact-dependent mechanism.  Therefore, selective 
inhibition of activated T cells with DAC HYP may occur through both direct and indirect 
mechanisms [Bielekova 2004; Bielekova 2009].   
Clinical Experience with Daclizumab in Multiple Sclerosis 
Initial clinical studies of daclizumab in MS were conducted with material manufactured by 
F. Hoffmann-La Roche, Ltd. (Roche) at their facilities in Nutley, New Jersey (DAC Nutley) 
[Bielekova 2004; Rose 2003; Rose 2004], and in Penzberg, Germany (DAC Penzberg) [Wynn 
2010].  Study 205MS301 is conducted with DAC HYP, which is produced using a different 
manufacturing process than the previous versions of daclizumab.  DAC HYP has characteristics 
that are similar to DAC Nutley and DAC Penzberg, although certain differences in 
physicochemical and biological characteristics have been observed (refer to the Investigator’s 
Brochure for details).   
Study 205MS201 (SELECT) was a double-blind, placebo-controlled study to evaluate the safety 
and efficacy of DAC HYP in subjects with RRMS that randomized 621 subjects in a 1:1:1 ratio 
to receive placebo, 150 mg DAC HYP, or 300 mg DAC HYP SC every 4 weeks over a 52-week 
treatment period.  Among subjects randomized to DAC HYP (150 mg, 300 mg) versus placebo, 
there was a significantly lower annualized relapse rate (ARR; 0.21, 0.23 versus 0.46; p < 0.001), 
a higher proportion of relapse-free subjects (81%, 80% versus 64%; p < 0.001), and a trend 
towards improvement in the MSIS-29 physical score (p = 0.128 for DAC HYP 300 mg versus 
placebo; p < 0.001 for DAC HYP 150 mg versus placebo).  There were significant reductions in 
the mean number of new or newly enlarging T2 lesions at 1 year (2.4, 1.7 versus 8.1) and in the 
mean number of new Gd+ lesions between Weeks 8 and 24 in a monthly MRI substudy 
(n = 307) (1.5, 1.0 versus 4.8) in the DAC HYP 150 mg and 300 mg groups versus placebo (p < 
0.001 for all comparisons).  The risk of 3-month sustained disability progression at 1 year, a 


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tertiary study endpoint, was reduced by 57% (p = 0.021) in the DAC HYP 150 mg group and by 
43% (p = 0.091) in the DAC HYP 300 mg group.   
Analysis of safety data from the SELECT study showed that, overall, DAC HYP was well 
tolerated in this patient population.  The most frequently reported (≥10%) AEs for subjects 
treated with DAC HYP, excluding MS relapse, were nasopharyngitis (14%), and headache and 
upper respiratory tract infection (10% each).  In the SELECT study, serious adverse events 
(SAEs) including MS relapses occurred in 26% of placebo-treated subjects and in 16% of 
subjects treated with DAC HYP.  Excluding MS relapses, SAEs occurred in 6% of the placebo 
group, in 7% of the DAC HYP 150 mg group, and in 9% of the DAC HYP 300 mg group.  One 
DAC HYP-treated subject died due to ischemic colitis following a complicated course of events.  
Adverse events observed more frequently in DAC HYP-treated patients included an increase in 
serious infections (2%), serious cutaneous events (1%), and elevations in liver function tests 
(ALT/AST) >5  ULN (4%). 
Upon completion of the 12-month treatment period in Study 205MS201 (SELECT), subjects 
were eligible to complete up to an additional 12 months of treatment with DAC HYP in a 
double-blind extension study (Study 205MS202 [SELECTION]), which will be completed in 
2012.  SELECTION also assesses the effects of DAC HYP washout in some subjects who were 
actively treated in Study 205MS201.  Subjects completing SELECTION can continue long-term 
therapy with open-label DAC HYP in ongoing extension Study 205MS203 (SELECTED), which 
will evaluate long-term safety and efficacy of DAC HYP monotherapy for an additional 
144 weeks.  
Study 205MS301 (DECIDE), an ongoing double-blind randomized, parallel-group study testing 
the superiority of DAC HYP monotherapy compared to Avonex® in preventing MS relapse, was 
initiated in May 2010; 1841 subjects with RRMS have been enrolled and randomized in a 1:1 
ratio to receive 150 mg DAC HYP given SC every 4 weeks, or Avonex 30 mcg given IM once 
weekly over a 96- to 144-week treatment period.  The primary endpoint is the ARR. 
The pharmacokinetics (PK) and immunogenicity of DAC HYP 150 mg SC administered every 
4 weeks using a prefilled syringe (PFS) is being investigated in 26 subjects in Study 205MS302 
(OBSERVE), an ongoing, single-arm, open-label study that has enrolled a total of 113 subjects 
with RRMS. 
Refer to the Investigator’s Brochure for additional details.  
5.2. 
Study Rationale 
This study will provide subjects who complete Phase 3 Study 205MS301 with the opportunity to 
receive open-label DAC HYP monotherapy prior to local product marketing approval for 
evaluation of long-term safety, efficacy, and immunogenicity of DAC HYP in subjects with 
RRMS.  In addition, this study will assess the safety, tolerability, and efficacy of switching to 
DAC HYP in subjects previously on long-term treatment with interferon β-1a in 
Study 205MS301. 


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5.3. 
Rationale for Dose and Schedule Selection 
The existing scientific and clinical experience with DAC HYP supports its further investigation 
in the management of MS.  The DAC HYP dose and schedule in this protocol were used in 
parent Study 205MS301 (DECIDE), and will be the treatment regimen used in the commercial 
setting. 
A single-use, disposable PFS will be provided to simplify the injection process and thereby 
reduce the burden of administering a long-term therapy such as DAC HYP in the clinic or at 
home.  At the Sponsor’s discretion, single-use autoinjectors containing PFS may be used to 
administer DAC HYP in 75-100 subjects at selected sites.  Autoinjectors will be dispensed to 
each subject for use on 6 consecutive scheduled dosing days. 


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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Objectives  
6.1.1. 
Primary Objective 
The primary objective of the study is to assess the safety and tolerability of long-term treatment 
with DAC HYP monotherapy in subjects who completed Study 205MS301. 
6.1.2. 
Secondary Objectives 
Secondary objectives of this study in this study population are as follows: 
 To assess the long-term immunogenicity of DAC HYP administered by PFS  
 To describe MS-related outcomes, including MS relapse, disability progression, MS 
lesion formation, and patient-reported impact of MS, following long-term treatment 
with DAC HYP 
 To assess the safety, tolerability, and efficacy of switching to DAC HYP in subjects 
previously on long-term treatment with interferon β-1a in Study 205MS301 
 To evaluate PD parameters that may be associated with treatment response 
6.2. 
Endpoints 
6.2.1. 
Primary Endpoints 
 Incidence of AEs including serious AEs (SAEs), discontinuation of DAC HYP due to 
AEs, and withdrawals due to AEs 
6.2.2. 
Secondary Endpoints 
 Shifts in clinical laboratory assessments (hematology and blood chemistry) 
 Incidence of depression as assessed by the Beck Depression Inventory, Second 
Edition (BDI-II)   
 Incidence of anti-DAC binding antibodies (ADAbs) over time 
 Incidence of anti-DAC HYP neutralizing antibodies (NAbs) over time 
 Relapse outcomes:  annualized relapse rate (ARR), and proportion of subjects who 
relapse 
 Sustained disability progression defined by at least a 1.0-point increase on the 
Expanded Disability Status Scale (EDSS) score from a baseline EDSS ≥1.0 that is 
sustained for 12 weeks, or at least a 1.5-point increase on the EDSS from a baseline 
EDSS <1.0 that is sustained for 12 weeks 
 Magnetic Resonance Imaging (MRI) outcomes:  total number and volume of new or 
newly enlarging T2 hyperintense lesions, Gd-enhancing lesions, T1 hypointense 


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lesions, and brain atrophy on brain MRI (Note:  The decision to collect and analyze 
brain atrophy data will be made after the analysis of Study 205MS301 is complete.  
Brain atrophy analysis may be omitted.) 
 Change in Multiple Sclerosis Functional Composite (MSFC) score 
 Change in EDSS score 
 Proportion of subjects who are free from disease activity. 
 Proportion of subjects with sustained improvement in disability as defined by the 
number of subjects with baseline EDSS of at least 2.0 who experience ≥1.0 decrease 
in EDSS that is sustained for 24 weeks. 
 Change in Multiple Sclerosis Impact Scale-29 (MSIS-29) physical and psychological 
scores  
 Change in quality of life as assessed by the European Quality of Life, 5 dimensions 
(EQ-5D and EQ-VAS)   
 Change in direct HRU (hospitalizations, emergency room visits, and unscheduled 
neurologist visits)  
 Change in treatment satisfaction as assessed by the subject 
 Change in subject productivity as assessed by the HRPQ 
 


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7. 
STUDY DESIGN 
7.1. 
Study Overview 
Subjects who participate in Study 205MS303 will roll over from parent Study 205MS301 
(DECIDE), a multicenter, double-blind, randomized, active-control, parallel-group study 
designed to evaluate the efficacy and safety of DAC HYP versus IFN β-1a in patients with 
RRMS.  In Study 205MS301 subjects are randomized in a 1:1 ratio into the following groups: 
Group 1: Approximately 900 subjects, DAC HYP 150 mg SC once every 4 weeks plus 
IFN β-1a placebo (A-PLC) IM once weekly for 96 to 144 weeks 
Group 2: Approximately 900 subjects, IFN β-1a 30 mcg IM once weekly plus 
DAC HYP placebo (D-PLC) SC once every 4 weeks for 96 to 144 weeks 
This multicenter extension study will provide subjects who complete Study 205MS301 with the 
opportunity to receive open-label DAC HYP monotherapy for the evaluation of the long-term 
safety, efficacy, and immunogenicity of DAC HYP in subjects with RRMS.  Up to 1841 subjects 
may participate in this study for up to approximately 3 years or until availability of commercial 
product (whichever is sooner), and in accordance with applicable laws and regulations.  All 
subjects will receive DAC HYP 150 mg by an SC injection every 4 weeks. 
7.2. 
Overall Study Duration and Follow-Up 
The study period will consist of baseline assessments, treatment (for up to approximately 
3 years), and post-treatment safety follow-up visits (from approximately 4 to 24 weeks after the 
last dose of DAC HYP). 
7.2.1. 
Baseline Assessments 
With the exception of LFTs, which must be repeated within 7 days prior to each administration 
of DAC HYP, tests/assessments performed at the subject’s last visit in Study 205MS301 and 
within 28 days of the subject’s first dose of DAC HYP (Week 0) in Study 205MS303 will be 
used as the baseline for Study 205MS303; if final Study 205MS301 tests/assessments are not 
performed within the 28-day window, they must be repeated upon entry into Study 205MS303 
and before the first dose of DAC HYP is administered.  
7.2.2. 
Treatment 
All subjects will receive open-label treatment with DAC HYP 150 mg SC using a PFS every 4 
weeks for up to approximately 3 years, or until availability of commercial product (whichever is 
sooner), and in accordance with applicable laws and regulations.  At the Sponsor’s discretion, 
75-100 subjects at selected sites may dose with DAC HYP using a single-use autoinjector that 
contains a PFS on 6 consecutive scheduled dosing days (Table 4). 
Eligible subjects will have clinic visits scheduled every 4 weeks for the first 12 weeks in this 
study, followed by clinic visits scheduled every 12 weeks for up to approximately 3 years of 
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Subjects who are dosing at home must be instructed to not administer their monthly dose 
of DAC HYP until the study site has contacted them to authorize dosing (after the Treating 
Neurologist or their backup has reviewed LFT results obtained during the previous 7 days). 
7.2.3. 
Post-Treatment Long-Term Follow-Up 
Subjects are to return to the study site for follow-up visits at 4, 8, 12, 16, and 24 weeks (±10 
days) after the last dose of DAC HYP. 
7.3. 
Study Stopping Rules 
Biogen Idec may terminate this study, after informing Investigators, at any time.  Investigators 
will be notified by Biogen Idec or designee if the study is placed on hold, completed, or closed. 
Until the analysis of Study 205MS301 is complete, an independent Safety Monitoring 
Committee (SMC) will make recommendations for continuation of the study based on a review 
of safety data from this study and from other ongoing trials of DAC HYP in subjects with MS 
conducted by the Sponsor. Thereafter, the independent SMC will no longer monitor Study 
205MS303 and the decision to continue the study will be made the by the Sponsor. 
7.4. 
End of Study 
The End of Study is last subject, last visit for final collection of data for the primary outcome. 


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8. 
SELECTION OF SUBJECTS 
8.1. 
Inclusion Criteria 
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at the 205MS303 Baseline Visit or at the timepoint specified in the individual eligibility criterion 
listed:  
1. Ability to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use protected health information (PHI) in 
accordance with national and local subject privacy regulations.   
2. Must be a subject currently participating in Study 205MS301 who has completed either 
the Week 144 Visit or the End of Study Visit (Week 96).  
Note:  Subjects who are not able to enroll into 205MS303 at the time of their Week 
144/End of Study Visit may be eligible to enroll into 205MS303 at a later time if they are 
still participating in the 6-month follow-up period of 205MS301 at the time of expected 
rollover into 205MS303. 
3. Women of childbearing potential must practice effective contraception during the study 
and be willing and able to continue contraception for 4 months after their last dose of 
study treatment. 
8.2. 
Exclusion Criteria 
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
the Study 205MS303 Baseline Visit or at the timepoint specified in the individual criterion listed 
(Note:  Day 1 is the day of the first dose in Study 205MS303): 
Medical History 
1. Any subject who permanently discontinued study treatment in Study 205MS301 prior to 
the end of the study treatment period, or had an Early Termination visit in 
Study 205MS301.   
Note:  Subjects for whom dosing was temporarily suspended in Study 205MS301 are not 
excluded from participation in this extension study if the criteria for resuming DAC HYP 
treatment under the Study 205MS301 protocol have been met at the time of enrollment 
into Study 205MS303.   
2. Any significant change in the subject’s medical history that would preclude 
administration of DAC HYP, including laboratory tests or a current clinically significant 
condition that, in the opinion of the Investigator, would have excluded the subject’s 
participation in Study 205MS301.  The Investigator must re-review the subject’s medical 
fitness for participation and consider any factors that would preclude treatment in 
Study 205MS303, including:   
 History of any significant cardiac, endocrine, hematological, hepatic, immunologic, 
metabolic, urologic, pulmonary, gastrointestinal, dermatologic, psychiatric, renal, 


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neurological (other than MS), and/or other major disease (e.g., malignancy) that 
would preclude administration of DAC HYP. 
 Clinically significant laboratory abnormalities (hematology and blood chemistry) 
from the most recently available test in Study 205MS301, as determined by the 
Investigator.  Laboratory findings mandating discontinuation of study treatment as 
defined in Protocol 205MS301 are exclusionary. 
3. Any of the following abnormal blood tests within the 7 days prior to Day 1:   
 alanine aminotransferase/serum glutamate pyruvate transaminase (ALT/SGPT), 
aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT), or 
gamma-glutamyl-transferase (GGT) >3  the upper limit of normal (ULN)   
Note:  Subjects ending 205MS301 on a treatment suspension may not enroll into 
205MS303 until ALT/SGPT and AST/SGOT are 2  ULN.   
 total bilirubin >2  ULN (subjects with an established diagnosis of Gilbert's syndrome 
are excluded if total bilirubin is >2.5  ULN)   
Note:  Subjects ending 205MS301 on a treatment suspension may not enroll into 
205MS303 until total bilirubin 1  ULN (subjects with an established diagnosis of 
Gilbert's syndrome may not enroll into 205MS303 until total bilirubin is 1.5  ULN).   
4. Other medical reasons that, in the opinion of the Investigator and/or Biogen Idec, make 
the subject unsuitable for enrollment.   
Treatment History 
5. Treatment with any prohibited concomitant medication during Study 205MS301. 
Note:  Subjects who start an approved, open-label IFN β preparation after completion of 
dosing in Study 205MS301 are not excluded, but IFN β treatment must be discontinued 
before the first dose of DAC HYP in Study 205MS303 is given. 
Miscellaneous 
6. Female subjects who are currently pregnant or breastfeeding, or considering becoming 
pregnant while in the study. 
7. Previous participation in Study 205MS303. 
8. History of drug or alcohol abuse (as defined by the Investigator) at any time after the start 
of Study 205MS301. 
9. Unwillingness or inability to comply with the requirements of the protocol, including the 
presence of any condition (physical, mental, or social) that is likely to affect the subject’s 
ability to comply with the protocol. 


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9. 
ENROLLMENT AND REGISTRATION PROCEDURES 
9.1. 
Enrollment and Screening 
Subjects must be consented before any procedures are performed.  At the time of consent, the 
subject will be enrolled into the study.   If a subject is excluded from the study, the reasons for 
exclusion will be documented in the subject’s source documents and on the enrollment log.  With 
the exception of LFTs, any test/assessment done at the subject’s last visit in Study 205MS301 
and within 28 days of the subject’s first dose in Study 205MS303 will be used as the baseline for 
Study 205MS303 and does not need to be repeated at entry into Study 205MS303.  Testing 
required at Week 0 that is done outside the 28-day window must be repeated upon entry into 
205MS303.  LFTs must be performed within 7 days prior to administration of DAC HYP. 
9.2. 
Registration of Subjects 
Subjects should be registered in the study after the Investigator has verified that they are eligible 
per the criteria in Sections 8.1 and 8.2 and all baseline assessments have been performed.  No 
subject may begin treatment prior to enrollment and registration.  Each subject will be registered 
in Study 205MS303 under the same identification number assigned to him or her in parent 
Study 205MS301. 
As confirmation, Biogen Idec will provide the Investigator with written verification of the 
subject’s registration by mail or fax.   
Refer to the Study Reference Manual for details on registration. 
 
 


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10. 
STUDY TREATMENT MANAGEMENT 
Study treatment (PFS or autoinjectors) must be stored in a secure location.  Accountability for 
study treatment is the responsibility of the Investigator.  Study treatment must only be dispensed 
by a Pharmacist or medically qualified staff, and stored in a secure, monitored, locked location in 
accordance with the conditions specified in current prescribing information or the Directions for 
Handling and Administration (DHA) included in the Study Reference Manual. 
Study treatment is to be dispensed only to subjects enrolled in this study.  Once treatment is 
dispensed to a subject, it can only be used by that subject. 
10.1. 
DAC HYP 
Prefilled Syringe (PFS) 
DAC HYP is supplied as a liquid in a 1-mL BD-staked PFS with a 29 gauge × ½ inch needle, 
comprising 150 mg/mL DAC HYP plus excipient materials (sodium succinate, sodium chloride, 
and polysorbate 80).  At a minimum, the study treatment label will include a study reference 
code, drug identifier, quantity of dosage units, lot number, and other pertinent information in 
accordance with local law.  Depending on country requirements, the Investigator’s name may 
also appear on the label.  DAC HYP must not be used after the expiration date unless a written 
notification of an expiration date extension is provided by Biogen Idec. 
Autoinjector  
The DAC HYP PFS is assembled inside a single-use, disposable autoinjector device.   
The autoinjector label will include the DAC HYP product code “BIIB019,” conditions for 
storage, Sponsor, and a caution statement.  Depending on country requirements, the 
Investigator’s name may also appear on the label.  DAC HYP must not be used after the 
expiration date unless a written notification of an expiration date extension is provided by 
Biogen Idec. 
10.2. 
DAC HYP Preparation 
Each DAC HYP PFS or autoinjector contains only one dose and is intended for SINGLE USE 
INJECTION ONLY.  Any drug that remains in the PFS after injection must not be used for 
another dose or another subject.  
After Week 12, subjects may choose to administer their DAC HYP dose at home, either by 
administering the injection themselves or by a designated caregiver.  The subject or designated 
caregiver will be trained by clinic staff on the correct PFS injection technique prior to initiating 
at-home DAC HYP dosing. 
Autoinjectors may be provided to selected sites and will be supplied injection-ready.  Study 
personnel or subjects at these sites do not need to insert the PFS into the device.  Study site 
personnel will receive appropriate autoinjector training from a Sponsor-designated trainer prior 
to initiation of autoinjector use. 


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10.3. 
DAC HYP Accountability 
The study site must maintain accurate records demonstrating dates and amount of study 
treatment received, to whom dispensed (subject-by-subject accounting), any amount returned by 
subject, and accounts of any study treatment accidentally or deliberately destroyed.   
Unless otherwise notified, all PFS and autoinjectors, both used and unused, must be saved for 
study treatment accountability.  At the end of the study, a final reconciliation must be made 
between the amount of study treatment supplied, dispensed, and subsequently destroyed or 
returned to Biogen Idec.  
A written explanation will be provided for any discrepancies.  After reconciliation, the 
Investigator must destroy or return to Biogen Idec all unused study treatment PFS and 
autoinjectors as instructed by Biogen Idec. 
If any study treatment supplies are to be destroyed at the site, the Principal Investigator(s) must 
obtain prior approval by Biogen Idec.  The Principal Investigator(s) must notify Biogen Idec, in 
writing, of the method, date, and location of destruction.   


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11. 
TREATMENT OF SUBJECTS 
Biogen Idec will provide DAC HYP (PFS or autoinjectors) to all study sites. 
Refer to Section 10 (Study Treatment Management) for specifics on the preparation, storage, 
handling, disposal, and accountability of study treatment. 
11.1. 
Study Treatment Schedule and Administration 
Starting at Week 0, all subjects will receive one DAC HYP 150 mg SC injection every 4 weeks 
for up to approximately 3 years or until availability of commercial product (whichever is 
sooner), and in accordance with applicable laws and regulations.   
DAC HYP will be administered by clinic staff at the monthly visits for the first 12 weeks of this 
study.  After Week 12, administration of DAC HYP may occur in the clinic or at home (by the 
subject or by a designated caregiver) depending on subject preference.  The subject or designated 
caregiver will be trained by clinic staff on the correct injection technique prior to initiating at-
home DAC HYP dosing.  Subjects who are dosing at home must be instructed to not 
administer their monthly dose of DAC HYP until the study site has contacted them to 
authorize dosing. 
Following review of LFT results by the Treating Neurologist or their backup, study personnel 
should promptly inform the subject whether the monthly dose of DAC HYP should be 
administered or whether study treatment is to be withheld based on the dosing criteria defined in 
Section 11.7.2.  Study personnel will document this communication with the subject.  Subjects 
should administer DAC HYP as soon as permission has been given and within 7 days of the 
LFT. 
11.2. 
Placebo or Reference Product Agents 
Not applicable. 
11.3. 
Treatment Precautions 
Anaphylactic-like and hypersensitivity reactions following administration of proteins such as 
DAC HYP can occur.  DAC HYP will be administered in the clinic under observation by 
qualified medical personnel for the first 12 weeks of this study.  Subjects will be educated by the 
Treating Neurologist or their back-up on the signs and symptoms of hypersensitivity reactions 
and instructed to contact the site if they experience any acute or delayed reactions post injection.   
11.4. 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded by study site staff. 
After Week 12, subjects will record treatment in a dosing diary that will be reviewed periodically 
by study site staff and the Clinical Monitor.  Subjects who choose at-home administration will 
return used PFS or autoinjectors to the clinic at their scheduled clinic visits.   


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11.5. 
Concomitant Therapy 
A concomitant therapy is any drug or substance administered from the Baseline Visit until 
completion of the study. A concomitant procedure is defined as any therapeutic intervention 
(e.g., surgery/biopsy, physical therapy) or diagnostic assessment (e.g., blood gas measurement, 
bacterial cultures) performed from the time the subject is enrolled in the study until the subject’s 
final clinic visit. 
Concomitant treatment with any of the following is not allowed during the study, unless 
approved by the Biogen Idec Medical Director(s) or the Advisory Committee, or as otherwise 
described in this protocol: 
 Any alternative disease modifying MS drug treatment such as chronic 
immunosuppressant therapy or other immunomodulatory treatments (including, but 
not limited to:  IFN-β, IFN-α, glatiramer acetate, cyclophosphamide, methotrexate, 
mycophenolate mofetil, mitoxantrone, cyclosporine, azathioprine, 4-aminopyridine or 
related products), except for subjects who were on a stable dose of commercially 
available Fampridine-SR prior to study enrollment. Initiation of Fampridine-SR after 
enrollment is not permitted, with the exception of acute management of protocol-
defined relapse (as described in Section 14.6). 
 Any investigational product, including investigational symptomatic therapies for MS 
and investigational therapies for non-MS indications. 
 Any monoclonal antibodies other than DAC HYP. 
 Intravenous immunoglobulin (IVIg), plasmapheresis or cytapheresis, total lymphoid 
irradiation, or T-cell or T-cell receptor vaccination. 
 Any systemic steroid therapy including, but not limited to, oral corticosteroids (e.g., 
prednisone) or periodic (e.g., monthly) treatment with IV methylprednisolone 
(IVMP), except for protocol-defined treatment of relapses as described in 
Section 14.6 or for limited, acute treatment of general medical conditions.  Steroids 
that are administered by non-systemic routes (e.g., topical, inhaled) are allowed. 
Note:  The guidelines for management of cutaneous events allow a limited course of 
systemic corticosteroids if medically indicated.  See Section 22 for full details.  
 Antineoplastic or chemotherapeutic agents, including, but not limited to, 
cyclophosphamide, methotrexate, azathioprine, cladribine, cytarabine, or flutamide. 
 Valproic acid, carbamazepine, lamotrigine, or phenytoin.  Subjects who have been 
taking 1 of these medications at a stable dose for at least 6 consecutive months may 
continue to receive the medication and may continue study treatment under this 
protocol.  However, if any of these medications must be initiated or dose escalated, 
study treatment must be permanently discontinued as described in Section 11.8.   
Subjects who have been treated with any of these medications for fewer than 
6 consecutive months, or who take more than 1 of these medications, or who have 
had dose escalations within the past 6 months must do 1 of the following: 


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 Discontinue the medication (any agent used for <6 consecutive months must be 
discontinued).  Subjects may use an alternative medication allowed by the 
protocol, if needed. 
 Subjects taking more than 1 agent must reduce to 1 agent (any agent that is 
continued must have been taken for at least 6 consecutive months). 
 In the case of dose escalation, revert to a previous dose that had been used for at 
least 6 months. 
 Permanently discontinue study treatment. 
 Isoniazid, propylthiouracil, or nimesulide.  Subjects who currently take any of these 
medications must either change to an alternative medication allowed by the protocol 
or permanently discontinue study treatment.   
Subjects who receive any of these restricted medications may be required to permanently 
discontinue study treatment as outlined in Section 11.8.  Subjects who permanently discontinue 
study treatment will be allowed to receive IVMP as treatment for MS relapse while they are 
participating in the study, as described in Section 11.8. 
Use of the following medications is strongly discouraged during the study, although they are 
permitted if alternative medications are not available: 
 Herbal or dietary supplements.  
 Agents that have established risks of hepatotoxicity or serious rash according to 
labeling information (examples include, but are not limited to, 
amoxicillin/clavulanate, clarithromycin, ketoconazole, minocycline, nitrofurantoin, 
trimethoprim/sulfamethoxazole, diclofenac, sulfasalazine, amiodarone, methyldopa, 
nefazodone, and halothane).  Alternatives to these therapies should be used whenever 
possible. 
Symptomatic therapy, such as treatment for spasticity, depression, or fatigue is not restricted, but 
should be optimized as early as possible in an attempt to maintain consistent treatment for the 
duration of the study.  
Subjects should be instructed not to start taking any new medications, including non-prescribed 
medications, unless they have received permission from the Investigator.  The use of live 
vaccines in humans concurrently treated with daclizumab has not been explored; therefore live 
vaccines should not be administered to MS subjects who are being treated with DAC HYP. 
The use of concomitant therapies or procedures defined in this section must be recorded on the 
subject’s case report form (CRF), according to instructions for CRF completion (Note: 
concomitant therapies in Study 205MS301 that continued at Study 205MS303 entry must be 
recorded on the CRF).  AEs related to administration of these therapies or procedures must be 
documented on the appropriate CRF.  For subjects who prematurely discontinue study treatment, 
all concomitant medications should be recorded throughout the remainder of the subject’s 
participation in the study.  


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11.6. 
Continuation of Treatment  
No further provisions are made for access to the study treatment.  If DAC HYP is proven to be 
beneficial, all regulatory requirements regarding poststudy access will be met. 
11.7. 
Treatment Schedule Modifications 
Subjects who experience a significant change in their medical status (e.g., neurological 
worsening/suspected MS relapse, possible injection-site reaction, infection, cutaneous event 
fever, abdominal pain, jaundice, nausea, vomiting, pruritus) must contact the Treating 
Neurologist as soon as possible and no more than 48 hours after symptom onset.  The subject 
should then be evaluated by the Treating Neurologist within no more than 72 hours for physical 
and neurological assessments and further treatment recommendations if appropriate.  These 
subjects should not administer additional DAC HYP until they have been evaluated by the 
Treating Neurologist or their backup. 
Additional treatment considerations for specific events are described below. 
11.7.1. 
Infections 
Subjects who have evidence of a clinically significant infection will be instructed to notify the 
Treating Neurologist or their backup within 48 hours of onset, and scheduled dosing of DAC 
HYP may be withheld.  If the subject’s infection resolves within 2 weeks of the scheduled DAC 
HYP dose, the subject may receive the previously scheduled dose of DAC HYP at that time.  If 
the infection has not resolved within the 2 weeks, dosing of DAC HYP will remain suspended, 
and the subject will miss a dose.   
11.7.2. 
Elevated Liver Function Tests 
Before a monthly dose of DAC HYP is given, LFT results (ALT, AST, and total bilirubin) from 
a test performed within the previous 7 days must be reviewed by the Treating Neurologist or 
their backup, and must be within the protocol-required limits shown below (LFT procedures are 
described in Section 14.4.3). 
Study treatment must be temporarily suspended if a subject develops any of the following:  
 ALT/SGPT or AST/SGOT >3  ULN   
 total bilirubin >2  ULN* 
 any other clinically significant hepatic test abnormality in the opinion of the 
Investigator   
Confirmatory laboratory testing should be performed as soon as medically indicated to guide 
subject management, but must also be performed in 1 week to determine whether the subject has 
met the permanent discontinuation criteria listed in Section 11.8.  (Note:  All confirmatory LFTs 
following a treatment suspension must be performed through the central laboratory until the LFT 
abnormality has resolved.) 
Study treatment must be suspended until all of the following parameters are met: 
 ALT/SGPT and AST/SGOT ≤2  ULN 


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 total bilirubin ≤ULN* 
* For subjects with an established diagnosis of Gilbert's syndrome, the total bilirubin suspension 
criterion is >2.5  ULN; the resolution criterion is ≤1.5  ULN or return to baseline.  
Subjects who require suspension of study treatment for 8 consecutive weeks will have study 
treatment permanently discontinued; subjects who require a second suspension of study 
treatment will also have study treatment permanently discontinued (see Section 11.8). 
An Unscheduled Hepatic Assessment Visit is to be performed as soon as possible (but within 
1 week) after permanent discontinuation of study treatment for subjects who are required to 
discontinue dosing due to elevated LFTs as described in Section 11.8.  
Resuming study treatment after temporary LFT suspension: 
Before resuming study treatment, LFTs must be re-evaluated within 7 days prior to the 
planned dose.  ALT and AST must be 2  ULN and total bilirubin must be ≤ULN for study 
treatment to continue.  If ALT, AST, or total bilirubin exceeds these values at this retest, 
study treatment must be permanently discontinued (see Section 11.8). 
11.8. 
Discontinuation of Study Treatment 
A subject must permanently discontinue DAC HYP 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 15.5.4. 
 The subject experiences a hypersensitivity or suspected allergic reaction to study 
treatment. 
 The subject develops a chronic viral infection (e.g., hepatitis C, HIV). 
 The subject develops elevated LFTs that meet any of the following criteria: 
 The subject develops an ALT/SGPT or AST/SGOT elevation >5  ULN that is 
confirmed by an immediate repeat test (preferably within 24 hours).  This requires 
immediate discontinuation of DAC HYP, and treatment may not resume unless a 
laboratory error is documented upon repeat testing.  
 Upon confirmatory tests 1 week apart, the subject has developed elevations of:  
o ALT/SGPT or AST/SGOT >3  ULN or  
o total bilirubin >2  ULN* 
* total bilirubin >2.5  ULN for subjects with an established diagnosis of 
Gilbert's syndrome   
 LFT abnormalities that have resulted in suspension of study treatment for 
8 consecutive weeks. 
 For subjects who previously had study treatment suspended for LFT abnormalities 
(including any suspension that occurred during Study 205MS301) and then 


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resumed dosing, LFT abnormalities that require a new suspension of study 
treatment. 
 After reinitiation of DAC HYP dosing following a suspension, and within 7 days 
prior to the next scheduled monthly visit, the subject develops ALT/SGPT or 
AST/SGOT >2  ULN, or total bilirubin > ULN** 
** total bilirubin >1.5  ULN or baseline (whichever is higher) for subjects with 
an established diagnosis of Gilbert's syndrome   
 The subject requires treatment with any of the disallowed concomitant medications, 
unless approval is given by the Advisory Committee.  Note:  IVMP for treatment of a 
protocol-defined relapse is allowed as detailed in the protocol.  Treatment with 
valproic acid, carbamazepine, lamotrigine, or phenytoin is only allowed under the 
conditions detailed in the protocol.   
 The subject experiences a medical emergency that necessitates permanent 
discontinuation of treatment.   
 The subject desires to discontinue treatment under this protocol.   
 At the discretion of the Investigator for medical reasons or for non-compliance.    
The reason for discontinuation of study treatment must be recorded in the subject’s CRF.   
The LFT abnormality that led to treatment discontinuation should continue to be monitored until 
resolution is documented.   
In addition, a careful review of all concomitant medications must be documented.  The 
Investigator should consider discontinuation of all potential hepatotoxic medications.  The 
subject should be referred to a physician with expertise in the diagnosis and treatment of liver 
disease, and additional hepatic studies should be performed according to local standard of care.  
The central laboratory may be utilized for additional hepatic testing per Investigator request.   
 Upon confirmatory tests 1 month apart, the subject’s hematology results are as 
follows in the absence of an identified reversible cause by the Investigator (e.g., 
infection):   
 white blood cell count is <2500 cells/ L, or   
 lymphocyte count is <800 cells/ L, or   
 platelet count is <75,000 cells/ L   
Subjects who meet the above criteria must have study treatment withheld until 
hematology retest results are available.   
Subjects who permanently discontinue DAC HYP treatment should complete all post-treatment 
safety follow-up evaluations (see Section 13.3). 
Subjects who permanently discontinue study treatment may be treated with alternative approved 
MS therapies according to local practices, and should remain in the study and complete safety 
follow-up evaluations as described in Sections 4.2 and 13. However, subjects who desire to 


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discontinue participation in this study or are unwilling or unable to comply with the protocol 
should be withdrawn from the study and complete an Early Termination Visit. 
The reason(s) for discontinuation of treatment must be recorded in the subject’s CRF. 
11.9. 
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 is unwilling or unable to comply with the protocol.   
 At the discretion of the Investigator for medical reasons.   
Subjects who withdraw from the study should complete the End of Treatment Visit assessments 
as described in Section 14.9 (subjects should be encouraged to complete all other post-treatment 
safety follow-up visits).  The reason for the subject’s withdrawal from the study must be 
recorded in the subject’s CRF. 
 


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12. 
EFFICACY,  DAC HYP CONCENTRATION, AND 
PHARMACODYNAMIC ASSESSMENTS 
12.1. 
Clinical Efficacy Assessments 
The following clinical tests/assessments will be performed to assess the efficacy of DAC HYP: 
 Relapse Assessment:  Subjects who suspect they are experiencing new symptoms or 
worsening symptoms need to contact the Treating Neurologist within 48 hours of the 
onset of the symptoms.   
 Refer also to Section 14.6 Unscheduled Relapse Assessment Visit for additional 
details.   
 EDSS [Kurtzke 1983]:  Review of EDSS procedures will be performed prior to study 
start as necessary for training purposes.   
 MSFC [Fischer 1999]:  Timed 25-Foot Walk, 9HPT with both upper extremities and 
PASAT 3   
 Brain MRI scan with and without Gd (T2 hyperintense lesions, T1 hypointense 
lesions, Gd+ lesions, brain atrophy).   
 Subjects will complete the following questionnaires at various timepoints specified in 
Section 4.2:   
 EQ-5D quality of life questionnaire (the EQ-5D descriptive system and the EQ-
VAS)   
 MSIS-29 (29-item physical and psychological assessment)   
 HRU (hospitalizations, emergency room visits, and unscheduled neurologist 
visits)   
 Treatment Satisfaction Questionnaire for Medication (with PFS use) or Treatment 
Satisfaction Survey (with autoinjector use)   
 HRPQ (productivity questionnaire)   
Refer to Section 4.2 for the timing of assessments.   
12.2. 
Pharmacokinetic Assessments 
Blood samples will be collected at selected timepoints throughout the study to determine DAC 
HYP serum concentrations. 
Refer to Section 4.2 for the timing of sample collection. 
12.3. 
Pharmacodynamic Assessments 
 




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13. 
SAFETY ASSESSMENTS 
13.1. 
Clinical Safety Assessments 
The following clinical assessments will be performed to determine the safety profile of DAC 
HYP: 
 Medical history 
 Physical and neurological examination  
 Vital sign measurements:  temperature, pulse rate, systolic and diastolic blood 
pressure, and respiratory rate (subjects must remain in the same body position quietly 
for 5 minutes prior to having their pulse and blood pressure taken)  
 Weight  
 Concomitant therapy and procedure recording  
 AE and SAE recording  
 Beck Depression Inventory, Second Edition (BDI-II)  
 Immunogenicity assessments  
 Alcohol Use Disorders Identification Test - Consumption Questionnaire (AUDIT-C)  
See Section 4.2 for the timing of assessments.  
13.2. 
Laboratory Safety Assessments 
The following laboratory tests will be performed to assess the safety profile of DAC HYP: 
 Hematology:  hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, red blood cell count, white 
blood cell count (with differential), and platelet count 
 Blood chemistry:  sodium, potassium, chloride, total bilirubin, alkaline phosphatase, 
ALT/SGPT AST/SGOT, lactate dehydrogenase, gamma glutamyl transferase, blood 
urea nitrogen (BUN), creatinine, and bicarbonate 
 Comprehensive hepatic panel (only required for subjects who permanently 
discontinue dosing due to elevated liver function tests as defined in Section 11.7.2).  
Testing will include screening for the following:  
 hepatitis A, B, C, and E  
 other viral infections:  Epstein-Barr virus (EBV), cytomegalovirus (CMV), human 
herpes virus 6 (HHV-6), varicella zoster virus (VZV), herpes simplex virus 
(HSV), and Parvovirus B19 
 gamma-globulins, including IgE and IgG levels 


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 autoantibodies:  antinuclear antibody (ANA), anti-smooth muscle antibody 
(anti-SM), anti-liver/kidney microsome-1 antibody (anti-LKM1), 
antimitochondrial antibody (AMA), and anti-soluble liver antigen (SLA) 
 metabolic disease:  ceruloplasmin  
 toxicology screen:  drugs of abuse  
Additional testing may be performed based on results of the above testing or the 
subject’s clinical history.  Additional hepatic assessments should be performed 
according to local standard of care.   
 Thyroid function panel, including TSH and T4  
 Urinalysis:  protein, blood, glucose, ketones, nitrite, leukocytes, pH, specific gravity 
by dipstick and microscopy  
 Urine pregnancy testing  
Refer to Section 4.2 for the timing of assessments. 
13.3. 
Study-Specific Safety Assessments 
Blood serum collection for binding and neutralizing anti-drug antibody testing will be 
performed.  Note:  When necessary, samples drawn for one purpose (e.g., immunogenicity) may 
be used to meet another protocol-defined objective (e.g., DAC HYP concentration assessment). 
 


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14. 
SCHEDULE OF EVENTS 
14.1. 
Overview 
A written, signed Informed Consent Form (ICF) and all authorizations required by local law 
(e.g., Protected Health Information [PHI] in North America) must be obtained prior to 
performing any tests or assessments under this protocol. 
Test results from the subject’s last visit in Study 205MS301 may be used as baseline data for 
Study 205MS303 if performed within 28 days prior to the first dose in Study 205MS303. 
Clinic visits will occur once every 4 weeks for the first 12 weeks, then every 12 weeks thereafter. 
Monthly LFTs (either at study site or local laboratory) will be performed before each dose 
(results required for dosing).  
On a dosing day, all tests and assessments must be performed prior to DAC HYP administration.  
When DAC HYP administration and MRI evaluation are required at the same visit, the MRI scan 
should be performed prior to DAC HYP administration. 
After Week 12, subjects will have the option of administering DAC HYP at home following 
Investigator review of monthly pre-dose LFT results.  Subjects who are not able to administer 
their own dose or prefer not to administer their own dose of DAC HYP will be given the option 
to choose another individual (caregiver) to administer their treatment at home or to have their 
treatment administered by staff at the study site. 
Follow-up visits will take place at 4, 8, 12, 16, and 24 weeks after each subject’s last dose of 
DAC HYP.  Unscheduled Relapse Assessment Visits (if necessary) should be scheduled within 
72 hours of the onset of any new neurological symptoms that may indicate neurological 
worsening or possible clinical relapse.  Unscheduled Hepatic Assessment Visits (if necessary) 
should be scheduled as soon as possible (but within 1 week) following discontinuation of study 
treatment due to elevated LFTs. 
14.2. 
Site Personnel 
For each subject, the Principal Investigator will designate the following study site personnel: 
 A primary and backup Treating Neurologist 
 A primary and backup Examining Neurologist 
 A primary and backup Treating Nurse (or Study Coordinator) 
 A primary and backup Examining Technician 
 An MRI Technician 
 A Pharmacist (or authorized designee) 
Both the Examining Neurologist and Treating Neurologist must have a minimum of 2 years of 
neurology specialty training and anticipate at least a 3-year commitment to the study, or be 
approved by the study Advisory Committee.  Examining Neurologists and Treating Neurologists 


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in parent Study 205MS301 must remain in the same roles in extension Study 205MS303 until 
completion of Study 205MS301.  When possible subjects should be evaluated by the same 
Examining Neurologist assigned to them in Study 205MS301.    
The primary Treating Neurologist will be responsible for: 
 Management of the routine neurological care of the subject 
 Assessment (including assignment of causality) and treatment of AEs and MS 
relapses 
 Review of selected hematology and all blood chemistry results from the central 
laboratory 
 Assessment of pre-dose LFT results, as detailed in Section 11.7.2  
 Monitoring and follow-up of any abnormal hepatic tests 
 Assessment of injection sites, as detailed in Table 4  
 Referral of subjects to a dermatologist if that subject experiences a cutaneous event as 
described in Section 14.7 
The Treating Neurologist may designate other medical personnel (i.e., the backup Treating 
Neurologist or the Treating Nurse) at the study site to perform some of the tests and evaluations 
that are designated to be performed by the Treating Neurologist.  If there is more than 1 Treating 
Neurologist available at a given site such that each one is assigned to particular subjects, then 
these Treating Neurologists may act as backup for each other.  The same holds true for the 
Treating Nurses and Examining Technicians. 
Hematology and blood chemistry data will be sent to the investigational sites to aid in 
management of the subject.  As with other laboratory and clinical information, this data should 
NOT be reviewed by the Examining Neurologist, the backup Examining Neurologist, the 
Examining Technician, or the backup Examining Technician.   
The primary Treating Nurse or Study Coordinator will be responsible for: 
 Assisting the Treating Neurologist in subject management, including the treatment of 
AEs, the treatment and assessment of disease relapses, and the recording of AEs and 
concomitant medications 
 Monitoring the EDSS scores (as determined by the Examining Neurologist) and 
informing the Treating Neurologist if a subject experiences at least a 1.0-point 
increase on the EDSS from a baseline EDSS ≥1.0 that is sustained for 12 weeks, or at 
least a 1.5-point increase on the EDSS from a baseline EDSS <1.0 that is sustained 
for 12 weeks 
 Administering the Multiple Sclerosis Impact Scale (MSIS-29), patient-reported 
questionnaires (BDI-II, MSIS-29, EQ-5D), HRU, and subject assessment of injection 
pain (VAS) 
 Collection of blood samples and obtaining vital signs 


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 Study treatment administration/dispensation/accountability 
The Examining Neurologist will be responsible for: 
 Obtaining an EDSS score based on a detailed neurological examination at the 
scheduled timepoints required in the protocol, and at every Unscheduled Relapse 
Assessment Visit 
The Examining Neurologist must not be involved with any other aspect of subject care and 
management and must remain blinded to AEs, concomitant medications, laboratory data, MRI 
data, and any other data that have the potential of revealing the previous treatment assignment in 
Study 205MS301.  Further, the Examining Neurologist is not to serve as Treating Neurologist for 
any subjects at a given study site.  To ensure consistency across sites, Examining Neurologists 
must have a current EDSS certification prior to obtaining an EDSS from subjects at their site.  
The backup Examining Neurologist will conduct a detailed neurological examination and obtain 
an EDSS score ONLY if the primary Examining Neurologist is unavailable due to illness, 
vacation, or travel. 
If an Examining Neurologist has to be replaced, the new Examining Neurologist must undergo a 
training session.  The communication of new findings on the neurological examination from the 
Examining Neurologist to the Treating Neurologist is permitted (because findings on the 
neurological examination may be important in the routine care of the subject, e.g., medical 
management of relapses) and will be provided via source documentation. 
The roles of Treating Neurologist and Examining Neurologist (primary and backup) are NOT 
interchangeable during this extension study.  For consistency in EDSS scoring, all sites should 
attempt to maintain the same assessor for each subject throughout the study. 
The Examining Neurologist (or the Examining Technician) will be responsible for: 
 Administering the components of the MSFC at each scheduled timepoint required in the 
protocol   
The Examining Technician must remain blinded to AEs, concomitant medications, laboratory 
data, 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.  It is not necessary for the 
Examining Technician to be a healthcare professional as long as he/she is qualified, in the 
opinion of the Principal Investigator, to administer the MSFC. 
The MRI Technician will be responsible for: 
 Performing a brain MRI scan with and without Gd at all protocol-required timepoints.  
Study-specific MRI scan procedures and protocols, which will be provided prior to 
study start, must be followed. 
The Pharmacist (or authorized designee) will be responsible for: 
 Storage, distribution, and accountability of study treatment. 


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14.3. 
Subject Management 
The following restrictions apply to all subjects enrolled into this study: 
 Subjects must follow the restrictions for concomitant medications and procedures 
described in Section 11.5.  
 Contraception requirements are to be followed as described in Section 15.5.3.  
 Whenever possible, a subject should undergo protocol-required tests and assessments 
at the same time of day throughout the study.  
 Subjects should not donate blood until 4 months after their last dose of DAC HYP.  
 Subjects should not receive live or live-attenuated vaccines during DAC HYP 
treatment or for at least 6 months after treatment with DAC HYP.  
14.4. 
Special Instructions for Tests and Assessments 
Note:  Information about the tests and assessments to be performed in this study is also provided 
in Sections 12 and 13, and in the Study Reference Manual. 
14.4.1. 
Rescreening 
Subjects who are not eligible for participation at baseline due to a temporary condition (e.g., 
acute infection) are allowed to be rescreened once the condition has resolved, provided they are 
rescreened and enrolled within 6 months of completing Study 205MS301. 
14.4.2. 
Pregnancy Testing 
 Pregnancy testing is only required for women of childbearing potential.  A urine 
pregnancy test is to be performed at the Baseline Visits and at other timepoints 
designated in Section 4.2 Schedule of Events.  Study treatment will be immediately 
discontinued if the subject has a positive pregnancy test at any time during the study. 
 Results from all urine pregnancy tests must be reviewed by the study site prior to dosing 
and must be negative.   
14.4.3. 
Monthly Liver Function Test Assessments Prior to DAC HYP Dosing 
Before a monthly dose of DAC HYP is given, LFT results from a test performed within the 
previous 7 days must be reviewed by the Treating Neurologist or their backup, and must be 
within protocol-required limits as described in Section 11.7.2.   
Note:  “Scheduled” clinic visits are those visits that must be performed at the study site.  
Scheduled clinic visits occur every 4 weeks during the first 12 weeks of the study and every 12 
weeks thereafter.   
LFTs can be performed as follows:   
 Samples for LFTs must be drawn within 7 days prior to administration of the monthly 
DAC HYP dose.   These samples may be tested either locally inside or outside of the 
clinic (e.g., at a local laboratory or by visiting nurses) or at the central laboratory at 


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the discretion of the Investigator and the results can then be used to determine 
whether dosing should continue or be suspended at the monthly dosing timepoint (see 
Section 11.1).   
 If the central laboratory is used to test LFTs prior to a scheduled clinic visit, samples 
for any other laboratory assessments required at that upcoming clinic visit may also 
be drawn within the 7 days prior to the visit and do not need to be repeated at that 
scheduled clinic visit.   
 If local LFTs have been used to determine whether dosing should continue or be 
suspended at the time of a scheduled clinic visit, LFTs must also be performed at the 
central laboratory at the time of that scheduled clinic visit.   
 If the subject is administering DAC HYP injections at home, site personnel must 
contact the subject after review of LFT results to authorize the monthly injection, or if 
LFT results warrant, to instruct the subject to withhold their injection.   
 Confirmatory LFTs following a treatment suspension must be performed through the 
central laboratory until the LFT abnormality has resolved.   
14.4.4. 
Other Assessments 
 Vital signs include supine systolic and diastolic blood pressure, pulse, and body 
temperature, and should be measured pre-dose. The subject must rest quietly for 5 
minutes prior to blood pressure and pulse measurements.  Weight will be collected at 
Baseline and at the time of first autoinjector use at selected sites. 
 The MSIS-29 must be administered prior to the subject’s visit with the Treating 
Neurologist.   
 Subject assessment of injection pain using a visual analog scale (VAS) should be 
completed as soon as possible after the injection is administered, but no later than 
60 minutes post-injection.   
 Additional visits to assess elevated LFTs may be required as described in 
Section 11.8.   
 If a subject experiences at least a 1.0-point increase on the EDSS from a baseline 
EDSS ≥1.0 or a 1.5-point increase on the EDSS from a baseline EDSS <1.0 , then the 
EDSS must be repeated within 12 weeks to determine whether protocol-defined 
disability progression has occurred.   
 The first 4 DAC HYP injections of the 3-year extension (i.e., Weeks 0 through 12) 
must be given in the clinic.  The first of these injections must be given by study 
personnel.  At subsequent visits, subjects and/or caregivers will be instructed on DAC 
HYP self-administration and may administer their scheduled dose under staff 
supervision.  After the subject completes the required in-clinic injections (i.e., after 
Week 12), DAC HYP may be dispensed to subjects for at-home administration if the 
subject chooses.  If necessary, drug dispensation may occur at monthly intervals.   


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14.5. 
Definition of MS Relapse and Disability Progression 
14.5.1. 
MS Relapse 
Relapses are defined as new or recurrent neurological symptoms not associated with fever or 
infection, lasting at least 24 hours, and accompanied by new objective neurological findings 
upon examination by the Examining Neurologist* or their backup.  The subject must have 
objective signs on the examination confirming the event.   
* When possible subjects should be evaluated by the same Examining Neurologist assigned to 
them in Study 205MS301 during this open-label study.   
New or recurrent neurologic symptoms that evolve gradually over months should be considered 
disability progression, not an acute relapse.  New or recurrent neurological symptoms that occur 
less than 30 days following the onset of a protocol-defined relapse should be considered part of 
the same relapse.  Management of MS relapse is described in Section 14.6. 
14.5.2. 
Disability Progression 
Disability progression can only be confirmed from the EDSS scores obtained according to the 
protocol-defined schedule of assessments at regular visits, and is defined as one of the following: 
 at least a 1.0-point increase on the EDSS from a baseline EDSS ≥1.0 that is sustained 
for 12 weeks, or  
 at least a 1.5-point increase on the EDSS from a baseline EDSS <1.0 that is sustained 
for 12 weeks  
14.6. 
Management of MS Relapse 
Subjects who experience new or worsening neurological symptoms must contact the Treating 
Nurse or Treating Neurologist or their backup within 48 hours after the onset of symptoms.  A 
standardized Suspected Relapse Questionnaire will be completed to determine the necessity of an 
Unscheduled Relapse Assessment Visit. 
If required, the subject will then be evaluated in person by the Treating Neurologist not more 
than 72 hours after the onset of the symptoms.  At the Unscheduled Relapse Assessment Visit, 
the Examining Neurologist is to perform a relapse assessment and obtain an EDSS score.  New 
objective findings on neurological examination performed by the Examining Neurologist* are 
required to determine if a suspected protocol-defined relapse has occurred. Treatment of an acute 
relapse event with intravenous methylprednisolone (IVMP) may proceed at the discretion of the 
Treating Neurologist after the examination and will not affect the subject’s eligibility to continue 
in the study. 
 * When possible subjects should be evaluated by the same Examining Neurologist assigned to 
them in Study 205MS301 during this open-label study.   
Subjects who experience a relapse will be required to re-consent for continued study 
participation at the next scheduled study visit.  Subjects who prematurely discontinue study 
treatment should complete follow-up evaluations (see Sections 4.2 and 13).   


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Subjects who permanently discontinue DAC HYP treatment should complete the visit schedule 
described in Section 11.8.   
14.7. 
Cutaneous Events 
Subjects who experience a clinically significant cutaneous event (e.g., rash, dermatitis, eczema, 
acne, folliculitis) should be referred to and evaluated by a local dermatologist.  The 
dermatologist is to document the cutaneous event, take photographs, and if appropriate, obtain a 
biopsy prior to prescribing treatment.  Systemic corticosteroids may be administered if medically 
indicated.   
Subjects presenting with a diffuse cutaneous eruption/rash are to be evaluated and managed as 
described in Section 22.   
If a generalized allergic or hypersensitivity reaction to study treatment is suspected, study 
treatment must be permanently discontinued as per Section 11.8.   
All photographs and biopsy slides will be sent to a central dermatology consultant for further 
evaluation (see Section 22 and the Study Reference Manual).  The incidence and nature of 
cutaneous events will be monitored by the SMC (see Section 19.2.2). 
14.8. 
Unscheduled Hepatic Assessment Visit 
The following tests/assessments will be performed as soon as possible (but within 1 week) after 
discontinuation of study treatment for subjects who are required to discontinue dosing due to 
elevated LFTs as described in Section 11.8, unless a definite cause of the LFT abnormality 
leading to treatment discontinuation has already been established through other testing. 
 Vital signs  
 Comprehensive hepatic panel 
 Recording of concomitant therapy 
 Monitor and record AE/SAEs 
 Protocol compliance 
14.9. 
Post-Treatment Safety Follow-Up Visit Schedule for All Subjects  
All subjects should complete the following schedule of safety follow-up visits after their last 
dose of DAC HYP: 
 End of Treatment Visit (i.e., the assessments required at Week 144).  For subjects 
who prematurely discontinue study treatment before Week 144, these assessments 
should be performed 4 weeks (±4 days) after the subject’s last dose of DAC HYP.    
 Post-treatment safety follow-up visits at 8, 12, 16, and 24 weeks after the subject’s 
last dose.  The details of these visits are shown in Table 3. 


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15. 
SAFETY DEFINITIONS, MONITORING, AND REPORTING 
Throughout the course of the study, every effort must be made to remain alert to possible AEs.  
If an AE occurs, the first concern should be for the safety of the subject.  If necessary, 
appropriate medical intervention should be provided. 
At the signing of the ICF, each subject must be given the names and telephone numbers of study 
site staff for reporting AEs and medical emergencies. 
15.1. 
Definitions 
15.1.1. 
Serious Pretreatment Event 
A serious pretreatment event is any event that meets the criteria for serious adverse event (SAE) 
reporting (as defined in Section 15.1.3) and occurs after the subject signs the ICF, but before 
administration of study treatment. 
15.1.2. 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
15.1.3. 
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, or 
 results in a congenital anomaly/birth defect. 
An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or convulsions occurring at home that do not 
require an inpatient hospitalization. 


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15.2. 
Monitoring and Recording Events 
15.2.1. 
Serious Pretreatment Events 
A serious pretreatment event experienced by the subject after signing and dating the ICF, but 
before administration of study treatment is to be recorded on the SAE Form and faxed to the 
contract research organization (CRO), 
 within 
24 hours of the study site staff becoming aware of the event (see Section 15.2.5).  
15.2.2. 
Adverse Events 
Any AE experienced by the subject between the time of signing the ICF and subject’s final visit 
is to be recorded on the CRF, regardless of the severity of the event or its relationship to study 
treatment. 
15.2.3. 
Serious Adverse Events 
Any SAE experienced by the subject between the time of the first dose of study treatment and 
subject’s final 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 the Sponsor (or designee). 
Any SAE ongoing when the subject completes the study or discontinues from the study will be 
followed by the Investigator until the event has resolved, stabilized, or returned to baseline 
status. 
Subjects will be followed for all SAEs until the subject’s final visit.  Thereafter, the event should 
only be recorded if the Investigator considers it related to study treatment. 
15.2.4. 
All Events 
All events must be assessed to determine the following: 
 If the event meets the criteria for an SAE as defined in Section 15.1.3. 
 The relationship of the event to study treatment as defined in Section 15.3.1. 
 The severity of the event as defined in Section 15.3.2. 
15.2.5. 
Immediate Reporting of Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify 
 within 24 hours of the study site staff becoming aware of the SAE.  It is the 
Investigator’s responsibility to ensure that the SAE reporting information and procedures are 
used and followed appropriately. 
 
 


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Reporting Information for SAEs 
Any Serious Event that occurs between the time the subject has signed informed consent and 
subject’s final visit must be reported to Biogen Idec SABR or 
 within 24 hours of the study 
site staff becoming aware of the event.  Thereafter, the event should only be recorded if the 
Investigator considers it related to study treatment. 
A report must be submitted to 
 regardless of the following: 
 whether or not the subject has undergone study-related procedures 
 whether or not subject has received study treatment 
 the severity of the event 
 the relationship of the event to study treatment 
To report initial or follow-up information on a Serious Event, fax a completed SAE form to the 
following:   
North America:  
 
Latin America:  
 
Europe and Asia Pacific:  
 
 
(Country-specific fax numbers are provided in the Study Reference Guide.) 
15.2.5.1. Deaths 
Death is an outcome of an event.  The event that resulted in death should be recorded and 
reported on the appropriate CRF.  All causes of death must be reported as SAEs.  The 
Investigator should make every effort to obtain and send death certificates and autopsy reports to 
Biogen Idec SABR or designee. 
15.3. 
Safety Classifications 
15.3.1. 
Relationship of Events to Study Treatment 
The following definitions should be considered when evaluating the relationship of AEs and 
SAEs to the study treatment: 


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Relationship of Event to Study Treatment 
Not related 
An adverse event will be considered “not related” to the use of the investigational drug if 
there is not a possibility that the event has been caused by the product under 
investigation.  Factors pointing toward this assessment include, but are not limited to:  the 
lack of reasonable temporal relationship between administration of the drug and the 
event, the presence of a biologically implausible relationship between the product and the 
adverse event (e.g., the event occurred before administration of drug), or the presence of a 
more likely alternative explanation for the adverse event. 
Related 
An adverse event will be considered “related” to the use of the investigational drug if 
there is a possibility that the event may have been caused by the product under 
investigation.  Factors that point toward this assessment include, but are not limited to:  a 
positive rechallenge, a reasonable temporal sequence between administration of the drug 
and the event, a known response pattern of the suspected drug, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between the drug 
and the adverse event, or a lack of an alternative explanation for the adverse event. 
15.3.2. 
Severity of Events 
The following definitions should be considered when evaluating the severity of AEs and SAEs: 
Severity of Event 
Mild 
Symptom(s) barely noticeable to subject or does not make subject uncomfortable; does 
not influence performance or functioning; prescription drug not ordinarily needed for 
relief of symptom(s) but may be given because of personality of subject. 
Moderate 
Symptom(s) of a sufficient severity to make subject uncomfortable; performance of daily 
activity is influenced; subject is able to continue in study; treatment for symptom(s) may 
be needed. 
Severe 
Symptom(s) cause severe discomfort; symptoms cause incapacitation or significant 
impact on subject’s daily life; severity may cause cessation of treatment with study 
treatment; treatment for symptom(s) may be given and/or subject hospitalized. 
15.3.3. 
Expectedness of Events 
Expectedness of all AEs will be determined according to the Investigator’s Brochure.   
15.4. 
Prescheduled or Elective Procedures or Routinely Scheduled 
Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized; the study site must document all of the following: 
 The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining the subject’s 
consent to participate in the study. 
 The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 


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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. 
15.5. 
Procedures for Handling Special Situations 
15.5.1. 
Overdose 
An overdose is any dose of study treatment given to a subject or taken by a subject that exceeds 
the dose described in the protocol.  Overdoses are not considered AEs; however, all overdoses 
should be recorded on an Overdose Form and faxed to 
 within 24 hours.  An overdose 
should be reported even if it does not result in an AE.  Overdoses do not need to be recorded in 
the CRF; dosing information is recorded on a CRF. 
15.5.2. 
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 
Medical Monitor at one of the following phone numbers: 
North America (USA and Canada):  
 
Latin America: 
 
Europe and Asia Pacific: 
 
15.5.3. 
Contraception Requirements 
All women of childbearing potential must practice effective contraception during the study and 
be willing and able to continue contraception for 4 months after their last dose of study 
treatment. 
For the purposes of this study, women of childbearing potential are defined as all women 
physiologically capable of becoming pregnant, UNLESS they meet one of the following 
conditions: 
 Postmenopausal:  12 months of natural (spontaneous) amenorrhea or 6 weeks after 
surgical bilateral oophorectomy with or without hysterectomy 
 Posthysterectomy 
For the purposes of the study, effective contraception is defined as follows: 
For females: 
 Using 1 or more of the following acceptable methods of contraception:  surgical 
sterilization (e.g., bilateral tubal ligation), intrauterine contraception/device, hormonal 
contraception, or any 2 barrier methods (a combination of male or female condom with 
spermicide; diaphragm, sponge, cervical cap) 
 Abstinence can be considered an acceptable method of contraception at the discretion of 
the Investigator.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, 


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post-ovulation methods) and withdrawal are not considered acceptable methods of 
contraception. 
15.5.4. 
Pregnancy 
Subjects should not become pregnant during the study.  If a female subject becomes 
pregnant, study treatment must be discontinued immediately. 
The Investigator must report the pregnancy by faxing the appropriate form to 
 
Pharmacovigilance within 24 hours of the study site staff becoming aware of the pregnancy 
(refer to Section 15.2.5 for reporting information).  The Investigator or study site staff must 
report the outcome of the pregnancy to 
 Pharmacovigilance. 
Please note that congenital abnormalities/birth defects in the offspring of male or female subjects 
should be reported when conception occurred during the study treatment period. 
15.5.5. 
Regulatory Reporting 
Suspected Unexpected Serious Adverse Reactions (SUSARs) are SAEs that are unexpected and 
judged by the Investigator or the Sponsor to be related to the study treatment administered. 
Biogen Idec Safety and Benefit-Risk Management (SABR) will report SUSARs to the 
appropriate regulatory authorities and Investigators as required, according to local law. 
15.6. 
Investigator Responsibilities 
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 of the pregnancy. 
 Complete an SAE form for each serious event and fax it to 
 within 24 hours of 
the study site staff becoming aware of the event. 
 Pursue SAE follow-up information actively and persistently.  Follow-up information 
must be reported to 
 within 24 hours of the study site staff becoming aware of 
new information. 
 Ensure all AE and SAE reports are supported by documentation in the subjects’ 
medical records. 
 Report SAEs to local ethics committees, as required by local law. 


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15.7. 
Biogen Idec Responsibilities 
Biogen Idec’s responsibilities include the following: 
 Before study site activation and subject enrollment, the Clinical Monitor or designee 
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 Idec is to notify all appropriate regulatory authorities, central ethics 
committees, and Investigators of SAEs, as required by local law, within required time 
frames. 


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16. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
16.1. 
Description of Objectives 
See Section 6.1, Objectives. 
16.2. 
Description of Endpoints 
See Section 6.2, Endpoints. 
16.3. 
Demography and Baseline Disease Characteristics 
Demographic data collected at baseline will be summarized (i.e., age, gender, ethnicity, and 
weight).  Medical history and baseline characteristic data (e.g., EDSS, number of relapses in the 
previous study, MRI endpoints) will also be summarized. 
16.4. 
Safety and Efficacy 
16.4.1. 
Analysis Population 
Safety Population 
The safety population will include all subjects who received at least 1 dose of DAC HYP in 
Study 205MS303.  All safety analyses will be completed on the safety population. 
Intent-to-Treat Population 
The intent-to-treat (ITT) population will include all subjects who received at least 1 dose of DAC 
HYP in Study 205MS303.  This population will be utilized for the efficacy analyses.   
16.4.2. 
General Methods of Analysis 
Summary statistics will be presented.  For continuous endpoints, summary statistics will 
generally include the number of subjects with data, mean, standard deviation, median, and range.  
Categorical endpoints will include the number of subjects with data and the percentage in each 
category. 
The data will be summarized by previous treatment group (Avonex or DAC HYP 150 mg during 
Study 205MS301).  The analysis will focus on Study 205MS303 data although selected analyses 
will present data after combining data from Studies 205MS301 and 205MS303. 
 Analyses will generally be descriptive in nature.  However, for relevant efficacy analyses, 
statistical comparisons may be made between efficacy in Study 205MS301 and efficacy in 
Study 205MS303 among subjects previously randomized to Avonex in Study 205MS301. 
Covariates included for inclusion in the statistical models for efficacy analyses for 
Study 205MS303 will generally be the same as those used for corresponding models in 
Study 205MS301. 


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All statistical tests will be 2-sided with an overall Type I error of 5%.  Adjustments for multiple 
comparisons will not be considered. 
16.4.3. 
Primary Endpoints Analysis 
Clinical Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities. All treatment-
emergent events will be included in the evaluation of safety.  Treatment emergent includes any 
event that either occurs or worsens in severity after the onset of study treatment.  The incidence 
of treatment-emergent events will be summarized by treatment group (prior Avonex, prior 
DAC HYP 150 mg), overall, by severity, and by relationship to study treatment.  The summary 
tables will include incidence estimates for the overall system organ class as well as for preferred 
terms within each system organ class.  In order to assess whether the incidence of events changes 
over time, the incidence of key events may also be summarized by time period (e.g., 6-month 
time intervals).   
16.4.4. 
Other Safety Endpoint Analyses 
Laboratory Data 
Changes in laboratory values will be summarized using shift tables.  Shift tables will include 
hematology, liver function tests, kidney function tests, electrolytes, and other blood chemistry 
tests.  Shifts will be presented from baseline of DAC treatment (Study 205MS303 baseline for 
subjects randomized to Avonex in Study 205MS301 and Study 205MS301 baseline for subjects 
randomized to DAC HYP 150 mg in Study 205MS301).  Summaries of worst post-baseline 
laboratory values by clinically relevant categories may also be presented for selected parameters 
of interest by treatment group.  For example, for LFT (alkaline phosphatase, ALT, AST, GGT 
and total bilirubin), categories may be defined based on cutoff values relative to the ULN. 
Vital Signs 
Vital signs collected will be examined to determine the incidence of clinically relevant 
abnormalities.  These abnormalities are described in Table 5.  For the purpose of the shifts from 
baseline, the baseline evaluation at the start of DAC HYP treatment will be used. 
For each vital sign, the number of subjects evaluated and the number and percentage of subjects 
with the defined abnormality at any time post dosing will be presented by treatment group.   
Table 5:   
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs 
Vital Sign 
Criteria for Abnormalities 
Temperature  
>38°C or an increase from baseline of ≥1°C 
Pulse 
>120 beats per minute (bpm) or an increase from baseline of 
20 bpm 
<50 bpm or a decrease from baseline of >20 bpm 
Systolic Blood Pressure 
>180 mmHg or an increase from baseline of >40 mmHg 
<90 mmHg or a decrease from baseline of >30 mmHg 
Diastolic Blood Pressure 
>105 mmHg or an increase from baseline of >30 mmHg 
<50 mmHg or a decrease from baseline of >20 mmHg 


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Physical Examination 
The physical examination findings will be summarized by treatment group. 
16.4.5. 
Efficacy Endpoints Analyses 
Annualized Relapse Rate 
Relapses will be summarized by prior treatment group over the 3 years of follow-up in 
Study 205MS303 as well as over the 5-6 years of the combined study period (Studies 205MS301 
and 205MS303).   
A negative binomial regression model will be used to estimate the adjusted ARR.   
Proportion of Subjects with a Relapse 
The proportion of subjects relapsed will be estimated using a Kaplan-Meier curve.   
Disability Progression   
Sustained disability progression is defined as at least a 1.0 point increase on the EDSS from 
baseline EDSS 1.0 that is sustained for 12 weeks, or at least a 1.5 point increase on the EDSS 
from baseline EDSS <1.0 that is sustained for 12 weeks.  Progression will be assessed relative to 
the baseline EDSS in Study 205MS303 as well as to baseline scores in the previous study.  The 
proportion of subjects with progression will be summarized using a Kaplan-Meier curve.  
Progression will be summarized by previous treatment group during the combined study period 
(Studies 205MS301 and 205MS303) as well as in each study separately.  In addition, summary 
statistics for EDSS and for the change from baseline in EDSS will be presented by visit by 
previous treatment group.   
MSFC 
Changes in the MSFC z-score will be summarized by treatment group and study visit.  Details on 
the calculations of the z-score for each component will be described in the statistical analysis 
plan. 
MRI Endpoints 
MRI endpoints will be summarized with descriptive statistics overall and over time by treatment 
group, both as a continuous variable and categorically.  A negative binomial regression model 
will be used for the analysis of new or newly enlarging T2 lesions.  The change in volume of 
lesions and percent change of brain atrophy will be analyzed using an analysis of covariance.   
Quality of Life Outcomes 
Actual scores and change from baseline in quality of life endpoints will be summarized by visit.  
Pharmacodynamics and Pharmacokinetics 
The population for DAC HYP concentration and PD analyses will include all subjects who 
received at least 1 dose of study medication and who have at least 1 sample available for 
analysis.  


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Pharmacokinetics 
Serum concentration levels will be summarized with descriptive statistics by treatment group and 
visit.  PK data from this study will be used in combination with PK data from other DAC HYP 
trials for population PK analysis.  Details on the analysis will be described in a separate 
population PK-PD analysis plan. 
Pharmacodynamics 
Summary statistics for PD variables will be summarized by treatment group and study visit. 
Antigenicity/Immunogenicity Data 
Immunogenicity (i.e., anti-DAC antibodies) will be assessed on all subjects.  Positive samples 
will be further tested for neutralizing anti-DAC antibodies using a specific neutralizing antibody 
(NAb) assay.  Results will be tabulated by time period, treatment group, and overall. 
16.5. 
Interim Analyses 
No formal interim analyses are planned for this study.  However, analyses may be performed 
prior to the end of the study at the discretion of the Sponsor.  
16.6. 
Sample Size Considerations 
There is no formal sample size calculation.  The number of subjects in this study is determined 
by the number of subjects who participate in Study 205MS301. 
 


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17. 
ETHICAL REQUIREMENTS 
Biogen Idec and the Investigator must comply with all instructions, regulations, and agreements 
in this protocol and applicable International Conference on Harmonisation (ICH) and Good 
Clinical Practice (GCP) guidelines and conduct the study according to local regulations. 
17.1. 
Declaration of Helsinki 
The Investigator and Biogen Idec must adhere to the principles set forth by the Declaration of 
Helsinki dated October 2008. 
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. The Sponsor may submit documents on behalf of the 
study sites in countries other than the US as applicable.  
If the Investigator makes any changes to the ICF, Biogen Idec must approve the changes before 
the ICF is submitted to the ethics committee.  A copy of the approved ICF must be provided to 
Biogen Idec.  After approval, the ICF must not be altered without the agreement of the relevant 
ethics committee and Biogen Idec. 
It is the responsibility of the Principal Investigator(s) to ensure that all aspects of institutional 
review are conducted in accordance with current governmental regulations. 
Biogen Idec 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 study site must submit a close-out letter to the 
ethics committee and Biogen Idec. 
17.3. 
Subject Information and Consent 
Prior to performing any study-related activities under this protocol, including baseline tests and 
assessments, written informed consent with the approved ICF must be obtained from the subject 
or subject’s legally authorized representative, as applicable, in accordance with local practice and 
regulations.  Written informed consent must be obtained from all subjects participating in a 
clinical study conducted by Biogen Idec. 
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.  The subject 
must be given sufficient time to consider whether to participate in the study. 
A copy of the ICF, signed and dated by the subject, must be given to the subject.  Confirmation 
of a subject’s informed consent must also be documented in the subject’s medical record prior to 
any testing under this protocol, including baseline tests and assessments. 


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Each consent form should contain an authorization allowing the Principal Investigator(s) and 
Biogen Idec to use and disclose PHI (i.e., subject-identifiable health information) in compliance 
with local law. 
The signed consent form will be retained with the study records. 
17.4. 
Subject Data Protection 
Prior to any testing under this protocol, including baseline tests and assessments, candidates must 
also provide all authorizations required by local law (e.g., PHI authorization in North America). 
The subject will not be identified by name in the CRF or in any study reports and these reports 
will be used for research purposes only.  Biogen Idec, its partner(s) and designee(s), ethics 
committees, and various government health agencies may inspect the records of this study.  
Every effort will be made to keep the subject’s personal medical data confidential. 
17.5. 
Compensation for Injury 
Biogen Idec maintains appropriate insurance coverage for clinical trials 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 the 
Sponsor) 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 Idec will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations. 


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18. 
ADMINISTRATIVE PROCEDURES 
18.1. 
Study Site Initiation 
The Investigator must not enroll any subjects prior to completion of a study initiation visit, 
conducted by Biogen Idec 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 Idec or 
the regulatory authorities may wish to perform on-site audits.  The Investigator will be expected 
to cooperate with any audit and to provide assistance and documentation (including source data) 
as requested. 
18.3. 
Monitoring of the Study 
The Principal Investigator(s) must permit study-related monitoring by providing direct access to 
source data and to the subjects’ medical histories. 
The Clinical Monitor(s) will visit the Investigator(s) at regular intervals during the course of 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.   
The 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 study site and its facilities. 
18.4. 
Study Funding 
Biogen Idec is the Sponsor of the study and is funding the study.  All financial details are 
provided in the separate contract(s) between the institution, Investigator, and Biogen Idec. 
18.5. 
Publications 
Details are included in the clinical trial agreement for this study. 
 


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19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION 
Biogen Idec will be responsible for all administrative aspects of this study including, but not 
limited to, study initiation, monitoring, management of AEs, and data management. 
19.1. 
External Contract Organizations 
19.1.1. 
Contract Research Organization  
 will be responsible for administrative aspects of the study including, but not limited to, 
study initiation, monitoring, and management of SAE reports. Before subjects are screened at 
each study site, 
 will review study responsibilities with the Investigators and other study site 
staff, as appropriate. 
19.1.2. 
Electronic or Remote Data Capture 
Subject information will be captured and managed by study sites on electronic CRFs via a 
remote data capture (RDC) developed and supported by 
 and 
configured by Biogen Idec. 
19.1.3. 
Central Laboratories for Laboratory Assessments 
 has been selected by Biogen Idec to analyze all hematology, blood 
chemistry, and urine samples collected for this study. 
LFTs may be assessed locally for dosing decisions.  LFTs performed locally must be repeated 
through the central laboratory at the scheduled monthly visit. 
19.1.4. 
Central Facility for Other Assessments 
MRI Reading Center 
All scheduled MRI scans with and without Gd will be evaluated at a central MRI reading center.  
All study sites will be required to send a test scan 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 study site is permitted to enroll any subjects into the study. 
Original MRI images are to be sent to the MRI Reading Center for review (MRI shipping 
instructions will be provided prior to the start of enrollment at each site).   
Additional and more detailed MRI scans with and without Gd procedures and instructions are 
included in the study MRI manual (to be provided under separate cover prior to start of the 
study). 
 


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19.2. 
Study Committees 
19.2.1. 
Advisory Committee 
The Advisory Committee from parent Study 205MS301 will oversee the administrative progress 
and provide scientific and medical direction for this study while Study 205MS301 is ongoing. 
Advisory Committee will monitor subject accrual and compliance with the protocol at individual 
study sites.  The Advisory Committee will determine whether the study should be stopped or 
amended for reasons other than safety. 
Members of the Advisory Committee will include the Medical Director, Clinical Trial Manager, 
and Project Statistician from Biogen Idec (and/or their designees), and participating 
Investigators.  Biogen Idec will designate one of the participating Investigators to be the 
Chairperson of the Advisory Committee. 
19.2.2. 
Safety Monitoring Committee 
A SMC will be formed to review interim safety data. Safety data will be provided to the SMC for 
review of all AEs and key laboratory tests for all subjects prior to completion of 
Study 205MS301. 
The Advisory Committee for Study 205MS301 (DECIDE) will also provide scientific and 
medical direction for Study 205MS303. 
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 Idec 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 subject consent form may require similar 
modifications (see Sections 17.2 and 17.3). 
19.4. 
Ethics Committee Notification of Study Completion or Termination 
Where required, the Health Authorities and ethics committees must be notified of completion or 
termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines. 
19.5. 
Retention of Study Data 
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local laws or regulations.  Prior to 
proceeding with destruction of records, the Investigator must notify Biogen Idec in writing and 


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receive written authorization from Biogen Idec to destroy study records.  In addition, the 
Investigator must notify Biogen Idec of any changes in the archival arrangements including, but 
not limited to, archival at an off-site facility or transfer of ownership if the Investigator leaves the 
site. 
19.6. 
Study Report Signatory 
Biogen Idec 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 Idec. 
Biogen Idec will follow all applicable local regulations pertaining to study report signatories.  
 


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20. 
REFERENCES 
 
Bielekova B, Richert N, Howard T, et al. Humanized anti-CD25 (daclizumab) inhibits disease 
activity in multiple sclerosis patients failing to respond to interferon beta. Proc Natl Acad Sci U 
S A. 2004;101(23):8705-8. 
 
Bielekova B, Howard T, Packer AN, et al. Effect of anti-CD25 antibody daclizumab in the 
inhibition of inflammation and stabilization of disease progression in multiple sclerosis. Arch 
Neurol. 2009;66(4):483-9. 
 
Fischer JS, LaRocca NG, Miller DM, et al. Recent developments in the assessment of quality of 
life in multiple sclerosis (MS). Mult Scler. 1999;5(4):251-9. 
 
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status 
scale (EDSS). Neurology. 1983;33(11):1444-52. 
 
Rose JW. Treatment of Multiple Sclerosis with a Humanized Monoclonal Antibody Specific for 
IL-2 Receptor Chain. Neurology. 2003;60(Suppl 1):A478-9. 
 
Rose JW, Watt HE, White AT, et al. Treatment of multiple sclerosis with an anti-interleukin-2 
receptor monoclonal antibody. Ann Neurol. 2004;56(6):864-7. 
 
Wynn D, Kaufman M, Montalban X, et al. Daclizumab in active relapsing multiple sclerosis 
(CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with 
interferon beta. Lancet Neurol. 2010;9(4):381-90. 
 
 
 
 


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21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL 
I have read the foregoing protocol, “A Multicenter, Open-Label, Extension Study to Evaluate the 
Long term Safety and Efficacy of BIIB019, Daclizumab High Yield Process (DAC HYP), 
Monotherapy in Subjects With Multiple Sclerosis Who Have Completed Study 205MS301” 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) 


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22. 
APPENDIX 1: GUIDELINES FOR MANAGEMENT OF 
CUTANEOUS EVENTS FOR SUBJECTS PARTICIPATING IN 
BIOGEN IDEC CLINICAL STUDIES OF DAC HYP 
The following guidelines apply to subjects receiving open-label treatment with DAC HYP, or 
subjects potentially receiving DAC HYP treatment in blinded studies.   
22.1. 
Background  
Serious adverse events (SAEs) involving cutaneous reactions have been reported in subjects 
participating in ongoing, blinded MS studies with DAC HYP.  All of these events have been 
reviewed by the 205MS201 (SELECT) study’s central dermatologist; some of the events have 
been characterized as progressive skin eruptions consistent with systemic drug hypersensitivity 
reactions.  Although it is not known whether DAC HYP is the causative agent of these reactions, 
the following guidelines have been developed for prompt recognition and treatment of these 
events for subjects who may be participating in DAC HYP clinical studies.   
Cases presenting as diffuse maculopapular eruptions are considered to be at risk for worsening 
in severity.  Although such eruptions may be of varying severity at presentation, some have 
become more generalized over a period of weeks to involve >75% of the body surface area and 
resulted in hospitalization for treatment.   
Subjects who have presented with localized or highly circumscribed rashes have typically had 
a favorable course even with continuation of study treatment, but dermatologists and 
investigators are cautioned that all clinically significant cutaneous events in subjects in 
DAC HYP clinical studies should be followed closely until resolution.    
The relationship between the cutaneous reactions and the duration of study treatment dosing is 
not established.  The onset of the cutaneous eruptions has not been temporally associated with 
the administration of the SC injection.  
In cases of diffuse or severe skin reactions, response to administration of high-dose 
systemic corticosteroids has generally been favorable, and it is currently believed that this 
treatment may be able to promote recovery and limit the severity of these events.  Unless 
contraindicated, strong consideration should be given to the use of high-dose systemic 
glucocorticosteroids (oral or parenteral) for the treatment of widespread, diffuse, maculopapular 
rashes.   
For additional information on the occurrence of cutaneous events in DAC HYP clinical studies, 
please refer to the Investigator’s Brochure. 
22.2. 
General Management of Cutaneous Events 
Any subject participating in a DAC HYP clinical study who develops a clinically significant 
cutaneous event (e.g., rash, dermatitis, eczema, acne, folliculitis) should be evaluated by a 
dermatologist.   
The dermatologist is to document the event, take photographs, and if appropriate, obtain a biopsy 
prior to prescribing treatment.   


Protocol 205MS303 
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Long-Term Extension Study to Evaluate the Safety and Efficacy of DAC HYP 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen Idec Inc. 
76 
Additional diagnostic procedures and careful evaluation for systemic conditions such as 
infections should be considered as appropriate.   
Systemic corticosteroids may be administered if medically indicated (see below).   
When the cutaneous event is localized or highly circumscribed, it should be managed according 
to local practices per the dermatologist.  The decision to discontinue study treatment, either 
temporarily, during the period of evaluation and treatment of the skin event, or permanently 
should be made by the Principal Investigator in consultation with the dermatologist.  If an 
allergic or hypersensitivity reaction to study treatment is suspected, study treatment must be 
permanently discontinued. 
Subjects presenting with a diffuse cutaneous eruption/rash are to be evaluated and 
managed as described in Section 22.3.   
22.3. 
Evaluation and Management of Diffuse Cutaneous Eruptions/Rash 
22.3.1. 
Evaluation of Diffuse Cutaneous Eruptions/Rash 
Any subject who: 
 is currently receiving study treatment (either open label DAC HYP or blinded study 
treatment), or 
 received a dose of study treatment within the last 6 months  
and develops a cutaneous eruption in a diffusely distributed pattern consistent with a 
possible drug-hypersensitivity reaction (refer to photographs in Section 22.4) should be 
evaluated by a dermatologist as soon as possible within 72 hours following event onset.  The 
dermatologist should: 
 assess the cutaneous event 
 photograph the affected body areas 
 perform a skin biopsy (if applicable) 
 take a detailed medication history 
 determine if there is a contraindication to treatment with corticosteroids  
Careful evaluation for systemic conditions such as infections should be considered.   
The Adverse Event of Special Interest form should be submitted to the Sponsor as soon as 
possible within 72 hours following the dermatology evaluation.  Photographs of the cutaneous 
eruption should be included whenever possible.  The report should also include the intended 
treatment plan.  If systemic corticosteroids are not administered as described below, the rationale 
should be provided.  If results of the skin biopsy are pending, they can be submitted as a 
follow-up (submission of the initial report to the Sponsor should not be delayed).   
Note:  If the event qualifies as an SAE, an SAE report form should be submitted within 24 hours 
of the staff becoming aware of the event as per the reporting requirements described in the 
protocol. 


Protocol 205MS303 
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Long-Term Extension Study to Evaluate the Safety and Efficacy of DAC HYP 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen Idec Inc. 
77 
Close follow-up (initially within 7 days of evaluation by the dermatologist) should be 
maintained for all cutaneous events that are not well localized or do not have an otherwise 
proven etiology and should continue at appropriate intervals until resolution or 
stabilization.   
22.3.2. 
Management of Diffuse Cutaneous Eruption/Rash 
For subjects with a diffuse or severe skin reaction, DAC HYP must be withheld until 
resolution.  The subject should also withhold all other non-essential medications, including 
protocol-required medications, and non-prescription drugs and supplements, at least until the 
cutaneous event has resolved.  The decision to permanently discontinue study treatment should 
be made by the Principal Investigator in consultation with the site dermatologist.  If an allergic 
or hypersensitivity reaction to study treatment is suspected, study treatment must be 
permanently discontinued.   
If the diffuse rash has any of the following characteristics:  
 is highly inflammatory at presentation  
 worsens to increasing body surface area, or to mucosal involvement, or to more 
numerous inflammatory lesions over a period of days to weeks  
 persists for more than a week without improvement 
and if there is no contraindication to the use of high-dose systemic corticosteroids, it is 
recommended that the subject receives treatment with a high dose of oral or parenteral 
corticosteroids (e.g., an equivalent of oral prednisone 60 mg/day or IV methylprednisolone 
1 g/day) for a period of approximately 5 days.  
It is recommended that systemic corticosteroid therapy be instituted as early in the course of the 
reaction as possible [Ann Allergy Asthma Immunol. 1999 Dec;83(6 Pt 3):665-700.].  
 If the cutaneous event has stabilized or improved after the initial treatment, then it is 
recommended that the subject tapers the corticosteroids gradually over the next 2 to 
3 weeks by reducing the daily dose of oral prednisone per standard medical practice.   
 If the cutaneous event worsens during the corticosteroid taper, retreatment with high-dose 
corticosteroids and a more gradual taper should be considered.  
 If the cutaneous event does not improve with corticosteroid treatment, additional 
treatments should be considered under the guidance of the dermatologist.  Additional 
consultation with the Sponsor should be arranged through the local medical monitor for 
the clinical study.  
If a contraindication to corticosteroids exists, the cutaneous event should be managed 
according to the local dermatologist.  Additional consultation with the central study 
dermatologist may be arranged through the Sponsor. 
Note:  A schematic of the evaluation and management process for subjects presenting with a 
diffuse cutaneous eruption is presented in Section 22.5. 
 


Protocol 205MS303 
Version 1 
Long-Term Extension Study to Evaluate the Safety and Efficacy of DAC HYP 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen Idec Inc. 
78 
22.4. 
Examples of Diffuse Maculopapular Eruptions/Rash in DAC HYP 
Clinical Studies 
Following are examples of the diffuse maculopapular eruptions (with and without urtication) that 
have occurred in subjects who experienced serious systemic drug hypersensitivity-like reactions 
in clinical studies of DAC HYP.   
These maculopapular eruptions were diffuse at presentation, or shortly after presentation, with 
involvement of face, trunk, and extremities. 
Treatment guidelines are as described in Section 22.3. 
 
 
 


Protocol 205MS303 
Version 1 
Long-Term Extension Study to Evaluate the Safety and Efficacy of DAC HYP 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen Idec Inc. 
79 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 205MS303 
Version 1 
Long-Term Extension Study to Evaluate the Safety and Efficacy of DAC HYP 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen Idec Inc. 
80 
22.5. 
Treatment Algorithm for Subjects Presenting with Diffuse 
Cutaneous Eruption/Rash 
 
A schematic for evaluation and treatment of subjects presenting with a diffuse cutaneous 
eruption/rash is presented on the next page. 
 
 



SAP_001.pdf: 


     Pr ot o c ol 2 0 5 M S 3 0 3  
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1  
2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  


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S T A TI S TI C A L A N A L Y SI S P L A N  
Pr o d u ct St u di e d: D a cli z u m a b H Y P  
Pr ot o c ol N u m b er : 2 0 5 M S 3 0 3  
A M ulti c e nt er, O p e n -L a b el, E xt e n si o n St u d y t o E v al u at e t h e L o n g -T er m S af et y a n d Effi c a c y of 
BII B 0 1 9, D a cli z u m a b Hi g h Yi el d Pr o c e s s ( D A C H Y P),  M o n ot h er a p y i n S u bj e ct s W it h M ulti pl e 
S cl er o si s  ( M S) W h o H a v e C o m pl et e d St u d y 2 0 5 M S 3 0 1  
D at e of Pr ot o c ol:  2 9  S e pt e m b er  2 0 1 7  ( V er si o n 5 ) 
D a t e of St ati sti c al A n al y si s Pl a n v 1. 0 :  0 8  M a y  2 0 1 8  
A ut h or e d B y:  
, S M T st ati sti ci a n  
D at e  
 
A p pr o v e d B y:  
, C D T st ati sti ci a n 
D at e  
 
, St u d y M e di c al D ir e ct or 
D at e  
 


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T A B L E O F C O N T E N T S  
1.
D E S C RI P TI O N O F S T U D Y  O B J E C TI V E S A N D E N D P OI N T S  ............................................ 7  
1. 1.  
Pri m ar y O bj e cti v e a n d E n d p oi nt s  .................................................................................... 7  
1. 2.  
S e c o n d ar y O bj e cti v e a n d E n d p oi nt s  ............................................................................... 7  
2.
S T U D Y D E SI G N  ................................................................................................................. 8  
3.
S C H E D U L E O F E V E N T S  ..................................................................................................1 0  
4.
I N T E RI M A N A L Y SI S ..........................................................................................................2 3  
5.
S T A TI S TI C A L M E T H O D S:  G E N E R A L C O N SI D E R A TI O N S  ..............................................2 3  
5. 1.  
A n al y si s P o p ul ati o n s  .....................................................................................................2 3  
5. 1. 1.  
2 0 5 M S 3 0 1 -2 0 5 M S 3 0 3 St u d y P o p ul ati o n  .............................................................................. 2 3  
5. 1. 2.  
2 0 5 M S 2 0 3 -2 0 5 M S 3 0 3 St u d y P o p ul ati o n  .............................................................................. 2 3  
5. 1. 3.  
2 0 5 M S 3 0 2 -2 0 5 M S 3 0 3 St u d y P o p ul ati o n  .............................................................................. 2 3  
5. 2.  
A n al y si s of b a s eli n e d at a  ...............................................................................................2 4  
5. 2. 1.  
2 0 5 M S 3 0 1 -2 0 5 M S 3 0 3 St u d y B a s eli n e s  ............................................................................... 2 4  
5. 2. 2.  
2 0 5 M S 2 0 3 -2 0 5 M S 3 0 3 St u d y B a s eli n e s  ............................................................................... 2 4  
5. 2. 3.  
2 0 5 M S 3 0 2 -2 0 5 M S 3 0 3 St u d y B a s eli n e s  ............................................................................... 2 5  
5. 3.  
K e y D at e s Ti m e P eri o d D efi niti o n s  ................................................................................2 5  
5. 4.  
G e n er al M et h o d s of A n al y si s  .........................................................................................2 5  
6.
S T U D Y S U B J E C T S  ...........................................................................................................2 7  
6. 1.  
S u bj e ct A c c o u nt a bilit y  ...................................................................................................2 7  
6. 2.  
D e m o gr a p h y a n d B a s eli n e Di s e a s e C h ar a ct eri sti c s  ......................................................2 7  
6. 2. 1.  
D e m o gr a p h y a n d B a s eli n e Di s e a s e C h ar a ct eri sti c s f or t h e 2 0 5 M S 3 0 1 -3 0 3 I T T P o p ul ati o n  2 7  
6. 2. 2.  
D e m o gr a p h y a n d B a s eli n e Di s e a s e C h ar a ct eri sti c s f or t h e 2 0 5 M S 2 0 3 -3 0 3 I T T P o p ul ati o n  2 7  
6. 2. 3.  
D e m o gr a p h y a n d B a s eli n e Di s e a s e C h a r a ct eri sti c s f or t h e 2 0 5 M S 3 0 2-3 0 3 I T T P o p ul ati o n  2 8  
6. 3.  
E xt e nt of E x p o s ur e  ........................................................................................................2 8  
6. 3. 1.  
E xt e nt of E x p o s ur e f or t h e 2 0 5 M S 3 0 1 -2 0 5 M S 3 0 3 St u d y P o p ul ati o n  ................................... 2 8  
6. 3. 2.  
E xt e nt of E x p o s ur e f or t h e 2 0 5 M S 2 0 3 -2 0 5 M S 3 0 3 St u d y P o p ul ati o n  ................................... 2 8  
6. 3. 3.  
E xt e nt of E x p o s ur e f or t h e 2 0 5 M S 3 0 2 -2 0 5 M S 3 0 3 St u d y P o p ul ati o n  ................................... 2 8  
6. 4.  
C o n c o mit a nt T h er a p y  ....................................................................................................2 8  
7.
E F FI C A C Y D A T A  ...............................................................................................................2 9  
7. 1.  
S u m m ar y of Effi c a c y A n al y s e s  ......................................................................................2 9  
7. 2.  
A n n u ali z e d R el a p s e R at e  ..............................................................................................3 6  
7. 2. 1.  
A n n u ali z e d R el a p s e R at e i n t h e 2 0 5 M S 3 0 1 -3 0 3 I T T P o p ul ati o n  .......................................... 3 6  
7. 2. 2.  
A n n u ali z e d R el a p s e R at e i n t h e 2 0 5 M S 2 0 3 -3 0 3 I T T P o p ul ati o n  .......................................... 3 7  
7. 2. 3.  
A n n u ali z e d R el a p s e R at e i n t h e 2 0 5 M S 3 0 2 -3 0 3 I T T P o p ul ati o n  .......................................... 3 8  
7. 3.  
Pr o p orti o n of S u bj e ct s w h o R el a p s e d  ............................................................................3 8  
7. 3. 1.  
Pr o p orti o n of S u bj e ct s wit h R el a p s e i n t h e 2 0 5 M S 3 0 1 -3 0 3 I T T P o p ul ati o n  ......................... 3 8  
7. 3. 2.  
Pr o p orti o n of S u bj e ct s wit h R el a p s e i n t h e 2 0 5 M S 2 0 3 -3 0 3 I T T P o p ul ati o n  ......................... 3 9  
7. 3. 3.  
Pr o p orti o n of S u bj e ct s wit h R el a p s e i n t h e 2 0 5 M S 3 0 2 -3 0 3 I T T P o p ul ati o n  ......................... 3 9  
7. 4.  
S u st ai n e d 6 -m o nt h Di s a bilit y Pr o gr e s si o n  .....................................................................3 9  
7. 4. 1.  
S u st ai n e d 6 -m o nt h Di s a bilit y Pr o gr e s si o n i n t h e 2 0 5 M S 3 0 1 -3 0 3 I T T P o p ul ati o n  ................ 3 9  


 
             
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S u st ai n e d 6 -m o nt h Di s a bilit y Pr o gr e s si o n i n t h e 2 0 5 M S 2 0 3 -3 0 3 I T T P o p ul ati o n  ................ 4 1  
7. 4. 3.  
S u st ai n e d 6 -m o nt h Di s a bilit y Pr o gr e s si o n i n t h e 2 0 5 M S 3 0 2 -3 0 3 I T T P o p ul ati o n  ................ 4 2  
7. 5.  
M SI S -2 9  ........................................................................................................................4 2  
7. 6.  
M RI E n d p oi nt s  ...............................................................................................................4 2  
7. 6. 1.  
M RI E n d p oi nt s A n al y s e s f or t h e 2 0 5 M S 3 0 1 -3 0 3 I T T P o p ul ati o n  .......................................... 4 2  
7. 6. 2.  
M RI E n d p oi nt s A n al y s e s f or t h e 2 0 5 M S 2 0 3 -3 0 3 I T T P o p ul ati o n  .......................................... 4 5  
7. 6. 3.  
M RI E n d p oi nt s A n al y s e s f or t h e 2 0 5 M S 3 0 2 -3 0 3 I T T P o p ul ati o n  .......................................... 4 5  
7. 7.  
E D S S  ............................................................................................................................4 5  
7. 7. 1.  
E D S S i n t h e 2 0 5 M S 3 0 1 -3 0 3 I T T P o p ul ati o n  ......................................................................... 4 5  
7. 7. 2.  
E D S S i n t h e 2 0 5 M S 2 0 3 -3 0 3 I T T P o p ul ati o n  ......................................................................... 4 5  
7. 7. 3.  
E D S S i n t h e 2 0 5 M S 3 0 2 -3 0 3 I T T P o p ul ati o n  ......................................................................... 4 5  
7. 8.  
E Q -5 D  ...........................................................................................................................4 5  
7. 8. 1.  
E Q -5 D i n t h e 2 0 5 M S 3 0 1 -3 0 3 I T T P o p ul ati o n  ....................................................................... 4 6  
7. 8. 2.  
E Q -5 D i n t h e 2 0 5 M S 2 0 3 -3 0 3 I T T P o p ul ati o n  ....................................................................... 4 6  
7. 8. 3.  
E Q -5 D i n t h e 2 0 5 M S 3 0 2 -3 0 3 I T T P o p ul ati o n  ....................................................................... 4 6  
7. 9.  
H e alt h R e s o ur c e Utili z ati o n ( H R U)  ................................................................................4 6  
7. 9. 1.  
H R U i n t h e 2 0 5 M S 3 0 1 -3 0 3 I T T P o p ul ati o n  ........................................................................... 4 6  
7. 9. 2.  
H R U i n t h e 2 0 5 M S 2 0 3 -3 0 3 I T T P o p ul ati o n  ........................................................................... 4 6  
7. 9. 3.  
H R U i n t h e 2 0 5 M S 3 0 2 -3 0 3 I T T P o p ul ati o n  ........................................................................... 4 7  
7. 1 0.  H e alt h R el at e d Pr o d u cti vit y Q u e sti o n n air e ( H R P Q)  .......................................................4 7  
7. 1 0. 1.  
H R P Q i n t h e 2 0 5 M S 3 0 1 -3 0 3 I T T P o p ul ati o n  .................................................................... 4 7  
7. 1 0. 2.  
H R P Q i n t h e 2 0 5 M S 2 0 3 -3 0 3 I T T P o p ul ati o n  .................................................................... 4 7  
7. 1 0. 3.  
H R P Q i n t h e 2 0 5 M S 3 0 2 -3 0 3 I T T P o p ul ati o n  .................................................................... 4 7  
7. 1 1.  S y m b ol Di git M o d aliti e s T e st ( S D M T)  ............................................................................4 7  
7. 1 2.  3 S e c o n d P a c e d A u dit or y S eri al A d diti o n T e st ( P A S A T 3)  ..............................................4 7  
7. 1 3.  Pr o p orti o n of s u bj e ct s w h o ar e fr e e fr o m di s e a s e a cti vit y  ..............................................4 8  
8.  
S A F E T Y D A T A  ..................................................................................................................4 8  
8. 1.  
S u m m ar y of S af et y A n al y s e s  .........................................................................................4 8  
8. 2.  
Cli ni c al A d v er s e E v e nt s  .................................................................................................4 8  
8. 3.  
A d v er s e E v e nt s of I nt er e st  .............................................................................................4 9  
8. 4.  
A d diti o n al Effi c a c y a n d S af et y E n d p oi nt s  .......................................................................5 1  
8. 4. 1.  
B e c k D e pr e s si o n I n v e nt or y S c or e  ......................................................................................... 5 1  
8. 4. 2.  
Tr e at m e nt S ati sf a cti o n Q u e sti o n n air e f or M e di c ati o n  ........................................................... 5 1  
8. 4. 3.  
M S F C S c or e  .......................................................................................................................... 5 1  
8. 5.  
L a b or at or y D at a  .............................................................................................................5 4  
8. 6.  
S u b gr o u p a n al y si s  .........................................................................................................5 7  
8. 7.  
Vit al Si g n s  .....................................................................................................................5 8  
8. 8.  
P h y si c al E x a mi n ati o n  ....................................................................................................5 9  
8. 9.  
I m m u n o g e ni cit y D at a .....................................................................................................5 9  
9.  
P H A R M A C O KI N E TI C S A N D  P H A R M A C O D Y N A MI C S ......................................................5 9  
9. 1.  
P h ar m a c o ki n eti c s  ..........................................................................................................5 9  


 
             
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P h ar m a c o d y n a mi c s  .......................................................................................................5 9  
1 0.  S A M P L E SI Z E J U S TI FI C A TI O N  ........................................................................................5 9  
1 1.  R E F E R E N C E S  ..................................................................................................................6 0  
 
 
 
Li st  of T a bl e s  
 
T a bl e  1:  
S c h e d ul e of A cti viti e s:  B a s eli n e T hr o u g h W e e k 8 4  f or S u bj e ct s E nr olli n g Fr o m 
St u d y  2 0 5 M S 3 0 1 I nt o St u d y  2 0 5 M S 3 0 3  ............................................................................1 0  
T a bl e  2:  
S c h e d ul e of A cti viti e s:  W e e k 9 6 t hr o u g h W e e k 1 4 4 f or S u bj e ct s E nr olli n g Fr o m 
St u d y 2 0 5 M S 3 0 1 I nt o St u d y 2 0 5 M S 3 0 3  ............................................................................1 3  
T a bl e  3:  
S c h e d ul e of A cti viti e s:  E ntr y Vi sit ( W e e k  1 4 4) f or S u bj e ct s E nr olli n g Fr o m St u d y 
2 0 5 M S 2 0 3 or St u d y  2 0 5 M S 3 0 2 I nt o St u d y  2 0 5 M S 3 0 3  ......................................................1 5  
T a bl e  4:  
S c h e d ul e of A cti viti e s:  W e e k 1 5 6 t hr o u g h W e e k 2 4 0 ( E n d of Tr e at m e nt) f or 
S u bj e ct s E nr olli n g Fr o m St u d y  2 0 5 M S 3 0 1, St u d y  2 0 5 M S 2 0 3, or St u d y  2 0 5 M S 3 0 2 I nt o 
St u d y  2 0 5 M S 3 0 3  ...............................................................................................................1 7  
T a bl e  5:  
S c h e d ul e of A cti viti e s:  P o st -Tr e at m e nt S af et y F oll o w -U p  ......................................2 0  
T a bl e  6:  
S c h e d ul e of A cti viti e s:  U n s c h e d ul e d A s s e s s m e nt s  ...............................................2 1  
T a bl e  7: S u m m ar y of p o p ul ati o n s a n d tr e at m e nt p eri o d s f or effi c a c y a n al y s e s  .........................2 9  
T a bl e  8: S u m m ar y of effi c a c y a n al y z e s f or t h e 2 0 5 M S 3 0 1 -3 0 3 I T T p o p ul ati o n  .........................3 1  
T a bl e 9: S u m m ar y of effi c a c y a n al y z e s f or t h e 2 0 5 M S 2 0 3 -3 0 3 I T T p o p ul ati o n  .........................3 4  
T a bl e 1 0: S u m m ar y of effi c a c y a n al y z e s f or t h e 2 0 5 M S 3 0 2 -3 0 3 I T T p o p ul ati o n  .......................3 5  
T a bl e 1 1: S u m m ar y of p o p ul ati o n s f or s af et y a n al y s e s o v er t h e 2 0 5 M S 3 0 3 Tr e at m e nt P eri o d  .4 8  
T a bl e  1 2: A d v er s e E v e nt s of S p e ci al I nt er e st  ............................................................................4 9  
T a bl e  1 3: Crit eri a f or P ot e nti all y Cli ni c all y Si g nifi c a nt H e m at ol o g y A b n or m aliti e s  ......................5 6  
T a bl e  1 4: S e v erit y Gr a d e s f or H e m at ol o g y  ................................................................................5 6  
T a bl e  1 5: S e v erit y Gr a d e s f or L F T s  ..........................................................................................5 6  
T a bl e  1 6: Cr it eri a t o d et er mi n e cli ni c all y r el e v a nt a b n or m aliti e s i n vit al si g n s ............................5 8  


 
             
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LI S T O F A B B R E VI A TI O N S  
 
9 H P T  
9 -h ol e p e g t e st  
A E  
a d v er s e e v e nt  
A L T  
al a ni n e a mi n o tr a n sf era s e  
A R R  
a n n u ali z e d r el a p s e r at e  
A S T  
a s p art at e a mi n o tr a n sf era s e  
B DI -II 
B e c k D e pr e s si o n I n v e nt or y, S e c o n d E diti o n  
b p m  
b e at s p er mi n ut e  
B U N  
bl o o d ur e a nitr o g e n  
C or º C 
d e gr e e s C el si u s  
C T C  
c o m m o n t o xi cit y crit eri a  
D A C H Y P  
d a cli z u m a b hi g h yi el d pr o c e s s  
E D S S  
E x p a n d e d Di s a bilit y St at u s S c al e  
E Q -5 D  
E ur o p e a n Q u alit y of Lif e, 5 D i m e n si o n s  
E Q -V A S  
E ur o p e a n Q u alit y of Lif e,  Vi s u al A n al o g u e S c al e  
G d  
g a d oli ni u m  
G G T  
g a m m a -gl ut a m yl tr a n s p e pti d a s e  
H R P Q  
H e alt h r el at e d pr o d u cti vit y q u e sti o n n air e  
H R U  
h e alt h r e s o ur c e utili z ati o n  
H Y P  
hi g h yi el d pr o c e s s  
I T T 
i nt e nt t o tr e at 
L F T  
li v er f u n cti o n t e st s 
M e d D R A  
M e di c al Di cti o n ar y f or R e g ul at or y Aff air s  
m g  
milli gr a m  
m m H g  
milli m et er s of m er c ur y  
MI  
m ulti pl e i m p ut ati o n  
M RI  
m a g n eti c r e s o n a n c e i m a gi n g  
M S  
m ulti pl e s cl er o si s  
M S F C  
M ulti pl e S cl er o si s F u n cti o n al C o m p o sit e  
M SI S -2 9  
M ulti pl e S cl er o si s I m p a ct S c al e -2 9  
N A b s  
n e utr ali zi n g a nti b o d i e s 
P A S A T  
P a c e d A u dit or y S eri al A d diti o n T e st  
P D  
p h ar m a c o d y n a mi c s  
P F S  
pr efill e d s yri n g e  
P K  
p h ar m a c o ki n eti c s  
P T  
Pr ef err e d t er m  
Q o L  
q u alit y of lif e  
S A P  
st ati sti c al a n al y si s pl a n  
S A E  
s eri o u s a d v er s e e v e nt  
S C  
s u b c ut a n e o u s  
S G O T  
s er u m gl ut a mi c o x al o a c eti c tr a n s a mi n a s e  
S G P T  
s er u m gl ut a m at e -p yr u v at e tr a n s a mi n a s e  
S M Q  
st a n d ar di s e d M e d D R A q u er y  
S O C  
s y st e m or g a n cl a s s  
T 4  
t h yr o xi n e 
T S H  
t h yr oi d sti m ul ati n g h or m o n e 
V A S  
Vi s u al A n al o g u e S c al e  
W B C  
w hit e bl o o d c ell  
W H O  
W orl d H e alt h Or g a ni z ati o n  


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
Fi n al V er si o n 1. 0  
 
 
7  
1.  D e s cri pti o n of St u d y O bj e cti v e s a n d E n d p oi nt s  
1. 1.  Pri m ar y O bj e cti v e a n d E n d p oi nt s  
 
T h e pri m ar y o bj e cti v e of t h e st u d y i s t o a s s e s s  t h e s af et y a n d t ol er a bilit y of l o n g-t er m tr e at m e nt 
wit h D A C H Y P m o n ot h er a p y i n s u bj e ct s w h o c o m pl et e d St u d y 2 0 5 M S 3 0 1, St u d y  2 0 5 M S 2 0 3, or 
St u d y  2 0 5 M S 3 0 2.  
T h e pri m ar y e n d p oi nt s of t hi s st u d y ar e  i n ci d e n c e of a d v er s e e v e nt s ( A E s) a n d  i n ci d e n c e of 
s eri o u s A E s  ( S A E s). 
1. 2.  S e c o n d ar y O bj e cti v e a n d E n d p oi nt s  
 
S e c o n d ar y o bj e cti v e s of t hi s st u d y i n t hi s st u d y p o p ul ati o n ar e a s f oll o w s:  
•  
T o d e s cri b e M S -r el at e d o ut c o m e s, i n cl u di n g M S r el a p s e, di s a bilit y pr o gr e s si o n, M S 
l e si o n f or m ati o n, a n d p ati e nt-r e p ort e d i m p a ct of M S, f oll o wi n g l o n g-t er m tr e at m e nt 
wit h D A C H Y P  
•  
T o a s s e s s t h e l o n g -t er m i m m u n o g e ni cit y of D A C H Y P a d mi ni st er e d b y pr efill e d 
s yri n g e ( P F S )  
•  
T o a s s e s s t h e s af et y, t ol er a bilit y, a n d effi c a c y of s wit c hi n g t o D A C H Y P i n s u bj e ct s 
pr e vi o u sl y o n l o n g -t er m tr e at m e nt wit h i nt erf er o n β -1 a  (I F N β -1 a ) i n St u d y 2 0 5 M S 3 0 1 
 
T h e s e c o n d ar y e n d p oi nt s of t hi s st u d y ar e a s f oll o w s:  
•  
R el a p s e o ut c o m e s:  a n n u ali z e d r el a p s e r at e ( A R R), a n d pr o p orti o n of s u bj e ct s w h o 
r el a p s e 
•  
S u st ai n e d di s a bilit y pr o gr e s si o n d efi n e d b y at l e a st a 1. 0 -p oi nt i n cr e a s e o n t h e 
E x p a n d e d Di s a bilit y St at u s S c al e ( E D S S) s c or e fr o m a b a s eli n e E D S S ≥1. 0 t h at i s 
s u st ai n e d f or 2 4 w e e k s, or at l e a st a 1. 5 -p oi nt i n cr e a s e o n t h e E D S S fr o m a b a s eli n e 
E D S S < 1. 0 t h at i s s u st ai n e d f or 2 4 w e e k s  
•  
M a g n eti c R e s o n a n c e I m a gi n g ( M R I) o ut c o m e s:  t ot al n u m b er a n d v ol u m e of n e w or 
n e wl y e nl ar gi n g T 2 h y p eri nt e n s e l e si o n s, G d -e n h a n ci n g l e si o n s, T 1 h y p oi nt e n s e 
l e si o n s, a n d br ai n v ol u m e c h a n g e o n br ai n M RI  
•  
C h a n g e i n M ulti pl e S cl er o si s F u n cti o n al C o m p o sit e ( M S F C) s c or e  
•  
C h a n g e i n E D S S s c or e  
•  
C h a n g e i n S y m b ol Di git M o d aliti e s T e st ( S D M T) s c or e  
•  
C h a n g e i n 3 S e c o n d P a c e d A u dit or y S eri al A d diti o n T e st ( P A S A T 3) s c or e  
•  
Pr o p orti o n of s u bj e ct s w h o ar e fr e e fr o m di s e a s e a cti vit y.  


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
Fi n al V er si o n 1. 0  
 
 
8  
•  
C h a n g e i n M ulti pl e S cl er o si s I m p a ct S c al e -2 9 ( M SI S -2 9) p h y si c al a n d p s y c h ol o gi c al 
s c or e s  
•  
C h a n g e i n q u alit y of lif e a s a s s e s s e d b y t h e E ur o p e a n Q u alit y of Lif e, 5 di m e n si o n s  
a n d E ur o p e a n Q u alit y of Lif e,  Vi s u al A n al o g u e S c al e  ( E Q-5 D a n d E Q -V A S)   
•  
C h a n g e i n dir e ct h e alt h r e s o ur c e utili z ati o n ( H R U; h o s pit ali z ati o n s, e m er g e n c y r o o m 
vi sit s, a n d u n s c h e d ul e d n e ur ol o gi st vi sit s)  
•  
C h a n g e i n tr e at m e nt s ati sf a cti o n a s a s s e s s e d b y t h e s u bj e ct  
•  
C h a n g e i n s u bj e ct pr o d u cti vit y a s a s s e s s e d b y t h e H e alt h R el at e d Pr o d u cti vit y 
Q u e sti o n n air e ( H R P Q)  
•  
C h a n g e s i n cli ni c al l a b or at or y a s s e s s m e nt s ( h e m at ol o g y a n d bl o o d c h e mi str y)  
•  
L o c al t ol er a bilit y a s a s s e s s e d b y s u bj e ct -r e p ort e d i nj e cti o n sit e p ai n, Vi s u al A n al o g u e 
S c al e  ( V A S) a n d cli ni ci a n i nj e cti o n sit e a s s e s s m e nt s 
•  
I n ci de n c e of a nti -dr u g a nti b o di e s ( A D A s) t o D A C  H Y P o v er ti m e  
•  
I n ci d e n c e of n e utr ali zi n g a nti b o di e s ( N A b s) t o D A C H Y P o v er ti m e  
 
2.  St u d y D e si g n  
 
T h e d e si g n of St u d y 2 0 5 M S 3 0 3 i s pr o vi d e d i n Fi g ur e  1 . A p pr o xi m at el y 1 5 0 0 s u bj e ct s will e nr oll 
i n t hi s st u d y. T hi s i n cl u d e s a p pr o xi m at el y 1 2 0 0  s u bj e ct s w h o c o m pl et e d St u d y 2 0 5 M S 3 0 1.  
A d diti o n all y, a p pr o xi m at el y 3 0 0  s u bj e ct s fr o m t h e ot h er D A C  H Y P e xt e n si o n st u di e s ( 2 0 5 M S 2 0 3 
[ S E L E C T E D] a n d 2 0 3 M S 3 0 2 [ O B S E R V E]) will b e eli gi bl e t o e nt er St u d y 2 0 5 M S 3 0 3 at 
W e e k  1 4 4 of St u d y  2 0 5 M S 3 0 3 ( St u d y  2 0 5 M S 3 0 1, St u d y  2 0 5 M S 2 0 3, a n d St u d y  2 0 5 M S 3 0 2 
h a v e b e e n r ef err e d t o a s p ar e nt st u di e s i n t h e pr ot o c ol).   
All s u bj e ct s will r e c ei v e t h e  s a m e d o s e of D A C H Y P a s r e c ei v e d i n t h e p ar e nt st u di e s; i. e., 
1 5 0  m g b y a  s u b c ut a n e o u s ( S C ) i nj e cti o n e v er y 4 w e e k s.  T h e d ur ati o n of D A C  H Y P tr e at m e nt i s 
u p t o a p pr o xi m at el y 5  y e ar s, or u ntil a v ail a bilit y of c o m m er ci al pr o d u ct  ( w hi c h e v er i s s o o n er). 
N ot e t h at per s p o n s or di s cr eti o n , t h e st u d y w a s cl o s e d e arl y a n d d o si n g w a s t er mi n at e d b y 
M ar c h 3 0
t h, 2 0 1 8. 
 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
Fi n al V er si o n 1. 0  
 
 
9  
Fi g ur e  1 : 
St u d y D e si g n  f or 2 0 5 M S 3 0 3 st u d y 
 






 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
Fi n al V er si o n 1. 0  
 
 
1 2  
5If l ocal L F Ts ha ve bee n use d t o deter mi ne w het her d osi n g s h o ul d c o nti n ue or be s us pe n de d at t he ti me of a sc he d ule d cli nic vi sit, L F Ts m ust als o be perf or me d 
at t he ce ntral la b orat or y at t he ti me of t he sc he d ule d cl i nic visit ( N ote:  Sc he d ule d cli nic visits occ ur e ver y 4 wee ks d uri n g t he first 1 2 wee ks of t he st u d y a n d 
e ver y 1 2 wee ks t hereafter).   
7S u bj ects w h o d i d n ot c o nse nt t o D N A c ollecti o n i n 2 0 5 M S 3 0 1 will be re-a p pr oac he d f or t his c o nse nt u p o n e ntr y i nt o St u d y 2 0 5 M S 3 0 3.  A se p arate i nf or me d 
c o nse nt f or m ma y be use d f or D N A sa m ple c ollecti o n.  Sa m ples f or D N A a nal ysis ma y be c ollecte d after t he B aseli ne Visit , if necessar y. 
8Pre g na nc y test res ults m ust b e ne gati ve pri or t o d osi n g.  
9M SI S -2 9 t o be a d mi nistere d pri or t o seei n g t he St u dy Ne ur ol o gist .  
1 0T o be perf or me d after t he D A C H Y P i nj ecti o n at t his visit.  
1 1M RI sca n ca n be perf or me d u p t o 4 da ys pri or t o t he  visit.  
1 2B ef ore a m o nt hl y d ose of D A C H Y P is gi ve n, L F T res ults fr o m a pri or test perf or me d wit hi n t he pre vi o us 3 2 da ys m ust b e re vie w e d b y t he St u dy Ne ur ol o gist  
or t heir bac k u p.  
1 3A wi n d o w of 4 da ys a p plies t o D A C H Y P d ose e ve n if it is d o ne at h o me.  
1 4At t he W ee k 4, 8, a n d 1 2 Visits, s u bj ects will be i nstr ucte d o n D A C H Y P self -a d mi nistrati o n a n d ma y a d mi nister t heir sc he d ule d d ose u n der staff s u p er visi o n. 
After W ee k 1 2, D A C H Y P ma y be dis pe nse d t o s u bj ects f or at -h o me a d mi nistrati o n if t he s u bj ect c h o oses.








 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
Fi n al V er si o n 1. 0  
 
 
1 6  
D A C H Y P A d mi ni str ati o n/ Di s p e n s ati o n 6  
X  
C o nc o mita nt T hera p y a n d A Es  
X  
Pr ot oc ol C o m plia nce a n d D A C H Y P 
Acc o u nta bilit y  
X  
1W he n p ossi ble, s u bj ects s h o ul d be e val uate d b y t he sa me St u dy Ne ur ol o gist  assi g ne d t o t he m i n t he pare nt st u dies.  
2W ee k  1 4 4 (start of Year  4) of St u d y  2 0 5 M S 3 0 3 will be t he ti me p oi nt at w hic h s u bj ects fr o m St u d y  2 0 5 M S 2 0 3 a n d St u d y  2 0 5 M S 3 0 2 e nter St u d y  2 0 5 M S 3 0 3. 
E ntr y Visit m ust ta ke place wit hi n 6 m o nt hs of t he last D A C  H Y P d o se i n t he pare nt st u dies (i.e., St u d y 2 0 5 M S 2 0 3 or St u d y  2 0 5 M S 3 0 2).   
3A L T/ S G P T, A S T/ S G O T, al kali ne p h os p hatase, t otal bilir u bi n, a n d G G T o nl y.   
5Pre g na nc y test res ults m ust b e ne gati ve pri or t o d osi n g.  
6B ef ore a m o nt hl y d ose of D A C H Y P is gi ve n at t he cli nic, L F T res ults fr o m a pri or test perf or me d wit hi n t he pre vi o us 3 2 da ys m ust b e re vie we d b y t he St u dy 
Ne ur ol o gist  or t heir bac k u p.   
N ote:  M RI assess me nt will n ot b e d o ne at t he Wee k 1 4 4/ E ntr y Visit f or St u d y 2 0 5 M S 3 0 3.  
 
 






 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
Fi n al V er si o n 1. 0  
 
 
1 9  
1 F or s u bj ects w h o pre mat urel y disc o nti n ue d osi n g, t he E n d of Treat me nt ( Earl y T er mi nati o n) Visit s h o ul d be perf or me d 2 8 ± 4 da ys f oll o wi n g t he s u bject’s last 
d ose of st u d y treat me nt.  
2 A L T/ S G P T, A S T/ S G O T, al kali ne p h os p hatase, t otal bilir u bi n, a n d G G T o nl y.  
3 If l ocal L F Ts ha ve bee n use d t o deter mi ne w het her d osi n g s h o ul d c o nti nue or be s us pe n de d at t he ti me of a sc he d ule d cli nic visit, L F Ts m ust als o be perf or me d 
at t he ce ntral la b orat or y at t he ti me of t he sc he d ule d cli nic visit ( N ote:  Sc he d ule d cli nic visits occ ur e ver y 1 2 wee ks )  
 
5 Pre g na nc y test res ults m ust b e ne gati ve pri or t o d o si n g. 
6 M RI sca n ca n be perf or me d u p t o 4 da ys pri or t o t he visit.  
7 M RI assess me nt is o pti o nal  f or t he Earl y T er mi nati o n visit. U n der  pr ot oc ol versi o n 4, M RI assess me nts were a d de d at W ee ks 1 9 2 a n d 2 4 0 t o better assess t he 
efficac y of dacliz u ma b o n M RI o utc o mes o ver a l o n ger peri o d of ti me as c o m pare d t o t he pre vi o us versi o n of t he pr ot oc ol, i n w hic h t he last M RI assess me nt 
was at Wee k 1 4 4.  
8 W he n p ossi ble, s u bj ects s h o ul d be e val uate d b y t he sa me ne ur ol o gist assi g ne d t o t he m i n t he pare nt st u dies.  
9 P erf or me d o nl y f or s u bj ects ori gi nall y e nr olle d fr o m St u d y 2 0 5 M S 3 0 1  u n der pr ot oc ol versi o n 3 a n d t hereafter . 
1 0 B ef ore a m o nt hl y d ose of D A C H Y P is gi ve n, L F T res ults fr o m a pri or test perf or me d wit hi n t he pre vi o us 3 2 da ys m ust be re vie we d b y t he St u dy Ne ur ol o gist  
or t heir bac k u p.  
1 1 A wi n d o w of ± 4 da ys a p plies t o D A C H Y P d ose e ve n if it is d o ne at h o me.  






 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
2 2  
9P erf or me d b y t he St u dy Ne ur ol o gist  or t heir bac k -u p wit hi n 7 2 h o urs of a s us pecte d rela pse.   
1 0 Refer t o Pr ot oc ol Secti o n 1 1. 7. 3 f or i nf or mati o n o n w he n t o perf or m t hese assess me nts. 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
2 3  
4.  I nt eri m A n al y si s  
T hi s st ati sti c al a n al y si s pl a n ( S A P) i s i nt e n d e d t o d e s cri b e t h e pl a n n e d a n al y si s m et h o d s a n d 
c o n si d er ati o n s f or t h e fi n al a n al y si s b a s e d o n d at a aft er d at a b a s e l o c k s c h e d ul e d f or Q 4 of 2 0 1 8. 
O n e i nt eri m a n al y si s w a s c o n d u ct e d i n 2 0 1 4 f or a n i nt eri m cli ni c al st u d y r e p ort. N ot e t h at t hi s i nt eri m 
a n al y si s w a s c o n d u ct e d pri or t o t h e pr ot o c ol a m e n d m e nt s t o i n cl u d e p ati e nt s pr e vi o u sl y e nr oll e d i n 
t h e 2 0 5 M S 2 0 3 a n d 2 0 5 M S 3 0 2 st u di e s, a n d t h er ef or e i n cl u d e d d at a o nl y f or p ati e nt s pr e vi o u sl y 
e nr oll e d i n t h e 2 0 5 M S 3 0 1 st u d y.    
5.  St ati sti c al M et h o d s: G e n er al C o n si d er ati o n s  
5. 1.  A n al y si s P o p ul ati o n s  
A s t hi s a n al y si s i s m a d e u p fr o m 3 c o h ort s of p ati e nt s o bt ai n e d fr o m diff er e nt st u di es, s e p ar at e 
a n al y si s p o p ul ati o n s will b e d efi n e d wit hi n e a c h c o h ort . 
5. 1. 1.  2 0 5 M S 3 0 1 -2 0 5 M S 3 0 3 S t u d y P o p ul ati o n  
2 0 5 M S 3 0 1 -3 0 3  I T T P o p ul ati o n  
St u d y 2 0 5 M S 3 0 1 -3 0 3  i nt e nt-t o-tr e at (I T T) p o p ul ati o n c o n si st s  of all s u bj e ct s w h o c o m pl et e d St u d y 
2 0 5 M S 3 0 1  a n d  r e c ei v e d at l e a st o n e d o s e of D A C H Y P d uri n g t h e 2 0 5 M S 3 0 3 st u d y , w hi c h i s t h e 
p o p ul ati o n f or a n al y s e s of effi c a c y i n t hi s c o h ort .  
 
2 0 5 M S 3 0 1 -3 0 3  S af et y P o p ul ati o n  
St u d y  2 0 5 M S 3 0 1 -3 0 3  s af et y p o p ul ati o n c o n si st s of all s u bj e ct s w h o  p arti ci p at e d i n St u d y 2 0 5 M S 3 0 1 
a n d r e c ei v e d at l e ast o n e d o s e of D A C H Y P tr e at m e nt  d uri n g t h e 2 0 5 M S 3 0 3 st u d y . T hi s i s t h e 
p o p ul ati o n f or a n al y s e s of s af et y  i n t hi s c o h ort.  
5. 1. 2.  2 0 5 M S 2 0 3 -2 0 5 M S 3 0 3 S t u d y P o p ul ati o n  
2 0 5 M S 2 0 3 -3 0 3  I T T P o p ul ati o n  
St u d y 2 0 5 M S 2 0 3 -3 0 3  i nt e nt-t o-tr e at (I T T) p o p ul ati o n  c o n si st s  of all s u bj e ct s w h o c o m pl et e d St u d y 
2 0 5 M S 2 0 3 a n d  r e c ei v e d at l e a st o n e d o s e of D A C H Y P d uri n g t h e 2 0 5 M S 3 0 3 st u d y, w hi c h i s  t h e 
p o p ul ati o n f or a n al y s e s of effi c a c y  i n t hi s c o h ort. 
 
2 0 5 M S 2 0 3 -3 0 3  S af et y  P o p ul ati o n   
St u d y 2 0 5 M S 2 0 3 -3 0 3  s af et y p o p ul ati o n  c o n si st s  of all s u bj e ct s w h o c o m pl et e d St u d y 2 0 5 M S 2 0 3 a n d  
r e c ei v e d at l e a st o n e d o s e of D A C H Y P d uri n g t h e 2 0 5 M S 3 0 3 st u d y, w hi c h i s  t h e p o p ul ati o n f or 
a n al y s e s of s af et y  i n t hi s c o h ort. 
5. 1. 3.  2 0 5 M S 3 0 2 -2 0 5 M S 3 0 3 S t u d y P o p ul ati o n  
2 0 5 M S 3 0 2 -3 0 3  I TT P o p ul ati o n   
St u d y 2 0 5 M S 3 0 2 -3 0 3  i nt e nt-t o-tr e at (I T T) p o p ul ati o n c o n si st s  of all s u bj e ct s w h o c o m pl et e d St u d y 
2 0 5 M S 3 0 2 a n d  r e c ei v e d at l e a st o n e d o s e of D A C H Y P d uri n g t h e 2 0 5 M S 3 0 3 st u d y, w hi c h i s  t h e 
p o p ul ati o n f or a n al y s e s of effi c a c y  i n t hi s c o h ort. 
 
2 0 5 M S 3 0 2 -3 0 3  S af et y  P o p ul ati o n   


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
2 4  
St u d y 2 0 5 M S 3 0 2 -3 0 3  s af et y p o p ul ati o n  c o n si st s  of all s u bj e ct s w h o c o m pl et e d St u d y 2 0 5 M S 3 0 2 a n d  
r e c ei v e d at l e a st o n e d o s e of D A C H Y P d uri n g t h e 2 0 5 M S 3 0 3 st u d y, w hi c h i s  t h e p o p ul ati o n f or 
a n al y s e s of s af et y  i n t hi s c o h ort. 
 
5. 2.  A n al y si s of b a s eli n e d at a  
 
T h e d efi niti o n of b a s eli n e will b e d e p e n d e nt o n t h e a n al y si s p erf or m e d a n d t h e c o h ort of p ati e nt s  
utili z e d. T h e f oll o wi n g ar e t h e v ari o u s d efi niti o n s of b a s eli n e t h at m a y b e u s e d i n t h e a n al y s e s:  
5. 2. 1.  2 0 5 M S 3 0 1 -2 0 5 M S 3 0 3 S t u d y B a s eli n e s  
2 0 5 M S 3 0 1 B a s eli n e  
St u d y 2 0 5 M S 3 0 1 B a s eli n e i s d efi n e d a s t h e l at e st a v ail a bl e v al u e pri or t o or o n t h e d at e of t h e fir st 
d o s e of st u d y tr e at m e nt i n St u d y 2 0 5 M S 3 0 1.  
 
2 0 5 M S 3 0 3 B a s eli n e  
St u d y 2 0 5 M S 3 0 3 B a s eli n e i s d efi n e d a s t h e l at e st a v ail a bl e v al u e pri or  t o or o n t h e d at e of t h e fir st 
d o s e of st u d y tr e at m e nt i n St u d y 2 0 5 M S 3 0 3.  
 
D e m o gr a p hi c c h ar a ct eri sti c s, b a s eli n e di s e a s e c h ar a ct eri sti c s  a n d m e di c al hi st or y  will b e 
s u m m ari z e d u si n g t h e 2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n at t h e 2 0 5 M S 3 0 1 B a s eli n e  a n d at t h e 
2 0 5 M S 3 0 3 B a s eli n e . 
  
D A C H Y P B a s eli n e  
D A C H Y P B a s eli n e i s e q u al t o t h e 2 0 5 M S 3 0 1 b a s eli n e f or s u bj e ct s r a n d o mi z e d t o D A C H Y P i n 
2 0 5 M S 3 0 1, or t h e 2 0 5 M S 3 0 3 b a s eli n e f or s u bj e ct s r a n d o mi z e d t o  I F N β-1 a  i n 2 0 5 M S 3 0 1. If n o 
a s s e s s m e nt s, or if m ulti pl e m e a s ur e m e nt s w er e p erf or m e d o n t h e d a y of fir st d o s e of D A C H Y P, t h e 
l a st m e a s ur e m e nt pri or t o t h e fir st d o s e of D A C H Y P will b e u s e d.  
 
U nl e s s ot h er wi s e s p e cifi e d, t h e D A C H Y P B a s eli n e will b e utili z e d i n m e a s ur e m e nt s  f or s af et y 
a s s e s s m e nt s s u c h a s l a b or at or y v al u e s a n d vit al si g n s.  
 
5. 2. 2.  2 0 5 M S 2 0 3 -2 0 5 M S 3 0 3 S t u d y B a s eli n e s  
2 0 5 M S 3 0 3 B a s eli n e  i s d efi n e d a s t h e l at e st a v ail a bl e v al u e pri or t o or o n t h e d at e of t h e fir st d o s e of 
st u d y tr e at m e nt i n St u d y 2 0 5 M S 3 0 3.  
 
D A C H Y P B a s eli n e  
S u bj e ct s e nr oll e d fr o m 2 0 5 M S 2 0 3 st u d y h a d c o m pl et e d t h e 2 0 5 M S 2 0 1, 2 0 5 M S 2 0 2, a n d 2 0 5 M S 2 0 3 
st u di e s . F or s u bj e ct s  r a n d o mi z e d t o D A C H Y P eit h er 1 5 0 m g or 3 0 0 m g i n 2 0 5 M S 20 1,  t h e D A C H Y P 
B a s eli n e i s d efi n e d a s t h e 2 0 5 M S 2 0 1 b a s eli n e.  F or s u bj e ct s r a n d o mi z e d t o pl a c e b o i n 2 0 5 M S 2 0 1 , 
t h e D A C H Y P B a s eli n e i s d efi n e d a s t h e 2 0 5 M S 2 0 2 B a s eli n e. If n o a s s e s s m e nt s, or if m ulti pl e 
m e a s ur e m e nt s w er e p erf or m e d o n t h e d a y of fir st d o s e of D A C H Y P, t h e l a st m e a s ur e m e nt pri or t o 
t h e fir st d o s e of D A C H Y P will b e u s e d.  
 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
2 5  
5. 2. 3.  2 0 5 M S 3 0 2 -2 0 5 M S 3 0 3 S t u d y B a s eli n e s  
2 0 5 M S 3 0 3 B a s eli n e  
St u d y 2 0 5 M S 3 0 3 B a s eli n e i s d efi n e d a s t h e l at e st a v ail a bl e v al u e pri or t o or o n t h e d at e of t h e fir st 
d o s e of st u d y tr e at m e nt i n St u d y 2 0 5 M S 3 0 3.  
 
D A C H Y P B a s eli n e  
D A C H Y P B a s eli n e i s e q u al t o t h e 2 0 5 M S 3 0 2  b a s eli n e f or all s u bj e ct s  i n t h e 2 0 5 M S 3 0 2 -3 0 3  s af et y 
p o p ul ati o n . If n o a s s e s s m e nt s, or if m ulti pl e m e a s ur e m e nt s w er e p erf or m e d o n t h e d a y of fir st d o s e 
of D A C H Y P, t h e l a st m e a s ur e m e nt pri or t o t h e fir st d o s e of D A C H Y P will b e u s e d .  
 
5. 3.  K e y D at e s Ti m e P eri o d D efi niti o n s  
 
T h e f oll o wi n g ti m e p eri o d s will b e d efi n e d f or effi c a c y a n d s af et y a n al y s e s:  
 
2 0 5 M S 3 0 1 Tr e at m e nt P eri o d  
T h e 2 0 5 M S 3 0 1 Tr e at m e nt P eri o d i s t h e ti m e p eri o d a s  d efi n e d i n t h e 2 0 5 M S 3 0 1 st ati sti c al a n al y si s 
pl a n a n d i n cl u d e s d at a c oll e ct e d fr o m t h e fir st d o si n g d at e t o t h e e n d of tr e at m e nt p eri o d vi sit  i n t h e 
2 0 5 M S 3 0 1 st u d y . F or s u bj e ct s w h o c o m pl et e d st u d y tr e at m e nt t hi s i s t h e d at e of t h e l a st s c h e d ul e d 
tr e at m e nt p eri o d vi sit i n t h at st u d y.  
 
2 0 5 M S 3 0 3 Tr e at m e nt  P eri o d  r ef ers t o t h e ti m e b et w e e n t h e fir st d o s e d at e i n 2 0 5 M S 3 0 3 a n d t h e 
d at e of t h e l a st a v ail a bl e m e a s ur e m e nt  pri or t o 1 8 0 d a y s aft er t h e l a st d o s e d at e i n 2 0 5 M S 3 0 3. T hi s 
i s t h e ti m e p eri o d f or m o st of t h e effi c a c y a n al y s e s a n d f or all t h e s af et y a n al y s e s f or all t h e 
p o p ul ati o n s.  
 
C o m bi n e d  St u d y P eri o d   
F or t h e 2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n, th e C o m bi n e d St u d y P eri o d  i s t h e c o m bi n e d p eri o d of t h e 
2 0 5 M S 3 0 1 a n d 2 0 5 M S 3 0 3 st u di e s , t hat  i s t h e ti m e b et w e e n t h e fir st d o s e d at e i n 2 0 5 M S 3 0 1 a n d t h e 
d at e of t h e l a st a v ail a bl e m e a s ur e m e nt  pri or t o 1 8 0 d a y s a ft er l a st d o s e d at e i n 2 0 5 M S 3 0 3.  
N ot e t h at f or t h e 2 0 5 M S 2 0 3 -3 0 3 I T T p o p ul ati o n  a n d t h e 2 0 5 M S 3 0 2 -3 0 3 I T T p o p ul ati o n , t h e 
c o m b i n e d st u d y p eri o d i s n ot n e c e s s ar y  d u e t o t h e li mit e d n u m b er of p ati e nt s  i n e a c h p o p ul ati o n. 
 
5. 4.  G e n er al M et h o d s of A n al y si s  
 
F or t h e 2 0 5 M S 3 0 1 -3 0 3 I T T p o p ul ati o n, e ffi c a c y an al y s e s will f o c u s o n  d at a fr o m t h e 2 0 5 M S 3 0 3 
tr e at m e nt p eri o d b ut will i n cl u d e s o m e  a d diti o n al a n al y s e s a cr o s s  t h e c o m bi n e d st u d y p eri o d. I n 
g e n er al,  s u m m ar y st ati sti c s will b e pr e s e nt e d b y pr e vi o u s tr e at m e nt gr o u p of t h e 2 0 5 M S 3 0 1 st u d y 
(I F N β -1 a  3 0 μ g a n d 1 5 0 m g D A C H Y P).  S af et y a n al y s e s will i n cl u d e s u bj e ct s i n t h e 2 0 5 M S 3 0 1 -3 0 3  
S af et y P o p ul ati o n  a n d u s e  t h e d at a fr o m t h e 2 0 5 M S 3 0 3 Tr e at m e nt  p eri o d  o nl y.  A n al y s e s  will b e 
pr e s e nt e d b y pr e vi o u s tr e at m e nt gr o u p of t h e 2 0 5 M S 3 0 1 st u d y ( I F N β-1 a 3 0 μ g a n d 1 5 0 m g D A C 
H Y P)  a n d f or all s u bj e ct s c o m bi n e d . 
 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
2 6  
F or t h e 2 0 5 M S 2 0 3 -3 0 3  I T T p o p ul ati o n, e ffi c a c y a n al y s e s will f o c u s o n d at a fr o m t h e 2 0 5 M S 3 0 3 
tr e at m e nt p eri o d. S u m m ar y st ati sti c s will b e s u m m ari z e d f or all s u bj e ct s c o m bi n e d.  S af et y a n al y s e s 
will i n cl u d e t h e d at a fr o m t h e 2 0 5 M S 3 0 3 Tr e at m e nt  p eri o d, a n d will b e pr e s e nt e d f or all s u bj e ct s 
c o m bi n e d.  N ot e t h at s u b j e ct s e nr oll e d fr o m t h e 2 0 5 M S 2 0 3 st u d y m a y r e c ei v e D A C H Y P at a hi g h er 
d o s e ( 3 0 0  m g) d uri n g t h e 2 0 5 M S 2 0 1 a n d/ or 2 0 5 M S 2 0 2 st u di e s . Gi v e n t h e l o n g d ur ati o n ti m e si n c e 
l a st e x p o s ur e t o hi g h d o s e of D A C H Y P a n d t o b e c o n si st e nt wit h t h e a n al y s e s i n t h e 2 0 5 M S 2 03 
cli ni c al st u d y r e p ort, a n al y s e s will n ot b e pr e s e nt e d b y  hi g h /l o w d o s e  l e v el i n pr e vi o u s st u di e s. 
 
F or t h e 2 0 5 M S 3 0 2 -3 0 3  I T T p o p ul ati o n, effi c a c y a n d s af et y a n al y s e s  will f o c u s o n s u bj e ct d at a fr o m 
t h e 2 0 5 M S 3 0 3 tr e at m e nt  p eri o d , a n d will b e pr e s e nt e d f or all s u bj e ct s c o m bi n e d . 
 
A n al y s e s will g e n er all y b e d e s cri pti v e i n n at ur e. F or r el e v a nt effi c a c y a n al y s e s, c o nfi d e n c e i nt er v al s 
will b e pr o vi d e d f or e a c h tr e at m e nt gr o u p w h er e a p pr o pri at e t o c h ar a ct eri z e t h e v ari a bilit y ar o u n d t h e 
p oi nt e sti m at e s . S t ati sti cal h y p ot h e si s t e sti n g m a y b e c o m pl et e d f or s el e ct e d a n al y s e s 
 
 
 
   
 
Vi sit Wi n d o w s  
F or b y -vi sit a n al y s e s, vi sit wi n d o w s will b e utili z e d. D at a will b e wi n d o w e d t o t h e n e ar e st s c h e d ul e d 
vi sit. If t w o or m or e e v al u ati o n s o c c ur i n t h e s a m e vi sit wi n d o w, t h e e val u ati o n m e a s ur e d o n a d a y 
cl o s e st t o t h e t ar g et vi sit d a y will b e s el e ct e d f or i n cl u si o n i n t h e a n al y si s. If m ulti pl e e v al u ati o n s ar e 
e q u all y cl o s e t o t h e t ar g et vi sit d a y, t h e n t h e e v al u ati o n wit h a n e arli e st d a y will b e s el e ct e d f or 
i n cl u si o n i n t h e a n al y si s. If s e v er al s a m pl e s ar e c oll e ct e d o n t h e s a m e d a y b ut at diff er e nt ti m e s, t h e 
e arli e st ti m e will b e u s e d.  
 
Mi s si n g m e a s ur e m e nt s  
I n g e n er al, no i m p ut ati o n f or mi s si n g m e a s ur e m e nt s will b e p erf or m e d , u nl e s s s p e cifi e d ot h er wi s e. 
 
Mi s si n g d at e s  
F or st art d at e of a d v er s e e v e nt s, if all a v ail a bl e st art d at e i nf or m ati o n i s t h e s a m e a s t h at of t h e d at e 
of fir st d o s e i n 2 0 5 M S 3 0 3, a n d t h e e v e nt di d n ot e n d pri or t o fir st d o s e, t h e d at e of fir st d o s e i n 
2 0 5 M S 3 0 3 will b e u s e d a s t h e i m p ut e d d at e.  Ot h er wi s e f or a d v er s e e v e nt s, a n d al w a y s f or t h e st art 
of c o n c o mit a nt m e di c ati o n s, t h e e arli e st p o s si bl e st art d at e b a s e d o n a v ail a bl e p arti al i nf or m ati o n will 
b e u s e d.  N a m el y, if o nl y t h e d a y i s mi s si n g, t h e 1 st of t h e m o nt h will b e u s e d; if t h e m o nt h i s al s o 
mi s si n g, J a n u ar y 1 st will b e u s e d. E n d d at e s f or c o n c o mit a nt m e di c ati o n s a n d a d v er s e e v e nt s will n ot 
b e i m p ut e d.  F or e v al u ati o n s ot h er t h a n a d v er s e e v e nt s a n d c o n c o mit a nt m e di c ati o n s , mi s si n g or 
i n c o m pl et e d at e s t h at ar e n e e d e d f or a n al y si s will al s o b e i m p u t e d. If t h e d a y i s mi s si n g f or a st u d y 
pr o c e d ur e or a s s e s s m e nt b ut t h e m o nt h a n d y e ar ar e pr e s e nt, t h e d a y will b e i m p ut e d a s t h e 1 5 t h of 
t h e m o nt h. M o nt h a n d y e ar will n ot b e i m p ut e d f or st u d y pr o c e d ur e s or a s s e s s m e nt s.  T h e s e s a m e 
r ul e s will b e a p pli e d t o mi s si n g or i n c o m pl et e d at e s f or r el a p s e s.   
 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
2 7  
6.  St u d y S u bj e ct s  
6. 1.  S u bj e ct A c c o u nt a bilit y  
 
T h e di s p o siti o n of s u bj e ct s will b e s u m m ari z e d  f or t h e 2 0 5 M S 3 0 1 -3 0 3  I T T po p ul ati o n , i n cl u di n g t h e 
n u m b er a n d p er c e nt a g e of s u bj e ct s w h o r e c ei v e d tr e at m e nt, di s c o nti n u e d t r e at m e nt, or wit h dr e w 
fr o m t h e st u d y. R e a s o n s f or wit h dr a w al or tr e at m e nt di s c o nti n u ati o n will al s o b e s u m m ari z e d.  
T h e di s p o siti o n of s u bj e ct s  e nr olli n g f r o m St u d y 2 0 5 M S 2 0 3 or St u d y 2 0 5 M S 3 0 2 I nt o St u d y 
2 0 5 M S 3 0 3  will b e s u m m ari z e d, i n cl u di n g t h e n u m b er a n d p er c e nt a g e of s u bj e ct s w h o r e c ei v e d 
tr e at m e nt, di s c o nti n u e d tr e at m e nt, or wit h dr e w fr o m t h e st u d y. R e a s o n s f or wit h dr a w al or tr e at m e nt 
di s c o nti n u ati o n will al s o b e s u m m ari z e d.  
 
6. 2.  D e m o gr a p h y a n d B a s eli n e Di s e a s e C h ar a ct eri sti c s  
6. 2. 1.  D e m o gr a p h y a n d B a s eli n e Di s e a s e C h ar a ct eri sti c s  f or t h e 2 0 5 M S 3 0 1 -3 0 3  
I T T Po p ul ati o n  
D e m o gr a p hi c d at a c o ll e ct e d at t h e st art of 2 0 5 M S 3 0 1 st u d y  (2 0 5 M S 3 0 1  B a s eli n e ) a n d at t h e st art of 
2 0 5 M S 3 0 3 st u d y  (2 0 5 M S 3 0 3 B a s eli n e ) f or t h e 2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n will b e s u m m ari z e d b y 
pr e vi o u s 2 0 5 M S 3 0 1 tr e at m e nt gr o u p a n d f or all s u bj e ct s c o m bi n e d.  D e m o gr a p hi c d at a will i n cl u d e  
a g e at b a s eli n e ( y e ar s), a g e c at e g or y ( < 1 8, 1 8-1 9, 2 0 -2 9, 3 0 -3 9, 4 0 -4 9, 5 0 -5 5, a n d > 5 5, al s o <  3 5, > 
3 5 ), g e n d er, h ei g ht, r a c e c at e g or y a n d w ei g ht ( k g).  
M e di c al hi st or y ( c oll e ct e d at t h e st art of 2 0 5 M S 3 0 1 a n d u p d at e d si n c e) will b e s u m m ari z e d b y pri or  
tr e at m e nt gr o u p i n t h e 2 0 5 M S 3 0 1 st u d y a n d f or all s u bj e ct s c o m bi n e d f or t h e 2 0 5 M S 3 0 1 -3 0 3  I T T 
p o p ul ati o n . Ot h er b a s eli n e c h ar a ct eri sti c d at a at 2 0 5 M S 3 0 1  B a s eli n e  a n d at 2 0 5 M S 3 0 3 B a s eli n e  
( e. g., E D S S t e st s c or e s , t h e n u m b er of r el a p s e s  i n a y e ar pri or t o b a s eli n e, M RI e n d p oi nt s) will al s o 
b e s u m m ari z e d f or t h e 2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n u si n g d e s cri pti v e st ati sti c s b y 2 0 5 M S 3 0 1 
tr e at m e nt gr o u p a n d f or all s u bj e ct s c o m bi n e d.  
E D S S t e st s c or e at t h e 2 0 5 M S 3 0 3 b a s eli n e i s d efi n e d a s s c or e at t h e m o st r e c e nt a s s e s s m e nt pri or 
t o t h e fir st d o s e i n 2 0 5 M S 3 0 3, e x cl u di n g a s s e s s m e nt s o c c urri n g wit hi n 2 9 d a y s aft er a r el a p s e o n s et.  
T h e f oll o wi n g M RI c h ar a ct eri sti c s will b e pr e s e nt e d f or t h e 2 0 5 M S 3 0 1 b a s eli n e a n d t h e 2 0 5 M S 3 0 3 
b a s eli n e i n t h e 2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n: t h e n u m b er of G d l e si o n s, t h e n u m b er a n d v ol u m e of 
T 2 h y p eri nt e n s e  l e si o n s, a n d t h e n u m b er a n d v ol u m e of T 1 h y p oi nt e n s e l e si o n s.  
 
6. 2. 2.  D e m o gr a p h y a n d B a s eli n e Di s e a s e C h ar a ct eri sti c s f or  t h e 2 0 5 M S 2 0 3 -3 0 3  
I T T Po p ul ati o n  
D e m o gr a p hi c d at a c oll e ct e d at t h e st art of 2 0 5 M S 3 0 3 st u d y ( 2 0 5 M S 3 0 3 B a s eli n e) f or t h e 2 0 5 M S 2 0 3 -
3 0 3  I T T p o p ul ati o n will b e s u m m ari z e d f or all s u bj e ct s c o m bi n e d.  
M e di c al hi st or y ( c oll e ct e d at t h e st art of 2 0 5 M S 2 0 1 a n d u p d at e d si n c e) will b e s u m m ari z e d f or all 
s u bj e ct s c o m bi n e d f or t h e 2 0 5 M S 2 0 3 -3 0 3  I T T p o p ul ati o n. Ot h er b a s eli n e c h ar a ct eri sti c d at a at 
2 0 5 M S 3 0 3 B a s eli n e ( e. g., E D S S t e st s c or e s, t h e n u m b er of r el a p s e s i n a y e ar pri or t o b a s eli n e) will 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
2 8  
al s o b e s u m m ari z e d f or t h e 2 0 5 M S 2 0 3 -3 0 3  I T T p o p ul ati o n u si n g d e s cri pti v e st ati sti c s f or all s u bj e ct s 
c o m bi n e d.  
 
6. 2. 3.  D e m o gr a p h y a n d B a s eli n e Di s e a s e C h ar a ct eri sti c s f or t h e 2 0 5 M S 3 0 2 -3 0 3  
I T T P o p ul ati o n  
D e m o gr a p hi c d at a c o ll e ct e d at t h e st art of 2 0 5 M S 3 0 3 st u d y  (2 0 5 M S 3 0 3 B a s eli n e ) f or t h e 2 0 5 M S 3 0 2-
3 0 3  I T T p o p ul ati o n will b e s u m m ari z e d f or all s u bj e ct s c o m bi n e d.  
M e di c al hi st or y ( c oll e ct e d at t h e st art of 2 0 5 M S 3 0 2  a n d u p d at e d si n c e) will b e s u m m ari z e d f or t h e 
2 0 5 M S 3 0 2 -3 0 3  I T T p o p ul ati o n. Ot h er b a s eli n e c h ar a ct eri sti c d at a at 2 0 5 M S 3 0 3 B a s eli n e  ( e. g., 
E D S S t e st  s c or e s , t h e n u m b er of r el a p s e s  i n a y e ar pri or t o b a s eli n e ) will al s o b e s u m m ari z e d f or t h e 
2 0 5 M S 3 0 2 -3 0 3  I T T p o p ul ati o n.  
 
6. 3.  E xt e nt of E x p o s ur e  
6. 3. 1.  E xt e nt of E x p o s ur e  f or t h e 2 0 5 M S 3 0 1 -2 0 5 M S 3 0 3 S t u d y Po p ul ati o n  
T h e n u m b er of d o s e s of D A C H Y P r e c ei v e d i n 2 0 5 M S 3 0 3  a n d i n t ot al , p er s u bj e ct, will b e 
s u m m ari z e d f or t h e 2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n b y pri or  tr e at m e nt gr o u p i n t h e 2 0 5 M S 3 0 1 st u d y 
a n d f or all s u bj e ct s c o m bi n e d.   
Ti m e o n st u d y ( d a y s) will b e c o m p ut e d f or e a c h s u bj e ct a s ( d at e of st u d y c o m pl eti o n or wit h dr a w al) –  
( d at e of fir st d o s e i n 2 0 5 M S 3 0 3) + 1 d a y.  
 
6. 3. 2.  E xt e nt of E x p o s ur e f or t h e  2 0 5 M S 2 0 3 -2 0 5 M S 3 0 3 S t u d y P o p ul ati o n  
T h e n u m b er of d o s e s of D A C H Y P r e c ei v e d i n t h e 2 0 5 M S 3 0 3  st u d y  a n d i n t ot al , p er s u bj e ct, will b e 
s u m m ari z e d f or all s u bj e ct s c o m bi n e d .  
Ti m e o n st u d y ( d a y s) i n t h e 2 0 5 M S 3 0 3 st u d y  will b e c o m p ut e d f or e a c h s u bj e ct a s ( d at e of st u d y 
c o m pl eti o n or wit h dr a w al) –  ( d at e of fir st d o s e i n 2 0 5 M S 3 0 3) + 1 d a y.  
 
6. 3. 3.  E xt e nt of E x p o s ur e f or t h e  2 0 5 M S 3 0 2 -2 0 5 M S 3 0 3 S t u d y P o p ul ati o n  
T h e n u m b er of d o s e s of D A C H Y P r e c ei v e d i n t h e 2 0 5 M S 3 0 3  st u d y a n d i n t ot al , p er s u bj e ct, will b e 
s u m m ari z e d f or all s u bj e ct s c o m bi n e d .  
Ti m e o n st u d y ( d a y s) i n t h e 2 0 5 M S 3 0 3 st u d y  will b e c o m p ut e d f or e a c h s u bj e ct a s ( d at e of st u d y 
c o m pl eti o n or wit h dr a w al) –  ( d at e of fir st d o s e i n 2 0 5 M S 3 0 3) + 1 d a y.  
 
6. 4.  C o n c o mit a nt T h er a p y  
 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
2 9  
M e di c ati o n s ( pr e s cri b e d or o v er -t h e-c o u nt er) a n d n o n -dr u g t h er a pi e s ar e c o n si d er e d c o n c o mit a nt if 
t h e y ar e u s e d d uri n g t h e st u d y (i. e., eit h er st art e d pri or t o t h e st u d y an d c o nti n u e d w hil e o n st u d y or 
st art e d aft er t h e fir st d o s e of st u d y tr e at m e nt).  M e di c ati o n s st art e d m or e t h a n 1 8 0 d a y s aft er t h e l a st 
d o s e of st u d y tr e at m e nt ar e n ot c o n si d er e d c o n c o mit a nt. T h e W orl d H e alt h Or g a ni z ati o n ( W H O) 
di cti o n ar y will b e u s e d f or c o di n g c o n c o mit a nt m e di c ati o n, a n d t h e M e di c al Di cti o n ar y f or R e g ul at or y 
Aff air s ( M e d D R A) will b e u s e d f or c o di n g c o n c o mit a nt n o n -dr u g t h er a pi e s.  
T h e n u m b er a n d p er c e nt a g e of s u bj e ct s t a ki n g a n y c o n c o mit a nt m e di c ati o n s  i n 2 0 5 M S 3 0 3 will b e 
r e p ort e d f or t h e 2 0 5 M S 3 0 1 -3 0 3  s af et y p o p ul ati o n , t h e 2 0 5 M S 2 0 3 -3 0 3  S af et y P o p ul ati o n , a n d t h e 
2 0 5 M S 3 0 2 -3 0 3  S af et y P o p ul ati o n , r e s p e cti v el y. T h e m o st fr e q u e nt c o n c o mit a nt m e di c ati o n s, d efi n e d 
a s t h o s e t a k e n b y at l e a st 1 0 % of s u bj e ct s, a n d u s e of alt er n ati v e M S m e di c ati o n s a n d st er oi d s m a y  
al s o b e s u m m ari z e d.   
T h e li st of p ot e nti al h e p at ot o xi c m e di c ati o n s i s d efi n e d a n d a gr e e d b y S A B R pri or t o d at a b a s e l o c k . 
T h e n u m b er a n d p er c e nt a g e of s u bj e ct s t a ki n g a n y p ot e nti al h e p at ot o xi c c o n c o mit a nt m e di c ati o n s  i n 
2 0 5 M S 3 0 3  will b e r e p ort e d f or t h e 2 0 5 M S 3 0 1 -3 0 3  s af et y p o p ul ati o n, t h e 2 0 5 M S 2 0 3 -3 0 3  S af et y 
P o p ul ati o n, a n d t h e 2 0 5 M S 3 0 2 -3 0 3  S af et y P o p ul ati o n , r e s p e cti v el y.  
 
7.  Effi c a c y D at a  
7. 1.  S u m m ar y of Effi c a c y A n al y s e s  
T a bl e  7  s h o w s t h e o v er all s u m m ar y of t h e effi c a c y a n al y s e s.  
 
F or t h e 2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n, e ffi c a c y a n al y s e s will b e p erf or m e d i n t h e 2 0 5 M S 3 0 3 
Tr e at m e nt  P eri o d a n d  t h e C o m bi n e d St u d y P eri o d. S el e ct e d a n al y s e s will b e al s o d o n e f or t h e 
2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n i n t h e 2 0 5 M S 3 0 1 Tr e at m e nt P eri o d f or e v al u ati o n  wit h c orr e s p o n di n g 
r e s ult s i n t h e 2 0 5 M S 3 0 3 Tr e at m e nt p eri o d ( e. g., f or t h e a n n u ali z e d r el a p s e r at e). F or t h e c o m bi n e d 
st u d y p eri o d, d at a  fr o m t h e l a st d o s e of st u d y tr e at m e nt i n 2 0 5 M S 3 0 1 t o t h e fir st d o s e of st u d y 
tr e at m e nt i n 2 0 5 M S 3 0 3 will al s o  b e i n cl u d e d i n t h e a n al y si s.  
 
F or t h e 2 0 5 M S 2 0 3 -3 0 3  I T T p o p ul ati o n, e ffi c a c y a n al y s e s will b e p erf or m e d i n t h e 2 0 5 M S 3 0 3 
Tr e at m e nt P eri o d, a n d will b e  s u m m ari z e d f or all s u bj e ct s c o m bi n e d . F or t h e 2 0 5 M S 3 0 2 -3 0 3  I T T 
p o p ul ati o n, e ffi c a c y a n al y s e s will b e p erf or m e d i n th e 2 0 5 M S 3 0 3 Tr e at m e nt P eri o d . N ot e t h at f or 
s u bj e ct s i n t h e 2 0 5 M S 2 0 3 -3 0 3 I T T p o p ul ati o n a n d t h e 2 0 5 M S 3 0 2 -3 0 3 I T T p o p ul ati o n , d u e t o t h e 
i n h er e nt differ e n c e i n d o si n g a n d tr e at m e nt i n t h eir pr e vi o u s st u di e s , effi c a c y a n al y s e s will o nl y b e 
p erf or m e d i n t h e 2 0 5 M S 3 0 3 Tr e at m e nt P eri o d.  
 
T a bl e  7 : S u m m ar y of p o p ul ati o n s  a n d tr e at m e nt  p eri o d s  f or effi c a c y a n al y s e s 
P o p ul ati o n  
St u d y/ Tr e at m e nt P eri o d  
B a s eli n e  
2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n 
2 0 5 M S 3 0 1  Tr e at m e nt P eri o d  
2 0 5 M S 3 0 1 B a s eli n e  
2 0 5 M S 3 0 3 Tr e at m e nt P eri o d  
2 0 5 M S 3 0 3  B a s eli n e  
C o m bi n e d St u d y P eri o d   
2 0 5 M S 3 0 1 B a s eli n e  
2 0 5 M S 2 0 3 -3 0 3 I T T p o p ul ati o n  
2 0 5 M S 3 0 3 Tr e at m e nt P eri o d  
2 0 5 M S 3 0 3  B a s eli n e  
2 0 5 M S 3 0 2 -3 0 3 I T T p o p ul ati o n  
2 0 5 M S 3 0 3 Tr e at m e nt P eri o d  
2 0 5 M S 3 0 3  B a s eli n e  
 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
3 0  
 
T h e f oll o wi n g t hr e e t a bl es  i n cl u d e e n d p oi nt s, a n al y si s p o p ul ati o n s , b a s eli n e t y p e wit h a s h ort 
s u m m ar y of  st ati sti c al m e t h o d s f or t h e effi c a c y a n al y s e s.  S e cti o n s b el o w i n cl u d e m o r e d et ail s a b o ut 
t h e s e a n al y s e s.  
 
 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
          3 1  
T a bl e  8 : S u m m ar y of effi c a c y a n al y z e s  f or t h e 2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n  
E n d p oi nt  
P o p ul ati o n  
St u d y/ Tr e at m e nt 
P eri o d  
B a s eli n e  
St ati sti c al M et h o d s  
A n n u ali z e d r el a p s e r at e  
 
2 0 5 M S 3 0 1 -3 0 3  I T T 
p o p ul ati o n  
C o m bi n e d St u d y 
P eri o d   
2 0 5 M S 3 0 1 
B a s eli n e  
U n a dj u st e d a n d a dj u st e d A R R.  A dj u st e d A R R 
will b e e sti m at e d fr o m t h e n e g ati v e bi n o mi al 
m o d el, a dj u sti n g f or a g e, pri or I F N b et a, 
b a s eli n e E D S S a n d b a s eli n e r el a p s e r at e at 
t h e 2 0 5 M S 3 0 1 B a s eli n e . 
2 0 5 M S 3 0 1 
Tr e at m e nt P eri o d  
2 0 5 M S 3 0 1 
B a s eli n e  
A s a b o v e  
2 0 5 M S 3 0 3 
Tr e at m e nt  P eri o d  
2 0 5 M S 3 0 3 
B a s eli n e  
A s a b o v e.  C o v ari at e s will i n cl u d e pri or I F N 
b et a at t h e 2 0 5 M S 3 0 1 B a s eli n e , a g e at t h e 
2 0 5 M S 3 0 3  B a s eli n e , b a s eli n e E D S S , a n d t h e 
n u m b er of r el a p s e s i n a y e ar pri or t o 
2 0 5 M S 3 0 3 b a s eli n e.  
A n n u ali z e d r el a p s e r at e  
b y y e ar  
 
2 0 5 M S 3 0 1 -3 0 3  I T T 
p o p ul ati o n  
2 0 5 M S 3 0 1 
Tr e at m e nt P eri o d  
2 0 5 M S 3 0 1 
B a s eli n e  
U n a dj u st e d a n d a dj u st e d A R R.  A dj u st e d A R R 
will b e e sti m at e d fr o m t h e P oi s s o n  m o d el, 
a dj u sti n g f or a g e, pri or I F N b et a, b a s eli n e 
E D S S a n d b a s eli n e r el a p s e r at e at t h e 
2 0 5 M S 3 0 1 B a s eli n e.  
2 0 5 M S 3 0 3 
Tr e at m e nt  P eri o d  
2 0 5 M S 3 0 3 
B a s eli n e  
A s a b o v e.  C o v ari at e s will i n cl u d e pri or I F N 
b et a at t h e 2 0 5 M S 3 0 1 B a s eli n e , a g e at t h e 
2 0 5 M S 3 0 3  B a s eli n e , b a s eli n e E D S S , a n d t h e 
n u m b er of r el a p s e s i n a y e ar pri or t o 
2 0 5 M S 3 0 3 b a s eli n e.  
Pr o p orti o n of s u bj e ct s 
w h o r el a p s e d at s el e ct e d 
ti m e p oi nt s  
2 0 5 M S 3 0 1 -3 0 3  I T T 
p o p ul ati o n  
C o m bi n e d St u d y 
P eri o d  
2 0 5 M S 3 0 1 
B a s eli n e  
K a pl a n -M ei er c ur v e of ti m e t o fir st r el a p s e will 
b e u s e d t o e sti m at e t h e pr o p orti o n at s el e ct e d 
ti m e p oi nt s.  
2 0 5 M S 3 0 3  
Tr e at m e nt P eri o d  
2 0 5 M S 3 0 3 
B a s eli n e  
A s a b o v e  
Pr o p orti o n of s u bj e ct s 
wit h  6 -m o nt h  s u st ai n e d 
di s a bilit y pr o gr e s si o n 
m e a s ur e d b y E D S S at 
s e l ect e d ti m e  p oi nt s  
2 0 5 M S 3 0 1 -3 0 3  I T T 
p o p ul ati o n  
C o m bi n e d St u d y 
P eri o d  
2 0 5 M S 3 0 1  
B a s eli n e  
K a pl a n M ei er a n al y si s of ti m e t o t h e 6 -m o nt h 
s u st ai n e d di s a bilit y pr o gr e s si o n will b e u s e d t o 
e sti m at e t h e pr o p orti o n at s el e ct e d ti m e 
p oi nt s.  
2 0 5 M S 3 0 3 
Tr e at m e nt  P eri o d  
2 0 5 M S 3 0 3  
B a s eli n e  
A s a b o v e  
 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
3 2  
E n d p oi nt  
P o p ul ati o n  
St u d y/ Tr e at m e nt 
P eri o d  
B a s eli n e  
St ati sti c al M et h o d s  
E Q -5 D :  E Q 5 D V A S, 
E Q -5 D i n d e x s c or e a n d 
E Q -5 D i n di vi d u al 
q u e sti o n s  
2 0 5 M S 3 0 1 -3 0 3  I T T 
p o p ul ati o n  
2 0 5 M S 3 0 3 
Tr e at m e nt  P eri o d  
2 0 5 M S 3 0 3  
B a s eli n e  
D e s cri pti v e st ati sti c s b y pr e vi o u s tr e at m e nt 
gr o u p i n 2 0 5 M S 3 0 1 a n d b y st u d y vi sit i n 
2 0 5 M S 3 0 3.   
M RI e n d p oi nt s at 
s el e ct e d vi sit s  of t h e 
2 0 1 5 M S 3 0 1 a n d  
2 0 1 5 M S 3 0 3 st u di e s :  
1) t ot al n u m b er of n e w 
or n e wl y -e nl ar gi n g T 2 
h y p eri nt e n c e l e si o n s  
2) t ot al n u m b er of n e w 
T 1 h y p oi nt e n s e l e si o n s  
3)  t ot al n u m b er of G d 
l e si o n 
4) t ot al v ol u m e of T 2 
h y p eri nt e n c e l e si o n s  
5) t h e v ol u m e of n e w or 
n e wl y e nl ar gi n g T 2 
l e si o n s 
6) t ot al v ol u m e of n e w 
T 1 h y p oi nt e n s e l e si o n s   
7)  P er c e nt Br ai n V ol u m e 
C h a n g e ( P B V C)  
2 0 5 M S 3 0 1 -3 0 3  I T T 
p o p ul ati o n  
2 0 5 M S 3 0 1 
Tr e at m e nt P eri o d  
2 0 5 M S 3 0 1 
B a s eli n e  
D e s cri pti v e st ati sti c s b y pr e vi o u s tr e at m e nt 
gr o u p i n 2 0 5 M S 3 0 1 a n d b y st u d y vi sit i n 
2 0 5 M S 3 0 1 st u d y.   
F or t h e t ot al n u m b er of n e w or n e wl y 
e nl ar gi n g T 2 l e si o n s a n d t h e t ot al n u m b er of 
n e w T 1 l e si o n s: n e g ati v e bi n o mi al m o d el, 
a dj u st e d f or 3 0 1 b a s eli n e c h ar a ct eri sti c s.  
2 0 5 M S 3 0 1 -3 0 3  I T T 
p o p ul ati o n  
2 0 5 M S 3 0 3 
Tr e at m e nt  P eri o d  
2 0 5 M S 3 0 3  
B a s eli n e  
D e s cri pti v e st ati sti c s b y pr e vi o u s tr e at m e nt 
gr o u p i n 2 0 5 M S 3 0 1 a n d b y st u d y vi sit i n 
2 0 5 M S 3 0 3 st u d y .   
F or t h e t ot al n u m b er of n e w or n e wl y 
e nl ar gi n g T 2 l e si o n s a n d t h e  t ot al n u m b er of 
n e w T 1 l e si o n s: n e g ati v e bi n o mi al m o d el, 
a dj u st e d f or 3 0 3  b a s eli n e c h ar a ct eri sti c s.  
P B V C will b e a n al y z e d d uri n g t h e 2 0 5 M S 3 0 3 
tr e at m e nt p eri o d a n d wit h eit h er 2 0 5 M S 3 0 1 or 
2 0 5 M S 3 0 3 b a s eli n e.  
E D S S:  a ct u al s c or e a n d 
c h a n g e fr o m b a s eli n e  
2 0 5 M S 3 0 1 -3 0 3  I T T 
p o p ul ati o n  
2 0 5 M S 3 0 3 
Tr e at m e nt  P eri o d  
2 0 5 M S 3 0 3  
B a s eli n e  
D e s cri pti v e st ati sti c s b y pr e vi o u s tr e at m e nt 
gr o u p i n 2 0 5 M S 3 0 1 a n d b y st u d y vi sit i n 
2 0 5 M S 3 0 3.  
M S F C z -s c or e a n d 
c o m p o n e nt z -s c or e s : 
a ct u al v al u e a n d c h a n g e 
fr o m b a s eli n e 
 
2 0 5 M S 3 0 1 -3 0 3  I T T 
p o p ul ati o n  
C o m bi n e d St u d y 
P eri o d  
2 0 5 M S 3 0 1 
B a s eli n e  
D e s cri pti v e st ati sti c s b y pr e vi o u s tr e at m e nt 
gr o u p i n 2 0 5 M S 3 0 1 a n d b y st u d y vi sit i n 
2 0 5 M S 3 0 1 a n d 2 0 5 M S 3 0 3.  S e e s e cti o n 8. 4. 3.  
2 0 5 M S 3 0 3 
Tr e at m e nt  P eri o d  
2 0 5 M S 3 0 3  
B a s eli n e  
D e s cri pti v e st ati sti c s b y pr e vi o u s tr e at m e nt 
gr o u p i n 2 0 5 M S 3 0 1 a n d b y st u d y vi sit i n 
2 0 5 M S 3 0 3.  S e e s e cti o n 8. 4. 3.  
P A S A 3: a ct u al v al u e 
a n d c h a n g e fr o m 
b a s eli n e  
2 0 5 M S 3 0 1 -3 0 3  I T T 
p o p ul ati o n  
C o m bi n e d St u d y 
P eri o d  
2 0 5 M S 3 0 1 
B a s eli n e  
D e s cri pti v e st ati sti c s b y pr e vi o u s tr e at m e nt 
gr o u p i n 2 0 5 M S 3 0 1 a n d b y st u d y vi sit i n 
2 0 5 M S 3 0 1 a n d 2 0 5 M S 3 0 3.  


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
3 3  
E n d p oi nt  
P o p ul ati o n  
St u d y/ Tr e at m e nt 
P eri o d  
B a s eli n e  
St ati sti c al M et h o d s  
2 0 5 M S 3 0 3 
Tr e at m e nt  P eri o d  
2 0 5 M S 3 0 3  
B a s eli n e  
D e s cri pti v e st ati sti c s b y pr e vi o u s tr e at m e nt 
gr o u p i n 2 0 5 M S 3 0 1 a n d b y st u d y vi sit i n 
2 0 5 M S 3 0 3.  
S D M T:  a ct u al s c or e a n d 
c h a n g e fr o m b a s eli n e;  
pr o p orti o n of s u bj e ct s 
wit h a ≥ 3 or ≥ 4  d e cli n e  
fr o m b a s eli n e; 
pr o p orti o n of s u bj e ct s 
wit h a ≥ 3 or ≥ 4 
i n cr e a s e fr o m b a s eli n e. 
2 0 5 M S 3 0 1 -3 0 3  I T T 
p o p ul ati o n  
C o m bi n e d St u d y 
P eri o d  
2 0 5 M S 3 0 1 
B a s eli n e  
D e s cri pti v e st ati s ti c s b y pr e vi o u s tr e at m e nt 
gr o u p i n 2 0 5 M S 3 0 1 a n d b y st u d y vi sit i n 
2 0 5 M S 3 0 1 a n d 2 0 5 M S 3 0 3.  
2 0 5 M S 3 0 3 
Tr e at m e nt  P eri o d  
2 0 5 M S 3 0 3  
B a s eli n e  
D e s cri pti v e st ati sti c s b y pr e vi o u s tr e at m e nt 
gr o u p i n 2 0 5 M S 3 0 1 a n d b y st u d y vi sit i n 
2 0 5 M S 3 0 3.  
M SI S -2 9 p h y si c al s c or e  
a n d  
M SI S -2 9 p s y c h ol o gi c al 
s c or e : a ct u al s c or e a n d 
c h a n g e fr o m b a s eli n e;  
p r o p orti o n of s u bj e ct s 
wit h a > = 7. 5 w or s e ni n g 
fr o m b a s eli n e i n M SI S-
2 9 p h y si c al s c or e.  
2 0 5 M S 3 0 1 -3 0 3  I T T 
p o p ul ati o n  
2 0 5 M S 3 0 3 
Tr e at m e nt  P eri o d  
2 0 5 M S 3 0 3  
B a s eli n e  
D e s cri pti v e st ati sti c s b y pr e vi o u s tr e at m e nt 
gr o u p i n 2 0 5 M S 3 0 1 a n d b y st u d y vi sit i n 
2 0 5 M S 3 0 3.  
Pr o p orti o n of s u bj e ct s 
w h o ar e fr e e fr o m 
di s e a s e  a cti vit y  
2 0 5 M S 3 0 1 -3 0 3  I T T 
p o p ul ati o n  
2 0 5 M S 3 0 3 
Tr e at m e nt  P eri o d  
2 0 5 M S 3 0 3  
B a s eli n e  
D e s cri pti v e st ati sti c s b y pr e vi o u s tr e at m e nt 
gr o u p i n 2 0 5 M S 3 0 1  
H R U: M S -r el at e d a n d 
n o n -M S r el at e d vi sit s  
2 0 5 M S 3 0 1 -3 0 3  I T T 
p o p ul ati o n  
2 0 5 M S 3 0 1 
Tr e at m e nt P eri o d  
 
D e s cri pti v e st ati sti c s f or t h e n u m b er of 
u n s c h e d ul e d sit e vi sit s b y pr e vi o u s tr e at m e nt 
gr o u p i n 2 0 5 M S 3 0 1 a n d b y vi sit  i n 2 0 5 M S 3 0 1 
st u d y.   
2 0 5 M S 3 0 3 
Tr e at m e nt P eri o d  
 
D e s cri pti v e st ati sti c s f or t h e n u m b er of 
u n s c h e d ul e d sit e vi sit s b y pr e vi o u s tr e at m e nt 
gr o u p i n 2 0 5 M S 3 0 1 a n d b y vi sit  i n 2 0 5 M S 3 0 3 
st u d y.   
H R P Q  
2 0 5 M S 3 0 1 -3 0 3  I T T 
p o p ul ati o n  
2 0 5 M S 3 0 3 
Tr e at m e nt P eri o d  
 
D e s cri pti v e st ati sti c s b y pr e vi o u s tr e at m e nt 
gr o u p i n 2 0 5 M S 3 0 1 a n d b y st u d y vi sit i n 
2 0 5 M S 3 0 3 st u d y.   
 
 
 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
3 4  
T a bl e 9 : S u m m ar y of effi c a c y a n al y z e s  f or t h e 2 0 5 M S 2 0 3 -3 0 3  I T T p o p ul ati o n 
E n d p oi nt  
St u d y/ Tr e at m e nt 
P eri o d  
B a s eli n e  
St ati sti c al M et h o d s  
A n n u ali z e d r el a p s e r at e  
 
2 0 5 M S 3 0 3 
Tr e at m e nt P eri o d  
2 0 5 M S 3 0 3  
B a s eli n e  
U n a dj u st e d a n d a dj u st e d A R R f or all s u bj e ct s c o m bi n e d .  A dj u st e d 
A R R will b e e sti m at e d fr o m t h e n e g ati v e bi n o mi al/ P oi s s o n m o d el, 
a dj u sti n g f or b a s eli n e r el a p s e r at e at t h e 2 0 5 M S 3 0 3  B a s eli n e  
A n n u ali z e d r el a p s e r at e  b y 
4 8 -w e e k ti m e i nt er v al  
 
2 0 5 M S 3 0 3 
Tr e at m e nt P eri o d  
2 0 5 M S 3 0 3  
B a s eli n e  
U n a dj u st e d a n d a dj u st e d A R R  f or all s u bj e ct s c o m bi n e d.  A dj u st e d 
A R R will b e e sti m at e d fr o m t h e P oi s s o n m o d el, a dj u sti n g f or b a s eli n e 
r el a p s e r at e at t h e 2 0 5 M S3 0 3  B a s eli n e . 
Pr o p orti o n of s u bj e ct s w h o 
r el a p s e d at s el e ct e d ti m e 
p oi nt s  
2 0 5 M S 3 0 3 
Tr e at m e nt P eri o d  
2 0 5 M S 3 0 3  
B a s eli n e  
K a pl a n -M ei er c ur v e of ti m e t o fir st r el a p s e will b e u s e d t o e sti m at e t h e 
pr o p orti o n at s el e ct e d ti m e  p oi nt s  f or all s u bj e ct s c o m bi n e d  
Pr o p orti o n of s u bj e ct s wit h  6 -
m o nt h  s u st ai n e d di s a bilit y 
pr o gr e s si o n m e a s ur e d b y 
E D S S at s e l ect e d ti m e  p oi nt s  
2 0 5 M S 3 0 3 
Tr e at m e nt P eri o d  
2 0 5 M S 3 0 3  
B a s eli n e  
K a pl a n M ei er a n al y si s of ti m e t o t h e 6-m o nt h s u st ai n e d di s a bilit y 
pr o gr e s si o n  will b e u s e d t o e sti m at e t h e pr o p orti o n at s el e ct e d ti m e  
p oi nt s  f or all s u bj e ct s c o m bi n e d 
E D S S : a ct u al s c or e a n d 
c h a n g e fr o m b a s eli n e  
2 0 5 M S 3 0 3 
Tr e at m e nt P eri o d  
2 0 5 M S 3 0 3  
B a s eli n e  
D e s cri pti v e st ati sti c s b y st u d y vi sit i n 2 0 5 M S 3 0 3  f or all s u bj e ct s 
c o m bi n e d.   
E Q -5 D :  E Q 5 D V A S, E Q-5 D 
i n d e x s c or e a n d E Q-5 D 
i n di vi d u al q u e sti o n s 
2 0 5 M S 3 0 3 
Tr e at m e nt P eri o d  
2 0 5 M S 3 0 3  
B a s eli n e  
D e s cri pti v e st ati sti c s b y st u d y vi sit i n 2 0 5 M S 3 0 3  f or all s u bj e ct s 
c o m bi n e d.   
M RI e n d p oi nt s at s el e ct e d 
vi sit s of t h e 2 0 5 M S 3 0 3 st u d y  
2 0 5 M S 3 0 3  
Tr e at m e nt P eri o d  
 
D e s cri pti v e st ati sti c s b y st u d y vi sit i n 2 0 5 M S 3 0 3 st u d y  f or all s u bj e ct s 
c o m bi n e d.     
H R U: M S -r el at e d a n d n o n-
M S r el at e d vi sit s  
2 0 5 M S 3 0 3  
Tr e at m e nt P eri o d  
 
D e s cri pti v e st ati sti c s f or t h e n u m b er of u n s c h e d ul e d sit e vi sit s b y vi sit  
i n 2 0 5 M S 3 0 3 st u d y.   
H R P Q  
2 0 5 M S 3 0 3 
Tr e at m e nt P eri o d  
 
D e s cri pti v e st ati sti c s b y st u d y vi sit i n 2 0 5 M S 3 0 3 st u d y.   


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
          3 5  
T a bl e 1 0 : S u m m ar y of effi c a c y a n al y z e s  f or t h e 2 0 5 M S 3 0 2 -3 0 3  I T T p o p ul ati o n 
E n d p oi nt  
St u d y/ Tr e at m e nt 
P eri o d  
B a s eli n e  
St ati sti c al M et h o d s  
A n n u ali z e d r el a p s e r at e  
 
2 0 5 M S 3 0 3 Tr e at m e nt  
P eri o d  
2 0 5 M S 3 0 3  
B a s eli n e  
U n a dj u st e d a n d a dj u st e d A R R.  A dj u st e d A R R m a y 
b e e sti m at e d fr o m t h e n e g ati v e bi n o mi al/ P oi s s o n 
m o d el, a dj u sti n g f or b a s eli n e r el a p s e r at e at t h e 
2 0 5 M S 3 0 3  B a s eli n e . 
A n n u ali z e d r el a p s e r at e  b y 4 8 -w e e k 
i nt er v al 
 
2 0 5 M S 3 0 3 Tr e at m e nt  
P eri o d  
2 0 5 M S 3 0 3  
B a s eli n e  
U n a dj u st e d a n d a dj u st e d A R R.  A dj u st e d A R R m a y 
b e e sti m at e d fr o m t h e P oi s s o n m o d el, a dj u sti n g f or 
b a s eli n e r el a p s e r at e at t h e 2 0 5 M S 3 0 3  B a s eli n e . 
Pr o p orti o n of s u bj e ct s w h o r el a p s e d 
at s el e ct e d ti m e  p oi nt s  
2 0 5 M S 3 0 3 Tr e at m e nt  
P eri o d  
2 0 5 M S 3 0 3  
B a s eli n e  
K a pl a n -M ei er c ur v e of ti m e t o fir st r el a p s e will b e u s e d 
t o e sti m at e t h e pr o p orti o n at s el e ct e d ti m e p oi nt s.  
Pr o p orti o n of s u bj e ct s wit h  6 -m o nt h  
s u st ai n e d di s a bilit y pr o gr e s si o n 
m e a s ur e d b y E D S S at s e l ect e d ti m e  
p oi nt s  
2 0 5 M S 3 0 3 Tr e at m e nt  
P eri o d  
2 0 5 M S 3 0 3  
B a s eli n e  
K a pl a n M ei er a n al y si s of ti m e t o t h e 6-m o nt h 
s u st ai n e d di s a bilit y pr o gr e s si o n  will b e u s e d t o 
e sti m at e t h e pr o p orti o n at s el e ct e d ti m e  p oi nt s.  
E D S S : a ct u al s c or e a n d c h a n g e fr o m 
b a s eli n e  
2 0 5 M S 3 0 3 Tr e at m e nt  
P eri o d  
2 0 5 M S 3 0 3  
B a s eli n e  
D e s cri pti v e st ati sti c s b y st u d y vi sit i n 2 0 5 M S 3 0 3.   
E Q -5 D :  E Q 5 D V A S, E Q-5 D i n d e x 
s c or e a n d E Q -5 D i n di vi d u al q u e sti o n s 
2 0 5 M S 3 0 3 Tr e at m e nt  
P eri o d  
2 0 5 M S 3 0 3  
B a s eli n e  
D e s cri pti v e st ati sti c s b y st u d y vi sit i n 2 0 5 M S 3 0 3.   
M RI e n d p oi nt s at s el e ct e d vi sit s of t h e 
2 0 5 M S 3 0 3 st u d y  
2 0 5 M S 3 0 3 Tr e at m e nt 
P eri o d  
 
 
D e s cri pti v e st ati sti c s b y st u d y vi sit i n 2 0 5 M S 3 0 3 
st u d y.   
H R U: M S -r el at e d a n d n o n-M S r el at e d 
vi sit s  
2 0 5 M S 3 0 3  Tr e at m e nt 
P eri o d  
 
D e s cri pti v e st ati sti c s f or t h e n u m b er of u n s c h e d ul e d 
sit e vi sit s b y vi sit  i n 2 0 5 M S 3 0 3 st u d y.   
H R P Q  
2 0 5 M S 3 0 3 Tr e at m e nt 
P eri o d  
 
D e s cri pti v e st ati sti c s b y st u d y vi sit i n 2 0 5 M S 3 0 3 
st u d y.   
 
 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
          3 6  
7. 2.  A n n u ali z e d R el a p s e R at e  
7. 2. 1.  A n n u ali z e d R el a p s e R at e i n t h e 2 0 5 M S 3 0 1 -3 0 3  I T T P o p ul ati o n  
I n St u d y 2 0 5 M S 3 0 1, r el a p s e s w er e d efi n e d a s n e w or r e c urr e nt n e ur ol o gi c al s y m pt o m s n ot 
a s s o ci at e d wit h f e v er or i nf e cti o n, l a sti n g at l e a st 2 4 h o ur s, a n d a c c o m p a ni e d b y n e w o bj e cti v e 
n e ur ol o gi c al fi n di n g s u p o n e x a mi n ati o n b y t h e E x a mi ni n g N e ur ol o gi st . I n a d diti o n , t h e s e r el a p s e s 
m u st h a v e b e e n  r e vi e w e d a n d c o nfir m e d b y t h e I n d e p e n d e nt N e ur ol o g y E v al u ati o n C o m mitt e e 
(I N E C).  
 
I n St u d y 2 0 5 M S 3 0 3, rel a p s e s ar e d efi n e d a s n e w or r e c urr e nt n e ur ol o gi c al s y m pt o m s n ot a s s o ci at e d 
wit h f e v er or i nf e cti o n, l a sti n g at l e a st 2 4 h o ur s, a n d a c c o m p a ni e d b y n e w o bj e cti v e n e ur ol o gi c al 
fi n di n g s u p o n e x a mi n ati o n b y t h e St u d y N e ur ol o gi st . T h e s u bj e ct m u st h a v e o bj e cti v e si g n s o n t h e 
e x a mi n ati o n c o nfir mi n g t h e e v e nt.  
 
T h er ef or e, St u di e s 2 0 5 M S 3 0 1 a n d 2 0 5 M S 3 0 3 utili z e e s s e nti all y t h e s a m e d efi niti o n f or o bj e cti v e (i. e., 
pr ot o c ol -d efi n e d) r el a p s e s, wit h t h e e x c e pti o n  t h at t h er e i s n o I n d e p e n d e nt N e ur ol o g y E v al u ati o n 
C o m mitt e e (I N E C) i n St u d y 2 0 5 M S 3 0 3 . B e c a u s e r el a p s e s i n 2 0 5 M S 3 0 3 w er e n ot e v al u at e d b y a n 
i n d e p e n d e nt c o m mitt e e, all i n v e sti g at or-c o nfir m e d r el a p s e s fr o m 2 0 5 M S 3 0 1 ar e i n cl u d e d w h et h er or 
n ot i n d e p e n d e ntl y c o nfir m e d . N e w or r e c urr e nt n e ur ol o gi c al s y m pt o m s t h at o c c urr e d l e s s t h a n 3 0 
d a y s f oll o wi n g t h e o n s et of a pr ot o c ol -d efi n e d r el a p s e will b e c o n si d er e d p art of t h e s a m e r el a p s e 
(i. e., r el a p s e s wit h o n s et d a y s ≤2 9 d a y s of o n e a n ot h er, will b e c o u nt e d a s 1 r el a p s e). 
T h e a n n u ali z e d r el a p s e r at e will b e s u m m ari z e d u si n g t h e f oll o wi n g st u d y p o p ul ati o n a n d st u d y 
p eri o d s : 
•  
2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n i n t h e c o m bi n e d st u d y p eri o d 
•  
2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n i n t h e 2 0 5 M S 3 0 1 Tr e at m e nt P eri o d a n d t h e 2 0 5 M S 3 0 3 
Tr e at m e nt p eri o d.  
T h e r el a p s e r at e will b e r e p ort e d u si n g r el a p s e s t h at o c c urr e d o n or aft er t h e fir st d o s e d at e d uri n g 
t h e a p pli c a bl e st u d y p eri o d. R el a p s e s t h at o c c ur aft er s u bj e ct s r e c ei v e alt er n ati v e M S m e di c ati o n s  
will b e e x cl u d e d fr o m t h e a n al y s e s of r el a p s e r at e, a n d t h e s u bj e ct’ s ti m e o n st u d y will b e c e n s or e d at 
t h e ti m e t h e alt er n ati v e M S m e di c ati o n i s a d d e d. F or e a c h a n al y si s p eri o d, t h e s u bj e ct’ s ti m e o n 
st u d y will b e c e n s or e d at t h e ti m e t h e alt er n ati v e M S m e di c ati o n  i n t h e gi v e n p eri o d . F or e x a m pl e, if a 
s u bj e ct fr o m t h e 2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n t o o k alt er n ati v e m e di c ati o n i n t h e 2 0 5 M S 3 0 1  st u d y 
b ef or e  th e fir st d o s e i n st u d y 2 0 5 M S 3 0 3  a n d i n t h e 2 0 5 M S 3 0 3 st u d y , t hi s s u bj e ct will b e i n cl u d e d i n 
t h e a n al y s e s of t h e 2 0 5 M S 3 0 3 Tr e at m e nt p eri o d  a n d will b e c e n s or e d at t h e ti m e t h e alt er n ati v e M S 
m e di c ati o n  i n t h e 2 0 5 M S 3 0 3 st u d y.  
 
T h e u n a dj u st e d A R R will b e c al c ul at e d a s t h e t ot al n u m b er of r el a p s e s e x p eri e n c e d d uri n g t h e gi v e n 
p eri o d, di vi d e d b y t h e t ot al n u m b er  of d a y s i n t h e st u d y p eri o d or t h e ti m e of c e n s ori n g, a n d t h e r ati o 
t h e n m ulti pli e d b y 3 6 5. 2 5. R el a p s e r at e m a y b e t a b u l at e d b y t h e 2 0 5 M S 3 0 1  st u d y tr e at m e nt gr o u p 
(I F N β -1 a  3 0 μ g a n d 1 5 0 m g D A C H Y P) .   
 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
3 7  
F or t h e c o m bi n e d st u d y p eri o d a n d t h e 2 0 5 M S 3 0 1 Tr e at m e nt P eri o d, t h e r el a p s e r at e will al s o b e 
e sti m at e d u si n g a n e g ati v e bi n o mi al m o d el, wit h a dj u st m e nt f or t h e f oll o wi n g c h ar a ct eri sti c s at t h e 
2 0 5 M S 3 0 1 B a s eli n e: b a s eli n e r el a p s e r at e ( n u m b er of r el a p s e s i n t h e 3-y e ar s pri or t o st u d y e ntr y 
di vi d e d b y 3), hi st or y of pri or I F N β u s e ( y e s/ n o, c oll e ct e d a s a str atifi c ati o n v ari a bl e i n I V R S), 
b a s eli n e E D S S ( E D S S ≤ 2. 5 v er s u s E D S S  >  2. 5)  a n d b a s eli n e a g e ( a g e ≤ 3 5 v er s u s a g e > 3 5). T h e 
l o g arit h mi c tr a n sf or m ati o n of t h e n u m b er of d a y s i n t h e st u d y will b e i n cl u d e d i n t h e m o d el a s t h e 
“ off s et” p ar a m et er. If t h e d at a ar e u n d er-di s p er s e d ( a s s e s s e d u si n g t h e P e ar s o n C hi -S q u ar e d 
st ati sti c) or if t h e n e g ati v e bi n o mi al m o d el d o e s n ot c o n v er g e, a P oi s s o n r e gr e s si o n m o d el will b e 
u s e d i n st e a d.  T h e P oi s s o n m o d el will b e a dj u st e d f or o v er -di s p er si o n u si n g a P e ar s o n s c al e 
p ar a m et er.  T h e tr e at m e nt gr o u p i s t h e pr e vi o u s tr e at m e nt gr o u p of t h e 2 0 5 M S 3 0 1 st u d y . F or t h e 
2 0 5 M S 3 0 3 Tr e at m e nt P eri o d, a si mil ar a n al y si s will b e d o n e. T h e a dj u st m e nt will b e p erf or m e d wit h 
t h e f oll o wi n g c h ar a ct eri sti c s: n u m b er of r el a p s e s i n a y e ar pri or t o t h e fir st d o s e i n 2 0 5 M S 3 0 3, hi st or y 
of pri or I F N β u s e at t h e 2 0 5 M S 3 0 1 b a s eli n e , a g e  ( a g e ≤ 3 5 v er s u s a g e > 3 5) at t h e 2 0 5 M S 3 0 3 
B a s eli n e a n d E D S S  (E D S S ≤ 2. 5 v er s u s E D S S  >  2. 5)  at t h e 2 0 5 M S 3 0 3 B a s eli n e.   
 
T o f urt h er a s s e s s t h e d ur a bilit y of tr e at m e nt, t h e r el a p s e r at e will al s o b e s u m m ari z e d b y y e ar f or t h e 
2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n i n t h e 2 0 5 M S 3 0 1 Tr e at m e nt P eri o d a n d t h e 2 0 5 M S 3 0 3 Tr e at m e nt 
P eri o d.  F or t h e s e a n al y s e s, r at e s will b e t a b ul at e d b y e v al u ati n g t h e n u m b er of r el a p s e s i n e a c h ti m e 
p eri o d a n d t h e a m o u nt of f oll o w -u p ti m e i n t h e ti m e p eri o d. A  P oi s s o n m o d el will b e u s e d t o e sti m at e 
t h e r el a p s e r at e i n e a c h ti m e p eri o d u nl e s s d at a ar e o v er -di s p er s e d  i n w hi c h c a s e a n e g ati v e 
bi n o mi al m o d el will b e u s e d.  
 
7. 2. 2.  A n n u ali z e d R el a p s e R at e i n  t h e 2 0 5 M S 2 0 3 -3 0 3  I T T P o p ul ati o n  
T h e a n n u ali z e d r el a p s e r at e will b e s u m m ari z e d f or t h e 2 0 5 M S 2 0 3 -3 0 3  I T T p o p ul ati o n i n t h e 
2 0 5 M S 3 0 3 Tr e at m e nt  p eri o d . T h e r el a p s e r at e will b e r e p ort e d u si n g r el a p s e s t h at o c c urr e d o n or 
aft er t h e fir st D A C H Y P d o s e d at e i n t h e 2 0 5 M S 3 0 3 Tr e at m e nt  p eri o d. R el a p s e s t h at o c c ur aft er 
s u bj e ct s r e c ei v e alt er n ati v e M S m e di c ati o n s will b e e x cl u d e d fr o m t h e a n al y s e s of r el a p s e r at e, a n d 
t h e s u bj e ct’ s ti m e o n st u d y will b e c e n s or e d at t h e ti m e t h e alt er n ati v e M S m e di c ati o n i s a d d e d. 
T h e u n a dj u st e d A R R will b e c al c ul at e d a s t h e t ot al n u m b er of r el a p s e s e x p eri e n c e d d uri n g t h e gi v e n 
p eri o d, di vi d e d b y t h e t ot al n u m b er of d a y s i n t h e p e ri o d or t h e ti m e of c e n s ori n g, a n d t h e r ati o t h e n 
m ulti pli e d b y 3 6 5. 2 5. R el a p s e r at e will b e t a b ul at e d f or all s u bj e ct s c o m bi n e d .   
F or t h e 2 0 5 M S 3 0 3 Tr e at m e nt  p eri o d, t h e r el a p s e r at e will al s o b e e sti m at e d u si n g a n e g ati v e 
bi n o mi al m o d el, wit h a dj u st m e nt f or t h e n u m b er of r el a p s e s i n a y e ar pri or t o t h e fir st d o s e i n 
2 0 5 M S 3 0 3 . T h e l o g arit h mi c tr a n sf or m ati o n of t h e n u m b er of d a y s i n t h e st u d y will b e i n cl u d e d i n t h e 
m o d el a s t h e “ off s et” p ar a m et er. If t h e d at a ar e u n d er -di s p er s e d ( a s s e s s e d u si n g t h e P e ar s o n  C hi -
S q u ar e d st ati sti c) or if t h e n e g ati v e bi n o mi al m o d el d o e s n ot c o n v er g e, a P oi s s o n r e gr e s si o n m o d el 
will b e u s e d i n st e a d. T h e P oi s s o n m o d el will b e a dj u st e d f or o v er -di s p er si o n u si n g a P e ar s o n s c al e 
p ar a m et er.  
T o f urt h er a s s e s s t h e d ur a bilit y of tr e at m e nt, t h e r el a p s e r at e will al s o b e s u m m ari z e d b y 4 8 -w e e k 
ti m e i nt er v als  d efi n e d i n t h e 2 0 5 M S 3 0 3 Tr e at m e nt  P eri o d. F or t h e s e a n al y s e s, r at e s will b e t a b ul at e d 
b y e v al u ati n g t h e n u m b er of r el a p s e s i n e a c h ti m e i nt er v al a n d t h e a m o u nt of f oll o w -u p ti m e i n t h e 
ti m e i nt er v al. A P oi s s o n m o d el will b e u s e d t o e sti m at e t h e r el a p s e r at e i n e a c h ti m e i nt er v al u nl e s s 
d at a ar e o v er -di s p er s e d i n w hi c h c a s e a n e g ati v e bi n o mi al m o d el will b e u s e d.  


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
3 8  
7. 2. 3.  A n n u ali z e d R el a p s e R at e i n t h e 2 0 5 M S 3 0 2 -3 0 3  I T T P o p ul ati o n  
T h e  a n n u ali z e d r el a p s e r at e will b e s u m m ari z e d f or t h e 2 0 5 M S 3 0 2 -3 0 3  I T T p o p ul ati o n i n t h e 
2 0 5 M S 3 0 3 Tr e at m e nt  P eri o d.  T h e r el a p s e r at e will b e r e p ort e d u si n g r el a p s e s t h at o c c urr e d o n or 
aft er t h e fir st d o s e d at e d uri n g t h e 2 0 5 M S 3 0 3 Tr e at m e nt  p eri o d. R el a p s e s  t h at o c c ur aft er s u bj e ct s 
r e c ei v e alt er n ati v e M S m e di c ati o n s will b e e x cl u d e d fr o m t h e a n al y s e s of r el a p s e r at e, a n d t h e 
s u bj e ct’ s ti m e o n st u d y will b e c e n s or e d at t h e ti m e t h e alt er n ati v e M S m e di c ati o n i s a d d e d.  
T h e u n a dj u st e d A R R will b e c al c ul at e d a s t h e t ot al n u m b er of r el a p s e s e x p eri e n c e d d uri n g t h e gi v e n 
p eri o d, di vi d e d b y t h e t ot al n u m b er of d a y s i n t h e st u d y p eri o d or t h e ti m e of c e n s ori n g, a n d t h e r ati o 
t h e n m ulti pli e d b y 3 6 5. 2 5.  
T h e r el a p s e r at e m a y al s o b e e sti m at e d u si n g a n e g ati v e bi n o mi al m o d el, wit h a dj u st m e nt f or t h e 
n u m b er of r el a p s e s i n a y e ar pri or t o t h e fir st d o s e i n 2 0 5 M S 3 0 3 . T h e l o g arit h mi c tr a n sf or m ati o n of 
t h e n u m b er of d a y s i n t h e st u d y will b e i n cl u d e d i n t h e m o d el a s t h e “ off s et” p ar a m et er. If t h e d at a ar e 
u n d er -di s p er s e d ( a s s e s s e d u si n g t h e P e ar s o n C hi -S q u ar e d st ati sti c) or if t h e n e g ati v e bi n o mi al 
m o d el d o e s n ot c o n v er g e, a P oi s s o n r e gr e s si o n m o d el will b e u s e d i n st e a d. T h e P oi s s o n m o d el will 
b e a dj u st e d f or o v er -di s p er si o n u si n g a P e ar s o n s c al e p ar a m et er.  
T o f urt h er a s s e s s t h e d ur a bilit y of tr e at m e nt, t h e r el a p s e r at e m a y al s o b e s u m m ari z e d b y 4 8-w e e k 
i nt er v al s i n t h e 2 0 5 M S 3 0 3 Tr e at m e nt  P eri o d. F or t h e s e a n al y s e s, r at e s will b e t a b ul at e d b y 
e v al u ati n g t h e n u m b er of r el a p s e s i n e a c h ti m e i nt er v al a n d t h e a m o u nt of f oll o w -u p t i m e i n t h e ti m e 
i nt er v al. A P oi s s o n m o d el will b e u s e d t o e sti m at e t h e r el a p s e r at e i n e a c h ti m e i nt er v al u nl e s s d at a 
ar e o v er -di s p er s e d i n w hi c h c a s e a n e g ati v e bi n o mi al m o d el will b e u s e d.  
7. 3.  Pr o p orti o n of S u bj e ct s w h o R el a p s e d  
7. 3. 1.  Pr o p orti o n of S u bj e ct s  wit h  R el a p s e  i n t h e 2 0 5 M S 3 0 1 -3 0 3  I T T P o p ul ati o n  
T h e pr o p orti o n of s u bj e ct s w h o r el a p s e d will b e s u m m ari z e d u si n g t h e f oll o wi n g st u d y p o p ul ati o n a n d 
st u d y p eri o d s  
•  
2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n i n t h e c o m bi n e d st u d y p eri o d 
•  
2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n i n t h e 2 0 5 M S 3 0 3 Tr e at m e nt p eri o d 
R el a p s e will b e d efi n e d u si n g t h e s a m e d efi niti o n t h at w a s u s e d f or t h e a n n u ali z e d r el a p s e r at e 
e n d p oi nt. T h e pr o p orti o n of s u bj e ct s w h o r el a p s e d at s el e ct e d ti m e p oi nt s , b y tr e at m e nt gr o u p of  t h e 
2 0 5 M S 3 0 1 s t u d y, will b e e sti m at e d.  
 
K a pl a n -M ei er c ur v e of ti m e t o  t h e fir st r el a p s e d uri n g t h e st u d y p eri o d  (i. e., t h e K a pl a n-M ei er  
pr o d u ct -li mit e sti m at or) will b e u s e d t o e sti m at e t h e pr o p orti o n of s u bj e ct s w h o r el a p s e d . If t h er e ar e 
n o e a rl y wit h dr a w al s, t h e K a pl a n-M ei er e sti m at e of t h e pr o p orti o n of s u bj e ct s r el a p s e d i s s a m e a s t h e 
o b s er v e d pr o p orti o n of s u bj e ct s r el a p s e d.  If t h er e ar e e arl y wit h dr a w al s, t h e K a pl a n-M ei er e sti m at e 
h a s t h e a d v a nt a g e of t a ki n g i nt o a c c o u nt t h e l e n gt h of f oll o w -u p f or t h e e arl y wit h dr a w al s, wit h o ut 
h a vi n g a n y a s s u m pti o n s a b o ut w h et h er t h o s e s u bj e ct s r el a p s e d or n ot.  
 
S u bj e ct s wit h o ut a c o nfir m e d r el a p s e will b e  c e n s or e d at eit h er e arl y wit h dr a w al or t h e e n d of t h e 
c orr e s p o n di n g st u d y  p eri o d . If a s u bj e ct t o o k a n alt er n ati v e M S m e di cati o n  b ef or e t h e fir st r el a p s e , 
t h e s u bj e ct will b e c e n s or e d at t h e ti m e of t h e alt er n ati v e M S m e di c ati o n. K a pl a n -M ei er pl ot s of t h e 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
3 9  
ti m e t o fir st r el a p s e will al s o b e pr e s e nt e d a n d u s e d t o e sti m at e t h e m e di a n  ti m e ( a n d/ or t h e 2 5t h 
p er c e ntil e) b y t h e pr e vi o u s tr e at m e nt gr o u p of t h e 2 0 5 M S 3 0 1 st u d y.  
 
7. 3. 2.  Pr o p orti o n of S u bj e ct s  wit h R el a p s e  i n t h e 2 0 5 M S 2 0 3 -3 0 3  I T T Po p ul ati o n  
T h e pr o p orti o n of s u bj e ct s w h o r el a p s e d will b e s u m m ari z e d f or t h e 2 0 5 M S 2 0 3 -3 0 3  I T T p o p ul ati o n i n 
t h e 2 0 5 M S 3 0 3 Tr e at m e nt  p eri o d . R el a p s e will b e d efi n e d u si n g t h e s a m e d efi niti o n t h at w a s u s e d f or 
t h e a n n u ali z e d r el a p s e r at e e n d p oi nt. T h e pr o p orti o n of s u bj e ct s w h o r el a p s e d at s el e ct e d ti m e p oi nt s 
will b e e sti m at e d  a n d pr e s e nt e d  f or all s u bj e ct s c o m bi n e d. K a pl a n-M ei er c ur v e of ti m e t o t h e fir st 
r el a p s e d uri n g t h e st u d y p eri o d  will b e u s e d t o e sti m at e t h e pr o p orti o n of s u bj e ct s w h o r el a p s e d.  
S u bj e ct s wit h o ut a c o nfir m e d r el a p s e will b e c e n s or e d at eit h er e arl y wit h dr a w al or t h e e n d of t h e 
2 0 5 M S 3 0 3 Tr e at m e nt  p eri o d. If a s u bj e ct t o o k a n alt er n ati v e M S m e di c ati o n b ef or e t h e fir st r el a p s e, 
t h e s u bj e ct will b e c e n s or e d at t h e ti m e of t h e alt er n ati v e M S m e di c ati o n. K a pl a n-M ei er pl ot s of t h e 
ti m e t o fir st r el a p s e will al s o b e pr e s e nt e d a n d u s e d t o e sti m at e t h e m e di a n ti m e ( a n d/ or t h e 2 5t h 
p er c e ntil e)  f or all s u bj e ct s c o m bi n e d. 
7. 3. 3.  Pr o p orti o n of S u bj e ct s  wit h R el a p s e  i n t h e 2 0 5 M S 3 0 2 -3 0 3  I T T Po p ul ati o n  
T h e pr o p orti o n of s u bj e ct s w h o r el a p s e d will b e s u m m ari z e d f or t h e 2 0 5 M S 3 0 2 -3 0 3  I T T p o p ul ati o n i n 
t h e 2 0 5 M S 3 0 3 Tr e at m e nt  p eri o d . R el a p s e will b e d efi n e d u si n g t h e s a m e d efi niti o n t h at w a s u s e d f or 
t h e a n n u ali z e d r el a p s e r at e e n d p oi nt. T h e pr o p orti o n of s u bj e ct s w h o r el a p s e d at s el e ct e d ti m e p oi nt s 
will b e e sti m at e d. K a pl a n -M ei er c ur v e of ti m e t o t h e fir st r el a p s e d uri n g t h e st u d y  p eri o d will b e u s e d 
t o e sti m at e t h e pr o p orti o n of s u bj e ct s w h o r el a p s e d. S u bj e ct s wit h o ut a c o nfir m e d r el a p s e will b e 
c e n s or e d at eit h er e arl y wit h dr a w al or t h e e n d of t h e 2 0 5 M S 3 0 3 tr e at m e nt  p eri o d. If a s u bj e ct t o o k a n 
alt er n ati v e M S m e di c ati o n b ef or e t h e fir st r el a p s e, t h e s u bj e ct will b e c e n s or e d at t h e ti m e of t h e 
alt er n ati v e M S m e di c ati o n. K a pl a n -M ei er pl ot s of t h e ti m e t o fir st r el a p s e will al s o b e pr e s e nt e d a n d 
u s e d t o e sti m at e t h e m e di a n ti m e ( a n d/ or t h e 2 5t h p er c e ntil e).  
 
7. 4.  S u st ai n e d  6 -m o nt h Di s a bilit y Pr o gr e s si o n  
7. 4. 1.  S u st ai n e d 6 -m o nt h Di s a bilit y Pr o gr e s si o n i n t h e 2 0 5 M S 3 0 1 -3 0 3 I T T 
P o p ul ati o n  
 
Ti m e t o c o nfir m e d 6 -m o nt h di s a bilit y pr o gr e s si o n will b e s u m m ari z e d f or t h e f oll o wi n g p o p ul ati o n s 
a n d st u d y p eri o d s:  
 
•  
2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n d uri n g t h e 2 0 5 M S 3 0 3 Tr e at m e nt  P eri o d, fr o m t h e d at e of fir st 
d o s e i n 2 0 5 M S 3 0 3  
•  
2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n d uri n g t h e C o m bi n e d St u d y P eri o d, fr o m t h e d at e of fir st d o s e 
i n 2 0 5 M S 3 0 1 
S u st ai n e d di s a bilit y pr o gr e s si o n i s d efi n e d a s: at l e a st a 1 . 0 p oi nt i n cr e a s e o n t h e E D S S fr o m 
b a s eli n e  E D S S 1. 0 t h at i s s u st ai n e d f or 2 4 w e e k s, or at l e a st a 1. 5 p oi nt i n cr e a s e o n t h e E D S S fr o m 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
4 0  
b a s eli n e  E D S S = 0 t h at i s s u st ai n e d f or 2 4 w e e k s.  T h e d at e of t h e i niti al vi sit at w hi c h t h e mi ni m u m 
i n cr e a s e i n t h e E D S S i s m et will b e t h e d at e of o n s et of t h e pr o gr e s si o n.  T h e E D S S pr o gr e s si o n i s 
d efi n e d a s c o nfir m e d w h e n t hi s mi ni m u m E D S S c h a n g e i s pr e s e nt o n t h e n e xt st u d y vi sit o c c urri n g 
aft er 1 5 8 d a y s fr o m t h e i niti al o b s er v ati o n.  
F or t h e C o m bi n e d St u d y P eri o d, p r o gr e s si o n will b e c al c ul at e d r el ati v e t o t h e E D S S s c or e at t h e 
2 0 5 M S 3 0 1 b a s eli n e. F or t h e 2 0 5 M S 3 0 3  Tr e at m e nt  P eri o d , p r o gr e s si o n m u st st art aft er t h e fir st d o s e 
i n t h e 2 0 5 M S 3 0 3 st u d y a n d will b e c al c ul at e d r el ati v e t o 2 0 5 M S 3 0 3 b a s eli n e.  
 
Pr o gr e s si o n will  n ot b e c o nfir m e d at a vi sit w h er e a r el a p s e i s al s o o c c urri n g.  A s u bj e ct i s c o n si d er e d 
t o b e h a vi n g a r el a p s e f or at l e a st 2 9 d a y s aft er t h e st art d at e of a  pr ot o c ol -d efi n e d r el a p s e i n 
2 0 5 M S 3 0 1 or 2 0 5 M S 3 0 3 . If a s u bj e ct m e et s t h e d efi n e d crit eri a of s u st ai n e d pr o gr e s si o n a n d i s al s o 
h a vi n g a r el a p s e, t h e s u bj e ct will b e r e q uir e d t o m e et t h e d efi n e d mi ni m u m crit eri a at t h e s u b s e q u e nt 
vi sit.    
If a s u bj e ct h a d a t e nt ati v e pr o gr e s si o n pri or t o t h e st art of alt er n ati v e M S m e di c ati o n, t h e a p pr o pri at e 
E D S S e v al u ati o n p erf or m e d w hil e t a ki n g alt er n ati v e M S m e di c ati o n will b e u s e d t o a s s e s s  
c o nfir m ati o n of t h e pr o gr e s si o n.  D e at h d u e t o M S will b e c o u nt e d a s pr o gr e s si o n.  If t h e s u bj e ct w a s 
i n t h e mi d st of a t e nt ati v e pr o gr e s si o n at t h e ti m e of d e at h ( e. g. t h e E D S S e v al u ati o n pri or t o d e at h i s 
a t e nt ati v e pr o gr e s si o n), t h e pr o gr e s si o n d at e will b e t h e t e nt ati v e pr o gr e s si o n st art d at e. Ot h er wi s e, 
t h e pr o gr e s si o n d at e will b e t h e d at e of d e at h. If t h e d e at h w a s n ot d u e t o M S , t h e n t h e s u bj e ct will b e 
c e n s or e d u si n g t h e s a m e r ul e s a s f or s u bj e ct s w h o wit h dr a w fr o m t h e st u d y.   
 
S u bj e ct s w h o d o n ot h a v e a s u st ai n e d pr o gr e s si o n b a s e d o n t h e a b o v e r ul e s ( a n d h a v e s uffi ci e nt  
f oll o w u p d at a t o c o nfir m t h at t h er e i s n o pr o gr e s si o n) will b e c e n s or e d.  F or t h e a n al y s e s b a s e d o n 
eit h er 2 0 5 M S 3 0 3 tr e at m e nt p eri o d or t h e c o m bi n e d st u d y  p eri o d d at a, t h e c e n s or i n g d at e will b e t h e 
d at e of t h e l a st E D S S pri or t o t h e e n d d at e of t h e 2 0 5 M S 3 0 3 tr e at m e nt p eri o d. S u bj e ct s w h o 
wit h dr a w fr o m t h e st u d y aft er t h e b a s eli n e vi sit b ut pri or t o t h e fir st cli ni c al e v al u ati o n s c h e d ul e d vi sit 
will b e c e n s or e d at b a s eli n e.  
 
F or s u bj e ct s  wit h a t e nt ati v e pr o gr e s si o n t h at c a n n ot b e c o nfir m e d b e c a u s e t h er e ar e  n o a d diti o n al 
E D S S  a s s e s s m e nt s , t h e f oll o w-u p e n d s b ef or e a s u st ai n e d pr o gr e s si o n o c c ur s  (i. e., d u e  t o t h e 
s u bj e ct wit h dr a w i n g fr o m t h e st u d y or d u e t o t h e c ut off of dat a c oll e cti o n ), or b e c a u s e t h e 
c o nfir m at or y a s s e s s m e nt d o e s n ot m e et ot h er crit eri a (i. e., t h e l a st  E D S S a s s e s s m e nt i s < 1 5 8 d a y s 
aft er t h e  t e nt ati v e pr o gr e s si o n or t h e l a st E D S S a s s e s s m ent i s at t h e ti m e of a r el a p s e), t h e c e n s or 
d at e will b e  t h e d at e of t h e l a st E D S S a s s e s s m e nt.   
 
Ti m e t o c o nfir m e d di s a bilit y pr o gr e s si o n will b e e x pl or e d u si n g K a pl a n -M ei er m et h o d, wit h  t h e fir st 
d o s e d at e i n  t h e c orr e s p o n di n g st u d y p eri o d a s t h e st art d at e, b y t h e tr e at m e nt gr o u p of t h e 
2 0 5 M S 3 0 1 st u d y.  K a pl a n -M ei er m et h o d f or ti m e t o di s a bilit y pr o gr e s si o n will b e u s e d t o e sti m at e t h e 
pr o p orti o n of s u bj e ct s w h o e x p eri e n c e d pr o gr e s si o n  at s el e ct e d ti m e p oi nt s , b y tr e at m e nt gr o u p of 
t h e 2 0 5 M S 3 0 1 st u d y . A s u bj e ct wit h s u st ai n e d di s a bilit y pr o gr e s si o n d uri n g t h e 2 0 5 M S 3 0 1 Tr e at m e nt 
P eri o d  will still b e c o n si d er e d at ri s k i n t h e a n al y si s  f or t h e 2 0 5 M S 3 0 3  Tr e at m e nt  P eri o d . 
 
K a pl a n -M ei er pl ot s of t h e ti m e t o fir st pro g r e s si o n will b e pr e s e nt e d a n d u s e d t o e sti m at e t h e m e di a n 
ti m e ( a n d/ or 2 5t h p er c e ntil e) b y t h e pr e vi o u s tr e atm e nt gr o u p of t h e 2 0 5 M S 3 0 1 st u d y  f or e a c h st u d y 
p eri o d .  


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
4 1  
 
If t h e E D S S s c or e i s mi s si n g at t h e 2 0 5 M S 3 0 1 b a s eli n e vi sit, t h e 2 0 5 M S 3 0 1 s cr e e ni n g s c or e will b e 
u s e d i n st e a d  f or t h e 2 0 5 M S 3 0 1 b a s eli n e. If b ot h b a s eli n e a n d s cr e e ni n g s c or e s ar e mi s si n g, t h e fir st 
a v ail a bl e a s s e s s m e nt will b e u s e d a s t h e b a s eli n e E D S S s c or e.  F or t h e 2 0 5 M S 3 0 3 b a s eli n e, t h e l a st 
a v ail a bl e E D S S s c or e b ef or e or o n t h e fir st  d o s e i n t h e 2 0 5 M S 3 0 3 st u d y will b e u s e d. T h e st art d at e 
f or c al c ul ati o n of d a y t o pr o gr e s si o n or c e n s ori n g will b e t h e  fir st d o si n g d at e i n t h e c orr e s p o n di n g 
p eri o d.  
I m p ut ati o n of s u bj e ct s wit h t e nt ati v e pr o gr e s si o n at t heir l a st a s s e s s m e nt f or ( s e n siti vi t y a n al y si s) 
 
If a s u bj e ct h a s a t e nt ati v e pr o gr e s si o n at t h e  l a st E D S S a s s e s s m e nt a n d n o E D S S a s s e s s m ent s t o 
c o nfir m pr o gr e s si o n,  t h e pr e s e n c e or a b s e n c e of s u st ai n e d di s a bilit y pr o gr e s si o n will b e i m p ut e d 
u si n g a M ulti pl e I m p ut ati o n ( MI) a p pr o a c h  f or t h e s e n siti vit y a n al y si s . A m o n g s u bj e ct s wit h at l e a st 
o n e t e nt ati v e pr o gr e s si o n, t h e pr o b a bilit y of c o nfir m ati o n f or t h o s e wit h a mi s si n g E D S S t o c o nfir m 
pr o gr e s si o n will b e e sti m at e d vi a l o gi sti c m o d el a dj u sti n g f or tr e at m e nt gr o u p  of t h e 2 0 5 M S 3 0 1 st u d y , 
E D S S at b a s eli n e ( a s a c o nti n u o u s v ari a bl e), c h a n g e i n E D S S fr o m b a s eli n e t o t h e t e nt ati v e 
pr o gr e s si o n a n d pr e s e n c e ( or a b s e n c e) of a r el a p s e wit hi n t h e l a st 2 9 -d a y s of t h e t e nt ati v e 
pr o gr e s si o n.  F or t h e s u bj e ct s wit h m ulti pl e t e nt ati v e pr o gr e s si o n s, t h e c o n fir m e d (if s u bj e ct h a d a 
c o nfir m e d pr o gr e s si o n) or t h e l a st (if s u bj e ct di d n ot h a v e a n y t e nt ati v e pr o gr e s si o n s c o nfir m e d) 
t e nt ati v e pr o gr e s si o n r e c or d will b e r et ai n e d. B a s e d o n t h e s e pr o b a bilit y e sti m at e s, co nfir m e d 
pr o gr e s si o n fl a g s will b e i m p ut e d vi a m ulti pl e i m p ut ati o n s. T h e m ulti pl e i m p ut ati o n s vi a t hi s l o gi sti c 
r e gr e s si o n m o d el will b e c o n d u ct e d 5 0 ti m e s wit h pr e-s p e cifi e d r a n d o m s e e d t o g e n er at e 5 0 a n al y si s 
d at a s et s. A n al y s e s will b e c o n d u ct e d o n e a c h of t h e 5 0 d at a s et s. R e s ult s will b e c o m bi n e d t o 
pr o vi d e t h e fi n al a n al y si s r e s ult s.   
 
7. 4. 2.  S u st ai n e d 6 -m o nt h Di s a bilit y Pr o gr e s si o n i n t h e 2 0 5 M S 2 0 3 -3 0 3  I T T 
P o p ul ati o n  
Ti m e t o c o nfir m e d 6 -m o nt h di s a bilit y pr o gr e s si o n will b e s u m m ari z e d f or t h e 2 0 5 M S 2 0 3 -3 0 3  I T T 
p o p ul ati o n i n t h e 2 0 5 M S 3 0 3 Tr e at m e nt  p eri o d. F or t h e 2 0 5 M S 3 0 3 Tr e at m e nt  P eri o d, pr o gr e s si o n will 
b e c al c ul at e d r el ati v e t o t h e E D S S s c or e at t h e 2 0 5 M S 3 0 3  b a s eli n e. S u bj e ct s w h o d o n ot h a v e a 
s u st ai n e d pr o gr e s si o n will b e c e n s or e d o n t h e d at e of t h e l a st E D S S pri or t o t h e e n d d at e of t h e 
2 0 5 M S 3 0 3 tr e at m e nt p eri o d. F or s u bj e ct s wit h a t e nt ati v e pr o gr e s si o n t h at c a n n ot b e c o nfir m e d 
b e c a u s e t h er e ar e n o a d diti o n al E D S S a s s e s s m e nt s, t h e f oll o w -u p e n d s b ef or e a s u st ai n e d 
pr o gr e s si o n o c c ur s (i. e., d u e t o t h e s u bj e ct wit h dr a wi n g fr o m t h e st u d y or d u e  t o t h e c ut off of d at a 
c oll e cti o n), or b e c a u s e t h e c o nfir m at or y a s s e s s m e nt d o e s n ot m e et ot h er crit eri a (i. e., t h e l a st E D S S 
a s s e s s m e nt i s < 1 5 8 d a y s aft er t h e t e nt ati v e pr o gr e s si o n or t h e l a st E D S S a s s e s s m e nt i s at t h e ti m e 
of a r el a p s e), t h e c e n s or d at e w ill b e t h e d at e of t h e l a st E D S S a s s e s s m e nt. D u e t o t h e li mit e d 
n u m b er of s u bj e ct s, n o i m p ut ati o n will b e c o n d u ct e d f or s u bj e ct s wit h t e nt ati v e pr o gr e s si o n i n t h e 
2 0 5 M S 2 0 3 -3 0 3 I T T p o p ul ati o n.  
 
Ti m e t o c o nfir m e d di s a bilit y pr o gr e s si o n will b e e x pl or e d u si n g  K a pl a n -M ei er m et h o d, wit h t h e fir st 
d o s e d at e i n t h e 2 0 5 M S 3 0 3 Tr e at m e nt  p eri o d a s t h e st art d at e  f or all s u bj e ct s c o m bi n e d. K a pl a n-
M ei er m et h o d f or ti m e t o di s a bilit y pr o gr e s si o n will b e u s e d t o e sti m at e t h e pr o p orti o n of s u bj e ct s w h o 
e x p eri e n c e d pr o gr e s s i o n at s el e ct e d ti m e p oi nt s f or all s u bj e ct s c o m bi n e d.  
 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
4 2  
7. 4. 3.  S u st ai n e d 6 -m o nt h Di s a bilit y Pr o gr e s si o n i n t h e 2 0 5 M S 3 0 2 -3 0 3  I T T 
P o p ul ati o n  
Ti m e t o c o nfir m e d 6 -m o nt h di s a bilit y pr o gr e s si o n will b e s u m m ari z e d f or t h e 2 0 5 M S 3 0 2 -3 0 3  I T T 
p o p ul ati o n d uri n g t h e 2 0 5 M S 3 0 3 Tr e at m e nt  P eri o d. Ti m e t o c o nfir m e d di s a bilit y pr o gr e s si o n will b e 
e x pl or e d u si n g K a pl a n -M ei er m et h o d, wit h t h e fir st d o s e d at e i n t h e c orr e s p o n di n g st u d y p eri o d a s 
t h e st art d at e. K a pl a n -M ei er m et h o d f or ti m e t o di s a bilit y pr o gr e s si o n will b e u s e d t o e s ti m at e t h e 
pr o p orti o n of s u bj e ct s w h o e x p eri e n c e d pr o gr e s si o n at s el e ct e d ti m e p oi nt s. K a pl a n -M ei er pl ot s of t h e 
ti m e t o fir st pr o gr e s si o n will b e pr e s e nt e d a n d u s e d t o e sti m at e t h e m e di a n ti m e ( a n d/ or 2 5t h 
p er c e ntil e). D u e t o t h e li mit n u m b er of s u bj e ct s,  n o i m p ut ati o n will b e c o n d u ct e d f or s u bj e ct s wit h 
t e nt ati v e pr o gr e s si o n i n t h e 2 0 5 M S 30 2 -3 0 3  I T T p o p ul ati o n . 
 
7. 5.  M SI S -2 9  
 
S c ori n g al g orit h m d e s cri b e d i n H o b art J, L a m pi n g et al. ( 2 0 0 1) will b e u s e d t o c al c ul at e t h e M SI S -2 9 
P h y si c al I m p a ct a n d P s y c h ol o gi c al I m p a ct s c or e s. P h y si c al s c or e will b e b a s e d o n t h e r e s p o n s e s 
fr o m it e m s 1-2 0, w hil e p s y c h ol o gi c al s c or e i s b a s e d o n it e m s 2 1 -2 9.  Mi s si n g s c or e s will n ot b e 
i m p ut e d. M SI S -2 9 p h y si c al s c or e d at a o bt ai n e d aft er s u bj e ct s t a k e alt er n ati v e m e di c ati o n f or M S 
d uri n g t h e st u d y will b e s et t o mi s si n g.   
F or t h e 2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n, t h e a ct u al v al u e s f or M SI S -2 9 p h y si c al s c or e, M SI S -2 9  
p s y c h ol o gi c al s c or e, t h eir c h a n g e fr o m 2 0 5 M S 3 0 3  b a s eli n e , a n d t h e pr o p orti o n of s u bj e ct s wit h a > = 
7. 5 w or s e ni n g  i n 
M SI S-2 9 p h y si c al s c or e  fr o m t h e 2 0 5 M S 3 0 3  b a s eli n e  will b e s u m m ari z e d b y 
2 0 5 M S 3 0 1 tr e at m e nt gr o u p i n t h e C o m bi n e d St u d y P eri o d (b y st u d y vi sit i n 2 0 5 M S 3 0 3  st u d y ).  
N ot e t h at M SI S -2 9 i s n ot c oll e ct e d f or p ati e nt s e nr oll e d fr o m t h e 2 0 5 M S 2 0 3 or 2 0 5 M S 3 0 2 st u d y t o 
t h e 2 0 5 M S 3 0 3 st u d y.  
7. 6.  M RI E n d p oi nt s  
7. 6. 1.  M RI E n d p oi nt s A n al y s e s f or  t h e 2 0 5 M S 3 0 1 -3 0 3  I T T P o p ul ati o n  
M RI i s m e a s ur e d o n  all  s u bj e ct s i n t h e 2 0 5 M S 3 0 1 a n d 2 0 5 M S 3 0 3  st u d i e s. O b s er v e d M RI d at a 
m e a s ur e d aft er s u bj e ct s st art e d alt er n ati v e M S m e di c ati o n s will b e e x cl u d e d . T h e f oll o wi n g M RI 
p ar a m et er s will b e a n al y z e d  i n t h e 2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n: 
 
•  
T h e t ot al n u m b er of n e w or n e wl y e nl ar gi n g T 2 h y p eri nt e n s e l e si o n s r el ati v e t o t h e 2 0 5 M S 3 0 1 
b a s eli n e  
•  
T h e t ot al n u m b er of n e w or n e wl y e nl ar gi n g T 2 h y p eri nt e n s e l e si o n s r el ati v e t o t h e 2 0 5 M S 3 0 3 
b a s eli n e  
•  
T h e t ot al n u m b er of n e w T 1 h y p o i nt e n s e l e si o n s r el ati v e t o t h e 2 0 5 M S 3 0 1 b a s eli n e 
•  
T h e t ot al n u m b er of n e w T 1 h y p o i nt e n s e l e si o n s r el ati v e t o t h e 2 0 5 M S 3 0 3 b a s eli n e  
•  
T h e t ot al n u m b er of G d -e n h a n ci n g l e si o n s  at 2 0 5 M S 3 0 1 st u d y a n d 2 0 5 M S 3 0 3 st u d y  


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
4 3  
•  
T h e t ot al v ol u m e of T 2 h y p eri nt e n s e l e si o n s  
•  
T h e v ol u m e  of n e w or n e wl y e nl ar gi n g T 2 h y p eri nt e n s e l e si o n s c o m p ar e d t o t h e 2 0 5 M S 3 0 1 
b a s eli n e  
•  
T h e v ol u m e  of n e w or n e wl y e nl ar gi n g T 2 h y p eri nt e n s e l e si o n s c o m p ar e d t o t h e 2 0 5 M S 3 0 3  
b a s eli n e  
•  
T h e  v ol u m e of n e w T 1 h y p o i nt e n s e l e si o n s c o m p ar e d t o t h e 2 0 5 M S 3 0 1 b a s eli n e 
•  
T h e v ol u m e of n e w T 1 h y p o i nt e n s e l e si o n s c o m p ar e d t o t h e 2 0 5 M S 3 0 3  b a s eli n e  
•  
P er c e nt Br ai n V ol u m e C h a n g e ( P B V C)  r el ati v e t o t h e 2 0 5 M S 3 0 1 b a s eli n e 
•  
P er c e nt Br ai n V ol u m e C h a n g e ( P B V C)  relati ve t o t he 2 0 5 M S 3 0 3 baseli ne  
 
B a s eli n e:  
R e c or d s u p t o 2 8 d a y s aft er t h e fir st d o s e i n 2 0 5 M S 3 0 1 m a y b e u s e d a s t h e 2 0 5 M S 3 0 1 b a s eli n e 
a s s e s s m e nt s ; If t h er e ar e m ulti pl e r e c or d s f or t h e 2 0 5 M S 3 0 1 b a s eli n e, t h e n t h e  o b s er v ati o n cl o s e st 
t o t h e fir st d o s e will b e s el e ct e d (if ti e d, t h e n t h e r e c or d pri or t o d o si ng will b e d efi n e d a s b a s eli n e). 
F or t h e 2 0 5 M S 3 0 1 W e e k 9 6 M RI 
a s s e s s m e nt, r e c or d s c oll e ct e d u p t o 2 8 d a y s aft er 2 0 5 M S 3 0 3 
e xt e n si o n t ri al fir st d o s e will b e i n cl u d e d.   
F or t h e b a s eli n e a s s e s s m e nt i n 2 0 5 M S 3 0 3, t h e b a s eli n e M RI o bt ai n e d i n 2 0 5 M S 3 0 3 will b e u s e d a s 
t h e b as eli n e if it w a s o bt ai n e d u p t o  2 8 d a y s aft er t h e fir st d o s e i n 2 0 5 M S 3 0 3. If a s u bj e ct di d n ot 
h a v e a b a s eli n e M RI a s s e s s m e nt i n 2 0 5 M S 3 0 3, t h e n t h e l a st a s s e s s m e nt o bt ai n e d d uri n g 2 0 5 M S 3 0 1  
will b e u s e d at t h e b a s eli n e a s s e s s m e nt f or  th e t ot al n u m b er of G d -e n h a n ci n g l e si o n s  a n d t h e t ot al 
v ol u m e of T 2 h y p eri nt e n s e l e si o n s .    
T h e t ot al n u m b er of T 2 l e si o n s at 2 0 5 M S 3 0 3 b a s eli n e will b e c al c ul at e d  b y s u m mi n g t h e 2 0 5 M S 3 0 1 
b a s eli n e n u m b er of T 2 l e si o n s a n d t h e n u m b er of n e w or n e wl y e nl ar gi n g l e si o n s si n c e t h e pr e vi o u s 
vi sit at 2 0 5 M S 3 0 1 W e e k 2 4, 2 0 5 M S 3 0 1 W e e k 9 6, 2 0 5 M S 3 0 1 W e e k 1 4 4 (if a v ail a bl e) a n d 2 0 5 M S 3 0 3 
B a s eli n e (if a v ail a bl e).  T h e s a m e al g orit h m will b e a p pli e d  t o t h e t ot al n u m b er of T 1 l e si o n s a n d t h e 
t ot al v ol u m e of T 1 l e si o n s at 2 0 5 M S 3 0 3 b a s eli n e. 
D at a o bt ai n e d aft er alt er n ati v e M S m e d i c ati o n will b e s et t o mi s si n g. Mi s si n g d at a will n ot b e i m p ut e d.   
T h e t ot al n u m b er of n e w or n e wl y e nl ar gi n g T 2 h y p eri nt e n s e l e si o n s  
T h e n u m b er of n e w or n e wl y -e nl ar gi n g T 2 h y p eri nt e n s e l e si o n s r el ati v e t o t h e 2 0 5 M S 3 0 1 b a s eli n e 
will b e a n al y z e d f or W e e k 2 4 a n d W e e k 9 6 of t h e 2 0 5 M S 3 0 1 st u d y. T h e n u m b er of n e w or n e wl y -
e nl ar gi n g T 2 h y p eri nt e n s e l e si o n s r el ati v e t o t h e 2 0 5 M S 3 0 3 b a s eli n e will b e a n al y z e d f or W e e k s  4 8 , 
9 6, 1 4 4, 1 9 2,  a n d 2 4 0  (if a v ail a bl e) of t h e 2 0 5 M S 3 0 3 st u d y.  
A n e g at i v e bi n o mi al r e gr e s si o n m o d el will b e u s e d t o a n al y z e t h e o b s er v e d n e w or n e wl y e nl ar gi n g 
T 2 l e si o n s. T h e m o d el f or t h e a n al y si s r el a ti v e t o t h e 2 0 5 M S 3 0 1 b a s eli n e will b e a dj u st e d f or t h e 
f oll o wi n g c h ar a ct eri sti c s at t h e 2 0 5 M S 3 0 1 b a s eli n e: v ol u m e of T 2 h y p eri nt e n s e l e si o n s, hi st or y of 
pri or I F N β  u s e  a n d b a s eli n e a g e ( a g e ≤ 3 5  v er s u s a g e > 3 5 ). T h e m o d el f or t h e a n al y si s r el ati v e t o 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
4 4  
t h e 2 0 5 M S 3 0 3 b a s eli n e 
will b e a dj u st e d f or t h e f oll o wi n g c h ar a ct eri sti c s : t h e v ol u m e of T 2 
h y p eri nt e n s e l e si o n s at t h e 2 0 5 M S 3 0 3 b a s eli n e, hi st or y of pri or I F N β  u s e  at t h e 2 0 5 M S 3 0 1 b a s eli n e, 
a n d b a s eli n e a g e ( a g e ≤ 3 5  v er s u s a g e > 3 5 ) at t h e 2 0 5 M S 3 0 3 b a s eli n e.  
T h e t ot al n u m b er of n e w T 1  h y p oi nt e n s e le si o n s  
T h e t ot al n u m b er of n e w T 1 h y p eri nt e n s e l e si o n s r el ati v e t o t h e 2 0 5 M S 3 0 1 b a s eli n e a n d t h e 
2 0 5 M S 3 0 3 b a s eli n e will b e a n al y z e d u si n g t h e s a m e m et h o d ol o g y a s f or t h e a n al y si s n e w or n e wl y -
e nl ar gi n g T 2 h y p eri nt e n s e l e si o n s. T h e  e sti m at e d  n u m b er of l e si o n s will b e e v al u at e d  u si n g n e g ati v e 
bi n o mi al r e gr e s si o n, a dj u st e d f or t h e hi st or y of pri or I F N β u s e  at t h e 2 0 5 M S 3 0 1 b a s eli n e , a g e ( a g e ≤ 
3 5  v er s u s a g e > 3 5 ) at t h e c orr e s p o n di n g b a s eli n e, a n d  v ol u m e of T 1 h y p oi nt e n s e l e si o n s  at t h e 
c orr e s p o n di n g b a s eli n e.    
N u m b er of G d -E n h a n ci n g L e si o n s  
T h e t ot al n u m b er of G d -e n h a n ci n g l e si o n s will b e t a b ul at e d f or t h e f oll o wi n g vi sit s of t h e 2 0 5 M S 3 0 1 
st u d y: B a s eli n e, W e e k 2 4, W e e k 9 6 a n d W e e k 1 4 4, a n d f or t h e f oll o wi n g vi sit s of t h e 2 0 5 M S 3 0 3 
st u d y: B a s eli n e , W e e k s 4 8, 9 6, 1 4 4, 1 9 2, a n d 2 4 0  (if a v ail a bl e). S u m m ar y st ati sti c s b y t h e 2 0 5 M S 3 0 1 
tr e at m e nt gr o u p will al s o b e pr o vi d e d. 
T h e t ot al v ol u m e of T 2 h y p eri nt e n s e l e si o n s  
S u m m ar y st ati sti c s f or t h e t ot al v ol u m e of T 2 h y p eri nt e n s e l e si o n s a n d it s c h a n g e fr o m 2 0 5 M S 3 0 1 
b a s eli n e, b y 2 0 5 M S 3 0 1 tr e at m e nt gr o u p, will b e pr o vi d e d f or W e e k 2 4, W e e k 9 6 a n d W e e k 1 4 4 of 
t h e 2 0 5 M S 3 0 1 st u d y. Si mil ar a n al y si s will b e p erf or m e d f or W e e k s 4 8, 9 6, 1 4 4, 1 9 2, a n d 2 4 0  (if 
a v ail a bl e) of t h e 2 0 5 M S 3 0 3 st u d y ( wit h c h a n g e fr o m t h e 2 0 5 M S 3 0 3 b a s eli n e).  
V ol u m e of n e w or n e wl y e nl ar gi n g T 2 h y p eri nt e n s e  l e si o n s 
S u m m ar y st ati sti c s f or t h e v ol u m e of n e w or n e wl y e nl ar gi n g T 2 h y p eri nt e n s e l e si o n s, b y 2 0 5 M S 3 0 1 
tr e at m e nt gr o u p, will be pr o vi d e d f or t h e f oll o wi n g vi sit s of t h e 2 0 5 M S 3 0 1 st u d y: W e e k 2 4, W e e k 9 6 
a n d W e e k 1 4 4, a n d f or t h e f oll o wi n g vi sit s of t h e 2 0 5 M S 3 0 3 st u d y: B a s eli n e , W e e k s 4 8, 9 6, 1 4 4, 1 9 2, 
a n d 2 4 0  (if a v ail a bl e).  
V ol u m e of n e w T 1  h y p oi nt e n s e l e si o n s 
T h e crit eri a a n d a n al y si s f or t hi s e n d p oi nt will b e t h e s a m e a s u s e d f or t h e v ol u m e of n e w or n e wl y 
e nl ar gi n g T 2 h y p er i nt e n s e l e si o n s. 
 
P er c e nt Br ai n V ol u m e C h a n g e ( P B V C)  
S u m m ar y st ati sti c s f or t h e  ( a n n u ali z e d) P er c e nt Br ai n V ol u m e C h a n g e ( P B V C)  r el ati v e to eit h er t h e 
2 0 5 M S 3 0 1 b a s eli n e or t h e 2 0 5 M S 3 0 3 b a s eli n e, b y 2 0 5 M S 3 0 1 tr e at m e nt gr o u p, will b e pr o vi d e d f or 
t h e W e e k s 4 8, 9 6, 1 4 4, 1 9 2, a n d 2 4 0  (if a v ail a bl e) of t h e 2 0 5 M S 3 0 3 st u d y.  
 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
4 5  
7. 6. 2.  M RI E n d p oi nt s A n al y s e s f or  t h e 2 0 5 M S 2 0 3 -3 0 3  I T T P o p ul ati o n  
F or t h e  2 0 5 M S 2 0 3 -3 0 3 I T T p o p ul ati o n,  M RI w a s n ot c oll e ct e d at 2 0 5 M S 3 0 3 b a s eli n e, a n d m o st of 
t h e s u bj e ct s o nl y h a v e o n e M RI vi sit i n  t h e 2 0 5 M S 3 0 3 st u d y . B y vi sit s u m m ar y will  b e pr e s e nt e d f or 
s el e ct e d p ar a m et er s  i n cl u di n g t h e t ot al n u m b er of G d-e n h a n ci n g l e si o n s,  a n d  t h e t ot al v ol u m e of T 2 
h y p eri nt e n s e l e si o n s . N ot e t h at  d u e t o t h e  ti mi n g of i m pl e m e nt ati o n of pr ot o c ol v er si o n 4 , t h er e i s 
v er y  li mit e d d at a a v ail a bl e f or ot h er M RI p ar a m et er s a n d t h er ef or e t h e s e will n ot b e s u m m ari z e d . 
 
7. 6. 3.  M RI E n d p oi nt s A n al y s e s f or t h e 2 0 5 M S 3 0 2 -3 0 3  I T T Po p ul ati o n  
F or t h e 2 0 5 M S 3 0 2 -3 0 3  I T T p o p ul ati o n, M RI w a s n ot c oll e ct e d at 2 0 5 M S 3 0 3 b a s eli n e , a n d mo st of 
t h e s u bj e ct s o nl y h a v e o n e M RI vi sit i n t h e 2 0 5 M S 3 0 3 st u d y. B y vi sit s u m m ar y will  b e pr e s e nt e d f or 
t h e s el e ct e d p ar a m et er s, i n cl u di n g t h e t ot al n u m b er of G d-e n h a n ci n g l e si o n s, a n d t h e t ot al v ol u m e of 
T 2 h y p eri nt e n s e  l e si o n s. N ot e t h at d u e t o  t h e ti mi n g of i m pl e m e nt ati o n of pr ot o c ol ver si o n 4, t h er e i s 
v er y li mit e d d at a a v ail a bl e f or ot h er M RI p ar a m et er s a n d t h er ef or e t h e s e will  n ot b e s u m m ari z e d . 
 
7. 7.  E D S S  
7. 7. 1.  E D S S  i n t h e 2 0 5 M S 3 0 1-3 0 3 I T T P o p ul ati o n  
F or t h e 2 0 5 M S 3 0 1 -3 0 3 I T T p o p ul ati o n, t h e ED S S  s c or e wit h c h a n g e fr o m 2 0 5 M S 3 0 3  b a s eli n e  wi ll b e 
s u m m ari z e d b y 2 0 5 M S 3 0 1 tr e at m e nt gr o u p i n t h e 2 0 5 M S 3 0 3 Tr e at m e nt P eri o d ( b y st u d y vi sit i n 
2 0 5 M S 3 0 3 st u d y ).  
 
7. 7. 2.  E D S S  i n t h e 2 0 5 M S 2 0 3-3 0 3 I T T P o p ul ati o n  
F or t h e 2 0 5 M S 2 0 3 -3 0 3  I T T p o p ul ati o n, t h e E DS S  s c or e wit h c h a n g e fr o m 2 0 5 M S 3 0 3  b a s eli n e will b e 
s u m m ari z e d i n t h e 2 0 5 M S 3 0 3 Tr e at m e nt P eri o d (b y st u d y vi sit i n 2 0 5 M S 3 0 3 st u d y ) f or all s u bj e ct s 
t o g et h er.   
 
7. 7. 3.  E D S S  i n t h e 2 0 5 M S 3 0 2-3 0 3 I T T P o p ul ati o n  
F or t h e 2 0 5 M S 3 0 2 -3 0 3  I T T p o p ul ati o n, t h e E DS S  s c or e wit h c h a n g e fr o m 2 0 5 M S 3 0 3  b a s eli n e  wit h 
c h a n g e fr o m 2 0 5 M S 3 0 3  b a s eli n e will b e s u m m ari z e d b y st u d y vi sit i n 2 0 5 M S 3 0 3  f or all s u bj e ct s 
t o g et h er.  
 
7. 8.  E Q -5 D  
 
T h e E Q -5 D i s a g e n eri c h e alt h -r el at e d q u alit y of lif e ( Q o L) i n str u m e nt w hi c h h a s b e e n e xt e n si v el y 
v ali d at e d.  T h er e ar e t w o c o m p o n e nt s t o t h e E Q -5 D u s e d i n t hi s pr ot o c ol, a H e alt h St at e Pr ofil e a n d a 
Vi s u al A n al o g S c al e ( V A S). Wit h t h e H e alt h St at e Pr ofil e, p ati e nt s r e c or d t h eir l e v el of c urr e nt h e alt h 
f or fi v e d o m ai n s c o m pri si n g a h e alt h pr ofil e: m o bilit y, s elf-c ar e, u s u al a cti viti e s, p ai n/ di s c o mf ort, a n d 
a n xi et y/ d e pr e s si o n. A s c or e of 1, 2, or 3 ar e p o s si bl e r e s p o n s e s f or e a c h of t h e fi v e q u e sti o n s i n t h e 
H e alt h St at e Pr ofil e ( 1 = n o pr o bl e m s, 2 = s o m e pr o bl e m, 3 = s e v er e pr o bl e m s).  Wit h t h e Vi s u al 
A n al o g u e S c al e ( V A S) , p ati e nt s ar e a s k e d t o r at e t h eir c urr e nt h e alt h o n a 2 0 c m s c al e fr o m 0 t o 1 0 0 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
4 6  
w h er e 0 r e pr e s e nt s “ w or st i m a gi n a bl e h e alt h st at e” a n d 1 0 0 r e pr e s e nt s  “ b e st i m a gi n a bl e h e alt h 
st at e”. T h e E Q -5 D s u m m ar y i n d e x s c or e will b e c o m p ut e d fr o m t h e H e alt h St at e Pr of il e u si n g M V H 
A 1 T ariff ( D ol a n, 1 9 9 7). Mi s si n g v al u e s will  n ot b e i m p ut e d. T h e E Q -5 D s u m m ar y i n d e x s c or e d at a 
o bt ai n e d aft er s u bj e ct s t a k e alt er n ati v e m e di c ati o n f or M S d uri n g t h e st u d y will b e s et t o mi s si n g.  
 
7. 8. 1.  E Q -5 D i n t h e 2 0 5 M S 3 0 1-3 0 3  I T T P o p ul ati o n 
F or  t h e 2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n, t h e E Q-5 D H e alt h St at e Pr ofil e s c or e s, t h e E Q -V A S s c or e s 
wit h c h a n g e fr o m 2 0 5 M S 3 0 3 b a s eli n e, a n d t h e s u m m ar y i n d e x s c or e s wit h c h a n g e fr o m 2 0 5 M S 3 0 3 
b a s eli n e will b e s u m m ari z e d f or t h e 2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n b y 2 0 5 M S 3 01 tr e at m e nt gr o u p 
a n d b y st u d y vi sit i n 2 0 5 M S 3 0 3.  
 
7. 8. 2.  E Q -5 D i n t h e 2 0 5 M S 2 0 3-3 0 3  I T T P o p ul ati o n 
F or t h e 2 0 5 M S 2 0 3 -3 0 3  I T T p o p ul ati o n, t h e E Q-5 D H e alt h St at e Pr ofil e s c or e s, t h e E Q -V A S s c or e s 
wit h c h a n g e fr o m 2 0 5 M S 3 0 3  b a s eli n e, a n d t h e s u m m ar y i n d e x s c or e s w it h c h a n g e fr o m 2 0 5 M S3 0 3  
b a s eli n e will b e s u m m ari z e d f or all s u bj e ct s c o m bi n e d i n t h e2 0 5 M S 3 0 3 Tr e at m e nt  P eri o d ( b y st u d y 
vi sit i n 2 0 5 M S 3 0 3 st u d y ).   
 
7. 8. 3.  E Q -5 D i n t h e 2 0 5 M S 3 0 2-3 0 3  I T T P o p ul ati o n 
F or t h e 2 0 5 M S 3 0 2 -3 0 3  I T T p o p ul ati o n, t h e E Q-5 D H e alt h St at e Pr of il e s c or e s, t h e E Q-V A S s c or e s 
wit h c h a n g e fr o m 2 0 5 M S 3 0 3  b a s eli n e, a n d t h e s u m m ar y i n d e x s c or e s w it h c h a n g e fr o m 2 0 5 M S 30 3  
b a s eli n e will b e s u m m ari z e d b y st u d y vi sit i n 2 0 5 M S 3 0 3.  
 
7. 9.  H e alt h R e s o ur c e Utili z ati o n ( H R U)  
7. 9. 1.  H R U  i n t h e 2 0 5 M S 3 0 1-3 0 3  I T T P o p ul ati o n 
F or t h e 2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n, t h e t ot al n u m b er of u n s c h e d ul e d sit e vi sit s p er  c oll e cti o n ti m e 
will b e s u m m ari z e d s e p ar at el y f or M S -r el at e d a n d n o n-M S r el at e d vi sit s . S u m m ari e s will b e 
pr e s e nt e d  b y 2 0 5 M S 3 0 1 tr e at m e nt gr o u p i n t h e 2 0 5 M S 3 0 1 Tr e at m e nt Peri o d a n d t h e 2 0 5 M S 3 0 3 
Tr e at m e nt p eri o d.  T h e a n n u ali z e d r at e of u n s c h e d ul e d sit e vi sit s  will b e c al c ul at e d a s t h e t ot al 
n u m b er of  u n s c h e d ul e d vi sit s c oll e ct e d o n  P ati e nt H e alt h C ar e Tr e at m e nt C R F p a g e , di vi d e d b y t h e 
t ot al n u m b er of y e ar s .  
 
7. 9. 2.  H R U  i n t h e 2 0 5 M S 2 0 3 -3 0 3  I T T P o p ul ati o n 
F or t h e 2 0 5 M S 2 0 3 -3 0 3  I T T p o p ul ati o n, t h e t ot al n u m b er of u n s c h e d ul e d sit e vi sit s p er c oll e cti o n ti m e  
will b e s u m m ari z e d s e p ar at el y f or M S -r el at e d a n d n o n-M S r el at e d vi sit s. S u m m ari e s will b e 
pr e s e nt e d f or all s u bj e ct s c o m bi n e d in t h e 2 0 5 M S 3 0 3 Tr e at m e nt p eri o d. T h e a n n u ali z e d r at e of 
u n s c h e d ul e d sit e vi sit s will b e c al c ul at e d a s t h e t ot al n u m b er of u n s c h e d ul e d vi sit s c oll e ct e d o n 
P ati e nt H e alt h C ar e Tr e at m e nt C R F p a g e, di vi d e d b y t h e  t ot al n u m b er of y e ar s.  
 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
4 7  
7. 9. 3.  H R U  i n t h e 2 0 5 M S 3 02 -3 0 3  I T T P o p ul ati o n 
F or t h e 2 0 5 M S 3 0 2 -3 0 3  I T T p o p ul ati o n, t h e t ot al n u m b er of u n s c h e d ul e d sit e vi sit s p er c oll e cti o n ti m e  
will b e s u m m ari z e d s e p ar at el y f or M S -r el at e d a n d n o n-M S r el at e d vi sit s. T h e a n n u ali z e d r at e of 
u n s c h e d ul e d sit e vi sit s will b e c al c ul at e d a s t h e t ot al n u m b er of u n s c h e d ul e d vi sit s c oll e ct e d o n 
P ati e nt H e alt h C ar e Tr e at m e nt C R F p a g e, di vi d e d b y t h e t ot al n u m b er of y e ar s.  
 
7. 1 0.  H e alt h R el at e d Pr o d u cti vit y Q u e sti o n n air e ( H R P Q)  
7. 1 0. 1.  H R P Q  i n t h e 2 0 5 M S 3 0 1-3 0 3  I T T P o p ul ati o n 
F or  t h e 2 0 5 M S 3 0 1 -3 0 3  I T T po p ul ati o n , re s p o n s e s t o t h e H R P Q will b e s u m m ari z e d b y 2 0 5 M S 3 0 1 
tr e at m e nt gr o u p i n t h e 2 0 5 M S 3 0 3 Tr e at m e nt P eri o d .  
7. 1 0. 2.  H R P Q  i n t h e 2 0 5 M S 2 0 3 -3 0 3  I T T P o p ul ati o n 
F or  t h e 2 0 5 M S 2 0 3-3 0 3  I T T p o p ul ati o n, re s p o n s e s t o t h e H R P Q will b e s u m m ari z e d i n t h e 2 0 5 M S 3 0 3 
Tr e at m e nt P eri o d .  
 
7. 1 0. 3.  H R P Q  i n t h e 2 0 5 M S 3 0 2 -3 0 3  I T T P o p ul ati o n 
F or  t h e 2 0 5 M S 3 0 2-3 0 3  I T T p o p ul ati o n, re s p o n s e s t o t h e H R P Q will b e s u m m ari z e d i n t h e 2 0 5 M S 3 0 3 
Tr e at m e nt P eri o d .  
 
7. 1 1.  S y m b ol Di git M o d aliti e s T e st ( S D M T ) 
 
F or  t h e 2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n, S D M T a ct u al v al u e a n d c h a n g e fr o m 2 0 5 M S 3 0 1  b a s eli n e will 
b e s u m m ari z e d b y 2 0 5 M S 3 0 1 tr e at m e nt gr o u p i n t h e C o m bi n e d St u d y P eri o d (b y st u d y vi sit i n 
2 0 5 M S 3 0 1 a n d 2 0 5 M S 3 0 3 st u di e s ). A d diti o n all y, pr o p orti o n of  p ati e nt s wit h ≥3 p oi nt s or ≥4  p oi nt s  
i n cr e a s e fr o m 2 0 5 M S 3 0 1  b a s eli n e , a n d pr o p orti o n of p ati e nt s wit h ≥3 p oi nt s or ≥4 p oi nt s d e cr e a s e 
fr o m 2 0 5 M S 3 0 1  b a s eli n e  will b e s u m m ari z e d b y 2 0 5 M S 3 0 1 tr e at m e nt gr o u p  i n t h e C o m bi n e d St u d y 
P eri o d ( s e e al s o, B e n e di ct et. al 2 0 1 7 ). Si mil ar a n al y s e s will  b e d o n e f or t h e 2 0 5 M S 3 0 3 tr e at m e nt 
p eri o d wit h c h a n g e s fr o m 2 0 5 M S 3 0 3 b a s eli n e. N ot e t h at i n t h e 2 0 5 M S 3 0 3 st u d y, S D M T i s o nl y 
c oll e ct e d f or s u bj e ct s i n 2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n st arti n g fr o m w e e k 1 4 4 i n  t h e st u d y. 
 
S D M T i s n ot c oll e ct e d f or p ati e nt s e nr oll e d fr o m t h e 2 0 5 M S 2 0 3 or 2 0 5 M S 3 0 2 st u d y t o t h e 2 0 5 M S 3 0 3 
st u d y.  
 
7. 1 2.  3 S e c o n d P a c e d A u dit or y S eri al A d diti o n T e st  ( P A S A T 3) 
 
F or  t h e 2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n, P A S A T 3 a ct u al v al u e a n d c h a n g e fr o m 2 0 5 M S 3 0 1  b a s eli n e 
will b e s u m m ari z e d b y 2 0 5 M S 3 0 1 tr e at m e nt gr o u p i n t h e C o m bi n e d St u d y P eri o d (b y st u d y vi sit i n 
2 0 5 M S 3 0 1 a n d 2 0 5 M S 3 0 3 st u di e s ). Si mil ar a n al y s e s will  b e d o n e f or t h e 2 0 5 M S 3 0 3 tr e at m e nt 
p eri o d wit h c h a n g e s fr o m 2 0 5 M S 3 0 3 b a s eli n e.  
 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
4 8  
N ot e t h at P A S A T 3  i s n ot c oll e ct e d f or p ati e nt s e nr oll e d fr o m t h e 2 0 5 M S 2 0 3 or 2 0 5 M S 3 0 2 st u d y t o 
t h e 2 0 5 M S 3 0 3 st u d y. 
 
7. 1 3.  Pr o p orti o n of s u bj e ct s w h o ar e fr e e fr o m di s e a s e a cti vit y  
 
S u bj e ct s w er e c o n si d er e d fr e e of di s e a s e a cti vit y if t h e y w er e wit h o ut cli ni c al or r a di ol o gi c al a cti vit y. 
Cli ni c al a cti vi t y i n cl u d e d a n a s s e s s m e nt of r el a p s e s a n d of di s e a s e pr o gr e s si o n, a n d r a di ol o gi c al 
a cti vit y i n cl u d e d a n a s s e s s m e nt of G d + l e si o n s a n d n e w or e nl ar gi n g T 2 l e si o n s.  
F or  t h e 2 0 5 M S 3 0 1 -3 0 3  I T T p o p ul ati o n, pr o p orti o n of s u bj e ct s  w h o ar e fr e e fr o m di s e a s e a cti vi t y i n 
t h e 2 0 5 M S 3 0 3 tr e at m e nt p eri o d will  b e s u m m ari z e d b y 2 0 5 M S 3 0 1 tr e at m e nt gr o u p .  
 
 
8.  S af et y D at a  
8. 1.  S u m m ar y of S a fet y A n al y s e s  
A s s h o w n i n T a bl e 1 1 , s af et y a n al y s e s  will b e p erf or m e d  o v er t h e 2 0 5 M S 3 0 3 Tr e at m e nt p eri o d f or 
t h e 2 0 5 M S 3 0 1 -3 0 3  s af et y p o p ul ati o n,  t h e 2 0 5 M S 2 0 3 -3 0 3  s af et y p o p ul ati o n, a n d t h e 2 0 5 M S 3 0 2 -3 0 3  
s af et y p o p ul ati o n, r e s p e cti v el y. F or t h e 2 0 5 M S 3 0 1 -3 0 3 s af et y p o p ul ati o n, r e s ult s will b e s u m m ari z e d 
b y tr e at m e nt gr o u p i n t h e 2 0 5 M S 3 0 1 st u d y a n d f or all s u bj e ct s c o m bi n e d.  F or t h e 2 0 5 M S 2 0 3 -3 0 3  
s af et y p o p ul ati o n , r e s ults will b e s u m m ari z e d f or all s u bj e ct s c o m bi n e d. F or t h e 2 0 5 M S 3 0 2 -3 0 3  
s af et y p o p ul ati o n , r e s ults will b e s u m m ari z e d f or all s u bj e ct s c o m bi n e d. S e cti o n s b el o w  i n cl u d e m or e 
d et ail s a b o ut t h e s e a n al y s e s.  
 
T a bl e 1 1 : S u m m ar y of p o p ul ati o n s f or s af et y a n al y s e s  o v er t h e 2 0 5 M S 3 0 3 Tr e at m e nt  P eri o d  
P o p ul ati o n  
 
St ati sti c al M et h o d s  
2 0 5 M S 3 0 1 -3 0 3  s af et y 
p o p ul ati o n  
A E s, A E s of s p e ci al i nt er e st, l a b d at a , a n d vit al si g n s will b e d e s cri pti v el y 
s u m m ari z e d b y tr e at m e nt gr o u p i n t h e 2 0 5 M S 3 0 1  st u d y , a n d  f or all s u bj e ct s 
c o m bi n e d.  
2 0 5 M S 2 0 3 -3 0 3  s af et y 
p o p ul ati o n  
A E s, A E s of s p e ci al i nt er e st, l a b d at a , a n d vit al si g n s will b e d e s cri pti v el y 
s u m m ari z e d  f or all s u bj e ct s c o m bi n e d. 
2 0 5 M S 3 0 2 -3 0 3  s af et y 
p o p ul ati o n  
A E s, A E s of s p e ci al i nt er e st, l a b d at a , a n d vit al si g n s will b e d e s cri pti v el y 
s u m m ari z e d f or all s u bj e ct s c o m bi n e d . 
 
8. 2.  Cli ni c al A d v er s e E v e nt s  
All tr e at m e nt -e m er g e nt e v e nt s i n 2 0 5 M S 3 0 3 st u d y will b e i n cl u d e d i n t h e e v al u ati o n of s af et y.  A 
tr e at m e nt e m er g e nt e v e nt i s d efi n e d a s a n y e v e nt t h at eit h er o c c ur s or w or s e n s i n s e v erit y aft er t h e 
fir st d o s e of D A C H Y P tr e at m e nt i n 2 0 5 M S 3 0 3 st u d y. E v e nt s st arti n g aft er p er m a n e nt di s c o nti n u ati o n 
of st u d y dr u g will b e i n cl u d e d pr o vi d e d t h e st art d at e  w a s wit hi n 1 8 0 d a y s of t h e l a st d o s e. U nl e s s 
e x pli citl y st at e d ot h er wi s e, a n al y s e s of a d v er s e e v e nt s will b e li mit e d t o tr e at m e nt e m er g e nt e v e nt s i n 
t h e 2 0 5 M S 3 0 3 st u d y . If tr e at m e nt e m er g e n c e c a n n ot b e d et er mi n e d d u e t o i n c o m pl et e or p arti al st art 
a n d/ or e n d d at e s, t h e e v e nt will b e c o n si d er e d t o b e 2 0 5 M S 3 0 3 tr e at m e nt e m er g e nt.   
 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
4 9  
A d v er s e e v e nt s will b e c o d e d u si n g t h e M e di c al Di cti o n ar y f or R e g ul at or y Aff air s ( M e d D R A) v er si o n 
1 6. 1.  I n g e n er al, t h e i n ci d e n c e of tr e at m e nt e m er g e nt a d v er s e e v e nt s will b e pr e s e nt e d b y s y st e m 
or g a n cl a s s ( S O C) a n d pr ef err e d t er m s ( P T) b ut ot h er cl a s sifi c ati o n s m a y b e u s e d.  
 
T h e n u m b er a n d p er c e nt a g e of s u bj e ct s wit h at l e a st o n e e v e nt, at l e a st o n e s e v er e e v e nt a n d at 
l e a st o n e st u d y-dr u g r el at e d e v e nt will b e pr e s e nt e d.  T h e i n ci d e n c e of a d v er s e e v e nt s cl a s sifi e d b y 
t h e a p pr o pri at e s y st e m or g a n cl a s s a n d pr ef err e d t er m s will b e s u m m ari z e d b y s e v erit y a n d o v er all . If 
a p ati e nt e x p eri e n c e s a n e v e nt m or e t h a n o n c e wit h v ar yi n g s e v erit y d uri n g t h e st u d y, h e/ s h e will b e 
c o u nt e d o nl y o n c e wit h t h e m a xi m u m s e v erit y wit hi n e a c h s y st e m or g a n cl a s s/ pr ef err e d t er m. E v e nt s 
l e a di n g t o st u d y wit h dr a w al a n d/ or tr e at m e nt di s c o nti n u ati o n will b e s u m m ari z e d.  
 
I n g e n er al, for t h e 2 0 5 M S 3 0 1 -3 0 3 s af et y p o p ul ati o n , a d v er s e e v e nt s will b e s u m m ari z e d b y  tr e at m e nt 
gr o u p i n t h e 2 0 5 M S 3 0 1 st u d y a n d f or all s u bj e ct s c o m bi n e d . F or t h e 2 0 5 M S 2 0 3 -3 0 3  s af et y 
p o p ul ati o n , a d v er s e e v e nts will b e s u m m ari z e d f or all s u bj e ct s c o m bi n e d. F or t h e 2 0 5 M S 3 0 2 -3 0 3  
s af et y p o p ul ati o n , a d v er s e e v e nts will b e s u m m ari z e d f or all s u b j e ct s c o m bi n e d. 
 
A n y d e at h s t h at o c c urr e d d uri n g t h e st u d y will b e li st e d a n d r el e v a nt i nf or m ati o n i n cl u di n g ti mi n g of 
t h e d e at h r el ati v e t o st u d y tr e at m e nt, c o n c o mit a nt m e di c ati o n s, t h e i n v e sti g at or a s s e s s m e nt of t h e 
c a u s e of d e at h will b e pr o vi d e d.   
8. 3.  A d v er s e E v e nt s of I nt er e st  
 
T h e f oll o wi n g gr o u p s of a d v er s e e v e nt s ar e of s p e ci al i nt er e st d u e t o p ot e nti al m e c h a ni s m of a cti o n, 
t h er a p e uti c cl a s s, or pri or cli ni c al e x p eri e n c e wit h D A C H Y P. T h e gr o u p s of i nt er e st, a n d t h e 
M e d D R A -b a s e d or ot h er crit eri a utili z e d t o d et er mi n e t h e e v e nt s f alli n g i nt o e a c h gr o u p ar e d e s cri b e d 
i n t h e f oll o wi n g t a bl e. 
 
T a bl e  1 2 : A d v er s e E v e nt s of S p e ci al I nt er e st  
 
Gr o u p  
Crit eri a  
S u m m ar y  b y  
1.   I nf e cti o n s a n d s eri o u s 
i nf e cti o n s 
S O C of I nf e cti o n s a n d I nf e st ati o n s 
 
P T  a n d 
s eri o u s n e s s  
2.   S eri o u s s ki n r e a cti o n s  
S O C of S ki n a n d S u b c ut a n e o u s Ti s s u e Di s or d er s ; 
S M Q f or S e v er e c ut a n e o u s a d v er s e r e a cti o n s 
( S M Q) [ n arr o w t er m s o nl y] 
P T  
3.   H e p ati c e v e nt s  
S u bl e v el S M Q of Dr u g R el at e d H e p ati c Di s or d er s  –  
C o m pr e h e n si v e S e ar c h u n d er t h e S M Q of H e p ati c 
Di s or d er s  
S O C/ P T  
4.   C oliti s  
H L T of C oliti s ( E x cl I nf e cti v e), pri m ar y or s e c o n d ar y 
p at h w a y  
P T  
5.   A ut oi m m u n e h a e m ol yti c 
a n a e mi a  
S M Q H a e m ol yti c di s or d er s  
P T  


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
5 0  
6.   L y m p h a d e n o p at h y  
C u st o mi z e d s e ar c h  of t h e f oll o wi n g P T s:  
a b d o mi n al l y m p h a d e n o p at h y, a d e n oi diti s, 
a n gi ol y m p h oi d h y p er pl a si a wit h e o si n o p hili a, 
a ut oi m m u n e l y m p h o pr olif er ati v e s y n dr o m e, 
C a stl e m a n' s di s e a s e, hil ar l y m p h a d e n o p at h y, 
hi sti o c yti c n e cr oti si n g l y m p h a d e niti s, l y m p h n o d e 
p ai n, l y m p h n o d e p al p a bl e, l y m p h a d e niti s, 
l y m p h a d e n o c y st, l y m p h a d e n o p at h y, 
l y m p h a d e n o p at h y m e di a sti n al, l y m p h ati c di s or d er, 
l y m p h oi d ti s s u e h y p er pl a si a, l y m p h o pr olif er ati v e 
di s or d er, l y m p h o pr olif er ati v e di s or d er i n r e mi s si o n, 
m y el o pr olif er ati v e n e o pl a s m, p ar atr a c h e al 
ly m p h a d e n o p at h y, p er si st e nt g e n er ali s e d 
l y m p h a d e n o p at h y, P F A P A s y n dr o m e, 
r etr o p erit o n e al l y m p h a d e n o p at h y 
S O C/ P T  
7.   D e pr e s si o n a n d s ui ci d e  
S M Q of D e pr e s si o n a n d S ui ci d e/ S elf I nj ur y  
P T  
8.   M a li g n a n ci e s 
S u bl e v el S M Q of M ali g n a nt or U n s p e cifi e d 
T u m o ur s  u n d er t h e S M Q of M ali g n a n ci e s , t h e n 
c o nfir m e d a s m ali g n a n ci e s f oll o wi n g m e di c al 
r e vi e w. 
P T  
9.   H y p er s e n siti vit y  
S M Q of H y p er s e n siti vit y ( n arr o w s e ar c h t er m s)  
S O C/ P T  
1 0   A n a p h yl a cti c r e a cti o n s  
S M Q of A n a p h yl a cti c R e a cti o n s ( n arr o w s e ar c h 
t er m s) 
S A E s wit hi n 2 4 h o ur s aft er  d o si n g  
P T  
1 1   A n gi o e d e m a  
S M Q of A n gi o e d e m a ( n arr o w s e ar c h t er m s)  
P T  
1 2   O p p ort u ni sti c i nf e cti o n s  
C u st o mi z e d s e ar c h i n cl u di n g s el e ct e d pr ef err e d 
t er m s  
P T  
1 3   L y m p h o p e ni a  
P T s: L y m p h o p e ni a; l y m p h o c yt e c o u nt a b n or m al; 
L y m p h o c yt e c o u nt d e cr e a s e d; B -l y m p h o c yt e c o u nt 
d e cr e a s e d, L e u k o p e ni a, Diff er e nti al w hit e bl o o d c ell 
c o u nt a b n or m al; L y m p h o c yt e p er c e nt a g e d e cr e a s e d, 
L y m p h o c yt e p er c e nt a g e a b n or m al  
S O C/ P T  p er 
s e v erit y  
 
1 4   I m m u n e m e di at e d di s or d er s  
H L G T of A ut oi m m u n e Di s or d er s, pri m ar y or 
s e c o n d ar y p at h w a y, pl u s t h e a d diti o n al 1 P T of 
C o o m b s N e g ati v e H e m ol yti c A n e mi a, mi n u s t h e 2 
P T of M ulti pl e S cl er o si s a n d O pti c N e uriti s  
S O C/ P T  
1 5   S ar c oi d o si s  
Hi g h L e v el T er m: A c ut e a n d c hr o ni c s ar c oi d o si s 
a n d t h e Pr ef err e d T er m of H e erf or dt s s y n dr o m e  
P T  
 
 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
5 1  
T h e i n ci d e n c e of a d v er s e e v e nt s i n e a c h gr o u p will b e s u m m ari z e d  f or t h e 2 0 5 M S 3 0 1 -3 0 3  s af et y 
p o p ul ati o n, t h e 2 0 5 M S 2 0 3 -3 0 3  s af et y p o p ul ati o n, a n d t h e 2 0 5 M S 3 0 2 -3 0 3  s af et y p o p ul ati o n, 
r e s p e cti v el y; w h er e a p pr o pri at e, t h e a n al y si s will b e r e p e at e d f or s eri o u s e v e nt s. 
 
8. 4.  A d diti o n al Effi c a c y a n d S af et y E n d p oi nt s  
 
A d diti o n al effi c a c y a n d s af et y e n d p oi nt s d e s cri b e d i n t hi s s e cti o n will  b e a n al y z e d f or  t h e 2 0 5 M S 3 0 1-
2 0 5 M S 3 0 3 st u d y .  
 
8. 4. 1.  B e c k D e pr e s si o n I n v e nt or y S c or e  
D e pr e s si o n s c or e s will b e c al c ul at e d a c c or di n g t o t h e B DI -II m a n u al, S e co n d E diti o n.  S u bj e ct s wit h a 
t ot al s c or e of 1 8 or hi g h er will b e c o n si d er e d a s p o siti v e f or d e pr e s si o n.  F or t h e 2 0 5 M S 3 0 1 -3 0 3  
s af et y  p o p ul ati o n , B DI -II s c or e s, t h eir c h a n g e fr o m D A C H Y P  B a s eli n e , a n d t h e pr o p orti o n of s u bj e ct s 
p o siti v e f or d e pr e s si o n will b e s u m m ari z e d b y vi sit  i n t h e 2 0 5 M S 3 0 3 st u d y. If t h er e ar e m or e t h a n 2 
r e s p o n s e s f or t h e s a m e q u e sti o n, t h e r e s p o n s e wit h t h e hi g h e st ( w or st) r ati n g will b e u s e d i n t h e 
a n al y si s.  
N ot e t h at B e c k d e pr e s si o n i n v e nt or y s c or e  i s n ot c oll e ct e d f or p ati e nt s e nr oll e d fr o m 2 0 5 M S 2 0 3 or 
2 0 5 M S 3 0 2 st u d y t o t h e 2 0 5 M S 3 0 3 st u d y.  
 
8. 4. 2.  Tr e at m e nt S ati sf a cti o n Q u e sti o n n air e f or M e di c ati o n  
S u m m ar y st ati sti c s f or t h e tr e at m e nt s ati sf a cti o n q u e sti o n n air e f or m e di c ati o n, b y 2 0 5 M S 3 0 1 
tr e at m e nt gr o u p, will b e pr o vi d e d f or b a s eli n e a n d p o st -b a s eli n e vi sit s of t h e 2 0 5 M S 3 0 3 st u d y  f or t h e 
2 0 5 M S 3 0 1 -3 0 3 I T T p o p ul ati o n . T h e r e s p o n s e s t o t h e q u e sti o n n air e m a y b e gr o u p e d pr o p erl y.  
N ot e t h at tr e at m e nt s ati sf a cti o n q u e sti o n n air e f or m e di c ati o n i s n ot c oll e ct e d f or p ati e nt s e nr oll e d 
fr o m 2 0 5 M S 2 0 3 or 2 0 5 M S 3 0 2 st u d y t o t h e 2 0 5 M S 3 0 3 st u d y. 
 
8. 4. 3.  M S F C  S c or e  
T h er e ar e 3 c o m p o n e nt s t o t h e M S F C:   
( 1) t h e a v er a g e s c or e s fr o m t h e 4 tri al s o n t h e 9-h ol e p e g t e st ( 9 H P T) (t h e 2 tri al s f or e a c h h a n d ar e 
a v er a g e d, c o n v ert e d t o t h e r e ci pr o c al s of t h e 
m e a n ti m e s f or e a c h h a n d a n d t h e n t h e 2 
r e ci pr o c al s ar e a v er a g e d);  
( 2) t h e a v er a g e s c or e s of t h e 2 Ti m e d 2 5-F o ot W al k tri al s;  
( 3) t h e n u m b er c orr e ct o n t h e P a c e d A u dit or y S eri al A d diti o n ( P A S A T) 3 t e st.  
 
T h e M S F C z -s c or e i s c al c ul at e d b y cr e ati n g z -s c or e s f or e a c h c o m p o n e nt of t h e M S F C, a s e x pl ai n e d 
b el o w, a n d a v er a gi n g t h e m t o cr e at e a n o v er all c o m p o sit e s c or e, i. e.,  
M S F C z -s c or e = ( Z 2 5 -f o ot-w al k   + Z 9 H P T    + Z P A S A T 3 )/ 3, wh er e Z x x x r ef er s t o Z-s c or e s.  


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
5 2  
A z -s c or e r e pr e s e nt s t h e n u m b er of st a n d ar d d e vi ati o n s a s u bj e ct’ s t e st r e s ult i s hi g h er ( z > 0) or 
l o w er ( z < 0) t h a n t h e a v er a g e t e st r e s ult ( z = 0) of t h e r ef er e n c e p o p ul ati o n.   
C alc ul ati o n f or R a w a n d Z -sc ore f or e ac h c o m p one nt  
 
T h e f oll o wi n g d e s cri b e s t h e s c ori n g, r ul e s f or mi s si n g v al u e i m p ut ati o n f or e a c h c o m p o n e nt.  
Ti m e d 2 5 -F o ot W al k Z -s c or e C al c ul ati o n  
T h e Z -s c or e i s c al c ul at e d a s i n t h e f oll o wi n g f or m ul a:  
Z 2 5 -f o ot-w al k  = 
)
(
)
(
)2
/)
((
*
)1
(
2
1
r efer e nce
S D
r efer e nce
M E A N
t
t



, 
w h er e t1  a n d t2  ar e t h e ti m e (i n s e c o n d s) f r o m t h e t w o tri al s, a n d t h e m e a n (r ef er e n c e) a n d S D 
(r ef er e n c e) ar e t h e m e a n a n d st a n d ar d d e vi ati o n r e s p e cti v el y, of b a s eli n e v al u e s f or t h e r ef er e n c e 
p o p ul ati o n.  F or  s c or e s t o b e c o m p ar a bl e wit h s c or e s i n 2 0 5 M S 3 0 1, t h e s a m e r ef er e n c e p o p ul ati o n i s 
u s e d. B a s eli n e v al u e s f or t h e r ef er e n c e p o p ul ati o n ar e t h e v al u e s at t h e 2 0 5 M S 3 0 1 b a s eli n e f or t h e 
r ef er e n c e p o p ul ati o n ( 2 0 5 M S 3 0 1 I T T p o p ul ati o n). T h e s a m e i s a p pli c a bl e t o 9 H P T a n d P A S A T 3 Z-
s c or e s.    
Ti m e d 2 5 -F o ot W al k R a w S c or e C al c ul ati o n  
T h e r o w s c or e i s c al c ul at e d a s i n t h e f oll o wi n g f or m ul a:  
R 2 5 -f o ot-w al k  = 
2
/)
(
2
1
t
t 
, 
w h er e t1  a n d t2  ar e t h e ti m e (i n s e c o n d s) fr o m t h e t w o tri al s.  
Mi s si n g V al u e H a n dli n g f or Ti m e d 2 5 -F o ot W al k  
F or mi s si n g b a s eli n e a n d p o st -b a s eli n e v al u e s, if a s u bj e ct i s mi s si n g o nl y o n e tri al f or a n y p o st -
b a s eli n e vi sit, t h e n t h e s c or e fr o m t h e n o n -mi s si n g tri al will b e u s e d t o c al c ul at e b ot h t h e Z -s c or e a n d 
R a w s c or e, u nl e s s t h e r e a s o n f or t h e mi s si n g s c or e i s d u e t o M S r el at e d p h y si c al li mit ati o n or ot h er 
p h y si c al li mit ati o n s. If r e a s o n i s d u e  t o o n e of t h e r e a s o n s li st e d a b o v e, t h e s c or e f or t h at s p e cifi c tri al 
will b e b a c k -c al c ul at e d u si n g t h e Z -s c or e v al u e of -1 3. 7 ( s e e f or m ul a b el o w), a n d t h e n t h e a v er a g e of 
t h e t w o tri al s will b e t a k e n. T h e st e p s o utli n e d a b o v e will r e m ai n t h e s a m e.   
If bot h s c or e s fr o m t h e t w o tri al s ar e mi s si n g f or a n y p o st -b a s eli n e vi sit d u e t o M S r el at e d p h y si c al 
li mit ati o n or ot h er p h y si c al li mit ati o n s, ( b a s e d o n t h e mi s si n g d at a al g orit h m s u g g e st e d b y t h e M S F C 
al g orit h m) t h e s u bj e ct will b e gi v e n a Z -s c or e of -1 3. 7 f or t h e Ti m e d 2 5 -F o ot w al k. T h e R o w -s c or e will 
b e b a c k -c al c ul at e d u si n g t h e f oll o wi n g f or m ul a:  


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
5 3  
R 2 5 -f o ot-w al k  = M E A N(r ef er e n c e)  + 1 3. 7* S D(r ef er e n c e) . 
9 H P T Z -s c or e C al c ul ati o n  
Z -s c or e f or t h e 9 H P T i s c al c ul at e d a s i n t h e f oll o wi n g f or m ul a:  
 
Z 9 H P T  =  
)
(
)
(
)2
/) 2
/)
(
1
 2
/)
(
1
((
2 2
2 1
1 2
1 1
r efer e nce
S D
r efer e nce
M E A N
t
t
t
t




, 
 
w h er e t1 1,  t1 2,  t2 1,  t2 2 ar e t h e ti m e (i n s e c o n d s) t a k e n t o c o m pl et e f or d o mi n a nt h a n d tri al 1, d o mi n a nt 
h a n d tri al 2, n o n -d o mi n a nt h a n d tri al 1, a n d n o n -d o mi n a nt h a n d tri al 2, r e s p e cti v el y.  T h e m e a n 
(r ef er e n c e) a n d S D (r ef er e n c e) ar e t h e m e a n a n d st a n d ar d d e vi ati o n, r e s p e cti v el y, of r ef er e n c e 
p o p ul ati o n’ s b a s eli n e s c or e.     
9 H P T R a w S c or e C al c ul ati o n  
R a w -s c or e f or t h e 9 H P T i s c al c ul at e d a s i n t h e f oll o wi n g f or m ul a:  
R 9 H P T  = 
2
/)2
/)
(
2
/)
((
1 2
1 1
1 2
1 1
t
t
t
t



 
w h er e t1 1,  t1 2,  t2 1,  t2 2 ar e t h e ti m e (i n s e c o n d s) t a k e n t o c o m pl et e f or d o mi n a nt  h a n d tri al 1, d o mi n a nt 
h a n d tri al 2, n o n -d o mi n a nt h a n d tri al 1, a n d n o n -d o mi n a nt h a n d tri al 2, r e s p e cti v el y.  
Mi s si n g V al u e s f or 9 -h ol e P e g T e st  
F or mi s si n g b a s eli n e a n d p o st -b a s eli n e v al u e s, if a s u bj e ct i s mi s si n g o nl y o n e tri al f or a n y p o st -
b a s eli n e vi s it (f or eit h er d o mi n a nt or n o n-d o mi n a nt h a n d), t h e n t h e s c or e fr o m t h e n o n -mi s si n g tri al 
will b e u s e d t o c al c ul at e b ot h s c or e s, u nl e s s t h e r e a s o n f or t h e mi s si n g s c or e i s d u e t o M S r el at e d 
p h y si c al li mit ati o n or ot h er p h y si c al li mit ati o n s. If r e a s o n i s d u e  t o o n e of t h e r e a s o n s li st e d a b o v e, t h e 
s c or e f or t h at s p e cifi c tri al will b e i m p ut e d wit h a r a w s c or e v al u e of 7 7 7, a n d t h e n t h e a v er a g e of t h e 
t w o tri al s will b e t a k e n. T h e st e p s o utli n e d a b o v e will r e m ai n t h e s a m e.  
T h e mi s si n g d at a al g orit h m s u g g e st e d  b y t h e M S F C m a n u al will b e u s e d t o i m p ut e mi s si n g v al u e s.  If 
b ot h s c or e s fr o m eit h er h a n d s ar e mi s si n g f or a n y p o st -b a s eli n e vi sit, d u e t o M S r el at e d p h y si c al 
li mit ati o n or ot h er p h y si c al li mit ati o n s, t h e n t h e s u bj e ct will b e gi v e n a R o w-s c or e u si n g a v al u e of 
7 7 7. T h e Z -s c or e will b e c al c ul at e d wit h t h e f oll o wi n g f or m ul a:  


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
5 4  
Z 9 H P T  =  
)
(
)
(
 
7 7
7
1
r efer e nce
S D
r efer e nce
M E A N

, 
P A S A T 3 Z -s c or e C al c ul ati o n  
F or t h e P A S A T 3, t h e z -s c or e f or e a c h s u bj e ct at e a c h ti m e -p oi nt will b e cr e at e d b y s u btr a cti n g t h e 
r ef er e n c e p o p ul ati o n’ s b a s eli n e m e a n s c or e o n t h e P A S A T 3 fr o m t h e s u bj e ct’ s P A S A T 3 s c or e a n d 
di vi di n g b y t h e b a s eli n e S D o n t h e P A S A T 3 of t h e r ef er e n c e p o p ul ati o n, i. e.  
 
Z P A S A T 3 =  
)
(
)
(
s c ore
 
ra w
 3 
P A S A T
r efer e nce
S D
r efer e nce
M E A N

, 
a n d P A S A T 3 r a w s c or e = # of it e m s c orr e ct.    
Mi s si n g V al u e s  
F or mi s si n g p o st -b a s eli n e v al u e s, if a s u bj e ct i s mi s si n g t h e P A S A T 3 s c or e d u e t o M S di s e a s e 
li mit ati o n s, t h e n a s c or e of 0 will b e i m p ut e d a s t h e r a w s c or e. Mi s si n g b a s eli n e v al u e s will n ot b e 
i m p ut e d. 
 
F or t h e 2 0 5 M S 3 0 1 -3 0 3 I T T p o p ul ati o n, a ct u al v al u e, c h a n g e a n d p er c e nt a g e c h a n g e  fr o m t h e 
2 0 5 M S 3 0 1 b a s eli n e  i n t h e M S F C z-s c or e s a s w ell a s f or e a c h i n di vi d u al M S F C c o m p o n e nt z -s c or e s 
will b e s u m m ari z e d b y 2 0 5 M S 3 0 1 tr e at m e nt gr o u p i n C o m bi n e d St u d y P eri o d ( b y st u d y vi sit i n 
2 0 5 M S 3 0 1 a n d 2 0 5 M S 3 0 3 st u di e s). Si mil arl y, f or t h e 2 0 5 M S 3 0 1 -3 0 3 I T T p o p ul ati o n, t h e  M S F C z -
s c or e s a s w ell a s f or e a c h i n di vi d u al 
M S F C c o m p o n e nt z -s c or e s  wit h c h a n g e fr o m 2 0 5 M S 3 0 3 
b a s eli n e will b e s u m m ari z e d b y 2 0 5 M S 3 0 1 tr e at m e nt gr o u p i n  t h e 2 0 5 M S 3 0 3 Tr e at m e nt P eri o d ( b y 
st u d y vi sit i n 2 0 5 M S 3 0 3 st u d y).   
 
8. 5.  L a b or at or y D at a  
A n al y s e s of l a b or at or y a s s e s s m e nt s will b e p erf or m e d o n s u bj e ct s i n e a c h of t h e  s af et y p o p ul ati o n 
utili zi n g t h e f oll o wi n g r ul e: p o st -b a s eli n e d at a will i n cl u d e m e a s ur e m e nt s o c c urri n g aft er t h e fir st D A C 
H Y P d o s e d at e a n d d uri n g t h e 2 0 5 M S 3 0 3 Tr e at m e nt  P eri o d. F or s u bj e c t s w h o w er e r a n d o mi z e d t o 
I F N β -1 a  i n t h e 2 0 5 M S 3 0 1 st u d y, t hi s m e a n s t h at p o st-b a s eli n e d at a i n cl u d e s m e a s ur e m e nt s 
o c c urri n g aft er t h e fir st D A C H Y P d o s e d at e i n t h e 2 0 5 M S 3 0 3 st u d y. F or s u bj e ct s r a n d o mi z e d t o 
D A C H Y P i n t h e 2 0 5 M S 3 0 1 st u d y, t hi s m e a n s t h at p o st -b a s eli n e d at a i n cl u d e s m e a s ur e m e nt s 
o c c urri n g d uri n g t h e 2 0 5 M S 3 0 3 st u di e s o n or aft er t h e fir st D A C H Y P d o s e d at e i n 2 0 5 M S 3 0 3 . F or 
s u bj e ct s tr a n siti o n e d fr o m t h e 2 0 5 M S 2 0 3 st u d y or t h e 2 0 5 M S 3 0 2 st u d y, t hi s m e a n s t h at p o st -
b a s eli n e d at a i n cl u d e s m e a s ur e m e nt s o c c urri n g d uri n g t h e 2 0 5 M S 3 0 3 st u di e s o n or aft er t h e fir s t 
D A C H Y P d o s e d at e i n 2 0 5 M S 3 0 3 . 
 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
5 5  
T h e f oll o wi n g l a b or at or y p ar a m et er s will b e i n cl u d e d i n t h e af or e m e nti o n e d a n al y s e s:  
 
•  
H e m at ol o g y:  
•  
W hit e bl o o d c ell ( W B C) p ar a m et er s ( a s a b s ol ut e v al u e s a n d a s  p er c e nt a g e of W B C): 
b a s o p hil s, e o si n o p hil s, l y m p h o c yt e s, m o n o c yt e s , a n d s e g m e nt e d n e utr o p hil s  
•  
ot h er h e m at ol o g y p ar a m et er s: h e m at o crit, h e m o gl o bi n, M e a n C or p u s c ul ar 
H e m o gl o bi n ( M C H), m e a n c or p u s c ul ar h e m o gl o bi n c o n c e ntr ati o n  ( M C H C), m e a n 
c or p u s c ul ar v ol u m e  ( M C V), pl at el et s, r e d bl o o d c ell ( R B C) c o u nt, W B C 
 
•  
Bl o o d c h e mi str y:  
•  
li v er f u n cti o n t e st s ( L F T s): al k ali n e p h o s p h at a s e, al a ni n e a mi n otr a n sf er a s e ( A L T), 
a s p art at e a mi n otr a n sf er a s e  ( A S T), g a m m a-gl ut a m yl tr a n s p e pti d a s e ( G G T) a n d t ot al 
bilir u bi n.  
•  
r e n al f u n cti on t e st s a n d el e ctr ol yt e s: bl o o d ur e a nitr o g e n ( B U N), cr e ati ni n e, 
bi c ar b o n at e, c hl ori d e, p ot a s si u m a n d s o di u m.  
•  
t h yr oi d f u n cti o n t e st s: t ot al T 4, a n d t h yr oi d sti m ul ati n g h or m o n e ( T S H). 
 
•  
Uri n al y si s:  
•  
q u a ntit ati v e uri n al y si s p ar a m et er s: p H a n d s p e cifi c gr a vit y  
•  
c at e g ori c al uri n al y si s p ar a m et er s: c ol or a n d cl arit y , bl o o d, gl u c o s e, l e u k o c yt e 
e st er a s e, k et o n e s, nitrit e a n d pr ot ei n.  
 
S hift s t o a b n or m all y hi g h or a b n or m all y l o w v al u e s f or q u a ntit ati v e p ar a m et er s:  A n y s u bj e ct wit h a 
n o n -hi g h D A C H Y P b a s eli n e ( w h et h er l o w, n or m al or u n k n o w n) will b e c o u nt e d i n t h e ri s k s et f or 
s hift s t o hi g h.  Si mil arl y, a n y s u bj e ct wit h a n o n -l o w D A C H Y P b a s eli n e r e s ult will b e c o u nt e d i n t h e 
ri s k s et f or s hift s t o l o w. S hift s t a bl e s t o t h e m o st e xtr e m e v al u e i n t h e 2 0 5 M S 3 0 3 Tr e at m e nt P eri o d  
( hi g h e st f or s hift s t o hi g h, l o w e st f or s hift s t o l o w) will b e c o n d u ct e d . T h e r ati o n al e f or u si n g t h e m o st 
e xtr e m e v al u e s or w or st v al u e i s t h at s h o ul d a tr e at m e nt aff e ct a l a b or at or y v al u e, t h at v al u e c o ul d b e 
aff e ct e d at diff er e nt ti m e s f or diff er e nt s u bj e ct s.  T h er ef or e, t h e a n al y s e s pr e s e nt t h e m o st e xtr e m e 
v al u e s f or e a c h s u bj e ct o v er ti m e. F or t h e 2 0 5 M S 3 0 1 -3 0 3 s af et y p o p ul ati o n, t h e s hift t a bl e s will b e 
pr e s e nt e d b y  pr e vi o u s tr e at m e nt gr o u p of t h e 2 0 5 M S 3 0 1 st u d y  a n d  f or all s u bj e ct s c o m bi n e d. F or  t h e 
2 0 5 M S 2 0 3 -3 0 3 s af et y p o p ul ati o n  a n d 2 0 5 M S 3 0 2 -3 0 3 s af et y p o p ul ati o n , t h e s hift t a bl e s will b e 
pr e s e nt e d f or all s u bj e ct s c o m bi n e d wit hi n e a c h of t h e s af et y p o p ul ati o n .  
 
S hift s t o a b n or m al v al u e s f or c at e g ori c al p ar a m et er s:  A n y s u bj e ct wit h a n o n -a b n or m al D A C H Y P 
b a s eli n e ( w h et h er n or m al or u n k n o w n) will b e c o u nt e d i n t h e ri s k s et f or s hift s t o a b n or m al.  F or t h e 
2 0 5 M S 3 0 1 -3 0 3 s af et y p o p ul ati o n,  s hift s fr o m b a s eli n e t o t h e m o st e xtr e m e p o st -b a s eli n e v al u e will 
b e pr e s e nt e d b y pr e vi o u s tr e at m e nt g r o u p of t h e 2 0 5 M S 3 0 1 st u d y a n d f or all s u bj e ct s c o m bi n e d. F or 
t h e 2 0 5 M S 2 0 3-3 0 3 s af et y p o p ul ati o n  a n d t h e 2 0 5 M S 3 0 2 -3 0 3 s af et y p o p ul ati o n , t h e s hift t a bl e s will 
b e pr e s e nt e d f or all s u bj e ct s c o m bi n e d  wit hi n e a c h of t h e s af et y p o p ul ati o n .  
 
D e s cri pti v e s u m m ar y st ati sti c s o v er ti m e i n t h e 2 0 5 M S 3 0 3 Tr e at m e nt  P eri o d  f or q u a ntit ati v e 
p ar a m et er s, of a ct u al v al u e s, c h a n g e fr o m D A C H Y P b a s eli n e ( a n d w h e n a p pr o pri at e, p er c e nt 
c h a n g e fr o m b a s eli n e).  T h e s e st ati sti c s m a y b e di s pl a y e d a s fi g ur e s. Ti m e  p oi nt s a n al y z e d will b e 
b a s e d o n pr ot o c ol s c h e d ul e d a s s e s s m e nt s a n d a v ail a bilit y of d at a.  Vi sit wi n d o w s will b e u s e d t o 
s el e ct t h e l a b or at or y r e s ult u s e d f or e a c h ti m e  p oi nt i n t h e s u m m ar y.   


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
5 6  
 
T h e n u m b er a n d p er c e nt of s u bj e ct s wit h p ot e nti all y cli ni c all y si g nifi c a nt h e m a t ol o g y l a b or at or y 
a b n or m aliti e s will b e pr o vi d e d. T h e crit eri a of t h e p ot e nti all y si g nifi c a nt h e m at ol o g y l a b or at or y 
a b n or m aliti e s ar e pr o vi d e d b el o w. Li sti n g  of l y m p h o c yt es  f or s u bj e ct s wit h s e v er e a n d pr ol o n g e d 
l y m p h o p e ni a d efi n e d a s p o st D A C b a s eli n e l y mp h o c yt e s < 0. 5 x 1 0 ^ 9 c ell s/ L c o n s e c uti v el y f or at l e a st 
6 m o nt h s will b e pr o vi d e d . 
 
F or t h e b a s eli n e t h yr oi d f u n cti o n t e st p ar a m et er s, d e s cri pti v e s u m m ar y st ati sti c s of a ct u al v al u e s will 
b e gi v e n. F or uri n al y si s p ar a m et er s, a ct u al v al u e s will b e li st e d.  
 
T a bl e  1 3 : Crit eri a f or P ot e nti all y Cli ni c all y Si g nifi c a nt H e m at ol o g y A b n or m aliti e s  
T e st  
Crit eri a  
W hit e bl o o d c ell c o u nt ( 1 0 ^ 9 c ell s/ L)  
< 3. 0; > = 1 6. 0  
L y m p h o c yt e s ( 1 0 ^ 9 c ell s/ L)  
< 0. 8; < 0. 5; > 1 2. 0  
S e g m e nt e d n e utr o p hil s ( 1 0 ^ 9 c ell s/ L) 
< = 1. 0; < 1. 5; > = 1 2. 0  
R e d bl o o d c ell c o u nt ( 1 0 ^ 1 2 c ell s/ L)  
< = 3. 3; > = 6. 8  
H e m o gl o bi n ( g/ L)  
< = 1 0 0  
Pl at el et s ( 1 0 ^ 9 c ell s/ L)  
< = 1 0 0; > = 6 0 0  
 
I n a d diti o n, s u m m ar y of b a s eli n e a n d w or st p o st-b a s eli n e l a b or at or y v al u e s c at e g ori z e d b a s e d o n 
C T C ( c o m m o n t o xi cit y crit eri a) gr a d e, will  al s o b e pr e s e nt e d f or s el e ct e d p ar a m et er s of i nt er e st.  T h e 
d at a m a y al s o b e pr e s e nt e d i n gr a p h s. T h e crit eri a f or C T C  gr a d e f or h e m at ol o g y p ar a m et er s ar e 
pr o vi d e d b el o w.  
 
T a bl e  1 4 : S e v erit y Gr a d e s f or H e m at ol o g y  
T e st  
Gr a d e 1  
Gr a d e 2  
Gr a d e 3  
Gr a d e 4  
H e m o gl o bi n ( g/ L)  
[ 1 0 0, L L N) 
[ 8 0, 1 0 0) 
[ 6 5, 8 0) 
< 6 5  
L y m p h o c yt e s ( 1 0 ^ 9 c ell s/ L)  
[ 0. 8, L L N) 
[ 0. 5, 0. 8) 
[ 0. 2, 0. 5) 
< 0. 2  
Pl at el et s ( 1 0 ^ 9 c ell s/ L)  
[ 7 5, L L N) 
[ 5 0, 7 5) 
[ 2 5, 5 0) 
< 2 5  
S e g m e nt e d n e utr o p hil s ( 1 0 ^ 9 c ell s/ L)  
[ 1. 5, L L N) 
[ 1. 0, 1. 5) 
[ 0. 5, 1. 0) 
< 0. 5  
W hit e bl o o d c ell c o u nt ( 1 0 ^ 9 c ell s/ L)  
[ 3. 0, L L N) 
[ 2. 0, 3. 0) 
[ 1. 0, 2. 0) 
< 1. 0  
 
A d diti o n al A n al y s e s of Li v er F u n cti o n T e st s  
 
F or L F T s Al k ali n e p h o s p h at a s e, A L T, A S T, G G T a n d t ot al bilir u bi n, a d diti o n al c at e g ori e s will b e 
d efi n e d t o pr e s e nt b a s eli n e a n d p o st -b a s eli n e v al u e s ( s e e t a bl e b el o w). T h e i n ci d e n c e of A L T a n d/ or 
A S T el e v ati o n s > 3 X U L N b y c o n c urr e ntl y el e v at e d bilir u bi n will al s o b e s u m m ari z e d.  
 
 
 
T a bl e  1 5 : S e v erit y Gr a d e s f or L F T s  
T e st  
Gr a d e 1  
Gr a d e 2  
Gr a d e 3  
Gr a d e 4  
A L T  
( 1. 0, 3. 0) 
[3. 0, 5. 0]  
( 5. 0, 1 0. 0] 
( 1 0. 0, 2 0. 0] 
>  2 0. 0  
A S T  
( 1. 0, 3. 0) 
[3. 0, 5. 0]  
( 5. 0, 1 0. 0] 
( 1 0. 0, 2 0. 0] 
>  2 0. 0  


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
5 7  
T e st  
Gr a d e 1  
Gr a d e 2  
Gr a d e 3  
Gr a d e 4  
Al k ali n e p h o s p h at a s e  
( 1. 0, 2. 5] 
( 2. 5, 5. 0] 
( 5. 0, 2 0. 0] 
>  2 0. 0  
G G T  
( 1. 0, 2. 5] 
( 2. 5, 5. 0] 
( 5. 0, 2 0. 0] 
>  2 0. 0  
T ot al bilir u bi n  
( 1. 0, 1. 5] 
( 1. 5, 3. 0] 
( 3. 0, 1 0. 0] 
>  1 0. 0  
Gr a d e s d et er mi n e d b y m ulti pl e s of U L N.  Gr a d e 3 A L T a n d A S T r e s ult s will b e s u b di vi d e d a s s h o w n.  
 
Pl ot s of c o n c urr e nt a n d n o n -c o n c urr e nt p e a k bilir u bi n v er s u s p e a k A L T or A S T will b e pr e s e nt e d, a s  
m ulti pl e s of U L N o n t h e l o g s c al e. I n ci d e n c e of s u b j e ct s e x p eri e n ci n g t ot al bilir u bi n at or a b o v e 
2 x U L N a n d A L T or A S T a b o v e 3 x U L N ( eit h er c o n c urr e nt) will b e s u m m ari z e d.  
 
8. 6.  S u b gr o u p a n al y si s  
 
S u b gr o u p a n al y si s , b a s e d o n t h e D A C H Y P b a s eli n e c h ar a ct eri sti c s or u s a g e of p ot e nti al h e p at ot o xi c 
m e di c ati o n , will  b e p erf or m e d f or t h e f oll o wi n g s el e ct e d s af et y e n d p oi nt s f or e a c h of t h e t hr e e s af et y 
p o p ul ati o n s ( t h e 2 0 5 M S 3 0 1 -3 0 3  s af et y p o p ul ati o n , t h e 2 0 5 M S 2 0 3 -3 0 3 s af et y p o p ul ati o n, a n d t h e 
2 0 5 M S 3 0 2 -3 0 3 s af et y p o p ul ati o n ), o v er t h e 2 0 5 M S 3 0 3 Tr e at m e nt P eri o d . 
S el e ct e d s af et y e n d p oi nt s : 
o  A d v er s e e v e nt  
o  S eri o u s a d v er s e e v e nt  
o  H e p ati c a d v er s e e v e nt  
o  S eri o u s h e p ati c a d v er s e e v e nt  
o  Li v er f u n cti o n t e st  
T h e f oll o wi n g D A C H Y P b a s eli n e c h ar a ct eri sti c s  or u s a g e of p ot e nti al h e p at ot o xi c m e di c ati o n  ar e 
u s e d t o d efi n e s u b gr o u p s if a p pli c a bl e:  
o  A g e  at D A C H Y P b a s eli n e  ( a g e < 5 0 v er s u s a g e > = 5 0) 
o  P r e-e xi sti n g li v er c o n diti o n s at D A C b a s eli n e  b a s e d o n  h e p ati c  m e di c al hi st or y r e p ort  
o  T a ki n g p ot e nti al h e p at ot o xi c m e di c ati o n   
F or  t h e p ot e nti al h e p at ot o xi c m e di c ati o n s u b gr o u p  a n al y si s , p ati e nt s will b e c at e g ori z e d a s eit h er  
wit h o ut  t a ki n g p ot e nti al h e p at ot o xi c m e di c ati o n  or  t a ki n g p ot e nti al h e p at ot o xi c m e di c ati o n. F or 
p ati e nt s t a ki n g p ot e nti al h e p at ot o xi c m e di c ati o n s , t h e y will b e f urt h er c at e g ori z e d a s eit h er i niti ati n g 
fir st p ot e nti all y h e p at ot o xi c m e di c ati o n w hil e o n D A C H Y P  tr e at m e nt or  i niti ati n g fir st p ot e nti all y 
h e p at ot o xi c m e di c ati o n pri or t o D A C H Y P  tr e at m e nt. N ot e t h at t h e li st of p ot e nti al h e p at ot o xi c 
m e di c ati o n s i s d efi n e d a n d a gr e e d b y S A B R pri or t o d at a b a s e l o c k . 
 
I n ci d e n c e of a d v er s e e v e nt s a n d s eri o u s a d v er s e e v e nt s will b e s u m m ari z e d b y D A C b a s eli n e a g e 
s u b gr o u p , a n d b y s y st e m or g a n cl a s s a n d pr ef err e d t er m .  
 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
5 8  
S u m m ari e s o f h e p ati c e v e nt s, a s d efi n e d a s a n A E of s p e cial i nt er e st i n T a bl e 1 2,  will b e pr o vi d e d  b y 
s u b gr o u p  f or pr e-e xi sti n g li v er c o n diti o n s s u b gr o u p a n d p ot e nti al  h e p at ot o xi c m e di c ati o n s u b gr o u p , 
r e s p e cti v el y. I n a d diti o n, i n ci d e n c e of h e p ati c e v e nt s a n d s eri o u s h e p ati c e v e nt s will b e s u m m ari z e d 
b y s y st e m or g a n cl a s s a n d pr ef err e d t er m f or e a c h of t h e s u b gr o u p s of pr e -e xi sti n g li v er c o n diti o n s 
a n d p ot e nti al h e p at o xi c m e di c ati o n .  
 
S u m m ar i e s of m a xi m u m li v er f u n cti o n t e st v al u e s  will b e pr o vi d e d b y s u b gr o u p f or b ot h t h e pr e -
e xi sti n g li v er c o n diti o n s s u b gr o u p a n d t h e p ot e nti al h e p at ot o xi c m e di c ati o n s u b gr o u p.  
 
8. 7.  Vit al Si g n s  
 
Vit al si g n s c oll e ct e d  i n t h e 2 0 5 M S 3 0 3 st u d y will b e e x a mi n e d t o d et er mi n e t h e i n ci d e n c e of cli ni c all y 
r el e v a nt a b n or m aliti e s. F or e a c h of t h e  s af et y p o p ul ati o n, t h e n u m b er a n d p er c e nt a g e of s u bj e ct s 
wit h cli ni c all y r el e v a nt p o st -D A C H Y P b a s eli n e a b n or m aliti e s i n t h e 2 0 5 M S 3 0 3 st u d y will b e 
s u m m ari z e d . T h e d efi niti o n s of a b n or m aliti e s ar e pr o vi d e d i n  T a bl e 1 6 . F or t h e p ur p o s e of 
d et er mi ni n g s hift s, D A C H Y P b a s eli n e will  b e u s e d. S u m m ar y st ati sti c s f or a ct u al v al u e s a n d c h a n g e 
fr o m D A C H Y P b a s eli n e will al s o b e pr e s e nt e d. 
 
F or t h e 2 0 5 M S 3 0 1 -3 0 3 s af et y p o p ul ati o n, t h e s u m m ar y t a bl e s will b e pr e s e nt e d b y pr e vi o u s 
tr e at m e nt gr o u p of t h e 2 0 5 M S 3 0 1 st u d y, a n d f or all s u bj e ct s c om bi n e d.  F or t h e 2 0 5 M S 2 0 3 -3 0 3 
s af et y p o p ul ati o n  a n d t h e 2 0 5 M S 3 0 2-3 0 3 s af et y p o p ul ati o n, t h e s u m m ar y t a bl e s will b e pr e s e nt e d f or 
all s u bj e ct s c o m bi n e d  wit hi n e a c h s af et y p o p ul ati o n . 
 
T a bl e  1 6 : Crit eri a t o d et er mi n e cli ni c all y r el e v a nt a b n or m aliti e s i n vit al si g n s  
Vit al Si g n  
S hift  
Crit eri a f or A b n or m aliti e s  
T e m p er at ur e 
(º C) 
I n cr e a s e 
> 3 8º C a n d i n cr e a s e fr o m b a s eli n e of at l e a st 1º C 
P ul s e ( b p m)  
I n cr e a s e 
> 1 2 0 b e at s p er mi n ut e ( b p m) if ≤1 2 0 b p m at b a s eli n e, or  
i n cr e a s e fr o m b a s eli n e of m or e t h a n 2 0 b p m 
D e cr e a s e  
< 5 0 b p m if ≥5 0 b p m at b a s eli n e, or  
d e cr e a s e fr o m b a s eli n e of m or e t h a n 2 0 b p m  
S y st oli c bl o o d 
pr e s s ur e 
( m m H g) 
I n cr e a s e 
> 1 8 0 m m H g if ≤1 8 0 m m H g at b a s eli n e, or  
i n cr e a s e fr o m b a s eli n e of m or e t h a n 4 0 m m H g 
D e cr e a s e  
< 9 0 m m H g if ≥9 0 m m H g at b a s eli n e, or  
d e cr e a s e fr o m b a s eli n e of m or e t h a n 3 0 m m H g  
Di a st oli c bl o o d 
pr e s s ur e 
( m m H g) 
I n cr e a s e 
> 1 0 5 m m H g if ≤1 0 5 m m H g at b a s eli n e, or  
i n cr e a s e fr o m b a s eli n e of m or e t h a n 3 0 m m H g;  
D e cr e a s e  
< 5 0 m m H g if ≥5 0 m m H g at b a s eli n e, or  
d e cr e a s e fr o m b a s eli n e of m or e t h a n 2 0 m m H g  
 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
5 9  
8. 8.  P h y si c al E x a mi n ati o n  
A li sti n g of s u bj e ct s wit h c h a n g e fr o m n or m al t o a b n or m al st at u s i n p h y si c al e x a mi n ati o n at a n y ti m e 
d uri n g t h e 2 0 5 M S 3 0 3 st u d y will b e pr e s e nt e d  f or e a c h of t h e s af et y p o p ul ati o n . 
 
8. 9.  I m m u n o g e ni cit y D at a  
I m m u n o g e ni cit y t o d a cli z u m a b (i. e., a nti-dr u g a nti b o di e s ( A D A s) t h at bi n d t o D a cli z u m a b) will b e 
a s s e s s e d o n all s u bj e ct s i n 2 0 5 M S 3 0 3 wit h a v ail a bl e d at a.  P o siti v e s a m pl e s will b e f urt h er t e st e d f or 
n e utr ali zi n g a nti b o di e s u si n g a s p e cifi c n e utr ali zi n g a n ti b o d y ( N A b) a s s a y. R e s ult s will b e t a b ul at e d 
b y n o mi n al vi sit a n d o v er all.   
 
F or t h e 2 0 5 M S 3 0 1 -3 0 3 s af et y p o p ul ati o n, t h e s u m m ar y t a bl e s will b e pr e s e nt e d b y pr e vi o u s 
tr e at m e nt gr o u p of t h e 2 0 5 M S 3 0 1 st u d y, a n d f or all s u bj e ct s c o m bi n e d. F or t h e 2 0 5 M S 2 0 3-3 0 3 
s af et y p o p ul ati o n  a n d t h e 2 0 5 M S 3 0 2-3 0 3 s af et y p o p ul ati o n, t h e s u m m ar y t a bl e s will b e pr e s e nt e d f or 
all s u bj e ct s c o m bi n e d  wit hi n e a c h s af et y p o p ul ati o n .  
 
 
 
 
9.  P h ar m a c o ki n eti c s  a n d P h ar m a c o d y n a mi c s  
9. 1.  P h ar m a c o ki n eti c s  
Bl o o d s er u m will b e c oll e ct e d at s el e ct e d ti m e p oi nt s t hr o u g h o ut t h e st u d y t o d et er mi n e D A C H Y P 
s er u m c o n c e ntr ati o n s i n or d er t o m o nit or t h e dr u g tr o u g h l e v el a n d 
 
 
. Li sti n g s of D A C H Y P pl a s m a c o n c e ntr ati o n s b y s u bj e ct will b e  
pr e s e nt e d  f or e a c h of t h e s af et y p o p ul ati o n. 
 
9. 2.  P h ar m a c o d y n a mi c s  
 
 
   
 
1 0.  S a m pl e Si z e J u stifi c ati o n  
 
T h er e i s n o f or m al s a m pl e si z e  c al c ul ati o n f or t h e m ai n st u d y.  T h e n u m b er of s u bj e ct s i n t h e 
2 0 5 M S 3 0 3  st u d y i s d et er mi n e d b y t h e n u m b er of s u bj e ct s w h o c o m pl et e d s t u di e s 2 0 5 M S 3 0 1 , 
2 0 5 M S 2 0 3  a n d 2 0 5 M S 3 0 2 a n d w h o  w er e eli gi bl e t o a n d  c h o s e t o e nr oll i n st u d y 2 0 5 M S 3 0 3.   
 


 
             
        Pr ot o c ol 2 0 5 M S 3 0 3  
St ati sti c al A n al y si s Pl a n  
 
Fi n al V er si o n 1. 0  
 
 
6 0  
1 1.  R ef er e n c e s  
 
H o b art  J , L a m pi n g D , Fit z p atri c k R , Ri a zi A , T h o m p s o n A . T h e M ulti pl e S cl er o si s I m p a ct S c al e 
( M SI S-2 9): a n e w p ati e nt -b a s e d o ut c o m e m e a s ur e . Br ai n , 2 0 0 1 M a y; 1 2 4( Pt 5): 9 6 2-9 7 3.  
 
D ol a n P M o d eli n g V al u ati o n s f or E ur o Q ol H e alt h St at e s. M e di c al C ar e , 1 9 9 7, 1 1: 1 0 9 5-1 1 0 8.  
 
B e n e di ct R H, C o h a n S, L y n c h S G, Ri e st er K, W a n g P, C a str o -B orr er o W, El ki n s J, S a b at ell a G. 
I m pr o v e d c o g niti v e o ut c o m e s i n p ati e nt s wit h r el a p si n g– r e mitti n g m ulti pl e s cl er o si s tr e at e d wit h 
d a cli z u m a b b et a: R e s ult s fr o m t h e D E CI D E st u d y. M ulti pl e S c l er o si s J o ur n al. 2 0 1 7 M a y 
1: 1 3 5 2 4 5 8 5 1 7 7 0 7 3 4 5.