Conditions: Systemic Lupus Erythematosus Active Cutaneous Lupus Erythematosus
Keywords: CLE, SLE, Cutaneous Lupus Erythematosus, Systemic Lupus Erythematosus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 264
Healthy volunteers: no

Brief summary:
The primary purpose of the study is to evaluate the efficacy of BIIB059 (litifilimab) in reducing disease activity in participants with systemic lupus erythematosus (SLE) with active cutaneous manifestations and joint involvement (Part A), and in participants with active cutaneous lupus erythematosus (CLE) (Subacute cutaneous lupus erythematosus (SCLE) or chronic CLE, including discoid lupus erythematosus (DLE)) with or without systemic manifestations (Part B). The secondary objective is to evaluate additional efficacy parameters of BIIB059 in reducing SLE/CLE disease activity, pharmacokinetic parameters, safety and tolerability of BIIB059 (Parts A and B).

Detailed description:

Arms:
arm 1: BIIB059 450 mg administered SC, Q4W with an additional dose at Week 2 for a total of 7 doses (Weeks 0, 2, 4, 8, 12, 16, and 20) in participants with SLE with active skin manifestations and joint involvement. arm 2: BIIB059 matching placebo administered SC, Q4W with an additional dose at Week 2 for total of 7 doses (Weeks 0, 2, 4, 8, 12, 16, and 20) in participants with SLE with active skin manifestations and joint involvement. arm 3: BIIB059 50 mg administered SC, Q4W with an additional loading dose at Week 2 for a total of 5 doses (Weeks 0, 2, 4, 8, and 12) in participants with active CLE with or without systemic manifestations. arm 4: BIIB059 150 mg administered SC, Q4W with an additional loading dose at Week 2 for a total of 5 doses (Weeks 0, 2, 4, 8, and 12) in participants with active CLE with or without systemic manifestations. arm 5: BIIB059 450 mg administered, Q4W with an additional loading dose at Week 2 for a total of 5 doses (Weeks 0, 2, 4, 8, and 12) in participants with active CLE with or without systemic manifestations. arm 6: BIIB059 matching placebo administered SC, Q4W with an additional loading dose at Week 2 for a total of 5 doses (Weeks 0, 2, 4, 8, and 12) in participants with active CLE with or without systemic manifestations.

Interventions: intervention 1: BIIB059 (litifilimab) intervention 2: Placebo
Intervention descriptions: intervention 1: Administered as specified in the treatment arm. intervention 2: Administered as specified in the treatment arm.

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
1
Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
United States
PROTOCOL NUMBER:
230LE201
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead, Berkshire
SL6 4AY
United Kingdom
PHASE OF DEVELOPMENT:
2
PROTOCOL TITLE: A 2-Part Phase 2 Randomized, Double-Blind, Placebo-Controlled Study 
Evaluating the Efficacy and Safety of BIIB059 in Subjects with Systemic Lupus Erythematosus and 
Active Skin Manifestations and in Subjects with Active Cutaneous Lupus Erythematosus with or
without Systemic Manifestations 
EUDRA CT NO:
2015-004359-32  
DATE:
15 March 2019
Version 5.0
Final
Supersedes previous Version 4.0 dated 08 February 2018.
/ NCT02847598




Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
3
TABLE OF CONTENTS
SPONSOR SIGNATURE PAGE ....................................................................................................2
1.
SPONSOR INFORMATION .....................................................................................10
2.
LIST OF ABBREVIATIONS.....................................................................................11
3.
SYNOPSIS .................................................................................................................13
4.
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR STUDY 
230LE201 ...................................................................................................................18
4.1.
Study Schematic .........................................................................................................18
4.2.
Schedule of Activities.................................................................................................20
4.3.
Additional Information ...............................................................................................32
4.3.1.
Site Personnel .............................................................................................................32
4.3.2.
Skin RNA Tape Harvesting (Parts A and B)..............................................................32
4.3.3.
Joint Count Assessment (Part A Only).......................................................................32
4.3.4.
Skin Photography (Parts A and B)..............................................................................33
4.3.5.
Skin Biopsy (Part B Only)..........................................................................................33
4.3.5.1.
Skin Biopsy for Confirming CLE Diagnosis..............................................................33
4.3.5.2.
Optional Skin Biopsy..................................................................................................33
4.3.6.
CLASI Adjudication (Part B Only) ............................................................................33
4.3.7.
Blood RNA Paxgene and Skin Biopsy Immunohistochemistry Assessments............34
5.
INTRODUCTION......................................................................................................35
5.1.
Overview of Lupus Erythematosus ............................................................................35
5.2.
Current Therapies for Lupus Erythematosus..............................................................35
5.3.
Profile of Previous Experience with BIIB059............................................................36
5.3.1.
Nonclinical Experience...............................................................................................36
5.3.2.
Clinical Experience.....................................................................................................36
5.4.
Study Rationale...........................................................................................................38
5.5.
Rationale for Dosing Regimen ...................................................................................39
5.5.1.
Part A..........................................................................................................................39
5.5.2.
Part B ..........................................................................................................................39
5.5.3.
Rationale for Placebo..................................................................................................40
6.
STUDY OBJECTIVES AND ENDPOINTS..............................................................41
7.
STUDY DESIGN .......................................................................................................45


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
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The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
4
7.1.
Study Overview ..........................................................................................................45
7.2.
Overall Study Duration and Follow-Up (Part A) .......................................................46
7.2.1.
Screening ....................................................................................................................46
7.2.2.
Treatment....................................................................................................................46
7.2.3.
Follow-Up...................................................................................................................46
7.3.
Overall Study Duration and Follow-Up (Part B)........................................................47
7.3.1.
Screening ....................................................................................................................47
7.3.2.
Treatment....................................................................................................................47
7.3.3.
Follow-Up...................................................................................................................47
7.4.
Study Stopping Rules .................................................................................................48
7.5.
End of Study ...............................................................................................................48
8.
SELECTION OF SUBJECTS ....................................................................................49
8.1.
Inclusion Criteria ........................................................................................................49
8.1.1.
Inclusion Criteria (Parts A and B) ..............................................................................49
8.1.2.
Inclusion Criteria (Part A Specific) ............................................................................49
8.1.3.
Inclusion Criteria (Part B Specific) ............................................................................49
8.2.
Exclusion Criteria.......................................................................................................50
8.2.1.
Exclusion Criteria (Parts A and B).............................................................................50
9.
ENROLLMENT, REGISTRATION, AND RANDOMIZATION ............................54
9.1.
Screening and Registration.........................................................................................54
9.2.
Randomization of Subjects.........................................................................................54
9.3.
Blinding Procedures....................................................................................................54
10.
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY...........................................56
10.1.
Discontinuation of Study Treatment...........................................................................56
10.2.
Withdrawal of Subjects From Study...........................................................................56
11.
STUDY TREATMENT USE .....................................................................................57
11.1.
Study Treatment Regimen..........................................................................................57
11.1.1.
Part A..........................................................................................................................57
11.1.2.
Part B ..........................................................................................................................57
11.1.3.
BIIB059 ......................................................................................................................57
11.1.4.
Placebo........................................................................................................................57


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
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The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
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11.2.
Study Treatment Precautions......................................................................................57
11.3.
Study Treatment Compliance .....................................................................................58
11.4.
Concomitant Therapy and Procedures........................................................................58
11.4.1.
Concomitant Therapy .................................................................................................58
11.4.1.1.
Allowed Concomitant Therapy...................................................................................58
11.4.1.2.
Disallowed Concomitant Therapy..............................................................................65
11.4.1.3.
Rescue Medication Usage Guidelines During the Treatment Period .........................66
11.4.1.4.
Rescue Medication Usage Guidelines During the Safety Follow-Up Period.............66
11.4.2.
Concomitant Procedures.............................................................................................66
11.5.
Continuation of Treatment..........................................................................................66
12.
STUDY TREATMENT MANAGEMENT................................................................67
12.1.
BIIB059 ......................................................................................................................67
12.1.1.
BIIB059 Preparation...................................................................................................67
12.1.2.
BIIB059 Storage.........................................................................................................67
12.1.3.
BIIB059 Handling and Disposal.................................................................................68
12.1.4.
BIIB059 Accountability..............................................................................................68
12.2.
Placebo........................................................................................................................68
13.
EFFICACY ASSESSMENTS ....................................................................................69
13.1.
Clinical Efficacy Assessments....................................................................................69
13.2.
Pharmacokinetic Assessments....................................................................................69
69
70
70
14.
SAFETY ASSESSMENTS ........................................................................................71
14.1.
Clinical Safety Assessments.......................................................................................71
14.2.
Laboratory Safety Assessments..................................................................................71
14.3.
BIIB059 Specific Safety Assessments........................................................................71
15.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................72
15.1.
Definitions ..................................................................................................................72
15.1.1.
Adverse Event.............................................................................................................72
15.1.2.
Serious Adverse Event................................................................................................72


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
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15.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments................73
15.2.
Safety Classifications..................................................................................................73
15.2.1.
Investigator Assessment of Events .............................................................................73
15.2.2.
Relationship of Events to Study Treatment................................................................73
15.2.3.
Severity of Events.......................................................................................................74
15.2.4.
Expectedness of Events ..............................................................................................74
15.3.
Monitoring and Recording Events..............................................................................74
15.3.1.
Adverse Events ...........................................................................................................74
15.3.2.
Serious Adverse Events..............................................................................................74
15.3.3.
Immediate Reporting of Serious Adverse Events.......................................................75
15.3.3.1.
Deaths .........................................................................................................................75
15.3.4.
Suspected Unexpected Serious Adverse Reactions....................................................75
15.4.
Procedures for Handling Special Situations ...............................................................76
15.4.1.
Pregnancy ...................................................................................................................76
15.4.2.
Overdose.....................................................................................................................76
15.4.3.
Medical Emergency....................................................................................................76
15.4.3.1.
Unblinding for Medical Emergency...........................................................................76
15.5.
Contraception Requirements ......................................................................................77
15.6.
Safety Responsibilities................................................................................................77
15.6.1.
The Investigator..........................................................................................................77
15.6.2.
Biogen.........................................................................................................................78
16.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........79
16.1.
Efficacy.......................................................................................................................79
16.1.1.
Analysis Population....................................................................................................79
16.1.2.
Methods of Analysis...................................................................................................79
16.1.2.1.
Analysis of the Primary Endpoint...............................................................................80
16.1.2.2.
Analysis of the Secondary Endpoints.........................................................................81
16.1.2.3.
Exploratory Endpoints Analysis.................................................................................82
16.2.
Pharmacokinetics........................................................................................................82
16.2.1.
Analysis Population....................................................................................................82
16.2.2.
Methods of Analysis...................................................................................................82
82


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
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82
82
82
82
16.5.
Safety..........................................................................................................................83
16.5.1.
Analysis Population....................................................................................................83
16.5.2.
Methods of Analysis...................................................................................................83
16.5.2.1.
Adverse Events ...........................................................................................................83
16.5.2.2.
Clinical Laboratory Evaluations and Vital Signs .......................................................83
16.6.
Immunogenicity Data .................................................................................................84
16.6.1.
Analysis Population....................................................................................................84
16.6.2.
Methods of Analysis...................................................................................................84
16.7.
Interim Analyses.........................................................................................................84
16.7.1.
Interim Analysis 1:  Futility........................................................................................84
16.7.2.
Interim Analysis 2:  End of Treatment Periods ..........................................................84
16.8.
Sample Size Considerations .......................................................................................85
17.
ETHICAL REQUIREMENTS ...................................................................................86
17.1.
Declaration of Helsinki...............................................................................................86
17.2.
Ethics Committee........................................................................................................86
17.3.
Subject Information and Consent ...............................................................................86
17.4.
Subject Data Protection ..............................................................................................87
17.5.
Compensation for Injury.............................................................................................87
17.6.
Conflict of Interest......................................................................................................87
17.7.
Registration of Study and Disclosure of Study Results..............................................87
18.
ADMINISTRATIVE PROCEDURES.......................................................................88
18.1.
Study Site Initiation....................................................................................................88
18.2.
Quality Assurance.......................................................................................................88
18.3.
Monitoring of the Study..............................................................................................88
18.4.
Study Funding.............................................................................................................88
18.5.
Publications.................................................................................................................88
19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION........................89
19.1.
External Contract Organizations.................................................................................89


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
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19.1.1.
Contract Research Organization.................................................................................89
19.1.2.
Interactive Response Technology...............................................................................89
19.1.3.
Electronic Data Capture..............................................................................................89
19.1.4.
Central Laboratories for Laboratory Assessments .....................................................89
19.1.5.
Central Facility for Other Assessments ......................................................................89
19.2.
Study Committees.......................................................................................................89
19.2.1.
Independent Data Monitoring Committee..................................................................89
19.2.2.
CLASI Assessment and Adjudication ........................................................................89
19.3.
Changes to Final Study Protocol ................................................................................90
19.4.
Ethics Committee Notification of Study Completion or Termination........................90
19.5.
Retention of Study Data..............................................................................................90
19.6.
Study Report Signatory...............................................................................................90
20.
REFERENCES ...........................................................................................................91
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL.........................................96
APPENDIX A.
DESCRIPTIONS OF EFFICACY INSTRUMENTS........................................97
APPENDIX B.
TOPICAL CORTICOSTEROIDS NOT PERMITTED DURING THE 
STUDY.....................................................................................................................103
APPENDIX C.
AMERICAN COLLEGE OF RHEUMATOLOGY REVISED
CRITERIA FOR CLASSIFICATION OF SYSTEMIC LUPUS 
ERYTHEMATOSUS ...............................................................................................104
LIST OF TABLES
Table 1:
Schedule of Activities Part A .....................................................................................20
Table 2:
Schedule of Activities Part B......................................................................................26
Table 3:
Pharmacokinetic Assessments....................................................................................31
Table 4:
Study Objectives and Endpoints.................................................................................41
Table 5:
Prednisone Equivalence Values for Common Alternatives........................................59
Table 6:
Topical Corticosteroids Allowed During the Study ...................................................60
Table 7:
Oral Corticosteroid Tapering Schedule ......................................................................63
Table 8:
Disallowed Concomitant Therapy and Required Washout Periods Prior to 
Randomization............................................................................................................65
LIST OF FIGURES


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
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The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
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Figure 1:
Study Design Part A ...................................................................................................18
Figure 2:
Study Design Part B....................................................................................................19


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
10
1.
SPONSOR INFORMATION
Biogen 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
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.


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
11
2.
LIST OF ABBREVIATIONS
ACLE
acute cutaneous lupus erythematosus
ACR
American College of Rheumatology
AE
adverse event
ANCOVA
analysis of covariance
AUC
area under the concentration-time curve
BDCA2
blood dendritic cell antigen-2
BILAG
British Isles Lupus Activity Group
CCLE
chronic cutaneous lupus erythematosus
CL
clearance
CLASI
Cutaneous Lupus Erythematosus Disease Area and Severity Index
CLASI-A
CLASI–Activity
CLASI-D
CLASI– Damage
CLE
cutaneous lupus erythematosus
Cmax
maximum observed concentration
Cmin
minimum observed concentration 
CPK
creatine phosphokinase
CRO
contract research organization
DHA
Directions for Handling and Administration 
DLE
discoid lupus erythematosus
ECG
electrocardiogram
eCRF
electronic case report form
ET
early termination
GCP
Good Clinical Practice
HBV
hepatitis B virus
HCV
hepatitis C virus
HRQoL
health-related quality of life
IA 
interim analysis
IC90
concentration resulting in 90% inhibition of response
ICF
informed consent form
ICH
International Council for Harmonisation
IDMC
independent data monitoring committee
IFN 
interferon
IFN-α
interferon-alpha
IgG1
immunogloblulin, class G, type 1
IHC
immunohistochemistry
IRT
interactive response technology
IM
intramuscular
ITT
intent-to-treat
IV
intravenous
LE
lupus erythematosus
LTBI
latent tuberculosis infection


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
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MCP
metacarpophalangeal
MCP-Mod
Multiple Comparison Procedure - Modelling
MCS
Mental Component Summary
MMF
mycophenolate mofetil
MMRM
Mixed Effect Model Repeat Measurement 
MPS
mycophenolate sodium
mRNA
messenger RNA
 
NSAID
nonsteroidal anti-inflammatory drug
PCS
Physical Component Summary
PD
pharmacodynamic
pDC
plasmacytoid dendritic cell
PGA
Physician’s Global Assessment 
PGI
Physician’s Global Impression
PIP
proximal interphalangeal
PK
pharmacokinetics
PP
per-protocol
Q2W
every 2 weeks 
Q4W
every 4 weeks
RNA
ribonucleic acid
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SCLE 
subacute cutaneous lupus erythematosus
SELENA
Safety of Estrogen in Lupus: National Assessment
 
SLE
systemic lupus erythematosus
SLEDAI-2K 
Systemic Lupus Erythematosus  Disease Activity Index 2000
SoC
standard of care
SRI
Systemic Lupus Erythematosus Responder Index
SRI-4
Systemic Lupus Erythematosus Responder Index Response of ≥4
SUSAR
suspected unexpected serious adverse reaction 
t1/2
elimination half-life
TB
tuberculosis
TLG
tables, listings and graphs 
TLR
toll-like receptor
VAS
visual analog scale    
WOCF
worst observation carried forward


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
13
3.
SYNOPSIS 
Protocol Number:
230LE201
Protocol Title:
A 2-Part Phase 2 Randomized, Double-Blind, Placebo-Controlled 
Study Evaluating the Efficacy and Safety of BIIB059 in Subjects 
with Systemic Lupus Erythematosus and Active Skin 
Manifestations and in Subjects with Active Cutaneous Lupus 
Erythematosus with or without Systemic Manifestations
Version Number
5
Name of Study Treatment:
BIIB059
Study Indication:
Part A: Systemic lupus erythematosus with active joint and active 
skin manifestations
Part B: Active cutaneous lupus erythematosus (subacute or 
chronic cutaneous lupus erythematosus including discoid lupus 
erythematosus) with or without systemic manifestations
Study Rationale
Most therapies used to treat systemic lupus erythematosus (SLE) 
are only partially effective and are associated with considerable 
toxicity.  Furthermore, no medicines are specifically approved for 
the treatment of cutaneous lupus erythematosus (CLE).  
Blood dendritic cell antigen-2 (BDCA2) is a type II, C-type lectin 
receptor that is uniquely expressed on the cell surface of 
plasmacytoid dendritic cells (pDC) and was the first receptor 
described to negatively down-regulate the type I interferon (IFN) 
response in these cells.  In both CLE and SLE, type I IFN 
expression correlates with disease activity and severity.  By 
binding to BDCA2, BIIB059 treatment is expected to target pDC 
in affected tissues leading to decreased IFN production, as well as 
the reduction of other pDC-derived factors that contribute to SLE 
and CLE pathogenesis.
Phase of Development:
2
Study Objectives and 
Endpoints:
The primary objective of the study is to evaluate the efficacy of 
BIIB059 in reducing disease activity in subjects with SLE with 
active skin manifestations and joint involvement (Part A), and in 
subjects with active CLE (subacute CLE [SCLE] or chronic CLE 
[CCLE], including discoid lupus erythematosus [DLE]) with or 
without systemic manifestations (Part B).

Part A: The primary endpoint that relates to this 
objective is the change in active joint count (28-joint 
assessment) from Baseline to Week 24. The active 
joint count is defined as the sum of the tender joint 
count and the swollen joint count.


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
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
Part B: The primary endpoint that relates to this 
objective is the percent change in Cutaneous Lupus 
Erythematosus Disease Area and Severity Index--
Activity (CLASI-A) score from Baseline to Week 16.
Secondary Objectives and Endpoints
To evaluate additional efficacy parameters of BIIB059 in 
reducing SLE/CLE disease activity.
The endpoints that relate to this objective are:  
Skin related

CLASI-50, defined as a 50% improvement from 
baseline in CLASI-A score, at Week 24 (Part A) and 
at Weeks 12 and 16 (Part B).

Percent change in CLASI-A score from Baseline to 
Week 12, Week 16, and Week 24 (Part A) and Week 
12 (Part B).

A ≥4-point reduction in CLASI-A score at Week 24 
(Part A) and at Weeks 12 and 16 (Part B) compared 
with baseline.
SLE disease activity related (Part A Only)

Proportion of subjects with a composite response, defined as: 

SLE Responder Index (SRI) of ≥4 (SRI-4) at 
Week 24, where SRI-4 is defined as:
o
A reduction from baseline of ≥4 points  in 
Systemic Lupus Erythematosus  Disease 
Activity Index 2000 (SLEDAI-2K), and
o
No new organ system affected, as defined by 
no new British Isles Lupus Activity Group 
(BILAG)-2004 A and no more than one new 
BILAG-2004 B, and
o
No worsening from baseline in subject’s 
lupus disease activity defined by <0.3 point  
increase in the Physician’s Global 
Assessment (PGA) [visual analog scale 
(VAS)] 

No protocol-prohibited medication or treatment.

Concomitant corticosteroid dosage at Week 24 to 
be ≤10 mg/day.

Concomitant corticosteroid dosage at Week 24 to 
be ≤Day 1 corticosteroid dosage.

No increase in corticosteroid dose between 
Weeks 17 and 24.


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
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
Change from baseline to Week 24 in SLEDAI-2K score

Proportion of subjects with no new organ system affected, 
as defined by no new BILAG-2004 A and no more than 
one new BILAG-2004 B from baseline to Week 24

Change from baseline to Week 24 in PGA (VAS) score
Pharmacokinetics Objectives and Endpoints (Parts A and B): 
To evaluate the pharmacokinetic parameters of BIIB059, 
including:

BIIB059 clearance, volume of distribution, and absorption 
rate.
Safety and Tolerability Objectives and Endpoints (Parts A and B)
To evaluate the safety and tolerability of BIIB059.
The endpoints that relate to this objective are as follows: 

Nature, severity, relationship to study treatment, and 
incidence of adverse events (AEs) and serious 
adverse events (SAEs)

Change from baseline in standard laboratory 
parameters, vital signs and electrocardiogram (ECG) 
results  

Immunogenicity (antibodies to BIIB059)

Absolute and percent change from baseline over time 
in immunoglobulin levels and vaccine-related 
immunoglobulin titers
Additional study objectives are listed in Section 6.
Study Design:
2-part, randomized, double-blind, parallel group, placebo-
controlled study 
Study Location:
The study will be conducted at approximately 130 centers in the 
United States, Europe, Latin America, and Asia.
Number of Planned Subjects:
Part A:  
The maximum number of subjects in Part A is approximately 
190 subjects.  Of these 190 subjects, approximately 100 subjects 
will be enrolled under protocol version 2 or subsequent versions.  
If the study is not stopped for futility at the interim analysis 
(IA 1), then up to 70 additional subjects may be added (up to a 
total of approximately 170 subjects under protocol version 2 or 
subsequent versions).  Subjects enrolled under protocol version 
1 will remain on their original treatment assignment (up to a 
total of approximately 20 subjects).


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
16
Part B:
The maximum number of subjects in Part B is approximately 
130 subjects.  Of these 130 subjects, approximately 100 subjects 
will be enrolled under protocol version 2 or subsequent versions.  
Subjects enrolled under protocol version 1 will remain on their 
original treatment assignment (up to a total of approximately 30 
subjects).
An interim analysis (IA 1) for futility of Part B and possible 
expansion of Part A will be performed.  IA 1 will be performed  
after approximately 45% of Part B subjects under protocol 
version 2 or subsequent versions have completed their Week 12 
Treatment Period visit.  At the time of this IA, it is estimated 
that over 50% of subjects in Part A will have completed their 
Week 12 Treatment Period visit.  Following the IA, up to an 
additional 70 subjects may be enrolled in Part A and the 
BIIB059 dose may be adjusted.  Details are provided in 
Section 16.7.1.
A second IA (IA 2) of efficacy and safety data will occur after 
the last subjects complete the Double-Blind Treatment Periods 
for Part A (at Week 24) and Part B (at Week 16).  Details are 
provided in Section 16.7.2.
For both IAs (1 and 2), all Investigators, study site personnel, 
and subjects will remain blinded to treatment assignments until 
after the final database lock.  
Study Population:
The study (Parts A and B) will be conducted in subjects 18 to 75 
years of age, inclusive. 
Part A:
All subjects must have a diagnosis of SLE according to the 1997 
revised American College of Rheumatology (ACR) 
classification for SLE along with active skin manifestations and 
joint involvement (Appendix C) .
At Screening and randomization, all subjects must have at least 
4 tender joints and at least 4 swollen joints, with at least 4 of the 
swollen joints in the proximal interphalangeal (PIP) joints, 
metacarpophalangeal (MCP) joints and/or wrist.  A joint that is 
both tender and swollen will be included in both categories 
(counts as 1 tender and 1 swollen).   
Subjects must also demonstrate at least one sign of active lupus 
skin disease, including ACLE, SCLE, and/or CCLE (e.g., DLE), 
with skin activity defined by SLEDAI-2K at the time of 
Screening and randomization.  


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
17
Part B:
All subjects must have active skin manifestations (CLASI-A ≥8) 
and a diagnosis of CLE that has been histologically confirmed 
(in the past or at Screening), with or without SLE 
manifestations.  Active CLE is defined as follows: 

SCLE with a CLASI-A erythema score ≥2
and/or

CCLE, including DLE, with at least 1 active DLE 
lesion with a minimum CLASI-A erythema score 
≥2, and a CLASI-D scarring score ≥1.
Detailed criteria are described in Section 8.
Treatment Groups:
Part A:  
Subjects will be randomized in a 1:1 ratio to 1 of  2 treatment 
groups to receive subcutaneous BIIB059 (450 mg) or placebo 
every 4 weeks, with an additional dose at Week 2, for a total of 
7 doses (Weeks 0, 2, 4, 8, 12, 16, and 20).  This randomization 
scheme will apply to the approximately 100 subjects randomized 
under protocol version 2 or subsequent versions and to any 
additional subjects if a decision to expand is made following the 
IA. 
Part B:  
Subjects will be randomized in a 1:1:1:1 ratio to 1 of 4 treatment 
groups to receive subcutaneous BIIB059 (50 mg, 150 mg, or 
450 mg) or placebo every 4 weeks, with an additional dose at 
Week 2, for a total of 5 doses (Weeks 0, 2, 4, 8, and 12).  This 
randomization scheme will apply to the approximately 100 
subjects randomized under protocol version 2 or subsequent 
versions. 
Duration of Treatment and 
Follow-up:
Part A:
Study duration for each subject may be up to 40 weeks:
Screening Period:  up to 4 weeks
Treatment Period:  24 weeks
Follow-up Period:  12 weeks 
Part B:
Study duration for each subject may be up to 32 weeks:
Screening Period:  up to 4 weeks
Treatment Period:  16 weeks
Follow-up Period:  12 weeks


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
18
4.
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR STUDY 230LE201
4.1.
Study Schematic  
Figure 1:
Study Design Part A
Abbreviations: ANA=antinuclear antigen; dsDNA= double-stranded DNA; IA=interim analysis;  FU=follow-up visit; MCP=metacarpophalangeal joints; 
OCS=oral corticosteroid; PIP=proximal interphalangeal joints;  Q4W=every 4 weeks; SoC=standard of care; TD1=Treatment Day 1.
** At least 4 of the swollen joints must be PIP, MCP, and/or wrist joints.  A joint that is both tender and swollen will be included in both categories (counts as  
1 tender and 1 swollen).
Black triangles represent dosing visits.


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
19
Figure 2:
Study Design Part B
Abbreviations: CLASI-A=Cutaneous Lupus Erythematosus Disease Area and Severity Index- Activity Scale; CLE=cutaneous lupus erythematosus; FU=follow-
up visit; IA=interim analysis; OCS=oral corticosteroid; Q4W=every 4 weeks; SoC=standard of care; TD1=Treatment Day 1
1 Histologically confirmed in the past or at Screening.
Black triangles represent dosing visits.


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
20
4.2.
Schedule of Activities 
Table 1:
Schedule of Activities Part A
Screening 
Period
Treatment Period
Follow-up Period1
Study Week
Within 4 
Weeks Prior to 
Randomization
0
1
2
4
8
12
16
20
24/ET
FU4
FU8
FU12
            Study Day
13
8
(±2D)
153
(±2D)
293
(±3D)
573
(±3D)
853
(±3D)
1133
(±3D)
1413
(±3D)
169
(±3D)
197
(±5D)
225
(±5D)
253
(±5D)
Tests and 
Assessments2,3
Informed Consent 
Form(s)
X
Inclusion/ 
Exclusion Criteria
X
X
Randomization
X
Demographic data
X
SLE and other 
medical history
X
Documentation of 
SLE by ACR 
Criteria
X
12-lead ECG4
X
X
Chest x-ray5 (if 
required by local 
regulation)
X
Tuberculosis test6
X
Serum virology 
RNA (HIV,  
hepatitis B and C)
X
Urine drug screen
X


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
21
Screening 
Period
Treatment Period
Follow-up Period1
Study Week
Within 4 
Weeks Prior to 
Randomization
0
1
2
4
8
12
16
20
24/ET
FU4
FU8
FU12
            Study Day
13
8
(±2D)
153
(±2D)
293
(±3D)
573
(±3D)
853
(±3D)
1133
(±3D)
1413
(±3D)
169
(±3D)
197
(±5D)
225
(±5D)
253
(±5D)
Tests and 
Assessments2,3
Serum pregnancy 
test
X
Urine pregnancy 
test7
X
X
X
X
X
X
X
X
X
X
X
Physical 
examination,  
weight, height8
X
X
X
X
X
X
X
X
X
X
X
Vital signs9
X
X
X
X
X
X
X
X
X
X
X
X
X
BILAG-2004
X
X
X
X
X
X
X
X
CLASI
X
X
X
X
X
X
X
X
X
X
Physicians Global 
Assessment of SLE 
(VAS)10
X
X
X
X
X
X
X
X
X
X
Skin photography 
of target lesion11
X
X
X12
Joint Count (28 
joint assessment)
X
X
X
X
X
X
X
X
X
X


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
22
Screening 
Period
Treatment Period
Follow-up Period1
Study Week
Within 4 
Weeks Prior to 
Randomization
0
1
2
4
8
12
16
20
24/ET
FU4
FU8
FU12
            Study Day
13
8
(±2D)
153
(±2D)
293
(±3D)
573
(±3D)
853
(±3D)
1133
(±3D)
1413
(±3D)
169
(±3D)
197
(±5D)
225
(±5D)
253
(±5D)
Tests and 
Assessments2,3
Study treatment 
administration13
X
X
X
X
X
X
X
Corticosteroid 
diary14
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessment
Hematology
X
X
X
X
X
X
X
X
X
X
X
Blood chemistry
X
X
X
X
X
X
X
X
X
X
X
Urinalysis 
(including 
microscopic 
examination)
X
X
X
X
X
X
X
X
X
X
X
Urine protein-
creatinine Ratio 
(spot urine)
X
X
X
X
X
X
X
X
X
X
X
Direct Coombs 
Analysis
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
CD19+ B Cell 
count15
X
Pharmacokinetics
Serum BIIB05916
X
X
X
X
X
X
X
X


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
23
Screening 
Period
Treatment Period
Follow-up Period1
Study Week
Within 4 
Weeks Prior to 
Randomization
0
1
2
4
8
12
16
20
24/ET
FU4
FU8
FU12
            Study Day
13
8
(±2D)
153
(±2D)
293
(±3D)
573
(±3D)
853
(±3D)
1133
(±3D)
1413
(±3D)
169
(±3D)
197
(±5D)
225
(±5D)
253
(±5D)
Tests and 
Assessments2,3
Subject-Reported Questionnaires20


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
24
Screening 
Period
Treatment Period
Follow-up Period1
Study Week
Within 4 
Weeks Prior to 
Randomization
0
1
2
4
8
12
16
20
24/ET
FU4
FU8
FU12
            Study Day
13
8
(±2D)
153
(±2D)
293
(±3D)
573
(±3D)
853
(±3D)
1133
(±3D)
1413
(±3D)
169
(±3D)
197
(±5D)
225
(±5D)
253
(±5D)
Tests and 
Assessments2,3
Safety
Serum for vaccine-
related 
immunoglobulin 
titers21
X
X
Antibodies to 
BIIB059
X
X
X
X
X
Immunoglobulin 
(total, IgG, IgA, 
IgM)
X
X
X
Concomitant 
medication/ 
procedures
Monitor and record from signing of informed consent through the end of the study
Serious adverse 
events
Monitor and record from signing of informed consent through the end of the study
Adverse events 
Monitor and record from time of first dose through the end of the study
Abbreviations:  ACR=American College of Rheumatology; BILAG=British Isles Lupus Activity Group; CLASI=Cutaneous Lupus Disease Area and Severity 
Index; CLE=cutaneous lupus erythematosus; C=complement; CPK=creatine phosphokinase; CRP=C-reactive protein; D=day; DNA=deoxyribonucleic acid; 
dsDNA=double-stranded DNA; ECG=electrocardiogram; ESR=erythrocyte sedimentation rate; ET=early termination; FU=follow-up; h=hour(s); HIV=human 
immunodeficiency virus; Ig=immunoglobulin; 
;
; 


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
25
RNA=ribonucleic acid; 
; SLE=systemic lupus erythematosus; SLEDAI-
2K=Systemic Lupus Erythematosus Disease Activity Index 2000; TB=tuberculosis; VAS=visual analog scale.
1 Follow-up visit will be conducted 4, 8, and 12 weeks after the last Treatment Period Visit (Week 24 or ET). 
2 Assessments (e.g., CPK, ECG, etc.) may be performed as required to confirm SLEDAI-2K and BILAG findings.  
3 On each dosing day (Day 1, Day 15, Day 29, Day 57, Day 85, Day 113, and Day 141) all assessments should be performed prior to dosing.
4 To be performed locally.
5 Where mandated by local regulation, a chest x-ray will be obtained locally during the screening period, unless a previous chest x-ray or the documented results 
from a chest x-ray obtained within 12 weeks prior to screening are available.  The chest x-ray or x-ray results will be reviewed by the Investigator (or designee) 
in order to exclude patients with active TB infection from entering the study.
6 Testing to be performed locally.  Indeterminate Quantiferon or T-SPOT tests may be repeated once and will be considered positive if retest results are positive 
or indeterminate. Subjects with documented BCG vaccination must perform a TB test at Screening and will be excluded if they exhibit skin induration  ≥5 mm 
or a positive Quantiferon or positive or borderline T-SPOT (Elispot) test. 
7 To be performed locally.
8 Height should be measured only once; i.e., at the Day 1/baseline visit.
9 Vital signs include seated arterial blood pressure, heart rate, and oral body temperature.  
 
11 One lesion is to be selected at baseline as the target lesion (the most severe active CLE lesion is recommended).  The  target lesion must be the same lesion 
used for tape  harvesting and the same lesion over time.
12 If the ET Visit occurs before Week 16, skin photography should be performed at the ET Visit.
13 Following administration of study treatment, subjects should remain at the study center for 1 hour to be observed for the development of potential allergic or 
anaphylactic reactions.
14Subject paper diaries for recording corticosteroid use will be distributed on Day 1, reviewed with site staff at each study visit, and collected by the study site at 
the final study visit. 
15 Only for subjects with prior B cell directed therapies within 52 weeks of Screening; this test should be performed at a central laboratory.
16 Pharmacokinetic evaluations will be conducted as follows: Study Day 1 (predose –1 h and  post-dose 4 h ±1 h), Day 8 (any time during visit), Day 29 (predose 
–1 h and postdose 4 h ±1 h), Day 85 (predose –1 h and postdose 4 h±1 h), Day 113 (predose –1 h), and Day 169 (any time during visit). During the Follow-up 
Period, 1 sample will be collected on Days 197 and 253 (any time during the visit) [Table 3].  The time and date of PK sample collection and BIIB059 dose 
should be recorded in the eCRF.
 
 
21 Vaccine-related immunoglobulin titers for tetanus, diphtheria, and Pneumococcus will be collected. 


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
26
Table 2:
Schedule of Activities Part B
Screening 
Period
Treatment Period
Follow-up Period1
Study Week
Within 4 
Weeks Prior to 
Randomization
0
1
2
4
8
12 
16/ ET
FU4
FU8
FU12
                                          Study Day
13
8
(±2D)
153
(±2D)
293
(±3D)
573
(±3D)
853
(±3D)
113
(±3D) 
141
(±5D)
169
(±5D)
197
(±5D)
Tests and Assessments2,3
Informed Consent Form(s)
X
Inclusion/Exclusion Criteria
X
X
Randomization
X
Demographic Data
X
CLE, SLE and Other Medical History
X
Documentation of SLE by ACR Criteria
X
12-lead ECG4
X
X
Chest x-ray5 (if required by local 
regulation)
X
Tuberculosis Test6
X
Serum Virology (HIV, Hepatitis B and 
C) RNA
X
Urine Drug Screen
X
Serum Pregnancy Test
X
Urine Pregnancy Test7
X
X      
X
X
X
X
X
X
X
Physical Examination, Weight, Height8
X
X
X
X
X
X
X
X
X
Vital Signs9
X
X
X
X
X
X
X
X
X
X
X
CLASI10
X
X
X
X
X
X
X
X


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
27
Screening 
Period
Treatment Period
Follow-up Period1
Study Week
Within 4 
Weeks Prior to 
Randomization
0
1
2
4
8
12 
16/ ET
FU4
FU8
FU12
                                          Study Day
13
8
(±2D)
153
(±2D)
293
(±3D)
573
(±3D)
853
(±3D)
113
(±3D) 
141
(±5D)
169
(±5D)
197
(±5D)
Tests and Assessments2,3
Physicians Global Assessment of SLE 
(VAS) 11,12
X
X
X
X
X
X
X
Skin photography of target lesion13
X
X
X
X
Study treatment administration14
X
X
X
X
X
Corticosteroid Diary15
X
X
X
X
X
X
X
X
X
X
Laboratory Assessment
Hematology
X
X
X
X
X
X
X
X
X
Blood Chemistry
X
X
X
X
X
X
X
X
X
Urinalysis (including microscopic 
examination)
X
X
X
X
X
X
X
X
X
Urine Protein-Creatinine Ratio (spot 
urine)
X
X
X
X
X
X
X
X
X
CD19+ B Cell Counts16
X
Pharmacokinetics
Serum BIIB05917
X
X
X
X
X
X
X
X


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
28
Screening 
Period
Treatment Period
Follow-up Period1
Study Week
Within 4 
Weeks Prior to 
Randomization
0
1
2
4
8
12 
16/ ET
FU4
FU8
FU12
                                          Study Day
13
8
(±2D)
153
(±2D)
293
(±3D)
573
(±3D)
853
(±3D)
113
(±3D) 
141
(±5D)
169
(±5D)
197
(±5D)
Tests and Assessments2,3
Safety
Antibodies to BIIB059
X
X
X
X
Immunoglobulin (total, IgG, IgA, IgM)
X
X
X


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
29
Screening 
Period
Treatment Period
Follow-up Period1
Study Week
Within 4 
Weeks Prior to 
Randomization
0
1
2
4
8
12 
16/ ET
FU4
FU8
FU12
                                          Study Day
13
8
(±2D)
153
(±2D)
293
(±3D)
573
(±3D)
853
(±3D)
113
(±3D) 
141
(±5D)
169
(±5D)
197
(±5D)
Tests and Assessments2,3
Concomitant Medication/Procedures
Monitor and record from signing of informed consent through the end of the study
Serious Adverse Events
Monitor and record from signing of informed consent through the end of the study
Adverse Events 
Monitor and record from time of first dose through the end of the study
Abbreviations:  ACR=American College of Rheumatology; C = complement; CLASI = Cutaneous Lupus Disease Area and Severity Index; CLE = cutaneous lupus 
erythematosus; CRP = C-reactive protein; D = day; DNA = deoxyribonucleic acid; dsDNA = double-stranded DNA; ECG = electrocardiogram; ESR = erythrocyte 
sedimentation rate; ET = early termination; FU = follow-up; HIV = human immunodeficiency virus; Ig = immunoglobulin; 
; RNA = 
ribonucleic acid; 
; SLE = systemic lupus erythematosus; SLEDAI-2K = Systemic 
Lupus Erythematosus Disease Activity Index; TB = tuberculosis; VAS = visual analog scale.
  
1 Follow-up visits will be conducted 4, 8, and 12 weeks after the last Treatment Period Visit (Week 16 or ET). 
2 Assessments (e.g., CPK, ECG, etc.) may be performed as required to confirm SLEDAI-2K findings.
3 On each dosing day (Day 1, Day 15, Day 29, Day 57, and Day 85) all assessments should be performed prior to dosing.
4 To be performed locally.
5 Where mandated by local regulation, a chest x-ray will be obtained locally during the screening period, unless a previous chest x-ray or the documented results 
from a chest x-ray obtained within 12 weeks prior to screening are available.  The chest x-ray or x-ray results will be reviewed by the Investigator (or designee) 
in order to exclude patients with active TB infection from entering the study.
6 Testing to be performed locally.  Indeterminate Quantiferon or T-SPOT tests may be repeated once, and will be considered positive if retest results are positive 
or indeterminate. Subjects with documented BCG vaccination must perform a tuberculosis test at Screening and will be excluded if they exhibit skin induration 
≥5 mm or a positive Quantiferon or positive or borderline T-SPOT (Elispot) test.
7 To be performed locally.
8 Height should be measured only once; i.e., at the Day 1/baseline Visit.
9 Vital signs include seated arterial blood pressure, heart rate, and oral body temperature.
10 CLASI will be assessed by the Investigator or a trained designee at all  assessments (Section 19.2.2 ).  CLASI scores at Screening will be verified by an 
Independent CLASI Adjudicator to confirm eligibility.
14 Following administration of study treatment, subjects should remain at the study center for 1 hour to be observed for the development of potential allergic or 
anaphylactic reactions.


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
30
15 Subject paper diaries for recording corticosteroid use will be distributed on Day 1, reviewed with site staff at each study visit, and collected by the study site at 
the final study visit.
16 Only for subjects with prior B cell directed therapies within 52 weeks of Screening; this test should be performed at a central laboratory.
17 Pharmacokinetic evaluations will be conducted as follows:  Day 1 (pre-dose –1 h and post-dose 4 h ±1 h), Day 8 (any time during the visit), Day 29 (predose –
1 h and postdose 4 h ±1 h), Day 85 (predose –1 h and postdose 4 h ±1 h), and Day 113 (any time during the visit).  During the Follow-up Period, 1 sample will 
be collected on Days 141, 169, and 197 (any time during the visit) [Table 3].
  


Protocol 230LE201
Version 5.0
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
31
Table 3:
Pharmacokinetic Assessments
Study Week
0
1
2
4
8
12
16
20
24
Follow-Up 
Period
Study Day
1
8
(±2 d)
15
(±2 d)
29
(±3 d)
57
(±3 d)
85
(±3 d)
113
(±3 d)
141
(±3 d)
169
(±3 d)
Part A
Day 197 and 
253 (±5 d)
Part B
Day 141, 
169, and 197 
(±5 d)
Part A
PK Sampling 
Timepoint(s)
Predose 
(–1 h)
Postdose 
(4 h ±1 h)
Any 
time 
during 
visit

Predose 
(–1 h)

Postdose 
(4 h ±1 h)

Predose 
(–1 h)

Postdose 
(4 h ±1 h)
Predose   
(–1 h)
Any time 
during 
visit
Any time 
during 
visit
Part B
PK Sampling 
Timepoint(s)
Predose 
(–1 h)
Postdose 
(4 h ±1 h)
Any 
time 
during 
visit

Predose 
(–1 h)

Postdose 
(4 h ±1 h)

Predose 
(–1 h)

Postdose 
(4 h ±1 h)
Any time 
during 
visit 
Any time 
during 
visit
Abbreviations:  d=days; h=hour(s); PK=pharmacokinetic


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4.3.
Additional Information 
4.3.1.
Site Personnel 
For each subject, the Principal Investigator (or a qualified designee)  will be responsible for 
administering the following instruments throughout the study.  Every effort will be made to 
ensure that assessments are performed by the same evaluator for a given subject over time. 

Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI)

British Isles Lupus Activity Group 2004 (BILAG) [Part A only] 

Systemic Lupus Erythematosus Disease Activity Index – 2000 (SLEDAI-2K) [all 
subjects in Part A and subjects in Part B with SLE by American College of 
Rheumatology criteria at Screening] 

 

 

 
 
An unblinded pharmacist (or authorized designee) will be responsible for the storage, 
distribution, preparation and accountability of study treatment.  The unblinded pharmacist will 
also be responsible for maintaining the unblinded pharmacy record separate from the main study 
file in order to support the study blind.
4.3.2.
Skin RNA Tape Harvesting (Parts A and B)
Skin tape harvesting (tapings on the target lesion site only; the most severe active CLE lesion is 
recommended) will be collected at Week 0 (baseline), Week 4, and Week 16 for Part A and 
Part B.  Only 1 affected target lesion of active CLE should be tested. The same target lesion 
sampled at baseline should be sampled at subsequent timepoints to study the evolution of the 
same lesion over time.  
Refer to the Study Reference Guide for instructions on collection and processing of samples.
4.3.3.
Joint Count Assessment (Part A Only)
Joint counts will be evaluated at all visits by a trained independent joint assessor.  The joint 
counts for an individual subject must be performed by the same joint assessor throughout the 
trial.
For this study, the joint assessment will be carried out on 28 joints. The joints to be assessed 
bilaterally include the shoulders, elbows, wrists (radiocarpal, carpal, and carpometacarpal bones 
are considered as a single unit), metacarpophalangeal (MCP) joints (MCP 1, 2, 3, 4, and 5), 
proximal interphalangeal (PIP) joints (PIP 1, 2, 3, 4 and 5), and the knees.  Artificial and 
ankylosed or fused joints will be excluded from tenderness and swelling assessments.


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4.3.4.
Skin Photography (Parts A and B)
Part A
In Part A, close-up clinical photographs of the target skin lesion (most severe active CLE lesion) 
will be obtained at Week 0 (baseline), Week 4, and Week 16 (or at early termination, if 
applicable).  The target skin lesion is the same lesion that will be used for tape harvesting. 
Part B
In Part B, for skin lesions with CLASI-A score greater than 0, photographs of each lesion and of 
the corresponding region with lesion(s) will be obtained at Screening, Week 0 (baseline), 
Week 4, and Week 16 (or at early termination, if applicable).  Photographs taken at Screening 
will be evaluated by a central adjudicator to verify the CLASI-A score assignment by the 
Investigator and confirm eligibility.  
One lesion is to be selected at baseline as the target lesion (the most severe active CLE lesion is 
recommended).  The same target lesion must be photographed and used for tape harvesting and 
optional biopsy at each applicable timepoint.
Identical technical settings should be maintained.  Biogen will provide cameras and devices for 
standardized photography.  These photographs will be sent electronically to the central database.  
On the day of photography, subjects are requested to avoid applying ointments, creams, or make-
up onto their skin prior to the visit.
For further details please see the Study Reference Guide.
4.3.5.
Skin Biopsy (Part B Only) 
4.3.5.1.
Skin Biopsy for Confirming CLE Diagnosis 
For subjects without historical biopsy data, diagnosis will be confirmed during Screening by skin 
biopsy that can be read at a local laboratory or the central laboratory, at the  discretion of the 
Investigator. A punch biopsy will be performed for diagnostic purposes. Subjects with an 
available historical biopsy do not need a screening biopsy for diagnosis. 
4.3.5.2.
Optional Skin Biopsy
 
 A punch biopsy should be performed. 
Biopsies should be taken from the same lesion at both timepoints, and a biopsy from the edge of 
the active lesion is preferred.  For further details on skin biopsy, see the Study Reference Guide.
4.3.6.
CLASI Adjudication (Part B Only)
CLASI will be assessed by the Investigator or a trained designee and entered by the Investigator 
at all assessments (Section 19.2.2). CLASI scores at Screening will be verified by an 
Independent CLASI Adjudicator to confirm eligibility.


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4.3.7.
Blood RNA Paxgene and Skin Biopsy Immunohistochemistry Assessments 
Blood samples will be collected from all subjects to evaluate  biomarkers that may be related to 
BIIB059 activity or indicative of subjects who may respond to BIIB059.  Biomarkers may 
include but are not limited to baseline levels of interferon (IFN)-inducible messenger RNA 
(mRNA) [i.e., type I IFN signature].  Effects of BIIB059 on these or other markers of disease 
may also be evaluated.
Classical immunohistochemistry in CLE skin biopsies (Part B) will be performed to study 
changes in PD  biomarkers that may be related to BIIB059 activity in the skin, including but not 
limited to IFN-related proteins.  In situ hybridization may also be performed to study changes in 
IFN-regulated or cytokine and chemokine mRNA levels after BIIB059 treatment. 


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5.
INTRODUCTION 
BIIB059 is a humanized immunoglobulin class G, type 1 (IgG1) monoclonal antibody that 
specifically recognizes blood dendritic cell antigen 2 (BDCA2), a type II, C-type lectin receptor 
expressed exclusively on the surface of human plasmacytoid dendritic cells (pDCs).  BDCA2 
receptor engagement in pDC prevents or diminishes toll-like receptor 
(TLR)7- and TLR9-induced production of IFN-α, and pDC-derived cytokines and chemokines 
[Cao 2007; Dzionek 2001; Fanning 2006; Röck 2007].  In non-clinical studies, BIIB059 has been 
shown to potently inhibit all TLR9-induced type I IFNs, as well as other pDC-derived cytokines 
and chemokines.  BIIB059 ligation leads to rapid internalization of BDCA2 from the cell surface 
of human pDC and its co-localization with TLR9 in the late endolysosomal compartment, which 
appears to be necessary f or inhibition of TLR9 signaling.  In vitro, BIIB059 also triggers 
internalization of CD32a which may prevent immune complex stimulation of pDC [Pellerin 
2015].  By binding to BDCA2, BIIB059 treatment should target pDC in affected tissues in 
patients with SLE and CLE and decrease production of IFN-α, as well as other IFN subtypes and 
pDC-derived cytokines and chemokines that contribute to SLE and CLE pathogenesis.
5.1.
Overview of Lupus Erythematosus
Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organ 
systems and is unpredictable in disease severity, with periods of illness or flares alternating with 
periods of remission.  The diverse presentation of lupus can range from rash and arthritis, anemia 
and thrombocytopenia, serositis, nephritis, seizures and psychosis.  At its onset, SLE may 
involve one or more organ systems, including the musculoskeletal, cutaneous, vascular, renal, 
pulmonary, hematologic, and nervous systems.  Disease prevalence is approximately 1 in 1000 
individuals overall, but varies with race and ethnicity.  SLE is more common in women than in 
men (up to 10 times more common).  Subjects with moderate to-severe SLE consider their 
health-related quality of life (HRQoL) to be poor [Fauci and Longo 2008; Jiménez 2003].
Cutaneous lupus erythematosus is a chronic autoimmune disease that may present with or 
without SLE. Up to 80% of subjects with SLE will have cutaneous manifestations.  Based on 
histopathological findings, the cutaneous manifestations of lupus erythematosus (LE) may be 
classified into LE-specific and LE-nonspecific skin lesions (e.g., urticarial vasculitis, livedo 
reticularis), which may be observed in other autoimmune diseases.  LE-specific skin lesions may 
be further subdivided based on clinical and histopathological characteristics into acute cutaneous 
LE, subacute cutaneous LE (SCLE), and chronic cutaneous LE (CCLE), representing, 
respectively, 15%, 8%, and 73% of all CLE [Gilliam and Sontheimer 1981; Grönhagen and 
Nyberg 2014].  In CCLE, the most common form (80%) is DLE, which is rarely associated with 
systemic LE manifestation.  Less than 10% of patients with DLE fulfill 4 of the SLE American 
College of Rheumatology (ACR) criteria, and between 5% and 10% of individuals with DLE 
will develop full SLE [Biazar 2013; Koskenmies 2008; Okon and Werth 2013; Vasquez 2013].
5.2.
Current Therapies for Lupus Erythematosus
Most therapies used to treat SLE are only partially effective and have considerable toxicity.  
Nonsteroidal anti-inflammatory drugs (NSAIDs) and antimalarials are commonly used as 


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first-line therapies for mild disease.  Corticosteroids and immunosuppressive drugs continue to 
be the mainstay for treating flares of moderate-to-severe SLE disease.  Although 
immunosuppressive drugs can partially improve the outcome of severe SLE, very often the 
disease is incompletely controlled.  In addition, immunosuppressive and corticosteroid drugs are 
associated with serious side effects [Doria 2014; Petri 2013; Ruiz-Arruza 2014].  Belimumab 
(Benlysta®) is the only targeted therapy approved to treat SLE.  Subjects treated with belimumab 
and standard of care (SoC) had an increased rate of treatment response compared with those 
receiving placebo and SoC; however, the treatment effect was small, with 9% to 13% of patients 
achieving an SLE Responder Index (SRI) response of 4 in the registration studies [Furie 2011; 
Navarra 2011; van Vollenhoven 2012].
To date, no medications have been specifically approved for the treatment of CLE.  Current 
therapies consist of topical corticosteroids, topical calcineurin inhibitors, and intralesional 
corticosteroids (for scalp lesions).  For subjects who are refractory to topical therapy or who have 
widespread or scarring skin disease, systemic therapy, including the antimalarial agents 
hydroxychloroquine, chloroquine, or quinacrine, is used.  Other systemic medications that can be 
useful in moderate and/or severe CLE subject subsets include dapsone, retinoids, azathioprine, 
methotrexate, thalidomide, and occasionally systemic corticosteroids [Okon and Werth 2013; 
Schultz 2015; Winkelmann 2013].  Unsatisfactory effectiveness and/or associated toxicities limit 
the use of antimalarial therapies in moderate-to-severe CLE and/or DLE.  In a prospective study 
including 300 subjects with CLE (86 SCLE, 160 DLE, 54 others), in subjects who were treated 
with hydroxychloroquine, only 21% (men) to 41% (women) reported clinical remission after at 
least 12 weeks of therapy.  Complete remission was negatively correlated with DLE diagnosis 
and male sex [Francès 2012].  Use of antimalarial agents is also associated with toxicities, 
including retinal toxicity, gastrointestinal disorders, skin hyperpigmentation, myopathy, and 
white discoloration of lighter skin [Chang 2011].  
5.3.
Profile of Previous Experience with BIIB059
5.3.1.
Nonclinical Experience
Nonclinical toxicology studies in cynomolgus monkeys showed that BIIB059 administered every 
2 weeks (Q2W), with up to 26-weeks of exposure at doses up to 125 mg/kg, was well tolerated, 
with no mortalities and no general or organ toxicity observed.  No effect on the central nervous, 
respiratory, or cardiovascular systems, no alteration in the immune cell population, and no 
clinical or histopathological evidence of injection-site reactions were associated with intravenous 
(IV) or subcutaneous (SC) administration of BIIB059.  
See the Investigator’s Brochure for detailed information on nonclinical studies.
5.3.2.
Clinical Experience
BIIB059 is under development as a first-in-class therapy for the treatment of SLE.  It has been 
evaluated in a Phase 1 single-ascending-dose (SAD) and multiple-ascending-dose (MAD) study 
(230LE101).  Briefly, this first-in-human study was a randomized, blinded, placebo-controlled 
study designed to evaluate the safety, tolerability and pharmacokinetics (PK) of single and 
multiple ascending doses of BIIB059.  The study consisted of 3 parts and included healthy 
volunteers and subjects with SLE who fulfilled the 1997 ACR classification criteria.  In Part 1, 


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healthy volunteers received a single IV dose of BIIB059 that ranged from 0.05 to 20 mg/kg, in 
order to assess the safety and tolerability of BIIB059 and determine its PK and 
pharmacodynamic (PD) activity.  The bioavailability of a single BIIB059 50 mg (fixed) dose 
administered SC to healthy volunteers was also determined in Part 1.  In Part 2, subjects with 
SLE and skin manifestations received a single BIIB059 IV dose of 20 mg/kg.  In Part 3, healthy 
volunteers received up to 3 doses of BIIB059 that ranged from 20 mg to 300 mg every 2 weeks 
(Q2W) or every 4 weeks (Q4W); SLE subjects received 2 doses of BIIB059 50 mg SC Q4W or 
3 doses of BIIB059 ≤300 mg SC Q2W, for a total of 3 doses.
The PK data from Study 230LE101 demonstrate that maximum observed concentration (Cmax) 
and area under the concentration-time curve (AUC) for BIIB059 increased with dose following 
single IV administration (0.05 mg/kg to 20 mg/kg).  Target-mediated clearance (CL) for 
BIIB059 was observed at lower doses e.g., <1 mg/kg and became saturated at doses ≥1 mg/kg.  
Following SC administration to healthy volunteers, BIIB059 Cmax was reached in approximately 
6 days, with a bioavailability of approximately 50%.  The AUC∞in SLE subjects was 39% lower 
when compared to healthy volunteers at IV doses of 20 mg/kg. Following multiple SC 
administrations (20 mg to 300 mg) the AUC0-28d in SLE subjects was 40% lower as compared 
with healthy volunteers at SC doses of 50 mg.  The accumulation ratio for AUC was lower in 
SLE subjects (2.58) compared to healthy volunteers (2.66), after BIIB059 SC administration. 
Overall, the targeted mechanism of action of BIIB059, the absence of toxicological findings up 
to the highest dose tested, and the available clinical safety data support the ongoing evaluation of 
BIIB059 in subjects with SLE and CLE.  The safety data obtained to date in healthy volunteers 
and subjects with SLE supports the evaluation of BIIB059 in this Phase 2 clinical Study 
230LE201.
Study 230LE101 results indicated that complete BDCA2 internalization (i.e., target engagement 
and PD activity) was achieved at all dose levels, the duration of which was dose dependent.  
Reappearance of BDCA2 on circulating pDCs occurred when serum concentrations of BIIB059 
decreased to approximately 1g/mL.  BDCA2 internalization was similar for healthy volunteers 
and subjects with SLE.  In addition, Study 230LE101 demonstrated proof of biological activity 
in SLE, whereby the IFN signature was dampened both in the blood and skin of SLE subjects, 
consistent with the mechanism of action of BIIB059.  
Skin biopsies in 6 of 8 subjects receiving BIIB059 revealed a reduction in cutaneous myxovirus 
A, an IFN-associated protein, at Week 4.  Notably, those same 6 subjects had at least a 4-point 
reduction in CLASI score at Week 4 and/or Week 12, indicating that the PD signal was 
associated with a clinical reduction in skin involvement in this exploratory analysis [Furie 2016].
Data from Part 1 of the first-in-human study, which included 54 healthy volunteers (38 received 
BIIB059), indicated that BIIB059 treatment was well tolerated at single doses up to 20 mg/kg in 
these SAD cohorts, with no severe AEs.  Data from Part 2 (SAD), which included 12 SLE 
subjects (8 received BIIB059), indicated that BIIB059 treatment was well tolerated at single 
doses of 20 mg/kg [Furie 2016].  Data from Part 3 (MAD), which included 33 healthy volunteers 
(25 received BIIB059) and 10 SLE subjects (8 received BIIB059), indicated that BIIB059 
treatment was well tolerated at multiple doses up to 300 mg in this study.  Three SLE subjects 
experienced SAEs: 1 subject enrolled in Part 2 of the study (BIIB059 20 mg/kg IV) and 2 
subjects enrolled in Part 3b of the study (BIIB059 50 mg SC and BIIB059 300 mg SC).  None of 


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the SAEs was considered related to BIIB059 as assessed by the Investigator.  No SAEs were 
reported in healthy volunteers in Part 1 or 3a of the study.  In Part 3a, 1 subject discontinued 
study treatment due to an AE not related to BIIB059; however, none withdrew from the study 
due to an AE.
See the Investigator’s Brochure for detailed information on BIIB059 clinical studies. 
5.4.
Study Rationale
A hallmark of SLE and CLE is the production of autoantibodies to a variety of nuclear antigens 
that account for some of the pathological manifestations [Achtman and Werth 2015; Fauci and 
Longo 2008; Rahman and Isenberg 2008].  Although the pathogenesis of SLE and CLE is not 
fully understood, there is increasing evidence that the cytokine family of type I IFNs, most 
notably IFN-α, plays a central role in the pathogenesis of SLE, including the cutaneous 
manifestations seen in CLE.  In both CLE and SLE, type I IFN expression correlates with both 
disease activity and severity [Braunstein 2012; Dall'era 2005; Hellquist 2009; Järvinen 2010; 
Niewold 2012].  Furthermore, the “IFN signature” that represents a messenger RNA expression 
pattern of IFN-inducible genes has been observed in more than half of SLE patients and in 70% 
to 75% of patients with active disease [Furie 2015; Kalunian 2016].  Although not predictive of 
flares or changes in disease activity, a high IFN signature is associated with greater disease 
activity [Baechler 2003; Petri 2009].  
In CLE, type I IFNs are thought to be involved in amplifying intralesional inflammation by 
inducing IFN-inducible chemokines and recruitment of T cells into the skin.  As pDC have been 
identified as the main IFN-producing cells in CLE [Farkas 2001; Ghoreishi 2012; Vallin 1999]
blocking pDC and the IFN pathway may provide clinical benefit.  Recent data from  Phase 2 
studies with IFN-α-blocking agents (sifalimumab and anifrolumab) demonstrated improvement 
in systemic lupus disease activity and, more specifically, cutaneous manifestations, further 
supporting the rationale for blocking the IFN pathway in patients with SLE and CLE with or 
without systemic manifestations [Furie 2015; Khamashta 2014].  
BDCA2 is a type II, C-type lectin receptor that is uniquely expressed on the cell surface of pDC 
and was the first receptor described to negatively down-regulate the type I IFN response in these 
cells [Cao 2007; Dzionek 2001; Fanning 2006; Röck 2007].  In SLE, pDC are found to be 
decreased in the blood and to be present in target organs such as the skin or the kidney [Farkas 
2001; Vermi 2009].  By binding to BDCA2, BIIB059 treatment should target pDC in affected 
tissues in patients with SLE and CLE and decrease production of IFN-α, as well as other IFN 
subtypes and pDC-derived cytokines and chemokines that contribute to SLE and CLE 
pathogenesis.  In addition, BIIB059 may decrease localization of pDC in SLE- or CLE-affected 
organs such as the skin and restore the number of circulating pDC in the blood.
Altogether, given the lack of highly efficacious and safe treatments for active SLE and CLE, and 
the large impact of this disease on health-related quality of life (HRQoL) in SLE and CLE 
patients, there is currently a large unmet need for new targeted therapies.  Based on its 
mechanism of action, BIIB059 has the potential to decrease skin disease activity.  In addition, 
based on data currently available, BIIB059 presents an acceptable safety profile, and hence it is 
therefore justified to evaluate its potential efficacy in subjects with active SLE or CLE.


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5.5.
Rationale for Dosing Regimen
5.5.1.
Part A
Single IV as well as multiple SC doses of BIIB059 up to and including 20 mg/kg and 300 mg, 
respectively, in healthy volunteers have demonstrated acceptable tolerability in the Phase 1 
Study (230LE101).  In general,  BIIB059 serum concentrations were slightly lower in subjects 
with SLE than in healthy volunteers following dosing with BIIB059 50 mg SC (single and 
multiple dose administration).  Additionally, the median percent change from baseline in 
BDCA2 on pDC surfaces was equivalent between SLE and healthy subjects following SC doses 
of 50 mg.  
Single doses of 450 mg administered SC Q4W, with an additional dose at Week 2, will be used 
in Part A.  The dosing regimen was selected based on Phase 1 safety, PK, PK-BDCA2 
internalization relationship and extrapolated inhibitory potency (concentration resulting in 90% 
inhibition of response [IC90]) of pDC IFN-α production [Pellerin 2015].  The BIIB059 fixed dose 
of 450 mg SC Q4W, with an additional dose at Week 2, was selected to achieve Cmin levels 
similar to 3-fold of the calculated IC90 for IFN-α inhibition. Furthermore, this dose regimen with 
an additional dose of 450 mg at Week 2 and a bioavailability (F) of 0.45 is expected to result in 
cumulative exposure comparable to or lower than that achieved by the single dose of 20 mg/kg 
IV for a 65-kg person, the highest dose tested in healthy volunteers. 
5.5.2.
Part B
The dosing regimen was selected based on the Phase 1 safety, PK, PK-BDCA2 internalization 
relationship, and extrapolated inhibitory potency (concentration resulting in 90% inhibition of 
response [IC90]) of pDC IFN-α production [Pellerin 2015]. BIIB059 fixed doses of 50, 150 and 
450 mg SC Q4W, with an additional dose at Week 2, were selected for the Phase 2 study because 
simulations conducted, based upon the population PK model developed using the phase 1 data, 
predicted that:

At the low dose of 50 mg SC Q4W, BIIB059 is expected to achieve plasma 
concentrations sufficient to maintain 90% BDCA2 internalization for the majority of the 
dosing interval.

At the middle dose of 150 mg SC Q4W, BIIB059 is expected to achieve plasma 
concentrations similar to or in excess of the calculated IC90 for IFN-α for the majority of 
the dosing interval.

At the top dose of 450 mg SC Q4W, BIIB059 is expected to achieve Cmin levels similar to 
3-fold of the calculated IC90 for IFN-α inhibition. 
The selected doses are considered safe and tolerable, based upon the results of the Phase 1 
study. The dosing regimen of 450 mg SC Q4W, with an additional dose of 450 mg at Week 2 
and a bioavailability (F) of 0.45, is expected to result in cumulative exposure over 12 weeks that 
is comparable to or lower than that achieved by the single dose of 20 mg/kg IV for a 65-kg 
person, the highest dose tested in healthy volunteers.


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5.5.3.
Rationale for Placebo 
The use of placebo is justified because subjects assigned to placebo may also be receiving 
background lupus SoC.  Any prior lupus background medication allowed in this study that has 
been initiated prior to Screening will be authorized according to the protocol specifications 
(Section 11.4.1.1.1).  


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6.
STUDY OBJECTIVES AND ENDPOINTS
Table 4:
Study Objectives and Endpoints
Primary Objective
Primary Endpoint
To evaluate the efficacy of 
BIIB059 in reducing disease 
activity in subjects with SLE with 
active cutaneous manifestations 
and joint involvement (Part A), 
and in subjects with active CLE 
(SCLE or chronic CLE, including 
DLE) with or without systemic 
manifestations (Part B).
Part A:  
Change in active joint count (28-joint assessment) from Baseline 
to Week 24; the active joint count is defined as the sum of tender 
and swollen joint counts.
Part B:  
Percent change in CLASI-A score from Baseline to Week 16.
Secondary Objectives 
Secondary Endpoints
To evaluate additional efficacy 
parameters of BIIB059 in 
reducing SLE/CLE disease 
activity.
Skin related (Part A and 
Part B):
SLE disease activity related   
(Part A only):

CLASI-50, defined as a 50% improvement from baseline in 
CLASI-A score at Week 24 (Part A) and Weeks 12 and 16 
(Part B)

Percent change in CLASI-A score from baseline to Weeks 12, 
16, and 24 (Part A) and Week 12 (Part B)

A ≥4-point reduction in CLASI-A score relative to baseline at 
Week 24 (Part A) and at Weeks 12 and 16 (Part B)

Proportion of subjects with a composite response, defined as: 

SLE Responder Index (SRI) of ≥4 (SRI-4) at 
Week 24, where SRI-4 is defined as:
o
A reduction from baseline of ≥4 points  in 
Systemic Lupus Erythematosus  Disease 
Activity Index 2000 (SLEDAI-2K)  and
o
No new organ system affected, as defined by 
no new BILAG-2004 A and no more than one 
new BILAG-2004 B and
o
No worsening from baseline in subject’s lupus 
disease activity defined by <0.3 point  


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increase in PGA (VAS) 

No protocol-prohibited medication or treatment.

Concomitant corticosteroid dosage at Week 24 to 
be ≤10 mg/day

Concomitant corticosteroid dosage at Week 24 to 
be ≤Day 1 corticosteroid dosage

No increase in corticosteroid dose between Weeks 
17 and 24

Change from baseline to Week 24 in SLEDAI-2K score

Proportion of subjects with no new organ system affected, as 
defined by no new BILAG-2004 A and no more than one new 
BILAG-2004 B from baseline to Week 24

Change from baseline to Week 24 in PGA VAS score
To evaluate pharmacokinetic 
parameters of BIIB059 (Parts A 
and B)

BIIB059 clearance, volume of distribution, and absorption rate
To evaluate the safety and 
tolerability of BIIB059 (Parts A 
and B)

Nature, severity, relationship to study treatment and incidence 
of AEs and SAEs

Change from baseline in standard laboratory parameters, vital 
signs and ECGs 

Immunogenicity (antibodies to BIIB059)

Absolute and percent change from baseline over time in 
immunoglobulin levels and vaccine-related immunoglobulin 
titers
 

 
 

 

 

 



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
 

 
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
 

 

 
 

 
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
 

 

 

 

 
 
 

 

 
 
 
 

 
 
 




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
 
 

 
 
 

 
 
 
Abbreviations:  ACR = American College of Rheumatology; AE = adverse event; BILAG = British Isles Lupus Activity Group; 
CLASI-A = Cutaneous Lupus Erythematosus Disease Area and Severity Index – Activity; 
 
; CLE = cutaneous lupus erythematosus; ECG = electrocardiogram; 
; 
; 
; PGA = 
Physician’s Global Assessment; 
; SAE = serious adverse event; 
 
; SLE = systemic lupus erythematosus; SLEDAI-2K = Systemic Lupus 
Erythematosus Disease Activity Index – 2000; SRI-4 = SLE Responder Index of ≥4; VAS = visual analog scale.
 
 
 


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7.
STUDY DESIGN
7.1.
Study Overview
This is a 2-part randomized, double-blind, parallel-group, placebo-controlled, multicenter 
Phase 2 trial designed to evaluate the efficacy and safety of BIIB059 in subjects with SLE with 
active skin manifestations and joint involvement (Part A) or active CLE, defined as SCLE  or 
CCLE, including DLE, with or without SLE (Part B). The study will be conducted at 
approximately 130 centers in the United States, Europe, Latin America, and Asia.
Study treatment will begin following a 28-day Screening period.
In Part A, subjects will be randomly assigned to 1 of 2 treatment groups in a 1:1 ratio and will 
receive either BIIB059 (450 mg) or placebo subcutaneously every 4 weeks (Q4W) for 24 weeks, 
with an additional dose at Week 2, for a total of 7 doses (Figure 1). The maximum number of 
subjects in Part A is approximately 190 subjects.  Of these 190 subjects, approximately 100 
subjects will be enrolled under protocol version 2 or subsequent versions.  If the study is not 
stopped for futility at the interim analysis (IA), then up to 70 additional subjects may be added 
(up to a total of approximately 170 subjects under protocol version 2 or subsequent versions).  
Subjects enrolled under protocol version 1 will remain on their original treatment assignment (up 
to a total of approximately 20 subjects) and will not be reconsented under protocol version 2.  
Randomization will be stratified by oral corticosteroid usage (≤10 mg vs. >10 mg) and by 
geographic region (United States vs. Asia vs. Latin America and Europe).
In Part B, approximately 130 subjects will be randomized; of these, approximately 100 subjects 
will be enrolled under protocol version 2 or subsequent versions.  Subjects enrolled under 
protocol version 1 will remain on their original treatment assignment and may be reconsented 
under protocol version 2 unless they have completed the Week 12 / Early Termination Visit.  
Subjects enrolled in protocol version 2 or subsequent versions will be randomly assigned to 1 of 
4 treatment groups in a 1:1:1:1 ratio, with approximately 25 subjects per treatment arm to receive 
either a fixed dose of BIIB059 (50 mg, 150 mg, or 450 mg) or placebo SC every 4 weeks (Q4W) 
for 16 weeks, with an additional dose at Week 2, for a total of 5 doses (Figure 2).  
Randomization will be stratified by CLASI-A score (≤10 vs. >10) and DLE (presence, absence).
An IA (IA 1) for futility of Part B and possible expansion of Part A will be performed.  IA 1 will 
be performed  after approximately 45% of Part B subjects under protocol version 2 or subsequent 
versions have completed their Week 12 Treatment Visit.  At the time of this IA, it is estimated 
that over 50% of subjects in Part A will have completed their Week 12 treatment visit.  
Following the IA, up to an additional 70 subjects maybe enrolled in Part A and BIIB059 dose 
may by adjusted.  The additional subjects in Part A may be enrolled based on a more inclusive 
criteria to include an expanded SLE population.  Details are provided in Section 16.7.1.
An interim database lock and IA (IA 2) of efficacy and safety data will occur after the last 
subjects complete the Double-Blind Treatment Periods for Part A (at Week 24) and Part B (at 
Week 16). Details are provided in Section 16.7.2. 
For both IAs (1 and 2), all Investigators, study site personnel, and subjects will remain blinded to 
treatment assignments until after the final database lock. 


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7.2.
Overall Study Duration and Follow-Up (Part A) 
The total duration of study participation for each subject who completes Part A of the study will 
be approximately 40 weeks (a 4-week Screening Period, a 24-week double-blind Treatment 
Period, and a 12-week Follow-up Period).  Details on the timing of assessments during the study 
are presented in Table 1.  
7.2.1.
Screening
Subject eligibility for the study will be determined within 4 weeks prior to randomization.  
Laboratory assessments for eligibility may be repeated once if the results are out of eligibility 
range, but considered not clinically significant by the Investigator.
See Section 9 for details on screening and registration of subjects.
7.2.2.
Treatment
Subject eligibility will be reconfirmed prior to randomization on Day 1.  Eligible subjects will 
receive study treatment on Day 1 and return to the study site for additional dosing every 4 weeks 
through Week 20, with an additional dose at Week 2.  Following each administration of study 
treatment, subjects should remain at the study center for 1 hour to be monitored for the 
development of potential allergic or anaphylactic reactions.  Subjects will receive study 
treatment at baseline (Day 1), Week 2 (Day 15),  Week 4 (Day 29), Week 8 (Day 57), Week 12 
(Day 85), Week 16 (Day 113), and Week 20 (Day 141) for a total of 7 doses.    
Subjects will undergo study assessments (see Table 1) at each of the dosing visits and will also 
undergo assessments at Week 1 (Day 8) and Week 24 (Day 169), though study treatment is not 
administered at these visits.  The last dose of study treatment will be administered at Week 20 
(Day 141). 
7.2.3.
Follow-Up
Subjects are to return to the study site for follow-up (FU) visits at 4, 8, and 12 weeks after the 
last Treatment Period visit (Week 24 or Early Termination [ET] Visit).  Follow-up visits will be 
conducted at Week FU4 (Day 197), Week FU8 (Day 225) and Week FU12 (Day 253).  The final 
study visit will be Week FU12.    
Subjects who prematurely discontinue study treatment during the Double-blind Treatment 
Period should complete all study assessments for the Week 24/ET Visit as soon as possible, but 
within 4 weeks.  Subjects who discontinue study treatment should also complete the study 
assessments for the Safety FU Visits at Week FU4, Week FU8, and Week FU12 after their ET 
Visit. 
Subjects who are prematurely withdrawn from the study during the Double-blind Treatment 
Period should complete all study assessments for the Week 24/ET Visit as soon as possible, but 
within 4 weeks.  Withdrawn subjects should also be encouraged to complete the study 
assessments for the Safety FU Visits at Week FU4, Week FU8, and Week FU12, after their ET 
Visit.  However, if the subject is unwilling or unable to attend the study FU Visits, or at 
minimum the ET Visit, and decides to withdraw consent, the reason for withdrawal will be 
documented and no further assessments will be obtained.  


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7.3.
Overall Study Duration and Follow-Up (Part B)
The total duration of study participation for each subject who completes Part B of the study will 
be approximately 32 weeks (a 4-week Screening Period, a 16-week double-blind Treatment 
Period, and a 12-week Follow-up Period).  Details on the timing of assessments during the study 
are presented in Table 2.  
7.3.1.
Screening
Subject eligibility for the study will be determined within 4 weeks prior to randomization.  
Laboratory assessments for eligibility may be repeated once if the results are out of eligibility 
range but considered not clinically significant by the Investigator.
For subjects without a historical biopsy-proven diagnosis of CLE, eligibility will be confirmed 
during Screening by a skin biopsy that can be read at a local laboratory (if a pathologist is 
present) or at a central laboratory.  Subjects with a documented historical biopsy do not need a 
Screening biopsy for diagnosis. 
See Section 9 for details on screening and registration of subjects.
7.3.2.
Treatment
Subject eligibility will be reconfirmed prior to randomization on Day 1.  Eligible subjects will 
receive study treatment on Day 1 and return to the study site for additional dosing every 4 weeks 
through Week 12, with an additional dose at Week 2.  Following each administration of study 
treatment, subjects should remain at the study center for 1 hour to be monitored for the 
development of potential allergic or anaphylactic reactions.  Subjects will receive study 
treatment at baseline (Day 1), Week 2 (Day 15),  Week 4 (Day 29), Week 8 (Day 57), and 
Week 12 (Day 85), for a total of 5 doses.    
Subjects will undergo study assessments (see Table 2 ) at each of the dosing visits and will also 
undergo assessments at  Week 1 (Day 8) and Week 16 (Day 113), though study treatment is not 
administered at these visits.  The last dose of study treatment will be administered at Week 12 
(Day 85).
7.3.3.
Follow-Up
Subjects are to return to the study site for follow-up visits on Week FU4 (Day 141), Week FU8 
(Day 169), and Week FU12 (Day 197) after the last Treatment Period visit (Week 16 or ET 
Visit).  The final study visit will be Week FU12.  
Subjects who prematurely discontinue study treatment during the Double-blind Treatment 
Period should complete all study assessments for the Week 16/ET Visit as soon as possible, but 
within 4 weeks.  Subjects who discontinue study treatment should also complete the study 
assessments for the Safety FU Visits at Week FU4, Week FU8, and Week FU12 after their ET 
Visit. 
Subjects who are prematurely withdrawn from the study during the Double-blind Treatment 
Period should complete all study assessments for the Week 16/ET Visit as soon as possible, but 
within 4 weeks.  Withdrawn subjects should be encouraged to complete the study assessments 
for the Safety FU Visits at Week FU4, Week FU8, and Week FU12 after their ET Visit.  


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However, if the subject is unwilling or unable to attend the study FU Visits, or at minimum the 
ET Visit, and decides to withdraw consent, the reason for withdrawal will be documented and no 
further assessments will be obtained.
7.4.
Study Stopping Rules
Biogen will notify Investigators, ethics committees and any applicable regulatory agencies when 
the study is to be placed on hold, completed, or terminated.  
Conditions that may warrant termination of the study include, but are not limited to the 
following: 

The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled 
in the study

A decision on the part of Biogen to suspend or discontinue testing, evaluation, or 
development of the product
7.5.
End of Study
The end of study is last subject’s last visit.


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8.
SELECTION OF SUBJECTS
8.1.
Inclusion Criteria 
8.1.1.
Inclusion Criteria (Parts A and B) 
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at Screening or at the time point specified in the individual eligibility criterion listed:  
1. Ability of the subject to understand the purpose and risks of the study and provide signed 
and dated informed consent and authorization to use confidential health information in 
accordance with national and local subject privacy regulations.  
2. Age 18 to 75 years old, inclusive, at the time of informed consent.  
3. All women of childbearing potential and all men must practice effective contraception 
during the study and for 16 weeks after their last dose of study treatment.  For further 
details of contraceptive requirements for this study, please refer to Section 15.5.
8.1.2.
Inclusion Criteria (Part A Specific) 
1. Diagnosis of SLE fulfilling at least 4 out of 11 of the 1997 revised ACR classification 
criteria for SLE (Appendix C), with a diagnosis made ≥24 weeks prior to signing the 
informed consent form (ICF).
2. Positive antinuclear antibody test at Screening (central laboratory titer ≥1:80) and/or 
elevated anti-double-stranded DNA (≥30 IU/mL).
3. At least one sign of active skin disease, including acute, subacute, and/or chronic 
cutaneous lupus (e.g., discoid lupus erythematosus), with skin activity defined by 
SLEDAI-2K.   
4. Must have at least 4 tender joints based on assessment of 28 joints as described in 
Section 4.3.3. 
5. Must have at least 4 swollen joints based on assessment of 28 joints as described in 
Section 4.3.3, with at least 4 occurring in the PIP, MCP, or wrist joints.  Note:  A joint 
that is both tender and swollen will be included in both categories (counts as 1 tender and 
1 swollen). 
6. To allow for accurate assessment of joint tenderness and swelling, subjects who may be 
taking NSAIDs or other analgesics, including narcotics or medical marijuana, must agree 
not to take a dose of these medications within 24 hours prior to the joint assessment 
visits.
8.1.3.
Inclusion Criteria (Part B Specific)  
1. Must have diagnosis of CLE that has been histologically confirmed (in the past or at 
Screening), with or without systemic LE manifestations.  The histological diagnosis 
confirmation should be documented at Screening. For subjects without historical biopsy 


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data, a skin biopsy must be performed at Screening to confirm CLE diagnosis prior to 
randomization. All subjects must also have active skin manifestations that fulfill the 
following:  

Subacute CLE with a CLASI-A erythema score of ≥2
and/or

Chronic CLE, including DLE, with at least 1 active DLE lesion with a minimum 
CLASI-A erythema score ≥2 and in addition, CLASI-D scarring score ≥1
2. CLASI-A ≥8 at Screening and randomization.
3. Must have active CLE despite an adequate trial of conventional therapies (defined as 
either topical corticosteroids or an antimalarial agent used for at least 12 weeks prior to 
Screening) OR previously documented failure to respond to these agents when used for at 
least 12 weeks OR the requirement to discontinue these agents due to side effects or poor 
tolerability.
8.2.
Exclusion Criteria 
8.2.1.
Exclusion Criteria (Parts A and B) 
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
Screening, or at the timepoint specified in the individual criterion listed:
1. Current enrollment or a plan to enroll in any interventional clinical study in which an 
investigational treatment or approved therapy for investigational use is administered.  A 
washout period of at least 12 weeks or 5 half-lives (whichever is longer) is required prior 
to randomization.  Participation in observational registries is allowed.
2. For subjects who previously received an investigational or approved treatment that blocks 
IFN-α, a washout  period of 24 weeks is required prior to randomization.
3. For subjects who previously received BIIB059 in  the phase 1 study, a washout period of 
24 weeks is required prior to randomization in the present study.  Subjects who 
discontinued previous BIIB059 study participation due to AEs are not eligible.
4. Inability to comply with study requirements.
5. Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the 
subject unsuitable for enrollment.
Medical Condition
6. History or positive test result at Screening for human immunodeficiency virus.  
7. Current active hepatitis C virus (HCV) infection, determined as HCV RNA above the 
limit of detection, in subjects with positive HCV antibody titer.
8. Positive test result at Screening for hepatitis B virus (HBV; defined as positive for either 
hepatitis B surface antigen or hepatitis B core antibody).


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9. Active lupus nephritis or moderate-to-severe or chronic kidney disease (urine protein to 
creatinine ratio >2.0 or estimated glomerular filtration rate <30 mL/min/1.73 m2 
calculated using the abbreviated Modification of Diet in Renal Disease equation) 
[Stevens 2007].
10. Subjects with a history of suicide attempt or suicidal ideation within 1 year prior to 
Screening.
11. Active neuropsychiatric SLE including but not limited to the following: seizure, new or 
worsening impaired level of consciousness, psychosis, delirium or confused state, aseptic 
meningitis, ascending or transverse myelitis, chorea, cerebellar ataxia, mononeuritis 
multiplex, or demyelinating syndromes.
12. Any active skin conditions other than CLE that may interfere with skin assessments (e.g., 
psoriasis, non-LE skin lesions, non-LE alopecia areata, drug-induced lupus).  
13. History of severe herpes infection, such as herpes encephalitis, ophthalmic herpes, or 
disseminated herpes.
14. History of chronic, recurrent (3 or more of the same type of infection in a 52-week 
period), or recent serious infection (e.g., pneumonia, septicemia, herpes zoster) as 
determined by the Investigator and requiring anti-infective treatment within 12 weeks 
prior to Screening.
15. Signs of herpes or varicella zoster viral infection (specifically chicken pox, shingles, or 
herpes zoster) within 12 weeks prior to Screening.
16. History of or current diagnosis of active tuberculosis (TB), or untreated latent TB 
infection (LTBI), determined by a TB skin test with purified protein derivative as 
evidenced by induration ≥5 mm or a positive Quantiferon, positive or borderline T-SPOT 
(Elispot) test performed locally, either at Screening or documented with results within 12 
weeks of the Screening Visit.  Subjects who have previously completed appropriate and 
documented LTBI treatment will not be required to be tested. Subjects must have 
received complete LTBI treatment prior to Screening without evidence of re-exposure 
prior to entering the study.

Subject with current household contacts with active TB will also be excluded unless 
the subject is being treated and there is evidence that household contacts are being 
treated.

Indeterminate Quantiferon or T-SPOT tests may be repeated once, and will be 
considered positive if retest results are positive or indeterminate. Subjects with 
documented BCG vaccination must perform a TB test at Screening and will be 
excluded if skin induration ≥5 mm or a positive Quantiferon or positive or borderline 
T-SPOT (Elispot) test. 
17. Presence of New York Heart Association class III or IV congestive heart failure.
18. Known hypersensitivity to BIIB059 or any of the components of the formulated BIIB059 
or matching placebo.  


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19. History of, or ongoing, malignant disease, including solid tumors and hematologic 
malignancies with the exception of basal cell carcinomas and squamous cell carcinomas 
and carcinoma in situ of the cervix that have been completely excised and considered 
cured >2 years prior to Screening. 
20. History of any clinically significant cardiac, endocrinologic, hematologic, hepatic, 
immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric and 
renal, or other major disease, as determined by the Investigator.  Specifically, a diagnosis 
of any other systemic autoimmune disease other than secondary Sjögren’s syndrome, 
such as rheumatoid arthritis, psoriatic arthritis, dermatopolymiositis, systemic sclerosis 
(scleroderma), etc, which may confound the evaluation of the effect of investigational 
product. 
21. History of substance abuse (except for cannabinoid) within 24 weeks prior to Screening, 
based on the Investigator’s opinion.
22. Female subjects who are pregnant, currently lactating, have stopped lactating in the past 
12 weeks, or are planning to become pregnant during the study and for 16 weeks after the 
last dose of study treatment.
Previous Therapies
23. Use of IV or intramuscular (IM), or intra-articular (Part A only) corticosteroids within 12 
weeks prior to randomization.
24. Use of high-potency topical corticosteroid and/or topical agents (immunosuppressant) for 
skin lesions within 7 days prior to randomization.
25. Use of high-potency intralesional corticosteroid within 4 weeks prior to randomization.  
26. Part A subjects who are receiving systemic corticosteroid treatment at a dose exceeding 
20 mg/day prednisone (or its equivalent), or if any dose of prednisone (or its equivalent) 
has not been stable for ≥4 weeks prior to randomization.  
27. Part B subjects who are receiving systemic corticosteroid treatment at a dose exceeding 
15 mg/day of prednisone (or its equivalent), or if any dose of prednisone (or its 
equivalent) has not been stable for ≥4 weeks prior to randomization.  
28. Use of thalidomide or lenalidomide, IV or SC immunoglobulin, or plasmapheresis within 
12 weeks of randomization.  
29. Use of tacrolimus, pimecrolimus, or sirolimus within 4 weeks prior to randomization.
30. Use of oral or parenteral rituximab, ocrelizumab, or other B cell-directed biologic 
therapies within 24 weeks prior to randomization.  Subjects with prior B cell-directed 
therapies within 52 weeks of Screening will be excluded if total CD19 B cell level is <25 
cells/µL as measured at Screening at the central laboratory.  
31. Use of cyclophosphamide, cyclosporine, mixoribine, atacicept, abatacept, belimumab, 
tocilizumab, or tumor necrosis factor (TNF) inhibitors within 12 weeks or 5 half-lives 
(whichever is longer) prior to randomization. 


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32. Use of immunosuppressive or disease-modifying treatments for SLE or CLE (via an oral, 
IV, or SC route) that were initiated less than 12 weeks prior to randomization, have not 
been at a stable dose for at least 4 weeks prior to randomization, or have been taken 
during the last 12 weeks at doses above the prescribed maximum listed here (medication 
list includes, but is not limited to the following):  antimalarial medications 
(hydroxychloroquine up to 400 mg/day, quinacrine 100 mg/day maximum, chloroquine 
250 mg/day), dapsone 150 mg/day, methotrexate 25 mg/week, azathioprine 200 mg/day, 
6-mercaptopurine 100 mg/day, and mycophenolate mofetil (MMF) 3 g/day or 
mycophenolate sodium (MPS) 2160 mg/day. 
33. Immunizations with live or live-attenuated vaccines within 4 weeks before Screening and 
throughout the study and for 16 weeks after the last dose of study treatment.
Laboratory abnormalities
34. Aspartate aminotransferase or alanine aminotransferase >2.0 times the upper limit of 
normal at Screening.  
35. Hemoglobin <5.5 mmol/L [9 g/dL], neutrophils <1.5 x 103/µL, platelets <75 x 109/L at 
Screening.
36. Any abnormal laboratory test result at Screening that is considered clinically significant 
and unrelated to the underlying disease (SLE/CLE), as determined by the Investigator, 
and would preclude the subject from participating in the study.  Clinical laboratory tests 
may be repeated one time, at the discretion of the Investigator, if there are questionable 
results, or if abnormalities are felt to be due to inherent variability of the test procedure.  


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9.
ENROLLMENT, REGISTRATION, AND RANDOMIZATION
9.1.
Screening and Registration
Subjects (or their legally authorized representative [e.g., parent or legal guardian], where 
applicable) must provide informed consent before any screening tests are performed (see 
Section 17.3).  When a subject signs the ICF, that subject is considered to be enrolled in the 
study.  Participating study sites are required to document all screened candidates initially 
considered for inclusion in this study.  If a subject is excluded from the study, the reasons for 
exclusion will be documented in the subject’s source documents and on the screening log.
For subjects entering Part A, screening tender and swollen joint counts will be performed by an 
independent joint assessor at each site prior to study entry.    
For subjects entering Part B, screening CLASI scores will be verified by an independent CLASI 
Adjudicator (Section 19.2.2) prior to study entry.  
Subjects will be registered at the Screening Visit; as part of study screening, potential subjects 
will have the study risks and benefits explained to them, the associated ICF reviewed with them, 
and all their questions answered.
If a subject initially fails any of the screening criteria and is deemed as a screen failure by the 
end of the initial 28-day screening period, they will be allowed to be rescreened one time at the 
discretion of the Investigator.  Upon rescreening, and in consultation with the Medical Monitor , 
subjects should repeat the Screening assessments and receive a new Screening Number.
9.2.
Randomization of Subjects
Subjects will be randomized at the Day 1 Visit only after all screening assessments have been 
completed and the Investigator has verified that the subjects are eligible per criteria in Section 8.  
In addition, subjects will only be randomized after review of the narrative of SLE and CLE 
disease history, including relevant medical history that encompasses past infection, histological 
confirmation of CLE diagnosis (Part B) and receipt of the approval from the Medical Monitor.  
Randomization will be stratified by randomization factors (Section 7.1).
No subject may begin treatment prior to assignment of a unique identification number 
(registration) and randomization through the interactive response technology (IRT) system. Any 
subject identification numbers or randomization schedule assignments that have been assigned 
will not be reused even if the subject does not receive treatment.  Rescreened subjects will be 
assigned a new number.
Subjects who withdraw from the study after randomization may not be replaced.
Refer to the Study Reference Guide for details on registration and randomization.
9.3.
Blinding Procedures
This is a randomized, double-blind, placebo-controlled study.


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All study staff will be blinded to the subject treatment assignments.  To maintain the study blind, 
it is imperative that subject treatment assignments are not shared with the subjects, their families, 
or any member of the study team, either at the study site or at Biogen, except the unblinded 
Pharmacist (or designee) and the unblinded Pharmacy Monitor.  
 
  Efforts will be made to ensure that no members of the team involved in study conduct 
will be unblinded.  Unblinding is permitted only in the case of a medical emergency or serious 
medical condition, when knowledge of the study treatment is essential for the immediate clinical 
management or welfare of the study subject, as judged by the Investigator.  
Refer to the Study Reference Guide for details about unblinding.
There will be two IAs in the study. 
For IA 1, a team of Biogen personnel independent of the study team will be set up to conduct the 
unblinded analysis for futility, as discussed in Section 16.7.1.
For IA 2, members of the Biogen study team not in direct contact with the study sites will have 
access to the study data after all subjects complete all Week 24 assessments in Part A and all
Week 16 assessments in Part B. Members of the Biogen study team who become unblinded to 
the data for the IA at the end of the treatment periods, as described in Section 16.7.2, will have 
no further contact with study sites until after the final database lock.
All Investigators, study site personnel, and subjects will remain blinded to treatment assignments 
until after the final database lock.


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10.
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY
10.1.
Discontinuation of Study Treatment
A subject must permanently discontinue study treatment for any of the following reasons:

The subject becomes pregnant.  Study treatment must be discontinued immediately.  
Report the pregnancy according to the instructions in Section 15.4.1.

The subject withdraws consent to continue study treatment.  

The subject experiences a medical emergency that necessitates permanent 
discontinuation of study treatment.

The subject experiences a medical emergency that necessitates unblinding of the 
subject’s treatment assignment.

The subject is unwilling or unable to comply with the protocol.

At the discretion of the Investigator for medical reasons.
The reason for discontinuation of study treatment must be recorded in the subject’s electronic 
case report form (eCRF).   
Subjects who prematurely discontinue study treatment during the Double-blind Treatment 
Period should complete all study assessments for the ET Visit as soon as possible, but within 4 
weeks.  Subjects who discontinue study treatment should also complete the study assessments for 
the Safety FU Visits at 4, 8, and 12 weeks after the ET Visit.
10.2.
Withdrawal of Subjects From Study
Subjects must be withdrawn from the study for any one of the following reasons:

The subject withdraws consent.

The subject enrolls into another interventional clinical study in which an 
investigational treatment or approved therapy for investigational use is administered.

The subject is unwilling or unable to comply with the protocol.
Subjects who are prematurely withdrawn from the study during the Double-blind Treatment 
Period should complete all study assessments for the ET Visit as soon as possible, but within 4 
weeks.  Withdrawn subjects should be encouraged to complete the study assessments for the 
Safety FU Visits at 4, 8, and 12 weeks after the ET Visit.  However, if the subject is unwilling or 
unable to attend the study FU Visits, or at minimum the ET Visit, and decides to withdraw 
consent, the reason for withdrawal will be documented and no further assessments will be 
obtained.
The reason for the subject’s withdrawal from the study must be recorded in the subject’s eCRF. 
The level of consent withdrawal (e.g., whether samples collected but not yet analyzed can still be 
used/analyzed, and so on) should also be recorded in the eCRF.


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11.
STUDY TREATMENT USE
11.1.
Study Treatment Regimen
11.1.1.
Part A
Subjects will be randomized in a 1:1 ratio to 1 of the following 2 treatment groups:

BIIB059 450 mg 

Placebo 
Dose regimen:  every 4 weeks (Q4W) SC, with an additional dose at Week 2, for a total of 7 
doses.  
11.1.2.
Part B 
Subjects will be randomized in a 1:1:1:1 ratio to 1 of the following 4 treatment groups:

BIIB059 50 mg

BIIB059 150 mg  

BIIB059 450 mg 

Placebo 
Dose regimen:  every 4 weeks SC (Q4W), with an additional dose at Week 2, for a total of 5 
doses.
11.1.3.
BIIB059
Biogen will provide BIIB059 to sites.
11.1.4.
Placebo
Placebo (0.9% sodium chloride) will be commercially available saline supplied by the study site 
or Sponsor based on local regulations.
11.2.
Study Treatment Precautions
Following administration of study treatment, subjects should remain at the study center for 
1 hour to monitor for the development of potential allergic or anaphylactic reactions.  
Epinephrine for SC injection, diphenhydramine (or equivalent) for IV injection, and any other 
medications and resuscitation equipment for the emergency management of anaphylactic 
reactions must be available in the room where the infusion is being performed.
BIIB059 or placebo should be administered within the stated window of the scheduled visit (±2 
or 3 days; see Table 1 and Table 2).  If a subject misses a planned dose (i.e., outside of the 2- or 
3-day window), the missed dose should be administered as soon as possible, and no later than 
5 days after the last day of the planned window.  If the Week 2 dose (the second dose to be 


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administered in the study) can't be given within the planned window, the missed dose should be 
skipped and the subject should receive the next scheduled dose as per protocol.
11.3.
Study Treatment Compliance
Compliance with treatment dosing is to be monitored and recorded by site staff.
11.4.
Concomitant Therapy and Procedures
11.4.1.
Concomitant Therapy
A concomitant therapy is any drug or substance administered between Screening and the final 
study visit.
11.4.1.1.
Allowed Concomitant Therapy
All permitted therapies, unless indicated otherwise, should be taken at a stable dose starting from 
the Screening Visit until the end of the Treatment Period.  A stable dose is defined as no increase 
or decrease during a specified time period.  Dose decrease is allowed where specified by 
protocol.
Any medications, other than those excluded per Section 8.2, that are considered necessary for the 
subject’s welfare and that do not interfere with the trial conduct or assessments, may be given at 
the Investigator’s discretion and should be recorded in the eCRF dedicated page.
11.4.1.1.1. Background Therapies for Lupus 
11.4.1.1.1.1.Systemic Lupus Erythematosus 
Standard of care therapy that may be continued during the study for SLE includes 1 of the 
following single immunosuppressants or immunomodulators, delivered via IV, SC, or oral 
administration: azathioprine (up to 200 mg/day), 6-mercaptopurine (up to 100 mg/day), 
mycophenolate (either as MMF at up to 3 g/day or MPS up to 2160 mg/day), and methotrexate 
(up to 25 mg/week).  Other permitted SoC therapies include antimalarial medications such as 
(hydroxychloroquine (up to 400 mg/day), quinacrine (100 mg/day), chloroquine (up to 250 
mg/day), and dapsone (up to 150 mg/day) as well as corticosteroids (see Section 11.4.1.1.2) and 
NSAIDs (see Section 11.4.1.1.3.1).
All background therapy for SLE given prior to Screening or randomization must have been kept 
stable or discontinued as specified in the inclusion/exclusion criteria for a subject to be eligible 
for the study.  These medications must remain stable during Screening or randomization as well 
as the 24-week (Part A) or 16-week (Part B) Treatment Period, with the exception of the 2 
corticosteroid rescue attempts allowed during corticosteroid tapering in Part A of the study 
(Section 11.4.1.1.2).  No initiation of new immunosuppressant therapy or increase in dose of 
current immunosuppressant is allowed.  Subjects who initiate SLE SoC therapy during the study 
will be considered treatment failures.  They are encourage to continue receiving study treatment 
and complete the study at the Investigator’s discretion.
Standard of care medications that are part of the subject’s previous SLE treatment will not be 
provided by Biogen.


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11.4.1.1.1.2.Cutaneous Lupus Erythematosus 
All background therapy for CLE given prior to Screening must have been kept stable or 
discontinued as specified in the inclusion/exclusion criteria (Section 8 ) for a subject to be 
eligible for the study.  These medications must remain stable during the Screening Period as well 
as the Treatment Period.
11.4.1.1.2. Corticosteroid Usage During the Study 
In Part A, corticosteroid use at doses above 20 mg/day of prednisone or prednisone equivalent is 
not allowed (with the exception of Rescue 1 during corticosteroid tapering; see Table 7).  In 
Part B, corticosteroid use at doses above 15 mg/day of prednisone or prednisone equivalent is not 
allowed.  Doses stated are for a total daily dose of prednisone or prednisolone; other 
corticosteroids may be used instead at the equivalent doses listed.  See Table 5 for prednisone 
equivalence values of commonly used corticosteroids. 
Systemic (IM or IV) or intra-articular (Part A) administration of corticosteroids is not allowed 
for the duration of the study; a washout period of 12 weeks must be observed prior to 
randomization.
Nonsystemic corticosteroids (defined as otic, intranasal, inhaled, or ophthalmic) are permitted 
without restriction.  See Section 11.4.1.1.2.1 for guidance on the use of topical steroids.  
Table 5:
Prednisone Equivalence Values for Common Alternatives
Medication
Equivalent (mg) to 1 mg of Prednisone
Betamethasone
0.15
Cortisone
5
Dexamethasone
0.15
Hydrocortisone
4
Prednisolone
1
Methylprednisolone
0.8
Triamcinolone
0.8
11.4.1.1.2.1. Topical and Intralesional Corticosteroids 
Intralesional corticosteroids are not allowed during the screening and treatment periods.  The use 
of low or lower mid-potency topical steroids is allowed during the study.  Table 6 provides 
guidance for topical corticosteroid use.  Subjects are requested to avoid use of topical 
corticosteroids on the day of CLASI assessments throughout the study, and for 24 hours prior to 
the primary endpoint CLASI assessment at the Week 16 Visit.
High-potency steroids and/or topical agents (immunosuppressant) for skin lesions, including 
intralesional corticosteroids, are prohibited.


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Table 6:
Topical Corticosteroids Allowed During the Study
Examples of Low-Potency or Lower Mid-Potency Topical Corticosteriods 
Low-Potency
Hydrocortisone acetate 0.1 to 0.25% 
Desonide 0.05% cream
Methylprednisolone 0.25% 
Fluocinolone acetonide 0.01%
Lower Mid-Potency
Fluocinolone acetonide 0.025%  cream
Triamcinolone acetonide 0.1%
Fluticasone propionate 0.05% cream
Hydrocortisone butyrate 0.1% cream
Betamethasone valerate 0.05% 
Clobetasone butyrate 0.05%.
For a list of commonly used topical corticosteroids that are not permitted during the study, see 
Appendix B. The Investigator is invited to contact the Sponsor’s Medical Monitor with 
questions about topical corticosteroid use during the study.
11.4.1.1.2.2.Part A Specific Instructions
Intra-articular Corticosteroids 
Intra-articular administration of corticosteroids is not allowed for the duration of the study;  a 
washout period of 12 weeks must be observed prior to randomization.
Oral Corticosteroids
Eligible subjects will have active SLE with joint and skin manifestations at Screening and 
randomization.  Subjects may be treated with SLE background SoC therapies as per exclusion 
criterion #31 and, if taking corticosteroids, must have been on stable dosage for at least 4 weeks 
prior to randomization.  Subjects who are not receiving corticosteroids at Screening or baseline 
are permitted to participate in the study.
Doses of corticosteroid must remain stable during Screening and during the first 4 weeks after 
the first dose of study treatment (i.e., until Day 28).  The tapering schedule should begin 4 weeks 
(Week 5; Days 29 to 35) after the first dose of study treatment. The tapering regimen is intended 
to reduce the daily dose of prednisone (or equivalent) to 10 mg/day or lower by Week 12 (Day 
85) of the study, as outlined in Table 7.
If a subject deviates from the planned tapering schedule, they might be considered a treatment 
failure (see Section 16.1.2.1).  Subjects are allowed to continue to receive the investigational 
product and to complete the study at the discretion of the Investigator.  
Subjects who achieve the Week 12 dose of 10 mg of prednisone (or equivalent) or lower may 
remain on this dose or continue to taper between Week 13 and Week 16 at the discretion of the 
Investigator.  The dose of prednisone (or equivalent) will remain stable (at the Week 16 dose) 
between Week 17 and Week 24.
Screening: 
Subjects who are receiving corticosteroids must receive a stable dose throughout the Screening 
period; no initiation, increase, or decrease of corticosteroid dose is permitted.


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The maximum daily dose of corticosteroid allowed is 20 mg of prednisone (or equivalent).
Treatment period:
Oral corticosteroid dose tapering (as described in Table 7) is mandatory within the rules for dose 
changes outlined below. 
Briefly, oral corticosteroids dosing guidelines are as follow: 

Stable corticosteroid dose from Day 1 to Week 4 (Day 1 to Day 28) 

Decrease in corticosteroid dose from baseline between Week 5 and Week 11 
(Days 29 to 78)

Stable corticosteroid dose at Week 12 (Days 79 to 85)

Stable Week 12 corticosteroid dose, or decrease by 2.5 mg between Week 13 and 
Week 16 (Day 86 to 113) 

Stable corticosteroid dose (at Week 12 dose) between Week 17 and Week 24 (Days 
114 to 169)
Between Day 1 to Week 4, the corticosteroid dose can be increased to a maximum of 10 mg/day 
above Day 1 dosage, but must return to Day 1 level within 7 days (Rescue 1).  Between Week 5 
and Week 7 (Rescue 2), OR between Week 9 and Week 11 (Rescue 3), the corticosteroid dose 
can be increased to the previous dosage level for up to 1 week before resuming the tapering 
schedule.  Only two rescues out of the three described above are allowed, at the discretion of the 
Investigator.
Overall, TWO corticosteroid rescues are allowed:  

Rescue 1 and Rescue 2; OR

Rescue 1 and Rescue 3; OR 

Rescue 2 and Rescue 3.
Any other increase in corticosteroid dose may be considered a treatment failure and/or a protocol 
deviation (depending on the timing or severity of the deviation) for the analysis (see Section 
16.1.2.1).  Subjects who cannot fulfill the corticosteroid tapering schedule should still complete 
the study and remain on the investigational product.  Corticosteroid dose should be recorded in 
the subject diary (Section 11.4.1.1.2.4).
Day 1 to Week 4:
Stable dosage at Day 1 dose level, 1 oral corticosteroid rescue (Rescue 1) for SLE activity is 
allowed up to a dose no higher than 10 mg above the baseline level (maximum of 30 mg/day), 
but the dose must return to baseline (Day 1) level within 7 days. A dose increase is strongly 
recommended to be avoided within 1 week of a planned study visit.
Week 5 to Week 7:
Decrease as per the tapering schedule.  One oral corticosteroid rescue (Rescue 2) for SLE 
activity is allowed up to a dose no higher than the previous dosage level, but the dose must be 


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returned to the last oral corticosteroid dosage prior to rescue level within 7 days.  A dose increase 
is not permitted within 1 week of a planned study visit.
Week 8:
Decrease as per tapering schedule.  No increases are allowed.
Week 9 to Week 11:
Decrease as per tapering schedule. One oral corticosteroid rescue (Rescue 3) for SLE activity is 
allowed up to a dose no higher than the previous dosage level, but the dose must be returned to 
last oral corticosteroid dosage prior to rescue level within 7 days.  A dose increase is not 
permitted within 1 week of a planned study visit.
Week 12:
No increase or decrease allowed.
Week 13 to Week 16:
Stable dosage or decrease as per the tapering schedule (no increase is allowed).  The 
corticosteroid dose must always be ≤Week 12 dose.
Week 17 to Week 24:
Stable dosage at Week 16 dosage, no increases or decreases are allowed.


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Table 7:
Oral Corticosteroid Tapering Schedule 
Allowable 
OCS Rescue 
Dosing1
Timing 
by Weeks 
(Days)
OCS Starting Dose Prior to Tapering (mg/day)
20 mg
17.5 mg
15 mg
12.5 mg
10 mg
7.5 mg
5 mg
2.5 to <5 mg
Rescue 1
Week 1-42  
(Day 1 to 
28)
Stable
1 OCS rescue for SLE activity allowed up to maximum 10 mg/day above Day 1 dosage, 
but must return to Day 1 level within 7 days
Rescue 2
Week 53
(Day 29 to 
35)
17.5
15
12.5
10
7.5
5
5 or 2.5
2.5 to <5
Week 63
(Day 36 to 
43)
17.5
15
12.5
10
7.5
5
5 or 2.5
2.5 to <5
Week 73
(Day 44 to 
50)
15
12.5
12.5
10
7.5
5
5 or 2.5
2.5
Week 8
(Days 51 to 
57)
15
12.5
10
7.5
7.5
5
5 or 2.5
2.5
Rescue 3
Week 93
(Days 58 to 
64)
12.5
10
10
7.5
5
2.5
2.5
0 to 2.5
Week 103
(Days 65 to 
71)
12.5
10
10
7.5
5
2.5
2.5
0 to 2.5
Week 113
(Days 72 to 
78)
10
7.5
7.5
5
2.5 to 
<5
2.5
2.5
0 to 2.5
Week 12
(Days 79 to 
85)
10
7.5
7.5
5
2.5 to 
<5
2.5
2.5
0 to 2.5
Week 13-
16
(Days 86 to 
113)
Stable at Week 12 dose or decrease
Week 17-
24
(Days 114 
to 169)
Stable at Week 16 dose
Abbreviations:  OCS = oral corticosteroids; SLE = systemic lupus erythematosus.
1 Two rescues are allowed out of the three described. 


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2 Between Weeks 1 and 4 (Rescue 1).  Once a dose is reduced  it must not be re-increased, with the exception of the 1 time 
rescue.
3 Between Weeks 5 and 7 (Rescue 2) and between Weeks 9 and 11 (Rescue 3), the dose can be increased to the previous dose 
level for up to 1 week before restarting the tapering schedule.
11.4.1.1.2.3.Part B Specific Instructions
Oral Corticosteroid
No corticosteroid tapering schedule is planned for subjects in Part B.  The dose of corticosteroids 
given at Screening should not exceed 15 mg/day and should remain stable (no increase 
throughout the Screening, Treatment, and Follow-up Periods) .  
An increase of corticosteroid dose will be considered a treatment failure (see Section 16.1.2.1).  
Subjects are allowed to remain in study and receive the investigational product.   
11.4.1.1.2.4.Subject Diaries
Subjects will be issued a paper diary to record daily corticosteroid use (topical and oral) between 
study visits.  Subjects will be instructed to bring the diary to the clinic at each visit, where it will 
be collected and reviewed by site personnel.  
11.4.1.1.3. Pain Medication
11.4.1.1.3.1.Nonsteroidal Anti-inflammatory Treatments
Subjects taking stable doses of NSAIDs (e.g., ibuprofen, naproxen, aspirin) for SLE symptoms at 
Screening should continue to do so throughout the trial; however, subjects should refrain from 
using NSAIDs within 24 hours before each study visit.  Subjects taking stable doses of NSAIDs 
for reasons other than SLE are encouraged to titrate down as tolerated.
Low-dose aspirin (<350 mg/day) at stable doses for cardiovascular prophylaxis is permitted 
during the study.  
11.4.1.1.3.2.Acetaminophen
Acetaminophen (paracetamol) may be initiated for pain control of SLE symptoms during the 
study.  The medication should be titrated down as tolerated. The maximum dose of 
acetaminophen or pain medications that contain acetaminophen is 3 g/day.
11.4.1.1.3.3.Other Pain Medications
Other pain medications, including opiates, other narcotics, and medical marijuana, may be used 
to treat symptoms of arthritis and other extra-articular conditions in SLE as needed; however, 
these medications may not be used within 24 hours of a study visit if they are used as needed. If 
opiates are chronically taken prior to Screening, a stable dose should be maintained from 
Screening until the end of the Treatment Period.


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11.4.1.1.4. Vitamin D and Calcium Supplements 
Use of vitamin D3 (≥400 IU/day) and calcium supplements (≥800 mg/day) is recommended for 
prevention of glucocorticoid- or postmenopausal-induced bone loss.  Subjects should continue 
these medications per SoC with no change in dose during the study.  
11.4.1.1.5. Vaccines
Live and live-attenuated vaccines are not permitted within 4 weeks before Screening and 
throughout the study, and for 16 weeks after the last dose of study treatment.
11.4.1.2.
Disallowed Concomitant Therapy
Table 8 provides a list of medications prohibited during study participation (and during the 
prescribed washout period prior to randomization).  
Table 8:
Disallowed Concomitant Therapy and Required Washout Periods Prior to 
Randomization
Generic Name
Washout Period Prior to Randomization
Biologics (monoclonal antibodies and and fusion proteins) 
Rituximab, ocrelizumab, other B-cell directed 
therapies1
24 weeks
Abatacept, belimumab, tocilizumab, TNF inhibitors
12 weeks or 5 half-lives (whichever is longer)
Immunosuppressants
Tacrolimus, pimecrolimus, sirolimus 
4 weeks
High-potency topical corticosteroid and/or topical 
agents (immunosuppressive) for skin lesions
7 days 
High-potency intralesional corticosteroids
4 weeks
IV or IM corticosteroids (Parts A and B)
12 weeks
Intra-articular corticosteroids (Part A)
12 weeks
Cyclophosphamide, cyclosporine, mixoribine
12 weeks or 5 half-lives (whichever is longer)
Other
IV and SC immunoglobulin
12 weeks
Plasmapheresis
12 weeks 
Thalidomide or lenalinomide
12 weeks
Investigational or approved agent that blocks IFN-α
24 weeks 
Any investigational therapy, including BIIB059, 
and any not mentioned above
24 weeks
IFN = interferon; IM=intramuscular; IV = intravenous; SC=subcutaneous; TNF = tumor necrosis factor
1Subjects with history of B-cell directed therapies more than 24 weeks but less than 52 weeks prior to Screening will 
be excluded if the total CD19 B-cell level is <25 cells/μL as measured at Screening.


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11.4.1.3.
Rescue Medication Usage Guidelines During the Treatment Period
Rescue medications to mitigate local effects that have occurred at the administration site (e.g., 
injection-site reactions) of study treatment are allowed.  These may include topical or systemic 
antihistamines, acetaminophen, NSAIDs, or low-potency topical corticosteroids.  Any 
medications used should be recorded in the eCRF.  
Treatment for severe SLE flares leading to the use of rescue medication per SoC will be 
considered as a protocol deviation for the analysis.  Subjects are allowed to stay in the study and 
remain on the investigational product.  Any medications used should be recorded in the eCRF.
See Section 11.4.1.1 for medications permitted during the Treatment Period.
See Section 11.4.1.1.2 for detailed guidance on oral corticosteroid use.
See Section 11.4.1.3 for detailed guidance on the use of oral corticosteroid as rescue medication 
for SLE disease activity (Part A only).
11.4.1.4.
Rescue Medication Usage Guidelines During the Safety Follow-Up Period
Subjects will be treated according to local SoC during the Follow-up Period.  The initiation of 
immunosuppressants, immunomodulators, and/or biologics should be avoided during the 
Follow-up Period (approximately 5 half-lives of study treatment) at the discretion of the 
Investigator.  Any medications used should be recorded in the eCRF.
11.4.2.
Concomitant Procedures
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
the time the subject is enrolled in the study and the last Follow-up Visit.  
The following nondrug therapy is not permitted during the study (from the initial Screening Visit 
until the last Follow-up Visit, unless the subject has been previously stabilized on the therapy):

Allergen desensitization
The following nondrug procedures are not permitted during the study (from initial Screening 
Visit until the last Follow-up Visit):

Major medical procedures (e.g., invasive diagnostic procedures, such as arthroscopy)

Surgical procedures and acupuncture
The use of concomitant treatment or procedures defined above must be recorded on the subjects’ 
eCRF according to the instructions for eCRF completion. AEs related to the administration of 
these therapies or procedures must be documented on the appropriate eCRF. 
11.5.
Continuation of Treatment 
No further provisions are made for access to the study treatment.  If BIIB059 is proven to be 
beneficial, all regulatory requirements regarding post-study access will be met.


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12.
STUDY TREATMENT MANAGEMENT
Study site staff should follow the Directions for Handling and Administration (DHA) for specific 
instructions on the handling, preparation, administration, and disposal of the study treatment.  
The DHA supersedes all other references (e.g., protocol).
Study treatment must be dispensed only by a pharmacist or appropriately qualified staff.  Study 
treatment is to be dispensed only to subjects enrolled in this study.  Once study treatment is 
prepared for a subject, it can be administered only to that subject.  Following administration of 
study treatment, subjects should remain at the study center for 1 hour to observe for the 
development of potential allergic or anaphylactic reactions.  Study treatment is for one-time use 
only; do not use any study treatment remaining in the vial for another subject.
12.1.
BIIB059
BIIB059 is a fully humanized antibody consisting of 2 glycosylated human IgG1 heavy chains 
and 2 human kappa light chains.  The deglycosylated antibody has a calculated molecular mass 
of 146.4 kDa.  The antibody is produced in Chinese hamster ovary cells stably transfected with 
expression vectors containing the human anti-BDCA2 heavy- and light-chain genes.  BIIB059 is 
manufactured in accordance with Good Manufacturing Practice.  
BIIB059 is supplied as a sterile liquid drug product containing 150 mg/mL BIIB059, 20 mM 
histidine, 100 mM L-arginine hydrochloride, 3% sucrose, 0.05% polysorbate 80 and at a pH of 
5.5.  It is provided in 3-mL vials containing 255 mg of BIIB059 per vial.
The BIIB059 label includes conditions for storage, batch/lot number, and other pertinent 
information such as Sponsor, caution statement, and, when required, manufacturer.  The 
expiration date will be provided separately if one is not provided on the kit.  BIIB059 should not 
be used after the expiration date.
The contents of the BIIB059 label will be in accordance with all applicable regulatory 
requirements
12.1.1.
BIIB059 Preparation
The individual preparing BIIB059 should carefully review the instructions provided in the DHA.
If the packaging is damaged or if there is anything unusual about the appearance or attributes of 
the vials, the study treatment should not be used.  The vial in question should be saved at the 
study site, and the problem should be immediately reported to Biogen.
12.1.2.
BIIB059 Storage
BIIB059 must be stored at 2°C to 8°C (36°F to 46°F) in a secure location, preferably a locked 
refrigerator with limited access.  BIIB059 vials are to be protected from light and are not to be 
frozen.  If BIIB059 is frozen, Biogen should be notified immediately, and the drug should not be 
used.  For the most up-to-date storage requirements, follow the instructions provided in the 
DHA.


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12.1.3.
BIIB059 Handling and Disposal
The Investigator must return all used and unused vials of BIIB059 as instructed by Biogen unless 
approved for onsite destruction.
If any BIIB059 supplies are to be destroyed at the study site, the institution or appropriate site 
personnel must obtain prior approval from Biogen, by providing, in writing, the destruction 
policy or details of the method of destruction.  After such destruction, Biogen must be notified, 
in writing, of the details of the study treatment destroyed (e.g., lot numbers, quantities), the date 
of destruction, and proof of destruction.
12.1.4.
BIIB059 Accountability
Accountability for study treatment is the responsibility of the Investigator.  The study site must 
maintain accurate records demonstrating dates and amount of study treatment received, to whom 
dispensed (subject-by-subject accounting), and accounts of any study treatment accidentally or 
deliberately destroyed or lost.  
Unless otherwise notified, all vials both used and unused, must be saved for study treatment 
accountability.  At the end of the study, reconciliation must be made between the amount of 
BIIB059 supplied, dispensed, and subsequently destroyed or returned to Biogen.  A written 
explanation must be provided for any discrepancies.
12.2.
Placebo 
The placebo (control agent) to be used in this study will be sterile normal saline (0.9% sodium 
chloride for SC administration).  Sterile normal saline will be supplied by the study site or 
Sponsor (based on local regulations).  The manufacturer’s directions for material storage and 
handling are to be followed, as are standard clinical practices for ensuring sterility of the 
material.


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13.
EFFICACY ASSESSMENTS
See Section 4 for the timing of all assessments.
13.1.
Clinical Efficacy Assessments
The following clinical assessments will be performed to evaluate the efficacy of BIIB059.

CLASI-A and 


BILAG-2004 (Part A only) 

Joint counts (tender joint count and swollen joint count based on a 28-Joint 
Assessment) [Part A only]

PGA of SLE (in Part B, only for subjects with SLE at Screening) 

 



 

Descriptions of the efficacy instruments are provided in Appendix A.
13.2.
Pharmacokinetic Assessments
Sparse PK serum samples to measure levels of BIIB059 over time will be obtained from all 
subjects at timepoints specified in the Schedule of Assessments (Table 3).  


 


 

 
 
 
 


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14.
SAFETY ASSESSMENTS
Refer to Section 4 for the timing of all safety assessments.
14.1.
Clinical Safety Assessments
The following clinical assessments will be performed to evaluate the safety profile of BIIB059: 

AE and SAE recording

Physical examinations, including weight and height measurements (height will be 
measured only on Day 1/baseline)

Vital signs (e.g., seated arterial blood pressure, heart rate, and oral body temperature)

12-lead ECG

Concomitant therapy and procedure recording
14.2.
Laboratory Safety Assessments
The following laboratory assessments will be performed to evaluate the safety profile of 
BIIB059:

Hematology:  Complete blood count with differential and platelet count, and absolute 
neutrophil count

Blood chemistry:  total protein, albumin, creatinine, blood urea nitrogen, uric acid, 
bilirubin (total and direct), alkaline phosphatase, alanine aminotransferase, aspartate 
aminotransferase, gamma-glutamyl transferase, glucose, calcium, phosphorus, 
bicarbonate, chloride, sodium and potassium. Creatine phosphokinase (CPK) will also 
be assessed in subjects in Part A.

Coagulation

Direct Coombs Test

Immunoglobulins IgG, IgM, and IgA

Immunoglobulins and vaccine-related immunoglobulin titers

Urinalysis:  dipstick for blood, protein, and glucose (microscopic examination, if 
abnormal) 

Urine protein:  creatinine ratio (spot urine)  
14.3.
BIIB059 Specific Safety Assessments
The following assessment will be performed to determine the safety of BIIB059

Immunogenicity (anti-BIIB059 antibodies)


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


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


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Relationship of Event to Study Treatment
Not related
An AE will be considered “not related” to the use of the investigational drug if there is 
not a reasonable 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 
AE, or the presence of a more likely alternative explanation for the AE.
Related
An AE will be considered “related” to the use of the investigational drug if there is a 
reasonable 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 AE, or a lack of an alternative explanation for the AE.
15.2.3.
Severity of Events
The following definitions should be considered when evaluating the severity of AEs and SAEs:
Severity of Event
Mild
Symptoms barely noticeable to subject or does not make subject uncomfortable; does not 
influence performance or functioning; prescription drug not ordinarily needed for relief of 
symptoms but may be given because of personality of subject.
Moderate
Symptoms of a sufficient severity to make subject uncomfortable; performance of daily 
activity is influenced; subject is able to continue in study; treatment for symptoms may be 
needed.
Severe
Symptoms cause severe discomfort; symptoms cause incapacitation or significant impact 
on subject’s daily life; severity may cause cessation of treatment with study treatment; 
treatment for symptoms may be given and/or subject hospitalized.
15.2.4.
Expectedness of Events
Expectedness of all AEs will be determined by Biogen according to the Investigator’s Brochure.  
15.3.
Monitoring and Recording Events
15.3.1.
Adverse Events
Any AE experienced by the subject between the time of first dose of study treatment and final 
follow-up visit is to be recorded on the eCRF, regardless of the severity of the event or its 
relationship to study treatment.
15.3.2.
Serious Adverse Events
Any SAE experienced by the subject between the time of the signing of the ICF and final follow-
up 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 safety vendor listed in the Study 


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Reference Guide within 24 hours as described in Section 15.3.3.  Follow-up information 
regarding an SAE also must be reported with 24 hours.  
Events occurring after the final follow-up visit should be reported as described in the Study 
Reference Guide only if the Investigator considers the SAE to be related to study treatment.
Any SAE that is ongoing when the subject completes or discontinues the study will be followed 
by the Investigator until the event has resolved, stabilized, or returned to baseline status.
15.3.3.
Immediate Reporting of Serious Adverse Events
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify the safety contact as described in the Study Reference Guide within 24 hours of 
the study site staff becoming aware of the SAE.  It is the Investigator’s responsibility to ensure 
that the SAE reporting information and procedures are used and followed appropriately.
Reporting Information for SAEs
Any SAE that occurs between the time that the subject has signed the ICF and final follow-up 
visit must be reported as described in the Study Reference Guide within 24 hours of the study 
site staff becoming aware of the event.  Thereafter, the event should be reported only if the 
Investigator considers it related to study treatment.
A report must be submitted as described in the Study Reference Guide regardless of the 
following:

Whether or not the subject has undergone study-related procedures

Whether or not the 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 an SAE, fax, or email a completed SAE form as 
described in the Study Reference Guide.
15.3.3.1.
Deaths
Death is an outcome of an event.  The event that resulted in death should be recorded on the 
appropriate eCRF.  All causes of death must be reported as SAEs within 24 hours of the site 
becoming aware of the event.  The Investigator should make every effort to obtain and send 
death certificates and autopsy reports as described in the Study Reference Guide.  The term death 
should be reported as an SAE only if the cause of death is not known and cannot be determined.
15.3.4.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are unexpected and 
judged by the Investigator or Biogen to be related to the study treatment administered.


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Appropriate personnel at Biogen will unblind SUSARs for the purpose of regulatory reporting.  
Biogen or designee will submit SUSARs (in blinded or unblinded fashion) to regulatory agencies 
according to local law.  Biogen or designee will submit SUSARs to Investigators in a blinded 
fashion.
15.4.
Procedures for Handling Special Situations
15.4.1.
Pregnancy
Subjects should not become pregnant or impregnate their partners during the study and 
for 16 weeks after their last dose of study treatment.  If a female subject becomes pregnant, 
study treatment must be discontinued immediately.
The Investigator must report a pregnancy occurring in a female subject by faxing or emailing the 
appropriate form as described in the Study Reference Guide within 24 hours of the study site 
staff becoming aware of the pregnancy.   The Investigator or study site staff must report the 
outcome of the pregnancy to Biogen or designee.  
Congenital abnormalities and birth defects in the offspring of male or female subjects should be 
reported as an SAE if conception occurred during the study treatment period.
15.4.2.
Overdose
An overdose is any dose of study treatment administered to a subject or taken by a subject that 
exceeds the dose assigned to the subject according to the protocol.  Overdoses are not considered 
AEs and should not be recorded as an AE on the eCRF; however, all overdoses must be recorded 
on an Overdose form and faxed to Biogen or designee within 24 hours of the site becoming 
aware of the overdose.  An overdose must be reported to Biogen or designee even if the overdose 
does not result in an AE.  If an overdose results in an AE, the AE must be recorded.  If an 
overdose results in an SAE, both the SAE and Overdose forms must be completed and faxed to 
Biogen or designee.  All study treatment-related dosing information must be recorded on the 
dosing eCRF.  Refer to the Study Reference Guide for additional details.
15.4.3.
Medical Emergency
In a medical emergency requiring immediate attention, study site staff will apply appropriate 
medical intervention, according to current SoC.  The Investigator (or designee) should contact 
the study’s Medical Director.  Refer to the Study Reference Guide’s Official Study Contact List 
for complete contact information.
15.4.3.1.
Unblinding for Medical Emergency
In a medical emergency when knowledge of the subject’s treatment assignment may influence 
the subject’s clinical care, the Investigator and, if applicable, designated personnel at Biogen 
may access the subject’s treatment assignment by IRT.  The Investigator must document the 
reasons for unblinding in the subject’s source documents.  The Investigator is strongly advised 
not to divulge the subject’s treatment assignment to any individual not directly involved in 
managing the medical emergency, nor to personnel involved with the analysis and conduct of the 
study.  The Investigator can contact Biogen or designee to discuss such situations.


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15.5.
Contraception Requirements
All women of childbearing potential and all men must practice highly effective contraception 
during the study and for 16 weeks after their last dose of study treatment.  In addition, subjects 
should not donate sperm or eggs for the duration of the study and for at least 16 weeks after their 
last dose of study treatment.
For the purposes of this study, women who do not meet one of the following criteria listed below 
are considered to be physiologically capable of becoming pregnant and are, therefore, defined as 
women of childbearing potential:

Postmenopausal
o
12 months of natural (spontaneous) amenorrhea without an alternative medical 
cause and a serum follicle-stimulating hormone level >40 mIU/mL 
o
6 weeks after surgical bilateral oophorectomy with or without hysterectomy

Posthysterectomy

Female surgical sterilization (e.g., bilateral tubal ligation)
For the purposes of the study, highly effective contraception is defined as the use of one of the 
following:
For females:

Established use of oral (birth control pills), injected, or implanted hormonal methods of 
contraception

Placement of an intrauterine device or intrauterine system.

Vasectomy of male sexual partner (with the appropriate postvasectomy documentation of 
the absence of sperm in the ejaculate).
For males:

Effective male contraception includes a vasectomy with negative semen analysis at 
follow-up, or the use of condoms with spermicide.
Complete abstinence, when this is consistent with the preferred and usual lifestyle of the subject, 
can be considered an acceptable method of contraception based on the evaluation of the 
Investigator who should also take into consideration the duration of the clinical trial.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are 
not considered acceptable methods of contraception.
Pregnancy reporting is described in Section 15.4.1.
15.6.
Safety Responsibilities
15.6.1.
The Investigator
The Investigator’s responsibilities include the following:


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
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 per Section 15.4.1

Complete an SAE form for each SAE and send it to Biogen or designee within 24 
hours of the study site staff becoming aware of the event.

Pursue SAE follow-up information actively and persistently.  Follow-up information 
must be reported to Biogen or designee within 24 hours of the study site staff 
becoming aware of new information.

Ensure all AE and SAE reports are supported by documentation in the subjects’ 
medical records.

Pursue AE follow-up information, if possible, until the event has resolved or become 
stable.

Report SAEs to local ethics committees, as required by local law.
15.6.2.
Biogen 
Biogen’s responsibilities include the following:

Before study site activation and subject enrollment, the Clinical Monitor is 
responsible for reviewing with study site staff the definitions of AE and SAE, as well 
as the instructions for monitoring, recording, and reporting AEs and SAEs.

Biogen is to notify all appropriate regulatory authorities, central ethics committees, 
and Investigators of SAEs, as required by local law, within required time frames.


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16.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The objectives of the study and the endpoints to be analyzed are listed in Table 4.
This is a 2-part study consisting of Part A and Part B.  
For Part A, subjects will be randomized in a 1:1 ratio (50 subjects each to 450 mg and placebo), 
and the randomization will be stratified by prior oral corticosteroid usage (≤10 mg/day vs. 
>10 mg/day) and by geographic region (United States vs. Asia vs. Latin America and Europe).  
This randomization scheme will apply to the approximately 100 subjects randomized under 
protocol version 2 or subsequent versions. 
For Part B, subjects will be randomized in a 1:1:1:1 ratio (25 subjects each to 50 mg, 150 mg, 
and 450 mg and placebo), and the randomization will be stratified by CLASI-A score (≤10 vs. 
>10) and DLE (presence, absence).  This randomization scheme will apply to the approximately 
100 subjects randomized under protocol version 2 or subsequent versions.  
For Part A and Part B, baseline is defined as the last nonmissing measurement prior to 
randomization to study treatment (Screening or Day 1), change from baseline is defined as post-
baseline value minus baseline value, and percent change is defined as 100 × (change/baseline).  
For each part, all primary, secondary and exploratory endpoints will be summarized by treatment 
group and, where applicable, by treatment group and visit, unless otherwise specified in the SAP.
Additional information is provided in the subsections below, analysis details will be provided in 
the SAP.  
16.1.
Efficacy
16.1.1.
Analysis Population
For Part A and Part B, analysis of efficacy endpoints will be based on the intent-to-treat (ITT) 
population and the per-protocol (PP) population.
The ITT population is defined as all randomized subjects who received at least 1 dose of study 
treatment (whether or not the subjects adhered to the protocol).  Subjects will be analyzed 
according to the study treatment to which they were randomized.  Analysis of other non-safety 
endpoints (e.g., demographics) will also be based on the ITT population, unless otherwise 
specified in the SAP.
The PP population is defined as all subjects in the ITT population who do not meet the criteria 
for exclusion from analysis.  The exclusion criteria will be defined prior to database lock for the 
final analysis.
16.1.2.
Methods of Analysis
Continuous endpoints will be summarized using descriptive statistics (number of subjects [n], 
mean, standard deviation, median, minimum, and maximum), and categorical endpoints using 
frequency and percentage of subjects.  


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16.1.2.1.
Analysis of the Primary Endpoint
Part A:
A Mixed Effect Model Repeat Measurement (MMRM) model will be used as the primary 
method to analyze change from baseline in the active joint count using treatment group, study 
visit, prior oral corticosteroid usage, region, and study visit-by-treatment interaction as fixed 
effect factors and baseline active joint count as covariate.  The primary treatment comparison 
will be the difference between the 450 mg dose and placebo at the end of the Week 24 on the 
change from baseline in active joint count. 
In addition, sensitivity analysis based on the MMRM model, with missing values imputed, will 
also be performed (imputation methods are defined in the SAP).
Due to the impact of corticosteroid and rescue medication use on active joint count, if a subject 
has an increase from baseline in corticosteroid use after Week 4 (excluding allowed 
corticosteroid use as described in Section 11.4.1.1.2) or uses any SLE rescue medication (as 
described in Section 11.4.1.1.1) during the 24-week treatment period of the study, the subject 
will be a treatment failure.  The subject’s joint count after the increased corticosteroid use or 
after SLE rescue medication will not be included in the primary analysis. For subjects who are 
treatment failures prior to the Week 24 assessment of joint count, a worst observation carried 
forward (WOCF) method will be applied using the patient’s last post-baseline joint count prior to 
treatment failure.  In addition, if a subject deviates from the planned tapering schedule (Table 7), 
they might be considered as a treatment failure depending on the severity and timing of 
deviation.  Additional details will be provided in the SAP.
Part B:
An MMRM model will be used to analyze the percent change from baseline in CLASI-A score 
using treatment group, study visit, study visit-by-treatment interaction, DLE (presence or 
absence), and SLE (presence or absence) as fixed effect factors, and baseline CLASI-A scores as 
a covariate.
The primary analysis of the primary endpoint is a test of dose-response, using the Multiple 
Comparison Procedure – Modelling (MCP-Mod) methodology [Bretz 2005].
Five dose-response trends will be tested using the appropriate contrasts, as determined by the 
MCP-Mod methodology, on the treatment effects obtained from the MMRM model.  Additional 
information will be provided in the SAP.
 
 
 
 
 
 
 
 


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The following analyses of the primary endpoint will also be performed:

Pairwise comparison of each BIIB059 treatment group versus placebo, based on the 
MMRM model.

Sensitivity analysis based on the MMRM model, with missing values imputed 
(imputation methods defined in the SAP).
Due to the impact of corticosteroid use on CLASI-A scores, if a subject has an increase from 
Screening in corticosteroid use, the subject’s CLASI-A scores after the increased corticosteroid 
use will not be included in the primary analysis. The missing data handling methodology will 
follow the methods described for Part A.  For subjects in Part B with a diagnosis of SLE in 
addition to CLE, see Section 11.4.1.1.1. Additional details will be provided in the SAP. 
16.1.2.2.
Analysis of the Secondary Endpoints
Part A:
The secondary efficacy endpoints are defined in Table 4.  All continuous endpoints, such as 
change from baseline over time in CLASI-A score and active joint count, will be summarized 
using standard descriptive statistics.  All categorical endpoints, such as CLASI-50 response at 
Week 12, will be summarized using frequency and percentage of subjects.
In addition, statistical hypothesis testing will be performed for all secondary endpoints, defined 
below, unless otherwise specified in the SAP.  
For the continuous endpoints, p-values for the pairwise comparison of each BIIB059 treatment 
group versus placebo and corresponding confidence intervals will be provided based on the 
MMRM model specified above for the primary analysis for Part A, with the analysis performed 
by visit.  For the categorical endpoints, p-values will be based on the Cochran-Mantel-Haenszel 
test stratified by geographic region (United States vs. Asia vs. Latin America and Europe) and 
prior oral corticosteroid usage (≤10 mg/day at baseline vs. >10 mg/day at baseline) comparing 
the BIIB059 treatment group versus placebo.
Part B:
The secondary efficacy endpoints are defined in Table 4.  All continuous and categorical 
endpoints will be summarized descriptively, as indicated for Part A.  
In addition, hypothesis testing will be performed for all secondary endpoints, defined below, 
unless otherwise specified in the SAP. 
For the continuous endpoints, p-values and confidence intervals will be based on the MMRM 
model specified above for the primary analysis for Part B, with the model performed by visit.  
For the categorical endpoints, p-values will be based on the Cochran-Mantel-Haenszel test 
stratified by CLASI-A score (≤10 vs. >10), and DLE (presence or absence)comparing each 
BIIB059 treatment group versus placebo.
For both Parts A and B, a WOCF method will be applied as outlined in Section 16.1.2.1 for 
subjects who are treatment failures. Additional details will be provided in the SAP.


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16.1.2.3.
Exploratory Endpoints Analysis
 
 
16.2.
Pharmacokinetics
16.2.1.
Analysis Population
For Part A and Part B, the PK population is defined as the ITT population with sufficient 
concentration data for the calculation of BIIB059 PK parameters.  
16.2.2.
Methods of Analysis
The serum concentration of BIIB059 will be summarized by visit using standard descriptive 
statistics.  Additionally, a population PK analysis  will be conducted to characterize the PK of 
BIIB059 in subjects with SLE and CLE, estimate population PK parameters of BIIB059, 
estimate random inter- and intrasubject variability, and estimate random residual variability 
associated with the estimation of PK model parameters. Population PK analysis may also be used 
to identify sources of variability (continuous and categorical covariates) that may influence the 
PK of BIIB059.  In addition, exposure-response (efficacy) analysis will be performed to evaluate 
the relationship between exposure of BIIB059 and clinical endpoints, which will be used to 
justify doses for Phase 3 studies.  The results of the analysis will be included in a separate 
population PK-PD report.   
 
 
 
  
 


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16.5.
Safety
16.5.1.
Analysis Population
For Part A and Part B, analysis of safety endpoints will be based on the safety population, 
defined as all subjects who received at least 1 dose of study treatment (whether randomized or 
not, or randomized in error).  Subjects will be analyzed according to the study treatment actually 
received.
16.5.2.
Methods of Analysis
For Part A and Part B, all continuous endpoints will be summarized by treatment group (50 mg, 
150 mg, 450 mg, and placebo) and, where applicable, by treatment group and visit, using 
standard descriptive statistics, and all categorical endpoints using frequency and percentage of 
subjects.  In addition to the by-treatment group summaries, AEs will also be summarized for all 
BIIB059 treatment groups combined versus placebo.  
No statistical hypothesis testing is planned.
16.5.2.1.
Adverse Events
For Part A and Part B, AEs will be coded using the available, current version of the Medical 
Dictionary for Regulatory Activities (MedDRA).  A TEAE will be defined as any AE that started 
or worsened in severity after initial dose of study treatment through the follow-up period; 
hereafter referred to simply as AE.  AEs will be grouped by system organ class, preferred term, 
and overall, and then summarized.  The incidence, severity, and relationship to study treatment 
will be summarized, separately for all AEs, treatment-related AEs, and SAEs.  
16.5.2.2.
Clinical Laboratory Evaluations and Vital Signs
For Part A and Part B, the raw values, changes from baseline, and shifts for clinical laboratory 
and vital signs parameters will be summarized, as appropriate.  In addition, clinical relevant 
abnormalities (values outside the normal range for each parameter) will be summarized.  Clinical 
abnormalities will be defined in the SAP.


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16.7.
Interim Analyses
16.7.1.
Interim Analysis 1:  Futility
Parts A and B:
An IA for futility of Part B and possible expansion of Part A will be performed.  The IA will be 
performed after approximately 45% of Part B subjects under protocol version 2 or subsequent 
versions have completed their Week 12 Treatment Visit.  At the time of the IA, it is estimated 
that over 50% of subjects in Part A will have completed their Week 12 treatment visit.  
Following the IA, up to 70 additional subjects may be enrolled in part A and BIIB059 dose may 
by adjusted.  At the IA, unblinded subject baseline characteristics (e.g., Joint Count, SLEDAI-
2K) will be assessed.  The randomization stratification factors will be re-evaluated in the 
expanded enrollment to achieve balance between treatment groups.  The 3 objectives for adding 
additional subjects to Part A after the IA are to: 1) potentially include an expanded SLE patient 
population based on more inclusive criteria,  2) potentially adjust the dose of BIIB059 and, 3) to 
provide greater precision for the Week 24 endpoints, including the SRI-4.  Unblinded tables, 
listings, or graphs (TLGs) will be generated by independent personnel (internal or external) not 
involved in the conduct of the study.  The IA will be performed by independent personnel 
(internal and/or external) not involved in the conduct of the study. At the discretion of Biogen, 
unblinded TLGs and/or data may be shared with Sponsor personnel who are not directly 
involved in the conduct of the study. Additional information will be provided in an unblinding 
plan.  Details of the data to be used for the IA and the analyses planned for futility and possible 
expansion will be provided in the SAP.
16.7.2.
Interim Analysis 2:  End of Treatment Periods
After the last subjects complete the Double-Blind Treatment Periods for Part A (at Week 24) and 
Part B (at Week 16), an interim database lock will occur and an IA of efficacy and safety data 
will be conducted.  All Investigators, study site personnel, and subjects will remain blinded to 
treatment assignments until after the end of the study. Members of the Biogen study team not in 
direct contact with the study sites will have access to the study data after all subjects complete all
Week 24 assessments in Part A and all Week 16 assessments in Part B. Members of the Biogen 
study team who become unblinded to the data for this IA will have no further contact with study 
sites until after the final database lock. 


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Unblinding details will be provided in an unblinding plan.  Details of the data to be used for the 
IA and the specific analyses to be performed will be provided in the SAP.
A complete final CSR will be written for the entire study after the final database lock (i.e., after 
the completion of the Safety Follow-up periods for Part A and Part B of the study).
16.8.
Sample Size Considerations
Part A:
The sample size for Part A is 100 subjects, randomized in a 1:1 ratio, with 50 subjects allocated 
to each treatment group. This sample size will provide approximately 71% power to detect a 
statistically significant difference in the Week 24 absolute change from baseline active joint 
count, assuming a standard deviation of 6, a maximal difference of BIIB059 over placebo of 2.5, 
a 20% dropout rate, and a 2-sided testing at the 0.2 level significance.  Additional information 
will be provided in the Statistical Analysis Plan (SAP). If the study is not stopped for futility at 
the IA (details in Section 16.7), then up to 70 additional subjects may be added to Part A.  If an 
additional 70 subjects are added, the power will increase to approximately 87% at Week 24.
Part B:
The planned sample size for Part B is 100 subjects, randomized in a 1:1:1:1 ratio, with 25 
subjects per dosage arm of BIIB059 (50 mg, 150 mg, and 450 mg) and placebo. This sample size 
will provide approximately 90% power to detect a dose-response relationship in the Week 16 
percent change from baseline score in CLASI-A score, assuming a standard deviation of 30, a 
maximal difference of BIIB059 over placebo of 27.5%, and a 20% dropout rate.  Five different 
dose-response relationships will be tested at the 2-sided 10% significance level with the MCP-
Mod method being used to control for multiplicity [Bretz 2005].  
 
 
 
 
 
 
 
 
 
 
 
 
 


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17.
ETHICAL REQUIREMENTS
Biogen, the Investigator, and any CRO or vendor assisting with the study must comply with all 
instructions, regulations, and agreements in this protocol and applicable International Council for 
Harmonisation (ICH) and Good Clinical Practice (GCP) guidelines and conduct the study 
according to local regulations.
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines.  The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated.
17.1.
Declaration of Helsinki
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki.
17.2.
Ethics Committee
The Investigator must obtain ethics committee approval of the protocol, ICF, and other required 
study documents prior to starting the study.  Biogen will submit documents on behalf of the 
investigational sites in countries other than the United States.  
If the Investigator makes any changes to the ICF, Biogen must approve the changes before the 
ICF is submitted to the ethics committee.  A copy of the approved ICF must be provided to 
Biogen.  After approval, the ICF must not be altered without the agreement of the relevant ethics 
committee and Biogen.
It is the responsibility of the Investigators to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations.
Biogen must receive a letter documenting ethics committee approval, which specifically 
identifies the protocol, protocol number, and ICF, prior to the initiation of the study.  Protocol 
amendments will be subject to the same requirements as the original protocol.
A progress report must be submitted to the ethics committee at required intervals and not less 
than annually.
At the completion or termination of the study, the investigational site must submit a close-out 
letter to the ethics committee and Biogen.
17.3.
Subject Information and Consent
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the subject 
or subject’s legally authorized representative (e.g., parent or legal guardian), as applicable, in 
accordance with local practice and regulations.  
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the subject must be explained to the subject (or the 


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subject’s legally authorized representative).  The subject must be given sufficient time to 
consider whether to participate in the study.
Subjects will be informed that their race and ethnicity will be collected and will be used during
analysis of study results.
A copy of the signed and dated ICF must be given to the subject.  The original signed and dated 
ICF will be retained with the study records.  Local regulations must be complied with in respect 
to the final disposition of the original (wet signature) and copies of the signed and dated ICFs.
Confirmation of informed consent must also be documented in the subject’s medical record.
17.4.
Subject Data Protection
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by local law (e.g., Protected Health Information 
authorization in North America).
Ethnicity data will be used during subgroup analysis of the safety, efficacy, and PK profile of the 
study treatment. Ethnic differences in drug absorption, distribution, metabolism and excretion 
have been described as well as differences in drug safety and efficacy in distinct ethnic 
groups. Multiple factors may contribute to observed variation in drug response during a clinical 
study. These observed differences may be due to intrinsic factors such as genetics and/or 
extrinsic factors such as diet, environmental exposure, and sociocultural issues that differ 
between ethnic groups. Subjects will be informed that their ethnicity will be collected and used 
during analysis of study results.
Study reports will be used for research purposes only.  The subject will not be identified by name 
in eCRFs, study-related forms, study reports, or any related publications. Biogen, its partners 
and designees, ethics committees, and various government health agencies may inspect the 
records of this study.  Every effort will be made to keep the subject’s personal medical data 
confidential.
17.5.
Compensation for Injury
Biogen maintains appropriate insurance coverage for clinical studies and will follow applicable 
local compensation laws.
17.6.
Conflict of Interest
The Investigators should address any potential conflicts of interest (e.g., financial interest in 
Biogen or its partners) 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 screen any subjects prior to completion of a study initiation visit, 
conducted by Biogen or designee.  This initiation visit will include a detailed review of the 
protocol and study procedures.
18.2.
Quality Assurance
During and/or after completion of the study, quality assurance officers named by Biogen or the 
regulatory authorities may wish to perform onsite audits or inspections.  The Investigator will be 
expected to cooperate with any audit or inspection and to provide assistance and documentation 
(e.g., source data) as requested.
18.3.
Monitoring of the Study
The Investigator must permit study-related monitoring by providing direct access to source data
and to the subjects’ medical histories.
The Clinical Monitor will visit the Investigator at regular intervals during the study and after the 
study has completed, as appropriate.
During these visits, eCRFs and supporting documentation related to the study will be reviewed 
and any discrepancies or omissions will be resolved.  
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure protocol adherence, quality of data, study treatment accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities.
18.4.
Study Funding
Biogen is the Sponsor of the study and is funding the study.  All financial details are provided in 
the separate contracts between the institution, Investigator, and Biogen.  
18.5.
Publications
Details are included in the clinical trial agreement for this study.


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19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION
19.1.
External Contract Organizations
19.1.1.
Contract Research Organization 
A CRO will be responsible for administrative aspects of the study including but not limited to 
study initiation, monitoring, management of SAE reports, and data management.  Before subjects 
are screened at each study site, the CRO will review study responsibilities with the Investigators 
and other study site staff, as appropriate.
19.1.2.
Interactive Response Technology
IRT will be used in this study.  Before subjects are screened or enrolled, the IRT vendor will 
provide each study site with the necessary training, a user manual, and access rights to the 
system.
19.1.3.
Electronic Data Capture
Subject information will be captured and managed by study sites on eCRFs by a web-based 
electronic data capture tool that is supported by a vendor and configured by Biogen or the CRO. 
With the exception of the corticosteroid diary, which will be a paper diary, all subject-reported 
outcomes will be captured in an electronic diary.  
19.1.4.
Central Laboratories for Laboratory Assessments
A central laboratory has been selected by Biogen to analyze the hematology, blood chemistry, 
and urine samples collected for this study
19.1.5.
Central Facility for Other Assessments
A central facility will be selected by Biogen to perform skin tape harvesting and skin biopsy 
assessments for this study.  A central reader will be used to adjudicate the skin photography 
assessments.
19.2.
Study Committees 
19.2.1.
Independent Data Monitoring Committee 
An independent data monitoring committee (IDMC) will be formed to review interim safety and 
efficacy data for this study.  A charter will be written for the IDMC.
19.2.2.
CLASI Assessment and Adjudication 
For Part B of the study, an independent CLASI Assessment Adjudicator will confirm CLASI 
scoring at Screening for the purpose of study eligibility.  The Adjudicator will review the 
photographs to determine if they meet CLASI criteria. 


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A charter for the establishment and operation of the CLASI assessment adjudication process will 
be provided by Biogen. 
19.3.
Changes to Final Study Protocol
All protocol amendments must be submitted to the ethics committee and regulatory authorities if 
required by local law.  Protocol modifications that affect subject safety, the scope of the 
investigation, or the scientific quality of the study must be approved by the ethics committee 
before implementation of such modifications to the conduct of the study.  If required by local 
law, such modifications must also be approved by the appropriate regulatory agency prior to 
implementation.
However, Biogen may, at any time, amend this protocol to eliminate an apparent immediate 
hazard to a subject.  In this case, the appropriate regulatory authorities will be notified 
subsequent to the modification.
In the event of a protocol modification, the ICF may require similar modifications (see 
Section 17).
19.4.
Ethics Committee Notification of Study Completion or Termination
Where required, the regulatory authorities and ethics committees must be notified of completion 
or termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines.
19.5.
Retention of Study Data
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local laws or regulations.  Prior to 
proceeding with destruction of records, the Investigator must notify Biogen in writing and 
receive written authorization from Biogen to destroy study records.  In addition, the Investigator 
must notify Biogen of any changes in the archival arrangements including but not limited to 
archival at an offsite facility or transfer of ownership if the Investigator leaves the site.
19.6.
Study Report Signatory
Biogen will designate one or more 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.


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20.
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Winkelmann RR, Kim GK, Del Rosso JQ. Treatment of Cutaneous Lupus Erythematosus: 
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Rheumatology (Oxford). 2010;49(9):1665-9.


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21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “A 2-Part Phase 2 Randomized, Double-blind, Placebo-
Controlled Study Evaluating the Efficacy and Safety of BIIB059 in Subjects with Systemic 
Lupus Erythematosus and Active Skin Manifestations and in Subjects with Active Cutaneous 
Lupus Erythematosus with or without Systemic Manifestations ” 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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APPENDIX A. DESCRIPTIONS OF EFFICACY INSTRUMENTS 
Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI)
The CLASI instrument was developed to specifically evaluate lupus skin manifestations.  It 
differentiates and separately scores disease activity (CLASI-A) and skin damage (CLASI-D).  
The activity scale includes measurements of erythema, scale and hypertrophy, and mucous 
membrane disease, whereas the damage scale measures hyperpigmentation, atrophy, and scarring 
alopecia.  Each part of the body is listed separately, from the scalp to the feet, in addition to 
sections focusing on mucous membrane involvement and alopecia.  For the activity score, points 
are given for the presence of erythema, scale, mucous membrane lesions, recent hair loss, and 
inflammatory alopecia.  For the damage score, points are given for the presence of 
dyspigmentation, scarring, and scarring alopecia.  Total dyspigmentation scores are doubled 
when most of the dyspigmentation has been present for more than 1 year.  Scores for each area 
are assigned based on the most severe lesion within the area of interest.  Of note, affected body 
parts are weighted equally regardless of surface area and number of lesions present.  Separate 
composite scores for activity and damage are calculated by simply summing the individual 
component scores.  CLASI-A scores of 0-9, 10-20, and 21-70 represent disease severity of mild, 
moderate, and severe, respectively [Bonilla-Martinez 2008; Klein 2010].
A copy of the CLASI is provided in the Study Reference Guide.
Systemic Lupus Erythematosus Disease Activity Index -2000 (SLEDAI-2K)
The SLEDAI-2K is a reliable, valid, simple, 1-page activity index that measures disease activity 
and records features of active lupus as present or not [Gladman 2002].  It is a modification of the  
SLEDAI to reflect persistent, active disease in those descriptors that had previously only 
considered new or recurrent occurrences.  The SLEDAI-2K has been validated against the 
SLEDAI, which has been shown to be reliable at different levels of disease activity [Gladman 
1994].  
The SLEDAI-2K uses a weighted checklist to assign a numeric score based on the presence or 
absence of 24 symptoms at the time of assessment or during the previous 28 days.  Each 
symptom present is assigned between 1 and up to 8 points based on its usual clinical importance, 
yielding a total score that ranges from 0 points (no symptoms) to 105 points (presence of all 
defined symptoms).  However, if scored correctly, it is rare for even the sickest patients to score 
more than 20 points.  The assessor is also requested to assess the subject’s symptoms using the 
visual analog scale (VAS) for the Physician’s Global Assessment (PGA).
SLEDAI-2K assessments should be conducted by the same trained evaluator at each visit.
A copy of the SLEDAI-2K and glossary is provided in the Study Reference Guide.
 
 
  
A mild/moderate flare is defined as any of the following:


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
Change in SLEDAI instrument score of 3 points or more (but not to >12)

New or worse discoid, photosensitive, profundus, cutaneous vasculitis, bullous lupus; 
nasopharyngeal ulcers; pleuritis; pericarditis; arthritis; or fever due to systemic lupus 
erythematosus (SLE)

Increase in prednisone requirement, but not to >0.5 mg/kg/day

Addition of NSAID or antimalarial medication for SLE activity

≥1.0 increase in PGA score, but not to >2.5
A severe flare is defined as any of the following:

Change in SLEDAI instrument score to >12

New or worse central nervous system SLE; vasculitis; nephritis; myositis; platelets 
<60,000/ml; or hemolytic anemia with hemoglobin <7 g/dL or decrease in 
hemoglobin >3 g/dL AND requiring: doubling prednisone dose, increase to >0.5 
mg/kg/day or hospitalization

Increase in prednisone dose to >0.5 mg/kg/day

New requirement for cyclophosphamide, azathioprine, methotrexate, or 
mycophenolate for SLE activity

Hospitalization for SLE activity

Increase in PGA score to >2.5
British Isles Lupus Activity Group - 2004 
The BILAG-2004 Disease Activity Index evaluates SLE activity in a number of organ systems, 
based on the principle of “physician’s intention to treat” [Isenberg 2005].  The primary purpose 
of the BILAG in this study is to assess possible worsening in specific organ systems.  Additional 
analyses of improvements in disease activity as assessed by the BILAG-2004 numeric scoring 
will also be performed [Yee 2010].
A separate alphabetic score is assigned to each organ system, corresponding in general to the 
following definitions:

BILAG A:  Severe disease activity requiring systemic high-dose oral corticosteroids, 
intravenous pulse corticosteroids, systemic immunosuppressants, therapeutic 
high-dose anticoagulation in the presence of high-dose corticosteroids, or prednisone 
≥20 mg/day.  Note that in the context of a clinical trial protocol with medication 
restrictions and blinded study treatment, the term “requiring” is not taken literally but 
indicates that if all else were equal this would be the degree of treatment indicated.  It 
is also understood that some patients respond differently to levels of medication than 
do others, so that in assessing patients with the BILAG, “intent- to- treat” really 
means that most patients with this degree of symptom would require this level of 
treatment, not necessarily the patient in question.

BILAG B:  Moderate disease activity requiring treatment with systemic low-dose oral 
glucocorticoids, intramuscular or intra-articular or soft tissue corticosteroid injection, 


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topical corticosteroid or immunosuppressants, or symptomatic therapy such as 
antimalarial medications or NSAIDs

BILAG C:  Mild disease

BILAG D:  System previously affected but now inactive

BILAG E:  System never involved
The BILAG-2004 is evaluated by scoring each item of a list of signs and symptoms as:
1. Improving
2. Same
3. Worse
4. New
0
Not present
(ND) Not done
For some items, appropriate responses may be:  

Y/N  OR numeric values where indicated 

Y/N and confirm this is due to SLE activity
All signs and symptoms scored must be due to SLE.  Use of a glossary provided with the 
BILAG-2004 instrument and training of assessors in use of the instrument are essential to 
obtaining reliable and consistent results.
Use of the BILAG-2004 index for evaluating flares has been identified as a robust way of 
evaluating the efficacy of drugs; this judgment has been corroborated by external advisors and 
regulatory authorities.
BILAG assessments should be conducted by a trained evaluator, with documentation of training.
A copy of the BILAG-2004 and glossary is provided in the Study Reference Guide.
Tender and Swollen Joint Counts 
Joint involvement is a frequent manifestation in patients affected by SLE and occurs in up to 
90% of patients at the onset or during the course of the disease [Ball and Bell 2012].  An active 
joint is defined as a joint with pain and signs of inflammation (e.g., tenderness, swelling or 
effusion).  A 28-joint assessment will be performed. The joints to be assessed bilaterally include 
the shoulders, elbows, wrists (radiocarpal, carpal, and carpometacarpal bones are considered as a 
single unit), metacarpophalangeal (MCP) joints (MCP 1, 2, 3, 4, and 5), proximal 
interphalangeal (PIP) joints (PIP 1, 2, 3, 4 and 5), and the knees. Artificial and ankylosed or 
fused joints will be excluded from tenderness and swelling assessments.
A copy of the joint count form is provided in the Study Reference Guide.


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Physician Global Assessment of SLE (VAS)
The PGA is used to quantify disease activity and is measured using an anchored VAS.  The PGA 
asks the Investigator to assess the subject’s current disease activity from a score of 0 (none) to 3 
(severe), with the assessment made relative not to the subject’s most severe state but the most 
severe state of SLE that might exist at study visits.
A copy of the PGA of SLE is provided in the Study Reference Guide.
 
 
 
 
 
  
 
 
 
 
 
 
 


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APPENDIX B. TOPICAL CORTICOSTEROIDS NOT PERMITTED 
DURING THE STUDY
Topical Corticosteroids Not Permitted During the Study – Non-Exhaustive List 
Potency 
Generic Name and Strength
Super Potent
(Class 1 United States classification)
Augmented Betamethasone Dipropionate 0.05% 
Clobetasol Propionate 0.05% 
Fluocinonide 0.1% 
Halobetasol Propionate 0.05%
Potent
(Class 2 United States classification)
Amcinonide 0.1% 
Desoximetasone 0.25% Cream
Desoximetasone 0.05% Gel
Naricort 0.025% C
Betamethasone valerate*
Diflorasone Diacetate 0.05% 
Fluocinonide 0.05% 
Halcinonide 0.1%
Mometasone Furoate 0.1%
Triamcinolone Acetonide 0.5%
Upper-mid Strength
(Class 3 United States classification)
Betamethasone Dipropionate 0.05% 
Betamethasone Valerate 0.1% 
Fluticasone Propionate 0.005% 
Diflorasone diacetate 0.05%
Clobetasone butyrate*
Mid Strength
(Class 4 United States classification)
Clocortolone Pivalate 0.1% 
Fluocinolone Acetonide*  
Flurandrenolide 0.05% 
Hydrocortisone Valerate 0.2%
Source: [Ference and Last 2009; Jacob and Steele 2006]
* See Table 6 for allowable strength


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APPENDIX C. AMERICAN COLLEGE OF RHEUMATOLOGY 
REVISED CRITERIA FOR CLASSIFICATION OF 
SYSTEMIC LUPUS ERYTHEMATOSUS 


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CONFIDENTIAL
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Biogen MA Inc.
1
Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead Berkshire
SL6 4AY
United Kingdom
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 230LE201
A 2-Part Phase 2 Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy 
and Safety of BIIB059 in Subjects with Systemic Lupus Erythematosus and Active Skin 
Manifestations and in Subjects with Active Cutaneous Lupus Erythematosus with or without 
Systemic Manifestations
Version 4.0
Date:  08 February 2018
EUDRA CT Number: 2015-004359-32  
Version 4.0 of the protocol has been prepared for this amendment, which supersedes Version 3.0.


Protocol 230LE201, Version 4
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Biogen MA Inc.
2
PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol Version 3.0 is to correct errors that were 
inadvertently made in Table 1: Schedule of Activities for Part A

Erroneous footnotes (footnote 10 and footnote 12, Version 3 numbering) and 
corresponding footnote indicators were deleted from Table 1. The remaining footnotes 
were renumbered accordingly.

Footnote 13 (Version 3 numbering) was corrected to accurately reflect the instructions for 
Part A.  
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 4.2, Schedule of Activities, Table 1:  Schedule of Activities Part A
Now reads: See Table 1 and table footnotes on the following pages.
Rationale:  These changes were made to correct errors in the footnotes and footnote indicators of  
Table 1:  Schedule of Activities Part A.


Protocol 230LE201, Version 4
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3
Table 1:
Schedule of Activities Part A
Screening 
Period
Treatment Period
Follow-up Period1
Study Week
Within 4 Weeks 
Prior to 
Randomization
0
1
2
4
8
12
16
20
24/ET
FU4
FU8
FU12
              Study Day
13
8
(±2D)
153
(±2D)
293
(±3D)
573
(±3D)
853
(±3D)
1133
(±3D)
1413
(±3D)
169
(±3D)
197
(±5D)
225
(±5D)
253
(±5D)
Tests and 
Assessments2,3
Informed Consent 
Form(s)
X
Inclusion/Exclusion 
Criteria
X
X
Randomization
X
Demographic data
X
SLE and other 
medical history
X
Documentation of 
SLE by ACR Criteria
X
12-lead ECG4
X
X
Chest X-Ray4,5 (if 
required by local 
regulation)
X
Tuberculosis test6
X
Serum virology RNA 
(HIV, hepatitis B and 
C)
X
Urine drug screen
X
Serum pregnancy 
test
X


Protocol 230LE201, Version 4
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Screening 
Period
Treatment Period
Follow-up Period1
Study Week
Within 4 Weeks 
Prior to 
Randomization
0
1
2
4
8
12
16
20
24/ET
FU4
FU8
FU12
              Study Day
13
8
(±2D)
153
(±2D)
293
(±3D)
573
(±3D)
853
(±3D)
1133
(±3D)
1413
(±3D)
169
(±3D)
197
(±5D)
225
(±5D)
253
(±5D)
Tests and 
Assessments2,3
Urine pregnancy 
test7
X
X
X
X
X
X
X
X
X
X
X
Physical 
examination, weight, 
height8
X
X
X
X
X
X
X
X
X
X
X
Vital signs9
X
X
X
X
X
X
X
X
X
X
X
X
X
BILAG-2004
X
X
X
X
X
X
X
X
CLASI10
X
X
X
X
X
X
X
X
X
X
Physicians Global 
Assessment of SLE 
(VAS) 11,12 10
X
X
X
X
X
X
X
X
X
X
Skin photography of 
target lesion1311
X
X
X14 12
Joint Count (28 joint 
assessment)
X
X
X
X
X
X
X
X
X
X


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Screening 
Period
Treatment Period
Follow-up Period1
Study Week
Within 4 Weeks 
Prior to 
Randomization
0
1
2
4
8
12
16
20
24/ET
FU4
FU8
FU12
              Study Day
13
8
(±2D)
153
(±2D)
293
(±3D)
573
(±3D)
853
(±3D)
1133
(±3D)
1413
(±3D)
169
(±3D)
197
(±5D)
225
(±5D)
253
(±5D)
Tests and 
Assessments2,3
Study treatment 
administration15 13
X
X
X
X
X
X
X
Corticosteroid 
diary16 14
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessment
Hematology
X
X
X
X
X
X
X
X
X
X
X
Blood chemistry
X
X
X
X
X
X
X
X
X
X
X
Urinalysis (including 
microscopic 
examination)
X
X
X
X
X
X
X
X
X
X
X
Urine protein-
creatinine Ratio (spot 
urine)
X
X
X
X
X
X
X
X
X
X
X
Direct Coombs 
Analysis
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
CD19+ B Cell 
count17 15
X
Pharmacokinetics
Serum BIIB05918 16
X
X
X
X
X
X
X
X


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Screening 
Period
Treatment Period
Follow-up Period1
Study Week
Within 4 Weeks 
Prior to 
Randomization
0
1
2
4
8
12
16
20
24/ET
FU4
FU8
FU12
              Study Day
13
8
(±2D)
153
(±2D)
293
(±3D)
573
(±3D)
853
(±3D)
1133
(±3D)
1413
(±3D)
169
(±3D)
197
(±5D)
225
(±5D)
253
(±5D)
Tests and 
Assessments2,3


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Screening 
Period
Treatment Period
Follow-up Period1
Study Week
Within 4 Weeks 
Prior to 
Randomization
0
1
2
4
8
12
16
20
24/ET
FU4
FU8
FU12
              Study Day
13
8
(±2D)
153
(±2D)
293
(±3D)
573
(±3D)
853
(±3D)
1133
(±3D)
1413
(±3D)
169
(±3D)
197
(±5D)
225
(±5D)
253
(±5D)
Tests and 
Assessments2,3
Safety
Serum for vaccine-
related 
immunoglobulin 
titers22 21
X
X
Antibodies to 
BIIB059
X
X
X
X
X
Immunoglobulin 
(total, IgG, IgA, 
IgM)
X
X
X
Concomitant 
medication/ 
procedures
Monitor and record from signing of informed consent through the end of the study
Serious adverse 
events
Monitor and record from signing of informed consent through the end of the study
Adverse events 
Monitor and record from time of first dose through the end of the study
Abbreviations:  ACR=American College of Rheumatology; BILAG=British Isles Lupus Activity Group; CLASI=Cutaneous Lupus Disease Area and Severity 
Index; CLE=cutaneous lupus erythematosus; C=complement; CPK=creatine phosphokinase; CRP=C-reactive protein; D=day; DNA=deoxyribonucleic acid; 
dsDNA=double-stranded DNA; ECG=electrocardiogram; ESR=erythrocyte sedimentation rate; ET=early termination; FU=follow-up; h=hour(s); HIV=human 
immunodeficiency virus; Ig=immunoglobulin; 
; 
; 
RNA=ribonucleic acid; 
; SLE=systemic lupus erythematosus; SLEDAI-2K=Systemic Lupus 
Erythematosus Disease Activity Index 2000; TB=tuberculosis; VAS=visual analog scale.
1 Follow-up visit will be conducted 4, 8 and 12 weeks after the last Treatment Period Visit (Week 24 or ET). 


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2 Assessments (e.g., CPK, ECG, etc.) may be performed as required to confirm SLEDAI-2K and BILAG findings.  
3 On each dosing day (Day 1, Day 15, Day 29, Day 57, Day 85, Day 113, and Day 141) all assessments should be performed prior to dosing.
4 To be performed locally.
4,5
Where mandated by local regulation, a chest X-ray will be obtained locally during the screening period, unless a previous chest X-ray or the 
documented results from a chest X-ray obtained within 12 weeks prior to screening are available.  The chest X-ray or X-ray results will be reviewed by the 
Investigator (or designee) in order to exclude patients with active TB infection from entering the study.
6 Testing to be performed locally.  Indeterminate Quantiferon or T-SPOT tests may be repeated once and will be considered positive if retest results are positive 
or indeterminate. Subjects with documented BCG vaccination must perform a TB test at Screening and will be excluded if they exhibit skin induration ≥5 mm 
or a positive Quantiferon or positive or borderline T-SPOT (Elispot) test. 
7 To be performed locally.
8 Height should only be measured only once; i.e., at the Day 1/baseline visit.
9 Vital signs include seated arterial blood pressure, heart rate, and oral body temperature.  
10CLASI will be assessed by the Investigator or a trained designee at all assessments (Section 19.2.2 ).  CLASI scores at Screening will be verified by an 
Independent CLASI Adjudicator to confirm eligibility.
1110Assessments results should be reported electronically.
12Only applicable for subjects with SLE.
1311For skin lesions with a CLASI-A score greater than 0, photographs of each lesion and of the corresponding region with lesion will be obtained.  Photographs 
will be evaluated by a central adjudicator to verify the CLASI-A score assignment by the Investigator. One lesion is to be selected at baseline as the target 
lesion (the most severe active CLE lesion is recommended).  The same target lesion must be photographed and the same lesion used for tape harvesting at each 
timepoint and the same lesion over time.  
1412If the ET Visit occurs before Week 16, skin photography should be performed at the ET Visit.
1513Following administration of study treatment, subjects should remain at the study center for 1 hour to be observed for the development of potential allergic or 
anaphylactic reactions.
1614Subject paper diaries for recording corticosteroid use will be distributed on Day 1, reviewed with site staff at each study visit, and collected by the study site 
at the final study visit. 
1715Only for subjects with prior B cell directed therapies within 52 weeks of Screening; this test should be performed at a central laboratory.
1816Pharmacokinetic evaluations will be conducted as follows: Study Day 1 (predose –1 h and  post-dose 4 h ±1 h), Day 8 (any time during visit), Day 29 
(predose –1 h and postdose 4 h ±1 h), Day 85 (predose –1 h and postdose 4 h±1 h), Day 113 (predose –1 h), and Day 169 (any time during visit). During the 
Follow-up Period, 1 sample will be collected on Days 197 and 253 (any time during the visit) [see Table 3].  The time and date of PK sample collection and 
BIIB059 dose should be recorded in the eCRF.
 
 
 
22 Vaccine-related immunoglobulin titers for tetanus, diphtheria, and Pneumococcus will be collected. 


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SUMMARY OF MINOR CHANGES TO THE PROTOCOL
The following minor changes were made to the protocol, as appropriate:

The version number and protocol date were updated throughout the protocol and 
synopsis.

Minor typographical corrections and formatting improvements were made.


CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
1
Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead Berkshire
SL6 4AY
United Kingdom
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 230LE201
A 2-Part Phase 2 Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy 
and Safety of BIIB059 in Subjects with Systemic Lupus Erythematosus and Active Skin 
Manifestations and in Subjects with Active Cutaneous Lupus Erythematosus with or without 
Systemic Manifestations
Version 3.0
Date: 11 December 2017
EUDRA CT Number: 2015-004359-32  Version 3.0 of the protocol has been prepared for this 
amendment, which supersedes Version 2.0.


Protocol 230LE201, Version 3.0
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Biogen MA Inc.
2
PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol 230LE201is to inform the sites of the correct 
type of screening biopsy to be performed. 
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 4.3.5.1, Skin Biopsy for Confirming CLE Diagnosis
Now reads:
For subjects without historical biopsy data, diagnosis will be confirmed during Screening by skin 
biopsy that can be read at a local laboratory or the central laboratory, at the discretion of the 
Investigator. A shave punch biopsy will be performed for diagnostic purposes. Subjects with an 
available historical biopsy do not need a screening biopsy for diagnosis. 
Rationale:  Shave biopsy was replaced by punch biopsy because it is not standard clinical 
practice to perform a shave biopsy for diagnostic purposes in patients with lupus erythematosus. 
This change also affects Section 4.2, Table 2: Schedule of Activities Part B (footnotes #20 and 
#21).


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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL
Changes to the protocol are presented chronologically.  New text is shown in bold type; deleted text is shown with a strikethrough.
Section 1, Synopsis
The Synopsis was revised to reflect changes made throughout the protocol.
Section 4.2, Schedule of Activities (Table 1: Schedule of Activities Part A)
Change:  The phrase “Where mandated by local regulation” was added within body of Table 1 and footnote #5.
Now reads:
Screening 
Period
Treatment Period
Follow-up Period1
Study Week
Within 4 Weeks 
Prior to 
Randomization
0
1
2
4
8
12
16
20
24/ET
FU4
FU8
FU12
              Study Day
13
8
(±2D)
153
(±2D)
293
(±3D)
573
(±3D)
853
(±3D)
1133
(±3D)
1413
(±3D)
169
(±3D)
197
(±5D)
225
(±5D)
253
(±5D
)
Tests and 
Assessments2,3
Informed Consent 
Form(s)
X
Inclusion/Exclusion 
Criteria
X
X
Randomization
X
Demographic data
X
SLE and other 
medical history
X
Documentation of 
SLE by ACR 
Criteria
X
12-lead ECG4
X
X


Protocol 230LE201, Version 3.0
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4
Screening 
Period
Treatment Period
Follow-up Period1
Study Week
Within 4 Weeks 
Prior to 
Randomization
0
1
2
4
8
12
16
20
24/ET
FU4
FU8
FU12
              Study Day
13
8
(±2D)
153
(±2D)
293
(±3D)
573
(±3D)
853
(±3D)
1133
(±3D)
1413
(±3D)
169
(±3D)
197
(±5D)
225
(±5D)
253
(±5D
)
Tests and 
Assessments2,3
Chest X-Ray4,5 (if 
required by local 
regulation)
X
Tuberculosis test6
X
Serum virology 
RNA (HIV,  
hepatitis B and C)
X
Urine drug screen
X
Serum pregnancy 
test
X
Urine pregnancy 
test7
X
X
X
X
X
X
X
X
X
X
X
Physical 
examination,  
weight, height8
X
X
X
X
X
X
X
X
X
X
X
Vital signs9
X
X
X
X
X
X
X
X
X
X
X
X
X
BILAG-2004
X
X
X
X
X
X
X
X
CLASI10
X
X
X
X
X
X
X
X
X
X


Protocol 230LE201, Version 3.0
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5
Screening 
Period
Treatment Period
Follow-up Period1
Study Week
Within 4 Weeks 
Prior to 
Randomization
0
1
2
4
8
12
16
20
24/ET
FU4
FU8
FU12
              Study Day
13
8
(±2D)
153
(±2D)
293
(±3D)
573
(±3D)
853
(±3D)
1133
(±3D)
1413
(±3D)
169
(±3D)
197
(±5D)
225
(±5D)
253
(±5D
)
Tests and 
Assessments2,3
Physicians Global 
Assessment of SLE 
(VAS) 11,12
X
X
X
X
X
X
X
X
X
X
Skin photography of 
target lesion13
X
X
X14
Joint Count (28 joint 
assessment)
X
X
X
X
X
X
X
X
X
X
Study treatment 
administration15
X
X
X
X
X
X
X
Corticosteroid 
diary16
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessment
Hematology
X
X
X
X
X
X
X
X
X
X
X
Blood chemistry
X
X
X
X
X
X
X
X
X
X
X
Urinalysis 
(including 
microscopic 
examination)
X
X
X
X
X
X
X
X
X
X
X
Urine protein-
creatinine Ratio 
(spot urine)
X
X
X
X
X
X
X
X
X
X
X


Protocol 230LE201, Version 3.0
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6
Screening 
Period
Treatment Period
Follow-up Period1
Study Week
Within 4 Weeks 
Prior to 
Randomization
0
1
2
4
8
12
16
20
24/ET
FU4
FU8
FU12
              Study Day
13
8
(±2D)
153
(±2D)
293
(±3D)
573
(±3D)
853
(±3D)
1133
(±3D)
1413
(±3D)
169
(±3D)
197
(±5D)
225
(±5D)
253
(±5D
)
Tests and 
Assessments2,3
Direct Coombs 
Analysis
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
CD19+ B Cell 
count17
X
Pharmacokinetics
Serum BIIB05918
X
X
X
X
X
X
X
X


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7
Screening 
Period
Treatment Period
Follow-up Period1
Study Week
Within 4 Weeks 
Prior to 
Randomization
0
1
2
4
8
12
16
20
24/ET
FU4
FU8
FU12
              Study Day
13
8
(±2D)
153
(±2D)
293
(±3D)
573
(±3D)
853
(±3D)
1133
(±3D)
1413
(±3D)
169
(±3D)
197
(±5D)
225
(±5D)
253
(±5D
)
Tests and 
Assessments2,3
Safety
Serum for vaccine-
related 
immunoglobulin 
titers23
X
X
Antibodies to 
BIIB059
X
X
X
X
X
Immunoglobulin 
(total, IgG, IgA, 
IgM)
X
X
X


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8
Screening 
Period
Treatment Period
Follow-up Period1
Study Week
Within 4 Weeks 
Prior to 
Randomization
0
1
2
4
8
12
16
20
24/ET
FU4
FU8
FU12
              Study Day
13
8
(±2D)
153
(±2D)
293
(±3D)
573
(±3D)
853
(±3D)
1133
(±3D)
1413
(±3D)
169
(±3D)
197
(±5D)
225
(±5D)
253
(±5D
)
Tests and 
Assessments2,3
Concomitant 
medication/ 
procedures
Monitor and record from signing of informed consent through the end of the study
Serious adverse 
events
Monitor and record from signing of informed consent through the end of the study
Adverse events 
Monitor and record from time of first dose through the end of the study
5 During the screening period Where mandated by local regulation, a chest X-ray will be obtained locally during the screening 
period, unless a previous chest X-ray or the documented results from a chest X-ray obtained within 12 weeks prior to screening are 
available.  The chest X-ray or X-ray results will be reviewed by the Investigator (or designee) in order to exclude patients with active 
TB infection from entering the study.
Rationale:  For countries that require a chest X-ray for tuberculosis screening, a provision to obtain a chest X-ray was added to the 
protocol.
This change also affects Section 4.2, Schedule of Activities, Table 2: Schedule of Activities Part B and footnote #5.
Section 4.2, Schedule of Activities (Table 1: Schedule of Activities Part A)
Change:  Pharmacokinetic (PK) evaluation timepoints were corrected for Day 85 and Day 113 in footnote #18.


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9
Now reads:18 Pharmacokinetic evaluations will be conducted as follows: Study Day 1 (predose –
1 h and post-dose 4 h ±1 h), Day 8 (any time during visit), Day 29 (predose –1 h and postdose 4 
h ±1 h), Day 85 (predose –1 h and postdose 4 h±1 h), Day 113 (predose –1 h and postdose 4 h 
±1 h), and Day 169 (any time during visit). During the Follow-up Period, 1 sample will be 
collected on Days 197 and 253 (any time during the visit).  See Table 3.  The time and date of 
PK sample collection and BIIB059 dose should be recorded in the eCRF.
Rationale:  The PK evaluation timepoints were corrected to align with the PK sampling 
timepoints presented in Table 3 (Pharmacokinetic Assessments). The description of collection 
timepoints for Week 12 (Day 85) and Week 16 (Day 113) were unintentionally inverted 
according to the site communication letter on PK assessment timepoints. 
Section 4.2, Schedule of Activities (Table 3, Pharmacokinetic Assessments)
Change:  The Follow-Up period was changed to Day 197 and 253 (±5 d) for Part A and Days
141, 169, and 197 (±5 d) for Part B. 
Now reads:
Table 3:Pharmacokinetic Assessments
Study Week
0
1
2
4
8
12
16
20
24
Follow-
Up 
Period
Study Day
1
8
(±2 d)
15
(±2 
d)
29
(±3 d)
57
(±3 
d)
85
(±3 d)
113
(±3 d)
141
(±3 
d)
169
(±3 d)
Part A
Day 197
, 225 or 
and 253 
(±5 d)
Part B
Day 
141, 
169,
orand
197 (±5 
d)
Part A
PK 
Sampling 
Timepoint(s)
Predose 
(–1 h)
Postdose 
(4 h ±1 
h)
Any 
tim
e 
duri
ng 
visi
t

Predose 
(–1 h)

Postdose 
(4 h ±1 
h)

Predose 
(–1 h)

Postdose 
(4 h ±1 
h)
Predose  
(–1 h)
An
y 
tim
e 
duri
ng 
visi
t
Any 
time 
during 
visit


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10
Part B
PK 
Sampling 
Timepoint(s)
Predose 
(–1 h)
Postdose
(4 h ±1 
h)
Any
tim
e 
duri
ng 
visi
t

Predose 
(–1 h)

Postdose 
(4 h ±1 
h)

Predose 
(–1 h)

Postdose 
(4 h ±1 
h)
Any 
time 
during 
visit 
Any 
time 
during 
visit
Rationale:  In Table 3, Follow-Up Period collection visits had been specified incorrectly. 
Collection visits were corrected to align with Table 1: Schedule of Activities Part A and Table 2: 
Schedule of Activities Part B.
Section 4.3.3, Joint Count Assessment (Part A Only)
Change:  The language for joint count assessment was revised to indicate that the same joint 
assessor must perform the joint count assessment for the same subject at every visit.
Now reads:
Joint counts will be evaluated at all visits by a trained independent joint assessor.  Joint counts 
will be evaluated at all visits by a trained independent joint assessor. The joint counts for 
an individual subject must be performed by the same joint assessor throughout the trial.
Rationale:  This change was made to ensure that investigational sites assign same joint assessor 
to the same subject at every visit. This practice is expected to prevent the occurrence of major 
protocol deviations.
Section 7.2.3, Follow-Up
Change:  The language pertaining to follow-up visits for subjects who prematurely discontinue 
study treatment and/or who prematurely withdraw from the study was revised.
Now reads:
Subjects are to return to the study site for follow-up (FU) visits at 4, 8, and 12 weeks after the 
last Treatment Period visit (Week 24 or Early Termination [ET] Visit). Follow-up visits will be 
conducted at Week FU4 (Day 197), Week FU8 (Day 225) and Week FU12 (Day 253).  The final 
study visit will be Week FU12.  Subjects who prematurely discontinue treatment during the 
double-blind treatment period should undergo ET Visit assessments and be encouraged to 
complete the Follow-up Period.
Subjects who prematurely discontinue study treatment during the Double blind Treatment 
Period should complete all study assessments for the Week 24/ET Visit as soon as possible, 
but within 4 weeks.  Subjects who discontinue study treatment should also complete the 
study assessments for the Safety FU Visits at Week FU4, Week FU8, and Week FU12 after 
their ET Visit. 


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11
Subjects who are prematurely withdrawn from the study during the Double blind 
Treatment Period should complete all study assessments for the Week 24/ET Visit as soon 
as possible, but within 4 weeks.  Withdrawn subjects should also be encouraged to 
complete the study assessments for the Safety FU Visits at Week FU4, Week FU8, and 
Week FU12 after their ET Visit.  However, if the subject is unwilling or unable to attend 
the study FU Visits, or at minimum the ET Visit, and decides to withdraw consent, the 
reason for withdrawal will be documented and no further assessments will be obtained.    
Rationale:  This new text provides more detailed instructions to the sites regarding study 
activities for subjects who discontinue study treatment and/or who are prematurely withdrawn 
from the study.
This change also affects Section 4.2, Schedule of Activities, footnote #1.
Section 7.3.3, Follow-Up
Change:  The language pertaining to follow-up visits for subjects who prematurely discontinue 
study treatment and/or who prematurely withdraw from the study was revised.
Now reads:
Subjects are to return to the study site for follow up visits on Week FU4 (Day 141), Week FU8 
(Day 169), and Week FU12 (Day 197) after the last Treatment Period visit (Week 16 or ET 
Visit).  The final study visit will be Week FU12.  Subjects who prematurely discontinue 
treatment during the double-blind Treatment Period should undergo ET visit assessments and be 
encouraged to complete the Follow up Period. 
Subjects who prematurely discontinue study treatment during the Double blind Treatment 
Period should complete all study assessments for the Week 16/ET Visit as soon as possible, 
but within 4 weeks.  Subjects who discontinue study treatment should also complete the 
study assessments for the Safety FU Visits at Week FU4, Week FU8, and Week FU12 after 
their ET Visit. 
Subjects who are prematurely withdrawn from the study during the Double blind 
Treatment Period should complete all study assessments for the Week 16/ET Visit as soon 
as possible, but within 4 weeks.  Withdrawn subjects should be encouraged to complete the 
study assessments for the Safety FU Visits at Week FU4, Week FU8, and Week FU12 after 
their ET Visit.  However, if the subject is unwilling or unable to attend the study FU Visits, 
or at minimum the ET Visit, and decides to withdraw consent, the reason for withdrawal 
will be documented and no further assessments will be obtained.
Rationale: This new text provides more detailed instructions to sites regarding study activities 
for subjects who discontinue study treatment and/or who are prematurely withdrawn from the 
study.
This change also affects Section 4.2, Schedule of Activities, footnote #1.


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Section 8.2.1, Exclusion Criteria (Parts A and B)
Change:  Exclusion criterion #7, regarding hepatitis C virus (HCV), was revised.
Now reads:
7. Current active hepatitis C virus (HCV) infection, determined as HCV RNA above the limit of 
detection. Current active hepatitis C virus (HCV) infection, determined as HCV RNA above 
the limit of detection, in subjects with positive HCV antibody titer.
Rationale: This exclusion criterion was revised to indicate that subjects must have a positive 
HCV antibody titer in order to confirm the diagnosis of current active HCV infection.
Section 8.2.1, Exclusion Criteria (Parts A and B), Medical History
Change:  A sentence was added to exclusion criterion #20 clarifying specific autoimmune 
diseases that may confound the evaluation of the effect of the investigational product (IP).
Now reads:
20. History of any clinically significant cardiac, endocrinologic, hematologic, hepatic, 
immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric and renal, 
or other major disease, as determined by the Investigator. Specifically, a diagnosis of any other 
systemic autoimmune disease other than secondary Sjögren’s syndrome, such as 
rheumatoid arthritis (RA), psoriatic arthritis (PsA), dermatopolymiositis (DM), systemic 
sclerosis (scleroderma), etc. which may confound the evaluation of the effect of IP.
Rationale: The added language to this exclusion criterion is intended to prevent study 
Investigators from excluding subjects who were diagnosed with secondary Sjögren’s syndrome 
(sicca syndrome), which is frequent and commonly allowed in clinical trials for SLE.
Section 8.2.1, Exclusion Criteria (Parts A and B), Laboratory abnormalities
Change:  In exclusion criterion 35, the unit of measure for neutrophils count was changed from 
L to µL.
Now reads:
35. Hemoglobin <5.5 mmol/L [9 g/dL], neutrophils <1.5 x 103/LµL, platelets <75 x 109/L at 
Screening.
Rationale: The operating laboratories at investigational sites provide results for neutrophils 
count equivalent to 103/ µL. The protocol incorrectly showed the unit for neutrophils as 103/L; 


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13
this change corrects the error. This correction will help investigational sites report clean data for 
neutrophil counts.
Section 10.1, Discontinuation of Study Treatment
Change:  The language for discontinuation of study treatment was revised.
Now reads: A subject must permanently discontinue study treatment for any of the following 
reasons:

The subject becomes pregnant.  Study treatment must be discontinued immediately.  
Report the pregnancy according to the instructions in Section 15.4.1.

The subject withdraws consent to continue study treatment.  

The subject experiences a medical emergency that necessitates permanent 
discontinuation of study treatment.

The subject experiences a medical emergency that necessitates unblinding of the 
subject’s treatment assignment.

The subject is unwilling or unable to comply with the protocol.

At the discretion of the Investigator for medical reasons.
The reason for discontinuation of study treatment must be recorded in the subject’s electronic 
case report form (eCRF). 
Subjects who prematurely discontinue study treatment during the Double blind Treatment 
Period should complete all study assessments for the ET Visit as soon as possible, but 
within 4 weeks.  Subjects who discontinue study treatment should also complete the study 
assessments for the Safety FU Visits at 4, 8, and 12 weeks after the ET Visit. protocol 
required tests and assessments during the follow-up visits (Week 4, 8, and 12 Follow-Up 
Visits)).  In the event that a subject withdraws from the study prematurely, at minimum, an Early 
Termination Visit should be performed as soon as possible, to be followed by Follow-up Visits at 
4, 8, and 12 weeks after last visit; all Early Termination assessments listed in the study schedule 
should be performed at this Early Termination visit. 
Rationale: This new text provides more detailed instructions to the sites regarding study 
activities for subjects who discontinue study treatment.
Section 10.2, Withdrawal of Subjects From Study
Change:  A sentence from Section 10.1 (Discontinuation of Study Treatment) was moved to 
Section 10.2.
Now reads:  Subjects must be withdrawn from the study for any one of the following reasons:

The subject withdraws consent.


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14

The subject enrolls into another interventional clinical study in which an 
investigational treatment or approved therapy for investigational use is administered.

The subject is unwilling or unable to comply with the protocol.
Subjects who are prematurely withdrawn from the study during the Double-blind 
Treatment Period should complete all study assessments for the ET Visit as soon as 
possible, but within 4 weeks.  Withdrawn subjects should be encouraged to complete the 
study assessments for the Safety FU Visits at 4, 8, and 12 weeks after the ET Visit.  
However, if the subject is unwilling or unable to attend the study FU Visits, or at minimum 
the ET Visit, and decides to withdraw consent, the reason for withdrawal will be 
documented and no further assessments will be obtained.
The reason for the subject’s withdrawal from the study must be recorded in the subject’s eCRF. 
The level of consent withdrawal (e.g., whether samples collected but not yet analyzed can still be 
used/analyzed, and so on) should also be recorded in the eCRF.
Rationale: The sentence describing visits and assessments to be performed for subjects who
withdraw from the study prematurely was mistakenly placed in Section 10.1 (Discontinuation of 
Study Treatment), which applies only to subjects who discontinue the study treatment. This 
change more appropriately places the information in Section 10.2.
Appendix A:  Description of Efficacy Instruments,
 
Change:  
 
Now reads:
 
 
 
 
 


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15
Rationale:
 
Appendix A:  Description of Efficacy Instruments,
 
 
 
 
  
 
   


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16
SUMMARY OF MINOR CHANGES TO THE PROTOCOL
The following minor changes were made to the protocol, as appropriate:

The version number and date were updated throughout the protocol.

Time periods or timepoints expressed in months were converted to weeks to maintain 
consistency throughout the protocol.

The wording “protocol version 2” was replaced with “protocol version 2 or 
subsequent versions” wherever applicable.

Typographical and formatting errors were corrected.


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Biogen MA Inc. 
1 
Biogen MA Inc. 
250 Binney Street 
Cambridge, MA  02142 
United States 
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead Berkshire 
SL6 4AY 
United Kingdom 
______________________________________________________________________ 
AMENDMENT SUMMARY 
Biogen Protocol 230LE201 
A 2-Part Phase 2 Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy 
and Safety of BIIB059 in Subjects with Systemic Lupus Erythematosus and Active Skin 
Manifestations and in Subjects with Active Cutaneous Lupus Erythematosus with or without 
Systemic Manifestations.   
Version 2 
Date:  16 May 2017 
EUDRA CT Number:  2015-004359-32 
Version 2 of the protocol has been prepared for this amendment, which supersedes Version 1. 


Protocol 230LE201, Amendment 1 
Amendment Summary 
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE 
  
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2 
PRIMARY REASON FOR AMENDMENT 
The primary reason for this amendment to Protocol 230LE201 is to modify the overall design of 
the 2-part study (Part A in subjects with systemic lupus erythematosus [SLE] with active skin 
manifestations, and Part B in subjects with cutaneous lupus erythematosus [CLE] with or without 
systemic manifestations). The study design changes take into account Biogen’s initial experience 
to more successfully enroll subjects into Part B and are intended to increase the focus of the 
study on CLE, which is the lead indication for BIIB059. 
Part A was initially designed as a dose-ranging study of the effects of BIIB059 on the skin 
manifestations of SLE measured by the Cutaneous Lupus Erythematosus Disease Area and 
Severity Index (CLASI). In the amended protocol, Part A has been modified to evaluate the 
effects of a single dosing regimen of BIIB059 on the joint and skin manifestations of SLE. The 
change was made because joint symptoms are a common systemic component of SLE that has 
been shown to improve in the first 6 months of treatment, based on recent Phase 2 comparator 
data. With this change, Part A of the study now is a proof-of-concept study to evaluate whether 
BIIB059 works beyond the skin in SLE. Key changes to Part A are as follows: 
 
Of the 3 BIIB059 dosing regimens in the original protocol (50, 150, and 450 mg 
subcutaneously [SC] every 4 weeks [Q4W]), the 450 mg Q4W regimen will continue to 
be evaluated, while the 50 mg Q4W and 150 mg Q4W regimens will be dropped. The 
450 mg Q4W regimen, with an additional loading dose at Week 2, was maintained based 
on Phase 1 safety, pharmacokinetic (PK), PK-blood dendritic cell antigen-2 (BDCA2) 
internalization relationship, and extrapolated inhibitory potency (concentration resulting 
in 90% inhibition of response [IC90]) of interferon-alpha (IFN-α) production by 
plasmacytoid dendritic cells). The Treatment Period remains 24 weeks. 
 Skin-related criteria for study eligibility were made less stringent. Per the original 
protocol, subjects in Part A were required to have a minimum CLASI-Activity (CLASI-
A) score of ≥8.  The CLASI requirement proved challenging for enrollment, so a specific 
CLASI threshold will no longer be required for Part A (but will still be required for Part 
B). Instead, subjects in Part A will be required to have some sign of active skin disease, 
as defined by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)-2K 
with no CLASI restriction. A requirement for skin involvement was maintained because 
data suggest that BIIB059 has its primary effect in the skin. Joint-related criteria for 
study eligibility were also added.  
 The primary endpoint was modified from the Week 12 percent change from baseline in 
CLASI-A score to the Week 24 change from baseline in active joint count (28-joint 
assessment), in line with the focus of Part A on joint manifestations instead of skin 
manifestations of SLE. This primary endpoint was selected because joint count is 
considered a reliable indicator of SLE disease activity, based on the medical literature, 
other clinical trials, and discussions with key opinion leaders, indicating that a high 
proportion of SLE patients have joint involvement.  
 The effect of BIIB059 on skin manifestations in patients with an SLE diagnosis 
(fulfilling 4 of 11 American College of Rheumatology [ACR] criteria) will be evaluated 
as secondary endpoints. The skin-related secondary endpoints were changed to reflect 


Protocol 230LE201, Amendment 1 
Amendment Summary 
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE 
  
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3 
the removal of a minimum CLASI score of ≥8 for eligibility. Since a minimum CLASI 
score is no longer required in Part A, the CLASI-50 and ≥4-point reduction endpoints 
will only be evaluable for subjects who have a baseline CLASI score of ≥4.  
Part B was initially designed as a single-dose study of the effects of BIIB059 in CLE. In the 
amended protocol, Part B has been modified to be a dose-ranging study of BIIB059 in CLE. A 
larger number of subjects will be enrolled into Part B (130 instead of 30 subjects). The larger 
sample size and addition of a dose-ranging evaluation will allow for a more thorough evaluation 
of the activity of BIIB059 in CLE observed in the Phase 1 study (230LE101) and to identify an 
efficacious dose for CLE. Key changes to Part B are as follows: 
 
BIIB059 dosing regimens of 50, 150, and 450 mg SC Q4W, with an additional loading 
dose at Week 2, were selected based on the results of the completed Phase 1 study 
(230LE101) and on a population PK model developed using Phase 1 data. 
 
The Treatment Period was extended from 12 weeks to 16 weeks to better characterize the 
effects of BIIB059 in CLE, including the CLASI-A response, because comparator data 
suggest that the CLASI response does not plateau until after 16 weeks. 
 
The primary endpoint was modified from the percent change at Week 12 from baseline in 
CLASI-A score to the percent change at Week 16 from baseline in CLASI-A score to 
reflect the longer treatment period. The skin-related secondary endpoints will be 
evaluated at both Week 12 and Week 16.  
 
The amended protocol specifies a larger planned sample size for Part B. A revised sample 
size of 100 subjects will provide approximately 90% power to detect a dose-response 
relationship in the percent change at Week 16 from baseline in CLASI-A score.     
An interim analysis (IA) was planned in the original protocol to occur approximately 12 weeks 
after 75% of subjects had been randomized into Part A. In the amended protocol, the IA for 
futility of Part B and possible expansion of Part A will be performed.  The IA will be performed 
after approximately 45% of Part B subjects under protocol Version 2 have completed their Week 
12 Treatment Period visit.  At the time of the IA, it is estimated that over 50% of subjects in 
Part A enrolled under Version 1 of the protocol will have completed their Week 12 Treatment 
Period visit.  Following the IA, up to an additional 70 subjects may be enrolled in Part A and 
BIIB059 dose may be adjusted.   The additional subjects in Part A may be enrolled based on a 
more inclusive criteria to include an expanded SLE population.  Details are provided in 
Section 16.7 of the protocol. 
Key sections of the protocol that are affected by the above changes are presented in this section. 
New text is shown in bold type; deleted text is shown with a strikethrough. 
 
Section 5.5, Rationale for Dosing Regimen 
Now reads: 
5.5.1 Part A 
A primary objective of this study is to evaluate the dose-response relationship of BIIB059 at 3 
different dose levels given SC Q4W with an additional loading dose at Week 2.  Dosing 


Protocol 230LE201, Amendment 1 
Amendment Summary 
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE 
  
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4 
regimens were selected based on emerging Single IV as well as multiple SC doses of BIIB059 
up to and including 20 mg/kg and 300 mg, respectively, in healthy volunteers have 
demonstrated acceptable tolerability in the Phase 1 Study (230LE101).  In general,  
BIIB059 serum concentrations were slightly lower in subjects with SLE than in healthy 
volunteers following dosing with BIIB059 50 mg SC (single and multiple dose 
administration).  Additionally, the median percent change from baseline in BDCA2 on 
pDC surfaces was equivalent between SLE and healthy subjects following SC doses of 
50 mg.   
 
Single doses of 450 mg, administered SC every 4 weeks (Q4W) with an additional dose at 
Week 2 will be used in Part A.  The dosing regimen was selected based on Phase 1 safety, 
PK, PK-BDCA2 internalization relationship and extrapolated inhibitory potency (concentration 
resulting in 90% inhibition of response [IC90]) of pDC IFN-α production [Pellerin 2015]. The 
BIIB059 fixed dose of 450 mg SC every 4 weeks (Q4W) with an additional dose at Week 2 
was selected to achieve Cmin levels similar to 3-fold of the calculated IC90 for IFN-α 
inhibition.  Furthermore, this dose regimen with an additional dose of 450 mg at Week 2 and a 
bioavailability (F) of 0.45 is expected to result in cumulative exposure comparable to that 
achieved by the single dose of 20 mg/kg IV for a 65-kg person, the highest dose tested in 
healthy volunteers.    
Single IV doses of BIIB059 up to and including 20 mg/kg in healthy have demonstrated 
acceptable tolerability to date in Part 1 of the Phase 1 SAD study (230LE101).  BDCA2 target 
engagement, as measured by BDCA2 internalization and reappearance, was observed in a 
dose-dependent manner across the dose range of 0.3 to 20 mg/kg.  EC90 values for BDCA2 
internalization were derived from population-based PK and PD modeling with the mean value of 
1.5 µg/mL.  IC90 for IFNα inhibition was estimated from in vitro to in vivo extrapolation of 
BDCA2 internalization and IFNα inhibition[Pellerin 2015].   
BIIB059 fixed doses of 50, 150 and 450 mg SC Q4W with an additional dose at Week 2 were 
chosen and are supported by the following:   
 The low dose of 50 mg SC Q4W was chosen to maintain BDCA2 internalization for 
the majority of the dosing interval  
 The middle dose of 150 mg SC Q4W was selected to achieve minimum observed 
concentration (Cmin) levels similar to the calculated IC90 for IFNα    
 The top dose of 450 mg SC Q4W was selected to achieve Cmin levels similar to 3-fold 
of the calculated IC90 for IFNα inhibition.  Furthermore, this dose regimen with an 
additional dose of 450 mg at Week 2 and a bioavailability (F) of 0.45 is expected to 
result in cumulative exposure over 3 months comparable to that achieved by the 
single dose of 20 mg/kg IV for a 65-kg person, the highest dose tested in healthy 
volunteers 
To ensure sufficient drug exposure and concentration levels above the target steady-state values 
within 1 month following SC administration, an SC loading dose on Week 2 (Day 15) will be 
included.   


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Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE 
  
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5 
The emerging PK data from the SAD study using weight-adjusted dosing show that body weight 
is not an influential covariate for BIIB059 exposure.  Further, population PK simulations showed 
that both weight-adjusted dosing and fixed dosing result in comparable BIIB059 exposure.  
Fixed dose regimens, therefore, are proposed for the Phase 2 study.  The proposed doses and/or 
dosing regimen may be modified based on additional PK and PD data emerging from subjects 
with SLE (20 mg/kg IV) and healthy volunteers (multiple doses SC) in the ongoing Phase 1 
study (230LE101). 
 
5.5.2 Part B 
A single high dose of 450 mg SC Q4W and a loading dose at Week 2 will be used in Part B.  
This approach is based on PK simulations using data from the ongoing Phase 1 study with both 
SC and IV Q2W regimens, and the expectation that the 450 mg dose level will have adequate 
target coverage to suppress pDC function, including the production of type I IFN, over the 12 
weeks preceding the primary endpoint.   
The dosing regimen was selected based on the Phase 1 safety, PK, PK-BDCA2 
internalization relationship, and extrapolated inhibitory potency (concentration resulting 
in 90% inhibition of response [IC90]) of pDC IFN-α production [Pellerin 2015]. BIIB059 
fixed doses of 50, 150 and 450 mg SC Q4W, with an additional loading dose at Week 2, 
were selected for the Phase 2 study because simulations conducted, based upon the 
population PK model developed using the Phase 1 data, predicted that: 
 
At the low dose of 50 mg SC Q4W is expected to achieve plasma concentrations 
sufficient to maintain 90% BDCA2 internalization for the majority of the dosing 
interval. 
 
 
At the middle dose of 150 mg SC Q4W is expected to achieve plasma concentrations 
similar to or in excess of the calculated IC90 for IFNα for the majority of the dosing 
interval. 
 
At the top dose of 450 mg SC Q4W is expected to achieve Cmin levels similar to 3-
fold of the calculated IC90 for IFN-α inhibition.  
The selected doses are considered safe and tolerable, based upon the results of Phase 1 
study.  The dosing regimen of 450 mg SC Q4W, with an additional dose of 450 mg at Week 
2 and a bioavailability (F) of 0.45, is expected to result in cumulative exposure over 3 
months comparable to that achieved by the single dose of 20 mg/kg IV for a 65-kg person, the 
highest dose tested in healthy volunteers. 
 
Section 6, Study Objectives and Endpoints (Primary) 
Now reads: 
Primary Objective 
To evaluate the efficacy of BIIB059 in skin reducing disease activity in subjects with SLE with 
active cutaneous manifestations and joint involvement (Part A), and in subjects with active 


Protocol 230LE201, Amendment 1 
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CLE (SCLE or chronic CLE, including DLE) with or without systemic manifestations (Part B). 
and to investigate the dose-response relationship in subjects with active SLE and skin 
manifestations (Part A only) 
Primary Endpoint  
Week 12 percent change from baseline in CLASI-A score 
Part A:  
Change in active joint count (28-joint assessment) from Baseline to Week 24; the active 
joint count is defined as the sum of tender and swollen joint counts. 
Part B:  
Percent change from baseline in CLASI-A score from Baseline to Week 1216 
 
 
Section 6, Study Objectives and Endpoints (Secondary Endpoints, Skin-related, Parts A and B) 
Now reads: 
 CLASI-50 response, defined as a 50% improvement from baseline in CLASI-A score at 
Week 24 (Part A) and Weeks 12 and 16 (Part B) 
Percent change in CLASI-A score from Baseline to Weeks 16 and 24 (Part A) and Week 12 (Part 
B) 
 A ≥4-point reduction in CLASI-A score relative to baseline at Week 24 (Part A) and at 
Weeks 12 and 16 (Part B) 
 
Section 6, Study Objectives and Endpoints (Secondary Endpoints, SLE-disease activity related 
(Part A only) 
Now reads: 
 Composite endpoint of SRI-4 at Week 24 compared with baseline, with concomitant oral 
corticosteroid dosage ≤ 10 mg/day and ≤ Day 1, and stable or decreased oral corticosteroid 
dose between Weeks 12 and 24.   
Composite endpoint SRI-4 is defined as:  
 A reduction from baseline of ≥ 4 points  in SLEDAI-2K score AND 
 No new organ system affected as defined by no new BILAG-2004 A or ≤ 2B 
AND  
 No worsening from baseline in subject’s lupus disease activity defined by ≤ 
0.3 point increase in PGA(VAS) AND 
No protocol-prohibited medication/treatment 
 


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7 
 Proportion of subjects with a composite response, defined as:  
 SLE Responder Index (SRI) of ≥4 (SRI-4) at Week 24, where SRI-4 is 
defined as: 
o A reduction from baseline of ≥4 points  in Systemic Lupus Erythematosus  
Disease Activity Index 2000 (SLEDAI-2K)  and 
o No new organ system affected, as defined by no new BILAG-2004 A and 
no more than one new BILAG-2004 B and 
o No worsening from baseline in subject’s lupus disease activity defined by 
<0.3 point  increase in PGA (VAS)  
 No protocol-prohibited medication or treatment. 
 Concomitant corticosteroid dosage at Week 24 to be ≤10 mg/day 
 Concomitant corticosteroid dosage at Week 24 to be ≤Day 1 corticosteroid 
dosage 
 No increase in corticosteroid dose between Weeks 17 and 24 
 
 
Change from baseline to Week 24 in SLEDAI-2K score 
 
Proportion of subjects with no new organ system affected, as defined by no new 
BILAG-2004 A and no more than one new BILAG-2004 B from baseline to Week 24 
 
Change from baseline to Week 24 in PGA VAS score 
 
Section 7.1, Study Overview 
Now reads: 
This is a 2-part randomized, double-blind, placebo-controlled, multicenter Phase 2 trial designed 
to evaluate the efficacy and safety of BIIB059 in subjects with SLE with skin manifestations 
(Part A) or active CLE, defined as discoid or subacute subtypes, with or without SLE (Part B). 
The study will be conducted at approximately 95 centers in the United States, Europe, 
Latin/South America and Asia.  
In Part A, subjects will be randomly assigned to 1 of 4 treatment groups in a 1:1:1:1 ratio and 
receive either fixed doses of  BIIB059 (50, 150 or 450 mg) or placebo subcutaneously Q4W for 
24 weeks with a loading dose at Week 2, for a total of 7 doses (Figure 1).  Randomization will be 
stratified by baseline CLASI-A score (≤ 10, >10) and prior oral corticosteroid usage (≤ 10 mg/d, 
>10 mg/d).  Approximately 100 subjects are planned to be randomized (25 per treatment group).  
An interim analysis is planned to occur approximately 12 weeks after 75% of subjects are 
randomized.  Following review of the interim analysis data, up to 40 additional subjects in each 
group (up to a total of approximately 260 subjects) may be enrolled based on pre-defined 
decision criteria.  See Section 16.7 for details.   
In Part B, 30 subjects will be randomly assigned to 1 of 2 treatment groups in a 2:1 ratio 
(20 subjects to BIIB059, 10 subjects to placebo) and receive either a fixed dose of BIIB059 
(450 mg) or placebo SC Q4W for 12 weeks with a loading dose at Week 2, for a total of 4 doses.  


Protocol 230LE201, Amendment 1 
Amendment Summary 
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE 
  
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(Figure 2).  Randomization will be stratified by CLASI-A score (≤ 10, >10) and SLE (presence, 
absence). Individual subjects may participate in EITHER Part A or Part B.   
This is a 2-part randomized, double-blind, parallel-group, placebo-controlled, multicenter 
Phase 2 trial designed to evaluate the efficacy and safety of BIIB059 in subjects with SLE with 
active skin manifestations and joint involvement (Part A) or active CLE, defined as SCLE  or 
chronic CLE including DLE, with or without SLE (Part B). The study will be conducted at 
approximately 130 centers in the United States, Europe, Latin/South America, and Asia.  
Study treatment will begin following a 28-day Screening period. 
In Part A, subjects will be randomly assigned to 1 of 2 treatment groups in a 1:1 ratio and receive 
either BIIB059 (450 mg) or placebo subcutaneously every 4 weeks (Q4W) for 24 weeks, with 
an additional dose at Week 2, for a total of 7 doses (Figure 1). The maximum number of 
subjects in Part A is approximately 190 subjects.  Of these 190 subjects, approximately 100 
subjects will be enrolled under protocol version 2.  If the study is not stopped for futility at 
the interim analysis, then up to 70 additional subjects may be added (up to a total of 
approximately 170 subjects under protocol version 2).  Subjects enrolled under protocol 
version 1 will remain on their original treatment assignment (up to a total of approximately 
20 subjects) and not be re-consented under protocol version 2.  Randomization will be 
stratified by oral corticosteroid usage (≤10 mg vs >10 mg) and by geographic region 
(United States vs. Asia vs. Latin America and Europe). 
In Part B, approximately 130 subjects will be randomized; of these, approximately 100 
subjects will be enrolled under protocol version 2.  Subjects enrolled under protocol 
version 1 will remain on their original treatment assignment and may be re-consented 
under protocol version 2 unless they have completed the Week 12/Early Termination Visit. 
Subjects enrolled in protocol version 2 will be randomly assigned to 1 of 4 treatment groups in 
a 1:1:1:1 ratio with approximately 25 subjects per treatment arm and receive either a fixed 
dose of BIIB059 (50 mg, 150 mg, or 450 mg) or placebo SC every 4 weeks (Q4W) for 16 
weeks with an additional dose at Week 2, for a total of 5 doses (Figure 5). Randomization will 
be stratified by CLASI-A score (≤10 vs >10) and DLE (presence, absence).  
An IA for futility of Part B and possible expansion of Part A will be performed.  The IA 
will be performed after approximately 45% of Part B subjects under protocol version 2 
have completed their Week 12 Treatment Visit.  At the time of the IA, it is estimated that 
over 50% of subjects in Part A will have completed their Week 12 treatment visit.  
Following the IA, up to an additional 70 subjects may be enrolled in Part A and BIIB059 
dose may by adjusted.  The additional subjects in Part A may be enrolled based on a more 
inclusive criteria to include an expanded SLE population.  Details are provided in Section 
16.7. 
 
Section 8.1.2, Inclusion Criteria (Part A Specific) 
Now reads:   


Protocol 230LE201, Amendment 1 
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Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE 
  
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 Diagnosis of SLE fulfilling at least 4 out of 11 1997 revised ACR classification criteria 
for SLE (Appendix C), with a diagnosis made ≥24 weeks prior to signing the informed 
consent form (ICF). 
 Positive antinuclear antibody test at Screening (central laboratory titer ≥1:80) and/or 
elevated anti-double-stranded DNA (≥30 IU/mL). 
 At least one sign of active skin disease, including acute, subacute, and/or chronic 
cutaneous lupus (e.g., discoid lupus erythematosus), with skin activity defined by 
SLEDAI-2K 
 Must have at least 4 tender joints based on assessment of 28 joints as described in 
Section 4.3.3.  
 Must have at least 4 swollen joints based on assessment of 28 joints as described in 
Section 4.3.3, with at least 4 occurring in the PIP, MCP, or wrist joints.  Note:  A 
joint that is both tender and swollen will be included in both categories (counts as 1 
tender and 1 swollen).  
 To allow for accurate assessment of joint tenderness and swelling, subjects who may 
be taking NSAIDs or other analgesics including narcotics or medical marijuana 
must agree not to take a dose of these medications within 12 hours prior to the joint 
assessment visits. 
 CLASI-A ≥ 8 at Screening and Randomization.   
 SLEDAI-2K ≥ 4 at Screening and Randomization (excluding fever). 
 
Section 8.1.3, Inclusion Criteria (Part B Specific) 
Now reads: 
 Must have diagnosis of CLE that has been histologically confirmed (in the past or at 
Screening), with or without systemic LE manifestations.  The histological diagnosis 
confirmation should be documented at Screening. For subjects without historical biopsy 
data, a skin biopsy must be performed at Screening to confirm CLE diagnosis prior to 
randomization. All subjects must also have active skin manifestations that fulfill the 
following:   
- Subacute CLE with a CLASI-A erythema score of ≥2 
and/or 
- Chronic CLE, including DLE, with at least 1 active CCLE lesion with a 
minimum CLASI-A erythema score ≥2 and in addition CLASI-D scarring ≥1 
 CLASI-A ≥8 at Screening and randomization 
 Must have active CLE despite an adequate trial of conventional therapies (defined as 
either topical corticosteroids or an antimalarial agent used for at least 12 weeks prior to 
Screening) OR previously documented failure to respond to these agents when used 


Protocol 230LE201, Amendment 1 
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Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE 
  
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10 
for at least 12 weeks OR the requirement to discontinue these agents due to side 
effects or poor tolerability. 
 
Section 8.2.1, Exclusion Criteria (Parts A and B), Previous Therapies 
Now reads:  
1. Concomitant and Previous Therapies 
2. 23. 
Use of IV, intramuscular (IM), or intra-articular (Part A only) corticosteroids 
within 12 weeks prior to randomization. 
Use of high potency topical and/or intralesional corticosteroid within 1 month prior to Screening 
and during the study. 
3. 24. 
Use of high-potency topical corticosteroid and/or topical agents 
(immunosuppressant) for skin lesions within 7 days prior to randomization. 
4. 25. 
Use of high-potency intralesional corticosteroid within 4 weeks prior to 
randomization.   
5. 26. 
Part A subjects who are receiving systemic corticosteroid treatment at a dose 
exceeding 20 mg/day prednisone (or its equivalent), or if any dose of prednisone (or 
its equivalent) has not been stable for ≥4 weeks prior to randomization.   
6. 27. 
Part B subjects who are receiving systemic corticosteroid treatment at a dose 
exceeding 15 mg/day of prednisone (or its equivalent), or if any dose of prednisone 
(or its equivalent) has not been stable for ≥4 weeks prior to randomization. 
Use of thalidomide or lenalidomide within 2 months of Screening and during the study.   
7. 28. 
Use of thalidomide or lenalidomide, IV or SC immunoglobulin, or 
plasmapheresis within 12 weeks of randomization.  
 Use of cyclosporine, tacrolimus, picrolimus, sirolimus, imiquimod, IV immunoglobulin, IV and 
oral cyclophosphamide and plasmapheresis within 3 months of Screening and during the study. 
 
29. 
Use of tacrolimus, pimecrolimus, and sirolimus within 4 weeks prior to randomization. 
 
Use of abatacept, belimumab, tocilizumab or tumor necrosis factor (TNF) inhibitors within 3 
months or 5 half-lives, whichever is longer, before Screening and during the study. 
8. 30.  
Use of oral or parenteral rituximab, atacicept, ocrelizumab, or other 
B cell-directed biologic therapies within 24 weeks prior to randomization.  Subjects 
with prior B cell-directed therapies within 12 months of Screening will be excluded if 
total CD19 B cell level is <25 cells/µL as measured at Screening at the central 
laboratory.   
31 
Use of cyclophosphamide, cyclosporine, mixoribine, atacicept, abatacept, 
belimumab, tocilizumab, or tumor necrosis factor (TNF) inhibitors within 12 weeks or 5 
half-lives (whichever is longer) prior to randomization.  


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11 
9. Initiation of disease-modifying antirheumatic agents or immunosuppressive treatments 
with the exception of those listed in exclusion criteria 31, within 3 months of Screening 
and during the study.   
10. 32. 
Use of immunosuppressive or disease-modifying treatments for SLE or CLE (via 
an oral, IV, or SC route) that were initiated less than 12 weeks prior to randomization, 
have not been at a stable dose for at least 4 weeks prior to randomization, or have been 
taken during the last 12 weeks at doses above the prescribed maximum listed here 
(medication list includes, but is not limited to the following):  antimalarial 
medications (hydroxychloroquine up to 400 mg/day, quinacrine 100 mg/day maximum, 
chloroquine 250 mg/day), dapsone 150 mg/day, methotrexate 25 mg/week, azathioprine 
200 mg/day, 6-mercaptopurine 100 mg/day, and mycophenolate mofetil (MMF) 3 g/day 
or mycophenolate sodium (MPS) 2160 mg/day.  
11. 33. 
Immunizations with live or live-attenuated vaccines within 4 weeks before 
Screening and throughout the study and for 16 weeks after the last dose of study 
treatment. 
12. Allergy shots or completion of desensitization therapy within 1 month prior to Screening.   
13.  
 
Section 9.1, Screening and Registration 
Now reads: 
9.1 
Screening and Enrollment Registration 
Subjects (or their legally authorized representative [e.g., parent or legal guardian], where 
applicable) must provide informed consent before any screening tests are performed (see Section 
17.3). When a subject signs the ICF, that subject is considered to be enrolled in the study.  
Participating study sites are required to document all screened candidates initially considered for 
inclusion in this study.  If a subject is excluded from the study, the reasons for exclusion will be 
documented in the subject’s source documents and on the screening log. 
A subject with a CLASI-A score of > 4 but < 8 and otherwise not meeting any other exclusion 
criteria may be rescreened on CLASI-A alone within 3 months to determine study eligibility or 
undergo full rescreening if beyond 3 months.   
For subjects entering Part A, screening tender and swollen joint scorescounts will be 
evaluatedperformed by an independent joint assessor at each site prior to study entry. 
For subjects entering Part B, screening CLASI scores will be verified by an independent 
CLASI Adjudicator (Section 19.2.2) prior to study entry.  
Subjects will be registered at the Screening Visit; as part of study screening, potential subjects 
will have the study risks and benefits explained to them, the associated ICF reviewed with 
them, and all their questions answered.   


Protocol 230LE201, Amendment 1 
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If a subject initially fails any of the screening criteria and is deemed as a screen failure by 
the end of the initial 28-day screening period, they will be allowed to be rescreened one 
time at the discretion of the Investigator.  Upon rescreening, and in consultation with the 
Medical Monitor, subjects should repeat the Screening assessments and receive a new 
Screening Number. 
 
Section 11.1, Study Treatment Regimen 
Part A 
Subjects will be randomized in a 1:1:1:1 ratio to 1 of the following 4 treatment groups: 
 BIIB059 50 mg  
 BIIB059 150 mg  
 BIIB059 450 mg  
 Placebo  
Dose regimen:  Q4W SC, with a loading dose at Week 2, for a total of 7 doses.   
Subjects will be randomized in a 1:1 ratio to 1 of the following 2 treatment groups: 
 BIIB059 450 mg  
 Placebo  
Dose regimen:  every 4 weeks (Q4W) SC, with an additional dose at Week 2, for a total of 
7 doses.   
Part B  
Subjects will be randomized in a 1:1 ratio to 1 of the following 2 treatment groups:   
 BIIB059 450 mg  
 Placebo  
Dose regimen:  Q4W SC, with a loading dose at Week 2, for a total of 4 doses. 
 
Subjects will be randomized in a 1:1:1:1 ratio to 1 of the following 4 treatment groups: 
 BIIB059 50 mg 
 BIIB059 150 mg   
 BIIB059 450 mg  
 Placebo  
Dose regimen:  every 4 weeks SC (Q4W), with an additional dose at Week 2, for a total of 5 
doses. 
 


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Section 16.1.2.1, Analysis of the Primary Endpoint 
Now reads: 
Part A: 
The primary analysis of the primary endpoint is a test of dose-response, using the Multiple 
Comparison Procedure – Modelling (MCP-Mod) methodology[Bretz 2005]. 
Three monotonic dose-response trends will be tested using the appropriate contrasts as 
determined by the MCP-Mod methodology in an analysis of covariance (ANCOVAA Mixed 
Effect Model Repeat Measurement (MMRM) model such that the overall Type 1 error rate for 
these 3 resulting p-values is controlled at 0.10 (2-sided testing).  Additional information will be 
provided inused as the SAP. 
The ANCOVA model will have Week 12 percentprimary method to analyze change from 
baseline score in CLASI-A score as the dependent variable,active joint count using treatment 
(50 mg, 150 mg, 450 mg, and placebo),group, study visit, prior oral corticosteroid usage,  
season of enrollment and smoking status asregion, and study visit-by-treatment interaction as 
fixed effect factors and baseline SLEDAI 2K and CLASI-A scoresactive joint count as 
covariates.  
In addition, the following analyses of thecovariate.  The primary endpoint will be performed: 
Pairwisetreatment comparison of each BIIB059 treatment group versus placebo, basedwill be 
the difference between the 450 mg dose and placebo at the end of the Week 24 on the 
ANCOVA model.change from baseline in active joint count.   
SensitivityIn addition, sensitivity analysis based on the ANCOVAMMRM model, with missing 
values imputed will also be performed (imputation methods are defined in the SAP). 
Due to the impact of corticosteroid and rescue medication use on CLASI-A scoresactive joint 
count, if a subject has an increase from baseline in corticosteroid use after Week 4 (excluding 
allowed corticosteroid use as described in Section 11.4.1.1.2) or uses any SLE rescue medication 
(as described in Section 11.4.1.1.1) during the 24-week treatment period of the study, the 
subject will be a treatment failure.  The subject’s CLASI-A scoresjoint count after the increased 
corticosteroid use or after SLE rescue medication will not be included in the primary analysis. 
For subjects who are treatment failures prior to the Week 1224 assessment of CLASI-A 
scorejoint count, a lastworst observation carried forward (LOCFWOCF) method will be 
applied using the patient’s last post-baseline CLASI-A scorejoint count prior to treatment failure. 
Additional  In addition, if a subject deviates from the planned tapering schedule (Table 7), 
they might be considered as a treatment failure depending on the severity and timing of 
deviation.  Additional details will be provided in the SAP. 
Part B: 
The primary analysis of the primary endpoint isAn MMRM model will be used to analyze the 
percent change from baseline  in CLASI-A score using treatment group, study visit, study 
visit-by-treatment interaction, DLE (presence or absence), and SLE (presence or absence) 
as fixed effect factors and baseline CLASI-A scores as a covariate. 


Protocol 230LE201, Amendment 1 
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Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE 
  
CONFIDENTIAL 
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14 
The primary analysis of the primary endpoint is a test of dose-response, using the Multiple 
Comparison Procedure – Modelling (MCP-Mod) methodology [Bretz 2005]. 
Five dose-response trends will be tested using the appropriate contrasts, as determined by 
the MCP-Mod methodology, on the treatment effects obtained from the MMRM model . 
Additional information will be provided in the SAP. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The credible interval will be derived from an ANCOVA model with Week 12 percent change 
from baseline score in CLASI-A score as the dependent variable, treatment (BIIB059 450 mg, 
placebo), SLE (presence, absence), season of enrollment and smoking status as factors, and 
baseline CLASI-A score as a covariate.   
In addition, theThe following analyses of the primary endpoint will also be performed: 
 ComparisonPairwise comparison of theeach BIIB059 treatment group versus 
placebo, based on the ANCOVA model (not using the Bayesian 
methodology).MMRM model. 
 Sensitivity analysis based on the ANCOVAMMRM model, with missing values 
imputed (imputation methods defined in the SAP). 
Due to the impact of corticosteroid use on CLASI-A scores, if a subject has an increase from 
screeningScreening in corticosteroid use, the subject’s CLASI-A scores after the increased 
corticosteroid use will not be included in the primary analysis. The missing data handling 
methodology will follow the methods described for Part A.  For subjects in Part B with a 
diagnosis of SLE in addition to CLE, please refer to Section 11.4.1.1.1 Additional details will be 
provided in the SAP.  
Section 11.4.1.1.1.  Additional details will be provided in the SAP. 
 
Section 16.7, Interim Analyses 


Protocol 230LE201, Amendment 1 
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Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE 
  
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15 
Now reads: 
Part A: 
An interim analysis is planned and B: 
An IA for futility of Part B and possible expansion of Part A will be performed.  The IA will 
be performed  after approximately 12 weeks after 7545% of Part B subjects under protocol 
version 2 have been randomized.completed their Week 12 Treatment Visit.  At the time of 
the IA, it is estimated that over 50% of subjects in Part A will have completed their Week 
12 treatment visit.  Following unblinded independent analysis of the interim analysis dataset, 
Biogen may expand enrollment in Part A withthe IA, up to 4070 additional subjects per 
group.maybe enrolled in part A and BIIB059 dose may by adjusted.  At the interim analysis, 
unblinded patientsubject baseline characteristics (eg, Joint Count, SLEDAI-2K) will be 
assessed.  The randomization stratification factors will be reevaluated in the expanded 
enrollment to achieve balance between treatment groups.  The objective3 objectives for adding 
additional subjects atto Part A after the interim analysis to Part A isare to: 1) potentially 
include an expanded SLE patient population based on a more inclusive criteria,  2) 
potentially adjust the dose of BIIB059 and, 3) to provide greater precision for the Week 24 
endpoints, including the SRI-4.  The details of the interim analysis plan will be specified in the 
SAP. Unblinded tables, listings, or graphs (TLGs) will be generated by independent personnel 
(internal or external) not involved in the conduct of the study.  Unblinded TLGsThe IA will be 
performed by independent personnel (internal and/or data willexternal) not be shared with 
subjects, investigators, or the study team members directly involved in the conduct of the study, 
prior to unblinding the study for final analysis or stopping for futility. . At the discretion of 
Biogen, unblinded TLGs and/or data may be shared with sponsorSponsor personnel who are not 
directly involved in the conduct of the study. Additional information will be provided in an 
unblinding plan.  Details of the data to be used for the interim analysis and the analyses 
planned for futility and possible expansion will be provided in the SAP. 
Details on data to be used for the interim analysis and the analyses planned will be provided in 
the SAP. 
Part B: 
No interim analysis is planned.   
Section 16.8, Sample Size Considerations 
Now reads (no strikethrough text is provided):   
Part A: 
The sample size for Part A is 100 subjects, randomized in a 1:1 ratio, with 50 subjects allocated 
to each treatment group. This sample size will provide approximately 71% power to detect a 
statistically significant difference in the Week 24 absolute change from baseline active joint 
count, assuming a standard deviation of 6, a maximal difference of BIIB059 over placebo of 2.5, 
a 20% drop out rate, and a 2-sided testing at the 0.2 level significance.  Additional information 
will be provided in the Statistical Analysis Plan (SAP). If the study is not stopped for futility at 
the interim analysis (details in Section 16.7), then up to 70 additional subjects may be added to 


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Part A.  If an additional 70 subjects are added, the power will increase to approximately 87% at 
Week 24. 
Part B: 
The planned sample size for Part B is 100 subjects, randomized in a 1:1:1:1 ratio, with 25 
subjects per dosage arm of BIIB059 (50 mg, 150 mg, and 450 mg) and placebo. This sample 
size will provide approximately 90% power to detect a dose-response relationship in the 
Week 16 percent change from baseline score in CLASI-A score, assuming a standard 
deviation of 30, a maximal difference of BIIB059 over placebo of 27.5%, and a 20% drop 
out rate.  Five different dose-response relationships will be tested at the 2-sided 10% 
significance level with the MCP-Mod method being used to control for multiplicity [Bretz 
2005].   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL 
Changes to the protocol are presented chronologically.  New text is shown in bold type; deleted 
text is shown with a strikethrough. 
 
Section 3, Synopsis 
The Synopsis was revised to reflect changes made throughout the protocol. 
 
Section 4.2, Schedule of Activities,Table 1 (Part A) and Table 2 (Part B) [Skin Photography] 
Change:  The whole-body skin photography requirement was removed from Part A; instead, a 
photograph of the target lesion only will be taken at the time of tape harvesting (Weeks 0, 4, and 
16). No adjudication of the target lesion photography will be necessary in Part A.  Footnote 10 
below Table 1 provides additional details and requirements. 
In Part B, whole-body photography was replaced by photography of each part of the body with 
skin involvement where a CLASI-A and/or CLASI-D score is present (including but not limited 
to the target lesions, biopsy lesions, head, and so on).  The photographs taken at Screening will 
be evaluated by a central adjudicator to verify the CLASI-A score assignment by the Investigator 
and confirm eligibility.  Also, the number of skin photography assessments was reduced from 6 
(at Screening, baseline, and Weeks 2, 4, 8, and 12) to 4 (at Screening  and Weeks 0, 4, and 16).  
Footnote 12 below Table 2 provides additional details and requirements. 
Now reads:   
(See Table 1, Schedule of Activities Part A, and Table 2, Schedule of Activities Part B, in the 
protocol.) 
Rationale:  Skin photography is a general enrollment barrier in subjects with skin rash. In order 
to facilitate subject enrollment, the necessity of this tool was reassessed across the study. In Part 
A, whole-body photography (and the associated adjudication process) proved unnecessary due to 
the change in outcome measure for the primary endpoint (from CLASI-A to joint count). 
In Part B, the procedure was streamlined to include only affected skin areas based on CLASI-A 
and/or CLASI-D.  The frequency was also reduced to focus on the most significant timepoints. 
This change also affects Section 4.3.4, Additional Information – Skin Photography. 
 
 
Section 4.2, Schedule of Assessments, (Table 1 (Part A) and Table 2 (Part B) 
Change: The timing, frequency, and/or associated guidance for several study assessments were 
revised as follows: 
 The following footnote was added to the “Tests and Assessments” column in Table 1 and 
Table 2: “2Assessments (e.g., CPK, ECG, etc.) may be performed as required to 
confirm SLEDAI-2K and BILAG findings” (“and BILAG findings” Table 1 only).  


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 The chest X-ray was removed as a requirement for both Part A and Part B, and a footnote 
on tuberculosis testing was added to Table 1 and Table 2:  “5Testing to be performed 
locally.  Indeterminate Quantiferon or T-SPOT tests may be repeated once and will 
be considered positive if retest results are positive or indeterminate. Subjects with 
documented BCG vaccination must perform a TB test at Screening and will be 
excluded if they exhibit skin induration ≥5 mm or a positive Quantiferon or positive 
or borderline T-SPOT (Elispot) test.” For further information, see the change to 
exclusion criterion 16 (Section 8.2) below. 
 Urine Pregnancy Test:  An assessment was added at Week 2. 
 A footnote was added to the Physical Examination, Weight, and Height assessment in 
Table 1 and Table 2:  “7Height should be measured only once; i.e., at the Day 
1/baseline visit.”  
 For the Vital Signs assessment, it was clarified in footnote 8 to Table 1 and Table 2 that 
oral body temperature should be measured. 
 
 
 
 
 
 Joint count assessments were added to Table 1 at Screening and Weeks 2, 4, 8, 16, 20, 
and FU12.  See detailed explanations in this document under  Primary Reason for 
Amendment and Section 8.1.2, Inclusion Criteria (Part A Specific). 
 The timing of PK assessments was revised in Table 1 and Table 2. In Table 1, 
assessments were removed at Weeks 2, 8, 20, and FU8.  In Table 2, assessments were 
removed at Weeks 2 and 8. Also, a separate table on PK assessments (Table 3) was added 
to specify when PK assessments should be done during each visit. The frequency of 
, complement, skin RNA 
tape harvesting, 
, and blood RNA [Paxgene]) was reduced in Table 
1 and Table 2. 
 The following footnote was added to Table 1 (footnote 15) and Table 2 (footnote 17) to 
provide more guidance on performing the ESR: 
 
 
 A footnote on which vaccine-related immunoglobulin titers will be collected in Part A 
was added to Table 1: “19Vaccine-related immunoglobulin titers for tetanus, 
diphtheria, and Pneumococcus will be collected.” 
 An electronic diary review of subject-reported questionnaires was added to Table 1 and 
Table 2. 
 The timing of CLASI assessments in Part B was revised (assessments were removed at 
Week 2). Additional guidance on CLASI assessment and adjudication was provided in 
the footnote: “9CLASI will be assessed by the Investigator or a trained designee at all  


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assessments (Section 19.2.2).  CLASI scores at Screening will be verified by an 
Independent CLASI Adjudicator to confirm eligibility.” 
 
 
 
 
 
 
 
 
 
 
 The skin biopsy for confirmation of CLE diagnosis and the optional skin biopsy for 
biomarkers were separated into 2 different assessments in Table 2. 
 The vaccine status assessment was removed from Table 2. 
Rationale: The timing and guidance provided on all study assessments was re-evaluated and, in 
some cases, revised in order to align with study design changes, ease patient burden, mitigate 
enrollment barriers, and provide clearer guidance on study assessments. 
 
) 
Change:  
 
Now reads: 
Additional Objectives 
 
Additional Endpoints 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
   
 


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. 
 
Section 8.2.1, Exclusion Criteria (Tuberculosis) 
Change:  The criterion related to tuberculosis history (now exclusion criterion 16) was revised to 
exclude any subjects who tested positive for tuberculosis, including subjects who are undergoing 
current treatment.  
Now reads: 
 History of or current diagnosis of active tuberculosis (TB), or untreated latent TB 
infection (LTBI), determined by a TB skin test with purified protein derivative as 
evidenced by induration ≥5 mm or a positive Quantiferon, positive or borderline 
T-SPOT (Elispot) test performed locally, either at Screening or documented with 
results within 12 weeks of the Screening Visit.  If the subject is undergoing current 
treatment for LTBI, they must have received at least 4 continuous weeks of an 
appropriate LTBI treatment prior to Screening without evidence of re-exposure. 
Subjects who have previously completed appropriate and documented LTBI 
treatment or who are undergoing current treatment for LTBI will not be required to be 
tested. If receiving LTBI treatment at Screening, the subject will be expected to 
complete an appropriate LTBI treatment regimen to remain in the trial.  Subjects 
must have received complete LTBI treatment prior to Screening without evidence of 
re-exposure prior to entering the study. 
 Subject with current household contacts with active TB will also be excluded 
unless the subject is being treated and there is evidence that household contacts 
are being treated 
 Indeterminate Quantiferon or T-SPOT tests may be repeated once, and will be 
considered positive if retest results are positive or indeterminate. Subjects with 
documented BCG vaccination must perform a TB test at Screening and will 
be excluded if skin induration ≥5 mm or a positive Quantiferon or positive or 
borderline T-SPOT (Elispot) test.  
 
Rationale: This change was made to support the removal of the chest X-ray assessment from the 
schedule of activities for both Part A and Part B.  
Investigators have indicated that performing the chest X-ray for all subjects as a screening tool 
for tuberculosis is unnecessary since tuberculosis is infrequently seen and subjects considered the 
chest X-ray burdensome. Furthermore, chest X-rays may not be permitted in some regions due to 
local regulations. However, in order to address the risk of enrolling a subject with active 


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tuberculosis in the absence of chest X-ray verification, the tuberculosis exclusion criterion was 
revise to exclude any subjects being treated for a latent tuberculosis infection as these subjects 
were previously allowed to participate.    
This change also affects Section 4.2, Schedule of Activities, Table 1 (Part A) and Table 2 (Part 
B). 
 
Section 8.2.1, Exclusion Criteria (IV, IM, intra-articular, and high-potency topical corticosteroid 
use prior to the study) 
Change:  In the original protocol, high-potency topical steroids were not allowed within 1 month 
prior to Screening and for the duration of Part B. In the amended protocol, more specific 
prerandomization guidance has been added on when IV, IM, intra-articular, and high-potency 
topical corticosteroids are allowed. 
Now reads: 
(New exclusion criterion 23) 
23. Use of IV, intramuscular (IM), or intra-articular corticosteroids within 12 weeks 
prior to randomization. 
(Revised exclusion criterion 24) 
24. Use of high-potency topical corticosteroid and/or topical agents 
(immunosuppressant) for skin lesions within 7 days prior to randomization. 
(Revised exclusion criterion 25) 
25. Use of high-potency intralesional corticosteroid within 4 weeks prior to randomization.  
25.  
Rationale:  The revised criterion will allow greater precision and improve clarity in selecting for 
steroid use in Part B; the same rule will apply for target lesions in Part A. The criteria pertaining 
to low- and medium-potency topical steroids are unchanged in the amended protocol. 
This change also affects Section 11.4.1.1.2.1, Topical and Intralesional Corticosteroids. 
 
Section 8.2.1, Exclusion Criteria (General) 
Change:  Several exclusion criteria were modified, as follows:  
Now reads: 
26. 1. Current enrollment or a plan to enroll in any interventional clinical study in which an 
investigational treatment or approved therapy for investigational use is administered.  A 
washout period of at least 3 months or 5 half-lives (whichever is longer) is required prior 
to randomization.  Participation in observational registries is allowed. 
 


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27. 2. For subjects who previously received an investigational or approved treatment that 
blocks IFN-α, a washout period of 6 months is required prior to randomization. 
3. For subjects who previously received BIIB059 in the phase 1 study, a washout 
period of 6 months is required prior to randomization in the present study.  Subjects 
who discontinued previous BIIB059 study participation due to AEs are not eligible. 
7. Current active hepatitis C virus (HCV) infection, determined as HCV RNA above the 
limit of detection. 
8. Positive test result at Screening for hepatitis B virus (HBV; defined as positive for either 
hepatitis B surface antigen or hepatitis B core antibody). 
12. Systemic comorbidities requiring systemic corticosteroid therapy (e.g. asthma or 
inflammatory bowel disease); systemic therapy is defined as treatment given orally, rectally, 
or by any injectable route of administration.  (Comorbidities that require corticosteroid use 
administered by other routes, including inhaled, ophthalmic, otic, and intranasal, are 
allowed). 
16. Active clinically significant viral, bacterial, or fungal infection, or any major episode of 
infection requiring hospitalization or treatment with parenteral anti-infectives within 4 weeks 
of or during Screening, or completion of oral anti-infectives within 2 weeks before or during 
Screening.  Vaginal candidiasis, onychomycosis, and genital or oral herpes simplex virus 
considered by the Investigator to be sufficiently controlled will not be exclusionary.  
20. History of severe allergic or anaphylactic reactions.   
19. History of, or ongoing, malignant disease, including solid tumors and hematologic 
malignancies with the exception of basal cell carcinomas and squamous cell carcinomas and 
carcinoma in situ of the cervix that have been completely excised and considered cured >2 
years prior to Screening.  
24. Female subjects who are pregnant, currently lactating, have stopped lactating in the 
past 12 weeks, or are planning to become pregnant during the study and for 4 months after 
the last dose of study treatment. 
26. Part A subjects who are receiving systemic corticosteroid treatment at a dose 
exceeding 20 mg/day prednisone (or its equivalent), or if any dose of prednisone (or its 
equivalent) has not been stable for ≥4 weeks prior to randomization.   
27. Part B subjects who are receiving systemic corticosteroid treatment at a dose 
exceeding 15 mg/day of prednisone (or its equivalent), or if any dose of prednisone (or 
its equivalent) has not been stable for ≥4 weeks prior to randomization.   
28. 37. Any abnormal laboratory test result at Screening that is considered clinically 
significant and unrelated to the underlying disease (SLE/CLE), as determined by the 
Investigator and would preclude the subject from participating in the study. Clinical 
laboratory tests may be repeated one time, at the discretion of the Investigator, if there 
are questionable results, or if abnormalities are felt to be due to inherent variability of 
the test procedure. A nonclinically significant out-of-range laboratory value would not be 
considered exclusionary. 


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8.2.2 Exclusion Criteria (Part A Specific)  
1. For subjects who have initiated systemic corticosteroids, a dose of prednisone exceeding 
20 mg/day (or its equivalent) or if the dose has not been stable for ≥ 1 month prior to  
Randomization.  (replaced with criterion 26 above) 
8.2.3 Exclusion Criteria (Part B Specific) 
1. For subjects who have initiated systemic corticosteroids, a dose of prednisone exceeding 
15 mg/day (or its equivalent) or if the dose has not been stable for ≥ 1 month prior to  
Randomization. (replaced with criterion 27 above) 
29.  
Rationale:  The study exclusion criteria were generally simplified to increase study enrollment 
and, in some cases, made more stringent to ensure a more controlled analysis population.  
 
Section 9.1, Screening and Registration 
Change: The title of Section 9.1 was changed from “Screening and Enrollment” to “Screening 
and Registration” to better reflect the content of the section. (Information about randomization 
was placed in a new section, Section 9.2, Randomization of Subjects.)   Text was added to 
describe the role of the independent joint assessor (Part A) and the independent CLASI 
Adjudicator (Part B) at Screening.  A description of rescreening criteria was added.  
Now reads: 
Subjects (or their legally authorized representative [e.g., parent or legal guardian], where 
applicable) must provide informed consent before any screening tests are performed (see 
Section 17.3).  When a subject signs the ICF, that subject is considered to be enrolled in the 
study.  Participating study sites are required to document all screened candidates initially 
considered for inclusion in this study.  If a subject is excluded from the study, the reasons for 
exclusion will be documented in the subject’s source documents and on the screening log. 
For subjects entering Part A, screening tender and swollen joint counts will be performed 
by an independent joint assessor at each site prior to study entry.     
For subjects entering Part B, screening CLASI scores will be verified by an independent 
CLASI Adjudicator (Section 19.2.2) prior to study entry.   
Subjects will be registered at the Screening Visit; as part of study screening, potential subjects 
will have the study risks and benefits explained to them, the associated ICF reviewed with 
them, and all their questions answered. 
If a subject initially fails any of the screening criteria and is deemed as a screen failure by 
the end of the initial 28-day screening period, they will be allowed to be rescreened one 
time at the discretion of the Investigator. Upon rescreening, and in consultation with the 
Medical Monitor, subjects should repeat the screening assessments and receive a new 
Screening Number. 


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Rationale:  The revision provides information about the roles of independent central review of 
key tests for eligibility.  The revision also provides clarification of the circumstance under which 
a subject can be rescreened for study entry.  
 
Section 9.3, Blinding Procedures 
Change:  Text to clarify study unblinding was added.  
Now reads: 
 
  Efforts will be made to ensure that no members of the team involved in study conduct 
will be unblinded.  Unblinding is permitted only in the case of a medical emergency or 
serious medical condition, when knowledge of the study treatment is essential for the 
immediate clinical management or welfare of the study subject, as judged by the 
Investigator.  Details of unblinding will be provided in the Study Reference Manual. 
A team of Biogen personnel, independent of the study team, will be set up to conduct the 
unblinded interim analyses as discussed in Section 16.7. 
Rationale:  The revision provides further information about study unblinding directly in the 
protocol instead of a separate unblinding plan, as indicated in the original protocol.  
 
Section 10.1, Discontinuation of Study Treatment 
Change:  More detailed guidance on early study termination was added.  
 
Now reads:   
Subjects who discontinue treatment are allowed to remain in the study and will be encouraged 
to continue protocol-required tests and assessments during the follow-up visits (Week 4, 8, and 
12 Follow-Up Visits).  In the event that a subject withdraws from the study prematurely, at 
minimum, an Early Termination visit should be performed as soon as possible, to be 
followed by follow-up visits at 4, 8, and 12 weeks after last visit; all Early Termination 
assessments listed in the study schedule should be performed at this Early Termination 
visit. 
Rationale:  The revision provides further information about early termination, including the 
desired visit window and guidance on assessments to be performed at study end.  
 
Section 11.2, Study Treatment Precautions 
Change:  In the original protocol, there was no specific guidance on monitoring subjects 
immediately after study treatment administration. In the amended protocol, subjects will be 
asked to remain at the study center for 1 hour after study treatment administration for 
observation.  A description of the process for handling missed doses of study treatment was also 


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added to this section, and the section title was changed from “Modification of Dose and/or 
Treatment” to “Study Treatment Precautions.” 
Now reads: 
Following administration of study treatment, subjects should remain at the study center for 
1 hour to monitor for the development of potential allergic or anaphylactic reactions.   
Epinephrine for subcutaneous injection, diphenhydramine (or equivalent) for IV injection, and 
any other medications and resuscitation equipment for the emergency management of 
anaphylactic reactions must be available in the room where the infusion is being performed. 
BIIB059 or placebo should be administered within the stated window of the scheduled visit 
(+/ 2 or 3 days; see Table 2 and Table 3).  If a subject misses a planned dose (i.e., outside of 
the 2 or 3 day window), the missed dose should be administered as soon as possible, and no 
later than 5 days after the last day of the planned window.  If the Week 2 dose (the second 
dose to be administered in the study) can't be given within the planned window, the missed 
dose should be skipped and the subject should receive the next scheduled dose as per 
protocol.  
Rationale:  This change was made because BIIB059 is a monoclonal antibody and, as with all 
monoclonal antibodies, has the potential to be immunogenic and trigger an allergic reaction. 
Therefore, a period of observation after administration is appropriate. If a severe allergic reaction 
occurs, the study treatment must be discontinued immediately and the subject must 
be immediately treated appropriately.  Most severe acute allergic or anaphylactic reactions 
happen within 60 minutes after administration; therefore, observation for this time period is in 
the interest of subject safety. 
This change also affects Sections 4.2, Schedule of Activities (Parts A and B); 7.2.2, Overall 
Study Duration and Follow-up (Part A) – Treatment; 7.3.2, Overall Study Duration and Follow-
up (Part B) – Treatment; and 12, Study Treatment Management. 
 
The detailed description of the process for handling missed doses of study treatment was added 
to improve clarity on this issue and to help ensure safety; i.e., so subjects do not receive study 
treatment dosing <2 weeks apart. 
 
Section 11.4.1.1.2.2, Part A Specific Instructions – Oral Corticosteroids 
Change:  In the original version of the protocol, a prescribed corticosteroid tapering regimen 
was recommended for all subjects in Part A after 4 weeks of study treatment.  The tapering 
schedule allowed 1 rescue either during the first 4 weeks OR between Weeks 13 and 16. Subjects 
who could not fulfill the tapering scheme, based on Investigator judgment, could remain in the 
study and receive immunosuppressive treatment as required.  
In the amended protocol, the corticosteroid tapering regimen will be mandatory for all subjects in 
Part A. The prescribed tapering regimen has also been revised and is now more aggressive. 
During the tapering schedule, rescue oral corticosteroid dosing is allowed up to 2 times for any 
one subject at specified periods; i.e., during the first 4 weeks of treatment, between Weeks 5 and 


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7 (inclusive), and between Weeks 9 and 11 (inclusive). Subjects are allowed to revert to the 
previous dose level once and for only 1 week. Subjects who cannot fulfill the tapering scheme 
will be considered treatment failures and will be allowed to receive standard of care treatment. 
Subjects who are treatment failures will be allowed to continue to receive the investigational 
product and to complete the study, at the discretion of the Investigator. 
Now reads: 
 
Eligible subjects will have active SLE with joint and skin manifestations at Screening and 
randomization.  Subjects may be treated with SLE background SoC therapies as per 
exclusion criterion #31, and if taking corticosteroids, must have been on stable dosage for 
at least 4 weeks prior to randomization.  Subjects who are not receiving corticosteroids at 
Screening or baseline are permitted to participate in the study. 
Doses of corticosteroid must remain stable during Screening and during the first 4 weeks after 
the first dose of study treatment (i.e. until Day 28).  The tapering schedule should begin 
4 weeks (Week 5; Days 29 to 35) after the first dose of study treatment. The tapering regimen 
is intended to reduce the daily dose of prednisone (or equivalent) to 10 mg/day or lower by 
Week 12 (Day 85) of the study as outlined in Table 1.  
If a subject deviates from the planned tapering schedule (Table 7), they might be 
considered a treatment failure (See Section 16.1.2.1).  Subjects are allowed to continue to 
receive the investigational product (IP) and to complete the study, at the discretion of the 
Investigator.   
Subjects achieving the Week 12 dose of 10 mg of prednisone (or equivalent) or lower may 
remain on this dose or continue to taper between Week 13 and Week 16 at the discretion of the 
Investigator.  The dose of prednisone (or equivalent) will remain stable (at the Week 16 
dose) between Week 17 and Week 24. 
 
Screening:  
Subjects who are receiving corticosteroids must receive a stable dose throughout the 
Screening period; no initiation, increase, or decrease of corticosteroid dose is permitted. 
The maximum daily dose of corticosteroid allowed is 20 mg prednisone (or equivalent). 
Treatment period: 
Oral corticosteroid dose tapering (as described in Table 1 ) is mandatory within the rules for 
dose changes outlined below.  
Briefly, oral corticosteroids dosing guidelines are as follow:  
 Stable corticosteroid dose from Day 1 to Week 4 (Day 1 to Day 28),  
 Decrease in corticosteroid dose from baseline between Week 5 and Week 11 
(Days 29 to 78), 
 Stable corticosteroid dose at Week 12 (Days 79 to 85) 


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 Stable Week 12 corticosteroid dose or decrease by 2.5 mg between Week 13 and 
Week 16 (Day 86 to 113),  
 Stable corticosteroid dose (at a minimum of Week 12 dose) between Week 17 and 
Week 24 (Days 114 to 169) 
 
Between Day 1 to Week 4 the corticosteroid dose can be increased to a maximum of 
10 mg/day above Day 1 dosage, but must return to Day 1 level within 7 days (Rescue 1).  
Between Week 5 and Week 7 (Rescue 2), OR between Week 9 and Week 11 (Rescue 3), the 
corticosteroid dose can be increased to the previous dosage level for up to 1 week before 
resuming the tapering schedule.  Only two rescues out of the three described above are 
allowed, at the discretion of the Investigator. 
Overall, TWO corticosteroid rescues are allowed:    
 Rescue 1 and Rescue 2; OR  
 Rescue 1 and Rescue 3; OR  
 Rescue 2 and Rescue 3. 
 
Any other increase in corticosteroid dose may be considered a treatment failure and/or 
protocol deviation (depending on the timing or severity of the deviation) for the analysis 
(see Section 0).  Subjects who cannot fulfill the corticosteroid tapering schedule should still 
complete the study and remain on IP.  Corticosteroid dose should be recorded in the subject 
diary (Section 11.4.1.1.2.4). 
Day 1 to Week 4: 
Stable dosage at Day 1 dose level, 1 oral corticosteroid rescue (Rescue 1) for SLE activity is 
allowed up to a dose no higher than 10 mg above the baseline level (maximum of 30 mg/day), 
but the dose must return to baseline (Day 1) level within 7 days. A dose increase is strongly 
recommended to be avoided within 1 week of a planned study visit. 
Week 5 to Week 7: 
Decrease as per the tapering schedule.  One oral corticosteroid rescue (Rescue 2) for SLE 
activity is allowed up to a dose no higher than the previous dosage level, but the dose must be 
returned to the last oral corticosteroid dosage prior to rescue level within 7 days.  A dose 
increase is not permitted within 1 week of a planned study visit. 
Week 8: 
Decrease as per tapering schedule.  No increases are allowed. 
Week 9 to Week 11: 
Decrease as per tapering schedule. One oral corticosteroid rescue (Rescue 3) for SLE activity is 
allowed up to a dose no higher than the previous dosage level, but the dose must be returned 


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to last oral corticosteroid dosage prior to rescue level within 7 days.  A dose increase not 
permitted within 1 week of a planned study visit. 
Week 12: 
No increase or decrease allowed. 
Week 13 to Week 16: 
Stable dosage or decrease as per the tapering schedule (no increase is allowed).  The 
corticosteroid dose must always be ≤Week 12 dose. 
Week 17 to Week 24: 
Stable dosage at Week 16 dosage, no increases or decreases are allowed. 
 
Table 1: 
Oral Corticosteroid Tapering Schedule 
Table 2: 
Suggested corticosteroidOral Corticosteroid Tapering Schedule  
Allowable 
OCS Rescue 
Dosing1 
Timing by 
Weeks 
(Days) 
CorticosteroidOCS Starting Dose Prior to Tapering (mg/day) 
20 mg 
17.5 mg 
15 mg 
12.5 mg 
10 mg 
7.5 mg 
5 mg 
2.5 - < to <5 
mg 
Rescue 1 
Week 1-42   
(Day 1 to 
28) 
Stable 
1 OCS rescue for SLE activity allowed up to maximum 10mg/day above Day 1 dosage, but 
must return to Day 1 level within 7 days 
Rescue 2 
Week 53 
(Day 29 to 
35) 
17.5 
15 
12.5 
10 
7.5 
7.5 
5 or 2.5 
2.5 - < to <5 
Week 63 
(Day 36 to 
43) 
17.5 
15 
12.5 
10 
7.5 
7.5 
5 or 2.5 
2.5 - < to <5 
Week 73 
(Day 44 to 
50) 
15 
12.5 
1012.5 
10 or 
7.5 
7.5 
7.5 or 5 
5 or 2.5 
2.5 - < 5 
Week 8 
(Days 51 to 
57) 
12.515 
12.5 
10 
10 or 
7.5 
7.5 
7.5 or 5 
5 or 2.5 
0 or 2.5 - < 
5 
Rescue 3 
Week 93 
(Days 58 to 
64) 
12.5 
10 
10 or 7.5 
7.5 
7.5 or 
5 
72.5 or 
5* 
5 or 2.5 
0 orto 2.5< 
5 
Week 103 
(Days 65 to 
71) 
12.5 
10 
10 
7.5 
5 
2.5 
2.5 
0 to 2.5 


Protocol 230LE201, Amendment 1 
Amendment Summary 
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE 
  
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
29 
Allowable 
OCS Rescue 
Dosing1 
Timing by 
Weeks 
(Days) 
CorticosteroidOCS Starting Dose Prior to Tapering (mg/day) 
20 mg 
17.5 mg 
15 mg 
12.5 mg 
10 mg 
7.5 mg 
5 mg 
2.5 - < to <5 
mg 
Week 113 
(Days 72 to 
78) 
10 
10 or 7.5 
7.5 or 5 
7.5 or 
5 
72.5 or 
to <5 
5 or 2.5 
2.5 
0 orto 2.5 - 
< 5 
Week 11-12 
(Days 79 to 
85) 
Stable 
at 
Week 
10 
dose10 
7.5 
7.5 
5 
2.5 to 
<5 
2.5 
2.5 
0 to 2.5 
Week 13-16 
(Days 86 to 
113) 
Stable or Decrease by 2.5 mg as tolerated.   
1 OCS rescue for SLE activity allowed up to Day 1 corticosteroid at Week 12 dose 
(maximum 20 mg/day), however must be returned to week 12 level within 7 days.or 
decrease 
Week 17-24 
(Days 114 
to 169) 
Stable at Week 16 dose 
Abbreviations:  OCS = oral corticosteroids; SLE = systemic lupus erythematosus. 
1 Two rescues are allowed out of the three described.  
2 Between Week 1 and 4 (Rescue 1).  Once a dose is reduced  it can be maintained stable but must not be re-increased, with 
the exception of the 1 time rescue. 
3Between Week 5 and Week 7 (Rescue 2) and between Week 1 and 49 and 11(Rescue 3), the dose can be increased to the 
previous dose level for up to 1 week before restarting the tapering schedule. 
2One oral corticosteroid rescue for SLE activity allowed up to a dose no higher than baseline level, but must be 
returned to last OCS dosage prior to rescue level within 7 days 
  
Rationale:  A lower therapeutic level of corticosteroid (or complete washout) will lower the 
responder rate in the placebo group.  
This change also affects Sections 6, Study Objectives and Endpoints; 11.4.1.1.1.1, Background 
Therapy for Lupus - Systemic Lupus Erythematosus; 11.4.1.3, Rescue Medication Usage 
Guidelines During the Treatment Period; and 11.4.1.4, Rescue Medication Usage Guidelines 
During the Safety Follow-up Period. 
 
Section 19.2.2, CLASI Assessment and Adjudication 
Change:  Reference to the BILAG Assessment and Adjudication Committee was removed. 
Reference to the CLASI Assessment Adjudicator was added. 
Now reads:   


Protocol 230LE201, Amendment 1 
Amendment Summary 
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE 
  
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
30 
BILAG Assessment and Adjudication Committee 
Variability of BILAG data due to reporting issues will be monitored with  an ongoing  review of 
the data. 
An independent BILAG Assessment and Adjudication Committee may be convened to confirm 
the individual attribution of BILAG scoring.  The Adjudication Committee will review the 
assessments reported by the Investigators to determine if the assessments meet BILAG criteria. 
Information reviewed may include laboratory, pathology and/or imaging data (e.g., 
photographic), physical descriptions, and any other data deemed relevant. The committee will be 
masked to assigned study treatment to ensure the unbiased assessment of clinical outcome. A 
charter for the establishment and operation of the independent BILAG Assessment and 
Adjudication Committee will be provided. 
For Part B of the study, an independent CLASI Assessment Adjudicator will confirm 
CLASI scoring at Screening for the purpose of study eligibility.  The Adjudicator will 
review the photograph to determine if they meet CLASI criteria.  
A charter for the establishment and operation of the CLASI assessment adjudication 
process will be provided by Biogen. 
Rationale:  No BILAG Assessment and Adjudication Committee is planned for this study.  
 


Protocol 230LE201, Amendment 1 
Amendment Summary 
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE 
  
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
31 
SUMMARY OF MINOR CHANGES TO THE PROTOCOL 
 
The following minor changes were made to the protocol:    
 The version number and date were updated throughout the protocol. 
 Section 2, List of Abbreviations, was updated. 
 Text was modified throughout the protocol to further clarify guidance and instructions. 
Typographical errors and formatting were corrected. 
 The definition of washout periods for allowed medications was changed from number of 
months to “half-lives,” where appropriate. 
 Throughout the protocol, the units for maximum dose of allowed medications was 
changed from mg/kg/day to a fixed dose/day.   
 Section 11.4.1.1, Allowed Concomitant Therapy:  A statement was added to define the 
term “stable” as applies to corticosteroid dosing.     
 Section 11.4.1.1.1.1, Systemic Lupus Erythematosus:  The routes of administration (IV, 
SC, or oral) were specified for the standard of care (SoC) therapy that subjects with SLE 
can receive during the trial.  Also, dapsone (up to 150 mg/day) was added to the list of 
allowed SoC medications.  
 Section 11.4.1.1.2.3, Part B Specific Instructions – Oral Corticosteroids:  An explicit 
statement was added to state that no corticosteroid tapering schedule was required for 
subjects in Part B and that no increase beyond 15 mg/day was permitted. 
 Section 11.4.1.1.3.1, Nonsteroidal Anti-Inflammatory Treatments (NSAIDs): Ibuprofen 
and naproxen were added to the list of examples of NSAIDs; the original protocol listed 
only aspirin as an example.  
 Section 11.4.1.1.3.2, Acetaminophen:  The maximum allowed dose of acetaminophen or 
pain medications with acetaminophen was specified to be 3 g/day. 
 Section 11.4.2, Concomitant Procedures: In the original protocol, allergy desensitization 
treatment was not permitted in the study. In the amended protocol, subjects are allowed to 
participate in allergy desensitization treatment if they have been previously stabilized on 
the therapy prior to screening. Also, the amended protocol contains additional guidance 
regarding which details about concomitant treatment or procedures must be recorded in 
the electronic CRF.  
Section 14, Safety Assessments:  Text was added to clarify that oral body temperature should be 
measured for vital signs. Creatine phosphokinase was added as a blood chemistry laboratory 
safety assessment.  
Section 15.5, Contraception Requirements:  The contraception requirements were changed from 
“effective” in the original protocol to “highly effective” in the amended protocol.  


Protocol 230LE201, Amendment 1 
Amendment Summary 
Phase 2 Study to Evaluate BIIB059 in CLE with or without SLE 
  
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
32 
Section 19.1.3, Electronic Data Capture:  It was specified that all subject-reported outcomes will 
be captured in an electronic diary, with the exception of the corticosteroid diary, which will be a 
paper diary. 
Appendix A. 1) Descriptions of Efficacy Instruments –Systemic Lupus Erythematosus Disease 
Activity Index -2000 (SLEDAI-2K):  The first sentence under this heading was deleted as it was 
not necessary as a description of the measure in this Appendix.  2) 
 
:  A typographical error in the order of items in the self-rating scale was 
corrected.   
Appendix B, Topical Corticosteroids Not Permitted During the Study:  This new appendix 
contains a table which provides a list of corticosteroids that are not permitted. 
Appendix C, American College of Rheumatology Revised Criteria for Classification of Systemic 
Lupus Erythematosus:  This new appendix contains a table which provides the 1982 ACR 
revised criteria for classification of SLE. 
 
 

SAP_001.pdf: 
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 1 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
230LE201 / NCT02847598
STATISTICAL ANALYSIS PLAN 
 




 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.  
 2 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
 
STATISTICAL ANALYSIS PLAN 
 
Product Studied: BIIB059 
Protocol Number(s): 230LE201 
 
 
A 2-Part Phase 2 Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy 
and Safety of BIIB059 in Subjects with Systemic Lupus Erythematosus and Active Skin 
Manifestations and in Subjects with Active Cutaneous Lupus Erythematosus with or without 
Systemic Manifestations 
Date of Protocol: 15 March 2019 
SAP Version: 2.0 
Date of Statistical Analysis Plan: 23 October 2019 
Written By: 
 
 
 
 
<Program Statistician: 
, PhD > 
 
Date 
 
 
 
 
 
 
 
 
 
<SMT Statistician: 
, PhD > 
 
Date 
 
 
 
 
Approved By: 
 
 
 
 
<Program Statistician: 
, PhD > 
 
Date 
 
 
 
 
 
 
 
 
 
<SMT Physician, 
, MD> 
 
Date 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
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 3 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
 
TABLE OF CONTENTS 
 
2 
LIST OF ABBREVIATIONS .................................................................................................... 7 
1. STUDY OBJECTIVES AND ENDPOINTS .................................................................... 11 
1.1. 
Primary Objective and Endpoint .......................................................................... 11 
1.2. 
Secondary Objectives and Endpoints ................................................................... 11 
1.3. 
Additional Objectives and Endpoints ................................................................... 12 
2. STUDY DESIGN .............................................................................................................. 18 
2.1. 
Study Overview .................................................................................................... 18 
2.1.1. 
Protocol changes ............................................................................................................ 18 
2.1.2. 
Subject recruitment and treatment .................................................................................. 22 
3. STATISTICAL ANALYSIS ............................................................................................. 23 
3.1. 
General Considerations ........................................................................................ 23 
3.2. 
Changes to Protocol Planned Analyses ................................................................ 25 
3.3. 
Changes made in the Statistical Analysis Plan ..................................................... 27 
4. ANALYSIS 
POPULATIONS, 
STRATIFICATION 
FACTORS 
AND 
VISIT 
DEFINITIONS .................................................................................................................. 29 
4.1. 
Definitions of Analysis Populations for Part A and Part B .................................. 29 
4.2. 
Stratification Factors ............................................................................................ 32 
4.3. 
Visit/Analysis Week Definitions .......................................................................... 33 
5. STUDY SUBJECTS .......................................................................................................... 36 
5.1. 
General Consideration .......................................................................................... 36 
5.2. 
Subject Disposition............................................................................................... 36 
5.3. 
Demography and Baseline Disease Characteristics – Part A and B ..................... 36 
5.4. 
Prior Medications ................................................................................................. 40 
5.5. 
Concomitant Therapies ......................................................................................... 41 
5.6. 
Treatment Exposure and Compliance .................................................................. 42 
5.7. 
Protocol Deviations .............................................................................................. 43 
5.8. 
Treatment Failure ................................................................................................. 43 
6. EFFICACY ANALYSES .................................................................................................. 44 


 
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 4 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
6.1. 
General Considerations ........................................................................................ 44 
6.1.1. 
Part A Efficacy Analyses Considerations ....................................................................... 45 
6.1.2. 
Part B Efficacy Analyses Considerations ....................................................................... 46 
6.2. 
Analysis of Primary Endpoint .............................................................................. 48 
6.2.1. 
Primary Analysis ............................................................................................................ 48 
6.2.2. 
Sensitivity Analysis ........................................................................................................ 51 
6.3. 
Analysis of Secondary Efficacy Endpoints .......................................................... 51 
6.3.1. 
CLASI-50 Response (Yes/No) ....................................................................................... 51 
6.3.2. 
A 4-Point Reduction in CLASI-A Response (yes/no) at Week 24 (Part A) and Weeks 12 
and 16 (Part B) 
52 
6.3.3. 
A 7 Point Reduction in CLASI-A Response (yes/no) at Week 24 (Part A) and Weeks 12 
and 16 (Part B) 
52 
6.3.4. 
Percent Change in CLASI-A Score from Baseline at Week 12, 16 and 24 (Part A) and 
Week 12 (Part B) 
53 
6.3.5. 
Proportion of Subjects with an SLE Responder Index (SRI) Response of ≥4 at Week 24 
(Part A Only) 
53 
6.3.6. 
Change from Baseline to Week 24 in SLEDAI-2K Score (Part A Only) ....................... 54 
6.3.7. 
Proportion of Subjects with No New BILAG-2004 A and no More than One New 
BILAG-2004 B at Week 24 (Part A Only) .......................................................................................... 54 
6.3.8. 
Change from Baseline to Week 24 in PGA of SLE (VAS) Score (Part A Only) ........... 54 
 
 54 
6.5. 
Multiplicity Adjustment ....................................................................................... 62 
6.6. 
Handling of Missing Data .................................................................................... 62 
6.6.1. 
Continuous Endpoints .................................................................................................... 63 
6.6.2. 
Binary Endpoints ............................................................................................................ 65 
6.6.3. 
Missing Data in Subcomponents .................................................................................... 65 
6.7. 
Per-Protocol Analyses .......................................................................................... 66 
 
 67 
 
 69 
6.10. 
Additional Analysis .............................................................................................. 69 
7. SAFETY ANALYSES ...................................................................................................... 71 
7.1. 
General Considerations ........................................................................................ 71 
7.2. 
Analysis of Adverse Events (AEs) ....................................................................... 71 


 
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 5 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
7.3. 
Analysis of Laboratory Tests ............................................................................... 73 
7.3.1. 
Shift Analysis for Lab Tests ........................................................................................... 73 
7.3.2. 
Analysis of Change from Baseline and Actual Values ................................................... 73 
7.3.3. 
Analysis of Potentially Clinically Significant Abnormalities ......................................... 73 
7.4. 
Vital Signs ............................................................................................................ 76 
7.5. 
ECG ...................................................................................................................... 76 
7.6. 
Physical Examination ........................................................................................... 76 
8. PK ANALYSES ................................................................................................................ 77 
9. OTHER ANALYSES ........................................................................................................ 77 
9.1. 
Immunogenicity Data ........................................................................................... 78 
10. INTERIM ANALYSES .................................................................................................... 80 
10.1. 
Interim Analysis 1 (IA1): Futility......................................................................... 80 
10.2. 
Interim Analysis 2 (IA2): End of Treatment Periods ........................................... 81 
11. SAMPLE SIZE JUSTIFICATION .................................................................................... 81 
12. REFERENCES .................................................................................................................. 83 
APPENDICES ......................................................................................................................... 85 
 
 
85 
 
88 
Appendix B: Summary of Additional Interim Analyses ........................................................ 92 
Appendix C Efficacy Instruments .......................................................................................... 95 
C.1 Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) .............................. 95 
C.2 Systemic Lupus Erythematosus Disease Activity Index -2000 (SLEDAI-2K) ............................. 95 
C.3 British Isles Lupus Activity Group - 2004 .................................................................................... 96 
C.4 Tender and Swollen Joint Counts .................................................................................................. 98 
C.5 Physician Global Assessment of SLE (VAS) ................................................................................ 98 
 
 
98 
 99 
 99 
 
101 


 
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 6 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
 101 
 102 
 
 103 
Appendix D MCP-MOD candidate models ......................................................................... 105 
Appendix E Oral Corticosteroid Tapering Schedule ............................................................ 106 


 
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 7 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
List of Abbreviations  
ACLE  
Acute cutaneous lupus erythematosus  
ACR  
American College of Rheumatology  
AE  
Adverse event  
AIC 
Akaike information criterion 
ALT 
Alanine aminotransferase 
ANA 
Antinuclear antigen 
ANCOVA  
Analysis of covariance  
AST 
Aspartate aminotransferase 
AUC  
Area under the concentration-time curve  
BDCA2  
Blood dendritic cell antigen-2  
BICLA 
BILAG-2004 based Composite Lupus Assessment 
BILAG  
British Isles Lupus Activity Group  
BLQ 
Below the level of quantification 
BOCF 
Baseline observation carried forward 
CCLE  
Chronic cutaneous lupus erythematosus  
CI 
Confidence interval 
CL  
Clearance  
CLASI  
Cutaneous Lupus Erythematosus Disease Area and Severity Index  
CLASI-A  
CLASI–Activity  
  
  
CLE  
Cutaneous lupus erythematosus  
Cmax  
Maximum observed concentration  
Cmin  
Minimum observed concentration  
CPK  
Creatine phosphokinase  
CRO  
Contract research organization  
CRP 
C-reactive protein 
CSR 
Clinical study report 
DHA  
Directions for Handling and Administration  
DLE  
Discoid lupus erythematosus  


 
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 8 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
dsDNA 
double-stranded DNA 
ECG  
Electrocardiogram  
eCRF  
Electronic case report form  
ESR 
Erythrocyte sedimentation rate 
ET  
Early termination  
FU 
Follow-up visit 
GCP  
Good Clinical Practice  
HBV  
Hepatitis B virus  
HCV  
Hepatitis C virus  
  
  
IA  
Interim analysis  
IC90  
Concentration resulting in 90% inhibition of response  
ICF  
Informed consent form  
ICH  
International Council for Harmonization  
IFN  
Interferon  
IFN-α  
Interferon-alpha  
IgG1  
Immunoglobulin, class G, type 1  
IHC  
Immunohistochemistry  
IRT  
Interactive response technology  
IM  
Intramuscular  
IP  
Investigational product  
ITT  
Intent-to-treat  
IV  
Intravenous  
LE  
Lupus erythematosus  
LOCF 
Last observation carried forward 
LS 
Least squares 
LTBI  
Latent tuberculosis infection  
  
  
MAD 
Multiple ascending dose 
MAR 
Missing at random 
MCMC 
Markov chain Monte Carlo 


 
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 9 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
MCP  
Metacarpophalangeal  
MCP-Mod  
Multiple comparison procedure - modelling  
  
  
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
MITT 
Modified intent-to-treat population 
MMF  
Mycophenolate mofetil  
MMRM  
Mixed effect model repeat measurement  
MNAR 
Missing not at random 
MPS  
Mycophenolate sodium  
mRNA  
Messenger RNA  
NRI 
Non-responder imputation 
  
  
NSAID  
Nonsteroidal anti-inflammatory drug  
PCS  
Physical component summary  
PD  
Pharmacodynamic  
pDC  
Plasmacytoid dendritic cell  
PGA  
Physician’s global assessment  
  
  
PIP  
Proximal interphalangeal  
PK  
Pharmacokinetics  
PP  
Per-protocol  
PV1 
Protocol version 1 
PV2 
Protocol version 2 
OCS 
Oral corticosteroid 
Q2W  
Every 2 weeks  
Q4W  
Every 4 weeks  
RNA  
Ribonucleic acid  
PIP 
Proximal interphalangeal joints 
PT 
Preferred term 
PV 
Protocol version 


 
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 10 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
Q1 
First quartile 
Q3 
Third quartile 
RBC 
Red blood cell 
SAE  
Serious adverse event  
SAP  
Statistical analysis plan  
SC  
Subcutaneous  
SCLE  
Subacute cutaneous lupus erythematosus  
SD 
Standard deviation 
SELENA  
Safety of Estrogen in Lupus: National Assessment  
  
  
SLE  
Systemic lupus erythematosus  
SLEDAI-2K  
Systemic Lupus Erythematosus Disease Activity Index 2000  
SoC  
Standard of care  
SOC 
System organ class 
SRI  
Systemic Lupus Erythematosus Responder Index  
SRI-4  
Systemic Lupus Erythematosus Responder Index Response of ≥4  
SUSAR  
Suspected unexpected serious adverse reaction  
t1/2  
Elimination half-life  
TB  
Tuberculosis  
TD 
Treatment day 
TLG  
Tables, listings and graphs  
TLR  
Toll-like receptor  
TP 
Treatment period 
USA 
United States of America 
VAS  
Visual analog scale  
Vd 
Volume of distribution 
WHO 
World Health Organization 
WK 
Week 
 
 
 


 
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 11 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
1. STUDY OBJECTIVES AND ENDPOINTS 
1.1. Primary Objective and Endpoint 
    Primary Objective 
• To evaluate the efficacy of BIIB059 in reducing disease activity in SLE subjects with 
active skin manifestations and joint involvement (Part A), and in subjects with active 
CLE (subacute CLE [SCLE] or chronic CLE [CCLE], including discoid lupus 
erythematosus [DLE]) with or without systemic manifestations (Part B).  
 
  Primary Endpoints 
• Part A: Change in active joint count (28-joint assessment) from baseline to Week 24. 
The active joint count is defined as the sum of the tender joint count and the swollen 
joint count.  
• Part B: Percent change in Cutaneous Lupus Erythematosus Disease Area and Severity 
Index-Activity (CLASI-A) score from baseline to Week 16.  
 
1.2. Secondary Objectives and Endpoints 
     Secondary Objective 
• To evaluate additional efficacy parameters of BIIB059 in reducing SLE/CLE disease 
activity  
• To evaluate the safety and tolerability of BIIB059   
• To evaluate the pharmacokinetic (PK) of BIIB059 
 
    Secondary Endpoints 
Efficacy endpoints: 
• Proportion of subjects with a CLASI-50 response, defined as a 50% improvement 
from baseline in CLASI-A score, at Week 24 (Part A) and at Weeks 12 and 16 (Part 
B).  
• Percent change in CLASI-A score from Baseline to Week 12, Week 16, and Week 24 
(Part A) and Week 12 (Part B). 


 
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 12 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
• Proportion of subjects with a ≥4-point reduction in CLASI-A score at Week 24 (Part 
A) and at Weeks 12 and 16 (Part B) compared with baseline.  
• Proportion of subjects with a ≥7-point reduction in CLASI-A score at Week 24 (Part 
A) and at Weeks 12 and 16 (Part B) compared with baseline.  
• Proportion of subjects achieving a SLE Responder Index (SRI) of ≥4 (SRI-4) at Week 
24 (see Section 6.3.5 for a detailed description of this endpoint) (Part A only). 
• Change from baseline to Week 24 in Systemic lupus erythematosus disease activity 
index 2000 (SLEDAI-2K) score (Part A only). 
• Proportion of subjects with no new organ system affected, as defined by no new 
BILAG-2004 grade A and no more than one new BILAG-2004 grade B, from 
baseline at Week 24 (Part A only).  
• Change from baseline to Week 24 in PGA of SLE (VAS) score (Part A only). 
Pharmacokinetics Endpoints (Part A and Part B): 
• PK parameters, including, but not limited to, clearance (Cl), volume of distribution 
(Vd) and absorption rate (ka). 
Safety and Tolerability Endpoints (Part A and Part B): 
• Incidence, nature, severity, and relationship to study treatment of adverse events 
(AEs) and serious adverse events (SAEs) 
• Change/shift from baseline in standard laboratory parameters, vital signs and 
electrocardiogram (ECG) results 
• Incidence of anti-BIIB059 antibodies in serum 
• Absolute and percent change from baseline over time in immunoglobulin levels (IgA, 
IgG and IgM) and immunoglobin titers for tetanus, diphtheria, and Pneumococcus 
vaccines 
 
 
 
• 
 
• 
 
   


 
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 13 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
• 
 
• 
 
 
• 
 
 
 
• 
 
 
  
• 
 
• 
  
• 
 
 
• 
 
• 
  
• 
 
 
• 
  
 
  
 
     
• 
 
  
• 
 
 
• 
 
 
 


 
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 14 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
• 
 
 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
. 
• 
 
 
• 
 
 
• 
 
 
 
 
 


 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.  
 15 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
 
  
• 
 
 
 
 
• 
 
 
• 
 
 
 
• 
 
• 
 
 
  
 
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 16 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
 
 
• 
 
 
 
• 
 
 
 
 
• 
 
• 
  
o 
 
 
 
 
o 
 
 
 
. 
o 
 
 
 
 
o 
 
 
o 
 
 


 
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 17 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
o 
 
 
 
 
 


 
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 18 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
2. STUDY DESIGN 
2.1. Study Overview 
This is a 2-part randomized, double-blind, parallel-group, placebo-controlled, multicenter 
Phase 2 trial. The protocol version 1 (PV1) was designed to evaluate the efficacy and safety 
of BIIB059 in SLE subjects with active skin manifestations (Part A) or active CLE, defined 
as discoid or subacute subtypes, with or without SLE (Part B). The study was to be conducted 
at approximately 95 centers in the United States, Europe, Latin America and Asia. In PV1 
Part A, 100 subjects were planned to be randomly assigned to 1 of 4 treatment groups in a 
1:1:1:1 ratio and receive either fixed doses of BIIB059 (50, 150 or 450 mg) or placebo 
subcutaneously Q4W for 24 weeks with a loading dose at Week 2, for a total of 7 doses. 
Randomization was stratified by baseline CLASI-A score (≤ 10, >10) and prior oral 
corticosteroid usage (≤ 10 mg/d, >10 mg/d).  In PV1 Part B, 30 subjects were planned to be 
randomly assigned to 1 of 2 treatment groups in a 2:1 ratio (20 subjects to BIIB059, 10 
subjects to placebo) and receive either a fixed dose of BIIB059 (450 mg) or placebo SC Q4W 
for 12 weeks with a loading dose at Week 2, for a total of 4 doses. Randomization was 
stratified by CLASI-A score (≤ 10, >10) and SLE (presence, absence).  
2.1.1. Protocol changes 
The protocol was first amended on 16 May 2017. Protocol version 2 (PV2) was designed to 
evaluate the efficacy and safety of BIIB059 in subjects with SLE and active skin 
manifestations and joint involvement (Part A) or active CLE, defined as SCLE or CCLE, 
including DLE, with or without SLE (Part B). As part of the amendment, the number of sites 
was expanded to approximately 130 centers across United States, Europe, Latin America, and 
Asia. Two additional amendments were done after PV2 but were administrative in nature and 
didn’t impact the study design and statistical analyses plan.    
The key changes between PV1 and PV2 (and subsequent versions) are listed below: 
Part A 
o In PV2 (and subsequent versions), oral corticosteroid tapering in Part A is 
now mandatory. Under PV1, it was encouraged but was not mandatory. 


 
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 19 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
o In PV2 (and subsequent versions), the subjects will be randomized to fixed 
dose of BIIB059 450 mg or placebo. In PV1, subjects were planned to be 
randomized to either fixed doses of BIIB059 (50, 150 or 450 mg) or 
placebo. 
o In PV2 (and subsequent versions), change in inclusion criteria included: 
removal of the CLASI-A score requirement of 8 or higher at entry and 
addition of joint count, requiring at least 4 swollen and 4 tender joints 
based on assessment of 28 joints (see Section 4.3.3 of the protocol), with at 
least 4 occurring in the PIP, MCP, or wrist joints. Note: A joint that is both 
tender and swollen will be included in both categories (counts as 1 tender 
and 1 swollen). 
Part B 
o In PV1, last dose was originally planned at week 8, with end of treatment 
period at week 12. Under PV2 (and subsequent versions), an additional 
week 12 dose was added (with end of treatment period now moved to week 
16). 
o In PV2 (and subsequent versions), the subjects will be randomized to either 
fixed doses of BIIB059 (50, 150 or 450 mg) or placebo. In PV1, subjects 
were to be randomized to fixed dose of BIIB059 450 mg or placebo. 
The study design for PV2 (and subsequent versions) Part A and Part B is shown in Figure 1 
and Figure 2 below: 


 
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 20 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
Figure 1: Study Design PV2 (and subsequent versions) Part A 
 
Abbreviations: ANA=antinuclear antigen; dsDNA= double-stranded DNA; FU=follow-up visit; MCP=metacarpophalangeal joints; 
OCS=oral corticosteroid; PIP=proximal interphalangeal joints; Q4W=every 4 weeks; SoC=standard of care; TD1=Treatment Day 1. 
** At least 4 of the swollen joints must be PIP, MCP, and/or wrist joints. A joint that is both tender and swollen will be included in 
both categories (counts as 1 tender and 1 swollen). Black triangles represent dosing visits.  
 


 
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 21 
 
 
Statistical Analysis Plan 
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<V 2.0> 
 
Figure 2 Study Design PV2 (and subsequent versions) Part B 
 
Abbreviations: CLASI-A=Cutaneous Lupus Erythematosus Disease Area and Severity Index- Activity Scale; CLE=cutaneous lupus 
erythematosus; FU=follow-up visit; OCS=oral corticosteroid; Q4W=every 4 weeks; SoC=standard of care; TD1=Treatment Day 1  
1 Histologically confirmed in the past or at Screening.  
Black triangles represent dosing visits 


 
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Statistical Analysis Plan 
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2.1.2. Subject recruitment and treatment 
In Part A (PV2), approximately 100 subjects will be randomized to receive either subcutaneous 
injections of 450 mg BIIB059 or placebo in a 1:1 ratio every 4 weeks (Q4W) for 24 weeks, with 
an additional dose at Week 2 (for a total of 7 doses, Figure 1). Up to 70 additional subjects may 
be added at the interim analysis (see Section 10). Randomization will be stratified by oral 
corticosteroid usage (≤10 mg vs. >10 mg) and by geographic region (United States vs. Asia vs. 
Latin America and Europe). In Part A (PV1), prior to the amendment, subjects were randomly 
assigned to 1 of 4 treatment groups in a 1:1:1:1 ratio and received either fixed doses of BIIB059 
(50, 150 or 450 mg) or placebo. Randomization, in Part A (PV1), was stratified by oral 
corticosteroid usage (≤10 mg vs. >10 mg) and by CLASI-A score (≤10 vs. >10). Subjects who 
have been enrolled in PV1 before the amendment were to remain on their original treatment 
assignment and were not allowed to reconsent under PV2 and subsequent version.  
In Part B (PV2), approximately 100 subjects will be randomized to 1 of 4 treatment groups in a 
1:1:1:1 ratio and will receive either fixed doses of BIIB059 (50, 150 or 450 mg) or placebo 
subcutaneously every 4 weeks (Q4W) for 16 weeks, with an additional dose at week 2, for a total 
of 5 doses (Figure 2). Randomization will be stratified by CLASI-A score (≤10 vs. >10) and 
DLE (presence, absence). In Part B (PV1), prior to the amendment, subjects were randomized to 
either 450 mg BIIB059 or placebo (in a 2:1 ratio). Randomization, in Part B (PV1), was stratified 
by SLE status (presence, absence) and by CLASI-A score (≤10 vs. >10). Subjects enrolled under 
PV1 were to remain on their original treatment assignment but could be reconsented under PV2 
and subsequent versions.  
Additional details of the study design can be found in full protocol of 230LE201. 


 
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Statistical Analysis Plan 
230LE201 
<V 2.0> 
3. STATISTICAL ANALYSIS 
3.1. General Considerations 
Three analyses are planned for this study and apply to PV2 and subsequent versions: 
1. The IA for futility in Part B will be performed after approximately 45% of the subjects in 
Part B (PV2 and subsequent version) have completed their week 12 treatment visit. Further 
details are included in Section 10. 
2. The final analysis for Part A will be performed when all subjects in Part A have completed 
the last study visit including follow-up period. 
3. The final analysis of Part B will be performed when all subjects in part B have completed 
the last study visit including follow-up period. 
 
A separate analysis will be performed for Part A and Part B, unless otherwise specified. 
 
Within each part, data from PV1 will be pooled with PV2 (and subsequent versions), by 
treatment group, for each planned analysis as per the following criteria.  
 
Part A: 
• For the planned analyses of the primary and other endpoints associated with the joint 
count assessment, pool (by treatment group) only the data from PV1 and PV2 (and 
subsequent versions) subjects who satisfy the following inclusion criteria at baseline:   
o Must have at least 4 tender joints based on assessment of 28 joints. 
o Must have at least 4 swollen joints based on assessment of 28 joints, as described 
above, with at least 4 of the swollen joints occurring in the PIP, MCP, or wrist 
joints. 
• For all the planned analyses of endpoints associated with CLASI-A assessment, pool (by 
treatment group) PV1 data with only the data from PV2 (and subsequent versions), 
subjects with baseline CLASI-A ≥ 8. 


 
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Statistical Analysis Plan 
230LE201 
<V 2.0> 
• For the planned analyses of all other endpoints pool (by treatment group) all the data 
from PV1 and PV2 (and subsequent version) subjects. 
 
Part B: Pool (by treatment group) all the data from PV1 and PV2 (and subsequent versions), 
subjects.   
 
A list of all the primary and secondary analyses and target population is provided in Appendix 
A1 (Part A) and Appendix A2 (Part B). 
 
This statistical analysis plan covers the planned analyses for both the unblinded IA and the final 
analyses (Part A and Part B). All efficacy, safety and PK endpoints described in this plan will be 
included in the final analyses, while a subset of the endpoints will be included in the unblinded 
IA (see Appendix B for more details). For each endpoint, the same analysis method will be used 
for both the interim and final analyses, unless otherwise specified. 
 
Within each part (Part A and Part B), all data will be summarized by treatment group. In addition 
for each part (Part A and Part B), the data described in Section 5 which includes patient 
disposition, baseline characteristics and demography data, and concomitant medications will be 
summarized overall, and the safety data described in Section 7 will also be summarized for all 
BIIB059 groups combined. 
 
A pooled analysis (pooled data from Part A and Part B) may also be performed on Part B 
endpoints associated with CLASI-A assessment. Only the data from Part A subjects that meet the 
following criteria will be pooled (by treatment group) for the combined (Part A and Part B) 
analyses: 
- 
Baseline CLASI-A ≥ 8 
The pooled analyses will be performed using the same analysis method as for the CLASI-A 
endpoints within Part B, where applicable.   
The statistical software, SAS® version 9.3 or above, will be used for all summaries and analyses.  


 
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Statistical Analysis Plan 
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<V 2.0> 
3.2. Changes to Protocol Planned Analyses 
• 
 
 
• 
 
 
  
• A secondary endpoint was added:  
o Proportion of subjects with a ≥7-point reduction in CLASI-A score at Week 
24 (Part A) and at Weeks 12 and 16 (Part B) compared with baseline.  
• 
  
o 
 
 
o 
 
 
o 
 
 
o 
 
 
o 
 
 
o 
 
 
o 
 
 
o 
 
 
o 
 
 


 
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Statistical Analysis Plan 
230LE201 
<V 2.0> 
o 
 
 
o 
 
 
 
o 
 
 
o 
 
 
o 
 
 
o 
 
 
 
o 
 
 
 
 
o 
 
 
 
 
o 
 
 
 
• 
 
o 
 
 


 
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 27 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
 
 
 
 
 
 
 
o 
 
 
 
 
 
 
 
 
 
• The baseline*visit interaction term was added to MMRM model as covariates used 
for analyses of continuous endpoints. 
• In Part A, for binary endpoints related to CLASI-A score, CLASI-A score (≤10 vs. >10) 
was added to the logistic model as a covariate. In both Part A and B, for binary 
endpoints dichotomized from a continuous endpoint other than CLASI-A, the 
baseline of the corresponding continuous endpoint was added to the logistic model 
as a covariate.  
 
3.3. Changes made in the Statistical Analysis Plan  
• Interim analysis 2 is added to the statistical analysis plan according to the changes 
made in protocol version 5.0. 
• Patients who have usage of disallowed concomitant therapy or SLE standard of care 
therapy that deviate from the protocol will be considered as major deviations that 


 
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 28 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
could impact the efficacy assessments and will be excluded from the per-protocol 
population (Part A and B). 
• Failing Inclusion criteria 8.1.3 is now considered to impact the efficacy analysis. 
• Endpoint ‘proportion of subjects with no worsening from baseline in subjects with 
lupus disease activity defined by <10% increase in PGA (VAS)’ is now changed to 
‘by <1 point increase in PGA (VAS)’, so as the corresponding components in SRI-4, 
-5, -6 and BICLA. 
• 
 
 
• 
 
 
 
• Subgroup analysis will be modeled by MMRM model. To avoid inconsistency, if the 
MMRM model does not converge for some subgroups, ANCOVA model will no 
longer be performed for these same subgroups. 
 
 


 
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 29 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
4. ANALYSIS POPULATIONS, STRATIFICATION FACTORS and VISIT 
DEFINITIONS 
4.1. Definitions of Analysis Populations for Part A and Part B 
Modified Intent-to-Treat (MITT) Population 
The MITT population is defined as all randomized subjects who received at least 1 dose of study 
treatment (whether the subjects adhered to the protocol). Subjects will be analyzed according to 
the study treatment to which they were randomized. Analysis of other non-safety endpoints (e.g., 
demographics) will also be based on the MITT population. 
 
Safety Population 
The safety population will include the same subjects as defined for the MITT population. 
However, subjects will be analyzed by actual treatment received. If all subjects take the 
treatment as they were randomly assigned to, the safety population will be the same as the MITT 
population. 
 
Per-Protocol (PP) Population 
The per-protocol population will include the MITT subjects who do not have any major 
protocol deviations that could impact the efficacy assessments. Subjects will be analyzed by 
randomized treatment. Major deviations that could impact the efficacy assessments are: 
Part A  
- 
Actual treatment received is different from the planned treatment (e.g., patients received 
BIIB059 treatment while randomized to the placebo arm). 
- 
Patients who have usage of disallowed concomitant therapy or SLE standard of care 
therapy that deviate from the protocol (specific rules for each concomitant therapy will be 
described in an addendum). 
- 
Failing Inclusion/exclusion criteria that might potentially affect efficacy. The criteria 
listed in Table 1 are considered not going to affect efficacy, thus they are not considered 
for per-protocol population.  
- 
< 80% treatment compliance with study medication 


 
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 30 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
- 
> 120% treatment compliance with study medication 
 
Part B 
- 
Actual treatment received is different from the planned treatment (e.g., patients received 
BIIB059 treatment while randomized to the placebo arm). 
- 
Patients who have usage of disallowed concomitant therapy or SLE standard of care 
therapy that deviate from the protocol (specific rules for each concomitant therapy will be 
described in an addendum). 
- 
Failing Inclusion/exclusion criteria that might potentially affect efficacy. The criteria 
listed in Table 1 are considered not going to affect efficacy, thus they are not considered 
for per-protocol population. 
- 
< 80% treatment compliance with study medication 
- 
> 120% treatment compliance with study medication 
 
Table 1 Inclusion/Exclusion Criteria not Considered for Per-Protocol Population 
 
Section in 
Protocol 
Item 
Affect Efficacy 
8.1.1 
Inclusion 
Criteria 
(Parts A 
and B) 
1. Ability of the subject to understand the purpose 
and risks of the study and provide signed and dated 
informed consent and authorization to use 
confidential health information in accordance with 
national and local subject privacy regulations.  
Not related to 
efficacy 
2. Age 18 to 75 years old, inclusive, at the time of 
informed consent. 
Relaxed to age 12 to 
80 
3. All women of childbearing potential and all men 
must practice effective contraception during the 
study and for 16 weeks after their last dose of study 
treatment.  
Not related to 
efficacy 
8.2.1 
Exclusion 
5. Other unspecified reasons that, in the opinion of 
the Investigator or Biogen, make the subject 
unsuitable for enrollment.  
Not related to 
efficacy 


 
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Statistical Analysis Plan 
230LE201 
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Criteria 
(Parts A 
and B) 
10. Subjects with a history of suicide attempt or 
suicidal ideation within 1 year prior to Screening.  
Not related to 
efficacy 
13. History of severe herpes infection, such as 
herpes encephalitis, ophthalmic herpes, or 
disseminated herpes.  
Not related to 
efficacy 
14. History of chronic, recurrent (3 or more of the 
same type of infection in a 12-month period), or 
recent serious infection (e.g., pneumonia, 
septicemia, herpes zoster) as determined by the 
Investigator and requiring anti-infective treatment 
within 12 weeks prior to Screening.  
Not related to 
efficacy 
15. Signs of herpes or varicella zoster viral infection 
(specifically chicken pox, shingles, or herpes zoster) 
within 12 weeks prior to Screening.  
Not related to 
efficacy 
16. History of or current diagnosis of active 
tuberculosis (TB), or untreated latent TB infection 
(LTBI), determined by a TB skin test with purified 
protein derivative as evidenced by induration ≥5 
mm or a positive Quantiferon, positive or borderline 
T-SPOT (Elispot) test performed locally, either at 
Screening or documented with results within 12 
weeks of the Screening Visit. Subjects who have 
previously completed appropriate and documented 
LTBI treatment will not be required to be tested. 
Subjects must have received complete LTBI 
treatment prior to Screening without evidence of re-
exposure prior to entering the study.  
 
Subject with current household contacts with active 
TB will also be excluded unless the subject is being 
treated and there is evidence that household contacts 
are being treated.  
 
Indeterminate Quantiferon or T-SPOT tests may be 
repeated once and will be considered positive if 
retest results are positive or indeterminate. Subjects 
with documented BCG vaccination must perform a 
TB test at Screening and will be excluded if skin 
induration ≥5 mm or a positive Quantiferon or 
positive or borderline T-SPOT (Elispot) test.  
Not related to 
efficacy 
18. Known hypersensitivity to BIIB059 or any of 
the components of the formulated BIIB059 or 
matching placebo.  
Not related to 
efficacy 
19. History of, or ongoing, malignant disease, 
including solid tumors and hematologic 
Not related to 
efficacy 


 
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Statistical Analysis Plan 
230LE201 
<V 2.0> 
malignancies with the exception of basal cell 
carcinomas and squamous cell carcinomas and 
carcinoma in situ of the cervix that have been 
completely excised and considered cured >2 years 
prior to Screening.  
21. History of substance abuse (except for 
cannabinoid) within 24 weeks prior to Screening, 
based on the Investigator’s opinion.  
Not related to 
efficacy 
22. Female subjects who are pregnant, currently 
lactating, have stopped lactating in the past 12 
weeks, or are planning to become pregnant during 
the study and for 4 months after the last dose of 
study treatment.  
Not related to 
efficacy 
 
PK Population 
The PK population will include the safety subjects who have at least one PK concentration 
measurement. Subjects will be analyzed by the actual treatment received. 
 
4.2. Stratification Factors 
The randomization stratification used for both Part A and B under each protocol versions (PV1 
and PV2) is shown below:  
Part A  
PV1  
• Oral Corticosteroid Usage (≤10 mg/d vs. >10 mg/d) 
• CLASI-A score (≤10 vs > 10) 
 
PV2 (or later)  
• Oral Corticosteroid Usage (≤10 mg/d vs. >10 mg/d) 
• Geographic Region (United States vs. Asia vs. Latin America and Europe) 
 
Part B  
PV1 
• 
CLASI-A score (≤10 vs. >10) 


 
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 33 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
• 
SLE (Yes/No) 
PV2 (or later) 
• 
CLASI-A score (≤10 vs. >10) 
• 
DLE (Yes/No) 
 
4.3. Visit/Analysis Week Definitions 
The definition of visits below applies to both parts A and B. 
 
Baseline 
Baseline will refer to the last non-missing value prior to the first randomized dose. 
 
Treatment Day [TD] (Days relative to the first randomized dose) 
To facilitate the analysis of the data in the treatment period (TP), TD will be calculated for each 
day in the study as the number of days between the date of the first randomized dose and the 
specific day of interest. For a day that is on or after the day of the first randomized dose, the TD is a 
positive value and will be calculated as (date of study day – date of the first randomized dose +1). For a 
day that is prior to the date of the first randomized dose, the TD is a negative value and will be 
calculated as (date of study day – date of the first randomized dose). The study starts at TD1. 
 
Analysis Week 
Observations that are collected after the first randomized dose as scheduled visit will be used to 
the corresponding analysis week.  Baseline corresponds to “Week 0” in the protocol or the 
latest non-missing value prior to first study drug administration if Week 0 assessment is 
missing. 
 
Data from Early Termination or Unscheduled Visits 
In general, when data are summarized by visit/analysis week, the Early Termination Visit or 
Unscheduled Visit will be assigned to an appropriate scheduled visit/analysis week (PV2 or 
later) by using a window scheme as follows. 


 
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 34 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
 
The lower bound and the upper bound for the visit windows are defined as the midpoints of the 
scheduled visits (PV2 or later). If the date and time from early termination visit falls in 
between the lower bound and the upper bound for a scheduled visit, then it will be assigned to 
that visit. If there are 2 or more assessments available in the same analysis window for a 
subject, the assessment that is closest to the target visit day will be used for analysis. If there 
are 2 or more assessments in the same analysis window with the same distance from the target 
visit day, the earlier assessment will be used. 
 
The windowing scheme for the primary endpoint in Part A and Part B is shown in Table 2 and 
Table 3 below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Statistical Analysis Plan 
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Table 2 Visit Windows for Primary Endpoint (Joint Count) in Part A 
 
 
 
 
 
 
 
 
 
 
 
Table 3 Visit Windows for Primary Endpoint (CLASI) in Part B 
 
 
Analysis visit 
Target visit day 
Analysis visit window 
Baseline (Week 0) 
1 
Most recent non-missing pre-dose value 
Week 2 
15 
[2, 22] 
Week 4 
29 
[23, 43] 
Week 8 
57 
[44, 71] 
Week 12 
85 
[72, 99] 
Week 16 
113 
[100, 127] 
Week 20 
141 
[128, 155] 
Week 24 
169 
[156, 197] 
Follow-up 12 
253 
≥198 
Analysis visit 
Target visit day  
Analysis visit window 
Baseline (Week 0) 
1 
Most recent non-missing pre-dose value 
Week 2 
15 
[2, 22] 
Week 4 
29 
[23, 43] 
Week 8 
57 
[44, 71] 
Week 12 
85 
[72, 99]  
Week 16 
113 
[100, 141]  
Follow-up 12 
197 
≥142 
*For Part B subjects in PV1 who didn’t reconsent to PV2 and hence don’t have week 16 visit, the follow-up 
period days and lower and upper bound of visit window will shift back by 28 days 


 
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 36 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
5. STUDY SUBJECTS 
5.1. General Consideration 
Unless otherwise specified, all variables in Section 5 will be summarized for the MITT 
population for both Parts A and B. 
 
5.2. Subject Disposition 
For randomized subjects, the numbers and percentages of subjects who were randomized and 
dosed, discontinued study treatment in treatment period (including reasons for discontinuation), 
completed the study treatment, completed the study, and withdrew from the study in the treatment 
period (including reasons for withdrawal) will be summarized by treatment group.  
Additionally, a listing of subjects who discontinued treatment and/or withdrew from study during 
the treatment period and the associated reasons for discontinuation/withdrawal will be provided. 
The number and percentage of subjects in each treatment group will be summarized for the MITT 
population. 
 
5.3. Demography and Baseline Disease Characteristics – Part A and B 
The following demographic and baseline characteristics will be summarized for the MITT 
population only – note that if the safety population differs from the MITT population (i.e. if not all 
subjects receive their randomized treatment) then the summaries will be repeated for the safety 
population only. 
 
Part A 
• Age categories (<40 years, ≥40 - <65 years, ≥65) 
• Age (years) 
• Sex (male/female) 
• Ethnicity (Hispanic or Latino/not Hispanic or Latino/ Not reported due to confidentiality 
regulations) 
• Race (American Indian or Alaska Native/Asian/Black or African American/ Native 


 
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 37 
 
 
Statistical Analysis Plan 
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<V 2.0> 
Hawaiian or Other Pacific Islander/White/Not reported due to confidentiality 
regulations/Other) 
• Height (cm) 
• Weight (kg) 
• Body Mass Index (kg/m^2) 
• Geographic region (United States, Asia, Latin America, Europe) 
• CLE (Yes/No) 
• CLE subtypes  
o ACLE 
o SCLE 
o DLE 
o CCLE other 
▪ Panniculitis 
▪ Chiblain 
▪ Tumidus 
 
Additionally, the following baseline assessments will be summarized. 
 
• Total active joint count 
• Tender joint count 
• Swollen joint count 
• CLASI-A score 
• 
 
• CLASI-A (≤10, >10) 
• SLEDAI-2K score 
• SLEDAI-2K (<10, ≥10) 
• BILAG-2004 score 
• BILAG-2004 grade (A, B, C, D, E) 
• PGA of SLE (VAS) score 


 
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 38 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
• 
 
• 
 
• 
 
• 
 
 
• 
 
• 
 
• 
 
• Concomitant medications 
o Antimalarials (Yes/No) 
o Corticosteroids (Yes/No) 
o Corticosteroids and antimalarials (Yes/No) 
o Azathioprine (Yes/No) 
o Methotrexate (Yes/No) 
o Mycophenolate (Yes/No) 
o Other allowed Medications (Yes/No) 
• 
 
• 
 
• 
 
• 
 
 
Part B 
• Age categories (<40 years, ≥40 - <65 years, ≥65 years) 
• Age (years) 
• Sex (male/female) 
• Ethnicity (Hispanic or Latino/not Hispanic or Latino/ Not reported due to confidentiality 
regulations) 


 
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 39 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
• Race (American Indian or Alaska Native/Asian/Black or African American/ Native 
Hawaiian or Other Pacific Islander/White/Not reported due to confidentiality 
regulations/Other) 
• Height (cm) 
• Weight (kg) 
• Body Mass Index (kg/m^2) 
• Geographic region (United States, Asia, Latin America, Europe) 
• SLE (Yes/No) 
• CLE subtypes  
o ACLE 
o  SCLE 
o DLE 
o CCLE other 
▪ Panniculitis 
▪ Chiblain 
▪ Tumidus 
 
Additionally, the following baseline assessments will be summarized. 
 
• CLASI-A score 
• CLASI-A (≤10, >10) 
• 
 
• SLEDAI-2K score 
• SLEDAI-2K (<10, ≥10) 
• PGA of SLE (VAS) score 
• 
 
• 
 
• 
 


 
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 40 
 
 
Statistical Analysis Plan 
230LE201 
<V 2.0> 
• 
 
 
• 
 
• 
 
• 
  
• Concomitant medications 
o Antimalarials (Yes/No) 
o Corticosteroids (Yes/No) 
o Corticosteroids and antimalarials (Yes/No) 
o Azathioprine (Yes/No) 
o Methotrexate (Yes/No) 
o Mycophenolate (Yes/No) 
o Other Allowed Medications (Yes/No) 
• 
 
• 
 
 
All baseline characteristics will also be presented in subject listings. 
 
5.4. Prior Medications  
Prior medications used for SLE and/or CLE 
Previous medications used for the treatment of SLE and/or 
CLE(NSAIDS/Immunosuppressants/corticosteroids/antimalarials/others) will be summarized. 
A listing of previous medications used for the treatment of SLE and CLE will be presented, 
including the previous medication used, duration of treatment, used at screening (yes/no), and 
reasons for discontinuation if not using at screening (lack of efficacy/side effects/or other). 
 
Prior medications used for non SLE/CLE  
Previous medications used for the non SLE/CLE related treatment will be summarized. 


 
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A listing of previous medications used for the non SLE/CLE related treatment will be presented, 
including the previous medication used, duration of treatment, used at screening (yes/no), and 
reasons for discontinuation if not using at screening (lack of efficacy/side effects/or other). 
 
5.5. Concomitant Therapies 
A concomitant therapy (including medication or non-drug therapy) is defined as any therapy 
(other than the treatment) that is taken on or after the date/time of the randomized dose. This 
includes therapies that are started prior to the date/time of randomized dose if their use 
continues on or after Treatment Day 1.  
 
In order to define concomitant for therapies with missing start or stop date, the following 
additional criteria are defined:  
• if both the start and stop dates of a therapy are missing, that therapy is considered 
concomitant;  
• if the start date of a therapy is missing and the stop date of that therapy falls on or after 
the date of randomized dose, that therapy is considered concomitant;  
• if the start date of a therapy is prior to the date/time of randomized dose and the stop 
date of that therapy is missing, that therapy is considered concomitant;  
• if the start and the stop dates of a therapy is prior to the date/time of randomized 
dose, that therapy is considered prior. 
 
All concomitant medications will be coded using the World Health Organization (WHO) 
medication dictionary (March 2017 Version). All concomitant non-drug treatments will be coded 
by Medical Dictionary for Regulatory Activities (MedDRA) preferred term (Version 21.1 or the 
most updated version at data base lock). 
 
Concomitant medications will be summarized separately for medications used to treat SLE, 
medications used to treat CLE, and medications used for other indications. The number and 


 
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percentage of subjects taking each medication as collected in the eCRF will be summarized. All 
concomitant medications will be presented in the data listings. 
 
5.6. Treatment Exposure and Compliance 
The duration of treatment exposure during the treatment period will be based on the number of 
days between the date of first dose and the date of the last dose + 28 days. Each dose should be 
administered in the clinic during the randomization visit and recorded in the electronic case 
report form (eCRF).  
The number and percentage of subjects in each of the following cumulative durations of 
exposure categories will be summarized for each part as follows:  
 
Part A  
At least 2, 4, 8, 12, 16, 20, weeks. In addition, days of exposure to the treatment will be 
summarized as a continuous variable with summary statistics. 
 
Part B  
at least 2, 4, 8, 12, weeks. In addition, days of exposure to the treatment will be summarized as a 
continuous variable with summary statistics. 
 
BIIB059 treatment compliance during the treatment period will be assessed based on the drug 
administered as recorded in the eCRF. Overall compliance for each subject will be calculated 
and summarized for each treatment group. The compliance will be calculated using the following 
formula: 
 
Percent Compliance = (actual number of doses administered)/(number of doses expected to be 
administered) *100 
 


 
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Note: For part B subjects, the “number of doses expected” in the formula above will depend on 
the protocol version to which the subject consents. For discontinued subjects, “number of doses 
expected” will be relative to the time of discontinuation. 
 
5.7. Protocol Deviations 
Protocol deviations identified during site monitoring will be captured in a Protocol Deviation Log 
and will be categorized as major or minor deviations based on protocol deviation classification prior 
to the final database lock. The major protocol deviations will be summarized and listed. The minor 
protocol deviations will also be listed. All summaries for protocol deviations will be presented 
only by treatment group. 
Subjects that had at least one major protocol deviation that led to exclusion from the per-protocol 
population (see Section 4.1) will also be summarized. 
 
5.8. Treatment Failure 
For each part below, subjects who meet any of the following criteria will be considered as a 
treatment failure and considered as a non-responder in the efficacy analysis: 
 
Part A 
• Subjects who initiate or increase SLE standard of care therapy or other disallowed 
concomitant therapy (Table 8 of the latest protocol version) during the treatment period 
of the study.  
• Subjects with corticosteroid dose increase above baseline during the treatment period 
except for what is allowed under rescue 1 during week 1 to 4. 
• Subjects with more than 2 allowed rescues between week 1 to week 12. 
• Subjects with any increase in corticosteroid during treatment period after week 20. 
 
 


 
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Part B 
• Subjects who initiate disallowed concomitant therapy during treatment period of Part B 
(see Table 8 of the latest protocol version). 
• Subjects who initiate or increase SLE/CLE standard of care therapy during the treatment 
period of the study. 
• Subjects who initiate or increase corticosteroid dose above baseline during the treatment 
period of the study (oral or topical except those in Table 6 of the latest protocol version).  
 
Note: Treatment failure subjects would be allowed to remain in the trial and receive 
investigational product, as applicable) 
 
More detailed definition regarding specific concomitant therapy is described in and addendum to 
this SAP. For both parts, subjects’ data considered as treatment failure will be handled as 
described in Section 6.6.  
6. EFFICACY ANALYSES 
6.1. General Considerations 
For both Part A and Part B, the efficacy analyses will be performed using the MITT 
population and will be considered as the primary analyses.  For each endpoint, additional 
conditions may apply for pooling of data across protocol versions (see Section 3.1). The 
final model for each analysis in the MITT population will also be used for the PP analysis. 
A complete list of all the planned analyses and target population for the primary and 
secondary endpoints is provided in Appendix A1 (Part A) and Appendix A2 (Part B). 
 
Unless otherwise specified, statistical testing across all efficacy endpoint will be performed to 
compare each BIIB059 dose (Part A: 450 mg; Part B: 50, 150 or 450 mg) with placebo at the 
2-sided, 0.05 significance level. P-values and corresponding 95% confidence intervals (CI) will 
be provided. P-values will be rounded to three decimal points before assessing statistical 
significance.  
 


 
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Summary statistics will be presented for all endpoints at all visits including follow-up visits. 
For continuous variables, the summary statistics will include number of subjects with data, 
mean, standard deviation (SD), median, first quartile (Q1), third quartile (Q3), minimum and 
maximum. For categorical endpoints, the summary statistics will generally include: number of 
subjects in the corresponding analysis population, number and percentage of subjects in each 
category. 
 
Unless otherwise specified, week 2, 4, 8, 12, 16, 20 and, 24 will be included in all Part A “by 
visit” MMRM analyses. 
Unless otherwise specified, week 2, 4, 8, 12 and,16 will included in all Part B “by visit” 
MMRM analyses.    
Additional study part specific efficacy analyses considerations are described in Section 6.1.1 
(Part A) and Section 6.1.2 (Part B) 
 
6.1.1. Part A Efficacy Analyses Considerations 
Continuous endpoint 
All Part A continuous efficacy endpoints will be analyzed using the following described 
method, unless otherwise specified.    
A Mixed Effect Model Repeat Measurement (MMRM) model will be used as the primary 
method to analyze endpoint of interest using treatment group (BIIB059 450 mg vs. placebo), 
study visit (week 2, 4, 8, 12, 16, 20, 24), baseline corticosteroid usage level (≤ 10 mg, >10 
mg), region (USA, Asia, Latin America & Europe),  study visit-by-treatment interaction, 
baseline value of the endpoint, and baseline-by-visit interaction as fixed effect covariates. An 
unstructured covariance matrix will be used to model the within-patient variance-covariance 
errors.  If the unstructured covariance structure matrix results in a lack of convergence, the 
heterogeneous Toeplitz covariance structure followed by the heterogeneous first-order 
autoregressive covariance structure will be used.  The Kenward-Roger approximation will be 
used to estimate the denominator degrees of freedom. The primary treatment comparison will 
be the difference between the BIIB059 450 mg dose and placebo at the end of the Week 24 


 
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visit. Handling of missing data and data from treatment failures subjects is provided in 
Section 6.6. 
 
Binary endpoint 
The binary endpoints will be analyzed using logistic regression with covariates of treatment 
(BIIB059 450 mg vs. placebo), baseline corticosteroid usage level (≤ 10 mg, >10 mg) and region 
(USA, Asia, Latin America & Europe). For binary endpoints related to CLASI-A score, CLASI-A 
score (≤10 vs. >10) will be added to the above covariates list. For endpoints dichotomized from a 
continuous endpoint (such as PGA VAS < 1 point increase) the baseline of the continuous endpoint will 
be added to the above covariates list. The odds ratio, its 95% CI and the p-value for BIIB059 450 
mg dose compared to placebo will be presented. Early discontinuation(s) and/or treatment failures 
will be handled using non-responder imputation approach as discussed in Section 6.6. 
 
 
 
 
 
 
 
 
 
  
 
6.1.2. Part B Efficacy Analyses Considerations 
Continuous endpoint 
All Part B continuous efficacy endpoints will be analyzed using the following described 
method, unless otherwise specified. 
A Mixed Effect Model Repeat Measurement (MMRM) model will be used as the primary 
method to analyze endpoint of interest using treatment group, study visit (week 2, 4, 8, 12, 16), 


 
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study visit-by-treatment interaction, DLE (Yes/No), CLASI-A score (≤10 vs. >10), baseline 
value of the endpoint and baseline-by-visit interaction as fixed effect covariates. An unstructured 
covariance matrix will be used to model the within-patient variance-covariance errors.  If the 
unstructured covariance structure matrix results in a lack of convergence, the heterogeneous 
Toeplitz covariance structure followed by the heterogeneous first-order autoregressive 
covariance structure will be used.  The Kenward-Roger approximation will be used to estimate 
the denominator degrees of freedom. The primary treatment comparison between each BIIB059 
treated group and placebo will be at the end of the Week 16. Handling of missing data and data 
from treatment failures subjects is provided in Section 6.6. 
 
Binary endpoint 
The binary endpoints will be analyzed using logistic regression with covariates of treatment and 
DLE (Yes/No) and CLASI-A score (≤10 vs. >10).  For binary endpoints dichotomized from a 
continuous endpoint (such as PGA VAS < 1 point increase, the baseline of the continuous endpoint will 
be added to the above covariates list. The odds ratio, its 95% CI and the p-value for each BIIB059 
dose compared to placebo will be presented. Early discontinuation(s) and/or treatment failures will be 
handled using non-responder imputation approach as discussed in Section 6.6. 
 
 
 
 
 
 
 
Censoring rules: Subjects who do not experience an event by Week 16 or early termination will 
be censored at the date of last assessment during the treatment period. The start date for 
calculation of day to censor or event will be the date of first dose. 
 


 
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6.2. Analysis of Primary Endpoint 
6.2.1. Primary Analysis 
Part A 
The primary analysis will be performed on MITT subjects with a baseline and at least one post-
baseline joint count assessment. For joint count assessments, the analyses will be conducted 
using pooled subjects’ data from PV2 and PV1 who meet the criteria as described in Section 
3.1.  
The continuous primary endpoint, change from baseline to week 24 in the active joint count, 
will be analyzed as described for continuous endpoint analysis in Section 6.1.1 
 
Part B 
The primary analysis will be performed on MITT subjects with a baseline and at least one 
post-baseline CLASI-A assessment. The analyses will be conducted using pooled subjects’ 
data from PV2 and PV1 who meet the criteria as described in Section 3.1.  
 
The primary analysis of the primary endpoint, percent change from baseline to week 16 in 
CLASI-A score, is a test of dose-response, using the Multiple Comparison Procedure – 
Modelling (MCP-Mod) methodology [Bretz 2005]. 
 
Five dose-response trends will be tested using the appropriate contrasts, as determined by 
the MCP-Mod methodology, on the treatment effects obtained from the MMRM model. 
The MMRM model will be applied to percent change from baseline in CLASI-A score as 
described for endpoint analysis in Section 6.1.2 
For MCP-Mod Candidate Models, two families of dose-response models (or ‘candidate 
models’) will be considered: 
  
• SigEmax models (4 candidates) - parameters to estimate: e0, emax, h and ED50  
 
SigEmax — μd = e0 + emax * d^h/(ED50^h + d^h), 


 
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where: emax = asymptotic maximum effect; ED50 = Dose giving half of the asymptotic 
maximum effect; e0 = placebo effect and h = shape parameter. 
• Beta model (non-monotonic, 1 candidate)  
            Beta model — μd = e0 + emax B(𝛿1, 𝛿2) x 𝛿1 (1-x) 𝛿2 
where: emax = asymptotic maximum effect; e0 = placebo effect; 
B(𝛿1, 𝛿2) =  (𝛿1 + 𝛿2) (𝛿1 + 𝛿2)/ (𝛿1 𝛿1 𝛿2 𝛿2); x = d/scale 
 
The initial parameters for candidate models are as follows: 
- 
SigEmax model 1: (ED50 = 25, h = 2.5) 
- 
SigEmax model 2: (ED50 = 50, h = 2.1) 
- 
SigEmax model 3: (ED50 = 90, h = 2.5) 
- 
SigEmax model 4: (ED50 = 450, h = 1) 
- 
Beta Model: (scale = 720) (𝛿1 = 0.6425, 𝛿2 = 1.235) 
 
The maximum treatment effect (over placebo within the dose range) is assumed to be 27.5 at 
week 16. The four candidate SigEmax models were considered in order to capture different 
ED50 values (ranging from 25 to 450 mg).  The beta model was considered to capture the 
scenario where maximum benefit is not observed at the highest but is observed at a lower dose.  
  
If at least one model is significant, there is an indication for evidence of a dose-response 
effect. A candidate model will be selected using model selection criteria AIC (Akaike 
Information Criteria). The selected model will be used to produce estimates of target doses 
using modeling and simulations. 
 
To further understand the dose-response relationship, based on the model type (sigmoid Emax 
model or Beta model) selected from the MCP-Mod method, a sigmoid Emax model or Beta 
model will be fitted using data from week 16. For subjects who are missing with week 16 visit 
data, the predicted value from the MMRM model will be used to fit the does-response model. 


 
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The dose-response model parameters, such as Emax and ED50, will be estimated as well as the 
treatment effect of each dose group.  
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
  
 
  
  
  


 
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6.2.2. Sensitivity Analysis 
 
A sensitivity analysis will be performed on both part A and part B primary endpoints using the 
same methods as described in Section 6.2.1 but using a different missing data handling approach, 
reference based multiple imputation, as described in Section 6.6.  
 
6.3. Analysis of Secondary Efficacy Endpoints 
6.3.1.  CLASI-50 Response (Yes/No) 
Part A 
The percent reduction from baseline to Week 24 in the CLASI-A score will be calculated for 
each subject. The proportion of subjects who had CLASI-50 response, defined as a ≥ 50% 
reduction in the CLASI-A score from baseline, will be analyzed as described for binary endpoint 
analysis in Section 6.1.1  
 
Part B 
The percent reduction from baseline to Week 12 and 16 in the CLASI-A score will be 
calculated for each subject. The proportion of subjects who had CLASI-50 Response at week 
12 and 16, defined as a ≥ 50% reduction in the CLASI-A score from baseline, will be analyzed 
separately for each time point as described for binary endpoint analysis in Section 6.1.2. 
 


 
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6.3.2. A 4-Point Reduction in CLASI-A Response (yes/no) at Week 24 (Part A) and Weeks 
12 and 16 (Part B) 
Part A 
The reduction from baseline to Week 24 in the CLASI-A score will be calculated for each 
subject. The proportion of subjects who had ≥4-point CLASI-A response at week 24, defined 
as a ≥ 4-point reduction in the CLASI-A score from baseline at week 24, will be analyzed as 
described for binary endpoint analysis in Section 6.1.1. 
 
Part B 
The reduction from baseline to Week 12 and 16 in the CLASI-A score will be calculated for 
each subject. The proportion of subjects who had ≥4-point CLASI-A  response at week 12 or 
week 16, defined as a ≥ 4-point reduction in the CLASI-A score from baseline at week 12 or 16, 
will be analyzed separately for each time point as described for binary endpoint in Section 6.1.2. 
 
6.3.3. A 7 Point Reduction in CLASI-A Response (yes/no) at Week 24 (Part A) and Weeks 
12 and 16 (Part B) 
Part A 
The reduction from baseline to Week 24 in the CLASI-A score will be calculated for each 
subject. The proportion of subjects who had ≥7-point CLASI-A response at week 24, defined 
as a ≥ 7-point reduction in the CLASI-A score from baseline at week 24, will be analyzed as 
described for binary endpoint analysis in Section 6.1.1  
 
Part B 
The reduction from baseline to Week 12 and 16 in the CLASI-A score will be calculated for 
each subject. The proportion of subjects who had ≥7-point CLASI-A  response at week 12 or 
week 16, defined as a ≥ 7-point reduction in the CLASI-A score from baseline at week 12 or 16, 
will be analyzed separately for each time point as described for binary endpoint in Section 6.1.2. 
 


 
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6.3.4. Percent Change in CLASI-A Score from Baseline at Week 12, 16 and 24 (Part A) 
and Week 12 (Part B) 
 
The change from baseline to each post-baseline week in the CLASI-A score will be analyzed will 
be analyzed as described for continuous endpoint analysis in Section 6.1.1  (Part A) and Section 6.1.2 
(Part B). Summary statistics for actual values and change from baseline will also be presented by 
week based on observed data. 
 
6.3.5. Proportion of Subjects with an SLE Responder Index (SRI) Response of ≥4 at Week 
24 (Part A Only) 
SLE Responder Index (SRI) of ≥4 (SRI-4) at Week 24 is a categorical response variable (yes/no) 
incorporating the following criteria for achievement of responder status (i.e., all criteria must be 
met to achieve responder status):  
• A reduction from baseline of ≥4 points in Systemic Lupus Erythematosus Disease 
Activity Index 2000 (SLEDAI-2K), and  
• No new organ system affected, as defined by no new British Isles Lupus Activity Group 
(BILAG)-2004 grade A and no more than one new BILAG-2004 grade B, and  
• No worsening from baseline in subject’s lupus disease activity defined by <1 point 
increase in the Physician’s Global Assessment (PGA) [visual analog scale (VAS)] (in the 
scale of 0-10) and 
• No changes to protocol specified medications rules as described below (all criteria must 
be met):  
o No initiation or increase of SLE standard of care therapy or other disallowed 
concomitant therapy (see table 8 from latest protocol for protocol-prohibited list). 
o Concomitant corticosteroid dosage at Week 24 to be ≤10 mg/day.  
o Concomitant corticosteroid dosage at Week 24 to be ≤Day 1.  
o No increase in corticosteroid dose between weeks 17 and 24. 
 


 
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The proportion of subjects who had a composite response, as defined above, will be analyzed as 
described for binary endpoint analysis in Section 6.1.1. Proportion of subjects who responded to 
each of the 4 criteria will also be reported. 
 
6.3.6. Change from Baseline to Week 24 in SLEDAI-2K Score (Part A Only)  
The change from baseline to each post-baseline week in the SLEDAI -2K score will be analyzed 
as described for continuous endpoint analysis in Section 6.1.1. 
 
6.3.7. Proportion of Subjects with No New BILAG-2004 A and no More than One New 
BILAG-2004 B at Week 24 (Part A Only) 
The proportion of subjects who had no new BILAG-2004 A and no more than one new BILAG-
2004 B from baseline to Week 24 will be analyzed as described for binary endpoint analysis in 
Section 6.1.1.  
 
6.3.8. Change from Baseline to Week 24 in PGA of SLE (VAS) Score (Part A Only) 
The change from baseline to week 24 in the PGA of SLE (VAS) score will be analyzed as 
described for continuous endpoint analysis in Section 6.1.1. 
 
 
 
 
 
 
 
 
 
 
• 
 
• 
 


 
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• 
 
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• 
 
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o 
 
 
  
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o 
 
 
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• 
 
 
 
 
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• 
 
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• 
 
  
 
 
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• 
 
 
 
 
 
6.5. Multiplicity Adjustment 
Part A 
There will be no adjustment for multiplicity at interim or final analysis for the primary or 
secondary endpoints in Part A. 
 
Part B 
Multiple Comparison Procedure-Modeling (MCP-Mod) methodology (Bretz et al, 2005) will be 
used to test the dose-response relationship across 3 doses of BIIB059 and PBO for the percent 
change from baseline in CLASI-A score at interim and final analysis. Five dose-response trends 
will be tested using the optimal contrasts as determined by the MCP-Mod methodology such that 
the overall Type I error rate is controlled at 0.05 (one-sided testing). 
There will be no adjustment for multiplicity with secondary efficacy endpoints at interim or final 
analysis. 
 
6.6. Handling of Missing Data 
The handling of missing data and data from treatment failure subjects is summarized here and 
applies to all the endpoints unless otherwise specified. For composite endpoints (e.g.: SRI-4), the 
missing values will be imputed at each component endpoint level, as applicable, using the rules 
described below.  
 


 
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6.6.1. Continuous Endpoints 
The primary approach described below will apply to both part A and part B continuous 
endpoints, unless otherwise specified. The sensitivity approach will be applied to the primary 
endpoints.  
 
Primary approach 
For subjects who are considered as treatment failures, as defined in Section 5.8, the worse 
observation of the baseline and the last observation before treatment failure carried forward will 
be used as the primary method to impute values for all the visits post treatment failure visit. 
Under this approach, subject’s post treatment failure data will be censored and then imputed with 
the subject’s worst case non-missing data prior to treatment failure. 
  
Data after treatment discontinuation will be censored and treated as missing data. For all other 
monotone and non-monotone missing data, including missingness post treatment 
discontinuation, mixed-effects model repeated measures (MMRM) model based approach will be 
used as the primary approach. MMRM assumes data is missing at random (MAR). 
 
A few subjects from PV1 part B might have completed treatment up to week 12 but could not 
reconsent to PV2 and therefore will have missing week 16 data. These subjects will have week 
16 data imputed using predicted value from the MMRM model. 
              
Sensitivity analyses approach 
For subjects who are considered as treatment failures, as defined in Section 5.8, the worse 
observation of the baseline and the last observation before treatment failure carried forward will 
be used to impute values for all the visits post treatment failure visit. Under this approach, 
subject’s post treatment failure data will be censored and then imputed with the subject’s worse 
case between the baseline and the last non-missing data prior to treatment failure. 
 


 
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For all the other missing data, including missingness post treatment discontinuation, reference-
based Multiple Imputation (MI) approach will be used to consider a missing not at random 
(MNAR) mechanism for monotonic missing data. Imputed values of subjects in the BIIB059 
group will be based on the Placebo group. This approach assumes no sustained benefit of 
BIIB059 after discontinuation of study treatment and limits post-discontinuation effects to that of 
placebo. 
 
Intermittent (non-monotonic) missing data will be imputed based on the MAR assumption and 
with an imputation model using Markov chain Monte Carlo (MCMC) method within each 
treatment group. The imputation models will include baseline value and the values at each 
post-baseline week for endpoint of interest. The MCMC method in the MI procedure in SAS 
will be used with a single chain, with a burn-in of 1000, and a thinning of 100 and non- 
informative priors for all parameters. 
 
The remaining, monotonic missing data for all subjects who discontinue study treatment early 
will be imputed using sequential regression MI model estimated based on data from the placebo 
group only. Each sequential regression model (i.e., for imputation of values at a given week) will 
include terms for baseline score, the stratification factors, and all the continuous endpoint scores. 
Missing values at a given week in placebo and BIIB059 groups will be imputed from the same 
imputation model. No rounding or range restrictions will be applied to imputed continuous 
values. 
 
200 imputations will be performed. Each of the 200 imputed datasets will be analyzed using 
the following method. 
 
Results from analysis of each imputed dataset, i.e., least square (LS) mean differences from 
placebo and their SEs, will be combined using Rubin’s method [Rubin 1987] as implemented in 
the SAS MIANALYZE procedure to produce a pooled LS mean estimate of treatment 
difference, its 95% CI, and a pooled p-value. A p-value will only be presented for the primary 


 
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comparison at primary timepoint. The LS means of change from baseline to each post-baseline 
week will be plotted by treatment group. 
 
A figure of the change from baseline to the primary timepoint will be presented; for data 
imputed using the MI methodology described above the least square mean of the 200 imputed 
values will be used. 
 
A few subjects from PV1 part B might have completed treatment up to week 12 but could not 
reconsent to PV2 and therefore will have missing week 16 data. These subjects’ week 16 data 
will be considered MAR and imputed using MMRM. 
 
6.6.2. Binary Endpoints 
The non-responder imputation (NRI) approach will apply to both part A and part B binary 
endpoints, unless otherwise specified. 
 
Subjects who are considered as treatment failures, as defined in Section 5.8, will be considered 
as non-responders for all the visits post treatment failure visit.    
 
Subjects who discontinued treatment will be classified as non-responders for all the visits 
following treatment discontinuation. Intermittent (non-monotonic) missing data will be imputed 
based on last observation carried forward (LOCF) approach.  Subjects who completed treatment but 
had a missing score at primary timepoint (Week 24 of Part A or Week 12, 16 of Part B) will also 
be classified as non-responder for that timepoint, except for subjects from PV1 Part B who 
completed treatment up to week 12. These subjects will have the binary response derived based 
on the imputation of week 16 data under MAR assumption as discussed in Section 6.6.1. 
 
6.6.3. Missing Data in Subcomponents 
For missingness in subcomponents of efficacy instruments, such as subcomponents in joint 
counts, CLASI, SLEDAI-2K, BILAG and etc., imputation will be performed for the missing 


 
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subcomponents first. If there are ≤50% subcomponents missing at one visit, missing data of 
subcomponents will be imputed based on LOCF approach. If there are >50% subcomponents 
missing at one visit, this visit will be considered missing and the missingness will be imputed at 
the component level based on approaches described in Section 6.6.1 and Section 6.6.2. The same 
rule will apply to subcomponents of each component of the composite endpoints (e.g.: SRI-4). 
For endpoints with more than 1 level of subcomponents, where the overall score consists of 
multiple domains and each domain consists of multiple subcomponents, this rule will be applied 
to subcomponents under each domain.  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
6.7. Per-Protocol Analyses 
Part A 
The primary efficacy endpoint, active joint count, and the following secondary efficacy 
endpoints will be analyzed for the per-protocol population using the same analysis methods as 
for the MITT population. 
- 
Percent change in CLASI-A score from Baseline  
- 
SRI-4 response 


 
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Part B 
The primary efficacy endpoint, percent change from baseline in CLASI-A score, and the 
following secondary efficacy endpoints will be analyzed for the per-protocol population using 
the same analysis methods as for the MITT population. 
- 
Proportion of subjects with a CLASI-50 response, defined as a 50% improvement 
from baseline in CLASI-A score by visit 
- 
Proportion of subjects with a ≥4-point reduction in CLASI-A score by visit  
- 
Proportion of subjects with a ≥7-point reduction in CLASI-A score by visit  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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6.10. Additional Analysis 
The following additional analyses will be performed on primary continuous endpoints of both 
part A and part B. 
 
“Retrieved dropout” analysis 
 
Part A 
The primary analysis and sensitivity analyses of the primary endpoint only utilize the active joint 
count data observed before treatment failure visit or subjects discontinued the study treatment. In 
this study, subjects who were considered as treatment failures or discontinued the study 
treatment were encouraged to stay in the study and complete the assessments. 
 
 
 The change in joint count score will be 
computed based on all active joint count scores collected, and the same MMRM model as for the 
primary analysis. 
 
The “retrieved dropout” analysis addresses a different estimand (effectiveness estimand) than the 
primary and sensitivity analyses (efficacy estimand) of the primary endpoint, by using joint 
count scores collected after cessation of study treatment, including while being treated with other 
therapies. Therefore, results of this analysis will not be considered as a sensitivity analysis of the 
primary endpoint but as an additional analysis addressing a complementary question. 


 
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To examine the pattern of missing data, the number and percentage of subjects with an active 
joint count score at each treatment week will be presented by treatment group for both the 
observed on-treatment data and the retrieved dropout data. 
 
Part B 
The primary analysis and sensitivity analyses of the primary endpoint only utilize the CLASI-A 
score observed before treatment failure visit or subjects discontinued the study treatment. In this 
study, subjects who were considered as treatment failures or discontinued the study treatment 
were encouraged to stay in the study and complete the assessments. 
 
 
 The change in CLASI-A score will be computed 
based on all CLASI-A score scores collected, and the same MMRM model as for the primary 
analysis. 
 
The “retrieved dropout” analysis addresses a different estimand (effectiveness estimand) than the 
primary and sensitivity analyses (efficacy estimand) of the primary endpoint, by using CLASI-A 
scores collected after cessation of study treatment, including while being treated with other 
therapies. Therefore, results of this analysis will not be considered as a sensitivity analysis of the 
primary endpoint but as an additional analysis addressing a complementary question. 
 
To examine the pattern of missing data, the number and percentage of subjects with an active 
joint count score at each treatment week will be presented by treatment group for both the 
observed on-treatment data and the retrieved dropout data. 
 
 


 
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7. SAFETY ANALYSES 
7.1. General Considerations 
All safety analyses will be performed for the safety population. No statistical testing will be 
performed on the safety data. 
 
7.2. Analysis of Adverse Events (AEs) 
All AEs will be coded by system organ class and preferred term using the MedDRA dictionary 
(Version 21.1 or the most updated version at data base lock). In this study, only treatment 
emergent AEs (i.e. those that occurred or worsened after the first randomized dose through the 
end of study) will be analyzed. Such AEs will have an onset date on or after the date of first 
randomized dose or will have presented prior to the first randomized dose and subsequently 
worsened. Therefore, whenever an analysis of summary of AEs is mentioned, it is intended that 
this is in reference to treatment-emergent AEs. 
 
The number and percentage of subjects experiencing one or more treatment-emergent AEs in the 
following categories will be summarized. 
• Any AE 
• Any mild AE 
• Any moderate AE 
• Any severe AE 
• Any related AE 
• Any serious AE 
• Any related serious AE 
• Any AE that led to withdrawal of study drug 
• Any AE that led to study withdrawal 
• Any AE that led to drug interrupted, dose not changed 
• Deaths 
 


 
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The following summaries will be presented. 
• AEs by system organ class (SOC) and preferred term (PT) 
• AEs by PT 
• AEs by PT with an incidence of 5% or more in any of the treatment groups 
• AEs by PT with at least 2% higher in incidence for either BIIB059 group compared 
to placebo 
• Serious AEs by SOC and PT 
• Treatment-related serious AEs by SOC and PT 
• Severe AEs by SOC and PT 
• AEs by relationship to study treatment by SOC and PT 
• Treatment-related AEs by SOC and PT 
• AEs that led to discontinuation of study drug by SOC and PT 
• AEs that led to withdrawal from study by SOC and PT 
• AEs by maximum severity by SOC and PT 
• Suspected unexpected serious adverse reactions (SUSAR) by SOC and PT 
 
To count the number of subjects who experience each AE, a subject experiencing the same AE 
multiple times will only be counted once for that preferred term. Similarly, if a subject 
experiences multiple AEs within the same system organ class, that subject will be counted only 
once for that system. For subjects experiencing the same AE more than once, the occurrence of 
the AE with the greatest severity will be used in the calculation of incidence by severity. 
 
The following listings will be presented. 
• Listing of serious AEs 
• Listing of AEs that led to discontinuation of study drug 
• Listing of AEs that led to withdrawal from study 
• Listing of all AEs 
 


 
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7.3. Analysis of Laboratory Tests 
7.3.1. Shift Analysis for Lab Tests 
Laboratory abnormalities will be summarized with shift from baseline tables. Each 
hematology and chemistry value will be flagged as “low”, “normal”, or “high” relative to the 
normal ranges of the laboratory that performed the assay, or as “unknown” if no results are 
available. Each urinalysis value will be flagged as “positive”, “negative”, or “unknown” if no 
values are available. 
Shift from baseline to high/low status for hematology and chemistry parameters and shifts from 
baseline to high/positive for urinalysis will be presented. In each summary, the denominator for 
the percentage is the number of patients at risk for the shift. The number at risk for a shift to low 
is the number of subjects whose baseline value was not low and who had at least one post- 
baseline value. The number at risk for a shift to high is the number of subjects whose baseline 
value was not high and who had at least one post-baseline value. Subjects will be counted only 
once for each parameter and each type of shift regardless of how many post-dosing assessments 
had that type of shift. A shift to high includes normal to high, low to high, and unknown to 
high; a shift to low includes normal to low, high to low, and unknown to low. A shift to positive 
includes ‘negative’ to ‘positive’ and ‘unknown’ to ‘positive’. 
 
A listing of normal ranges will be provided for all laboratory parameters. 
 
7.3.2. Analysis of Change from Baseline and Actual Values 
The absolute and percent changes from baseline by visit will be summarized for quantitative 
laboratory parameters using descriptive statistics. Actual values will also be summarized in a 
similar way. 
 
7.3.3. Analysis of Potentially Clinically Significant Abnormalities 
The number and percentage of subjects with potentially clinically significant abnormal values for 
laboratory parameters will be summarized. A listing of potentially clinically significant abnormal 


 
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values will also be presented. Potential clinical significance will be determined for selected 
parameters based on the criteria listed below. 
 
Parameter Name 
 PCS Low 
PCS High 
Hematology 
White Blood Cells 
<3.0 x 103/mm3 
>16 x 103/mm3 
Neutrophils 
<1.5 k/mm3 
>13.5 k/mm3 
Lymphocytes 
<0.8 k/mm3 
>12 k/mm3 
Monocytes 
N/A 
>2.5k/mm3 
Eosinophils 
N/A 
>1.6 k/mm3 
Basophils 
N/A 
>1.6 k/mm3 
Hemoglobin 
 for Females
 For Males
 
≤ 9.5 g/dL 
≤ 11.5 g/dL 
 
≥ 17.5 g/dL 
≥ 19.0 g/dL 
Hematocrit  
         for Females  
                          
                    for Males 
  
  ≤ 32% 
<37% 
 
≥ 54% 
≥ 60% 
Red Blood Cells (RBC) 
≤ 3.5 x 106/mm3 
≥ 6.4 x 106/mm3 
Platelet count 
≤ 75 x 103/mm3 
≥ 700 x 103/mm3 
Chemistry 
Sodium 
≤ 126 mEq/L 
≥ 156 mEq/L 
Potassium 
≤ 3.0 mEq/L 
≥ 6 mEq/L 
Chloride 
≤ 90 mEq/L 
≥ 118 mEq/L 
Bicarbonate 
≤ 16 mEq/L 
≥ 35 mEq/L 
Calcium 
<8.0 mg/dL 
≥ 12 mg/dL 
Magnesium 
<1.2 mEq/L 
>2.3 mEq/L 
Inorganic Phosphorous 
≤ 1.7 mg/dL 
≥ 5.3 mg/dL 
Aspartate aminotransferase (AST) 
N/A 
≥ 3 xULN 
Alanine Aminotransferase (ALT) 
N/A 
≥ 3 x ULN 
Alkaline phosphatase 
N/A 
≥ 3 x ULN 


 
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Creatinine 
N/A 
>1.5xULN 
Total Bilirubin 
N/A 
>1.5xULN 
Total Protein 
≤ 4.5 g/dL 
≥ 10 g/dL 
Albumin 
≤ 2.5 g/dL 
N/A 
Uric Acid for 
Females 
for Males 
N/ A 
≥ 8.5 mg/dL 
≥ 10.5 mg/dL 
Glucose (Fasting) 
 
(Non-fasting) 
≤ 40 mg/dL 
≤ 40 mg/dL 
≥ 160 mg/dL 
≥ 250 
Creatinine Phosphokinase (CPK) 
N/A 
>3x ULN 
Total Cholesterol 
N/A 
>300 mg/dL 


 
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7.4. Vital Signs 
The number and percentage of subjects with clinically relevant abnormalities in vital signs post- 
baseline will be summarized. Subjects evaluated will be safety subjects with a baseline and at 
least one post-baseline assessment for that vital sign. Abnormal vital signs will be determined by 
the following criteria. 
 
Vital Sign 
Criteria to determine clinically relevant abnormal vital signs 
Temperature 
>38°C and an increase from pre-dose of at least 1°C 
Pulse 
>100 beat per minute (bpm) and an increase from baseline of more than 20 
bpm, or <50 bpm and a decrease from baseline of more than 20 bpm. 
Systolic Blood Pressure 
>160 mmHg and an increase from baseline of more than 40 mmHg, or 
<90 mmHg and a decrease from baseline of more than 30 mmHg 
Diastolic Blood Pressure 
>100 mmHg and an increase from pre-dose of more than 30 mmHg, or 
<45 mmHg and a decrease from pre-dose of more than 20 mmHg 
 
A listing of all vital sign values will be presented for subjects with any vital signs abnormalities. 
Clinically relevant abnormal vital signs will be flagged in the listing. 
 
7.5. ECG 
The number and percentage of subjects with shifts from normal at baseline to abnormal in ECG 
results will be summarized. If there is no ECG result at baseline, the subject will be counted in 
the unknown category. A shift to abnormal will include a shift from “unknown” or “normal” at 
baseline to “abnormal” post- baseline. 
 
7.6. Physical Examination 
Abnormal findings which are noted after subjects received study treatment and are deemed by the 
investigator as clinically significant will be reported as AEs and included in AE analyses. 
 


 
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8. PK ANALYSES 
For the PK population, serum concentration of BIIB059 will be summarized descriptively using 
nominal time points. The mean values (+/- SD) will be plotted over time by treatment group on 
the linear and log linear scale.  Measurements that are below the level of quantification (BLQ) 
will be set to missing before statistics are calculated, if the BLQ occurs before the first 
measurable concentration (such as predose), it should be set to zero. If the value of the 
concentration is "Non-Determinable", then the concentration value will be set to missing. 
Additionally, a population PK analysis will be conducted to characterize the PK of BIIB059 in 
subjects with SLE and CLE, estimate population PK parameters of BIIB059, estimate random 
inter- and intrasubject variability, and estimate random residual variability associated with the 
estimation of PK model parameters. The PK parameters calculations are detailed in a separate 
PK analysis plan. PK parameters will be summarized with the following statistics: n, mean, SD, 
percent coefficient of variation, median, minimum, maximum, and geometric mean. 
 
The population PK analysis may also be used to identify sources of variability (continuous and 
categorical covariates) that may influence the PK of BIIB059 in patients. In addition, exposure-
response (efficacy) analysis may be performed to evaluate the relationship between exposure of 
BIIB059 and clinical endpoints, which will be used to justify doses for Phase 3 studies. Further 
details can be found in the PK analysis plan.  
 
9.  OTHER ANALYSES 
The quantitative or qualitative analysis of the relationship between the BIIB059 exposure and the 
primary and secondary endpoints will be performed. As described in Section 8, details of the 
analysis will be included in a separate PK analysis plan for the PKPD modeling. 
 
 
 


 
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9.1. Immunogenicity Data 
The analysis population for immunogenicity is defined as all subjects who are randomized and 
who have been dosed with study treatment and have at least 1 post-dose immunogenicity sample 
collected. 
Summary of positive anti-BIIB059 serum antibodies will be presented by visits and by treatment 
group.   
To define immunogenicity status the following rules will be used 
▪ The baseline value is defined as the latest immunogenicity data collected at any 
time prior to the first dose.  If no immunogenicity data are collected prior to the 
first dose, the baseline value is missing and will be imputed as anti-drug antibody 
negative for immunogenicity analyses.  
▪ Subjects with at least one confirmed post-treatment positive result will be 
considered positive for anti-BIIB059 antibodies if their baseline result is negative. 
▪ Subjects where none of the post-treatment samples were positive for anti-BIIB059 
antibodies will be considered negative regardless of their baseline result. 
▪ For subjects that are confirmed positive at baseline and have at least one post-
treatment sample with a ≥ 4-fold increase in titer will be considered positive for 
anti-BIIB059 antibodies. Subjects that are positive at baseline, with subsequent 
post-treatment samples titers that are within 2-fold will be considered negative for 
anti-BIIB059 antibodies.  
▪ In addition, for subjects that are considered anti-BIIB059 antibody positive with 
final immunogenicity data, the following may be evaluated: 
• Persistence of the anti-BIIB059 antibody response: More than one 
positive evaluation that are ≥112 days apart or a positive evaluation at 
the last time point with no further samples available.  
• Transient anti-BIIB059 antibody response: A single positive evaluation 
or more than one positive evaluation <112 days apart. 
 
The impact of anti-BIIB059 antibodies on PK parameters may be evaluated by considering 
antibody status (positive or negative, persistent/transient) as a co-variate in the analysis. The 
impact on efficacy may be evaluated by summarizing key efficacy endpoints by antibody status 
(positive or negative, persistent/transient). In addition, to determine the relationship (if any) of 


 
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anti-BIIB059 antibodies on safety, incidence of adverse events, serious adverse events and 
events of particular interest will be presented by antibody status (positive or negative, 
persistent/transient) as well as by timing of the events. 
 


 
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10. INTERIM ANALYSES 
10.1. Interim Analysis 1 (IA1): Futility 
An unblinded interim analysis for futility Part B (and possible expansion of Part A) will be 
performed. The IA will be performed after approximately 45% of the subjects in Part B (PV2 and 
subsequent version) have completed their Week 12 Treatment Visit. 
At the time of the IA, it is estimated that approximately 50% of subjects in Part A will have 
completed their Week 12 treatment visit. Depending on the outcome of the IA, BIIB059 doses 
may be adjusted (downwards or upwards), with predicted exposures within what was shown to 
be safe and well tolerated. In addition, up to 70 subjects may further be enrolled into Part A, 
which objectives are as follow:  
 
1) potentially include an expanded SLE patient population based on more inclusive criteria,  
2) potentially adjust the dose of BIIB059 and,  
3) To provide greater precision for the Week 24 endpoints, including the SRI-4. 
 
Unblinded subject baseline characteristics (e.g., Joint Count, SLEDAI-2K) will be assessed. The 
randomization stratification factors will be re-evaluated in the expanded enrollment to achieve 
balance between treatment groups.  
 
The IA will be performed by independent personnel (internal and/or external) not involved in the 
conduct of the study. Unblinded tables, listings, or graphs (TLGs) will be generated by 
independent personnel (internal or external) not involved in the conduct of the study. 
The team that performs the unblinded interim analysis must not be involved in the study conduct 
between the interim DBL and the final DBL. They can however be part of the final analysis team 
after the final DBL has occurred. At the discretion of Biogen, unblinded TLGs and/or data may 
be shared with Sponsor personnel who are not directly involved in the conduct of the study. 
Additional information will be provided in an unblinding plan. 
 
The endpoints and analysis to be included in the IA1 are listed in Appendix B. 


 
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10.2. Interim Analysis 2 (IA2): End of Treatment Periods 
After the last subjects complete the Double-Blind Treatment Periods for Part A (at Week 24) 
and Part B (at Week 16), an interim database lock will occur and an IA of efficacy and safety 
data will be conducted. All Investigators, study site personnel, and subjects will remain blinded 
to treatment assignments until after the end of the study. Members of the Biogen study team not 
in direct contact with the study sites will have access to the study data after all subjects 
complete all Week 24 assessments in Part A and all Week 16 assessments in Part B. Members 
of the Biogen study team who become unblinded to the data for this IA will have no further 
contact with study sites until after the final database lock. 
Unblinding details will be provided in the unblinding plan.  
 
The endpoints and analysis to be included in the IA1 and IA2 are listed in Appendix B. 
 
11. SAMPLE SIZE JUSTIFICATION 
Part A:  
The sample size for Part A is 100 subjects, randomized in a 1:1 ratio, with 50 subjects allocated 
to each treatment group. This sample size will provide approximately 71% power to detect a 
statistically significant difference in the Week 24 absolute change from baseline active joint 
count, assuming a standard deviation of 6, a maximal difference of BIIB059 over placebo of 2.5, 
a 20% dropout rate, and a 2-sided testing at the 0.2 level significance. If the study is not stopped 
for futility at the IA, then up to an additional 70 subjects may be enrolled into Part A. These may 
increase the power to approximately 87% at Week 24.  
 
Part B:  
The planned sample size for Part B is 100 subjects, randomized in a 1:1:1:1 ratio, with 25 
subjects per dosage arm of BIIB059 (50 mg, 150 mg, and 450 mg) and placebo. This sample size 
will provide approximately 90% power to detect a dose-response relationship in the Week 16 
percent change from baseline score in CLASI-A score, assuming a standard deviation of 30, a 
maximal difference of BIIB059 over placebo of 27.5%, and a 20% dropout rate. Five different 


 
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dose-response relationships will be tested at the 2-sided 10% significance level with the MCP-Mod 
method being used to control for multiplicity. Further details about the dose-response analyses can 
be found in Section 6.2. 
 
 
 
 
 
 
 
 
 
 
 The power calculations are based on assuming a 
standard deviation of 30, a maximal difference of BIIB059 over placebo of 27.5% at 450 mg, 
and a 20% dropout rate. 
  


 
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12. REFERENCES 
 
▪ Ball EM, Bell AL. Lupus arthritis--do we have a clinically useful classification? 
Rheumatology (Oxford). 2012 May;51(5):771-9. 
▪ Bretz, F; Pinheiro, JC; Branson, M. Combining multiple comparisons and modeling 
techniques in dose-response studies. Biometrics. 2005;61(3):738-48. 
▪ Bonilla-Martinez, Z.; Albrecht, J.; Troxel, AB; Taylor, L.; Okawa, J; Dulay, S; Werth, 
VP. The Cutaneous Lupus Erythematosus Disease Area and Severity Index. Arch 
Dermatol. 2008; 144(2): 173-180. 
▪ 
 
 
 
▪ Gladman, DD; Goldsmith, CH; Urowitz, MB; Bacon, P; Bombardier, C; Isenberg, D; 
Kalunian, K; Liang, MH; Maddison, P; Nived, O; et al. Sensitivity to change of 3 
Systemic Lupus Erythematosus Disease Activity Indices: international validation. J 
Rheumatol. 1994 Aug;21(8):1468-71. 
▪ Gladman, DD; Ibañez, D; Urowitz, MB. Systemic lupus erythematosus disease activity 
index 2000. J Rheumatol. 2002 Feb; 29(2):288-91. 
▪ 
 
 
 
▪ Isenberg DA, Rahman A, Allen E, Farewell V, Akil M, Bruce IN, D'Cruz D, Griffiths B, 
Khamashta M, Maddison P, McHugh N, Snaith M, Teh LS, Yee CS, Zoma A, Gordon C. 
BILAG 2004. Development and initial validation of an updated version of the British 
Isles Lupus Assessment Group's disease activity index for patients with systemic lupus 
erythematosus. Rheumatology (Oxford). 2005 Jul;44(7):902-6. 
▪ Klein R, Moghadam-Kia S, Taylor L, Coley C, Okawa J, LoMonico J, Chren MM, Werth 
VP. Quality of life in cutaneous lupus erythematosus. J Am Acad Dermatol. 2011 
May;64(5):849-58. 


 
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▪ Little RJA, Rubin DB. Statistical Analysis with Missing Data. 1st ed. New York: John 
Wiley & Sons, Inc; 1987. 
▪ LupusQoL instrument scoring, RWS Life Sciences. 
http://www.corptransinc.com/sites/lupusqol/instrument-information 
▪ McElhone K, Abbott J, Shelmerdine J, Bruce IN, Ahmad Y, Gordon C, Peers K, Isenberg 
D, Ferenkeh-Koroma A, Griffiths B, Akil M, Maddison P, Teh LS. Development and 
validation of a disease-specific health-related quality of life measure, the LupusQol, for 
adults with systemic lupus erythematosus. Arthritis Rheum. 2007 Aug 15;57(6):972-9. 
▪ Optum PRO CoRE smart measurement system manual, version 1.4. Optum, Inc., 
Johnston, RI; 2019 Mar. 
▪ Rubin, D. B. Multiple Imputation for Nonresponse in Surveys. New York: John Wiley & 
Sons; 1987 
▪ 
 
▪ Ware JE Jr. SF-36 health survey update. Spine (Phila Pa 1976). 2000 Dec 
15;25(24):3130-9. 
▪ Yee CS, Cresswell L, Farewell V, Rahman A, Teh LS, Griffiths B, Bruce IN, Ahmad Y, 
Prabu A, Akil M, McHugh N, D'Cruz D, Khamashta MA, Isenberg DA, Gordon C. 
Numerical scoring for the BILAG-2004 index. Rheumatology (Oxford). 2010 
Sep;49(9):1665-9. 
 
 
 
 
 
 
 
 
 


 
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APPENDICES 


 
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Appendix B: Summary of Additional Interim Analyses 
 
 
Section of 
the SAP 
Note: 
Study Part  
Subject disposition 
5.2 
IA1and IA2, MITT population 
Part A and B 
Demography and 
baseline disease 
characteristics 
5.3 
IA1and IA2, MITT population 
Part A and B 
Previous medications 
used for the treatment 
of SLE and/or CLE 
5.4 
 IA1and IA2 
Part A and B 
Treatment exposure  
5.5 
IA1and IA2 
Part A and B 
Concomitant 
therapies 
5.6 
IA1and IA2 
Part A and B 
Protocol Deviations 
5.7 
IA2: Summary of major protocol 
deviations 
Part A and B 
Primary endpoint: 
Primary analysis 
6.2 
IA1 and IA2: Part B: Model based and 
summary statistics over time 
Part A, IA1 Descriptive statistics by 
visit; IA2: Model based and summary 
statistics over time. 
Part A and B 
Secondary and 
additional efficacy 
endpoints 
  
6.3, 6.4 
Part A, IA1: Descriptive statistics by 
visit of the following endpoints- SRI-4, 
TJC, SJC, PGA of SLE (VAS), 
SLEDAI-2K, BILAG-2004, CLASI-A 
based endpoints, 
 
 
Part A, IA2: Model based and summary 
statistics by visit of the following 
endpoints- SRI-4, TJC, SJC, PGA of 
Part A 


 
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SLE (VAS), SLEDAI-2K, proportion of 
subjects with no new organ system 
affected, CLASI-A based endpoints, 
BILAG based severe flare; 
Descriptive statistics by visit for the 
following endpoints- BILAG-2004 
score, 
 
 
 
Secondary and 
additional efficacy 
endpoints 
 
 
6.3, 6.4 
Part B, IA1: Model based and summary 
statistic over time- CLASI-A based 
endpoints;  
Descriptive statistics by visit of the 
following endpoints- SLEDAI-2K, 
, 
Physicians Global assessment of SLE 
(VAS), 
. 
Part B, IA2: Model based and summary 
statistic over time - CLASI-A based 
endpoints, SLEDAI-2K; 
Descriptive statistics by visit of the 
following endpoints - 
, PGA 
of SLE (VAS), 
 
 
Part B 
Immunoglobulins 
(IgG, IgA, IgM) 
change from baseline 
by visit 
7.3.2 
Part A and B, IA1: Descriptive statistics 
by visit. 
 
Part A and B 


 
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Safety analyses 
7 
IA2: Selection of adverse events 
analysis and laboratory analysis 
Part A and B 
PK concentrations 
and parameters 
9 
IA1 and IA2: PK concentration data 
needed for Pop PK analyses   
Part A and B 
 
 
 
 
 
 
 
 


 
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Appendix C Efficacy Instruments  
C.1 Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) 
The CLASI instrument was developed to specifically evaluate lupus skin manifestations. It 
differentiates and separately scores disease activity (CLASI-A) 
. The 
activity scale includes measurements of erythema, scale and hypertrophy, and mucous membrane 
disease, whereas the damage scale measures hyperpigmentation, atrophy, and scarring alopecia. Each 
part of the body is listed separately, from the scalp to the feet, in addition to sections focusing on 
mucous membrane involvement and alopecia. For the activity score, points are given for the presence 
of erythema, scale, mucous membrane lesions, recent hair loss, and inflammatory alopecia. For the 
damage score, points are given for the presence of dyspigmentation, scarring, and scarring alopecia. 
Total dyspigmentation scores are doubled when most of the dyspigmentation has been present for 
more than 1 year. Scores for each area are assigned based on the most severe lesion within the area of 
interest. Of note, affected body parts are weighted equally regardless of surface area and number of 
lesions present. Separate composite scores for activity and damage are calculated by simply summing 
the individual component scores. CLASI-A scores of 0-9, 10-20, and 21-70 represent disease severity 
of mild, moderate, and severe, respectively [Bonilla-Martinez 2008; Klein 2010].  
 
C.2 Systemic Lupus Erythematosus Disease Activity Index -2000 (SLEDAI-2K)  
The SLEDAI-2K is a reliable, valid, simple, 1-page activity index that measures disease activity and 
records feature of active lupus as present or not [Gladman 2002]. It is a modification of the SLEDAI 
to reflect persistent, active disease in those descriptors that had previously only considered new or 
recurrent occurrences. The SLEDAI-2K has been validated against the SLEDAI, which has been 
shown to be reliable at different levels of disease activity [Gladman 1994].  
The SLEDAI-2K uses a weighted checklist to assign a numeric score based on the presence or 
absence of 24 symptoms at the time of assessment or during the previous 28 days. Each symptom 
present is assigned between 1 and up to 8 points based on its usual clinical importance, yielding a 
total score that ranges from 0 points (no symptoms) to 105 points (presence of all defined 
symptoms). However, if scored correctly, it is rare for even the sickest patients to score more than 20 
points. The assessor is also requested to assess the subject’s symptoms using the visual analog scale 
(VAS) for the Physician’s Global Assessment (PGA).  


 
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C.3 British Isles Lupus Activity Group - 2004  
The BILAG-2004 Disease Activity Index evaluates SLE activity in a number of organ systems, based 
on the principle of “physician’s intention to treat” [Isenberg 2005]. The primary purpose of the 
BILAG in this study is to assess possible worsening in specific organ systems. Additional analyses of 
improvements in disease activity as assessed by the BILAG-2004 numeric scoring will also be 
performed [Yee 2010].  
A separate alphabetic score is assigned to each organ system, corresponding in general to the 
following definitions:  
 BILAG A: Severe disease activity requiring systemic high-dose oral corticosteroids, intravenous 
pulse corticosteroids, systemic immunosuppressants, therapeutic high-dose anticoagulation in the 
presence of high-dose corticosteroids, or prednisone ≥20 mg/day. Note that in the context of a 
clinical trial protocol with medication restrictions and blinded study treatment, the term “requiring” 
is not taken literally but indicates that if all else were equal this would be the degree of treatment 
indicated. It is also understood that some patients respond differently to levels of medication than do 
others, so that in assessing patients with the BILAG, “intent- to- treat” really means that most 
patients with this degree of symptom would require this level of treatment, not necessarily the patient 
in question.  
 BILAG B: Moderate disease activity requiring treatment with systemic low-dose oral 
glucocorticoids, intramuscular or intra-articular or soft tissue corticosteroid injection, topical 
corticosteroid or immunosuppressants, or symptomatic therapy such as antimalarial medications or 
NSAIDs  
 BILAG C: Mild disease  
 BILAG D: System previously affected but now inactive  
 BILAG E: System never involved  
 
The BILAG-2004 is evaluated by scoring each item of a list of signs and symptoms as:  
1. Improving  
2. Same  


 
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3. Worse  
4. New  
 
0 Not present  
(ND) Not done  
For some items, appropriate responses may be:  
 Y/N OR numeric values where indicated  
 Y/N and confirm this is due to SLE activity  


 
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All signs and symptoms scored must be due to SLE. Use of a glossary provided with the BILAG-
2004 instrument and training of assessors in use of the instrument are essential to obtaining reliable 
and consistent results. Use of the BILAG-2004 index for evaluating flares has been identified as a 
robust way of evaluating the efficacy of drugs; this judgment has been corroborated by external 
advisors and regulatory authorities.  
BILAG assessments should be conducted by a trained evaluator, with documentation of training.  
A copy of the BILAG-2004 and glossary is provided in the Study Reference Guide. 
 
C.4 Tender and Swollen Joint Counts  
Joint involvement is a frequent manifestation in patients affected by SLE and occurs in up to 90% of 
patients at the onset or during the course of the disease [Ball and Bell 2012]. An active joint is 
defined as a joint with pain and signs of inflammation (e.g., tenderness, swelling or effusion). A 28-
joint assessment will be performed. The joints to be assessed bilaterally include the shoulders, 
elbows, wrists (radiocarpal, carpal, and carpometacarpal bones are considered as a single unit), 
metacarpophalangeal (MCP) joints (MCP 1, 2, 3, 4, and 5), proximal interphalangeal (PIP) joints 
(PIP 1, 2, 3, 4 and 5), and the knees. Artificial and ankylosed or fused joints will be excluded from 
tenderness and swelling assessments. 
 
C.5 Physician Global Assessment of SLE (VAS)  
The PGA is used to quantify disease activity and is measured using an anchored VAS. The PGA asks 
the Investigator to assess the subject’s current disease activity from a score of 0 (none) to 3 (severe), 
with the assessment made relative not to the subject’s most severe state but the most severe state of 
SLE that might exist at study visits.  
A cop y of the PGA of SLE is provided in the Study Reference Guide.  
 
 
  
 
 
 
  


 
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o 
 
  
 
  
 
  
 
 
 
 


 
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Appendix D MCP-MOD candidate models 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Appendix E Oral Corticosteroid Tapering Schedule 
 
Timing by Weeks (Days) 
Allowable OCS Dosing (mg) 
Week 1-4 (Day 1 to 28) 
Stable;  
1 OCS rescue for SLE activity allowed up to maximum 
10mg/day above Day 1 dosage, but must return to Day 1 level 
within 7 days 
Week 5 (Day 29 – 35) 
17.5 
Week 6 (Day 36 – 43) 
17.5 
Week 7 (Day 44 – 50) 
15 
Week 8 (Days 51 to 57) 
15 
Week 9 (Days 58 – 64) 
12.5 
Week 10 (Days 65 to 71) 
12.5 
Week 11 (Days 72 to 78) 
10 
Week 12 (Days 79 to 85) 
10 
Week 13-16 
(Days 86 to 113) 
10  
 
Week 17-24 
(Days 114 to 169) 
10 
Note 1: Two rescues are allowed out of the three described.  
Note 2:  Between Weeks 1 and 4 (Rescue 1). Once a dose is reduced it must not be re-increased, with the exception of the 1-
time rescue.  
Note 3: Between Weeks 5 and 7 (Rescue 2) and between Weeks 9 and 11 (Rescue 3), the dose can be increased to the 
previous dose level for up to 1 week before restarting the tapering schedule.