Clinical trial NCT03573505
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Biogen
Start date: 2018-09-24; Completion date: 2019-11-14
Enrollment: 109 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the efficacy of BG00011 compared with placebo in participants with Idiopathic Pulmonary Fibrosis (IPF). The secondary objectives of this study are: to evaluate the efficacy of BG00011 compared with placebo in participants with IPF as determined by change in percent predicted forced (expiratory) vital capacity (FVC); to assess progression-free survival in participants who receive BG00011 compared with placebo; to assess the occurrence of IPF exacerbation in participants who receive BG00011 compared with placebo; to assess the incidence of absolute decline in FVC ≥10% in participants who receive BG00011 compared with placebo; to assess the time to death or lung transplantation in participants who receive BG00011 compared with placebo, and the transplant-free survival rate at Week 26 and Week 52; to assess the time to non-elective hospitalizations in participants who receive BG00011 compared with placebo; to assess additional pulmonary function test (PFT) findings in participants who receive BG00011 compared with placebo; To assess performance on the 6 minute walk test (6MWT) in participants who receive BG00011 compared with placebo; to evaluate the safety and tolerability of BG00011; and to evaluate the serum concentration of BG00011.

Detailed description:

Arms: arm 1: Participants will receive BG00011 56 mg once weekly by subcutaneous (SC) injection for 52 weeks. arm 2: Participants will receive placebo once weekly by (SC) injection for 52 weeks.
Interventions: intervention 1: BG00011 intervention 2: Placebo
Intervention descriptions: intervention 1: Administered as specified in the treatment arm. intervention 2: Administered as specified in the treatment arm.

Protocol documents:
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:
203PF203 / NCT03573505
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead, Berkshire
SL6 4AY
United Kingdom
PHASE OF DEVELOPMENT:
2b
PROTOCOL TITLE: A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of BG00011 in Patients With Idiopathic Pulmonary Fibrosis
EUDRA CT NUMBER:  2017-003158-18
DATE:
02 July 2019
Version 2
FINAL
Supersedes previous Version 1 dated 20 November 2017




Protocol 203PF203
Version 2
Phase 2b Efficacy and Safety Study of BG00011
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TABLE OF CONTENTS
SPONSOR SIGNATURE PAGE ....................................................................................................2
1.
SYNOPSIS ...................................................................................................................9
2.
LIST OF ABBREVIATIONS.....................................................................................13
3.
SPONSOR INFORMATION .....................................................................................16
4.
INTRODUCTION......................................................................................................17
4.1.
Overview of Idiopathic Pulmonary Fibrosis...............................................................17
4.2.
Diagnostic Criteria for IPF .........................................................................................18
4.3.
Current Therapies for Idiopathic Pulmonary Fibrosis................................................19
4.4.
Profile of Previous Experience With BG00011..........................................................21
4.4.1.
Mechanism of Action .................................................................................................21
4.4.2.
Nonclinical Experience...............................................................................................22
4.4.2.1.
Pharmacology Models ................................................................................................22
4.4.2.2.
Toxicology Summary .................................................................................................23
4.4.2.3.
Nonclinical Pharmacokinetics ....................................................................................23
4.4.3.
Clinical Experience.....................................................................................................24
4.5.
Study Rationale and Dose Selection...........................................................................26
5.
STUDY SCHEMATIC AND STUDY ACTIVITIES................................................29
5.1.
Study Schematic .........................................................................................................29
5.2.
Study Activities ..........................................................................................................30
6.
STUDY OBJECTIVES AND ENDPOINTS..............................................................36
7.
STUDY DESIGN .......................................................................................................40
7.1.
Study Overview ..........................................................................................................40
7.2.
Study Duration, Study Visits, and Follow-Up............................................................41
7.2.1.
Screening ....................................................................................................................41
7.2.2.
Placebo-Controlled Treatment Period ........................................................................42
7.2.3.
Safety Follow-Up Visit...............................................................................................42
7.2.4.
Study Treatment Discontinuation...............................................................................43
7.2.5.
Withdrawal From the Study........................................................................................43
7.2.6.
Unscheduled Visit for Acute Exacerbation of IPF .....................................................43
7.2.6.1.
Determination of IPF Exacerbation............................................................................44
7.3.
Study Stopping Rules .................................................................................................45


Protocol 203PF203
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7.4.
End of Study ...............................................................................................................45
8.
SELECTION OF SUBJECTS ....................................................................................46
8.1.
Inclusion Criteria ........................................................................................................46
8.2.
Exclusion Criteria.......................................................................................................47
9.
SCREENING AND RANDOMIZATION .................................................................50
9.1.
Screening ....................................................................................................................50
9.2.
Randomization............................................................................................................50
9.3.
Blinding Procedures....................................................................................................50
10.
DISCONTINUATION OF STUDY TREATMENT AND WITHDRAWAL 
OF SUBJECTS FROM THE STUDY........................................................................52
10.1.
Discontinuation of Study Treatment...........................................................................52
10.1.1.
Reasons for Study Treatment Discontinuation...........................................................52
10.1.1.1.
Safety Criteria for Study Treatment Discontinuation.................................................53
10.2.
Withdrawal of Subjects From the Study.....................................................................53
10.2.1.
Reasons for Withdrawal of Subjects from the Study..................................................53
10.3.
Lost to Follow-Up.......................................................................................................54
11.
STUDY TREATMENT USE .....................................................................................55
11.1.
Regimen......................................................................................................................55
11.2.
Modification of Dose and/or Treatment Schedule......................................................55
11.3.
Precautions..................................................................................................................55
11.4.
Compliance.................................................................................................................55
11.5.
Concomitant Therapy and Procedures........................................................................55
11.5.1.
Concomitant Therapy .................................................................................................55
11.5.1.1.
Allowed Concomitant Therapy...................................................................................55
11.5.1.2.
Disallowed Concomitant Therapy..............................................................................56
11.5.2.
Concomitant Procedures.............................................................................................56
11.6.
Continuation of Treatment..........................................................................................57
12.
STUDY TREATMENT MANAGEMENT................................................................58
12.1.
BG00011.....................................................................................................................58
12.1.1.
BG00011 Preparation .................................................................................................58
12.1.2.
BG00011 Storage........................................................................................................58
12.1.3.
BG00011 Handling and Disposal...............................................................................59


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12.1.4.
BG00011 Accountability............................................................................................59
12.2.
Reference Product.......................................................................................................59
13.
EFFICACY, PHARMACOKINETIC, 
 
ASSESSMENTS.........................................................................................................60
13.1.
Clinical Efficacy Assessments....................................................................................60
13.1.1.
Pulmonary Function Testing.......................................................................................60
13.1.1.1.
Spirometry ..................................................................................................................60
13.1.1.2.
Carbon Monoxide Diffusion Capacity........................................................................60
13.1.1.3.
Full-Body Plethysmography.......................................................................................60
13.1.2.
High-Resolution Computed Tomography ..................................................................61
13.1.3.
Acute Exacerbations of IPF........................................................................................61
13.1.4.
Respiratory Hospitalizations.......................................................................................62
13.1.5.
6-Minute Walk Test....................................................................................................62
62
63
63
63
13.2.
Pharmacokinetic Assessments....................................................................................63
63
64
64
14.
SAFETY ASSESSMENTS ........................................................................................65
14.1.
Clinical Safety Assessments.......................................................................................65
14.2.
Laboratory Safety Assessments..................................................................................66
14.3.
Immunogenicity Assessments ....................................................................................67
15.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................68
15.1.
Definitions ..................................................................................................................68
15.1.1.
Adverse Event.............................................................................................................68
15.1.2.
Serious Adverse Event................................................................................................68
15.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments................69
15.2.
Safety Classifications..................................................................................................69
15.2.1.
Investigator Assessment of Events.............................................................................69


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15.2.2.
Relationship of Events to Study Treatment................................................................70
15.2.3.
Severity of Events.......................................................................................................70
15.2.4.
Expectedness of Events ..............................................................................................70
15.3.
Monitoring and Recording Events..............................................................................70
15.3.1.
Adverse Events ...........................................................................................................70
15.3.2.
Serious Adverse Events..............................................................................................71
15.3.3.
Immediate Reporting of Serious Adverse Events.......................................................71
15.3.3.1.
Deaths .........................................................................................................................72
15.3.4.
Suspected Unexpected Serious Adverse Reactions....................................................72
15.4.
Procedures for Handling Special Situations ...............................................................72
15.4.1.
Pregnancy ...................................................................................................................72
15.4.2.
Overdose.....................................................................................................................73
15.4.3.
Medical Emergency....................................................................................................73
15.4.3.1.
Unblinding for Medical Emergency...........................................................................73
15.5.
Contraception Requirements ......................................................................................73
15.6.
Safety Responsibilities................................................................................................75
15.6.1.
The Investigator..........................................................................................................75
15.6.2.
The Sponsor................................................................................................................75
16.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........76
16.1.
Demography and Baseline Characteristics .................................................................76
16.2.
Efficacy.......................................................................................................................76
16.2.1.
Analysis Population....................................................................................................76
16.2.2.
Methods of Analysis...................................................................................................76
16.2.2.1.
General Considerations...............................................................................................76
16.2.2.2.
Analysis of the Primary Endpoint...............................................................................76
16.2.2.3.
Analysis of the Secondary Endpoints.........................................................................77
16.2.2.4.
Analysis of Additional Endpoints...............................................................................78
16.3.
Pharmacokinetics........................................................................................................78
16.3.1.
Analysis Population....................................................................................................78
16.3.2.
Methods of Analysis...................................................................................................78
79
79


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79
79
16.6.
Safety..........................................................................................................................79
16.6.1.
Analysis Population....................................................................................................79
16.6.2.
Methods of Analysis...................................................................................................80
16.6.2.1.
Adverse Events ...........................................................................................................80
16.6.2.2.
Clinical Laboratory Results........................................................................................80
16.6.2.3.
Vital Signs ..................................................................................................................80
16.6.2.4.
Electrocardiograms.....................................................................................................80
16.6.2.5.
Physical Examinations................................................................................................80
16.7.
Immunogenicity Data .................................................................................................80
16.7.1.
Analysis Population....................................................................................................80
16.7.2.
Methods of Analysis...................................................................................................80
16.8.
Interim Analyses.........................................................................................................81
16.9.
Sample Size Considerations .......................................................................................81
17.
ETHICAL REQUIREMENTS ...................................................................................82
17.1.
Declaration of Helsinki...............................................................................................82
17.2.
Ethics Committee........................................................................................................82
17.3.
Subject Information and Consent ...............................................................................83
17.4.
Subject Data Protection ..............................................................................................83
17.5.
Compensation for Injury.............................................................................................83
17.6.
Conflict of Interest......................................................................................................84
17.7.
Registration of Study and Disclosure of Study Results..............................................84
18.
ADMINISTRATIVE PROCEDURES.......................................................................85
18.1.
Study Site Initiation....................................................................................................85
18.2.
Quality Control and Quality Assurance......................................................................85
18.3.
Monitoring of the Study..............................................................................................85
18.4.
Study Funding.............................................................................................................86
18.5.
Publications.................................................................................................................86
19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION........................87
19.1.
External Contract Organizations.................................................................................87
19.1.1.
Contract Research Organization.................................................................................87


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Phase 2b Efficacy and Safety Study of BG00011
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19.1.2.
Interactive Response Technology...............................................................................87
19.1.3.
Electronic or Remote Data Capture............................................................................87
19.1.4.
Central Laboratories for Laboratory Assessments .....................................................87
19.1.5.
Central Facility for Other Assessments ......................................................................87
19.2.
Study Committees.......................................................................................................88
19.2.1.
Advisory Committee...................................................................................................88
19.2.2.
Data Safety Monitoring Board....................................................................................88
19.3.
Changes to Final Study Protocol ................................................................................88
19.4.
Ethics Committee Notification of Study Completion or Termination........................88
19.5.
Retention of Study Data..............................................................................................89
19.6.
Study Report Signatory...............................................................................................89
20.
SIGNED AGREEMENT OF THE STUDY PROTOCOL.........................................90
21.
REFERENCES ...........................................................................................................91
LIST OF TABLES
Table 1:
Summary of High-Resolution Computed Tomography and Surgical Lung 
Biopsy Criteria for Diagnosis of IPF..........................................................................19
Table 2:
Schedule of Events .....................................................................................................30
LIST OF FIGURES
Figure 1:
BG00011 Mechanism of Action.................................................................................22
Figure 2:
Plot of BG00011 Exposure and Change in pSMAD2 From Baseline (Study 
203PF201)...................................................................................................................27
Figure 3:
Schematic for Study 203PF203 ..................................................................................29


Protocol 203PF203
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Phase 2b Efficacy and Safety Study of BG00011
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1.
SYNOPSIS
Protocol Title:
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of BG00011 in Patients With Idiopathic Pulmonary 
Fibrosis
Protocol Number:
203PF203
Version Number:
2
Name of Study 
Treatment:
BG00011
Study Phase:
2b
Study Indication:
Idiopathic pulmonary fibrosis
Study Rationale:
This Phase 2b study in subjects with mild to moderate idiopathic pulmonary 
fibrosis (IPF) who may or may not be receiving background therapies is 
designed to evaluate the change in forced vital capacity (FVC) after 56 mg of 
BG00011 is administered subcutaneously (SC) once weekly for 52 weeks. 
In the previously completed, Phase 2a study (203PF201) in subjects with IPF, 
BG00011 demonstrated proof of biological activity by altering biomarkers in 
the lung. Therefore, the current study is being conducted to evaluate the 
clinical efficacy and safety of BG00011. The primary analysis will be 
conducted after 52 weeks of placebo-controlled treatment with BG00011.
Study Objectives 
and Endpoints:
Primary Objective
Primary Endpoint
To evaluate the efficacy of BG00011
compared with placebo in subjects 
with IPF.
Yearly rate of change in FVC 
(expressed in mL over 52 weeks) in 
subjects randomized to BG00011 
compared with placebo.
Secondary Objectives
Secondary Endpoints
To evaluate the efficacy of BG00011 
compared with placebo in subjects 
with IPF as determined by change in 
percent predicted FVC.
Yearly rate of change in FVC,
expressed in percent predicted, over 
52 weeks.
To assess progression-free survival in 
subjects who receive BG00011
Time to progression, as defined by a 
composite endpoint, including any of 


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compared with placebo.
the following events:
Absolute decline of 10% predicted in 
FVC (FVC percent predictedbaseline –
FVC percent predictedprogression
≥10%).
Nonelective hospitalization for 
respiratory events.
Lung transplantation or death.
To assess the occurrence of IPF 
exacerbation (using modified 
diagnostic criteria for acute IPF 
exacerbation derived from [Collard 
2007]) in subjects who receive 
BG00011 compared with placebo.  
Time to first acute exacerbation,
measured in days.
Proportion of subjects with at least 1 
acute exacerbation during the 52 
weeks on study.
Number of exacerbations during 52 
weeks.
To assess the incidence of absolute 
decline in FVC ≥10% in subjects who 
receive BG00011 compared with 
placebo.
Number of subjects with absolute 
decline of 10% predicted in FVC 
(FVC percent predictedbaseline – FVC 
percent predictedprogression ≥10%) over 
52 weeks.
To assess the time to death or lung 
transplantation in subjects who 
receive BG00011 compared with 
placebo, and the transplant-free 
survival rate at Week 26 and Week 
52.
Time to death or lung transplantation,
measured in days.
To assess the time to nonelective 
hospitalizations in subjects who 
receive BG00011 compared with 
placebo.
Time to all nonelective 
hospitalizations and to nonelective 
respiratory hospitalizations, measured 
in days.
To assess additional pulmonary 
function test (PFT) findings in 
subjects who receive BG00011 
compared with placebo.
Change in absolute and percent 
predicted FVC from baseline over 
time.
Carbon monoxide diffusion capacity 
(DLCO) absolute and percent 


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predicted changes from baseline over 
time.
Total lung capacity, as measured by 
plethysmography, absolute and 
percent predicted changes from 
baseline over time.
To assess performance on the 
6-Minute Walk Test (6MWT) in 
subjects who receive BG00011 
compared with placebo.
Change from baseline in 6MWT 
parameters at Weeks 26 and 52.
To evaluate the safety and tolerability 
of BG00011.
The incidence, severity, outcome, and 
relationship to study treatment of 
adverse events and serious adverse 
events.
Change from baseline in clinical 
laboratory test results, vital signs, 
electrocardiogram (ECG), PFT, and 
high-resolution computed 
tomography (HRCT) findings.
Immunogenicity (antibodies to 
BG00011).
To evaluate the serum concentration 
of BG00011.
Measurement of BG00011 serum 
concentrations using sparse 
pharmacokinetic (PK) sample 
collection at select timepoints during 
the study. 
Exploratory Objectives and Endpoints are listed in Section 6.
Study Design:
Phase 2b randomized, double-blind, placebo-controlled study to evaluate the 
efficacy, safety, PK, and tolerability of BG00011 in subjects with IPF.
Study Location:
Approximately 100 sites in up to 20 countries are planned, including North 
America, Europe, and Rest of World.
Number of Planned 
Subjects:
Approximately 290 subjects will be randomized.
Study Population:
This study will be conducted in subjects with mild to moderate IPF who may 
or may not be receiving background therapy (either nintedanib or pirfenidone, 


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though not both).
Detailed criteria are described in Section 8.
Treatment Groups:
Subjects will be randomized in a 1:1 ratio to receive BG00011 or placebo:

BG00011 group:  Approximately 145 subjects will receive BG00011 
56 mg once weekly by SC injection for 52 weeks.

Placebo group:  Approximately 145 subjects will receive placebo dosing 
once weekly by SC injection for 52 weeks.
Subjects will be stratified by the concomitant use of background therapy 
(nintedanib or pirfenidone) with a goal of a 1:1 ratio of BG00011 plus 
background therapy to BG00011 monotherapy. At least 20% of subjects will 
not be on background therapy at the time of randomization. 
Duration of 
Treatment and 
Follow-up:
Study duration for each subject will be approximately 65 weeks, including the 
following:  

5-week Screening Period

52-week Placebo-Controlled Treatment Period

8-week Follow-Up Period


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Phase 2b Efficacy and Safety Study of BG00011
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2.
LIST OF ABBREVIATIONS
Abbreviation
Definition
6MWT
6-Minute Walk Test
αvβ6
alpha v beta 6
AE
adverse event
ALAT
Latin American Thoracic Association
ALT
alanine transaminase
anti-HBc
total hepatitis B core antibody
anti-HBs
hepatitis B surface antibody
AUC
area under the concentration-time curve
AUCSS
area under the concentration-time curve at steady state
AST
aspartate transaminase
ATS
American Thoracic Society
BAL
bronchoalveolar lavage
CBC
complete blood count
CRF
case report form
DLCO
carbon monoxide diffusion capacity
DSMB
data safety monitoring board
ECG
electrocardiogram
ERS
European Respiratory Society
FEV1
forced expiratory volume over 1 second
FVC
forced (expiratory) vital capacity
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HRCT
high-resolution computed tomography 
IA
interim analysis
ICF
informed consent form


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Abbreviation
Definition
ICH
International Council for Harmonisation
IFN-
interferon-gamma
IgG1
immunoglobulin G subtype 1
ILD
interstitial lung disease
IPF
idiopathic pulmonary fibrosis 
IRB
institutional review board
IRT
interactive response technology
JRS
Japanese Respiratory Society
LAP
latency-associated peptide
LTBP-1
latent transforming growth factor-beta binding protein-1
mAb
monoclonal antibody
MITT
modified intent to treat
 
mRNA
messenger RNA
NOAEL
no observed adverse effect level
NOEL
no observed effect level
PFT
pulmonary function test
PHI
protected health information
PK
pharmacokinetic(s)
pSMAD2
phosphorylated SMAD2
QLF 
quantitative lung fibrotic reticulation score
RGD
arginine-glycine-aspartic acid
RNA
ribonucleic acid
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
subcutaneous(ly)
SP-A
surfactant A
SP-D
surfactant D


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Abbreviation
Definition
t1/2
half-life
TGF-β
transforming growth factor-beta
Tmax
time to reach maximum observed concentration
TLC
total lung capacity
UIP
usual interstitial pneumonia
ULN
upper limit of normal
WBC
white blood cell


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Phase 2b Efficacy and Safety Study of BG00011
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3.
SPONSOR INFORMATION
Biogen MA Inc. (hereafter referred to as “the Sponsor”) is the Sponsor of the study. 
Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead, Berkshire 
SL6 4AY
United Kingdom
For urgent medical issues in which the study’s Medical Director should be contacted, please 
refer to the Study Reference Guide’s Official Study Contact List for complete contact 
information.
Biogen may transfer any or all of its study-related responsibilities to a contract research 
organization (CRO) and other third parties; however, Biogen retains overall accountability for 
these activities.


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Phase 2b Efficacy and Safety Study of BG00011
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4.
INTRODUCTION 
BG00011 (humanized, immunoglobulin G subtype 1 [IgG1] anti-alpha v beta 6 [v6] 
monoclonal antibody [mAb]), formerly known as STX-100, is being developed by the Sponsor
as a novel therapeutic treatment for patients with idiopathic pulmonary fibrosis (IPF). BG00011 
binds to the v6 integrin, which inhibits the integrin from binding to and activating the latent 
form of transforming growth factor-beta (TGF-). TGF-β plays a critical role in the initiation 
and maintenance of fibrosis, and targeted inhibition of the v6/TGF-β pathway may prevent the 
development of fibrosis, organ scarring, and organ failure. The clinical development plan for 
BG00011 is designed to demonstrate that blocking v6 and inhibiting the activation of TGF-β 
in patients with IPF can prevent or reduce the progression of fibrosis, resulting in preservation of 
pulmonary function.
4.1.
Overview of Idiopathic Pulmonary Fibrosis 
IPF is a serious, chronic, progressively fatal lung disease involving replacement of normal lung 
tissue with fibrotic scar tissue.  IPF is a rare disease that predominantly affects the middle aged 
and elderly (after age 60 years; median age at diagnosis: 66 years [Raghu 2014]).  The disease is 
more common in men than women (male predominance approximately 1.3:1) [Raghu 2014]. 
Patients with IPF typically live for only 3 to 5 years after diagnosis, with a median survival time 
of approximately 3.5 years from diagnosis [Fernández Pérez 2010; Ley 2011; Raghu 2014].  The 
5-year survival rate is 30% to 50% [Raghu 2018],and fewer than 15% of patients live for 10 
years or longer [Lynch 2016].  IPF significantly impairs health-related quality of life [Swigris 
2005], and the majority of patients also have serious comorbid conditions [Raimundo 2016].
Globally, North America and Europe have the highest incidence and prevalence of IPF 
[Hutchinson 2015].  The incidence has been increasing steadily worldwide, in part due to an 
aging population.  The annual incidence of IPF is currently between 3 and 9 per 100,000 persons 
in Europe and North America.  In a review of studies published between 1990 and 2011, the 
prevalence of IPF ranged from 14.0 to 27.9 per 100,000 persons in the United States and from 
1.25 to 23.4 per 100,000 persons in Europe [Nalysnyk 2012].  Recent estimates from South 
Korea suggest the incidence and prevalence of IPF in Asia may be comparable to that of North 
America and Europe [Lee 2016].
Clinical features of IPF include progressive cough, dyspnea, restrictive ventilatory defect, and 
progressive fibrosis and destruction of the lung parenchyma [Lynch 2016]. The diagnosis is 
made in patients with the appropriate clinical features and the histologic pattern of usual 
interstitial pneumonia (UIP) [based on lung biopsy or high-resolution computed tomography 
(HRCT)]. Challenging factors for clinical management include older age, comorbid conditions, 
and acute unpredictable exacerbations. Acute exacerbations of IPF are defined as sudden 
(typically less than 30 days onset) unexplained worsening of underlying disease, including new 
radiological infiltrates (based on HRCT) or UIP pattern. The progressive deterioration of lung 
function results in respiratory failure. The prognosis following acute exacerbation and 
deterioration of lung function is poor, with 1-year and 5-year survival rates of 56.2% and 18.4% 


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following acute exacerbation, which is considerably shorter than in IPF patients without acute 
exacerbation [Song 2011]. 
The underlying pathophysiology of IPF is unknown.  Whatever the inciting event is, it triggers a 
TGF-β mediated fibrogenic response.  As a part of this response, alveolar epithelial cells via the 
production of signaling mediators, including TGF-β, tumor necrosis factor, endothelin 1, and 
cytokines, induce proliferation and activation of fibroblasts and myofibroblasts.  This leads to 
secretion of connective tissue matrix molecules, such as collagen, to replace the damaged tissue 
but also displaces healthy tissue leading to scarring and ultimately organ failure [du Bois 2010].
4.2.
Diagnostic Criteria for IPF
The diagnostic criteria for IPF used in this protocol are derived from evidence-based guidelines 
developed by the American Thoracic Society/European Respiratory Society/Japanese 
Respiratory Society/Latin American Thoracic Association (ATS/ERS/JRS/ALAT) joint task 
force for the diagnosis and management of IPF [Raghu 2018].
The diagnosis of IPF requires histopathologic and/or radiologic evidence of UIP and exclusion of 
other causes of idiopathic interstitial pneumonia and interstitial lung diseases (e.g., occupational 
or environmental exposures, drug toxicities, collagen vascular diseases).  
The ATS/ERS/JRS/ALAT joint task force concludes that, in the appropriate clinical setting, the 
diagnosis of IPF may be ascertained by HRCT alone if the HRCT image fulfills the criteria for 
“UIP pattern” or a “probable UIP pattern” in subjects >60 years old (i.e., surgical lung biopsy is 
not required). However, if the HRCT does not show a definitive UIP pattern or a probable UIP 
pattern in a subject >60 years old, then a surgical lung biopsy is necessary and specific 
combinations of the HRCT and histopathological criteria are used to determine the diagnosis of 
IPF (see Table 1).


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To be eligible for this study, subjects must meet the HRCT imaging and/or lung 
histopathological criteria for UIP shown in Table 1 (in addition to the other inclusion and 
exclusion criteria):
Table 1:
Summary of High-Resolution Computed Tomography and Surgical Lung 
Biopsy Criteria for Diagnosis of IPF
Surgical Lung Biopsy
Not Available
Histopathology:
UIP Pattern
Histopathology:
Probable UIP 
Pattern
Histopathology:
Indeterminate for 
UIP
Histopathology:
Alternative 
Diagnosis
HRCT: UIP 
Pattern
ELIGIBLE
ELIGIBLE
ELIGIBLE
ELIGIBLE
NOT ELIGIBLE
HRCT: Probable 
UIP Pattern
ELIGIBLE1
ELIGIBLE
ELIGIBLE
NOT ELIGIBLE 
NOT ELIGIBLE
HRCT: 
Indeterminate 
UIP Pattern 
NOT ELIGIBLE
ELIGIBLE
ELIGIBLE
NOT ELIGIBLE
NOT ELIGIBLE
HRCT: 
Alternative 
Diagnosis
NOT ELIGIBLE
NOT ELIGIBLE
NOT ELIGIBLE
NOT ELIGIBLE
NOT ELIGIBLE
HRCT = high-resolution computed tomography; IPF = idiopathic pulmonary fibrosis; UIP = usual interstitial pneumonia.
1Only subjects who are >60 years old at Screening are eligible.
4.3.
Current Therapies for Idiopathic Pulmonary Fibrosis
To date, no therapies have demonstrated efficacy in halting IPF disease progression.  
Historically, disease-modifying agents for IPF have included nonspecific anti-inflammatory or 
immunosuppressive agents (i.e., corticosteroids, azathioprine, and cyclophosphamide), which 
were used in the United States despite the absence of clinical studies to demonstrate their 
efficacy, with some ultimately demonstrating harm [Raghu 2012].
Two recently approved therapies, pirfenidone (Esbriet®) and nintedanib (Ofev®), have 
demonstrated a similar ability to slow deterioration in lung function by nearly 50%; however, 
patients are still faced with death or lung transplantation as the ultimate outcome [Kistler 2014].
Pirfenidone was approved based on the demonstration of a statistically significant benefit on the 
forced vital capacity (FVC) in subjects with mild to moderate IPF compared with placebo 
(Genentech Studies PIPF-004, PIPF-006, and PIPF-016 [Esbriet Prescribing Information 
2019/SmPC 2019]. The clinical development program included one 52-week and two nearly 


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identical 72-week clinical studies. The primary endpoint was the change in percent predicted 
FVC from baseline to study end. Secondary endpoints included the mean change from baseline 
in FVC and survival. Of the 3 studies, the 52-week study and 1 of the 72-week studies 
demonstrated that fewer subjects taking pirfenidone had a meaningful decline (10% or greater) in 
FVC versus placebo (17% versus 32%, respectively), whereas more subjects maintained stable 
lung function in the 52-week study (23% versus 10%, respectively). In the 52-week study, a 
significant reduction in the mean decline in FVC was observed in subjects receiving pirfenidone 
compared with placebo (difference of 193 mL). In one of the two 72-week studies, there was a 
significant treatment difference of 157 mL; however, there was no significant difference 
observed in the other 72-week study. There was no statistically significant difference in all-
cause mortality between pirfenidone and placebo. Adverse events (AEs) leading to 
discontinuation of treatment occurred in 14.6% of subjects treated with pirfenidone.  Adverse 
reactions associated with pirfenidone in >10% of subjects versus placebo include, but are not 
limited to, gastrointestinal disorders and photosensitivity.
Nintedanib was also approved based on the demonstration of a statistically significant benefit on 
FVC decline in subjects with mild to moderate IPF in three 52-week clinical studies [one Phase 2 
study and two identical Phase 3 studies] (Boehringer Ingelheim Studies 1199.30, 1199.32, and 
1199.34 [Ofev Prescribing Information 2015/SmPC]).  The primary endpoint in all 3 studies was 
the annual rate of decline in FVC.  Secondary endpoints included time to first acute IPF 
exacerbation, change from baseline in FVC percent predicted, and survival.  A statistically 
significant reduction in the annual rate of decline of FVC was demonstrated in subjects receiving 
nintedanib compared with subjects receiving placebo, with differences in the 3 studies of 131 mL 
(Phase 2 study) and 125 and 94 mL (in the 2 Phase 3 studies).  The change from baseline in the 
percent predicted FVC was lower in the group treated with nintedanib.  In addition, the time to 
first acute IPF exacerbation was significantly reduced in subjects receiving nintedanib in 2 of the 
3 studies (the Phase 2 and 1 of the Phase 3 studies), but there was no statistically significant 
difference in all-cause mortality.  The most common serious adverse reactions that were reported 
more frequently with nintedanib treatment than with placebo were bronchitis (1.2% versus 0.8%, 
respectively) and myocardial infarction (1.5% versus 0.4%, respectively).  AEs leading to 
discontinuation were reported in 21% of the subjects treated with nintedanib.  Adverse reactions 
associated with nintedanib in ≥10% of subjects compared with placebo included gastrointestinal
(GI) disorders such as diarrhea (most common), nausea, increased liver enzymes, and abdominal 
pain.
A study assessing the real-world experience with pirfenidone and nintedanib indicated that while 
side effects (predominantly GI with both therapies) are common, the side effects are managed in 
the majority of patients with a treatment discontinuation rate similar to what was observed in the 
clinical studies [Hughes 2016].  Among patients using pirfenidone, 16% of AEs resulted in a 
reduction in dose and 20% of AEs resulted in permanent discontinuation.  Among subjects using 
nintedanib, 15% had a reduction in dose and 26% discontinued treatment.
In real-world data, utilization of antifibrotic medications varies considerably by geographic 
region.  In 3 observational studies in the United States, the prevalence of pirfenidone and 
nintedanib use ranged from 14% to 55% [Viscidi 2017].  In Western Europe, utilization ranged 
from 29% to 69% [Behr 2015; Pesonen 2017; Sicras-Mainar 2017; Wuyts 2017]. Utilization 


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appears to be lower in Eastern Europe; among 107 IPF patients in a registry in Poland, 2% had 
used pirfenidone [Lewandowska 2017].  In a survey of 344 physicians in Latin America, 21% 
had prescribed pirfenidone to their IPF patients [Torres Villacreses 2017]. In an observational 
study in Japan, 33% of IPF patients used pirfenidone [Bando 2015]. 
As the disease continues to progress, lung transplants for appropriate surgical candidates may be 
considered.  However, the 5-year survival rate after lung transplantation ranged from 47% to 
53%, based on data from the International Society for Heart and Lung Transplantation and Organ 
Procurement and Transplantation Network [Kistler 2014]. Considerations regarding the utility of 
lung transplantation include the limited availability of donor organs, infection, rejection, and the 
requirement for lifetime immunosuppressive therapy.
Therapies that can halt or reverse disease progression, increase life expectancy, and improve 
quality of life while demonstrating minimal side effects remain a treatment goal for patients 
diagnosed with IPF.  
4.4.
Profile of Previous Experience With BG00011
4.4.1.
Mechanism of Action
TGF-β is a central mediator of fibrogenesis. TGF-β is upregulated and activated in fibrotic 
diseases, and its signaling results in myofibroblast differentiation and matrix deposition. The 
v6 integrin is a critical regulator of TGF-activation. TGF-is synthesized as a latent 
precursor protein consisting of latency-associated peptide (LAP) and TGF-. This complex 
cannot bind to the TGF-receptor and is not biologically active. The v6 integrin is expressed 
at low or undetectable levels in healthy adult tissues but is highly upregulated on epithelial cells 
during tissue injury and fibrosis. The integrin activates TGF-by binding to an arginine-
glycine-aspartic acid motif within the LAP component of latent TGF-leading to the localized 
activation of the cytokine (Figure 1). BG00011 is a mAb that binds to the v6 integrin and 
inhibits ligand binding. By blocking the binding of v6 to latent TGF-, BG00011 prevents 
v6-mediated TGF-activation, thereby decreasing TGF-signaling. Although other 
mechanisms of TGF-activation have been identified, studies carried out in v6-deficient mice 
and with v6-blocking mAbs suggest that v6-mediated activation of TGF-can prevent the 
development of fibrosis in the lung, kidney, and liver. Analysis of molecular signatures 
associated with the progression of fibrosis indicates that the therapeutic impact of the v6-
blocking antibodies is mechanistically linked to decreased TGF-activity. 
A key mediator of TGF-β activity is the signal transducer proteins SMAD, which when 
phosphorylated (phosphorylated SMAD [pSMAD]), regulate the transcriptional activity of 
TGF-β signaling (Figure 1).  Increased pSMAD levels have been positively correlated with lung 
fibrosis in both the murine bleomycin and radiation models of fibrosis [Chung 2016; Flechsig 
2012; Horan 2008].  Given its role in the TGF-β cascade and evidence of correlation with lung 
fibrosis, pSMAD and several downstream genes were selected as exploratory target engagement 
biomarkers in nonclinical and the clinical studies with BG00011 in subjects with IPF. 


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Figure 1:
BG00011 Mechanism of Action
αvβ6 = alpha v beta 6; LAP = latency-associated peptide; LTBP-1 = latent transforming growth factor-beta binding protein-1; 
mAb = monoclonal antibody; RGD = arginine-glycine-aspartic acid; TGF-β = transforming growth factor-beta.
v6 expression is up-regulated on epithelial cells during tissue injury and fibrosis.  v6 binds to an RGD motif in the latency-associated 
peptide region of the latent TGF-precursor protein, leading to local activation of TGF-.  Anti-v6 mAb interferes with this 
binding and blocks TGF-activation.
4.4.2.
Nonclinical Experience
Nonclinical pharmacology, pharmacokinetic (PK), and toxicology studies have been performed 
to support clinical development of BG00011. Inhibition of TGF-β signaling has been shown to 
be protective in a variety of models of fibrosis, identifying this pathway as an attractive target for 
therapeutic intervention in IPF. However, given the anti-inflammatory role for TGF-β signaling, 
appropriate modulation of TGF-β in a tissue specific manner is needed to avoid potentially 
deleterious systemic effects. 
BG00011 is a humanized mAb that cross-reacts with murine, nonhuman primate, and human 
αvβ6.  A murine form of BG00011 (m3G9, previously mu3G9) has demonstrated potent 
antifibrotic activity in several rodent models of lung, kidney, and liver fibrosis.  
4.4.2.1.
Pharmacology Models
Nonclinical pharmacology studies to determine the biological activity and safety of BG00011 
have been conducted using a murine anti-αvβ6 antibody (m3G9) in mice and BG00011 in 
cynomolgus monkeys.  Several rodent models of fibrosis show increased αvβ6 expression in 
epithelial cells of the affected tissue, including the lung, kidney, and liver.  Efficacy of m3G9 has 
been demonstrated in models of lung, kidney, and liver fibrosis, as measured by markers of 
tissue fibrosis, including collagen production and accumulation of α-smooth muscle actin  
positive fibroblasts [Hahm 2007; Horan 2008; Puthawala 2008].
Key nonclinical studies demonstrating efficacy in lung fibrosis were performed in the bleomycin 
mouse model, bleomycin-FTY720 mouse model, radiation mouse model, and influenza mouse 
model. Taken together, the data from these studies indicate that doses of m3G9 at 0.3 and 


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1.0 mg/kg were consistently associated with improvement in fibrotic response with no significant 
inflammation in these rodent models of epithelial tissue injury and fibrosis. 
In addition, preclinical studies demonstrated that αvβ6 blocking antibody treatment between 0.3 
and 1.0 mg/kg led to similar, significant steep reductions of pSMAD in bronchoalveolar lavage 
(BAL) cells in both mice and cynomolgus monkeys. See the BG00011 Investigator’s Brochure 
for additional information about these studies.
An increased incidence of acute allograft rejection was observed in a monkey kidney transplant 
study when BG00011 was administered with a standard calcineurin-based immunosuppressive 
regimen.  Therefore, it is recommended that patients with end-stage fibrotic disease requiring 
organ transplantation do not receive BG00011.  Any patient receiving BG00011 who progresses 
to the point of requiring organ transplantation should immediately discontinue the study 
treatment.
4.4.2.2.
Toxicology Summary
Nonclinical toxicology studies of up to 26 weeks in duration were conducted in the CD-1 mouse 
and cynomolgus monkey. Murine studies used m3G9, while monkey studies used BG00011. 
Histologic changes were limited to the lung. These consisted of partially reversed alveolar 
macrophages, alveolar cellular debris, perivascular lymphoid infiltration, and increases in lung 
weight in mice and partially reversed alveolar macrophages in monkeys. The no observed 
adverse effect levels (NOAELs) in the 6-month studies were 1.0 and 10 mg/kg in mice and 
monkeys, respectively. No carcinogenicity or genotoxicology studies were conducted with 
BG00011 or m3G9. In the repeat-dose mouse studies with m3G9, low incidences of tumors 
(such as bronchoalveolar adenoma) were observed sporadically and in a non-dose-related 
manner. Spontaneous bronchoalveolar lesions have been reported in mouse historical control 
data. No tumors were noted in monkey studies.  Transient elevations of lung tidal and minute 
volumes were observed in mice. There were no treatment-related changes in pulmonary 
function, blood pressure, or ECG in monkeys. No neurobehavioral abnormalities were observed,
and no histologic changes were found in the central nervous system tissues of mice or monkeys. 
There were no fertility effects in male and female mice and no teratogenic findings in mice up to 
the maximum dose of 10 mg/kg. Antidrug antibodies were observed in up to 43% of mice and 
25% of monkeys in repeat-dose toxicology studies. For additional information on toxicology 
studies with BG00011 or m3G9, see the Investigator's Brochure. 
4.4.2.3.
Nonclinical Pharmacokinetics
The nonclinical PK disposition profiles of BG00011 and m3G9 were characterized in the 
cynomolgus monkey and mouse, respectively.  Following intravenous (IV) administration of a 
single dose of BG00011 in cynomolgus monkeys, maximum observed concentration (Cmax) and 
area under the concentration time curve (AUC) increased with dose.  The mean half-life (t½) for 
both IV and subcutaneous (SC) administration was approximately 4 days.  BG00011 was 
maintained primarily within the vasculature, with a calculated bioavailability of approximately 
100%.  


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Following repeated dosing in monkeys in a 3-month toxicity study, BG00011 (1 to 10 mg/kg SC 
once weekly) demonstrated dose-proportional exposure, with the t½ ranging from 8 to 12 days.  
In a 6-month toxicity study in monkeys, BG00011 (0.1 to 10 mg/kg SC once weekly) showed a 
greater-than-dose-proportional increase in exposure, and t½ increased with increasing dose.  t½
ranged from 1.5 to 10 days.  In general, the presence of antidrug antibodies was inversely 
correlated with BG00011 exposure.
4.4.3.
Clinical Experience
As of 28 February 2017, a total of 61 subjects (31 subjects with IPF and 30 healthy volunteers) 
have received BG00011 in 2 completed clinical studies, Phase 1 Study STX-001 and Phase 2a 
Study 203PF201.  Brief summaries of each of these studies are as follows:
Study STX-001
Study STX-001, a Phase 1 randomized, double-blind, placebo-controlled, single-dose, dose-
escalation study, was conducted to evaluate the safety, tolerability, PK, and immunogenicity 
profile of BG00011 administered SC to healthy volunteers.  In this study, 40 subjects were 
enrolled into 5 ascending-dose cohorts (6 active:2 placebo subjects per cohort) and received a 
single SC dose of BG00011 (range: 0.003 to 0.3 mg/kg) or placebo (saline injection) and were 
monitored for 3 months after dosing.  BG00011 exposure was dose proportional in the 3 highest 
dose groups for which serum levels were measurable.  The t½ of BG00011 was approximately 
6 days, with peak serum concentrations observed at 5 days after administration.  BG00011 was 
well tolerated, with no deaths, serious adverse events (SAEs), or premature discontinuations 
related to an AE.  No clinically significant changes were noted for any safety measures including 
AEs, physical examination, vital signs, or clinical laboratory parameters, including pulmonary 
function tests (PFTs).  AEs occurred in 21 of 30 subjects (70%) who received BG00011 and 8 of 
10 subjects (80%) who received placebo.  The most common AEs were headache, diarrhea, 
vomiting, arthropod stings, nasopharyngitis, and nasal congestion.  
Study 203PF201
Study 203PF201, a Phase 2a, randomized, double-blind, placebo-controlled, multiple-dose, dose-
escalation study was conducted to evaluate the safety, tolerability, PK, and effects on biomarkers 
of BG00011 administered SC to subjects with IPF.  Forty-one subjects were enrolled into 
5 ascending-dose cohorts ranging from 0.015 to 3.0 mg/kg (planned as 3:1 ratio per cohort).  
Study treatment was administered as once-weekly SC injections for up to 8 weeks, and each 
subject was monitored during a follow-up period of 8 to 12 weeks (depending on the dose 
cohort).  Thirty-one subjects received BG00011, and 10 subjects received placebo.  
The study was monitored by an independent data safety monitoring board (DSMB) and included 
safety evaluations that would enable detection of respiratory events (e.g., IPF exacerbation; 
changes in lung function, including decreases from baseline in FVC by ≥12%, total lung capacity 
by ≥8%, and diffusing capacity of the lungs for carbon monoxide [DLCO] by ≥15%). Four 
cohorts completed dosing through 1.0 mg/kg. Prior to the completion of dosing in the fifth and 
highest dosing cohort (3.0 mg/kg), the study was stopped after meeting the prespecified protocol 


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stopping criteria, when 2 subjects experienced clinically significant sustained decreases from 
baseline respiratory status. Following the decision to stop the 3.0 mg/kg cohort and additional 
discussions with the DSMB, the Sponsor conducted a detailed analysis of the available PK, PD, 
and safety data from all cohorts and concluded that the potential benefit/risk of BG00011 was 
acceptable for dosing patients with IPF, with appropriate safety monitoring, at doses not 
exceeding 1.0 mg/kg. A summary of the PK, PD, and safety data for Study 203PF201 is as 
follows.
Pharmacokinetic data show that after repeated weekly SC administration, BG00011 exposure 
increased approximately proportionally to doses ranging from 0.015 to 1.0 mg/kg, but increased 
greater than proportionally at doses >1.0 mg/kg.  After the last dose, the mean terminal t½ of 
BG00011 ranged from 168 to 211 hours across the dose range (approximately 174 hours 
following repeated administration at doses <3.0 mg/kg).  Serum concentrations were relatively 
sustained throughout the 168-hour sampling period, with the time to reach maximum observed 
concentration (Tmax) after the last dose occurring at 24 to 48 hours.
In this study, BG00011 decreased the level of phosphorylated SMAD2 (pSMAD2) in BAL cells 
starting at the 0.3 mg/kg dose and achieved ≥70% reduction at the 1.0 mg/kg dose. In addition, a 
substantial decrease in gene expression of several prespecified genes linked to TGF-β signaling 
was also observed between the 0.3 and 1.0 mg/kg doses. These decreases in pSMAD and gene 
expression established proof of biology.
A total of 170 AEs were reported in the Phase 2a study.  Twenty-seven of 31 subjects (87%) who 
received BG00011 and 7 of 10 subjects (70%) who received placebo experienced at least 1 AE.  
The majority of AEs were mild or moderate in severity.  The most frequent AEs reported in 
subjects who received BG00011 were cough, dyspnea, and IPF exacerbation (5 subjects each), 
hypoxia (4 subjects), fatigue, viral upper respiratory infection, injection site pain, headache, and 
seasonal allergy (3 subjects each). 
Four subjects who received BG00011 experienced SAEs, including atrioventricular block and 
hypoxemia in a subject in the 0.015 mg/kg cohort, IPF exacerbation in a subject in the 1.0 mg/kg 
cohort; syncope, Type II second-degree atrioventricular block, fractured mandible, and IPF 
exacerbation in a subject in the 1.0 mg cohort; and respiratory failure in a subject in the 
3.0 mg/kg cohort.  None of the SAEs were assessed by the respective Investigators as related to 
study treatment.
One subject (who experienced syncope, Type II second-degree atrioventricular block, fractured 
mandible, and IPF exacerbation) died due to the IPF exacerbation after discontinuation from the 
study.
In summary, multiple SC doses of BG00011 up to 1.0 mg/kg were generally well tolerated in the 
population of subjects with IPF, with the incidence and severity of AEs, and changes in physical 
examination, vital signs, or clinical laboratory parameters comparable to those expected in the 
IPF population.  Based on a detailed review of the safety, PK, and PD data for Study 203PF201, 
the Sponsor considers that the potential benefit/risk of BG00011 is acceptable for dosing in 
subjects with IPF at doses not exceeding 1.0 mg/kg. 


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4.5.
Study Rationale and Dose Selection
This Phase 2b study is designed to evaluate the treatment effect (change in FVC) of BG00011 
administered SC once weekly for 52 doses in subjects with mild to moderate IPF who may or 
may not be receiving protocol-defined background therapies (i.e., nintedanib or pirfenidone).  
As a first-in-class treatment for patients with IPF, the reduction in pSMAD2 levels and gene 
expression required for clinical efficacy is unknown.  Across multiple mouse models of lung 
fibrosis, αvβ6-blocking antibody treatment with dosing between 0.3 and 1.0 mg/kg leads to 
significant reductions in pSMAD2 and reduced collagen expression (a marker of fibrosis) 
without inducing lung inflammation.  The steep dose response in pSMAD2 is consistently 
observed in subjects with IPF (Study 203PF201), in nonhuman primate biomarker studies, and in 
the rodent models of epithelial injury and fibrotic diseases.  
To guide dose selection, an exposure-response analysis was prepared based on reduction in 
pSMAD2 levels versus BG00011 exposure from observed individual subject data in Study 
203PF201 (Figure 2).  The area under the concentration time curve at steady state (AUCSS) of the 
dosing interval after the last dose was used as the exposure variable and the percent change from 
the baseline level of pSMAD2 was used as the PD response in the assessment of the PK/PD 
relationship.  This curve shows the steep dose response between the 0.3 and 1.0 mg/kg doses.


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Figure 2:
Plot of BG00011 Exposure and Change in pSMAD2 From Baseline (Study 
203PF201)
AUCtau = area under the plasma concentration-time curve for a dosing interval; pSMAD2 = phosphorylated 
SMAD2.
Note:  Two subjects from the 1.0 mg/kg cohort were excluded from the exposure response analysis because they
were identified to be outliers (outside 3 standard deviations), without baseline, or below the lower limit of 
quantitation.
Dose selection for the present study is supported by safety and PK data from the completed 
single-ascending-dose study in healthy volunteers and the 8-week study in subjects with IPF, 
along with the 26-week cynomolgus monkey studies, in which an exposure of 31,700 (hr × 
μg/mL) was identified as the NOAEL.  Based on an integrated analysis of safety, PK, and PD, a 
dose of 0.7 mg/kg (56 mg) of BG00011 was selected to provide the predicted therapeutic 
exposure that would allow for optimal evaluation of the exposure-response curve with PD 
responses predicted to have clinical efficacy (median predicted response of 65% [range: 40% to 
75%] pSMAD2 reduction) while not exceeding exposures observed at the 1.0 mg/kg dose level 
and providing an approximate 27-fold margin from the predicted human exposures to the 
monkey NOAEL. 
Since body weight was not identified as a covariate affecting exposure with the currently 
available data, there is limited pharmacological rationale to use body-weight based dosing over 
fixed dosing to reduce intersubject variability.  In addition, fixed dosing eliminates the need for 
subjects or caregivers to manually draw doses and mitigates the risk for overdosing or 
underdosing the desired amount.  This finding is also consistent with other PK analyses of 
therapeutic mAbs [Wang 2009].  An average weight of 80 kg for subjects with IPF, based on 


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data from prior clinical studies in IPF [Noble 2011; Richeldi 2014], has been used to select the 
dose of BG00011 56 mg (based on the selection of the target of 0.7 mg/kg dose).  Due to limited 
data in the lower ranges of body weight, subjects will be required to weigh greater than 60 kg to 
enroll in this Phase 2b study of BG00011.  


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5.
STUDY SCHEMATIC AND STUDY ACTIVITIES
Figure 3 shows a study schematic for Study 203PF203, and Table 2 shows a schedule of study 
activities.
5.1.
Study Schematic
Figure 3:
Schematic for Study 203PF203
  Week 52
       Placebo-Controlled Treatment Period
         Week 60
Safety 
Follow-Up 
Visit
Screening 
Period
≤35 days
prior to 
Baseline
Baseline
End of Study
Stratification by use or non-use of background therapy and 
Randomization 1:1 to BG00011 or placebo: 
Stratum 1 – Not on background therapy 

Placebo (~50% of stratum)

BG00011 (~50% of stratum)
Stratum 2 – On background therapy 

Placebo (~50% of stratum)

BG00011 (~50% of stratum)
Safety 
Follow Up 
Period


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5.2.
Study Activities
Table 2:
Schedule of Events 
Period
Screening 
Period
Placebo-Controlled Treatment Period
Safety 
Follow-
Up
Unscheduled
Study Visit
Screening1
Baseline
Day 52
Week   
4
Week   
8
Week 
12
Week 
16
Week 
20
Week 
26
Week 
32
Week 
38
Week 
44
Week 
52/ 
EoT3
Week 60
IPF 
Exacerbation
Study Day
≤35 days 
prior to 
Baseline
0
5
28
56
84
112
140
182
224
266
308
364
420
NA
Visit Window 
(Days)
NA
NA
+1
±3
±3
±3
±3
±3
±7
±7
±7
±7
±7
±7
NA
Informed Consent 
Form
X
Randomization
X
Medical History
X
X
Inclusion/Exclusion 
Criteria
X
X4
Physical 
Examination5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body Weight and 
Height
X
X
X
X
12-Lead ECG
X
X
X
X
X
X6
Vital Signs 
(temperature, blood 
pressure, heart rate, 
respiratory rate)7
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Period
Screening 
Period
Placebo-Controlled Treatment Period
Safety 
Follow-
Up
Unscheduled
Study Visit
Screening1
Baseline
Day 52
Week   
4
Week   
8
Week 
12
Week 
16
Week 
20
Week 
26
Week 
32
Week 
38
Week 
44
Week 
52/ 
EoT3
Week 60
IPF 
Exacerbation
Study Day
≤35 days 
prior to 
Baseline
0
5
28
56
84
112
140
182
224
266
308
364
420
NA
Visit Window 
(Days)
NA
NA
+1
±3
±3
±3
±3
±3
±7
±7
±7
±7
±7
±7
NA
Oxygen Saturation8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
High Resolution 
Computed 
Tomography 
(HRCT)9
X10
X11
X11
X6
Spirometry (FVC, 
FEV1)
X12
X
X
X
X
X
X
X
X
X
X
X
X
Carbon monoxide 
diffusion capacity
(DLCO)
X
X
X
X
X
X
X
X
X
Plethysmography
X
X
X
X
6-Minute Walk Test 
(6MWT)13
X
X
X


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Period
Screening 
Period
Placebo-Controlled Treatment Period
Safety 
Follow-
Up
Unscheduled
Study Visit
Screening1
Baseline
Day 52
Week   
4
Week   
8
Week 
12
Week 
16
Week 
20
Week 
26
Week 
32
Week 
38
Week 
44
Week 
52/ 
EoT3
Week 60
IPF 
Exacerbation
Study Day
≤35 days 
prior to 
Baseline
0
5
28
56
84
112
140
182
224
266
308
364
420
NA
Visit Window 
(Days)
NA
NA
+1
±3
±3
±3
±3
±3
±7
±7
±7
±7
±7
±7
NA
Serum pregnancy 
test14
X
HIV, HCV, HBsAg, 
anti-HBc, anti-HBs
Testing
X
Urine pregnancy 
test15
X
X
X
X
X
X
X
X
X
X
X
X
Hematology, blood 
chemistry, and 
urinalysis
X
X
X
X
X
X
X
X6
Serum for BG00011 
PK measurement
X16
X
X
X
X
X
X
X
X
X
X


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Period
Screening 
Period
Placebo-Controlled Treatment Period
Safety 
Follow-
Up
Unscheduled
Study Visit
Screening1
Baseline
Day 52
Week   
4
Week   
8
Week 
12
Week 
16
Week 
20
Week 
26
Week 
32
Week 
38
Week 
44
Week 
52/ 
EoT3
Week 60
IPF 
Exacerbation
Study Day
≤35 days 
prior to 
Baseline
0
5
28
56
84
112
140
182
224
266
308
364
420
NA
Visit Window 
(Days)
NA
NA
+1
±3
±3
±3
±3
±3
±7
±7
±7
±7
±7
±7
NA
Serum for anti-
BG00011 antibodies
X
X
X
X
X
X
Study diary training, 
administration, and 
review
X
Subject completion 
of study diary18
-----------------------------------------------------Ongoing throughout the study-------------------------------------------------------
Administration of 
study treatment in 
clinic
X19
Injection training
X
--------------------------------------Injection retraining to be offered as necessary-----------------------------
Weekly 
administration of 
study treatment
To be performed by subject or caregiver once weekly from Week 1 (second dose) through Week 51 
(final dose)
Dispense and/or 
collect study 
treatment
X
X
X
X
X
X
X
X
X
X
X


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Period
Screening 
Period
Placebo-Controlled Treatment Period
Safety 
Follow-
Up
Unscheduled
Study Visit
Screening1
Baseline
Day 52
Week   
4
Week   
8
Week 
12
Week 
16
Week 
20
Week 
26
Week 
32
Week 
38
Week 
44
Week 
52/ 
EoT3
Week 60
IPF 
Exacerbation
Study Day
≤35 days 
prior to 
Baseline
0
5
28
56
84
112
140
182
224
266
308
364
420
NA
Visit Window 
(Days)
NA
NA
+1
±3
±3
±3
±3
±3
±7
±7
±7
±7
±7
±7
NA
Compliance/drug 
accountability
X
X
X
X
X
X
X
X
X
X
X
Adverse event 
reporting20
--------------------------------------------------Monitor and record throughout Treatment and Follow-Up Periods --------------------------------
Serious adverse 
event reporting
--------------------------------------------------------------------Monitor and record throughout the study -----------------------------------------------------------------
Concomitant therapy 
and procedures 
recording21
-------------------------------------------------------------------Monitor and record throughout the study -----------------------------------------------------------------
Abbreviations not already defined in the table:  anti-HBc = total hepatitis B core antibody; anti-HBs = hepatitis B surface antibody; EoT = End of Treatment; FEV = forced 
expiratory volume; FEV1 = forced expiratory volume over 1 second; FVC = forced vital capacity; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; IPF = idiopathic pulmonary fibrosis; NA = not applicable; PK = pharmacokinetics.
1 The screening assessments are to occur within 35 days before the Baseline Visit (Day 0).
2 The Day 5 Visit is for blood collection only (for PK analysis) and may be done in the clinic or at home (by appropriate personnel).  Sample collection should 
occur on Day 5 (not sooner), with a +1 day window allowed (i.e., collection should occur on Day 5 but may occur on Day 6).
3 If study treatment is permanently discontinued prior to the end of the Treatment Period, an EoT Visit will occur as soon as possible, but within 4 weeks (see 
Section 10.1 for details).  If a subject is withdrawn from the study prior to the end of the Treatment Period, an EoT Visit will occur as soon as possible, but 
within 4 weeks (see Section 10.2 for details).  In either case (discontinuation of treatment or withdrawal from the study) all assessments planned for the Week 
52 Visit, except for the HRCT scan, will be performed at the EoT Visit.  However, if the EoT Visit falls within the visit window for the Week 26 Visit, the 
HRCT should be performed.
4 Entry criteria will be rechecked prior to dosing at the Baseline Visit (Day 0).  Investigator to confirm eligibility.


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5 A full physical examination will be performed at the Screening, Baseline, Week 26, and Week 52 Visits, and at the EoT Visit in cases of early withdrawal from 
the study.  At all other study visits, an abbreviated physical examination may be performed (must always include a cardiopulmonary examination and 
symptom-based examination).
6 Imaging studies, plethysmography (lung volumes), ECG, or clinical laboratory tests at the IPF Exacerbation Visit will be at the discretion of the Investigator.  
The optional imaging study at the IPF Exacerbation Visit may be a chest X-ray or HRCT scan.
7 Blood pressure is to be performed with the subject sitting, after at least 5 minutes at rest. Temperature may be taken by oral or tympanic method. 
8 Using pulse oximeter, oxygen saturation will be measured after the subject has been at rest for at least 5 minutes. The amount of supplemental oxygen the 
subject is receiving, if any, should be noted.
9 Noncontrast chest HRCT through the full chest at suspended full inspiration and full expiration will be performed at Screening, Week 26, and Week 52, as 
detailed in the imaging procedure manual.
10A chest HRCT scan performed within 12 months of Screening can be used to determine initial eligibility to enter Screening (to prevent further screening 
assessments if HRCT does not meet the criteria for IPF).  Regardless of whether a historical chest HRCT was submitted, all subjects are required to receive a 
chest HRCT at Screening.  For determination of subject eligibility, all HRCT scans, including the historical and Screening Visit scans, must be consistent with 
the protocol-defined eligibility of IPF.  Eligibility read of the HRCT will be performed by a central radiologist.  Historical biopsy data may be provided to 
support eligibility based on HRCT (see Section 7.2.1).
11HRCT will be performed at Weeks 26 and 52 for safety monitoring.  Additionally, change from baseline in pulmonary fibrosis will be evaluated by a central 
radiologist.
12Spirometry (before and after bronchodilator use) will be performed to determine eligibility. If the subject qualifies for the study, 1 subsequent spirometry 
evaluation, without bronchodilator administration, will be performed at the Baseline Visit.
13Each test consists of 2 walks.
14Serum pregnancy test for women of childbearing potential only.  Results must be negative for participation in the study.
15Urine pregnancy test for women of childbearing potential only.
16Baseline (Day 0) blood samples for PK 
 analysis are to be collected before dosing.
17Samples can be collected where approved by local regulatory authorities.  Subjects must sign a separate consent form.
18Documentation of background therapy dosing, including any changes in dose or dosing schedule, should be captured daily in the subject’s study diary.  Diary 
entries should be reviewed periodically by study site personnel to ensure compliance and completeness.
19Subjects will be observed in the clinic for a minimum of 1 hour following administration of study treatment.  
20Adverse events are to be captured after the first dose of study treatment through the final study visit.  Events that occur prior to dosing should be entered on the 
Medical History case report form.
21All concomitant medications being taken at the time of initial screening (including medications discontinued at that time) through the final study visit are to be 
recorded on the CRF.


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6.
STUDY OBJECTIVES AND ENDPOINTS
Primary Objective
Primary Endpoints
To evaluate the efficacy of BG00011 compared 
with placebo in subjects with IPF.
Yearly rate of change in FVC (expressed in mL 
over 52 weeks) in subjects randomized to 
BG00011 compared with placebo.
Secondary Objectives
Secondary Endpoints
To evaluate the efficacy of BG00011 compared 
with placebo in subjects with IPF as 
determined by change in percent predicted 
FVC.
Yearly rate of change in FVC, expressed in 
percent predicted, over 52 weeks.
To assess progression-free survival in subjects 
who receive BG00011 compared with placebo.
Time to progression, as defined by a composite 
endpoint, including any of the following 
events:

Absolute decline of 10% predicted in FVC 
(FVC percent predictedbaseline – FVC 
percent predictedprogression ≥10%).

Nonelective hospitalization for respiratory 
events.

Lung transplantation or death.
To assess the occurrence of IPF exacerbation 
(using modified diagnostic criteria for acute 
IPF exacerbation derived from [Collard 2007])
in subjects who receive BG00011 compared 
with placebo.  

Time to first acute exacerbation, measured 
in days.

Proportion of subjects with at least 1 acute 
exacerbation during the 52 weeks on study.

Number of exacerbations during 52 weeks.
To assess the incidence of absolute decline in 
FVC ≥10% in subjects who receive BG00011 
compared with placebo.
Number of subjects with absolute decline of 
10% predicted in FVC (FVC percent 
predictedbaseline – FVC percent 
predictedprogression ≥10%) over 52 weeks.


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To assess the time to death or lung 
transplantation in subjects who receive 
BG00011 compared with placebo, and the 
transplant-free survival rate at Week 26 and 
Week 52.
Time to death or lung transplantation,
measured in days.
To assess the time to nonelective 
hospitalizations in subjects who receive 
BG00011 compared with placebo,
Time to all nonelective hospitalizations and to 
nonelective respiratory hospitalizations,
measured in days.
To assess additional PFT findings in subjects 
who receive BG00011 compared with placebo.

Change in absolute and percent predicted 
FVC from baseline over time.

Carbon monoxide diffusion capacity
(DLCO), absolute and percent predicted 
changes from baseline over time.

Total lung capacity, as measured by 
plethysmography, absolute and percent 
predicted changes from baseline over time.
To assess performance on the 6MWT in 
subjects who receive BG00011 compared with 
placebo.
Change from baseline in 6MWT parameters at 
Weeks 26 and 52.
To evaluate the safety and tolerability of 
BG00011.

The incidence, severity, outcome, and 
relationship to study treatment of AEs and 
SAEs.

Change from baseline in clinical laboratory 
test results, vital signs, ECG, PFT results, 
and HRCT findings.

Immunogenicity (antibodies to BG00011).
To evaluate the serum concentration of 
BG00011.
Measurement of BG00011 serum
concentrations using sparse PK sample 
collection at select timepoints during the study.


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Exploratory Objectives
Exploratory Endpoints
 
 
 
 
 
 

 


 
 
 


 

 
 
 


 
 

 


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
 
 
  


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7.
STUDY DESIGN
7.1.
Study Overview
This is a Phase 2b randomized, double-blind, placebo-controlled study designed to evaluate the 
efficacy, safety, PK, and tolerability of BG00011 in subjects with IPF.  The study will be 
conducted at approximately 100 sites in up to 20 countries in North America, Europe, and Rest 
of World.  Approximately 290 subjects are planned to be randomized. 
To be eligible for the study, subjects must have a diagnosis of IPF consistent with adapted ATS/
ERS/JRS/ALAT guidelines (Section 4.2 and Table 1) and meet the eligibility criteria outlined in 
the protocol.  Eligibility for the study will be determined centrally. In addition, features of IPF at 
Screening must include:  FVC ≥50% of predicted value; DLCO (corrected for hemoglobin) ≥30% 
of predicted value; oxygen saturation ≥90% at rest (receiving ≤2 L/min of supplemental oxygen).  
Subjects with IPF who do not meet the criteria for participation in this study under Version 2 of 
the protocol may be rescreened one time only after discussion between the Principal Investigator 
and the Sponsor.  Subjects with IPF who did not meet the criteria for participation in this study 
(i.e., a screen failure) under Version 1 of the protocol due to previously adapted ATS 2011 
guidelines or hepatitis B criteria, may be screened and rescreened again under Version 2 of the 
protocol.
Subjects will be stratified by background therapy status (subjects receiving background therapy 
and subjects not receiving background therapy) and randomized in a 1:1 ratio of BG00011 to 
placebo (Figure 3).  Enrollment will also be monitored to ensure that subjects not receiving 
background therapy represent at least 20% of each treatment group.
Subjects will receive weekly injections of BG00011 or placebo, as a solution for SC injection in 
a prefilled syringe, for 52 consecutive weeks (a total of 52 doses).  The first dose will be 
administered at the Baseline (Day 0) Visit.  The rest of the doses may be administered 
independently (e.g., not at the study site) by the subject or the subject’s caregiver.
Background therapy for IPF with pirfenidone or nintedanib will be allowed during the study. 
The subject must be on a stable dose of either medication for at least 8 weeks prior to 
randomization.  The subject is not to be on both medications simultaneously and should not 
initiate background therapy during the study.  In cases where the Investigator feels that 
background therapy is clinically indicated, this therapy can be started, but the initiation of 
background therapy during the study will be considered a protocol deviation.  While 
participating in the study, every effort should be made to maintain the subject on a stable dose of 
background therapy, and dosing should not exceed the labeled maximum dose.  However, 
background therapy dosing may be adjusted or discontinued by the subject’s pulmonary care 
physician.  Note that a subject may continue in the study on their assigned study treatment if 
background therapy is initiated, adjusted, or discontinued. Subjects will maintain a diary to 
record background therapy dosing and any adjustments made in their therapy. 


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Assessment of pulmonary function by spirometry (FVC, FEV1, and FEV1/FVC) before and after 
bronchodilator use will be performed at Screening.  During the Treatment Period, spirometry 
evaluation (without bronchodilator use) will be performed at the Baseline Visit and at all 
Treatment Period visits (excluding Day 5).  Other PFTs include DLCO (corrected for Hgb), to be 
assessed at Screening, Baseline, and Weeks 4, 8, 16, 26, 38, and 52; and total lung capacity and 
residual volume, to be assessed by full-body plethysmography at Baseline, Week 26, and 
Week 52.  All PFT results will be reviewed centrally. 
An independent data safety monitoring board (DSMB) will review the unblinded safety and 
available PK data throughout the study (at least quarterly) to assess the overall safety profile (see 
Section 19.2.2 for additional information).
7.2.
Study Duration, Study Visits, and Follow-Up
Study duration for an individual subject is approximately 65 weeks, including a Screening Visit 
up to 5 weeks prior to the first dose of study treatment, a Placebo-Controlled Treatment Period of 
52 weeks, and a Safety Follow-Up Visit 8 weeks after the end of the Treatment Period.  
7.2.1.
Screening
Subjects will undergo screening assessments within 5 weeks (35 days) prior to dosing. 
Qualifying assessments including medical history, physical examination, vital signs, 12-lead 
ECG, oxygen saturation, PFTs (before and after bronchodilator administration), HRCT, and 
clinical laboratory tests including pregnancy testing (women of childbearing potential only), and 
testing for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or total 
hepatitis B core antibody (anti-HBc), hepatitis B surface antibody (anti-HBs) and hepatitis C 
virus (HCV) antibody will be performed.  If the HCV antibody test is positive, hepatitis viral 
load will be evaluated for active hepatitis C infection.
A chest HRCT scan performed within 12 months of Screening can be used to determine initial 
eligibility to enter Screening (to prevent further Screening assessments if HRCT does not meet 
criteria for IPF). Regardless of whether a historical chest HRCT was submitted, all subjects are 
required to receive a chest HRCT at Screening. For determination of subject eligibility, all 
HRCT scans, including the historical and Screening Visit scans, must be consistent with the 
protocol-defined eligibility of IPF. If a historical surgical lung biopsy was performed as part of 
the subject’s initial IPF diagnosis and is available, it must be submitted for central review. 
Surgical lung biopsies will not be offered as an assessment in this study.  The diagnosis of IPF 
used for eligibility by HRCT and surgical lung biopsy (if available) will be confirmed centrally.
If historical lung biopsy slides are submitted for screening, the central reviewer will return the 
slides to the site when the review is complete, and the site will return the slides to the original 
source or provider, as applicable. 
Screening assessments (e.g., clinical laboratory assessments or PFTs) for subjects with IPF who 
do not meet the criteria for participation in this study under Version 2 of the protocol may be 
rescreened one time only, after discussion between the Principal Investigator and the Sponsor, if 


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there are questionable results or if abnormalities are felt to be due to inherent variability of the 
test procedure.  Subjects with IPF who did not meet the criteria for participation in this study 
(i.e., a screen failure) under Version 1 of the protocol due to previously adapted ATS 2011 
guidelines or hepatitis B criteria may be screened and rescreened again under Version 2 of the 
protocol. If a subject must be rescreened for study entry, results from previous screening 
assessments may be used, as long as the screening windows for those assessments are met and all 
spirometry data used for subject qualification are derived from a single day.  If any PFTs are to 
be repeated, only the tests that are felt to be questionable should be repeated (i.e., spirometry, 
DLCO, or plethysmography). 
Following confirmation of eligibility on the Screening PFT, subjects will undergo 1 additional 
set of PFTs without bronchodilator administration to establish their baseline lung function; this 
assessment will be performed at the Baseline (Day 0) Visit.  
Upon fulfilling all of the inclusion criteria and none of the exclusion criteria, subjects will be 
scheduled to return to the clinic for the Baseline predose evaluations and to ensure that they still 
qualify for the study. 
7.2.2.
Placebo-Controlled Treatment Period
The Placebo-Controlled Treatment Period begins with the Baseline (Day 0) Visit and ends with 
the End of Treatment Visit at Week 52.  At the Baseline Visit, the subject’s medical history, 
physical examination, inclusion/exclusion criteria, vital signs, weight and height, oxygen 
saturation, ECG, and pregnancy status (women of childbearing potential only) will be assessed.  
Baseline evaluations of PFTs, 6MWT, 
 will be 
obtained.  Predose blood samples will be collected for baseline laboratory clinical laboratory 
tests, 
 PK, and antibody assessments.  After confirmation of inclusion and exclusion 
criteria, the subject will be stratified based on use or nonuse of background therapy and then 
randomized to receive BG00011 56 mg SC or placebo.  The subject and/or their caregiver will 
receive instruction and training on the administration of study treatment, documentation of 
administration in the study diary, and proper handling of study treatment supplies.  The first dose 
of study treatment will then be administered under the supervision of study site personnel.  The 
subject will be observed for a minimum of 1 hour following the first administration of study 
treatment.  The subject will then be discharged with instructions to return to the study site for 
Treatment Period visits at Day 5 (for collection of a blood sample for PK analysis only, which 
may also be done at the subject’s residence) and at Weeks 4, 8, 12, 16, 20, 26, 32, 38, 44, and 52 
(End of Treatment Visit).  See Table 2 for a complete schedule of assessments to be performed at 
each visit.  
7.2.3.
Safety Follow-Up Visit
A Safety Follow-Up Visit is to occur 8 weeks after the End of Treatment Visit.  Therefore, if the 
End of Treatment Visit occurs at Week 52, as planned, the Safety Follow-Up Visit will occur at 
Week 60.  See Table 2 for a schedule of assessments to be performed at the Safety Follow-Up 
Visit.   


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7.2.4.
Study Treatment Discontinuation
If study treatment is discontinued prematurely (i.e., before the subject completes the 52-dose 
regimen), the subject must return for an End of Treatment Visit as soon as possible but within 
4 weeks after discontinuation of treatment. If the End of Treatment Visit occurs in the visit 
window for the next scheduled visit, then the End of Treatment Visit may be substituted for the 
scheduled visit. Subjects will then complete all remaining visits as scheduled. See Section 10.1
for additional details about study treatment discontinuation.
7.2.5.
Withdrawal From the Study
If a subject is withdrawn from the study, an End of Treatment Visit will be scheduled or
performed as soon as possible but within 4 weeks. See Section 10.2 for additional details about 
withdrawal from the study.
7.2.6.
Unscheduled Visit for Acute Exacerbation of IPF
A subject who experiences a worsening of respiratory status at any time during the study should 
immediately contact their treating physician.  The subject should also notify the Investigator (if 
different than the treating physician) to schedule the IPF Exacerbation Visit as soon as possible 
so that the Investigator may assess and confirm the IPF exacerbation. Should the subject be 
unable to come to the clinic for the IPF Exacerbation Visit, the Investigator should attempt to 
complete the Investigator’s determination of IPF exacerbation (see Section 7.2.6.1) as soon as 
possible. 
The IPF Exacerbation Visit should include the following:

Physical examination 

Vital signs 

Oxygen saturation

Spirometry

DLCO

Imaging studies (chest X-ray or HRCT) if not performed at another facility

Investigator's determination of IPF exacerbation (see Section 7.2.6.1)
This visit may also include the following at the Investigator’s discretion:

ECG

Clinical laboratory tests (hematology, blood chemistry, and urinalysis)

Other tests or evaluations at the discretion of the Investigator
Note: If an IPF exacerbation is suspected at the time of a scheduled visit or is to be evaluated at 
a scheduled visit, the IPF exacerbation assessments listed above must be performed at the 
scheduled visit if not already included.


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A subject who is evaluated, treated, or hospitalized at a facility other than the study site should 
contact the study site following that visit to determine if the subject should come in for a 
stand-alone IPF Exacerbation Visit or have additional IPF exacerbation assessments during a 
routine, scheduled study visit.  In addition, if a subject was hospitalized or had IPF exacerbation 
assessments at another facility, study site personnel should make every effort to obtain sufficient 
medical records in order to determine the following:

Possible triggers or causes of the event.

The results of relevant tests and assessments, including but not limited to:

Detailed radiography reports and copies of images of all radiographic 
examinations (e.g., chest X-ray or HRCT scan) for submission to the central 
imaging vendor.

Spirometry, body plethysmography (lung volume), and/or DLCO testing reports.

Descriptions of the severity and duration of the event.

Details of the medical treatment provided, including relevant medications and other 
major elements of the clinical management.

The subject’s response to the treatment and clinical status at the time of discharge. 
7.2.6.1.
Determination of IPF Exacerbation
Based on the results obtained from evaluations at the IPF Exacerbation Visit and/or the records
obtained from a visit to another facility (if applicable), the Investigator will determine whether
an IPF exacerbation or suspected IPF exacerbation has occurred.
Specific criteria for acute exacerbation of IPF will be determined by the Investigator, using a 
modified definition of IPF exacerbation derived from the IPF Clinical Research Network 
(IPFnet) definition of acute exacerbations of IPF in 2007 [Collard 2007], as follows: 

Unexplained worsening or development of dyspnea within 30 days.

New diffuse pulmonary infiltrates on chest X-ray, and/or new HRCT parenchymal 
abnormalities with no pneumothorax or pleural effusion (new ground-glass opacities) 
since last visit.

Exclusion of infection per routine clinical practice and microbiological studies.

Exclusion of alternative causes per routine clinical practice, including the following:

left heart failure

pulmonary embolism

identifiable cause of acute lung injury


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The Investigator’s determination of IPF exacerbation based on 
 (2007 
) definitions 
should be documented on the appropriate CRF.
As noted, treatment for an acute exacerbation is at the discretion of the Investigator and 
medications (such as prednisone) can be freely initiated or increased at the Investigator’s 
discretion. 
7.3.
Study Stopping Rules
Biogen may terminate this study at any time. The Sponsor will notify Investigators if the study is 
to be placed on hold, completed, or terminated. 
The DSMB will conduct regular reviews of all safety data in an unblinded format.  Following 
each review, the DSMB will provide a recommendation to the Sponsor regarding the 
appropriateness of continuing the study from a safety perspective, as well as any other 
recommendations relevant to study conduct and/or subject safety. 
The DSMB may recommend discontinuing the study if the event rate in the BG00011 treated 
arm is 20% higher compared with placebo.  The events include, but may not be limited to:

cumulative number of deaths and/or;

number of lung transplantations and/or;

cumulative number of subjects with a confirmed absolute decline of % predicted FVC 
≥15 from baseline.
The meeting intervals and the procedures used to provide and assess the data will be described in 
detail in the DSMB charter.
7.4.
End of Study
The end of study is last subject, last visit.


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8.
SELECTION OF SUBJECTS
8.1.
Inclusion Criteria
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at the time of randomization, or at the timepoint specified in the individual eligibility criterion 
listed:
1. Ability of the subject or his/her legally authorized representative to understand the 
purpose and risks of the study and provide signed and dated informed consent and 
authorization to use confidential health information in accordance with national and local 
subject privacy regulations. 
2. Aged ≥40 years at the time of informed consent. 
3. Female subjects must be surgically sterile, postmenopausal (minimum 1 year without 
menses), or agree to use 1 or more of the following forms of highly effective 
contraception from the time of signing the informed consent form (ICF) until 3 months 
after the last injection of study medication:  hormonal (i.e., oral, transdermal, implant, or 
injection); intrauterine device; vasectomized partner (with appropriate postvasectomy 
documentation of the absence of sperm in the ejaculate); or abstinence.  Male subjects 
must also agree to use 1 or more of the above forms of birth control for either themselves 
or their partner(s), as appropriate, from the time of signing the ICF until 4 months after 
the last injection of study medication.
4. IPF diagnosed based on modified ATS/ ERS/JRS/ALAT IPF guideline for diagnosis and 
management, within 3 years of Screening (see Section 4.2).
5. Combination of HRCT pattern and, if one has been obtained, surgical lung biopsy 
pattern, as assessed by central reviewers, consistent with diagnosis of IPF (see 
Section 4.2).
Note: A chest HRCT performed within 12 months of Screening can be used to determine 
initial eligibility to enter Screening and must be submitted to the central imaging vendor 
for eligibility read (to prevent further Screening assessments if HRCT is not consistent
with IPF). Regardless of whether a historical chest HRCT was submitted, all subjects are 
required to receive a chest HRCT at Screening. If a historical HRCT is not available or 
not submitted, then the HRCT performed at the Screening Visit will be used to determine 
subject eligibility. For determination of subject eligibility, all HRCT scans, including the 
historical and Screening Visit scans, must be consistent with the eligibility criteria for 
IPF. Eligibility read of the HRCT will be performed by a central radiologist. 
6. DLCO (corrected for hemoglobin):  30% to 79% predicted of normal at Screening, with no 
clinically significant deterioration between the Screening Visit and randomization, as 
determined by the Investigator.


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7. FVC ≥50% predicted of normal at Screening, with no clinically significant deterioration 
between the Screening Visit and randomization, as determined by the Investigator.
8. If a subject is taking nintedanib or pirfenidone, they must be on a stable dose for at least 8 
weeks prior to randomization.
8.2.
Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
the time of Screening, the time of randomization, or at the timepoint specified in the individual 
criterion listed:
Lung Function
1. Unable to perform PFTs or undergo HRCT procedure.
2. Peripheral capillary oxygen saturation (SpO2) <90% at rest (if on oxygen
supplementation, must be ≤2 L/min at rest).
3. Findings that are diagnostic of a condition other than UIP based on the combination of 
surgical lung biopsy (if available), HRCT imaging, transbronchial lung biopsy, or BAL,
according to central review of imaging and pathology.
4. Airway obstruction (i.e., prebronchodilator FEV1/FVC <0.7) or evidence of a 
bronchodilator response as defined by an absolute increase of ≥12% and an increase of 
≥200 mL in FEV1 or FVC, or both, after bronchodilator use, compared with the values 
before bronchodilator use at Screening.
5. End-stage fibrotic disease likely requiring organ transplantation within 12 months, or if 
the subject has initiated active evaluation for organ transplantation.
6. The extent of emphysema in the lungs exceeds fibrosis, based on central review of HRCT 
scans.
7. In the opinion of the Investigator, the subject has experienced significant clinical 
deterioration between the Screening Visit and randomization.
Medical History
8. Body weight <60 kg at Screening.
9. History of or ongoing malignant disease, including solid tumors and hematologic 
malignancies, with the exception of basal cell carcinomas, squamous cell carcinomas, and 
carcinoma in situ of the cervix that have been completely excised and considered cured 
>2 years prior to Screening.


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10. Significant cardiac disease (e.g., New York Heart Association Class 3 or 4; myocardial 
infarction within the past 6 months; unstable angina; coronary angioplasty or coronary 
artery bypass graft within the past 6 months; uncontrolled atrial or ventricular cardiac 
arrhythmias; or pulmonary hypertension requiring pharmacologic treatment).
11. Clinical diagnosis of any connective tissue disease (including but not limited to 
scleroderma, polymyositis/dermatomyositis, systemic lupus erythematosus, and 
rheumatoid arthritis) or a diagnosis of interstitial pneumonia with autoimmune features as 
determined by the Investigator applying the recent ERS/ATS research statement   
[Fischer 2015].  Note:  Serological testing is not needed if not clinically indicated.
12. History of organ transplant at any time.
13. Female who is pregnant or breastfeeding.
14. Serious local infection (e.g., cellulitis, abscess) or systemic infection (e.g., septicemia) 
that required hospitalization or was clinically significant in the opinion of the 
Investigator, within 3 months prior to Screening.
15. Fever (body temperature > 38°C) or symptomatic viral or bacterial infection within 2 
weeks prior to the Screening Visit or the Baseline Visit.
16. History or positive test result at Screening for human immunodeficiency virus.  Current 
hepatitis C infection (defined as positive HCV antibody and detectable HCV ribonucleic 
acid [RNA]). Participants with positive HCV antibody and undetectable HCV RNA are 
eligible to participate in the study. Current hepatitis B infection (defined as positive for 
hepatitis B surface antigen [HBsAg] and/or anti-HBc. Participants with immunity to 
hepatitis B from previous natural infection (defined as negative HBsAg, positive anti-
HBc, and positive anti-HBs or vaccination (defined as negative HBsAg, negative anti-
HBc, and positive anti-HBs) are eligible to participate in the study.
17. Known hypersensitivity to BG00011 or components of the BG00011 formulation or 
matching placebo.
18. Active drug or alcohol abuse (as defined by the Investigator) within 3 months prior to 
Screening.
19. Other disease that may interfere with testing procedures or, in the judgment of the 
Investigator, may interfere with study participation or may put the patient at risk when 
participating in this study.
20. Has a disease other than IPF with a life expectancy <2.0 years (Investigator assessment).
21. Other unspecified reasons that, in the opinion of the Investigator or the Sponsor, make the 
subject unsuitable for enrollment.


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Laboratory Parameters
22. Screening values for the following laboratory tests (1 retest within 2 weeks is allowed):

Hemoglobin <10 g/dL

WBC count <3.00 × 103/μL

Neutrophils <1.50 × 103/μL

Platelets <80 × 103/μL

Total bilirubin >1.5 mg/dL

Aspartate transaminase (AST) or alanine transaminase (ALT) >2 × upper limit of 
normal (ULN)
Medications
23. Currently receiving high-dose corticosteroid, cytotoxic therapy (e.g., chlorambucil, 
azathioprine, cyclophosphamide, methotrexate), vasodilator therapy for pulmonary 
hypertension (e.g., bosentan), unapproved (e.g., IFN-γ, penicillamine, cyclosporine, 
mycophenolate, N-acetylcysteine [may vary by country]) and/or investigational therapy 
for IPF or administration of such therapeutics within 5 half-lives of the agent prior to 
initial screening in this study.  A current dose of ≤10 mg/day of prednisone or its 
equivalent is acceptable if the dose is expected to remain stable during the study.
24. Treatment with another investigational drug, investigational device, or approved therapy 
for investigational use within 5 half-lives of the agent prior to initial screening in this 
study.
25. Live/attenuated vaccinations within 12 weeks prior to Screening (inactivated influenza 
vaccine is permitted).
Other
26. 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.
27. Blood donation (1 unit or more) within 1 month prior to Screening.
28. Male or female planning a pregnancy during the duration of this study.  A serum 
pregnancy test will be performed on all female subjects of childbearing potential.
29. Inability to comply with study requirements.
30. Use of any tobacco product and/or inhaled substance, including but not limited to tobacco 
or marijuana products, and/or the use of any electronic cigarette or vaping device, within 
12 weeks prior to Screening (note that respiratory inhalers for delivery of prescribed 
medication for pulmonary disease are allowed).


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9.
SCREENING AND RANDOMIZATION
9.1.
Screening 
Subjects must provide informed consent before any screening tests are performed (Section 17.3).  
Participating study sites are required to document all screened candidates initially considered for 
inclusion in the study.  
Screen failures are defined as subjects who sign the ICF but are not subsequently randomized or 
dosed.  If a subject is considered a screen failure, the reasons for exclusion must be documented 
in the subject’s source documents and on the screening log.  A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials publishing requirements and to respond to queries 
from regulatory authorities.  Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAEs.  
Subjects with IPF who do not meet the criteria for participation in this study under Version 2 of 
the protocol may be rescreened one time only after discussion between the Principal Investigator 
and the Sponsor.  Subjects with IPF who did not meet the criteria for participation in this study
(i.e., a screen failure) under Version 1 of the protocol due to previously adapted ATS 2011 
guidelines or hepatitis B criteria, may be screened and rescreened again under Version 2 of the 
protocol.
9.2.
Randomization 
Subjects will be randomized after all screening assessments have been completed and after the 
Investigator has verified that the subjects are eligible per criteria in Sections 8.1 and 8.2.  
Subjects will be assigned a unique identification number that will be used on study-related 
documents pertaining to the subject.  Any subject identification numbers that are assigned will 
not be reused even if the subject does not receive treatment or continue in the study.
Randomization will be performed using interactive response technology (IRT).  Subjects will be 
randomized to receive BG00011 or placebo in a 1:1 ratio. 
Refer to the Study Reference Guide for details on randomization.
9.3.
Blinding Procedures
This is a randomized, double-blinded, placebo-controlled study.
All study staff will be blinded to the subject treatment assignments.  To maintain the study blind, 
it is imperative that subject treatment assignments are not shared with the subjects, their families, 


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or any member of the study team, either at the study site or at the Sponsor, except the unblinded 
Pharmacy staff and designated Sponsor personnel. 
At the end of the study (i.e., once the clinical study report is finalized), if unblinding will not 
jeopardize the results of ongoing related studies, the Sponsor will provide the randomization 
codes to Investigators, who then can inform their subjects about the treatment received.  


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10.
DISCONTINUATION OF STUDY TREATMENT AND 
WITHDRAWAL OF SUBJECTS FROM THE STUDY
10.1.
Discontinuation of Study Treatment
Study treatment discontinuation is defined as the premature ending of study treatment dosing,
i.e., when a subject permanently stops taking the study treatment before the last dose (the 
Week 51 dose).  Reasons for mandatory study treatment discontinuation are listed in
Section 10.1.1.  The primary reason for study treatment discontinuation must be recorded in the 
subject’s CRF.
Subjects who discontinue study treatment must return for an End of Treatment Visit as soon as 
possible, but within 4 weeks after discontinuation of treatment. All assessments planned for the 
Week 52 Visit except the HRCT scan will be performed.  If the End of Treatment Visit occurs in 
the visit window for the next scheduled visit, then the scheduled visit may serve as the End of 
Treatment Visit, and all assessments for the End of Treatment Visit should occur at that time. 
Subjects will go on to complete all remaining visits as scheduled, including the Week 52 and 
Safety Follow-Up Visits (see Table 2 for a list of assessments to occur at the End of Treatment 
and Safety Follow-Up Visits).  
Note:  A subject who misses 1 or more doses of study treatment should restart study treatment,
receive all remaining doses, and complete all remaining study visits. 
See Section 10.2 for information related to the withdrawal of subjects from study.
10.1.1.
Reasons for Study Treatment Discontinuation
A subject must permanently discontinue study treatment for any of the following reasons:

The subject becomes pregnant.  Study treatment must be discontinued immediately.  
Report the pregnancy according to the instructions in Section 15.4.1.

The subject experiences an AE that necessitates permanent discontinuation of study 
treatment.

If organ transplantation is planned to occur during the study treatment or Safety 
Follow-Up Period.

The subject experiences an urgent medical event 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.


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
The subject withdraws consent to continue study treatment.  
10.1.1.1.
Safety Criteria for Study Treatment Discontinuation
Liver Chemistry:
Liver chemistry threshold discontinuation criteria have been designed to ensure subject safety 
and to evaluate liver event etiology during administration of study treatment and during the 
Follow-Up Period. Study treatment will be discontinued if any of the following criteria are met:

AST or ALT 3 × ULN and total bilirubin level 2 × ULN

AST or ALT 5 × ULN: study treatment will be discontinued if the result is 
confirmed upon retest within 48 hours.

AST or ALT 3 × ULN: study treatment will be discontinued if associated with the 
appearance or worsening of rash or hepatitis symptoms (i.e., fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia).
10.2.
Withdrawal of Subjects From the Study
Study withdrawal is defined as the premature ending of study visits and assessments.  The
reasons for mandatory study withdrawal are listed below (Section 10.2.1 ).  Note that 
discontinuation of study treatment does not require withdrawal from the study if a subject 
continues to attend clinic visits and complete assessments.  
If a subject is withdrawn from the study, an End of Treatment Visit will be scheduled or 
performed as soon as possible but within 4 weeks.  All assessments planned for the Week 52 
Visit except the HRCT scan will be performed (see Table 2 for a list of assessments to occur at 
the End of Treatment Visit).  
If a subject is unwilling or unable to attend, at minimum, the End of Treatment Visit, and decides 
to withdraw consent, the reason for withdrawal will be documented and no further assessments 
will be obtained. 
Subjects who are withdrawn from the study will not be replaced.
10.2.1.
Reasons for Withdrawal of Subjects from the 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.


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10.3.
Lost to Follow-Up
Subjects will be considered lost to follow-up if they repeatedly fail to return for scheduled visits 
and are unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit:

The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether the subject wishes to and/or should continue in the 
study.

In cases in which the subject is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the subject.  These contact attempts 
should be documented in the subject’s medical record.

If the subject continues to be unreachable, that subject will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.


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11.
STUDY TREATMENT USE
11.1.
Regimen
Refer to and follow the Directions for Handling and Administration (DHA).
Approximately 290 subjects will be randomized into 2 dose groups as follows:

Group 1:  BG00011 56 mg by SC injection, once weekly for 52 weeks

Group 2:  Placebo by SC injection, once weekly for 52 weeks
The first dose of BG00011 or placebo (study treatment) will be administered at the study site 
during the Baseline Visit (Day 0).  All subsequent doses should be administered by the subject or 
the subject’s caregiver. 
11.2.
Modification of Dose and/or Treatment Schedule
The dosage and dosing schedule cannot be modified. A window of +2 days is allowed without 
qualifying as an overdose for non-Baseline Visits; however, subsequent doses should adhere to 
the dosing schedule initiated at the Baseline Visit.  
11.3.
Precautions
Subjects will be monitored by study site personnel for at least 1 hour after administration of the 
first dose of study treatment.
11.4.
Compliance
Compliance with study treatment dosing is to be documented by the subject or the subject’s 
caregiver in the electronic study diary and monitored at each study visit by study site personnel.
11.5.
Concomitant Therapy and Procedures
11.5.1.
Concomitant Therapy
A concomitant therapy is any drug or substance administered between the time a subject is 
screened for the study and the final study visit.
11.5.1.1.
Allowed Concomitant Therapy
A current dose of ≤10 mg/day of prednisone or its equivalent is acceptable if it has been stable 
for at least 8 weeks prior to randomization and it is anticipated that the dose will remain stable 
throughout the subject’s enrollment.


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During a subject’s enrollment, pirfenidone or nintedanib may be taken as background therapy for 
IPF. The subject must be on a stable dose of either drug for at least 8 weeks prior to 
randomization.  Both drugs are not to be used simultaneously.  Subjects should not initiate 
background therapy during the study.  In cases where the Investigator feels that background 
therapy is clinically indicated, this therapy can be started, but the initiation of background 
therapy during the study will be considered a protocol deviation.  Note that a subject may 
continue in the study on their assigned study treatment if background therapy is initiated, 
adjusted, or discontinued.
While participating in the study, every effort should be made to maintain the subject on a stable 
dose of background therapy.  However, background therapy dosing may be adjusted or 
discontinued by the physician responsible for the subject’s pulmonary care, with no dose to 
exceed the labeled maximum doses.  Subjects will maintain a diary to record background therapy 
dosing and any adjustments made in their background therapy. In the event of an IPF 
exacerbation meeting the definition described in this protocol, if the Investigator feels that 
additional therapy (other than pirfenidone or nintedanib) is clinically indicated, this therapy may 
be started and the medications, doses, and duration of treatment must be documented as 
concomitant medications.  The subject may continue in the study.
Subjects should be instructed to continue the medications that they were receiving at enrollment 
and to avoid starting any new medications or herbal preparations during the study, since these
may confound the results of the study.  However, medically indicated medication or treatment 
should not be withheld.  Subjects should inform the Investigator of any changes in the
medications they are taking.
11.5.1.2.
Disallowed Concomitant Therapy
Simultaneous use of pirfenidone and nintedanib. 
While participating in this study, subjects should not be receiving chronic high-dose 
corticosteroid (i.e., >10 mg/day of prednisone or its equivalent), cytotoxic therapy (e.g., 
chlorambucil, azathioprine, cyclophosphamide, methotrexate), vasodilator therapy for pulmonary 
hypertension (e.g., bosentan), unapproved (e.g., IFN-γ, penicillamine, cyclosporine, 
mycophenolate and N-acetylcysteine [may vary by country]), and/or any investigational therapy 
for IPF or administration of such therapeutics within 5 half-lives of the agent prior to initial 
screening in this study. Live or attenuated vaccinations within 12 weeks prior to Screening or 
during the study are not permitted (inactivated influenza vaccine is permitted).
All treatments previously used for clinical management or in previous investigational trials of 
IPF will be documented on the appropriate CRF.
11.5.2.
Concomitant Procedures
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy, 
pulmonary rehabilitation) or diagnostic assessment (e.g., blood gas measurement, bacterial 
cultures) performed between the time the subject is screened for the study and final study visit.


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11.6.
Continuation of Treatment 
No further provisions are made for access to the study treatment.  If BG00011 is proven to be 
beneficial, all regulatory requirements regarding poststudy access will be met.


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12.
STUDY TREATMENT MANAGEMENT
Study treatment will be manufactured, handled, and stored in accordance with applicable Good 
Manufacturing Practice.
Study site staff should follow the Directions for Handling and Administration, which is located 
in the pharmacy binder, for specific instructions on the handling, preparation, administration, and 
disposal of the study treatment.  The Directions for Handling and Administration 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 randomized in this study.  Once study treatment is 
prepared for a subject, it can be administered only to that subject.  Study treatment is for 
one-time use only; do not use any study treatment remaining in the syringe for another subject.
12.1.
BG00011
BG00011 drug product is a liquid formulation and supplied in a 1.0 mL syringe (prefilled to 
0.8 mL) and is intended for self-administration.  The pre-filled syringe contains 56 mg of 
BG00011 per syringe and is formulated in sodium citrate, methionine, L-arginine, and 
polysorbate 80 at pH 5.5.  The placebo consists of the formulation buffer.
The contents of the BG00011 label will be in accordance with all applicable regulatory 
requirements.  At a minimum, the label will include a study reference code, study treatment 
identifier, quantity of dosage units, lot number, and other pertinent information in accordance 
with local law.  The expiry or use-by date is stored in the IRT system, and printable assignment 
reports are available to site personnel.  Study treatment should not be used after the expiration, 
expiry, or use-by date.
12.1.1.
BG00011 Preparation
The individual preparing BG00011should carefully review the instructions provided in the 
Directions for Handling and Administration.  If the packaging is damaged, or if there is anything 
unusual about the appearance or attributes of the study treatment, do not use the study treatment.  
The study treatment in question should be saved at the study site and the problem immediately 
reported to the Sponsor.
12.1.2.
BG00011 Storage
Study treatment (BG00011 and placebo) must be stored in a secure location.  
BG00011 prefilled syringes are to be stored at 2C to 8C (36F to 46F), in a locked refrigerator 
with limited access.  For the most up-to-date storage requirements, follow the instructions 
provided in the Directions for Handling and Administration.


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12.1.3.
BG00011 Handling and Disposal
The Investigator must return all used and unused prefilled syringes of BG00011 as instructed by 
the Sponsor unless approved for onsite destruction.
If any BG00011 supplies are to be destroyed at the study site, the institution or appropriate site 
personnel must obtain prior approval from the Sponsor, by providing, in writing, the destruction 
policy or details of the method of destruction.  After such destruction, the Sponsor must be 
notified, in writing, of the details of the study treatment destroyed (e.g., lot or kit numbers, 
quantities), the date of destruction, and proof of destruction.
12.1.4.
BG00011 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), amount returned by the subject, and accounts of any 
study treatment accidentally or deliberately destroyed or lost.  
Unless otherwise notified, all prefilled syringes both used and unused, must be saved for study 
treatment accountability.  By the end of the study, reconciliation must be made between the 
amount of BG00011 supplied, dispensed, and subsequently destroyed, lost, or returned to the 
Sponsor.  A written explanation must be provided for any discrepancies.
12.2.
Reference Product
The placebo (control agent) to be used in this study is supplied in a 1.0 mL syringe (prefilled to 
0.8 mL) and intended for self-administration.  The prefilled syringe contains only the buffering 
solution used for the active drug product (sodium citrate, methionine, L-arginine, and 
polysorbate 80 at pH 5.5).  Labeling, preparation, storage, handling, and disposal instructions for 
the reference product are identical to those for BG00011.


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13.
EFFICACY, PHARMACOKINETIC, 
 
 ASSESSMENTS
See Section 5 for the timing of all efficacy, PK, 
 assessments.
13.1.
Clinical Efficacy Assessments
The following clinical assessments will be performed to evaluate the efficacy of BG00011.
13.1.1.
Pulmonary Function Testing
13.1.1.1.
Spirometry
Spirometry testing, including FVC, FEV1, and FEV1/FVC, both before and after bronchodilator 
use, will be performed at Screening.  During the Treatment Period, spirometry testing (without
bronchodilator use) will be performed at Baseline (Day 0) and at all scheduled study visits 
except Day 5. The spirometry evaluations performed at the Screening Visit will be used to 
determine whether the subject qualifies for the study and must be performed within 35 days prior 
to the first dose of study treatment.  At the Baseline Visit, spirometry test results will be obtained 
prior to the first dose of study treatment.  For each subject, spirometry testing should be 
conducted at approximately the same time of day.  
See the Study Reference Guide for full details of spirometry testing procedures.
All spirometry results will be electronically transmitted and confirmed by a central reader.  
Investigators will receive a report from the central reader.
13.1.1.2.
Carbon Monoxide Diffusion Capacity
DLCO measurement will be performed at Screening to determine study eligibility, and at the 
following study visits:  Baseline (Day 0), Week 4, Week 8, Week 16, Week 26, Week 38, and 
Week 52. 
Evaluation of DLCO will be performed by single-breath carbon monoxide diffusing capacity 
according to ATS/ERS recommendations.  See the Study Reference Guide for full details of the 
DLCO testing procedure.
13.1.1.3.
Full-Body Plethysmography
Lung volumes, including total lung capacity and residual volume, will be measured by full-body 
plethysmography at the following study visits:  Baseline (Day 0), Week 26, and Week 52.
See the Study Reference Manual for full details of body plethysmography testing procedures.


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13.1.2.
High-Resolution Computed Tomography
HRCT scanning will be performed at Screening, Week 26, and Week 52. Noncontrast chest CT 
through the full chest at suspended full inspiration and full expiration will be performed as 
detailed in the Imaging Procedure Manual. The HRCT scan performed at Screening will be 
centrally read, will be used to determine study eligibility, and will establish the predose baseline 
pattern and extent of disease for comparison with the Week 26 and Week 52 scans. 
An independent central radiologist experienced in the evaluation of diffuse lung diseases and 
blinded to treatment assignment will read all HRCT scans obtained during the study. The central 
radiologist will evaluate the Screening HRCT to determine eligibility and will also perform 
qualitative IPF change assessment from Screening and follow-up HRCT scans. 
 
 
See the Imaging Procedure Manual for full details on HRCT scanning procedures.
13.1.3.
Acute Exacerbations of IPF
Subjects should be advised of the importance of reporting worsening respiratory status to the 
Investigator.  The subject should also notify the Investigator (if different than the treating 
physician) to schedule the IPF Exacerbation Visit as soon as possible so that the Investigator 
may assess and confirm the IPF exacerbation. Should the subject be unable to come to the clinic 
for the IPF Exacerbation Visit, the Investigator should attempt to complete the Investigator’s 
determination of IPF exacerbation as soon as possible. See Section 7.2.6  for a detailed 
description of the IPF Exacerbation Visit.
Based on the results obtained from evaluations at the IPF Exacerbation Visit and/or the records 
obtained from a visit to another facility, using a modified definition of IPF exacerbation derived 
from IPFnet definition of acute exacerbations of IPF in 2007 [Collard 2007] (see
Section 7.2.6.1), the Investigator will determine whether an IPF exacerbation has occurred.
 
 
 
Analyses of IPF exacerbation events, based on 
 the modified definition of IPF exacerbation 
(2007)
 will include the following:

Time to first acute exacerbation, measured in days.

Proportion of subjects with at least 1 acute exacerbation during the 52 weeks on 
study.

Number of exacerbations during 52 weeks.


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See Section 16.2.2.3 and Section 16.2.2.4 for additional details of these analyses. 
13.1.4.
Respiratory Hospitalizations  
All nonelective hospitalizations will be assessed by the Investigator to determine whether the 
primary cause of the hospitalization was respiratory in nature. The determination of a respiratory 
hospitalization should be based on a fundamental change in respiratory status that is due either to 
intrinsic lung disease or to infectious etiology of the lung.  The change in respiratory status 
should not be the result of a secondary effect from another organ or system. 
In addition, study site personnel should obtain sufficient medical records to determine the 
following:

Possible triggers or causes of the event

The results of relevant tests and assessments (if performed), including but not limited to:

Detailed radiography reports and copies of images of all radiographic 
examinations (e.g., chest X-ray or HRCT scan) for submission to the central 
imaging vendor

Spirometry, lung volume, and/or DLCO testing reports

Echocardiogram

Microbiology data

Descriptions of the severity and duration of the event

Details of the medical treatment provided, including relevant medications and other 
major elements of the clinical management

The subject’s response to the treatment and clinical status at the time of discharge. 
13.1.5.
6-Minute Walk Test
The 6MWT will be administered at the following study visits:  Baseline (Day 0), Week 26, and 
Week 52.  This test, which includes 2 walks, assesses the distance in meters that a subject can 
walk in 6 minutes, will be conducted according to ATS criteria by study site staff in a suitable 
location with emergency response supplies available.  Detailed criteria for the conduct of the 
6MWT, including training requirements for administration of the test, availability of emergency 
supplies, use of oxygen supplementation during the test, and parameters for starting and stopping 
the test, are provided in the Study Reference Guide.
 


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13.2.
Pharmacokinetic Assessments
Blood samples for PK evaluation will be collected at the following visits: prior to dosing at 
Baseline (Day 0), Day 5, Week 4, Week 8, Week 12, Week 26, Week 38, Week 52, and 
Week 60.
The PK data obtained in this Phase 2b study will be combined with data from other studies in the 
clinical development program to develop a population PK model.  This model will be used to 
evaluate the effects of intrinsic and extrinsic covariates on the PK of BG00011 and to determine 
measures of individual exposure (such as steady-state trough, time-averaged concentration, or 
AUC).  Model-determined exposures will be used for exposure-response analyses of selected 
efficacy and safety endpoints.  Results of population PK and exposure-response analyses will be 
reported separately.
 
 
  
 


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14.
SAFETY ASSESSMENTS
Refer to Section 5 for the timing of all safety assessments.
Tests and evaluations affecting primary endpoints and/or analyses may need to be repeated if the 
original results are lost or damaged.  In these cases, subjects will be asked to return to the clinic 
to have the evaluations repeated.
14.1.
Clinical Safety Assessments
The following clinical assessments will be performed to evaluate the safety profile of BG00011:

AE and SAE monitoring and recording

Lung function
The assessment of changes in lung function during this study will be performed by 
comparing the subject’s spirometry parameters at Baseline to postbaseline values during the 
Treatment and Follow-Up Periods.  These evaluations will assess both the absolute and the 
percent predicted changes in FVC.  All spirometry tests will be reviewed centrally.
Expected fluctuations or expected deterioration of the underlying IPF and other pre-existing 
conditions should not be recorded as an AE except in the following circumstances:
o
Worsening of the disease meets the criteria for an SAE.
o
Action is taken with investigational treatment, such as when treatment is 
discontinued.
o
Additional treatment is required, such as when concomitant medication is added or 
changed.
o
In the opinion of the Investigator, an unexpected deterioration from baseline has 
occurred.
o
The event meets the criteria of an acute exacerbation of IPF or suspected exacerbation 
of IPF.
Specific criteria for acute exacerbation of IPF will be determined by the Investigator based 
on the following 2 definitions: 
Diagnostic Criteria for Acute IPF Exacerbation (2007)
o
Unexplained worsening or development of dyspnea within 30 days.
o
New diffuse pulmonary infiltrates on chest X-ray, and/or new HRCT parenchymal 
abnormalities with no pneumothorax or pleural effusion (new ground-glass opacities) 
since last visit.
o
Exclusion of infection per routine clinical practice and microbiological studies.
o
Exclusion of alternative causes per routine clinical practice, including the following:


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
congestive heart failure

pulmonary embolism

identifiable cause of acute lung injury
 
 
 

High-resolution computed tomography  
HRCT scans will be performed during Screening to establish the predose pattern and extent 
of disease and will serve as the baseline assessment.  An independent central radiologist 
experienced in the evaluation of diffuse lung diseases and blinded to treatment assignment 
will evaluate the HRCT scans, which will be performed at Screening, Week 26, and 
Week 52.  Every effort will be made to have sequential scans for individual subjects 
evaluated by the same radiologist. 

Other safety assessments
o
Medical history 
o
Concomitant therapy and procedure recording
o
Physical examination
o
Vital signs: oral or tympanic temperature (°C), heart rate (beats/min), respiratory rate 
(breaths/min), sitting blood pressure (mmHg) after at least 5 minutes’ rest
o
Body weight (kg) and height (cm)
o
12-lead ECG after at least 5 minutes’ rest
o
Oxygen saturation (pulse oximetry) after at least 5 minutes’ rest
o
Use of supplemental oxygen
o
Study discontinuations (all causes, and due to urgent need for transplantation)
o
Cumulative number of lung transplantations and number of deaths (respiratory and all 
causes)
o
Cumulative spirometry testing with percent change from baseline and change in 
percent predicted from baseline calculated at each visit
o
Cumulative number of nonelective hospitalizations
14.2.
Laboratory Safety Assessments
All samples will be analyzed using Good Laboratory Practice validated assays.


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The following laboratory assessments will be performed to evaluate the safety profile of 
BG00011:

Hematology:  Complete blood count, including red blood cell count, white blood cell 
count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular 
hemoglobin, and mean corpuscular hemoglobin concentration.

Serum chemistry, including:  albumin, alkaline phosphatase, alkaline phosphatase, 
ALT, AST, blood urea nitrogen, calcium, chloride, carbon dioxide, creatinine, 
bilirubin (total and direct), gamma-glutamyl transferase, glucose, lactate 
dehydrogenase, phosphorus, potassium, sodium, and total protein.

Urinalysis, including urine protein, glucose, ketones, occult blood, and white blood 
cells by dipstick, with microscopic examination if indicated.  

At Screening, blood samples for HCV antibody and RNA, HBsAg, anti-HBc, anti-
HBs and HIV antibody will be collected to establish eligibility.  Appropriate referrals 
must be made for any active HCV, positive HBsAg, or HIV test that is obtained,
according to applicable local laws.

Serum pregnancy test (Screening).

Urine pregnancy tests (all visits after Screening).
14.3.
Immunogenicity Assessments
The following assessments will be performed to determine the safety of BG00011:

Collection and analysis of serum samples for the presence and titer of anti-BG00011
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, or their legally authorized representative and/or main 
caregiver must be given the names and telephone numbers of study site staff for reporting AEs 
and medical emergencies.
15.1.
Definitions
15.1.1.
Adverse Event
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product.
Determination of whether an abnormal laboratory value, vital sign result, and/or ECG result 
meets the definition of an AE will be made by the Investigator.  Abnormal results are not 
considered AEs unless one or more of the following criteria are met:

The result meets the criteria for an SAE

The result requires the subject to receive specific corrective therapy

The result is considered by the Investigator to be clinically significant
15.1.2.
Serious Adverse Event
An SAE is any untoward medical occurrence that at any dose:

Results in death

In the view of the Investigator, places the subject at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred 
in a more severe form, might have caused death

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity


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
Results in a congenital anomaly/birth defect

Is a medically important event
A medically important event is an AE that, in the opinion of the Investigator, may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the definition 
above.  (Examples of such medical events include allergic bronchospasm requiring intensive 
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 preventative health procedure 
(e.g., colonoscopy) 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.


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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.
Relationship of Event to Study Treatment
Not related
An AE will be considered “not related” to the use of the investigational product 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 investigational 
product and the AE, 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 product 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 
investigational product and the AE, a known response pattern of the suspected product, 
improvement following discontinuation or dose reduction, a biologically plausible 
relationship between the product 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 the Sponsor according to the Investigator’s 
Brochure.  
15.3.
Monitoring and Recording Events
15.3.1.
Adverse Events
Any AE (including SAEs) experienced by the subject between the time of first dose of study 
treatment and the subject’s last study visit is to be recorded on the CRF, regardless of the 
severity of the event or its relationship to study treatment.  At each study visit, the Investigator 


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will assess the subject for AEs and will record any new AEs or updates to previously reported 
AEs on the CRF.
AE outcome will be recorded on the CRF, as applicable.
Expected fluctuations or expected deterioration of the underlying IPF and other pre-existing 
conditions should not be recorded as an AE except in the following circumstances:
o
Worsening of the disease meets the criteria for an SAE.
o
Action is taken with investigational treatment, such as when treatment is 
discontinued.
o
Additional treatment is required, such as when concomitant medication is added or 
changed.
o
In the opinion of the Investigator, an unexpected deterioration from baseline has 
occurred.
o
The event meets the criteria of an acute exacerbation of IPF.
15.3.2.
Serious Adverse Events
Any SAE experienced by the subject between the time of the signing of the ICF and the subject’s 
last study visit is to be recorded on an SAE form, regardless of the severity of the event or its 
relationship to study treatment.  SAEs must be reported to the Sponsor within 24 hours as 
described in Section 15.3.3.  Follow-up information regarding an SAE also must be reported 
within 24 hours.  See the Study Reference Guide’s Official Study Contact List for complete 
contact information.  
Subjects will be followed for all SAEs until their last study visit. Thereafter, the event should be 
reported to the Sponsor only if the Investigator considers the SAE to be related to study 
treatment.
SAEs that are 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.  SAE 
outcome will be recorded on the CRF, as applicable.  Only SAEs that are unresolved will be 
followed by the Investigator.
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 Sponsor within 24 hours of the study site staff becoming aware of the SAE.  
It is the Investigator’s responsibility to ensure that the SAE reporting information and procedures 
are used and followed appropriately.


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Reporting Information for SAEs
A report must be submitted to the Sponsor 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, a completed SAE form must be sent to the 
Sponsor; refer to the Study Reference Guide’s Official Study Contact List for complete contact 
information.  
15.3.3.1.
Deaths
Death is an outcome of an event.  The event that resulted in death should be recorded on the 
appropriate CRF.  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 to the Sponsor.  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 the Sponsor to be related to the study treatment administered.
Appropriate personnel at the Sponsor will unblind SUSARs for the purpose of regulatory 
reporting. The Sponsor will submit SUSARs (in blinded or unblinded fashion) to regulatory 
agencies according to local law.  The Sponsor 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 3 months after their last dose of study treatment.  If a female subject becomes pregnant, 
study treatment must be discontinued immediately.
The Investigator must report a pregnancy occurring in a female subject from first dose of study 
treatment up to 3 months after the last dose by faxing or emailing the appropriate form to the 
Sponsor within 24 hours of the study site staff becoming aware of the pregnancy. Refer to the 
Study Reference Guide’s Official Study Contact List for complete contact information. The 


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Investigator or study site staff must report the outcome of the pregnancy to the Sponsor. A 
pregnancy is not considered an AE and should not be recorded on the AE CRF.
Congenital abnormalities and birth defects in the offspring of male or female subjects should be 
reported as SAEs 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.  A window of +2 days is 
allowed without qualifying as an overdose for non-Baseline Visits; however, subsequent doses 
should adhere to the dosing schedule initiated at the Baseline Visit.  Overdoses are not 
considered AEs and should not be recorded as an AE on the CRF; however, all overdoses must 
be recorded on an Overdose form and faxed or emailed to the Sponsor within 24 hours of the site 
becoming aware of the overdose.  An overdose must be reported to the Sponsor 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 
or emailed to the Sponsor.  All study treatment-related dosing information must be recorded on 
the dosing CRF.
15.4.3.
Medical Emergency
In a medical emergency requiring immediate attention, study site staff will apply appropriate 
medical intervention, according to current standards of care.  The Investigator 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 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, or to 
personnel involved with the analysis and conduct of the study. The Investigator can contact the 
Sponsor to discuss such situations.
15.5.
Contraception Requirements
All women of childbearing potential and all men must practice highly effective contraception 
during the study.  Women in the study (and/or their partner) must continue highly effective 
contraception and must not donate eggs for 3 months after stopping study treatment.  Men in the 
study (and/or their partner) must continue effective contraception and must not donate sperm for 
4 months after stopping study treatment.  


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For the purposes of this study, women who do not meet one of the following criteria are 
considered to be physiologically capable of becoming pregnant and are, therefore, defined as 
women of childbearing potential:

Postmenopausal
o
12 continuous months of natural (spontaneous) amenorrhea without an alternative 
medical cause.
o
6 weeks after surgical bilateral oophorectomy with or without hysterectomy

Posthysterectomy

Female surgical sterilization (e.g., bilateral tubal ligation)  
For the purposes of the study, highly effective contraception is defined as use of 1 of the 
following: 
For females:

Established use of oral, intravaginal, or transdermal combined (estrogen and progestogen 
containing) hormonal methods of contraception associated with the inhibition of 
ovulation.

Established use of oral, injected, or implanted progestogen-only hormonal methods of 
contraception. 

Placement of an intrauterine device or intrauterine hormone-releasing system.

Sex with a male who has undergone surgical sterilization (with the appropriate 
postvasectomy documentation of the absence of sperm in the ejaculate). 
For males:

Vasectomy (with the appropriate postvasectomy documentation of the absence of sperm 
in the ejaculate).

Sex with a woman who uses the methods described for females if she is of childbearing 
potential.
True abstinence, when this is consistent with the preferred and usual lifestyle of the subject, can 
be considered an acceptable method of contraception based on the evaluation of the Investigator 
who should also take into consideration the duration of the clinical 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.


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15.6.
Safety Responsibilities
15.6.1.
The Investigator
The Investigator’s responsibilities include the following:

Monitor and record all AEs, including SAEs, on the CRF regardless of the severity or 
relationship to study treatment.

Determine the seriousness, relationship, and severity of each event.

Determine the onset and resolution dates of each event.

Monitor and record all pregnancies in female subjects and follow up on the outcome 
of all pregnancies.

Complete an SAE form for each SAE and fax or email it to the Sponsor within 24 
hours of the study site staff becoming aware of the event.

Pursue SAE follow-up information actively and persistently.  Follow-up information 
must be reported to the Sponsor 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.  Record AE follow-up information, including resolution, on the CRF, as 
applicable.

Report SAEs to local ethics committees, as required by local law.
15.6.2.
The Sponsor
The Sponsor’s responsibilities include the following:

Before a site can enroll any subjects, the Clinical Monitor is responsible for reviewing 
with study site staff the definitions of AE and SAE, as well as the instructions for 
monitoring, recording, and reporting AEs and SAEs.

The Sponsor 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 Section 6.
16.1.
Demography and Baseline Characteristics
Demographics and baseline data will be summarized by treatment group with summary statistics 
(mean, standard deviation [SD], median, and range) or with frequency distributions.
16.2.
Efficacy
16.2.1.
Analysis Population
The modified intent-to-treat (MITT) population, defined as all subjects who are randomized and 
receive at least 1 dose of study treatment, will be used for the efficacy analyses unless otherwise 
specified.  For each endpoint, additional conditions may apply to the definition of the population 
for the analysis.  Subjects will be analyzed in the groups to which they were randomized.
The per-protocol (PP) population, defined as all subjects who are randomized and without major 
protocol violations, will be used for sensitivity analysis for the primary endpoint. 
Subgroup analysis (e.g., background therapy strata as subgroup) will be done for the primary 
endpoint and some of the secondary endpoints. The details will be specified in the SAP.
16.2.2.
Methods of Analysis
16.2.2.1.
General Considerations
Summary statistics will be presented.  For continuous endpoints, summary statistics will 
generally include: number of subjects with data, mean, standard deviation, median, and range. 
For categorical endpoints, this will generally include number of subjects randomized, number of 
subjects with data, and percentage of subjects with data in each category.  Statistical testing for 
efficacy endpoints will be made between subjects treated with BG00011 and with placebo.
All statistical tests will be 2-sided.
16.2.2.2.
Analysis of the Primary Endpoint
The population for the primary endpoint analysis will be subjects in the MITT population with a 
baseline and at least 1 postbaseline FVC measurement.
The primary efficacy outcome variable is the yearly rate of change in FVC (actual value, 
expressed in mL, over 52 weeks).  The primary endpoint will be analyzed using a random 
coefficients linear regression model, with an absolute change in FVC as the outcome variable 


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assuming linear decline in lung function over time.  The model includes random coefficients for 
intercept and slope (time), and fixed-effect terms for treatment, randomization stratum 
(background therapy), age, and baseline FVC.  Interaction terms in the model will be the 
interaction between treatment and time, and the interaction between pirfenidone or nintedanib
and time.
Every effort should be made to reduce the amount of missing data.  In the analysis of the primary 
endpoint, missing data will be assumed to be missing at random.  An unstructured variance-
covariance structure will be used to model the within-patient measurements variability.  If it fails 
to converge, an AR(1) structure will be used.  The variance-covariance matrix, modeled to 
estimate the interindividual variability, is considered to have a variance components structure.  
Because the statistical model assumes a linear decline in lung function over time and, hence,
implicitly imputes missing data based on individual’s estimated rate of worsening of lung 
function prior to treatment discontinuation, similar to linear extrapolation.  If a subject who was 
not on background therapy at randomization initiates treatment with background therapy during 
the study, the subject’s data collected after the initiation of background therapy will be excluded 
from the primary analysis.  However, a sensitivity analysis that includes the excluded data will 
be performed.  
Support analyses for the primary endpoint includes:
1. Analysis using multiple imputation with pattern mixture models will be carried out.  
Details of sensitivity analysis and assumptions for different pattern will be described in 
the statistical analysis plan (SAP).
2. A mixed model of repeated measures model will be used to compare the difference 
between the 2 treatment groups in FVC change at 52 weeks and other scheduled visits.  
An unstructured variance-covariance structure will be used in this model.  If the model 
fails to converge, an AR(1) structure will be used.
3. Rate of decline in percent predicted FVC at 52 weeks will be analyzed by the same 
method as FVC actual value.
A model including the interaction between treatment and background therapy strata will be used 
to explore the treatment effects within each subgroup. 
16.2.2.3.
Analysis of the Secondary Endpoints
Time to progression will be presented using Kaplan-Meier curves, a stratified log-rank test will 
be used to compare the 2 treatment groups using randomization stratum as the stratification 
factor. The proportion of subjects who progressed in each arm will be summarized. Each 
component of progression will be summarized descriptively. If a subject who was not on 
background therapy at randomization initiates treatment with background therapy during the 
study, the subject will be censored at the time of new background therapy initiation.
Other time-to-event types of endpoints, e.g., time to first acute exacerbation, time to death or 
lung transplant, nonelective hospitalization (due to respiratory causes and due to all causes), and 


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survival rate (death from all causes and death due to respiratory causes) at 26 weeks and 
52 weeks will be analyzed similarly.
The number of subjects experiencing an absolute decline of 10% predicted in FVC will be 
analyzed using a logistic regression model, adjusting for the randomization stratification factor, 
patient age, and baseline FVC.
Other pulmonary function endpoints and the 6MWT at 52 weeks will be analyzed similarly to 
the primary endpoint. For other visits, an analysis of covariance model adjusting the 
randomization stratification factor, age, and FVC at Baseline will be used to compare the 
treatment groups.  The cumulative distribution of subjects by change in absolute and percent 
predicted FVC from Baseline to Week 52 will be presented in graph form.
Details of the analyses, including the handling of missing data, will be described in a SAP.
 
 
 
 
 
 
 
 
 
 
 
16.3.
Pharmacokinetics
16.3.1.
Analysis Population
The population for serum PK analyses is defined as all subjects in the MITT population who 
have at least 1 measurable BG00011 concentration in serum.
16.3.2.
Methods of Analysis
Samples for measuring serum concentrations of BG00011 will be collected as specified in 
Section 5.2.  BG00011 concentrations in serum will be summarized using descriptive statistics at 
the scheduled PK sample collection visits.
This study will collect only sparse PK samples; thus, the serum concentration data will be 
summarized descriptively by visit. No noncompartmental or compartmental methods will be 


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used to analyze the PK data for presentation in the clinical study report. Details of the PK 
analysis will be described in the SAP.
Mean serum concentrations of BG00011 will be plotted versus time on both a linear and a 
logarithmic scale.  No dose-proportionality assessments will be conducted because of the sparse 
PK data sampling.
Atypical drug concentrations (e.g., very low or very high) will be excluded from the analysis, if 
no apparent explanation exists.  Concentration observations will also be removed from the data 
set if corresponding dosing or sampling times are missing or cannot be reconstructed.
Concentration values below the limit of quantification will be removed from analysis.  All 
deletions of data points will be appropriately documented.
 
 
 
 
 
 
 
 
  
16.6.
Safety
16.6.1.
Analysis Population
The safety population is defined as all subjects who receive at least 1 dose of study treatment.


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16.6.2.
Methods of Analysis
16.6.2.1.
Adverse Events
AEs will be coded using the Medical Dictionary for Regulatory Activities.  All analyses of AEs 
will be based on the principle of treatment emergence. An AE is considered to be treatment 
emergent if it has an onset date on or after the date of first dosing, or if it was present prior to the 
first dose and subsequently worsened. The incidence of all AEs will be presented by system 
organ class and preferred term by treatment group. In addition, the incidence of all AEs will be 
presented by severity and by relationship to study treatment.
16.6.2.2.
Clinical Laboratory Results
Clinical laboratory evaluations include hematology, blood chemistry, and urinalysis evaluations. 
Analyses of clinically significant abnormalities, shifts from baseline to postbaseline relative to 
the normal range, as well as changes from baseline by visit will be presented by treatment group.
16.6.2.3.
Vital Signs
The analysis of vital signs will focus on clinically relevant abnormalities, which will be defined 
in more detail in the SAP. The incidence of clinically relevant abnormalities in vital signs will 
be summarized by treatment group.  
16.6.2.4.
Electrocardiograms
The analysis of ECG data will focus on clinically relevant abnormalities, which will be defined 
in more detail in the SAP. ECG changes from baseline may be summarized using descriptive 
statistics and presented by dose group, overall active treatment group, and visit.
16.6.2.5.
Physical Examinations
Abnormal findings during physical examinations will be recorded as AEs and will be reflected in 
the summary of AEs.
16.7.
Immunogenicity Data
16.7.1.
Analysis Population
The analysis population for immunogenicity is defined as all subjects who were randomized and 
received at least 1 dose of study treatment and who have at least 1 postdose immunogenicity 
sample evaluated for anti-BG00011 antibodies.
16.7.2.
Methods of Analysis
The incidence of anti-BG00011 antibodies will be summarized by treatment group over time.


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16.8.
Interim Analyses
After the last subjects complete the treatment period (up to Week 52), an interim database lock 
may occur and an interim analysis (IA) of efficacy and safety data may be conducted. All 
Investigators, study site personnel, and subjects will remain blinded to treatment assignments 
until after the end of the study. If this IA occurs, members of the Sponsor study team not in 
direct contact with the study sites will have access to the study data after all subjects complete all 
Week 52 assessments. Members of the Sponsor 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.
16.9.
Sample Size Considerations
The sample size calculation is based on the annual declining rate in FVC (mL/year). With 145 
subjects randomized per arm, and assuming a 15% dropout rate over a 1-year treatment period, 
the study has approximately 80% power to show that the BG00011 treatment arms differentiate 
from the arm without BG00011 at a 2-sided 15% α level, given a treatment effect of 
82.5 mL/year with a common standard deviation of 280 mL.  The calculation is based on the 
assumption that the FVC decline rate in subjects receiving placebo and no background therapy is 
220 mL/year, and in subjects receiving background but no BG00011 therapy it is assumed to be 
110 mL/year.  A 60% reduction in the FVC decline rate in the subjects receiving placebo would 
be a treatment effect of 132 mL/year.  A 30% reduction in the FVC decline rate in subjects 
receiving background therapy would be a treatment effect of 33 mL/year.  With the assumption 
that 50% of each type of subject are randomized in the study, the combined treatment effect is 
approximately 82.5 mL/year.  The 15% dropout rate for this study was estimated based on prior 
experience for the placebo arms in the Phase 3 studies for nintedanib and pirfenidone [King 
2014; Richeldi 2014].


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17.
ETHICAL REQUIREMENTS
The Sponsor, any designee, and the Investigator must comply with all instructions, regulations, 
and agreements in this protocol and applicable International Council for Harmonisation (ICH) 
and Good Clinical Practice (GCP) guidelines and conduct the study according to local 
regulations.
The investigator is responsible for endorsing all data on completed CRFs electronically, prior to 
any Interim lock or Database lock.
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines.  The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated.  The Investigator 
is responsible for supervising those individuals and for implementing procedures to ensure the 
integrity of the tasks performed and any data generated.
17.1.
Declaration of Helsinki
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki.
17.2.
Ethics Committee
The Investigator must obtain ethics committee approval of the protocol, ICF, and other required 
study documents prior to starting the study.   
If the Investigator makes any changes to the ICF, the Sponsor must approve the changes before 
the ICF is submitted to the ethics committee.  A copy of the approved ICF must be provided to 
the Sponsor.  After approval, the ICF must not be altered without the agreement of the relevant 
ethics committee and the Sponsor.
It is the responsibility of the Investigators to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations.
The Sponsor 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 the Sponsor.


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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., legal guardian), as applicable, in accordance 
with local practice and regulations.  
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the subject must be explained to the subject (or the 
subject’s legally authorized representative).  The subject must be given sufficient time to 
consider whether to participate in the study.
Subjects will be informed that their race and ethnicity will be collected during the study (unless 
the collection is not permitted by applicable law or not approved by the governing ethics 
committee) and the data will be used during analysis of study results.  (See Section 17.4.)
A copy of the signed and dated ICFs must be given to the subject or the subject’s legally 
authorized representative. The original signed and dated ICFs 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).
During the study, subjects’ race will be collected (unless the collection is not permitted by 
applicable law or not approved by the governing ethics committee).  These data will be used in 
the analysis of the safety and/or pharmacokinetic profile of the study treatment.  Subjects’ race is 
required for the calculation of the percent predicted equations used in pulmonary function 
testing.
Study reports will be used for research purposes only.  The subject will not be identified by name 
in CRFs, study-related forms, study reports, or any related publications.  The Sponsor, 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
The Sponsor maintains appropriate insurance coverage for clinical studies and will follow 
applicable local compensation laws.


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17.6.
Conflict of Interest
The Investigators should address any potential conflicts of interest (e.g., financial interest in the 
Sponsor) with the subject before the subject makes a decision to participate in the study.
17.7.
Registration of Study and Disclosure of Study Results
The Sponsor 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 the Sponsor.  This initiation visit will include a detailed review of the protocol and 
study procedures.
18.2.
Quality Control and Quality Assurance
Quality control procedures will be implemented at each stage of data handling to ensure that all 
data are reliable and have been processed correctly.  Data anomalies will be communicated to the 
sites for clarification and resolution, as appropriate. 
During and/or after completion of the study, quality assurance officers named by the Sponsor or 
the regulatory authorities may wish to perform onsite audits or inspections.  The Investigator will 
be expected to cooperate with any audit or inspection and to provide assistance and 
documentation (including source data) as requested.
18.3.
Monitoring of the Study
The Investigator must permit study-related monitoring by providing direct access to source data 
and to the subjects’ medical histories.  Source data must be attributable, legible, 
contemporaneous, original, accurate, and complete.  Changes to source data must be traceable, 
not obscure the original entry, and be explained if necessary (e.g., with an audit trail).  The 
Investigator should maintain a record of the location(s) of essential documents.
The Clinical Monitor will visit the study site at regular intervals during the study and after the 
study has completed, as appropriate.  A clinical site monitoring plan will detail who performs the 
monitoring, how often, and the extent of review.  It also will provide the monitoring strategy, 
with emphasis on subject safety, data integrity, and critical data and processes.
During these visits, CRFs, supporting documentation, and essential documentation related to the 
study will be reviewed and any discrepancies or omissions will be resolved.  Documentation of 
results will be provided to the Sponsor or designee in a timely fashion to allow follow-up and 
verification of compliance with the monitoring plan.  Remote evaluation of data (centralized 
monitoring) may also be conducted and reported as defined in the monitoring plan.
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure the protection of subject rights and well-being, protocol adherence, quality of data 
(accurate, complete, and verifiable), study treatment accountability, compliance with regulatory 
requirements, and continued adequacy of the investigational site and its facilities.


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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, and management of SAE reports, and data management.  Before 
subjects are screened at each study site, the CRO will review study responsibilities with the 
Investigators and other study site staff, as appropriate.
19.1.2.
Interactive Response Technology
IRT will be used in this study.  Before subjects are screened or enrolled, the IRT vendor will 
provide each study site with the necessary training, a user manual, and access rights to the 
system.
19.1.3.
Electronic or Remote Data Capture
Subject information will be captured and managed by study sites on electronic CRFs by a 
Web-based electronic data capture tool configured by the CRO and hosted by the electronic data 
capture vendor. 
Electronic Clinical Outcome Assessment (eCOA) data will be entered by the subject, the 
subject’s caregiver, and/or study site staff on a device developed and supported by the eCOA 
vendor. Site staff will monitor data via a secure Web portal developed and supported by the 
eCOA vendor. 
19.1.4.
Central Laboratories for Laboratory Assessments
A central laboratory has been selected by the Sponsor to store samples collected from subjects in 
this study for 
 
 drug concentrations, and anti-BG00011 antibodies in whole 
blood, plasma, and serum.  These samples may be analyzed by a central laboratory or a third-
party laboratory, as applicable.  A central laboratory will also perform the safety laboratory tests 
noted in the Schedule of Events (Table 2):  blood chemistry, hematology, urinalysis, serum 
pregnancy, HBsAg, anti-HBc, anti-HBs, HCV, and HIV panels.
A local laboratory may be used by the study site to analyze repeat tests if needed.
19.1.5.
Central Facility for Other Assessments
A central vendor has been selected by the Sponsor to read and interpret all HRCT scans for this 
study.


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A central vendor has been selected by the Sponsor to read and interpret lung function assessment 
data.
A central vendor has been selected by the Sponsor to read and interpret ECG data.
19.2.
Study Committees
19.2.1.
Advisory Committee
Advisory committees will be formed to provide scientific and medical direction for the study and 
to oversee the administrative progress of the study.  The advisory committees will be blinded to 
subject treatment assignments.  
19.2.2.
Data Safety Monitoring Board
An independent DSMB will be established to assess the overall safety profile throughout the 
conduct of the study. A DSMB charter will be developed to guide the overall governance plan 
for the DSMB in alignment with the Safety Monitoring Plan. The DSMB will review the 
unblinded safety (including but not limited to AEs, clinical laboratory data, ECGs, pulmonary 
function testing, and imaging data) and available PK data on an ongoing basis until the last 
subject completes dosing.  The meeting intervals and the procedures used to provide and assess 
the data will be described in detail in the DSMB charter.  Upon review of the data, the DSMB 
may recommend that the Sponsor discontinue the study, modify the study conduct, or continue 
the study with no changes.
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, the Sponsor 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.


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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, national, or regional laws or 
regulations.  Prior to proceeding with destruction of records, the Investigator must notify the 
Sponsor in writing and receive written authorization from the Sponsor to destroy study records.  
In addition, the Investigator must notify the Sponsor 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
The Sponsor will designate one of the participating Investigators as a signatory for the study 
report.  This determination will be made by several factors, including but not limited to the 
Investigator’s experience and reputation in the studied indication; the Investigator’s contribution 
to the study in terms of design, management, and/or subject enrollment; or by other factors 
determined to be relevant by the Sponsor.
The Sponsor will follow all applicable local regulations pertaining to study report signatories.


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20.
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “A Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of BG00011 in Patients With Idiopathic Pulmonary Fibrosis,” 
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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21.
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Fischer A, Antoniou KM, Brown KK, et al. An official European Respiratory Society/American 
Thoracic Society research statement: interstitial pneumonia with autoimmune features. Eur 
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Hughes G, Toellner H, Morris H, et al. Real World Experiences: Pirfenidone and Nintedanib are 
Effective and Well Tolerated Treatments for Idiopathic Pulmonary Fibrosis. J Clin Med. 
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Hutchinson J, Fogarty A, Hubbard R, et al. Global incidence and mortality of idiopathic 
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King TE, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with 
idiopathic pulmonary fibrosis. The New England journal of medicine. 2014;370(22):2083-92.
Kistler KD, Nalysnyk L, Rotella P, et al. Lung transplantation in idiopathic pulmonary fibrosis: a 
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Lee HE, Myong JP, Kim HR, et al. Incidence and prevalence of idiopathic interstitial pneumonia 
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Lewandowska KB, Kus J, Zolnowska B, et al. Idiopathic pulmonary fibrosis (IPF) patients in 
Poland – preliminary cohort analysis of EMPIRE registry. Presented at the 2017 International 
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Ley B, Collard HR, King TE. Clinical course and prediction of survival in idiopathic pulmonary 
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2010/10/08.
Lynch JP, Huynh RH, Fishbein MC, et al. Idiopathic Pulmonary Fibrosis: Epidemiology, 
Clinical Features, Prognosis, and Management. Semin Respir Crit Care Med. 2016;37(3):331-57. 
Epub 2016/05/27.
Nalysnyk L, Cid-Ruzafa J, Rotella P, et al. Incidence and prevalence of idiopathic pulmonary 
fibrosis: review of the literature. Eur Respir Rev. 2012;21(126):355-61.
Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary 
fibrosis (CAPACITY): two randomised trials. Lancet. 2011;377(9779):1760-9. Epub 
2011/05/13.
Nintendanib Summary of Product Characteristics, 15 January 2015, Boehringer Ingelheim 
International GmbH
Pesonen I, Ferrara G, Skold M, et al. Idiopathic pulmonary fibrosis in Finland and Sweden: 
Differences in the performance of two similar health care systems. Presented at the 2017 
International Congress of the European Respiratory Society (ERS).


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Phase 2b Efficacy and Safety Study of BG00011
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The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
93
Puthawala K, Hadjiangelis N, Jacoby SC, et al. Inhibition of integrin alpha(v)beta6, an activator 
of latent transforming growth factor-beta, prevents radiation-induced lung fibrosis. American 
journal of respiratory and critical care medicine. 2008;177(1):82-90.
Raghu G, Chen SY, Yeh WS, et al. Idiopathic pulmonary fibrosis in US Medicare beneficiaries 
aged 65 years and older: incidence, prevalence, and survival, 2001-11. Lancet Respir Med. 
2014;2(7):566-72. Epub 2014/05/27.
Raghu G, Collard HR, Anstrom KJ, et al. Idiopathic pulmonary fibrosis: clinically meaningful 
primary endpoints in phase 3 clinical trials. American journal of respiratory and critical care 
medicine. 2012;185(10):1044-8. Epub 2012/04/13.
Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of Idiopathic Pulmonary Fibrosis. An 
Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 
2018;198(5):e44-e68.
Raimundo K, Chang E, Broder MS, et al. Clinical and economic burden of idiopathic pulmonary 
fibrosis: a retrospective cohort study. BMC Pulm Med. 2016;16:2. Epub 2016/01/05.
Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic 
pulmonary fibrosis. The New England journal of medicine. 2014;370(22):2071-82. Epub 
2014/05/18.
Sicras-Mainar A, Somiedo Gutiérrez MD, Navarro-Artieda R, et al. Use Of Healthcare 
Resources And Associated Costs Of Idiopathic Pulmonary Fibrosis In Spain: A Real-Life Study. 
Presented at the 20th Annual European Congress of the International Society for 
Pharmacoeconomics And Outcomes Research (ISPOR).
Song JW, Hong SB, Lim CM, et al. Acute exacerbation of idiopathic pulmonary fibrosis: 
incidence, risk factors and outcome. Eur Respir J. 2011;37(2):356-63. Epub 2010/07/01.
Swigris JJ, Gould MK, Wilson SR. Health-related quality of life among patients with idiopathic 
pulmonary fibrosis. Chest. 2005;127(1):284-94.
Torres Villacreses MI, Calero E, Cherrez A, et al. Management Patterns and Attitudes About IPF 
(Idiopathic Pulmonary Fibrosis) Among Pulmonologist and General Physicians in Latin 
America. Presented at the 113th International Conference of the American Thoracic Society 
(ATS).
Viscidi EV, Wang N, Hall SA, et al. Utilization of Pirfenidone and Nintedanib in Patients with 
Idiopathic Pulmonary Fibrosis: An Analysis of U.S. Claims Data. Presented at the International 
Conference on Pharmacoepidemiology and Therapeutic Risk Management; 2017; Montreal, 
Canada.
Wang DD, Zhang S, Zhao H, et al. Fixed dosing versus body size-based dosing of monoclonal 
antibodies in adult clinical trials. J Clin Pharmacol. 2009;49(9):1012-24.


Protocol 203PF203
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Phase 2b Efficacy and Safety Study of BG00011
CONFIDENTIAL
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94
Wuyts WA, Dahlqvist C, Slabbynk H, et al. Demographics and Healthcare Utilization of Patients 
with Idiopathic Pulmonary Fibrosis (IPF) in a Real-World Setting: Updated Findings from 277 
Patients in the PROOF Registry. Presented at the 113th International Conference of the 
American Thoracic Society (ATS).
 


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:
203PF203 / NCT03573505
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead, Berkshire
SL6 4AY
United Kingdom
PHASE OF DEVELOPMENT:
2b
PROTOCOL TITLE: A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of BG00011 in Patients With Idiopathic Pulmonary Fibrosis
EUDRA CT NUMBER:  2017-003158-18
DATE:
20 November 2017 
Version 1
Final




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Phase 2b Efficacy and Safety Study of BG00011
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TABLE OF CONTENTS
SPONSOR SIGNATURE PAGE ....................................................................................................2
1.
SYNOPSIS ...................................................................................................................9
2.
LIST OF ABBREVIATIONS.....................................................................................13
3.
SPONSOR INFORMATION .....................................................................................16
4.
INTRODUCTION......................................................................................................17
4.1.
Overview of Idiopathic Pulmonary Fibrosis...............................................................17
4.2.
Diagnostic Criteria for IPF .........................................................................................18
4.3.
Current Therapies for Idiopathic Pulmonary Fibrosis................................................20
4.4.
Profile of Previous Experience With BG00011..........................................................22
4.4.1.
Mechanism of Action .................................................................................................22
4.4.2.
Nonclinical Experience...............................................................................................23
4.4.2.1.
Pharmacology Models ................................................................................................23
4.4.2.2.
Toxicology Summary .................................................................................................24
4.4.2.3.
Nonclinical Pharmacokinetics ....................................................................................24
4.4.3.
Clinical Experience.....................................................................................................25
4.5.
Study Rationale and Dose Selection...........................................................................27
5.
STUDY SCHEMATIC AND STUDY ACTIVITIES................................................30
5.1.
Study Schematic .........................................................................................................30
5.2.
Study Activities ..........................................................................................................31
6.
STUDY OBJECTIVES AND ENDPOINTS..............................................................37
7.
STUDY DESIGN .......................................................................................................40
7.1.
Study Overview ..........................................................................................................40
7.2.
Study Duration, Study Visits, and Follow-Up............................................................41
7.2.1.
Screening ....................................................................................................................41
7.2.2.
Placebo-Controlled Treatment Period ........................................................................42
7.2.3.
Safety Follow-Up Visit...............................................................................................42
7.2.4.
Study Treatment Discontinuation...............................................................................42
7.2.5.
Withdrawal From the Study........................................................................................42
7.2.6.
Unscheduled Visit for Acute Exacerbation of IPF .....................................................43
7.2.6.1.
Determination of IPF Exacerbation............................................................................44
7.3.
Study Stopping Rules .................................................................................................45


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7.4.
End of Study ...............................................................................................................45
8.
SELECTION OF SUBJECTS ....................................................................................46
8.1.
Inclusion Criteria ........................................................................................................46
8.2.
Exclusion Criteria.......................................................................................................47
9.
SCREENING AND RANDOMIZATION .................................................................50
9.1.
Screening ....................................................................................................................50
9.2.
Randomization............................................................................................................50
9.3.
Blinding Procedures....................................................................................................50
10.
DISCONTINUATION OF STUDY TREATMENT AND WITHDRAWAL 
OF SUBJECTS FROM THE STUDY........................................................................51
10.1.
Discontinuation of Study Treatment...........................................................................51
10.1.1.
Reasons for Study Treatment Discontinuation...........................................................51
10.2.
Withdrawal of Subjects From the Study.....................................................................52
10.2.1.
Reasons for Withdrawal of Subjects from the Study..................................................52
10.3.
Lost to Follow-Up.......................................................................................................52
11.
STUDY TREATMENT USE .....................................................................................53
11.1.
Regimen......................................................................................................................53
11.2.
Modification of Dose and/or Treatment Schedule......................................................53
11.3.
Precautions..................................................................................................................53
11.4.
Compliance.................................................................................................................53
11.5.
Concomitant Therapy and Procedures........................................................................53
11.5.1.
Concomitant Therapy .................................................................................................53
11.5.1.1.
Allowed Concomitant Therapy...................................................................................53
11.5.1.2.
Disallowed Concomitant Therapy..............................................................................54
11.5.2.
Concomitant Procedures.............................................................................................54
11.6.
Continuation of Treatment..........................................................................................54
12.
STUDY TREATMENT MANAGEMENT................................................................55
12.1.
BG00011.....................................................................................................................55
12.1.1.
BG00011 Preparation .................................................................................................55
12.1.2.
BG00011 Storage........................................................................................................55
12.1.3.
BG00011 Handling and Disposal...............................................................................56
12.1.4.
BG00011 Accountability............................................................................................56


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12.2.
Reference Product.......................................................................................................56
13.
EFFICACY, PHARMACOKINETIC, 
 
ASSESSMENTS.........................................................................................................57
13.1.
Clinical Efficacy Assessments....................................................................................57
13.1.1.
Pulmonary Function Testing.......................................................................................57
13.1.1.1.
Spirometry ..................................................................................................................57
13.1.1.2.
Carbon Monoxide Diffusion Capacity........................................................................57
13.1.1.3.
Full-Body Plethysmography.......................................................................................57
13.1.2.
High-Resolution Computed Tomography ..................................................................58
13.1.3.
Acute Exacerbations of IPF........................................................................................58
13.1.4.
Respiratory Hospitalizations.......................................................................................59
13.1.5.
6-Minute Walk Test....................................................................................................59
59
59
60
60
13.2.
Pharmacokinetic Assessments....................................................................................60
60
61
61
14.
SAFETY ASSESSMENTS ........................................................................................62
14.1.
Clinical Safety Assessments.......................................................................................62
14.2.
Laboratory Safety Assessments..................................................................................63
14.3.
Immunogenicity Assessments ....................................................................................64
15.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................65
15.1.
Definitions ..................................................................................................................65
15.1.1.
Adverse Event.............................................................................................................65
15.1.2.
Serious Adverse Event................................................................................................65
15.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments................66
15.2.
Safety Classifications..................................................................................................66
15.2.1.
Investigator Assessment of Events.............................................................................66
15.2.2.
Relationship of Events to Study Treatment................................................................67


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15.2.3.
Severity of Events.......................................................................................................67
15.2.4.
Expectedness of Events ..............................................................................................67
15.3.
Monitoring and Recording Events..............................................................................67
15.3.1.
Adverse Events ...........................................................................................................67
15.3.2.
Serious Adverse Events..............................................................................................68
15.3.3.
Immediate Reporting of Serious Adverse Events.......................................................68
15.3.3.1.
Deaths .........................................................................................................................69
15.3.4.
Suspected Unexpected Serious Adverse Reactions....................................................69
15.4.
Procedures for Handling Special Situations ...............................................................69
15.4.1.
Pregnancy ...................................................................................................................69
15.4.2.
Overdose.....................................................................................................................70
15.4.3.
Medical Emergency....................................................................................................70
15.4.3.1.
Unblinding for Medical Emergency...........................................................................70
15.5.
Contraception Requirements ......................................................................................70
15.6.
Safety Responsibilities................................................................................................72
15.6.1.
The Investigator..........................................................................................................72
15.6.2.
Biogen.........................................................................................................................72
16.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........73
16.1.
Demography and Baseline Characteristics .................................................................73
16.2.
Efficacy.......................................................................................................................73
16.2.1.
Analysis Population....................................................................................................73
16.2.2.
Methods of Analysis...................................................................................................73
16.2.2.1.
General Considerations...............................................................................................73
16.2.2.2.
Analysis of the Primary Endpoint...............................................................................73
16.2.2.3.
Analysis of the Secondary Endpoints.........................................................................74
16.2.2.4.
Analysis of Additional Endpoints...............................................................................75
16.3.
Pharmacokinetics........................................................................................................75
16.3.1.
Analysis Population....................................................................................................75
16.3.2.
Methods of Analysis...................................................................................................75
76
76
76


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76
16.6.
Safety..........................................................................................................................76
16.6.1.
Analysis Population....................................................................................................76
16.6.2.
Methods of Analysis...................................................................................................77
16.6.2.1.
Adverse Events ...........................................................................................................77
16.6.2.2.
Clinical Laboratory Results........................................................................................77
16.6.2.3.
Vital Signs ..................................................................................................................77
16.6.2.4.
Electrocardiograms.....................................................................................................77
16.6.2.5.
Physical Examinations................................................................................................77
16.7.
Immunogenicity Data .................................................................................................77
16.7.1.
Analysis Population....................................................................................................77
16.7.2.
Methods of Analysis...................................................................................................77
16.8.
Interim Analyses.........................................................................................................78
16.9.
Sample Size Considerations .......................................................................................78
17.
ETHICAL REQUIREMENTS ...................................................................................79
17.1.
Declaration of Helsinki...............................................................................................79
17.2.
Ethics Committee........................................................................................................79
17.3.
Subject Information and Consent ...............................................................................80
17.4.
Subject Data Protection ..............................................................................................80
17.5.
Compensation for Injury.............................................................................................80
17.6.
Conflict of Interest......................................................................................................81
17.7.
Registration of Study and Disclosure of Study Results..............................................81
18.
ADMINISTRATIVE PROCEDURES.......................................................................82
18.1.
Study Site Initiation....................................................................................................82
18.2.
Quality Control and Quality Assurance......................................................................82
18.3.
Monitoring of the Study..............................................................................................82
18.4.
Study Funding.............................................................................................................83
18.5.
Publications.................................................................................................................83
19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION........................84
19.1.
External Contract Organizations.................................................................................84
19.1.1.
Contract Research Organization.................................................................................84
19.1.2.
Interactive Response Technology...............................................................................84


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19.1.3.
Electronic or Remote Data Capture............................................................................84
19.1.4.
Central Laboratories for Laboratory Assessments .....................................................84
19.1.5.
Central Facility for Other Assessments ......................................................................84
19.2.
Study Committees.......................................................................................................85
19.2.1.
Advisory Committee...................................................................................................85
19.2.2.
Data Safety Monitoring Board....................................................................................85
19.3.
Changes to Final Study Protocol ................................................................................85
19.4.
Ethics Committee Notification of Study Completion or Termination........................85
19.5.
Retention of Study Data..............................................................................................86
19.6.
Study Report Signatory...............................................................................................86
20.
SIGNED AGREEMENT OF THE STUDY PROTOCOL.........................................87
21.
REFERENCES ...........................................................................................................88
LIST OF TABLES
Table 1:
Summary of High-Resolution Computed Tomography and Surgical Lung 
Biopsy Criteria for Diagnosis of IPF..........................................................................20
Table 2:
Schedule of Events .....................................................................................................31
LIST OF FIGURES
Figure 1:
Diagnostic Algorithm for IPF (Adapted from the ATS/ERS/JRA/ALAT 
Guidelines)..................................................................................................................19
Figure 2:
BG00011 Mechanism of Action.................................................................................23
Figure 3:
Plot of BG00011 Exposure and Change in pSMAD2 From Baseline (Study 
203PF201)...................................................................................................................28
Figure 4:
Schematic for Study 203PF203 ..................................................................................30


Protocol 203PF203
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Phase 2b Efficacy and Safety Study of BG00011
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1.
SYNOPSIS
Protocol Title:
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of BG00011 in Patients With Idiopathic Pulmonary 
Fibrosis
Protocol Number:
203PF203
Version Number:
1
Name of Study 
Treatment:
BG00011
Study Phase:
2b
Study Indication:
Idiopathic pulmonary fibrosis
Study Rationale:
This Phase 2b study in subjects with mild to moderate idiopathic pulmonary 
fibrosis (IPF) who may or may not be receiving background therapies is 
designed to evaluate the change in forced vital capacity (FVC) after 56 mg of 
BG00011 is administered subcutaneously (SC) once weekly for 52 weeks. 
In the previously completed, Phase 2a study (203PF201) in subjects with IPF, 
BG00011 demonstrated proof of biological activity by altering biomarkers in 
the lung. Therefore, the current study is being conducted to evaluate the 
clinical efficacy and safety of BG00011. The primary analysis will be 
conducted after 52 weeks of placebo-controlled treatment with BG00011.
Study Objectives 
and Endpoints:
Primary Objective
Primary Endpoint
To evaluate the efficacy of BG00011 
compared with placebo in subjects 
with IPF.
Yearly rate of change in FVC 
(expressed in mL over 52 weeks) in 
subjects randomized to BG00011 
compared with placebo.
Secondary Objectives
Secondary Endpoints
To evaluate the efficacy of BG00011 
compared with placebo in subjects 
with IPF as determined by change in 
percent predicted FVC.
Yearly rate of change in FVC,
expressed in percent predicted, over 
52 weeks.
To assess progression-free survival in 
subjects who receive BG00011
Time to progression, as defined by a 
composite endpoint, including any of 


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compared with placebo.
the following events:
Absolute decline of 10% predicted in 
FVC (FVC percent predictedbaseline –
FVC percent predictedprogression
≥10%).
Nonelective hospitalization for 
respiratory events.
Lung transplantation or death.
To assess the occurrence of IPF 
exacerbation (using modified 
diagnostic criteria for acute IPF 
exacerbation derived from [Collard 
2007]) in subjects who receive 
BG00011 compared with placebo.  
Time to first acute exacerbation,
measured in days.
Proportion of subjects with at least 1 
acute exacerbation during the 52 
weeks on study.
Number of exacerbations during 52 
weeks.
To assess the incidence of absolute 
decline in FVC ≥10% in subjects who 
receive BG00011 compared with 
placebo.
Number of subjects with absolute 
decline of 10% predicted in FVC 
(FVC percent predictedbaseline – FVC 
percent predictedprogression ≥10%) over 
52 weeks.
To assess the time to death or lung 
transplantation in subjects who 
receive BG00011 compared with 
placebo, and the transplant-free 
survival rate at Week 26 and Week 
52.
Time to death or lung transplantation,
measured in days.
To assess the time to nonelective 
hospitalizations in subjects who 
receive BG00011 compared with 
placebo.
Time to all nonelective 
hospitalizations and to nonelective 
respiratory hospitalizations, measured 
in days.
To assess additional pulmonary 
function test (PFT) findings in 
subjects who receive BG00011 
compared with placebo.
Change in absolute and percent 
predicted FVC from baseline over 
time.
Carbon monoxide diffusion capacity 
(DLCO) absolute and percent 


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predicted changes from baseline over 
time.
Total lung capacity, as measured by 
plethysmography, absolute and 
percent predicted changes from 
baseline over time.
To assess performance on the 
6-Minute Walk Test (6MWT) in 
subjects who receive BG00011 
compared with placebo.
Change from baseline in 6MWT 
parameters at Weeks 26 and 52.
To evaluate the safety and tolerability 
of BG00011.
The incidence, severity, outcome, and 
relationship to study treatment of 
adverse events and serious adverse 
events.
Change from baseline in clinical 
laboratory test results, vital signs, 
electrocardiogram (ECG), PFT, and 
high-resolution computed 
tomography (HRCT) findings.
Immunogenicity (antibodies to 
BG00011).
To evaluate the serum concentration 
of BG00011.
Measurement of BG00011 serum 
concentrations using sparse 
pharmacokinetic (PK) sample 
collection at select timepoints during 
the study. 
Exploratory Objectives and Endpoints are listed in Section 6.
Study Design:
Phase 2b randomized, double-blind, placebo-controlled study to evaluate the 
efficacy, safety, PK, and tolerability of BG00011 in subjects with IPF.
Study Location:
Approximately 100 sites in up to 20 countries are planned, including North 
America, Europe, and Rest of World.
Number of Planned 
Subjects:
Approximately 290 subjects will be randomized.
Study Population:
This study will be conducted in subjects with mild to moderate IPF who may 
or may not be receiving background therapy (either nintedanib or pirfenidone, 


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though not both).
Detailed criteria are described in Section 8.
Treatment Groups:
Subjects will be randomized in a 1:1 ratio to receive BG00011 or placebo:

BG00011 group:  Approximately 145 subjects will receive BG00011 
56 mg once weekly by SC injection for 52 weeks.

Placebo group:  Approximately 145 subjects will receive placebo dosing 
once weekly by SC injection for 52 weeks.
Subjects will be stratified by the concomitant use of background therapy 
(nintedanib or pirfenidone) with a goal of a 1:1 ratio of BG00011 
monotherapy to BG00011 plus background therapy.  Hence, it is intended that 
approximately 50% of subjects in each treatment group will be on background 
therapy and approximately 50% of subjects in each group will not be on 
background therapy at the time of randomization.  
Duration of 
Treatment and 
Follow-up:
Study duration for each subject will be approximately 65 weeks, including the 
following:  

5-week Screening Period

52-week Placebo-Controlled Treatment Period

8-week Follow-Up Period


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Phase 2b Efficacy and Safety Study of BG00011
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2.
LIST OF ABBREVIATIONS
Abbreviation
Definition
6MWT
6-Minute Walk Test
αvβ6
alpha v beta 6
AE
adverse event
ALAT
Latin American Thoracic Association
ALT
alanine transaminase
AUC
area under the concentration-time curve
AUCSS
area under the concentration-time curve at steady state
AST
aspartate transaminase
ATS
American Thoracic Society
BAL
bronchoalveolar lavage
CBC
complete blood count
CRF
case report form
DLCO
carbon monoxide diffusion capacity
DSMB
data safety monitoring board
ECG
electrocardiogram
ERS
European Respiratory Society
FEV1
forced expiratory volume over 1 second
FVC
forced (expiratory) vital capacity
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HCV
hepatitis C antibody
HIV
human immunodeficiency virus
HRCT
high-resolution computed tomography 
HRQoL
health-related quality of life
ICF
informed consent form
ICH
International Council for Harmonisation
IFN-
interferon-gamma


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Abbreviation
Definition
IgG1
immunoglobulin G subtype 1
ILD
interstitial lung disease
IPF
idiopathic pulmonary fibrosis 
IRB
institutional review board
IRT
interactive response technology
JRS
Japanese Respiratory Society
LAP
latency-associated peptide
LTBP-1
latent transforming growth factor-beta binding protein-1
mAb
monoclonal antibody
mRNA
messenger RNA
NOAEL
no observed adverse effect level
NOEL
no observed effect level
PFT
pulmonary function test
PHI
protected health information
PK
pharmacokinetic(s)
pSMAD2
phosphorylated SMAD2
QLF 
quantitative lung fibrotic reticulation score
RGD
arginine-glycine-aspartic acid
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
subcutaneous(ly)
SP-A
surfactant A
SP-D
surfactant D
t1/2
half-life
TGF-β
transforming growth factor-beta
Tmax
time to reach maximum observed concentration


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Phase 2b Efficacy and Safety Study of BG00011
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Abbreviation
Definition
TLC
total lung capacity
UIP
usual interstitial pneumonia
WBC
white blood cell


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Phase 2b Efficacy and Safety Study of BG00011
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3.
SPONSOR INFORMATION
Biogen MA Inc. (hereafter referred to as Biogen) is the Sponsor of the study. 
Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead, Berkshire 
SL6 4AY
United Kingdom
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 203PF203
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4.
INTRODUCTION 
BG00011 (humanized, immunoglobulin G subtype 1 [IgG1] anti-alpha v beta 6 [v6] 
monoclonal antibody [mAb]), formerly known as STX-100, is being developed by Biogen as a 
novel therapeutic treatment for patients with idiopathic pulmonary fibrosis (IPF). BG00011 
binds to the v6 integrin, which inhibits the integrin from binding to and activating the latent 
form of transforming growth factor-beta (TGF-). TGF-β plays a critical role in the initiation 
and maintenance of fibrosis, and targeted inhibition of the v6/TGF-β pathway may prevent the 
development of fibrosis, organ scarring, and organ failure. The clinical development plan for 
BG00011 is designed to demonstrate that blocking v6 and inhibiting the activation of TGF-β 
in patients with IPF can prevent or reduce the progression of fibrosis, resulting in preservation of 
pulmonary function.
4.1.
Overview of Idiopathic Pulmonary Fibrosis 
IPF is a serious, chronic, progressively fatal lung disease involving replacement of normal lung 
tissue with fibrotic scar tissue.  IPF is a rare disease that predominantly affects the middle aged 
and elderly (after age 60 years; median age at diagnosis: 66 years [Raghu 2014]).  The disease is 
more common in men than women (male predominance approximately 1.3:1) [Raghu 2014]. 
Patients with IPF typically live for only 3 to 5 years after diagnosis, with a median survival time 
of approximately 3.5 years from diagnosis [Fernández Pérez 2010; Ley 2011; Raghu 2014].  The 
5-year survival rate is 30% to 50% [Raghu 2011],and fewer than 15% of patients live for 10 
years or longer [Lynch 2016].  IPF significantly impairs health-related quality of life [Swigris 
2005], and the majority of patients also have serious comorbid conditions [Raimundo 2016].
Globally, North America and Europe have the highest incidence and prevalence of IPF 
[Hutchinson 2015].  The incidence has been increasing steadily worldwide, in part due to an 
aging population.  The annual incidence of IPF is currently between 3 and 9 per 100,000 persons 
in Europe and North America.  In a review of studies published between 1990 and 2011, the 
prevalence of IPF ranged from 14.0 to 27.9 per 100,000 persons in the United States and from 
1.25 to 23.4 per 100,000 persons in Europe [Nalysnyk 2012].  Recent estimates from South 
Korea suggest the incidence and prevalence of IPF in Asia may be comparable to that of North 
America and Europe [Lee 2016].
Clinical features of IPF include progressive cough, dyspnea, restrictive ventilatory defect, and 
progressive fibrosis and destruction of the lung parenchyma [Lynch 2016]. The diagnosis is 
made in patients with the appropriate clinical features and the histologic pattern of usual 
interstitial pneumonia (UIP) [based on lung biopsy or high-resolution computed tomography 
(HRCT)]. Challenging factors for clinical management include older age, comorbid conditions, 
and acute unpredictable exacerbations. Acute exacerbations of IPF are defined as sudden 
(typically less than 30 days onset) unexplained worsening of underlying disease, including new 
radiological infiltrates (based on HRCT) or UIP pattern. The progressive deterioration of lung 
function results in respiratory failure. The prognosis following acute exacerbation and 


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deterioration of lung function is poor, with 1-year and 5-year survival rates of 56.2% and 18.4% 
following acute exacerbation, which is considerably shorter than in IPF patients without acute 
exacerbation [Song 2011]. 
The underlying pathophysiology of IPF is unknown.  Whatever the inciting event is, it triggers a 
TGF-β mediated fibrogenic response.  As a part of this response, alveolar epithelial cells via the 
production of signaling mediators, including TGF-β, tumor necrosis factor, endothelin 1, and 
cytokines, induce proliferation and activation of fibroblasts and myofibroblasts.  This leads to 
secretion of connective tissue matrix molecules, such as collagen, to replace the damaged tissue 
but also displaces healthy tissue leading to scarring and ultimately organ failure [du Bois 2010].
4.2.
Diagnostic Criteria for IPF
The diagnostic criteria for IPF used in this protocol are derived from evidence-based guidelines 
developed by the American Thoracic Society/European Respiratory Society/Japanese 
Respiratory Society/Latin American Thoracic Association (ATS/ERS/JRS/ALAT) joint task 
force for the diagnosis and management of IPF (originally presented May 17, 2010 at the ATS 
Conference, New Orleans, LA) [Raghu 2011].
The diagnosis of IPF requires histopathologic and/or radiologic evidence of UIP and exclusion of 
other causes of idiopathic interstitial pneumonia and interstitial lung diseases (e.g., occupational 
or environmental exposures, drug toxicities, collagen vascular diseases).  
The ATS/ERS/JRS/ALAT joint task force concludes that, in the appropriate clinical setting, the 
diagnosis of IPF may be ascertained by HRCT alone if the HRCT image fulfills the criteria for 
“UIP pattern” (i.e., surgical lung biopsy is not required). However, if the HRCT does not show a 
definitive UIP pattern, then a surgical lung biopsy is necessary and specific combinations of the 
HRCT and histopathological criteria are used to determine the diagnosis of IPF (see Figure 1 and
Table 1).  


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Figure 1:
Diagnostic Algorithm for IPF (Adapted from the ATS/ERS/JRA/ALAT 
Guidelines)
Suspected IPF
Identifiable Causes for ILD?
HCRT
No
Surgical Biopsy
Multi-disciplinary 
Discussion
IPF/Not IPF per Tables
IPF
Not IPF
Possible UIP
Inconsistent with UIP
UIP
Probable UIP/Possible
Non-classifiable 
fibrosis
UIP
Yes
Not UIP
ATS/ERS/JRA/ALAT = American Thoracic Society/European Respiratory Society/Japanese Respiratory 
Society/Latin American Thoracic Association; ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis; 
UIP = usual interstitial pneumonia.  


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To be eligible for this study, subjects must meet the HRCT imaging and/or lung 
histopathological criteria for UIP shown in Table 1 (in addition to the other inclusion and 
exclusion criteria):
Table 1:
Summary of High-Resolution Computed Tomography and Surgical Lung 
Biopsy Criteria for Diagnosis of IPF
Surgical Lung Biopsy
Not Available
Histopathology:
UIP Pattern
Histopathology:
Probable UIP 
Pattern
Histopathology:
Possible UIP/ 
Nonclassifiable 
Fibrosis Pattern
Histopathology:
Not UIP Pattern 
HRCT:
UIP Pattern
ELIGIBLE
ELIGIBLE
(IPF diagnosed)
ELIGIBLE
(IPF diagnosed)
ELIGIBLE
(IPF diagnosed)
NOT Eligible
(No diagnosis of 
IPF)
HRCT:
Possible UIP 
Pattern 
NOT Eligible
ELIGIBLE
(IPF diagnosed)
ELIGIBLE
(IPF diagnosed)
NOT Eligible
(Probable IPF)
NOT Eligible
(No diagnosis of 
IPF)
HRCT:
Inconsistent with 
UIP Pattern
NOT Eligible
NOT Eligible
(Possible IPF)
NOT Eligible
(No diagnosis of 
IPF)
NOT Eligible
(No diagnosis of 
IPF)
NOT Eligible
(No diagnosis of 
IPF)
HRCT = high-resolution computed tomography; IPF = idiopathic pulmonary fibrosis; UIP = usual interstitial pneumonia.
Note:  Combined findings of HRCT and surgical biopsy that the guidelines classify as “Possible IPF” or as “Probable IPF” are 
not eligible for this study.
4.3.
Current Therapies for Idiopathic Pulmonary Fibrosis
To date, no therapies have demonstrated efficacy in halting IPF disease progression.  
Historically, disease-modifying agents for IPF have included nonspecific anti-inflammatory or 
immunosuppressive agents (i.e., corticosteroids, azathioprine, and cyclophosphamide), which 
were used in the United States despite the absence of clinical studies to demonstrate their 
efficacy, with some ultimately demonstrating harm [Raghu 2012].
Two recently approved therapies, pirfenidone (Esbriet®) and nintedanib (Ofev®), have 
demonstrated a similar ability to slow deterioration in lung function by nearly 50%; however, 
patients are still faced with death or lung transplantation as the ultimate outcome [Kistler 2014].
Pirfenidone was approved based on the demonstration of a statistically significant benefit on the 
forced vital capacity (FVC) in subjects with mild to moderate IPF compared with placebo 
(Genentech Studies PIPF-004, PIPF-006, and PIPF-016 [Esbriet Prescribing Information 
2015/SmPC]). The clinical development program included one 52-week and two nearly 


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identical 72-week clinical studies. The primary endpoint was the change in percent predicted 
FVC from baseline to study end. Secondary endpoints included the mean change from baseline 
in FVC and survival. Of the 3 studies, the 52-week study and 1 of the 72-week studies 
demonstrated that fewer subjects taking pirfenidone had a meaningful decline (10% or greater) in 
FVC versus placebo (17% versus 32%, respectively), whereas more subjects maintained stable 
lung function in the 52-week study (23% versus 10%, respectively). In the 52-week study, a 
significant reduction in the mean decline in FVC was observed in subjects receiving pirfenidone 
compared with placebo (difference of 193 mL). In one of the two 72-week studies, there was a 
significant treatment difference of 157 mL; however, there was no significant difference 
observed in the other 72-week study. There was no statistically significant difference in all-
cause mortality between pirfenidone and placebo. Adverse events (AEs) leading to 
discontinuation of treatment occurred in 14.6% of subjects treated with pirfenidone.  Adverse 
reactions associated with pirfenidone in >10% of subjects versus placebo include, but are not 
limited to, gastrointestinal disorders and photosensitivity.
Nintedanib was also approved based on the demonstration of a statistically significant benefit on 
FVC decline in subjects with mild to moderate IPF in three 52-week clinical studies [one Phase 2 
study and two identical Phase 3 studies] (Boehringer Ingelheim Studies 1199.30, 1199.32, and 
1199.34 [Ofev Prescribing Information 2015/SmPC]).  The primary endpoint in all 3 studies was 
the annual rate of decline in FVC.  Secondary endpoints included time to first acute IPF 
exacerbation, change from baseline in FVC percent predicted, and survival.  A statistically 
significant reduction in the annual rate of decline of FVC was demonstrated in subjects receiving 
nintedanib compared with subjects receiving placebo, with differences in the 3 studies of 131 mL 
(Phase 2 study) and 125 and 94 mL (in the 2 Phase 3 studies).  The change from baseline in the 
percent predicted FVC was lower in the group treated with nintedanib.  In addition, the time to 
first acute IPF exacerbation was significantly reduced in subjects receiving nintedanib in 2 of the 
3 studies (the Phase 2 and 1 of the Phase 3 studies), but there was no statistically significant 
difference in all-cause mortality.  The most common serious adverse reactions that were reported 
more frequently with nintedanib treatment than with placebo were bronchitis (1.2% versus 0.8%, 
respectively) and myocardial infarction (1.5% versus 0.4%, respectively).  AEs leading to 
discontinuation were reported in 21% of the subjects treated with nintedanib.  Adverse reactions 
associated with nintedanib in ≥10% of subjects compared with placebo included gastrointestinal
(GI) disorders such as diarrhea (most common), nausea, increased liver enzymes, and abdominal 
pain.
A study assessing the real-world experience with pirfenidone and nintedanib indicated that while 
side effects (predominantly GI with both therapies) are common, the side effects are managed in 
the majority of patients with a treatment discontinuation rate similar to what was observed in the 
clinical studies [Hughes 2016].  Among patients using pirfenidone, 16% of AEs resulted in a 
reduction in dose and 20% of AEs resulted in permanent discontinuation.  Among subjects using 
nintedanib, 15% had a reduction in dose and 26% discontinued treatment.
In real-world data, utilization of antifibrotic medications varies considerably by geographic 
region.  In 3 observational studies in the United States, the prevalence of pirfenidone and 
nintedanib use ranged from 14% to 55% [Viscidi 2017].  In Western Europe, utilization ranged 


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from 29% to 69% [Behr 2015; Pesonen 2017; Sicras-Mainar 2017; Wuyts 2017]. Utilization 
appears to be lower in Eastern Europe; among 107 IPF patients in a registry in Poland, 2% had 
used pirfenidone [Lewandowska 2017].  In a survey of 344 physicians in Latin America, 21% 
had prescribed pirfenidone to their IPF patients [Torres Villacreses 2017]. In an observational 
study in Japan, 33% of IPF patients used pirfenidone [Bando 2015]. 
As the disease continues to progress, lung transplants for appropriate surgical candidates may be 
considered.  However, the 5-year survival rate after lung transplantation ranged from 47% to 
53%, based on data from the International Society for Heart and Lung Transplantation and Organ 
Procurement and Transplantation Network [Kistler 2014]. Considerations regarding the utility of 
lung transplantation include the limited availability of donor organs, infection, rejection, and the 
requirement for lifetime immunosuppressive therapy.
Therapies that can halt or reverse disease progression, increase life expectancy, and improve 
quality of life while demonstrating minimal side effects remain a treatment goal for patients 
diagnosed with IPF.  
4.4.
Profile of Previous Experience With BG00011
4.4.1.
Mechanism of Action
TGF-β is a central mediator of fibrogenesis. TGF-β is upregulated and activated in fibrotic 
diseases, and its signaling results in myofibroblast differentiation and matrix deposition. The 
v6 integrin is a critical regulator of TGF-activation. TGF-is synthesized as a latent 
precursor protein consisting of latency-associated peptide (LAP) and TGF-. This complex 
cannot bind to the TGF-receptor and is not biologically active. The v6 integrin is expressed 
at low or undetectable levels in healthy adult tissues but is highly upregulated on epithelial cells 
during tissue injury and fibrosis. The integrin activates TGF-by binding to an arginine-
glycine-aspartic acid motif within the LAP component of latent TGF-leading to the localized 
activation of the cytokine (Figure 2). BG00011 is a mAb that binds to the v6 integrin and 
inhibits ligand binding. By blocking the binding of v6 to latent TGF-, BG00011 prevents 
v6-mediated TGF-activation, thereby decreasing TGF-signaling. Although other 
mechanisms of TGF-activation have been identified, studies carried out in v6-deficient mice 
and with v6-blocking mAbs suggest that v6-mediated activation of TGF-can prevent the 
development of fibrosis in the lung, kidney, and liver. Analysis of molecular signatures 
associated with the progression of fibrosis indicates that the therapeutic impact of the v6-
blocking antibodies is mechanistically linked to decreased TGF-activity. 
A key mediator of TGF-β activity is the signal transducer proteins SMAD, which when 
phosphorylated (phosphorylated SMAD [pSMAD]), regulate the transcriptional activity of 
TGF-β signaling (Figure 2).  Increased pSMAD levels have been positively correlated with lung 
fibrosis in both the murine bleomycin and radiation models of fibrosis [Chung 2016; Flechsig 
2012; Horan 2008].  Given its role in the TGF-β cascade and evidence of correlation with lung 
fibrosis, pSMAD and several downstream genes were selected as exploratory target engagement 
biomarkers in nonclinical and the clinical studies with BG00011 in subjects with IPF. 


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Figure 2:
BG00011 Mechanism of Action
αvβ6 = alpha v beta 6; LAP = latency-associated peptide; LTBP-1 = latent transforming growth factor-beta binding protein-1; 
mAb = monoclonal antibody; RGD = arginine-glycine-aspartic acid; TGF-β = transforming growth factor-beta.
v6 expression is up-regulated on epithelial cells during tissue injury and fibrosis.  v6 binds to an RGD motif in the latency-associated 
peptide region of the latent TGF-precursor protein, leading to local activation of TGF-.  Anti-v6 mAb interferes with this 
binding and blocks TGF-activation.
4.4.2.
Nonclinical Experience
Nonclinical pharmacology, pharmacokinetic (PK), and toxicology studies have been performed 
to support clinical development of BG00011. Inhibition of TGF-β signaling has been shown to 
be protective in a variety of models of fibrosis, identifying this pathway as an attractive target for 
therapeutic intervention in IPF. However, given the anti-inflammatory role for TGF-β signaling, 
appropriate modulation of TGF-β in a tissue specific manner is needed to avoid potentially 
deleterious systemic effects. 
BG00011 is a humanized mAb that cross-reacts with murine, nonhuman primate, and human 
αvβ6.  A murine form of BG00011 (m3G9, previously mu3G9) has demonstrated potent 
antifibrotic activity in several rodent models of lung, kidney, and liver fibrosis.  
4.4.2.1.
Pharmacology Models
Nonclinical pharmacology studies to determine the biological activity and safety of BG00011 
have been conducted using a murine anti-αvβ6 antibody (m3G9) in mice and BG00011 in 
cynomolgus monkeys.  Several rodent models of fibrosis show increased αvβ6 expression in 
epithelial cells of the affected tissue, including the lung, kidney, and liver.  Efficacy of m3G9 has 
been demonstrated in models of lung, kidney, and liver fibrosis, as measured by markers of 
tissue fibrosis, including collagen production and accumulation of α-smooth muscle actin  
positive fibroblasts [Hahm 2007; Horan 2008; Puthawala 2008].
Key nonclinical studies demonstrating efficacy in lung fibrosis were performed in the bleomycin 
mouse model, bleomycin-FTY720 mouse model, radiation mouse model, and influenza mouse 
model. Taken together, the data from these studies indicate that doses of m3G9 at 0.3 and 


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1.0 mg/kg were consistently associated with improvement in fibrotic response with no significant 
inflammation in these rodent models of epithelial tissue injury and fibrosis. 
In addition, preclinical studies demonstrated that αvβ6 blocking antibody treatment between 0.3 
and 1.0 mg/kg led to similar, significant steep reductions of pSMAD in bronchoalveolar lavage 
(BAL) cells in both mice and cynomolgus monkeys. See the BG00011 Investigator’s Brochure 
for additional information about these studies.
An increased incidence of acute allograft rejection was observed in a monkey kidney transplant 
study when BG00011 was administered with a standard calcineurin-based immunosuppressive 
regimen.  Therefore, it is recommended that patients with end-stage fibrotic disease requiring 
organ transplantation do not receive BG00011.  Any patient receiving BG00011 who progresses 
to the point of requiring organ transplantation should immediately discontinue the study 
treatment.
4.4.2.2.
Toxicology Summary
Nonclinical toxicology studies of up to 26 weeks in duration were conducted in the CD-1 mouse 
and cynomolgus monkey. Murine studies used m3G9, while monkey studies used BG00011. 
Histologic changes were limited to the lung. These consisted of partially reversed alveolar 
macrophages, alveolar cellular debris, perivascular lymphoid infiltration, and increases in lung 
weight in mice and partially reversed alveolar macrophages in monkeys. The no observed 
adverse effect levels (NOAELs) in the 6-month studies were 1.0 and 10 mg/kg in mice and 
monkeys, respectively. No carcinogenicity or genotoxicology studies were conducted with 
BG00011 or m3G9. In the repeat-dose mouse studies with m3G9, low incidences of tumors 
(such as bronchoalveolar adenoma) were observed sporadically and in a non-dose-related 
manner. Spontaneous bronchoalveolar lesions have been reported in mouse historical control 
data. No tumors were noted in monkey studies.  Transient elevations of lung tidal and minute 
volumes were observed in mice. There were no treatment-related changes in pulmonary 
function, blood pressure, or ECG in monkeys. No neurobehavioral abnormalities were observed,
and no histologic changes were found in the central nervous system tissues of mice or monkeys. 
There were no fertility effects in male and female mice and no teratogenic findings in mice up to 
the maximum dose of 10 mg/kg. Antidrug antibodies were observed in up to 43% of mice and 
25% of monkeys in repeat-dose toxicology studies. For additional information on toxicology 
studies with BG00011 or m3G9, see the Investigator's Brochure. 
4.4.2.3.
Nonclinical Pharmacokinetics
The nonclinical PK disposition profiles of BG00011 and m3G9 were characterized in the 
cynomolgus monkey and mouse, respectively.  Following intravenous (IV) administration of a 
single dose of BG00011 in cynomolgus monkeys, maximum observed concentration (Cmax) and 
area under the concentration time curve (AUC) increased with dose.  The mean half-life (t½) for 
both IV and subcutaneous (SC) administration was approximately 4 days.  BG00011 was 
maintained primarily within the vasculature, with a calculated bioavailability of approximately 
100%.  


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Following repeated dosing in monkeys in a 3-month toxicity study, BG00011 (1 to 10 mg/kg SC 
once weekly) demonstrated dose-proportional exposure, with the t½ ranging from 8 to 12 days.  
In a 6-month toxicity study in monkeys, BG00011 (0.1 to 10 mg/kg SC once weekly) showed a 
greater-than-dose-proportional increase in exposure, and t½ increased with increasing dose.  t½
ranged from 1.5 to 10 days.  In general, the presence of antidrug antibodies was inversely 
correlated with BG00011 exposure.
4.4.3.
Clinical Experience
As of 28 February 2017, a total of 61 subjects (31 subjects with IPF and 30 healthy volunteers) 
have received BG00011 in 2 completed clinical studies, Phase 1 Study STX-001 and Phase 2a 
Study 203PF201.  Brief summaries of each of these studies are as follows:
Study STX-001
Study STX-001, a Phase 1 randomized, double-blind, placebo-controlled, single-dose, dose-
escalation study, was conducted to evaluate the safety, tolerability, PK, and immunogenicity 
profile of BG00011 administered SC to healthy volunteers.  In this study, 40 subjects were 
enrolled into 5 ascending-dose cohorts (6 active:2 placebo subjects per cohort) and received a 
single SC dose of BG00011 (range: 0.003 to 0.3 mg/kg) or placebo (saline injection) and were 
monitored for 3 months after dosing.  BG00011 exposure was dose proportional in the 3 highest 
dose groups for which serum levels were measurable.  The t½ of BG00011 was approximately 6 
days, with peak serum concentrations observed at 5 days after administration.  BG00011 was 
well tolerated, with no deaths, serious adverse events (SAEs), or premature discontinuations 
related to an AE.  No clinically significant changes were noted for any safety measures including 
AEs, physical examination, vital signs, or clinical laboratory parameters, including pulmonary 
function tests (PFTs).  AEs occurred in 21 of 30 subjects (70%) who received BG00011 and 8 of 
10 subjects (80%) who received placebo.  The most common AEs were headache, diarrhea, 
vomiting, arthropod stings, nasopharyngitis, and nasal congestion.  
Study 203PF201
Study 203PF201, a Phase 2a, randomized, double-blind, placebo-controlled, multiple-dose, dose-
escalation study was conducted to evaluate the safety, tolerability, PK, and effects on biomarkers 
of BG00011 administered SC to subjects with IPF.  Forty-one subjects were enrolled into 
5 ascending-dose cohorts ranging from 0.015 to 3.0 mg/kg (planned as 3:1 ratio per cohort).  
Study treatment was administered as once-weekly SC injections for up to 8 weeks, and each 
subject was monitored during a follow-up period of 8 to 12 weeks (depending on the dose 
cohort).  Thirty-one subjects received BG00011, and 10 subjects received placebo.  
The study was monitored by an independent data safety monitoring board (DSMB) and included 
safety evaluations that would enable detection of respiratory events (e.g., IPF exacerbation; 
changes in lung function, including decreases from baseline in FVC by ≥12%, total lung capacity 
by ≥8%, and diffusing capacity of the lungs for carbon monoxide [DLCO] by ≥15%). Four cohorts 
completed dosing through 1.0 mg/kg. Prior to the completion of dosing in the fifth and highest 
dosing cohort (3.0 mg/kg), the study was stopped after meeting the prespecified protocol stopping 


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criteria, when 2 subjects experienced clinically significant sustained decreases from baseline 
respiratory status. Following the decision to stop the 3.0 mg/kg cohort and additional discussions 
with the DSMB, Biogen conducted a detailed analysis of the available PK, PD, and safety data from 
all cohorts and concluded that the potential benefit/risk of BG00011 was acceptable for dosing 
patients with IPF, with appropriate safety monitoring, at doses not exceeding 1.0 mg/kg. A summary 
of the PK, PD, and safety data for Study 203PF201 is as follows.
Pharmacokinetic data show that after repeated weekly SC administration, BG00011 exposure 
increased approximately proportionally to doses ranging from 0.015 to 1.0 mg/kg, but increased 
greater than proportionally at doses >1.0 mg/kg.  After the last dose, the mean terminal t½ of 
BG00011 ranged from 168 to 211 hours across the dose range (approximately 174 hours 
following repeated administration at doses <3.0 mg/kg).  Serum concentrations were relatively 
sustained throughout the 168-hour sampling period, with the time to reach maximum observed 
concentration (Tmax) after the last dose occurring at 24 to 48 hours.
In this study, BG00011 decreased the level of phosphorylated SMAD2 (pSMAD2) in BAL cells 
starting at the 0.3 mg/kg dose and achieved ≥70% reduction at the 1.0 mg/kg dose. In addition, a 
substantial decrease in gene expression of several prespecified genes linked to TGF-β signaling 
was also observed between the 0.3 and 1.0 mg/kg doses. These decreases in pSMAD and gene 
expression established proof of biology.
A total of 170 AEs were reported in the Phase 2a study.  Twenty-seven of 31 subjects (87%) who 
received BG00011 and 7 of 10 subjects (70%) who received placebo experienced at least 1 AE.  
The majority of AEs were mild or moderate in severity.  The most frequent AEs reported in 
subjects who received BG00011 were cough, dyspnea, and IPF exacerbation (5 subjects each), 
hypoxia (4 subjects), fatigue, viral upper respiratory infection, injection site pain, headache, and 
seasonal allergy (3 subjects each). 
Four subjects who received BG00011 experienced SAEs, including atrioventricular block and 
hypoxemia in a subject in the 0.015 mg/kg cohort, IPF exacerbation in a subject in the 1.0 mg/kg 
cohort; syncope, Type II second-degree atrioventricular block, fractured mandible, and IPF 
exacerbation in a subject in the 1.0 mg cohort; and respiratory failure in a subject in the 
3.0 mg/kg cohort.  None of the SAEs were assessed by the respective Investigators as related to 
study treatment.
One subject (who experienced syncope, Type II second-degree atrioventricular block, fractured 
mandible, and IPF exacerbation) died due to the IPF exacerbation after discontinuation from the 
study.
In summary, multiple SC doses of BG00011 up to 1.0 mg/kg were generally well tolerated in the 
population of subjects with IPF, with the incidence and severity of AEs, and changes in physical 
examination, vital signs, or clinical laboratory parameters comparable to those expected in the 
IPF population.  Based on a detailed review of the safety, PK, and PD data for Study 203PF201, 
Biogen considers that the potential benefit/risk of BG00011 is acceptable for dosing in subjects 
with IPF at doses not exceeding 1.0 mg/kg. 


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4.5.
Study Rationale and Dose Selection
This Phase 2b study is designed to evaluate the treatment effect (change in FVC) of BG00011 
administered SC once weekly for 52 doses in subjects with mild to moderate IPF who may or 
may not be receiving protocol-defined background therapies (i.e., nintedanib or pirfenidone).  
As a first-in-class treatment for patients with IPF, the reduction in pSMAD2 levels and gene 
expression required for clinical efficacy is unknown.  Across multiple mouse models of lung 
fibrosis, αvβ6-blocking antibody treatment with dosing between 0.3 and 1.0 mg/kg leads to 
significant reductions in pSMAD2 and reduced collagen expression (a marker of fibrosis) 
without inducing lung inflammation.  The steep dose response in pSMAD2 is consistently 
observed in subjects with IPF (Study 203PF201), in nonhuman primate biomarker studies, and in 
the rodent models of epithelial injury and fibrotic diseases.  
To guide dose selection, an exposure-response analysis was prepared based on reduction in 
pSMAD2 levels versus BG00011 exposure from observed individual subject data in Study 
203PF201 (Figure 3).  The area under the concentration time curve at steady state (AUCSS) of the 
dosing interval after the last dose was used as the exposure variable and the percent change from 
the baseline level of pSMAD2 was used as the PD response in the assessment of the PK/PD 
relationship.  This curve shows the steep dose response between the 0.3 and 1.0 mg/kg doses.


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Figure 3:
Plot of BG00011 Exposure and Change in pSMAD2 From Baseline (Study 
203PF201)
AUCtau = area under the plasma concentration-time curve for a dosing interval; pSMAD2 = phosphorylated 
SMAD2.
Note:  Two subjects from the 1.0 mg/kg cohort were excluded from the exposure response analysis because they
were identified to be outliers (outside 3 standard deviations), without baseline, or below the lower limit of 
quantitation.
Dose selection for the present study is supported by safety and PK data from the completed 
single-ascending-dose study in healthy volunteers and the 8-week study in subjects with IPF, 
along with the 26-week cynomolgus monkey studies, in which an exposure of 31,700 (hr × 
μg/mL) was identified as the NOAEL.  Based on an integrated analysis of safety, PK, and PD, a 
dose of 0.7 mg/kg (56 mg) of BG00011 was selected to provide the predicted therapeutic 
exposure that would allow for optimal evaluation of the exposure-response curve with PD 
responses predicted to have clinical efficacy (median predicted response of 65% [range: 40% to 
75%] pSMAD2 reduction) while not exceeding exposures observed at the 1.0 mg/kg dose level 
and providing an approximate 27-fold margin from the predicted human exposures to the 
monkey NOAEL. 


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Since body weight was not identified as a covariate affecting exposure with the currently 
available data, there is limited pharmacological rationale to use body-weight based dosing over 
fixed dosing to reduce intersubject variability.  In addition, fixed dosing eliminates the need for 
subjects or caregivers to manually draw doses and mitigates the risk for overdosing or 
underdosing the desired amount.  This finding is also consistent with other PK analyses of 
therapeutic mAbs [Wang 2009].  An average weight of 80 kg for subjects with IPF, based on 
data from prior clinical studies in IPF [Noble 2011; Richeldi 2014], has been used to select the 
dose of BG00011 56 mg (based on the selection of the target of 0.7 mg/kg dose).  Due to limited 
data in the lower ranges of body weight, subjects will be required to weigh greater than 60 kg to 
enroll in this Phase 2b study of BG00011.  


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5.
STUDY SCHEMATIC AND STUDY ACTIVITIES
Figure 4 shows a study schematic for Study 203PF203, and Table 2 shows a schedule of study 
activities.
5.1.
Study Schematic
Figure 4:
Schematic for Study 203PF203
  Week 52
       Placebo-Controlled Treatment Period
         Week 60
Safety 
Follow-Up 
Visit
Screening 
Period
≤35 days
prior to 
Baseline
Baseline
End of Study
Interim Analysis       
To be performed when 
50% of subjects have 
reached Week 52 
(~122 subjects, 
accounting for 
estimated dropouts)
Stratification by use or non-use of background therapy and 
Randomization 1:1 to BG00011 or placebo: 
Stratum 1 – Not on background therapy (~145 subjects)

Placebo (~50% of stratum)

BG00011 (~50% of stratum)
Stratum 2 – On background therapy (~145 subjects)

Placebo (~50% of stratum)

BG00011 (~50% of stratum)
       
Safety 
Follow Up 
Period


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5.2.
Study Activities
Table 2:
Schedule of Events 
Period
Screening 
Period
Placebo-Controlled Treatment Period
Safety 
Follow-
Up
Unscheduled
Study Visit
Screening1
Baseline
Day 52
Week   
4
Week   
8
Week 
12
Week 
16
Week 
20
Week 
26
Week 
32
Week 
38
Week 
44
Week 
52/ 
EoT3
Week 60
IPF 
Exacerbation
Study Day
≤35 days 
prior to 
Baseline
0
5
28
56
84
112
140
182
224
266
308
364
420
NA
Visit Window 
(Days)
NA
NA
+1
±3
±3
±3
±3
±3
±7
±7
±7
±7
±7
±7
NA
Informed Consent 
Form
X
Randomization
X
Medical History
X
X
Inclusion/Exclusion 
Criteria
X
X4
Physical 
Examination5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body Weight and 
Height
X
X
X
X
12-Lead ECG
X
X
X
X
X
X6
Vital Signs 
(temperature, blood 
pressure, heart rate, 
respiratory rate)7
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Period
Screening 
Period
Placebo-Controlled Treatment Period
Safety 
Follow-
Up
Unscheduled
Study Visit
Screening1
Baseline
Day 52
Week   
4
Week   
8
Week 
12
Week 
16
Week 
20
Week 
26
Week 
32
Week 
38
Week 
44
Week 
52/ 
EoT3
Week 60
IPF 
Exacerbation
Study Day
≤35 days 
prior to 
Baseline
0
5
28
56
84
112
140
182
224
266
308
364
420
NA
Visit Window 
(Days)
NA
NA
+1
±3
±3
±3
±3
±3
±7
±7
±7
±7
±7
±7
NA
Oxygen Saturation8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
High Resolution 
Computed 
Tomography 
(HRCT)9
X10
X11
X11
X6
Spirometry (FVC, 
FEV1)
X12
X
X
X
X
X
X
X
X
X
X
X
X
Carbon monoxide 
diffusion capacity
(DLCO)
X
X
X
X
X
X
X
X
X
Plethysmography
X
X
X
X6
6-Minute Walk Test 
(6MWT)
X
X
X


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Period
Screening 
Period
Placebo-Controlled Treatment Period
Safety 
Follow-
Up
Unscheduled
Study Visit
Screening1
Baseline
Day 52
Week   
4
Week   
8
Week 
12
Week 
16
Week 
20
Week 
26
Week 
32
Week 
38
Week 
44
Week 
52/ 
EoT3
Week 60
IPF 
Exacerbation
Study Day
≤35 days 
prior to 
Baseline
0
5
28
56
84
112
140
182
224
266
308
364
420
NA
Visit Window 
(Days)
NA
NA
+1
±3
±3
±3
±3
±3
±7
±7
±7
±7
±7
±7
NA
Serum pregnancy 
test13
X
HIV, HCV, HBsAg, 
HBcAb Testing
X
Urine pregnancy 
test14
X
X
X
X
X
X
X
X
X
X
X
X
Hematology, blood 
chemistry, and 
urinalysis
X
X
X
X
X
X
X
X6
Serum for BG00011 
PK measurement
X15
X
X
X
X
X
X
X
X
X
X
Serum for anti-
BG00011 antibodies
X
X
X
X
X
X


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Period
Screening 
Period
Placebo-Controlled Treatment Period
Safety 
Follow-
Up
Unscheduled
Study Visit
Screening1
Baseline
Day 52
Week   
4
Week   
8
Week 
12
Week 
16
Week 
20
Week 
26
Week 
32
Week 
38
Week 
44
Week 
52/ 
EoT3
Week 60
IPF 
Exacerbation
Study Day
≤35 days 
prior to 
Baseline
0
5
28
56
84
112
140
182
224
266
308
364
420
NA
Visit Window 
(Days)
NA
NA
+1
±3
±3
±3
±3
±3
±7
±7
±7
±7
±7
±7
NA
Study diary training, 
administration, and 
review
X
Subject completion 
of study diary17
-----------------------------------------------------Ongoing throughout the study-------------------------------------------------------
Administration of 
study treatment in 
clinic
X18
Injection training
X
--------------------------------------Injection retraining to be offered as necessary-----------------------------
Weekly 
administration of 
study treatment
To be performed by subject or caregiver once weekly from Week 1 (second dose) through Week 51 
(final dose)
Dispense and/or 
collect study 
treatment
X
X
X
X
X
X
X
X
X
X
X
Compliance/drug 
accountability
X
X
X
X
X
X
X
X
X
X
X
Adverse event 
reporting19
--------------------------------------------------Monitor and record throughout Treatment and Follow-Up Periods --------------------------------


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Period
Screening 
Period
Placebo-Controlled Treatment Period
Safety 
Follow-
Up
Unscheduled
Study Visit
Screening1
Baseline
Day 52
Week   
4
Week   
8
Week 
12
Week 
16
Week 
20
Week 
26
Week 
32
Week 
38
Week 
44
Week 
52/ 
EoT3
Week 60
IPF 
Exacerbation
Study Day
≤35 days 
prior to 
Baseline
0
5
28
56
84
112
140
182
224
266
308
364
420
NA
Visit Window 
(Days)
NA
NA
+1
±3
±3
±3
±3
±3
±7
±7
±7
±7
±7
±7
NA
Serious adverse 
event reporting
--------------------------------------------------------------------Monitor and record throughout the study -----------------------------------------------------------------
Concomitant therapy 
and procedures 
recording20
-------------------------------------------------------------------Monitor and record throughout the study -----------------------------------------------------------------
Abbreviations not already defined in the table:  EoT = End of Treatment; FEV = forced expiratory volume; FEV1 = forced expiratory volume over 1 second; FVC = forced vital 
capacity; HBsAg = hepatitis B surface antigen; HBcAb = hepatitis B core antibody; HCV = hepatitis C antibody; HIV = human immunodeficiency virus; IPF = idiopathic 
pulmonary fibrosis; NA = not applicable; PK = pharmacokinetics.
1 The Screening Visit is to occur within 35 days before the Baseline Visit (Day 0).
2 The Day 5 Visit is for blood collection only (for PK analysis) and may be done in the clinic or at home (by appropriate personnel).  Sample collection should occur on Day 5 (not 
sooner), with a +1 day window allowed (i.e., collection should occur on Day 5 but may occur on Day 6).
3 If study treatment is permanently discontinued prior to the end of the Treatment Period, an EoT Visit will occur as soon as possible, but within 4 weeks (see Section 10.1 for 
details).  If a subject is withdrawn from the study prior to the end of the Treatment Period, an EoT Visit will occur as soon as possible, but within 4 weeks (see Section 10.2 for 
details).  In either case (discontinuation of treatment or withdrawal from the study) all assessments planned for the Week 52 Visit, except for the HRCT scan, will be performed 
at the EoT Visit.  However, if the EoT Visit falls within the visit window for the Week 26 Visit, the HRCT should be performed.
4 Entry criteria will be rechecked prior to dosing at the Baseline Visit (Day 0).  Investigator to confirm eligibility.
5 A full physical examination will be performed at the Screening, Baseline, Week 26, and Week 52 Visits, and at the EoT Visit in cases of early withdrawal from the study.  At all 
other study visits, an abbreviated physical examination may be performed (must always include a cardiopulmonary examination and symptom-based examination).
6 Imaging studies, plethysmography (lung volumes), ECG, or clinical laboratory tests at the IPF Exacerbation Visit will be at the discretion of the Investigator.  The optional 
imaging study at the IPF Exacerbation Visit may be a chest X-ray or HRCT scan.
7 Blood pressure is to be performed with the subject sitting, after at least 5 minutes at rest.
8 Using pulse oximeter, oxygen saturation will be measured after the subject has been at rest for at least 5 minutes. The amount of supplemental oxygen the subject is receiving, if 
any, should be noted.
9 Noncontrast chest HRCT through the full chest at suspended full inspiration and full expiration will be performed at Screening, Week 26, and Week 52, as detailed in the imaging 
procedure manual.


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10 A chest HRCT scan performed within 12 months of Screening can be used to determine initial eligibility to enter Screening (to prevent further screening assessments if HRCT 
does not meet the criteria for IPF).  Regardless of whether a historical chest HRCT was submitted, all subjects are required to receive a chest HRCT at Screening.  For 
determination of subject eligibility, all HRCT scans, including the historical and Screening Visit scans, must be consistent with the diagnosis of IPF.  Eligibility read of the HRCT 
will be performed by a central radiologist.  Historical biopsy data may be provided to support eligibility based on HRCT (see Section 7.2.1).
11 HRCT will be performed at Weeks 26 and 52 for safety monitoring.  Additionally, change from baseline in pulmonary fibrosis will be evaluated by a central radiologist.
12 Spirometry (before and after bronchodilator use) will be performed to determine eligibility. If the subject qualifies for the study, 1 subsequent spirometry evaluation, without 
bronchodilator administration, will be performed at the Baseline Visit.
13 Serum pregnancy test for women of childbearing potential only.  Results must be negative for participation in the study.
14 Urine pregnancy test for women of childbearing potential only.
15 
Documentation of background therapy dosing, including any changes in dose or dosing schedule, should be captured daily in the subject’s study diary.  Diary entries should be 
reviewed periodically by study site personnel to ensure compliance and completeness.
18 Subjects will be observed in the clinic for a minimum of 1 hour following administration of study treatment.
19 Adverse events are to be captured after the first dose of study treatment through the final study visit.  Events that occur prior to dosing should be entered on the Medical History 
case report form.
20 All concomitant medications being taken at the time of initial screening (including medications discontinued at that time) through the final study visit are to be recorded on the 
CRF.


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6.
STUDY OBJECTIVES AND ENDPOINTS
Primary Objective
Primary Endpoints
To evaluate the efficacy of BG00011 compared 
with placebo in subjects with IPF.
Yearly rate of change in FVC (expressed in mL 
over 52 weeks) in subjects randomized to 
BG00011 compared with placebo.
Secondary Objectives
Secondary Endpoints
To evaluate the efficacy of BG00011 compared 
with placebo in subjects with IPF as 
determined by change in percent predicted 
FVC.
Yearly rate of change in FVC, expressed in 
percent predicted, over 52 weeks.
To assess progression-free survival in subjects 
who receive BG00011 compared with placebo.
Time to progression, as defined by a composite 
endpoint, including any of the following 
events:

Absolute decline of 10% predicted in FVC 
(FVC percent predictedbaseline – FVC 
percent predictedprogression ≥10%).

Nonelective hospitalization for respiratory 
events.

Lung transplantation or death.
To assess the occurrence of IPF exacerbation 
(using modified diagnostic criteria for acute 
IPF exacerbation derived from [Collard 2007])
in subjects who receive BG00011 compared 
with placebo.  

Time to first acute exacerbation, measured 
in days.

Proportion of subjects with at least 1 acute 
exacerbation during the 52 weeks on study.

Number of exacerbations during 52 weeks.
To assess the incidence of absolute decline in 
FVC ≥10% in subjects who receive BG00011 
compared with placebo.
Number of subjects with absolute decline of 
10% predicted in FVC (FVC percent 
predictedbaseline – FVC percent 
predictedprogression ≥10%) over 52 weeks.


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To assess the time to death or lung 
transplantation in subjects who receive 
BG00011 compared with placebo, and the 
transplant-free survival rate at Week 26 and 
Week 52.
Time to death or lung transplantation,
measured in days.
To assess the time to nonelective 
hospitalizations in subjects who receive 
BG00011 compared with placebo,
Time to all nonelective hospitalizations and to 
nonelective respiratory hospitalizations,
measured in days.
To assess additional PFT findings in subjects 
who receive BG00011 compared with placebo.

Change in absolute and percent predicted 
FVC from baseline over time.

Carbon monoxide diffusion capacity
(DLCO), absolute and percent predicted 
changes from baseline over time.

Total lung capacity, as measured by 
plethysmography, absolute and percent 
predicted changes from baseline over time.
To assess performance on the 6MWT in 
subjects who receive BG00011 compared with 
placebo.
Change from baseline in 6MWT parameters at 
Weeks 26 and 52.
To evaluate the safety and tolerability of 
BG00011.

The incidence, severity, outcome, and 
relationship to study treatment of AEs and 
SAEs.

Change from baseline in clinical laboratory 
test results, vital signs, ECG, PFT results, 
and HRCT findings.

Immunogenicity (antibodies to BG00011).
To evaluate the serum concentration of 
BG00011.
Measurement of BG00011 serum
concentrations using sparse PK sample 
collection at select timepoints during the study.
Exploratory Objectives
Exploratory Endpoints
 


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
 


 
 
 


 

 
 
 


 
 

 
 
 
 

 
 
  


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7.
STUDY DESIGN
7.1.
Study Overview
This is a Phase 2b randomized, double-blind, placebo-controlled study designed to evaluate the 
efficacy, safety, PK, and tolerability of BG00011 in subjects with IPF.  The study will be 
conducted at approximately 100 sites in up to 20 countries in North America, Europe, and Rest 
of World.  Approximately 290 subjects are planned to be randomized. 
To be eligible for the study, subjects must have a diagnosis of IPF consistent with current ATS/
ERS/JRS/ALAT guidelines (Section 4.2, Table 1, and Figure 1).  Eligibility for the study will be 
determined centrally. In addition, features of IPF at Screening must include:  FVC ≥50% of 
predicted value; DLCO (corrected for hemoglobin) ≥30% of predicted value; oxygen saturation 
≥90% at rest (receiving ≤2 L/min of supplemental oxygen).  Subjects with IPF who do not 
otherwise qualify for study eligibility may be rescreened once at the discretion of the Principal 
Investigator. 
Subjects will be stratified by background therapy status (subjects receiving background therapy 
and subjects not receiving background therapy) and randomized in a 1:1 ratio of BG00011 to 
placebo (Figure 4).  Enrollment will also be monitored to ensure that subjects receiving 
background therapy represent approximately 50% of each treatment group. 
Subjects will receive weekly injections of BG00011 or placebo, as a solution for SC injection in 
a prefilled syringe, for 52 consecutive weeks (a total of 52 doses).  The first dose will be 
administered at the Baseline (Day 0) Visit.  The rest of the doses may be administered 
independently (e.g., not at the study site) by the subject or the subject’s caregiver.
Background therapy for IPF with pirfenidone or nintedanib will be allowed during the study. 
The subject must be on a stable dose of either medication for at least 8 weeks prior to 
randomization.  The subject is not to be on both medications simultaneously and should not 
initiate background therapy during the study.  In cases where the Investigator feels that 
background therapy is clinically indicated, this therapy can be started, but the initiation of 
background therapy during the study will be considered a protocol deviation.  While 
participating in the study, every effort should be made to maintain the subject on a stable dose of 
background therapy, and dosing should not exceed the labeled maximum dose.  However, 
background therapy dosing may be adjusted or discontinued by the subject’s pulmonary care 
physician.  The subject may continue in the study if background therapy is discontinued.  
Subjects will maintain a diary to record background therapy dosing and any adjustments made in 
their therapy. 
Assessment of pulmonary function by spirometry (FVC, FEV1, and FEV1/FVC) before and after 
bronchodilator use will be performed at Screening.  During the Treatment Period, spirometry 
evaluation (without bronchodilator use) will be performed at the Baseline Visit and at all 
Treatment Period visits (excluding Day 5).  Other PFTs include DLCO (corrected for Hgb), to be 


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assessed at Screening, Baseline, and Weeks 4, 8, 16, 26, 38, and 52; and total lung capacity and 
residual volume, to be assessed by full-body plethysmography at Baseline, Week 26, and 
Week 52.  All PFT results will be reviewed centrally. 
An independent data safety monitoring board (DSMB) will review the unblinded safety and 
available PK data throughout the study (at least quarterly) to assess the overall safety profile (see 
Section 19.2.2 for additional information).
7.2.
Study Duration, Study Visits, and Follow-Up
Study duration for an individual subject is approximately 65 weeks, including a Screening Visit 
up to 5 weeks prior to the first dose of study treatment, a Placebo-Controlled Treatment Period of 
52 weeks, and a Safety Follow-Up Visit 8 weeks after the end of the Treatment Period.  
7.2.1.
Screening
Subjects will undergo screening assessments within 5 weeks (35 days) prior to dosing. 
Qualifying assessments including medical history, physical examination, vital signs, 12-lead 
ECG, oxygen saturation, PFTs (before and after bronchodilator administration), HRCT, and 
clinical laboratory tests including pregnancy testing (women of childbearing potential only), and 
testing for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or
hepatitis B core antibody (HBcAb), and hepatitis C (HCV) antibody will be performed.  If the 
HCV antibody test is positive, hepatitis viral load will be evaluated for active hepatitis C 
infection.
A chest HRCT scan performed within 12 months of Screening can be used to determine initial 
eligibility to enter Screening (to prevent further Screening assessments if HRCT does not meet 
criteria for IPF). Regardless of whether a historical chest HRCT was submitted, all subjects are 
required to receive a chest HRCT at Screening. For determination of subject eligibility, all 
HRCT scans, including the historical and Screening Visit scans, must be consistent with the 
diagnosis of IPF. If a historical surgical lung biopsy was obtained as part of the subject’s initial 
IPF diagnosis, it must be submitted for central review. Surgical lung biopsies will not be offered
as an assessment in this study.  The diagnosis of IPF used for eligibility by HRCT and surgical 
lung biopsy (if obtained) will be confirmed centrally.
Screening assessments (e.g., clinical laboratory assessments or PFTs) 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.  If a subject must be rescreened for study 
entry, results from previous screening assessments may be used, as long as the screening 
windows for those assessments are met and all spirometry data used for subject qualification are 
derived from a single day.  If any PFTs are to be repeated, only the tests that are felt to be 
questionable should be repeated (i.e., spirometry, DLCO, or plethysmography). 
Following confirmation of eligibility on the Screening PFT, subjects will undergo 1 additional 
set of PFTs without bronchodilator administration to establish their baseline lung function; this 
assessment will be performed at the Baseline (Day 0) Visit.  


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Upon fulfilling all of the inclusion criteria and none of the exclusion criteria, subjects will be 
scheduled to return to the clinic for the Baseline predose evaluations and to ensure that they still 
qualify for the study. 
7.2.2.
Placebo-Controlled Treatment Period
The Placebo-Controlled Treatment Period begins with the Baseline (Day 0) Visit and ends with 
the End of Treatment Visit at Week 52.  At the Baseline Visit, the subject’s medical history, 
physical examination, inclusion/exclusion criteria, vital signs, weight and height, oxygen 
saturation, ECG, and pregnancy status (women of childbearing potential only) will be assessed.  
Baseline evaluations of PFTs, 6MWT, 
 will be 
obtained.  Predose blood samples will be collected for baseline laboratory clinical laboratory 
tests, 
 PK, and antibody assessments.  After confirmation of inclusion and exclusion 
criteria, the subject will be stratified based on use or nonuse of background therapy and then 
randomized to receive BG00011 56 mg SC or placebo.  The subject and/or their caregiver will 
receive instruction and training on the administration of study treatment, documentation of 
administration in the study diary, and proper handling of study treatment supplies.  The first dose 
of study treatment will then be administered under the supervision of study site personnel.  The 
subject will be observed for a minimum of 1 hour following the first administration of study 
treatment.  The subject will then be discharged with instructions to return to the study site for 
Treatment Period visits at Day 5 (for collection of a blood sample for PK analysis only, which 
may also be done at the subject’s residence) and at Weeks 4, 8, 12, 16, 20, 26, 32, 38, 44, and 52 
(End of Treatment Visit).  See Table 2 for a complete schedule of assessments to be performed at 
each visit.  
7.2.3.
Safety Follow-Up Visit
A Safety Follow-Up Visit is to occur 8 weeks after the End of Treatment Visit.  Therefore, if the 
End of Treatment Visit occurs at Week 52, as planned, the Safety Follow-Up Visit will occur at 
Week 60.  See Table 2 for a schedule of assessments to be performed at the Safety Follow-Up 
Visit.   
7.2.4.
Study Treatment Discontinuation
If study treatment is discontinued prematurely (i.e., before the subject completes the 52-dose 
regimen), the subject must return for an End of Treatment Visit as soon as possible but within 4
weeks after discontinuation of treatment. If the End of Treatment Visit occurs in the visit 
window for the next scheduled visit, then the End of Treatment Visit may be substituted for the 
scheduled visit. Subjects will then complete all remaining visits as scheduled. See Section 10.1
for additional details about study treatment discontinuation.
7.2.5.
Withdrawal From the Study
If a subject is withdrawn from the study, an End of Treatment Visit will be scheduled or
performed as soon as possible but within 4 weeks. See Section 10.2 for additional details about 
withdrawal from the study.


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7.2.6.
Unscheduled Visit for Acute Exacerbation of IPF
A subject who experiences a worsening of respiratory status at any time during the study should 
immediately contact their treating physician.  The subject should also notify the Investigator (if 
different than the treating physician) to determine the need for an IPF Exacerbation Visit.  
The IPF Exacerbation Visit should include the following:

Physical examination 

Vital signs 

Oxygen saturation

Spirometry

DLCO

Imaging studies (chest X-ray or HRCT) if not performed at another facility

Investigator's determination of IPF exacerbation (see Section 7.2.6.1)
This visit may also include the following:

ECG

Clinical laboratory tests at the discretion of the Investigator

Other tests or evaluations at the discretion of the Investigator
Note: If an IPF exacerbation is suspected at the time of a scheduled visit or is to be evaluated at 
a scheduled visit, the IPF exacerbation assessments listed above should be included in the 
scheduled visit if not already included.
A subject who is evaluated, treated, or hospitalized at a facility other than the study site should 
contact the study site following that visit to determine the need for an IPF Exacerbation Visit.  
The site assessments at the IPF Exacerbation Visit following an evaluation, treatment, or 
hospitalization at another facility are the same as those performed at the study site.  In addition, 
study site personnel should obtain sufficient medical records in order to determine the following:

Possible triggers or causes of the event.

The results of relevant tests and assessments, including but not limited to:

Detailed radiography reports and copies of images of all radiographic 
examinations (e.g., chest X-ray or HRCT scan) for submission to the central 
imaging vendor.

Spirometry, lung volume, and/or DLCO testing reports.

Descriptions of the severity and duration of the event.

Details of the medical treatment provided, including relevant medications and other 
major elements of the clinical management.

The subject’s response to the treatment and clinical status at the time of discharge. 


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7.2.6.1.
Determination of IPF Exacerbation
Based on the results obtained from evaluations at the IPF Exacerbation Visit and/or the records 
obtained from a visit to another facility, the Investigator will determine whether an IPF 
exacerbation or suspected IPF exacerbation has occurred.
Specific criteria for acute exacerbation of IPF will be determined by the Investigator, using a 
modified definition of IPF exacerbation derived from the IPF Clinical Research Network 
(IPFnet) definition of acute exacerbations of IPF in 2007 [Collard 2007], as follows: 

Unexplained worsening or development of dyspnea within 30 days.

New diffuse pulmonary infiltrates on chest X-ray, and/or new HRCT parenchymal 
abnormalities with no pneumothorax or pleural effusion (new ground-glass opacities) 
since last visit.

Exclusion of infection per routine clinical practice and microbiological studies.

Exclusion of alternative causes per routine clinical practice, including the following:

left heart failure

pulmonary embolism

identifiable cause of acute lung injury
 
 
 
The Investigator’s determination of IPF exacerbation based on 
 (2007 
) definitions 
should be documented on the appropriate CRF.
As noted, treatment for an acute exacerbation is at the discretion of the Investigator and 
medications (such as prednisone) can be freely initiated or increased at the Investigator’s 
discretion. 


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7.3.
Study Stopping Rules
Biogen may terminate this study at any time. Biogen will notify Investigators if the study is to be 
placed on hold, completed, or terminated. 
The DSMB will conduct regular reviews of all safety data in an unblinded format.  Following 
each review, the DSMB will provide a recommendation to Biogen regarding the appropriateness 
of continuing the study from a safety perspective, as well as any other recommendations relevant 
to study conduct and/or subject safety. 
The DSMB may recommend discontinuing the study if the event rate in the BG00011 treated 
arm is 20% higher compared with placebo.  The events include, but may not be limited to:

cumulative number of deaths and/or;

number of lung transplantations and/or;

cumulative number of subjects with a confirmed absolute decline of % predicted FVC ≥15 
from baseline.
The meeting intervals and the procedures used to provide and assess the data will be described in 
detail in the DSMB charter.
7.4.
End of Study
The end of study is last subject, last visit.


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8.
SELECTION OF SUBJECTS
8.1.
Inclusion Criteria
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at the time of randomization, or at the timepoint specified in the individual eligibility criterion 
listed:
1. Ability of the subject or his/her legally authorized representative to understand the 
purpose and risks of the study and provide signed and dated informed consent and 
authorization to use confidential health information in accordance with national and local 
subject privacy regulations. 
2. Aged ≥40 years at the time of informed consent. 
3. Female subjects must be surgically sterile, postmenopausal (minimum 1 year without 
menses), or agree to use 1 or more of the following forms of highly effective 
contraception from the time of signing the informed consent form (ICF) until 3 months 
after the last injection of study medication:  hormonal (i.e., oral, transdermal, implant, or 
injection); intrauterine device; vasectomized partner (with appropriate postvasectomy 
documentation of the absence of sperm in the ejaculate); or abstinence.  Male subjects 
must also agree to use 1 or more of the above forms of birth control for either themselves 
or their partner(s), as appropriate, from the time of signing the ICF until 4 months after 
the last injection of study medication.
4. IPF diagnosed based on modified ATS/ ERS/JRS/ALAT IPF guideline for diagnosis and 
management, within 3 years of Screening (see Section 4.2).
5. Combination of HRCT pattern and, if one has been obtained, surgical lung biopsy 
pattern, as assessed by central reviewers, consistent with diagnosis of IPF (see 
Section 4.2).
Note: A chest HRCT performed within 12 months of Screening can be used to determine 
initial eligibility to enter Screening and must be submitted to the central imaging vendor 
for eligibility read (to prevent further Screening assessments if HRCT is not consistent 
with IPF). Regardless of whether a historical chest HRCT was submitted, all subjects are 
required to receive a chest HRCT at Screening. If a historical HRCT is not available or 
not submitted, then the HRCT performed at the Screening Visit will be used to determine 
subject eligibility. For determination of subject eligibility, all HRCT scans, including the
historical and Screening Visit scans, must be consistent with the eligibility criteria for 
IPF. Eligibility read of the HRCT will be performed by a central radiologist. 
6. DLCO (corrected for hemoglobin):  30% to 79% predicted of normal at Screening, with no 
clinically significant deterioration between the Screening Visit and randomization, as 
determined by the Investigator.


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7. FVC ≥50% predicted of normal at Screening, with no clinically significant deterioration 
between the Screening Visit and randomization, as determined by the Investigator.
8. If a subject is taking nintedanib or pirfenidone, they must be on a stable dose for at least 8 
weeks prior to randomization.
8.2.
Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
the time of Screening, the time of randomization, or at the timepoint specified in the individual 
criterion listed:
Lung Function
1. Unable to perform PFTs or undergo HRCT procedure.
2. Peripheral capillary oxygen saturation (SpO2) <90% at rest (if on oxygen
supplementation, must be ≤2 L/min at rest).
3. Findings that are diagnostic of a condition other than UIP based on the combination of 
surgical lung biopsy (if available), HRCT imaging, transbronchial lung biopsy, or BAL,
according to central review of imaging and pathology.
4. Airway obstruction (i.e., prebronchodilator FEV1/FVC <0.7) or evidence of a 
bronchodilator response as defined by an absolute increase of ≥12% and an increase of 
≥200 mL in FEV1 or FVC, or both, after bronchodilator use, compared with the values 
before bronchodilator use at Screening.
5. End-stage fibrotic disease likely requiring organ transplantation within 12 months, or if 
the subject has initiated active evaluation for organ transplantation.
6. The extent of emphysema in the lungs exceeds fibrosis, based on central review of HRCT 
scans.
7. In the opinion of the Investigator, the subject has experienced significant clinical 
deterioration between the Screening Visit and randomization.
Medical History
8. Body weight <60 kg at Screening.
9. History of or ongoing malignant disease, including solid tumors and hematologic 
malignancies, with the exception of basal cell carcinomas, squamous cell carcinomas, and 
carcinoma in situ of the cervix that have been completely excised and considered cured 
>2 years prior to Screening.


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10. Significant cardiac disease (e.g., New York Heart Association Class 3 or 4; myocardial 
infarction within the past 6 months; unstable angina; coronary angioplasty or coronary 
artery bypass graft within the past 6 months; uncontrolled atrial or ventricular cardiac 
arrhythmias; or pulmonary hypertension requiring pharmacologic treatment).
11. Clinical diagnosis of any connective tissue disease (including but not limited to 
scleroderma, polymyositis/dermatomyositis, systemic lupus erythematosus, and 
rheumatoid arthritis) or a diagnosis of interstitial pneumonia with autoimmune features as 
determined by the Investigator applying the recent ERS/ATS research statement   
[Fischer 2015].  Note:  Serological testing is not needed if not clinically indicated.
12. History of organ transplant at any time.
13. Female who is pregnant or breastfeeding.
14. Serious local infection (e.g., cellulitis, abscess) or systemic infection (e.g., septicemia) 
that required hospitalization or was clinically significant in the opinion of the 
Investigator, within 3 months prior to Screening.
15. Fever (body temperature > 38°C) or symptomatic viral or bacterial infection within 2 
weeks prior to the Screening Visit or the Baseline Visit.
16. History or positive test result at Screening for HIV. Positive test result at Screening for 
hepatitis B virus (defined as positive for HBsAg or HBcAb). Current active HCV
infection, determined by HCV RNA above the limit of detection.  In subjects with 
positive HCV antibody titer, active HCV will be detected using HCV RNA test.
17. Known hypersensitivity to BG00011 or components of the BG00011 formulation or 
matching placebo.
18. Active drug or alcohol abuse (as defined by the Investigator) within 3 months prior to 
Screening.
19. Other disease that may interfere with testing procedures or, in the judgment of the 
Investigator, may interfere with study participation or may put the patient at risk when 
participating in this study.
20. Has a disease other than IPF with a life expectancy <2.0 years (Investigator assessment).
21. Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the 
subject unsuitable for enrollment.
Laboratory Parameters
22. Screening values for the following laboratory tests (1 retest within 2 weeks is allowed):

Hemoglobin <10 g/dL


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
WBC count <3.00 x 103/μL

Neutrophils <1.50 x 103/μL

Platelets <80 x 103/μL

Total bilirubin >1.5 mg/dL

AST and ALT >2.0 times upper limit of normal
Medications
23. Currently receiving high-dose corticosteroid, cytotoxic therapy (e.g., chlorambucil, 
azathioprine, cyclophosphamide, methotrexate), vasodilator therapy for pulmonary 
hypertension (e.g., bosentan), unapproved (e.g., IFN-γ, penicillamine, cyclosporine, 
mycophenolate, N-acetylcysteine [may vary by country]) and/or investigational therapy 
for IPF or administration of such therapeutics within 5 half-lives of the agent prior to 
initial screening in this study.  A current dose of ≤10 mg/day of prednisone or its 
equivalent is acceptable if the dose is expected to remain stable during the study.
24. Treatment with another investigational drug, investigational device, or approved therapy 
for investigational use within 5 half-lives of the agent prior to initial screening in this 
study.
25. Live/attenuated vaccinations within 12 weeks prior to Screening (inactivated influenza 
vaccine is permitted).
Other
26. 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.
27. Blood donation (1 unit or more) within 1 month prior to Screening.
28. Male or female planning a pregnancy during the duration of this study.  A serum 
pregnancy test will be performed on all female subjects of childbearing potential.
29. Inability to comply with study requirements.
30. Use of any tobacco or “electronic cigarette” product within 12 weeks prior to Screening.


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9.
SCREENING AND RANDOMIZATION
9.1.
Screening 
Subjects must provide informed consent before any screening tests are performed (Section 17.3).  
Participating study sites are required to document all screened candidates initially considered for 
inclusion in the study.  
Screen failures are defined as subjects who sign the ICF but are not subsequently randomized or 
dosed.  If a subject is considered a screen failure, the reasons for exclusion must be documented 
in the subject’s source documents and on the screening log.  A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials publishing requirements and to respond to queries 
from regulatory authorities.  Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAEs.  
Subjects with IPF who do not meet the criteria for participation in this study (i.e., a screen 
failure) may be rescreened one time only, at the discretion of the Principal Investigator. 
9.2.
Randomization 
Subjects will be randomized after all screening assessments have been completed and after the 
Investigator has verified that the subjects are eligible per criteria in Sections 8.1 and 8.2.  
Subjects will be assigned a unique identification number that will be used on study-related 
documents pertaining to the subject.  Any subject identification numbers that are assigned will 
not be reused even if the subject does not receive treatment or continue in the study.
Randomization will be performed using interactive response technology (IRT).  Subjects will be 
randomized to receive BG00011 or placebo in a 1:1 ratio. 
Refer to the Study Reference Guide for details on randomization.
9.3.
Blinding Procedures
This is a randomized, double-blinded, placebo-controlled study.
All study staff will be blinded to the subject treatment assignments.  To maintain the study blind, 
it is imperative that subject treatment assignments are not shared with the subjects, their families, 
or any member of the study team, either at the study site or at Biogen, except the unblinded 
Pharmacy staff and designated Biogen personnel. 
At the end of the study (i.e., once the clinical study report is finalized), if unblinding will not 
jeopardize the results of ongoing related studies, Biogen will provide the randomization codes to 
Investigators, who then can inform their subjects about the treatment received.  


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10.
DISCONTINUATION OF STUDY TREATMENT AND 
WITHDRAWAL OF SUBJECTS FROM THE STUDY
10.1.
Discontinuation of Study Treatment
Study treatment discontinuation is defined as the premature ending of study treatment dosing,
i.e., when a subject permanently stops taking the study treatment before the last dose (the 
Week 51 dose).  Reasons for mandatory study treatment discontinuation are listed in
Section 10.1.1.  The primary reason for study treatment discontinuation must be recorded in the 
subject’s CRF.
Subjects who discontinue study treatment must return for an End of Treatment Visit as soon as 
possible, but within 4 weeks after discontinuation of treatment. All assessments planned for the 
Week 52 Visit except the HRCT scan will be performed.  If the End of Treatment Visit occurs in 
the visit window for the next scheduled visit, then the scheduled visit may serve as the End of 
Treatment Visit, and all assessments for the End of Treatment Visit should occur at that time. 
Subjects will go on to complete all remaining visits as scheduled, including the Week 52 and 
Safety Follow-Up Visits (see Table 2 for a list of assessments to occur at the End of Treatment 
and Safety Follow-Up Visits).  
Note:  A subject who misses 1 or more doses of study treatment should restart study treatment,
receive all remaining doses, and complete all remaining study visits. 
See Section 10.2 for information related to the withdrawal of subjects from study.
10.1.1.
Reasons for Study Treatment Discontinuation
A subject must permanently discontinue study treatment for any of the following reasons:

The subject becomes pregnant.  Study treatment must be discontinued immediately.  
Report the pregnancy according to the instructions in Section 15.4.1.

The subject experiences an AE that necessitates permanent discontinuation of study 
treatment.

The subject experiences an urgent medical event 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 subject withdraws consent to continue study treatment.  


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10.2.
Withdrawal of Subjects From the Study
Study withdrawal is defined as the premature ending of study visits and assessments.  The
reasons for mandatory study withdrawal are listed below (Section 10.2.1).  Note that 
discontinuation of study treatment does not require withdrawal from the study if a subject 
continues to attend clinic visits and complete assessments.  
If a subject is withdrawn from the study, an End of Treatment Visit will be scheduled or 
performed as soon as possible but within 4 weeks.  All assessments planned for the Week 52 
Visit except the HRCT scan will be performed (see Table 2 for a list of assessments to occur at 
the End of Treatment Visit).  
If a subject is unwilling or unable to attend, at minimum, the End of Treatment Visit, and decides 
to withdraw consent, the reason for withdrawal will be documented and no further assessments 
will be obtained. 
Subjects who are withdrawn from the study will not be replaced.
10.2.1.
Reasons for Withdrawal of Subjects from the 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.
10.3.
Lost to Follow-Up
Subjects will be considered lost to follow-up if they repeatedly fail to return for scheduled visits 
and are unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit:

The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether the subject wishes to and/or should continue in the study.

In cases in which the subject is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the subject.  These contact attempts should 
be documented in the subject’s medical record.

If the subject continues to be unreachable, that subject will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.


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11.
STUDY TREATMENT USE
11.1.
Regimen
Refer to and follow the Directions for Handling and Administration (DHA).
Approximately 290 subjects will be randomized into 2 dose groups as follows:

Group 1:  BG00011 56 mg by SC injection, once weekly for 52 weeks

Group 2:  Placebo by SC injection, once weekly for 52 weeks
The first dose of BG00011 or placebo (study treatment) will be administered at the study site 
during the Baseline Visit (Day 0).  All subsequent doses should be administered by the subject or 
the subject’s caregiver. 
11.2.
Modification of Dose and/or Treatment Schedule
The dosage and dosing schedule cannot be modified.
11.3.
Precautions
Subjects will be monitored by study site personnel for at least 1 hour after administration of the 
first dose of study treatment.
11.4.
Compliance
Compliance with study treatment dosing is to be documented by the subject or the subject’s 
caregiver in the electronic study diary and monitored at each study visit by study site personnel.
11.5.
Concomitant Therapy and Procedures
11.5.1.
Concomitant Therapy
A concomitant therapy is any drug or substance administered between the time a subject is 
screened for the study and the final study visit.
11.5.1.1.
Allowed Concomitant Therapy
A current dose of ≤10 mg/day of prednisone or its equivalent is acceptable if it has been stable 
for at least 8 weeks prior to randomization and it is anticipated that the dose will remain stable 
throughout the subject’s enrollment.
During a subject’s enrollment, pirfenidone or nintedanib may be taken as background therapy for 
IPF. The subject must be on a stable dose of either drug for at least 8 weeks prior to 


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randomization.  Both drugs are not to be used simultaneously.  Subjects should not initiate 
background therapy during the study.                        
While participating in the study, every effort should be made to maintain the subject on a stable 
dose of background therapy.  However, background therapy dosing may be adjusted or 
discontinued by the physician responsible for the subject’s pulmonary care, with no dose to 
exceed the labeled maximum doses.  The subject may continue in the study if background 
therapy is discontinued.  Subjects will maintain a diary to record background therapy dosing and 
any adjustments made in their background therapy. 
In the event of an IPF exacerbation meeting the definition described in this protocol, if the 
Investigator feels that additional therapy (other than pirfenidone or nintedanib) is clinically 
indicated, this therapy may be started and the medications, doses, and duration of treatment must 
be documented as concomitant medications.  The subject may continue in the study.
Subjects should be instructed to continue the medications that they were receiving at enrollment 
and to avoid starting any new medications or herbal preparations during the study, since these
may confound the results of the study.  However, medically indicated medication or treatment 
should not be withheld.  Subjects should inform the Investigator of any changes in the
medications they are taking.
11.5.1.2.
Disallowed Concomitant Therapy
Simultaneous use of pirfenidone and nintedanib. 
Subjects should not be receiving chronic high-dose corticosteroid (i.e., >10 mg/day of 
prednisone or its equivalent), cytotoxic therapy (e.g., chlorambucil, azathioprine, 
cyclophosphamide, methotrexate), vasodilator therapy for pulmonary hypertension (e.g., 
bosentan), unapproved (e.g., IFN-γ, penicillamine, cyclosporine, mycophenolate [may vary by 
country]), and/or any investigational therapy while participating in this study, nor can they have 
received such therapies within 5 half-lives of the agent prior to initial screening. Live or 
attenuated vaccinations within 12 weeks prior to Screening or during the study are not permitted 
(inactivated influenza vaccine is permitted).
All treatments previously used for clinical management or in previous investigational trials of 
IPF will be documented on the appropriate CRF.
11.5.2.
Concomitant Procedures
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy, 
pulmonary rehabilitation) or diagnostic assessment (e.g., blood gas measurement, bacterial 
cultures) performed between the time the subject is screened for the study and final study visit.
11.6.
Continuation of Treatment 
No further provisions are made for access to the study treatment.  If BG00011 is proven to be 
beneficial, all regulatory requirements regarding poststudy access will be met.


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12.
STUDY TREATMENT MANAGEMENT
Study treatment will be manufactured, handled, and stored in accordance with applicable Good 
Manufacturing Practice.
Study site staff should follow the Directions for Handling and Administration, which is located 
in the pharmacy binder, for specific instructions on the handling, preparation, administration, and 
disposal of the study treatment.  The Directions for Handling and Administration 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 randomized in this study.  Once study treatment is 
prepared for a subject, it can be administered only to that subject.  Study treatment is for 
one-time use only; do not use any study treatment remaining in the syringe for another subject.
12.1.
BG00011
BG00011 drug product is a liquid formulation and supplied in a 1.0 mL syringe (prefilled to 0.8 
mL) and is intended for self-administration.  The pre-filled syringe contains 56 mg of BG00011 
per syringe and is formulated in sodium citrate, methionine, L-arginine, and polysorbate 80 at pH 
5.5.  The placebo consists of the formulation buffer.
The contents of the BG00011 label will be in accordance with all applicable regulatory 
requirements.  At a minimum, the label will include a study reference code, study treatment 
identifier, quantity of dosage units, lot number, and other pertinent information in accordance 
with local law.  The expiry or use-by date is stored in the IRT system, and printable assignment 
reports are available to site personnel.  Study treatment should not be used after the expiration, 
expiry, or use-by date.
12.1.1.
BG00011 Preparation
The individual preparing BG00011should carefully review the instructions provided in the 
Directions for Handling and Administration.  If the packaging is damaged, or if there is anything 
unusual about the appearance or attributes of the study treatment, do not use the study treatment.  
The study treatment in question should be saved at the study site and the problem immediately 
reported to Biogen.
12.1.2.
BG00011 Storage
Study treatment (BG00011 and placebo) must be stored in a secure location.  
BG00011 prefilled syringes are to be stored at 2C to 8C (36F to 46F), in a locked refrigerator 
with limited access.  For the most up-to-date storage requirements, follow the instructions 
provided in the Directions for Handling and Administration.


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12.1.3.
BG00011 Handling and Disposal
The Investigator must return all used and unused prefilled syringes of BG00011 as instructed by 
Biogen unless approved for onsite destruction.
If any BG00011 supplies are to be destroyed at the study site, the institution or appropriate site 
personnel must obtain prior approval from Biogen, by providing, in writing, the destruction 
policy or details of the method of destruction.  After such destruction, Biogen must be notified, 
in writing, of the details of the study treatment destroyed (e.g., lot or kit numbers, quantities), the 
date of destruction, and proof of destruction.
12.1.4.
BG00011 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), amount returned by the subject, and accounts of any 
study treatment accidentally or deliberately destroyed or lost.  
Unless otherwise notified, all prefilled syringes both used and unused, must be saved for study 
treatment accountability.  By the end of the study, reconciliation must be made between the 
amount of BG00011 supplied, dispensed, and subsequently destroyed, lost, or returned to 
Biogen.  A written explanation must be provided for any discrepancies.
12.2.
Reference Product
The placebo (control agent) to be used in this study is supplied in a 1.0 mL syringe (prefilled to 
0.8 mL) and intended for self-administration.  The prefilled syringe contains only the buffering 
solution used for the active drug product (sodium citrate, methionine, L-arginine, and 
polysorbate 80 at pH 5.5).  Labeling, preparation, storage, handling, and disposal instructions for 
the reference product are identical to those for BG00011.


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13.
EFFICACY, PHARMACOKINETIC, 
 
 ASSESSMENTS
See Section 5 for the timing of all efficacy, PK, 
 assessments.
13.1.
Clinical Efficacy Assessments
The following clinical assessments will be performed to evaluate the efficacy of BG00011.
13.1.1.
Pulmonary Function Testing
13.1.1.1.
Spirometry
Spirometry testing, including FVC, FEV1, and FEV1/FVC, both before and after bronchodilator 
use, will be performed at Screening.  During the Treatment Period, spirometry testing (without
bronchodilator use) will be performed at Baseline (Day 0) and at all scheduled study visits 
except Day 5. The spirometry evaluations performed at the Screening Visit will be used to 
determine whether the subject qualifies for the study and must be performed within 35 days prior 
to the first dose of study treatment.  At the Baseline Visit, spirometry test results will be obtained 
prior to the first dose of study treatment.  For each subject, spirometry testing should be 
conducted at approximately the same time of day.  
See the Study Reference Guide for full details of spirometry testing procedures.
All spirometry results will be electronically transmitted and confirmed by a central reader.  
Investigators will receive a report from the central reader.
13.1.1.2.
Carbon Monoxide Diffusion Capacity
DLCO measurement will be performed at Screening to determine study eligibility, and at the 
following study visits:  Baseline (Day 0), Week 4, Week 8, Week 16, Week 26, Week 38, and 
Week 52. 
Evaluation of DLCO will be performed by single-breath carbon monoxide diffusing capacity 
according to ATS/ERS recommendations.  See the Study Reference Guide for full details of the 
DLCO testing procedure.
13.1.1.3.
Full-Body Plethysmography
Lung volumes, including total lung capacity and residual volume, will be measured by full-body 
plethysmography at the following study visits:  Baseline (Day 0), Week 26, and Week 52.
See the Study Reference Manual for full details of body plethysmography testing procedures.


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13.1.2.
High-Resolution Computed Tomography
HRCT scanning will be performed at Screening, Week 26, and Week 52. Noncontrast chest CT 
through the full chest at suspended full inspiration and full expiration will be performed as 
detailed in the Imaging Procedure Manual. The HRCT scan performed at Screening will be 
centrally read, will be used to determine study eligibility, and will establish the predose baseline 
pattern and extent of disease for comparison with the Week 26 and Week 52 scans. 
An independent central radiologist experienced in the evaluation of diffuse lung diseases and 
blinded to treatment assignment will read all HRCT scans obtained during the study. The central 
radiologist will evaluate the Screening HRCT to determine eligibility and will also perform
qualitative IPF change assessment from Screening and follow-up HRCT scans. 
 
 
See the Imaging Procedure Manual for full details on HRCT scanning procedures.
13.1.3.
Acute Exacerbations of IPF
Subjects should be advised of the importance of reporting worsening respiratory status to the 
Investigator.  The Investigator will determine whether the subject should come to the study site 
for an IPF Exacerbation Visit.  See Section 7.2.6  for a detailed description of the IPF 
Exacerbation Visit.
Based on the results obtained from evaluations at the IPF Exacerbation Visit and/or the records 
obtained from a visit to another facility, using a modified definition of IPF exacerbation derived 
from IPFnet definition of acute exacerbations of IPF in 2007 [Collard 2007](see Section 7.2.6.1),
the Investigator will determine whether an IPF exacerbation has occurred.
 
 
 
Analyses of IPF exacerbation events, based on 
 the modified definition of IPF exacerbation 
(2007)
, will include the following:

Time to first acute exacerbation, measured in days.

Proportion of subjects with at least 1 acute exacerbation during the 52 weeks on 
study.

Number of exacerbations during 52 weeks.
See Section 16.2.2.3  and Section 16.2.2.4 for additional details of these analyses. 


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13.1.4.
Respiratory Hospitalizations  
All nonelective hospitalizations will be assessed by the Investigator to determine whether the 
primary cause of the hospitalization was respiratory in nature. The determination of a respiratory 
hospitalization should be based on a fundamental change in respiratory status that is due either to 
intrinsic lung disease or to infectious etiology of the lung.  The change in respiratory status 
should not be the result of a secondary effect from another organ or system. 
In addition, study site personnel should obtain sufficient medical records to determine the 
following:

Possible triggers or causes of the event

The results of relevant tests and assessments (if performed), including but not limited to:

Detailed radiography reports and copies of images of all radiographic 
examinations (e.g. chest X-ray or HRCT scan) for submission to the central 
imaging vendor

Spirometry, lung volume, and/or DLCO testing reports

Echocardiogram

Microbiology data

Descriptions of the severity and duration of the event

Details of the medical treatment provided, including relevant medications and other 
major elements of the clinical management

The subject’s response to the treatment and clinical status at the time of discharge.
13.1.5.
6-Minute Walk Test
The 6MWT will be administered at the following study visits:  Baseline (Day 0), Week 26, and 
Week 52.  This test, which assesses the distance in meters that a subject can walk in 6 minutes, 
will be conducted according to ATS criteria by study site staff in a suitable location with 
emergency response supplies available.  Detailed criteria for the conduct of the 6MWT, 
including training requirements for administration of the test, availability of emergency supplies, 
use of oxygen supplementation during the test, and parameters for starting and stopping the test,
are provided in the Study Reference Guide.
 
 
 
 


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13.2.
Pharmacokinetic Assessments
Blood samples for PK evaluation will be collected at the following visits: prior to dosing at 
Baseline (Day 0), Day 5, Week 4, Week 8, Week 12, Week 26, Week 38, Week 52, and 
Week 60.
The PK data obtained in this Phase 2b study will be combined with data from other studies in the 
clinical development program to develop a population PK model.  This model will be used to 
evaluate the effects of intrinsic and extrinsic covariates on the PK of BG00011 and to determine 
measures of individual exposure (such as steady-state trough, time-averaged concentration, or 
AUC).  Model-determined exposures will be used for exposure-response analyses of selected 
efficacy and safety endpoints.  Results of population PK and exposure-response analyses will be 
reported separately.
 
 
  
 
  


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14.
SAFETY ASSESSMENTS
Refer to Section 5 for the timing of all safety assessments.
Tests and evaluations affecting primary endpoints and/or analyses may need to be repeated if the 
original results are lost or damaged.  In these cases, subjects will be asked to return to the clinic 
to have the evaluations repeated.
14.1.
Clinical Safety Assessments
The following clinical assessments will be performed to evaluate the safety profile of BG00011:

AE and SAE monitoring and recording

Lung function
The assessment of changes in lung function during this study will be performed by 
comparing the subject’s spirometry parameters at Baseline to postbaseline values during the 
Treatment and Follow-Up Periods.  These evaluations will assess both the absolute and the 
percent predicted changes in FVC.  All spirometry tests will be reviewed centrally.
Expected fluctuations or expected deterioration of the underlying IPF and other pre-existing 
conditions should not be recorded as an AE except in the following circumstances:
o
Worsening of the disease meets the criteria for an SAE.
o
Action is taken with investigational treatment, such as when treatment is 
discontinued.
o
Additional treatment is required, such as when concomitant medication is added or 
changed.
o
In the opinion of the Investigator, an unexpected deterioration from baseline has 
occurred.
o
The event meets the criteria of an acute exacerbation of IPF or suspected exacerbation 
of IPF.
Specific criteria for acute exacerbation of IPF will be determined by the Investigator based 
on the following 2 definitions: 
Diagnostic Criteria for Acute IPF Exacerbation (2007)
o
Unexplained worsening or development of dyspnea within 30 days.
o
New diffuse pulmonary infiltrates on chest X-ray, and/or new HRCT parenchymal 
abnormalities with no pneumothorax or pleural effusion (new ground-glass opacities) 
since last visit.
o
Exclusion of infection per routine clinical practice and microbiological studies.
o
Exclusion of alternative causes per routine clinical practice, including the following:


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
congestive heart failure

pulmonary embolism

identifiable cause of acute lung injury
 
 
 

High-resolution computed tomography  
HRCT scans will be performed during Screening to establish the predose pattern and extent 
of disease and will serve as the baseline assessment.  An independent central radiologist 
experienced in the evaluation of diffuse lung diseases and blinded to treatment assignment 
will evaluate the HRCT scans, which will be performed at Screening, Week 26, and 
Week 52.  Every effort will be made to have sequential scans for individual subjects 
evaluated by the same radiologist. 

Other safety assessments
o
Medical history 
o
Concomitant therapy and procedure recording
o
Physical examination
o
Vital signs: oral temperature (°C), heart rate (beats/min), respiratory rate 
(breaths/min), sitting blood pressure (mmHg) after at least 5 minutes’ rest
o
Body weight (kg) and height (cm)
o
12-lead ECG after at least 5 minutes’ rest
o
Oxygen saturation (pulse oximetry) after at least 5 minutes’ rest
o
Use of supplemental oxygen
o
Study discontinuations (all causes, and due to urgent need for transplantation)
o
Cumulative number of lung transplantations and number of deaths (respiratory and all 
causes)
o
Cumulative spirometry testing with percent change from baseline and change in 
percent predicted from baseline calculated at each visit
o
Cumulative number of nonelective hospitalizations
14.2.
Laboratory Safety Assessments
All samples will be analyzed using Good Laboratory Practice validated assays.


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The following laboratory assessments will be performed to evaluate the safety profile of 
BG00011:

Hematology:  Complete blood count, including red blood cell count, white blood cell 
count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular 
hemoglobin, and mean corpuscular hemoglobin concentration.

Serum chemistry, including:  albumin, alkaline phosphatase, alkaline phosphatase, 
alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, calcium, 
chloride, carbon dioxide, creatinine, bilirubin (total and direct), gamma-glutamyl 
transferase, glucose, lactate dehydrogenase, phosphorus, potassium, sodium, and total 
protein.

Urinalysis, including urine protein, glucose, ketones, occult blood, and white blood 
cells by dipstick, with microscopic examination if indicated.  

At Screening, blood samples for HCV antibody and RNA, HBsAg, HBcAb, and HIV 
antibody will be collected to establish eligibility.  Appropriate referrals must be made 
for any active HCV, positive HBsAg, or HIV test that is obtained, according to 
applicable local laws.

Serum pregnancy test (Screening).

Urine pregnancy tests (all visits after Screening).
14.3.
Immunogenicity Assessments
The following assessments will be performed to determine the safety of BG00011:

Collection and analysis of serum samples for the presence and titer of anti-BG00011
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, or their legally authorized representative and/or main 
caregiver must be given the names and telephone numbers of study site staff for reporting AEs 
and medical emergencies.
15.1.
Definitions
15.1.1.
Adverse Event
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product.
Determination of whether an abnormal laboratory value, vital sign result, and/or ECG result 
meets the definition of an AE will be made by the Investigator.  Abnormal results are not 
considered AEs unless one or more of the following criteria are met:

The result meets the criteria for an SAE

The result requires the subject to receive specific corrective therapy

The result is considered by the Investigator to be clinically significant
15.1.2.
Serious Adverse Event
An SAE is any untoward medical occurrence that at any dose:

Results in death

In the view of the Investigator, places the subject at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred 
in a more severe form, might have caused death

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity


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
Results in a congenital anomaly/birth defect

Is a medically important event
A medically important event is an AE that, in the opinion of the Investigator, may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the definition 
above.  (Examples of such medical events include allergic bronchospasm requiring intensive 
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 preventative health procedure 
(e.g., colonoscopy) 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.


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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.
Relationship of Event to Study Treatment
Not related
An AE will be considered “not related” to the use of the investigational product 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 investigational 
product and the AE, 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 product 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 
investigational product and the AE, a known response pattern of the suspected product, 
improvement following discontinuation or dose reduction, a biologically plausible 
relationship between the product 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 (including SAEs) experienced by the subject between the time of first dose of study 
treatment and the subject’s last study visit is to be recorded on the CRF, regardless of the 


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severity of the event or its relationship to study treatment.  At each study visit, the Investigator 
will assess the subject for AEs and will record any new AEs or updates to previously reported 
AEs on the CRF.
AE outcome will be recorded on the CRF, as applicable.
Expected fluctuations or expected deterioration of the underlying IPF and other pre-existing 
conditions should not be recorded as an AE except in the following circumstances:
o
Worsening of the disease meets the criteria for an SAE.
o
Action is taken with investigational treatment, such as when treatment is 
discontinued.
o
Additional treatment is required, such as when concomitant medication is added or 
changed.
o
In the opinion of the Investigator, an unexpected deterioration from baseline has 
occurred.
o
The event meets the criteria of an acute exacerbation of IPF.
15.3.2.
Serious Adverse Events
Any SAE experienced by the subject between the time of the signing of the ICF and the subject’s 
last study visit is to be recorded on an SAE form, regardless of the severity of the event or its 
relationship to study treatment.  SAEs must be reported to Biogen within 24 hours as described 
in Section 15.3.3.  Follow-up information regarding an SAE also must be reported within 24 
hours.  See the Study Reference Guide’s Official Study Contact List for complete contact 
information.  
Subjects will be followed for all SAEs until their last study visit. Thereafter, the event should be 
reported to Biogen only if the Investigator considers the SAE to be related to study treatment.
SAEs that are 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.  SAE 
outcome will be recorded on the CRF, as applicable.  Only SAEs that are unresolved will be 
followed by the Investigator.
15.3.3.
Immediate Reporting of Serious Adverse Events
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify Biogen within 24 hours of the study site staff becoming aware of the SAE.  It is 
the Investigator’s responsibility to ensure that the SAE reporting information and procedures are 
used and followed appropriately.


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Reporting Information for SAEs
A report must be submitted to Biogen 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, a completed SAE form must be sent to 
Biogen; refer to the Study Reference Guide’s Official Study Contact List for complete contact 
information.  
15.3.3.1.
Deaths
Death is an outcome of an event.  The event that resulted in death should be recorded on the 
appropriate CRF.  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 to the Biogen.  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.
Appropriate personnel at Biogen will unblind SUSARs for the purpose of regulatory reporting.  
Biogen will submit SUSARs (in blinded or unblinded fashion) to regulatory agencies according 
to local law.  Biogen 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 3 months after their last dose of study treatment.  If a female subject becomes pregnant, 
study treatment must be discontinued immediately.
The Investigator must report a pregnancy occurring in a female subject from first dose of study 
treatment up to 3 months after the last dose by faxing or emailing the appropriate form to Biogen 
within 24 hours of the study site staff becoming aware of the pregnancy. Refer to the Study 
Reference Guide’s Official Study Contact List for complete contact information. The 


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Investigator or study site staff must report the outcome of the pregnancy to Biogen. A pregnancy 
is not considered an AE and should not be recorded on the AE CRF.
Congenital abnormalities and birth defects in the offspring of male or female subjects should be 
reported as SAEs if conception occurred during the study treatment period.
15.4.2.
Overdose
An overdose is any dose of study treatment administered to a subject or taken by a subject that 
exceeds the dose assigned to the subject according to the protocol.  Overdoses are not considered 
AEs and should not be recorded as an AE on the CRF; however, all overdoses must be recorded 
on an Overdose form and faxed or emailed to Biogen within 24 hours of the site becoming aware 
of the overdose.  An overdose must be reported to Biogen 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 or emailed to Biogen.  All 
study treatment-related dosing information must be recorded on the dosing CRF.
15.4.3.
Medical Emergency
In a medical emergency requiring immediate attention, study site staff will apply appropriate 
medical intervention, according to current standards of care.  The Investigator 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 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, or to 
personnel involved with the analysis and conduct of the study. The Investigator can contact 
Biogen to discuss such situations.
15.5.
Contraception Requirements
All women of childbearing potential and all men must practice highly effective contraception 
during the study.  Women in the study (and/or their partner) must continue highly effective 
contraception and must not donate eggs for 3 months after stopping study treatment.  Men in the 
study (and/or their partner) must continue effective contraception and must not donate sperm for 
4 months after stopping study treatment.  
For the purposes of this study, women who do not meet one of the following criteria are 
considered to be physiologically capable of becoming pregnant and are, therefore, defined as 
women of childbearing potential:


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
Postmenopausal
o
12 continuous months of natural (spontaneous) amenorrhea without an alternative 
medical cause.
o
6 weeks after surgical bilateral oophorectomy with or without hysterectomy

Posthysterectomy

Female surgical sterilization (e.g., bilateral tubal ligation)  
For the purposes of the study, highly effective contraception is defined as use of 1 of the 
following: 
For females:

Established use of oral, intravaginal, or transdermal combined (estrogen and progestogen 
containing) hormonal methods of contraception associated with the inhibition of 
ovulation.

Established use of oral, injected, or implanted progestogen-only hormonal methods of 
contraception. 

Placement of an intrauterine device or intrauterine hormone-releasing system.

Sex with a male who has undergone surgical sterilization (with the appropriate 
postvasectomy documentation of the absence of sperm in the ejaculate). 
For males:

Vasectomy (with the appropriate postvasectomy documentation of the absence of sperm 
in the ejaculate).

Sex with a woman who uses the methods described for females if she is of childbearing 
potential.
True abstinence, when this is consistent with the preferred and usual lifestyle of the subject, can 
be considered an acceptable method of contraception based on the evaluation of the Investigator 
who should also take into consideration the duration of the clinical 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.


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15.6.
Safety Responsibilities
15.6.1.
The Investigator
The Investigator’s responsibilities include the following:

Monitor and record all AEs, including SAEs, on the CRF regardless of the severity or 
relationship to study treatment.

Determine the seriousness, relationship, and severity of each event.

Determine the onset and resolution dates of each event.

Monitor and record all pregnancies in female subjects and follow up on the outcome 
of all pregnancies.

Complete an SAE form for each SAE and fax or email it to Biogen within 24 hours of 
the study site staff becoming aware of the event.

Pursue SAE follow-up information actively and persistently.  Follow-up information 
must be reported to Biogen within 24 hours of the study site staff becoming aware of 
new information.

Ensure all AE and SAE reports are supported by documentation in the subjects’ 
medical records.

Pursue AE follow-up information, if possible, until the event has resolved or become 
stable.  Record AE follow-up information, including resolution, on the CRF, as 
applicable.

Report SAEs to local ethics committees, as required by local law.
15.6.2.
Biogen 
Biogen’s responsibilities include the following:

Before a site can enroll any subjects, the Clinical Monitor is responsible for reviewing 
with study site staff the definitions of AE and SAE, as well as the instructions for 
monitoring, recording, and reporting AEs and SAEs.

Biogen is to notify all appropriate regulatory authorities, central ethics committees, 
and Investigators of SAEs, as required by local law, within required time frames.


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16.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The objectives of the study and the endpoints to be analyzed are listed in Section 6.
16.1.
Demography and Baseline Characteristics
Demographics and baseline data will be summarized by treatment group with summary statistics 
(mean, standard deviation [SD], median, and range) or with frequency distributions.
16.2.
Efficacy
16.2.1.
Analysis Population
The intent-to-treat (ITT) population, defined as all subjects who are randomized and receive at 
least 1 dose of study treatment, will be used for the efficacy analyses unless otherwise specified.  
For each endpoint, additional conditions may apply to the definition of the population for the 
analysis.  Subjects will be analyzed in the groups to which they were randomized.
The per-protocol (PP) population, defined as all subjects who are randomized and without major 
protocol violations, will be used for sensitivity analysis for the primary endpoint. 
Subgroup analysis (e.g., background therapy strata as subgroup) will be done for the primary 
endpoint and some of the secondary endpoints. The details will be specified in the SAP.
16.2.2.
Methods of Analysis
16.2.2.1.
General Considerations
Summary statistics will be presented.  For continuous endpoints, summary statistics will 
generally include: number of subjects with data, mean, standard deviation, median, and range. 
For categorical endpoints, this will generally include number of subjects randomized, number of 
subjects with data, and percentage of subjects with data in each category.  Statistical testing for 
efficacy endpoints will be made between subjects treated with BG00011 and with placebo.
All statistical tests will be 2-sided.
16.2.2.2.
Analysis of the Primary Endpoint
The population for the primary endpoint analysis will be subjects in the ITT population with a 
baseline and at least 1 postbaseline FVC measurement.
The primary efficacy outcome variable is the yearly rate of change in FVC (actual value, 
expressed in mL, over 52 weeks).  The primary endpoint will be analyzed using a random 
coefficients linear regression model, with an absolute change in FVC as the outcome variable 


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assuming linear decline in lung function over time.  The model includes random coefficients for 
intercept and slope (time), and fixed-effect terms for treatment, randomization stratum 
(background therapy), age, and baseline FVC.  Interaction terms in the model will be the 
interaction between treatment and time, and the interaction between pirfenidone or nintedanib
and time.
Every effort should be made to reduce the amount of missing data.  In the analysis of the primary 
endpoint, missing data will be assumed to be missing at random.  An unstructured variance-
covariance structure will be used to model the within-patient measurements variability.  If it fails 
to converge, an AR(1) structure will be used.  The variance-covariance matrix, modeled to 
estimate the interindividual variability, is considered to have a variance components structure.  
Because the statistical model assumes a linear decline in lung function over time and, hence,
implicitly imputes missing data based on individual’s estimated rate of worsening of lung 
function prior to treatment discontinuation, similar to linear extrapolation.  If a subject who was 
not on background therapy at randomization initiates treatment with background therapy during 
the study, the subject’s data collected after the initiation of background therapy will be excluded 
from the primary analysis.  However, a sensitivity analysis that includes the excluded data will 
be performed.  
Support analyses for the primary endpoint includes:
1. Analysis using multiple imputation with pattern mixture models will be carried out.  
Details of sensitivity analysis and assumptions for different pattern will be described in 
the statistical analysis plan (SAP).
2. A mixed model of repeated measures model will be used to compare the difference 
between the 2 treatment groups in FVC change at 52 weeks and other scheduled visits.  
An unstructured variance-covariance structure will be used in this model.  If the model 
fails to converge, an AR(1) structure will be used.
3. Rate of decline in percent predicted FVC at 52 weeks will be analyzed by the same 
method as FVC actual value.
A model including the interaction between treatment and background therapy strata will be used 
to explore the treatment effects within each subgroup. 
16.2.2.3.
Analysis of the Secondary Endpoints
Time to progression will be presented using Kaplan-Meier curves, a stratified log-rank test will 
be used to compare the 2 treatment groups using randomization stratum as the stratification 
factor. The proportion of subjects who progressed in each arm will be summarized. Each 
component of progression will be summarized descriptively. If a subject who was not on 
background therapy at randomization initiates treatment with background therapy during the 
study, the subject will be censored at the time of new background therapy initiation.
Other time-to-event types of endpoints, e.g., time to first acute exacerbation, time to death or 
lung transplant, nonelective hospitalization (due to respiratory causes and due to all causes), and 


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survival rate (death from all causes and death due to respiratory causes) at 26 weeks and 52 
weeks will be analyzed similarly.
The number of subjects experiencing an absolute decline of 10% predicted in FVC will be 
analyzed using a logistic regression model, adjusting for the randomization stratification factor, 
patient age, and baseline FVC.
Other pulmonary function endpoints and the 6MWT at 52 weeks will be analyzed similarly to 
the primary endpoint. For other visits, an analysis of covariance model adjusting the 
randomization stratification factor, age, and FVC at Baseline will be used to compare the 
treatment groups.  The cumulative distribution of subjects by change in absolute and percent 
predicted FVC from Baseline to Week 52 will be presented in graph form.
Details of the analyses, including the handling of missing data, will be described in a SAP.
 
 
 
 
 
 
 
 
 
 
 
16.3.
Pharmacokinetics
16.3.1.
Analysis Population
The population for serum PK analyses is defined as all subjects in the ITT population who have 
at least 1 measurable BG00011 concentration in serum.
16.3.2.
Methods of Analysis
Samples for measuring serum concentrations of BG00011 will be collected as specified in 
Section 5.2.  BG00011 concentrations in serum will be summarized using descriptive statistics at 
the scheduled PK sample collection visits.
This study will collect only sparse PK samples; thus, the serum concentration data will be 
summarized descriptively by visit. No noncompartmental or compartmental methods will be 


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used to analyze the PK data for presentation in the clinical study report. Details of the PK 
analysis will be described in the SAP.
Mean serum concentrations of BG00011 will be plotted versus time on both a linear and a 
logarithmic scale.  No dose-proportionality assessments will be conducted because of the sparse 
PK data sampling.
Atypical drug concentrations (e.g., very low or very high) will be excluded from the analysis, if 
no apparent explanation exists.  Concentration observations will also be removed from the data 
set if corresponding dosing or sampling times are missing or cannot be reconstructed.
Concentration values below the limit of quantification will be removed from analysis.  All 
deletions of data points will be appropriately documented.
 
 
 
 
 
 
 
 
  
16.6.
Safety
16.6.1.
Analysis Population
The safety population is defined as all subjects who receive at least 1 dose of study treatment.


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16.6.2.
Methods of Analysis
16.6.2.1.
Adverse Events
AEs will be coded using the Medical Dictionary for Regulatory Activities.  All analyses of AEs 
will be based on the principle of treatment emergence. An AE is considered to be treatment 
emergent if it has an onset date on or after the date of first dosing, or if it was present prior to the 
first dose and subsequently worsened. The incidence of all AEs will be presented by system 
organ class and preferred term by treatment group. In addition, the incidence of all AEs will be 
presented by severity and by relationship to study treatment.
16.6.2.2.
Clinical Laboratory Results
Clinical laboratory evaluations include hematology, blood chemistry, and urinalysis evaluations. 
Analyses of clinically significant abnormalities, shifts from baseline to postbaseline relative to 
the normal range, as well as changes from baseline by visit will be presented by treatment group.
16.6.2.3.
Vital Signs
The analysis of vital signs will focus on clinically relevant abnormalities, which will be defined 
in more detail in the SAP. The incidence of clinically relevant abnormalities in vital signs will be 
summarized by treatment group.  
16.6.2.4.
Electrocardiograms
The analysis of ECG data will focus on clinically relevant abnormalities, which will be defined 
in more detail in the SAP. ECG changes from baseline may be summarized using descriptive 
statistics and presented by dose group, overall active treatment group, and visit.
16.6.2.5.
Physical Examinations
Abnormal findings during physical examinations will be recorded as AEs and will be reflected in 
the summary of AEs.
16.7.
Immunogenicity Data
16.7.1.
Analysis Population
The analysis population for immunogenicity is defined as all subjects who were randomized and 
received at least 1 dose of study treatment and who have at least 1 postdose immunogenicity 
sample evaluated for anti-BG00011 antibodies.
16.7.2.
Methods of Analysis
The incidence of anti-BG00011 antibodies will be summarized by treatment group over time.


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16.8.
Interim Analyses
An interim analysis will be performed for internal decision making (i.e., Phase 3 planning) when 
approximately 50% of study subjects have completed the Week 52 Visit.  Data from subjects 
who have completed the Week 26 Visit or later visits, or have completed the End of Treatment 
Visit, will be included in this analysis.  The actual timing of the interim analysis might be 
adjusted depending on the enrollment of each randomization stratum to ensure there is adequate 
information to enable decision making. This analysis will be carried out by an unblinded internal 
team (the blinding of the study will be maintained to the subjects, study sites, and study 
operation team). No Type I error adjustments will be made. Details of the interim analysis will 
be described in the SAP.
16.9.
Sample Size Considerations
The sample size calculation is based on the annual declining rate in FVC (mL/year). With 145 
subjects randomized per arm, and assuming a 15% dropout rate over a 1-year treatment period, 
the study has approximately 80% power to show that the BG00011 treatment arms differentiate 
from the arm without BG00011 at a 2-sided 15% α level, given a treatment effect of 
82.5 mL/year with a common standard deviation of 280 mL.  The calculation is based on the 
assumption that the FVC decline rate in subjects receiving placebo and no background therapy is 
220 mL/year, and in subjects receiving background but no BG00011 therapy it is assumed to be 
110 mL/year.  A 60% reduction in the FVC decline rate in the subjects receiving placebo would 
be a treatment effect of 132 mL/year.  A 30% reduction in the FVC decline rate in subjects 
receiving background therapy would be a treatment effect of 33 mL/year.  With the assumption 
that 50% of each type of subject are randomized in the study, the combined treatment effect is 
approximately 82.5 mL/year.  The 15% dropout rate for this study was estimated based on prior 
experience for the placebo arms in the Phase 3 studies for nintedanib and pirfenidone [King 
2014; Richeldi 2014].


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17.
ETHICAL REQUIREMENTS
Biogen, any designee, and the Investigator must comply with all instructions, regulations, and 
agreements in this protocol and applicable International Council for Harmonisation (ICH) and 
Good Clinical Practice (GCP) guidelines and conduct the study according to local regulations.
The investigator is responsible for endorsing all data on completed CRFs electronically, prior to 
any Interim lock or Database lock.
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines.  The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated.  The Investigator 
is responsible for supervising those individuals and for implementing procedures to ensure the 
integrity of the tasks performed and any data generated.
17.1.
Declaration of Helsinki
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki.
17.2.
Ethics Committee
The Investigator must obtain ethics committee approval of the protocol, ICF, and other required 
study documents prior to starting the study.   
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.


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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., legal guardian), as applicable, in accordance 
with local practice and regulations.  
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the subject must be explained to the subject (or the 
subject’s legally authorized representative).  The subject must be given sufficient time to 
consider whether to participate in the study.
Subjects will be informed that their race and ethnicity will be collected during the study (unless 
the collection is not permitted by applicable law or not approved by the governing ethics 
committee) and the data will be used during analysis of study results.  (See Section 17.4.)
A copy of the signed and dated ICFs must be given to the subject or the subject’s legally 
authorized representative. The original signed and dated ICFs 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).
During the study, subjects’ race will be collected (unless the collection is not
permitted by applicable law or not approved by the governing ethics committee).  These data will 
be used in the analysis of the safety and/or pharmacokinetic profile of the study treatment.  
Subjects’ race is required for the calculation of the percent predicted equations used in 
pulmonary function testing.    
Study reports will be used for research purposes only.  The subject will not be identified by name 
in CRFs, 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.


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17.6.
Conflict of Interest
The Investigators should address any potential conflicts of interest (e.g., financial interest in 
Biogen) with the subject before the subject makes a decision to participate in the study.
17.7.
Registration of Study and Disclosure of Study Results
Biogen will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations.


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18.
ADMINISTRATIVE PROCEDURES
18.1.
Study Site Initiation
The Investigator must not screen any subjects prior to completion of a study initiation visit, 
conducted by Biogen.  This initiation visit will include a detailed review of the protocol and 
study procedures.
18.2.
Quality Control and Quality Assurance
Quality control procedures will be implemented at each stage of data handling to ensure that all 
data are reliable and have been processed correctly.  Data anomalies will be communicated to the 
sites for clarification and resolution, as appropriate. 
During and/or after completion of the study, quality assurance officers named by Biogen or the 
regulatory authorities may wish to perform onsite audits or inspections.  The Investigator will be 
expected to cooperate with any audit or inspection and to provide assistance and documentation 
(including source data) as requested.
18.3.
Monitoring of the Study
The Investigator must permit study-related monitoring by providing direct access to source data 
and to the subjects’ medical histories.  Source data must be attributable, legible, 
contemporaneous, original, accurate, and complete.  Changes to source data must be traceable, 
not obscure the original entry, and be explained if necessary (e.g., with an audit trail).  The 
Investigator should maintain a record of the location(s) of essential documents.
The Clinical Monitor will visit the study site at regular intervals during the study and after the 
study has completed, as appropriate.  A clinical site monitoring plan will detail who performs the 
monitoring, how often, and the extent of review.  It also will provide the monitoring strategy, 
with emphasis on subject safety, data integrity, and critical data and processes.
During these visits, CRFs, supporting documentation, and essential documentation related to the 
study will be reviewed and any discrepancies or omissions will be resolved.  Documentation of 
results will be provided to Biogen or designee in a timely fashion to allow follow-up and 
verification of compliance with the monitoring plan.  Remote evaluation of data (centralized 
monitoring) may also be conducted and reported as defined in the monitoring plan.
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure the protection of subject rights and well-being, protocol adherence, quality of data 
(accurate, complete, and verifiable), study treatment accountability, compliance with regulatory 
requirements, and continued adequacy of the investigational site and its facilities.


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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, and management of SAE reports, and data management.  Before 
subjects are screened at each study site, the CRO will review study responsibilities with the 
Investigators and other study site staff, as appropriate.
19.1.2.
Interactive Response Technology
IRT will be used in this study.  Before subjects are screened or enrolled, the IRT vendor will 
provide each study site with the necessary training, a user manual, and access rights to the 
system.
19.1.3.
Electronic or Remote Data Capture
Subject information will be captured and managed by study sites on electronic CRFs by a 
Web-based electronic data capture tool configured by the CRO and hosted by the electronic data 
capture vendor. 
Electronic Clinical Outcome Assessment (eCOA) data will be entered by the subject, the 
subject’s caregiver, and/or study site staff on a device developed and supported by the eCOA 
vendor. Site staff will monitor data via a secure Web portal developed and supported by the 
eCOA vendor. 
19.1.4.
Central Laboratories for Laboratory Assessments
A central laboratory has been selected by Biogen to store samples collected from subjects in this 
study for 
, 
 drug concentrations, and anti-BG00011 antibodies in whole blood, 
plasma, and serum.  These samples may be analyzed by a central laboratory or a third-party 
laboratory, as applicable.  A central laboratory will also perform the safety laboratory tests noted 
in the Schedule of Events (Table 2):  blood chemistry, hematology, urinalysis, serum pregnancy, 
HBsAg, HBcAb, HCVAb, HIV panels.
A local laboratory may be used by the study site to analyze repeat tests if needed.
19.1.5.
Central Facility for Other Assessments
A central vendor has been selected by Biogen to read and interpret all HRCT scans for this study.
A central vendor has been selected by Biogen to read and interpret lung function assessment 
data.


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A central vendor has been selected by Biogen to read and interpret ECG data.
19.2.
Study Committees
19.2.1.
Advisory Committee
Advisory committees will be formed to provide scientific and medical direction for the study and 
to oversee the administrative progress of the study.  The advisory committees will be blinded to 
subject treatment assignments.  
19.2.2.
Data Safety Monitoring Board
An independent DSMB will be established to assess the overall safety profile throughout the 
conduct of the study. A DSMB charter will be developed to guide the overall governance plan 
for the DSMB in alignment with the Safety Monitoring Plan. The DSMB will review the 
unblinded safety (including but not limited to AEs, clinical laboratory data, ECGs, pulmonary 
function testing, and imaging data) and available PK data on an ongoing basis until the last 
subject completes dosing.  The meeting intervals and the procedures used to provide and assess 
the data will be described in detail in the DSMB charter.  Upon review of the data, the DSMB 
may recommend that the Sponsor discontinue the study, modify the study conduct, or continue 
the study with no changes.
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.


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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, national, or regional laws or 
regulations.  Prior to proceeding with destruction of records, the Investigator must notify Biogen 
in writing and receive written authorization from Biogen to destroy study records.  In addition, 
the Investigator must notify Biogen of any changes in the archival arrangements including but 
not limited to archival at an offsite facility or transfer of ownership if the Investigator leaves the 
site.
19.6.
Study Report Signatory
Biogen will designate one of the participating Investigators as a signatory for the study report.  
This determination will be made by several factors, including but not limited to the Investigator’s 
experience and reputation in the studied indication; the Investigator’s contribution to the study in 
terms of design, management, and/or subject enrollment; or by other factors determined to be 
relevant by Biogen.
Biogen will follow all applicable local regulations pertaining to study report signatories.


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20.
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “A Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of BG00011 in Patients With Idiopathic Pulmonary Fibrosis,” 
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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21.
REFERENCES
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Collard HR, Moore BB, Flaherty KR, et al. Acute exacerbations of idiopathic pulmonary 
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Esbriet Summary of Product Characteristics, 08 September 2015, Roche LTD.
Fernández Pérez ER, Daniels CE, Schroeder DR, et al. Incidence, prevalence, and clinical course 
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Fischer A, Antoniou KM, Brown KK, et al. An official European Respiratory Society/American 
Thoracic Society research statement: interstitial pneumonia with autoimmune features. Eur 
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Flechsig P, Dadrich M, Bickelhaupt S, et al. LY2109761 attenuates radiation-induced pulmonary 
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Hughes G, Toellner H, Morris H, et al. Real World Experiences: Pirfenidone and Nintedanib are 
Effective and Well Tolerated Treatments for Idiopathic Pulmonary Fibrosis. J Clin Med. 
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Hutchinson J, Fogarty A, Hubbard R, et al. Global incidence and mortality of idiopathic 
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King TE, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with 
idiopathic pulmonary fibrosis. The New England journal of medicine. 2014;370(22):2083-92.
Kistler KD, Nalysnyk L, Rotella P, et al. Lung transplantation in idiopathic pulmonary fibrosis: a 
systematic review of the literature. BMC Pulm Med. 2014;14:139. Epub 2014/08/16.
Lee HE, Myong JP, Kim HR, et al. Incidence and prevalence of idiopathic interstitial pneumonia 
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Lewandowska KB, Kus J, Zolnowska B, et al. Idiopathic pulmonary fibrosis (IPF) patients in 
Poland – preliminary cohort analysis of EMPIRE registry. Presented at the 2017 International 
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Ley B, Collard HR, King TE. Clinical course and prediction of survival in idiopathic pulmonary 
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Lynch JP, Huynh RH, Fishbein MC, et al. Idiopathic Pulmonary Fibrosis: Epidemiology, 
Clinical Features, Prognosis, and Management. Semin Respir Crit Care Med. 2016;37(3):331-57. 
Epub 2016/05/27.
Nalysnyk L, Cid-Ruzafa J, Rotella P, et al. Incidence and prevalence of idiopathic pulmonary 
fibrosis: review of the literature. Eur Respir Rev. 2012;21(126):355-61.
Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary 
fibrosis (CAPACITY): two randomised trials. Lancet. 2011;377(9779):1760-9. Epub 
2011/05/13.
Nintendanib Summary of Product Characteristics, 15 January 2015, Boehringer Ingelheim 
International GmbH
Pesonen I, Ferrara G, Skold M, et al. Idiopathic pulmonary fibrosis in Finland and Sweden: 
Differences in the performance of two similar health care systems. Presented at the 2017 
International Congress of the European Respiratory Society (ERS).


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Phase 2b Efficacy and Safety Study of BG00011
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
90
Puthawala K, Hadjiangelis N, Jacoby SC, et al. Inhibition of integrin alpha(v)beta6, an activator 
of latent transforming growth factor-beta, prevents radiation-induced lung fibrosis. American 
journal of respiratory and critical care medicine. 2008;177(1):82-90.
Raghu G, Chen SY, Yeh WS, et al. Idiopathic pulmonary fibrosis in US Medicare beneficiaries 
aged 65 years and older: incidence, prevalence, and survival, 2001-11. Lancet Respir Med. 
2014;2(7):566-72. Epub 2014/05/27.
Raghu G, Collard HR, Anstrom KJ, et al. Idiopathic pulmonary fibrosis: clinically meaningful 
primary endpoints in phase 3 clinical trials. American journal of respiratory and critical care 
medicine. 2012;185(10):1044-8. Epub 2012/04/13.
Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic 
pulmonary fibrosis: evidence-based guidelines for diagnosis and management. American journal 
of respiratory and critical care medicine. 2011;183(6):788-824.
Raimundo K, Chang E, Broder MS, et al. Clinical and economic burden of idiopathic pulmonary 
fibrosis: a retrospective cohort study. BMC Pulm Med. 2016;16:2. Epub 2016/01/05.
Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic 
pulmonary fibrosis. The New England journal of medicine. 2014;370(22):2071-82. Epub 
2014/05/18.
Sicras-Mainar A, Somiedo Gutiérrez MD, Navarro-Artieda R, et al. Use Of Healthcare 
Resources And Associated Costs Of Idiopathic Pulmonary Fibrosis In Spain: A Real-Life Study. 
Presented at the 20th Annual European Congress of the International Society for 
Pharmacoeconomics And Outcomes Research (ISPOR).
Song JW, Hong SB, Lim CM, et al. Acute exacerbation of idiopathic pulmonary fibrosis: 
incidence, risk factors and outcome. Eur Respir J. 2011;37(2):356-63. Epub 2010/07/01.
Swigris JJ, Gould MK, Wilson SR. Health-related quality of life among patients with idiopathic 
pulmonary fibrosis. Chest. 2005;127(1):284-94.
Torres Villacreses MI, Calero E, Cherrez A, et al. Management Patterns and Attitudes About IPF 
(Idiopathic Pulmonary Fibrosis) Among Pulmonologist and General Physicians in Latin 
America. Presented at the 113th International Conference of the American Thoracic Society 
(ATS).
Viscidi EV, Wang N, Hall SA, et al. Utilization of Pirfenidone and Nintedanib in Patients with 
Idiopathic Pulmonary Fibrosis: An Analysis of U.S. Claims Data. Presented at the International 
Conference on Pharmacoepidemiology and Therapeutic Risk Management; 2017; Montreal, 
Canada.
Wang DD, Zhang S, Zhao H, et al. Fixed dosing versus body size-based dosing of monoclonal 
antibodies in adult clinical trials. J Clin Pharmacol. 2009;49(9):1012-24.


Protocol 203PF203
Version 1
Phase 2b Efficacy and Safety Study of BG00011
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
91
Wuyts WA, Dahlqvist C, Slabbynk H, et al. Demographics and Healthcare Utilization of Patients 
with Idiopathic Pulmonary Fibrosis (IPF) in a Real-World Setting: Updated Findings from 277 
Patients in the PROOF Registry. Presented at the 113th International Conference of the 
American Thoracic Society (ATS).
 

SAP_001.pdf: 
Statistical Analysis Plan 
Study Number: 203PF203  
Statistical Analysis Plan 
Version No.: 1.0 
SPIRIT 
Statistical Analysis Plan
Version No.:  1.0 (12NOV2019) 
 Study Title: A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of BG00011 in Patients With Idiopathic Pulmonary Fibrosis 
Name of Study Treatment: BG00011 
Protocol No.: 203PF203 V1.0 (20NOV2017) / NCT03573505
Study Phase: Phase 2b 
Confidential Information 
The information contained in this Statistical Analysis Plan (SAP) is confidential and may 
not be reproduced or otherwise disseminated without the approval of Biogen, Inc.   




Statistical Analysis Plan 
 
Study Number: 203PF203   
Statistical Analysis Plan 
Version No.: 1.0 
 
Table of Contents 
LIST OF ABBREVIATIONS .................................................................................................................................... 5 
1 
INTRODUCTION ............................................................................................................................................. 6 
1.1 SCOPE OF WORK ......................................................................................................................................... 6 
1.2 TABLES, FIGURES AND LISTINGS ......................................................................................................... 6 
2 
STUDY OBJECTIVES AND ENDPOINTS.................................................................................................. 7 
3 
STUDY DESIGN.............................................................................................................................................. 10 
4 
SAMPLE SIZE JUSTIFICATION ............................................................................................................... 11 
5 
ANALYSIS POPULATIONS ........................................................................................................................ 12 
5.1 MODIFIED INTENT-TO-TREAT (MITT) POPULATION ................................................................................... 12 
5.2 SAFETY POPULATION .................................................................................................................................... 12 
5.3 IMMUNOGENICITY POPULATION.................................................................................................................... 12 
5.4 PHARMACOKINETIC (PK) POPULATION ........................................................................................................ 12 
6 
GENERAL ANALYSIS .................................................................................................................................. 13 
6.1 GENERAL CONSIDERATION ........................................................................................................................... 13 
6.1.1 
Analysis Visit and Study Day Definition......................................................................................... 13 
6.1.1.1 
Baseline...........................................................................................................................................13 
6.1.1.2 
Analysis Visit ..................................................................................................................................13 
6.1.1.3 
Study/Treatment Day .......................................................................................................................13 
6.1.1.4 
Early Termination or Unscheduled Visits for Acute Exacerbation of IPF ...........................................13 
6.2 SUBJECT DISPOSITION ................................................................................................................................... 15 
6.3 DEMOGRAPHY AND BASELINE DISEASE CHARACTERISTIC ......................................................................... 15 
6.3.1 
Summary of Demographic information .......................................................................................... 15 
6.3.2 
Baseline Disease Characteristics.................................................................................................... 15 
6.3.2.1 
GAP score .......................................................................................................................................15 
6.3.2.2 
Summary of Baseline Disease Characteristics ...................................................................................16 
6.4 CONCOMITANT THERAPY.............................................................................................................................. 16 
6.5 STUDY DRUG EXPOSURE AND STUDY DRUG COMPLIANCE ........................................................................ 17 
6.6 PROTOCOL DEVIATIONS ................................................................................................................................ 17 
6.7 MULTIPLICITY ADJUSTMENT ........................................................................................................................ 18 
7 
EFFICACY ANALYSIS ................................................................................................................................. 19 
7.1 GENERAL CONSIDERATIONS.......................................................................................................................... 19 
7.2 ANALYSIS OF PRIMARY ENDPOINT ............................................................................................................... 19 
7.2.1 
Primary Analysis .............................................................................................................................. 19 
7.2.2 
Supplementary Analysis ................................................................................................................... 20 
7.2.3 
Complementary Analysis ................................................................................................................. 21 
7.3 ANALYSIS OF SECONDARY EFFICACY ENDPOINTS ...................................................................................... 21 
7.3.1 
Analysis of Continuous Endpoints .................................................................................................. 21 
7.3.1.1 
Pulmonary Function Tests ................................................................................................................21 
7.3.1.2 
6-Minute Walk Test (6MWT)...........................................................................................................22 
7.3.2 
Analyses of Binary Endpoints.......................................................................................................... 22 
7.3.2.1 
IPF Acute Exacerbation....................................................................................................................22 
7.3.2.2 
Pulmonary Function Tests ................................................................................................................22 
7.3.3 
Analysis of Time-to-Event Endpoints.............................................................................................. 22 
7.3.3.1 
Composite endpoint .........................................................................................................................23 
7.3.3.2 
Other Time-to-Event endpoints.........................................................................................................23 
7.3.4 
Analysis of Other Endpoints ............................................................................................................ 23 
7.3.4.1 
Number of Occurrences....................................................................................................................23 
7.4 ANALYSIS OF EXPLORATORY EFFICACY ENDPOINTS .................................................................................. 24 
 
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8 
SAFETY ANALYSIS ...................................................................................................................................... 27 
8.1 GENERAL CONSIDERATION ........................................................................................................................... 27 
8.2 ANALYSIS OF ADVERSE EVENTS (AES)........................................................................................................ 27 
8.2.1 
Subgroup Analysis of AE ................................................................................................................. 28 
8.3 ANALYSIS OF LABORATORY TESTS .............................................................................................................. 29 
8.3.1 
Shift Analysis for Lab Tests ............................................................................................................. 30 
8.3.2 
Analysis of Clinically Significant Abnormalities ........................................................................... 30 
8.4 VITAL SIGNS .................................................................................................................................................. 31 
8.5 ELECTROCARDIOGRAM (ECG) ..................................................................................................................... 32 
8.6 PHYSICAL EXAMINATION .............................................................................................................................. 32 
8.7 IMMUNOGENICITY (ANTI-BG00011 ANTIBODIES) ...................................................................................... 32 
9 
PHARMACOKINETICS (PK) ANALYSIS................................................................................................ 34 
 
 
 
 
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REFERENCE ................................................................................................................................................... 36 
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Study Number: 203PF203   
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List of Abbreviations  
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance  
AST 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CI 
confidence interval 
CSR 
clinical study report 
CV 
coefficient of variation 
DLco 
carbon monoxide diffusion capacity 
DLco/Hb 
carbon monoxide diffusion capacity, corrected for hemoglobin 
DSMB 
Data Safety Monitoring Board 
EOT 
End of Treatment 
ECG 
electrocardiogram 
FEV1 
a ratio of the forced expiratory volume in one second 
FVC 
forced vital capacity 
Hb 
hemoglobin 
HRCT 
high resolution computed tomography 
ICH 
International Conference on Harmonization 
IPF 
idiopathic pulmonary fibrosis 
LDH 
lactate dehydrogenase 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
PFT 
pulmonary function test 
PK 
pharmacokinetic 
PT 
preferred term 
QLF 
quantitative lung fibrotic reticulation score 
qHC 
quantitative honeycomb 
qGG 
quantitative ground-glass 
RV 
residual volume 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous(ly) 
SD 
standard deviation 
SLB 
surgical lung biopsy 
SOC 
system organ class 
TEAE 
treatment emergent adverse event 
TFLs 
Tables, Figures, and Listings 
UIP 
usual interstitial pneumonia  


Statistical Analysis Plan 
 
Study Number: 203PF203   
Statistical Analysis Plan 
Version No.: 1.0 
 
 
 
1 INTRODUCTION 
The intent of this document is to provide guidance for analyses of data for this Phase 2b study. 
This statistical analysis plan (SAP) has been developed after review of the Clinical Study 
Protocol 203PF203 (version 1 dated 20NOV2017).  
On 16 August 2019, the BG00011 independent Data Safety and Monitoring Board (DSMB) met 
for a routinely scheduled bi-monthly meeting. During that meeting the DSMB recommended that 
study 203PF203 be stopped due to an imbalance in the prespecified safety composite endpoint. A 
separate unblinded team at Biogen has reviewed the data and accepted the DSMB 
recommendation. Because of the study early termination, the version 2 protocol dated on 02 
JULY 2019 was not implemented, it is not used as reference for developing this SAP. 
As the study was stopped early, all endpoints will be analyzed and summarized by descriptive 
statistics only with exception of primary and key secondary efficacy endpoints (i.e. Percent 
Predicted FVC, Absolute DLco corrected for hemoglobin and Percent Predicted Absolute DLco 
corrected for hemoglobin). The safety data will be analyzed in full. This version 1.0 SAP 
supersedes the statistical considerations identified in the protocol. 
1.1 SCOPE OF WORK 
This statistical analysis plan (SAP) covers the analyses includes all available subjects who 
enrolled in the study before the early termination due to the urgent safety measure.   
All analyses of efficacy, safety, PK and exploratory endpoints described in this plan will be 
included in the final analysis. 
The final analysis will employ a two-part database lock, with unblinding occurring after Part I 
data are available. The details of unblinding at the end of study is documented in the unblinding 
plan version 1.2 dated on 07NOV2019. The SAP will be finalized prior to the lock of Part I data.  
No changes to the SAP post finalization are expected. However, if any changes are necessary, 
the SAP will be updated to a new version with all revisions documented. 
1.2 TABLES, FIGURES AND LISTINGS  
A detailed description of the planned Tables, Figures, and Listings (TFLs) to be presented in the 
clinical study report (CSR) is provided in the accompanying TFLs shell document. When the 
SAP and TFL shells are agreed upon and finalized, they will serve as the template for this 
study’s CSR. 
 


Statistical Analysis Plan 
 
Study Number: 203PF203   
Statistical Analysis Plan 
Version No.: 1.0 
 
2 STUDY OBJECTIVES AND ENDPOINTS 
Primary Objective 
Primary Endpoints 
To evaluate the efficacy of BG00011 
compared with placebo in subjects with IPF. 
Yearly rate of change in forced vital capacity 
(FVC, expressed in mL over 52 weeks) in 
subjects randomized to BG00011 compared 
with placebo. 
Secondary Objectives 
Secondary Endpoints 
To evaluate the efficacy of BG00011 
compared with placebo in subjects with IPF 
as determined by change in percent predicted 
FVC. 
Yearly rate of change in FVC, expressed in 
percent predicted, over 52 weeks. 
To assess progression-free survival in 
subjects who receive BG00011 compared 
with placebo. 
Time to progression, as defined by a 
composite endpoint, including any of the 
following events: 
• Absolute decline of 10% predicted in FVC 
(FVC percent predictedbaseline – FVC 
percent predictedprogression  ≥10%). 
• Nonelective hospitalization for respiratory 
events.  
• Lung transplantation or death. 
To assess the occurrence of IPF exacerbation 
(using modified diagnostic criteria for acute 
IPF exacerbation derived from [Collard 
2007]) in subjects who receive BG00011 
compared with placebo.   
• Time to first acute exacerbation, measured 
in days. 
• Proportion of subjects with at least 1 acute 
exacerbation during the 52 weeks on 
study. 
• Number of exacerbations during 52 
weeks. 
To assess the incidence of absolute decline in 
FVC ≥10% in subjects who receive BG00011 
compared with placebo.  
Number of subjects with absolute decline of 
10% predicted in FVC (FVC percent 
predictedbaseline – FVC percent 
predictedprogression ≥10%) over 52 weeks. 
To assess the time to death or lung 
transplantation in subjects who receive 
BG00011 compared with placebo, and the 
transplant-free survival rate at Week 26 and 
Week 52. 
Time to death or lung transplantation, 
measured in days. 


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To assess the time to nonelective 
hospitalizations in subjects who receive 
BG00011 compared with placebo, 
Time to all nonelective hospitalizations and to 
nonelective respiratory hospitalizations, 
measured in days. 
To assess additional PFT findings in subjects 
who receive BG00011 compared with 
placebo.  
• Change in absolute and percent predicted 
FVC from baseline over time. 
• Carbon monoxide diffusion capacity 
(DLco), absolute and percent predicted 
changes from baseline over time. 
• Total lung capacity, as measured by 
plethysmography, absolute and percent 
predicted changes from baseline over 
time. 
To assess performance on the 6MWT in 
subjects who receive BG00011 compared 
with placebo. 
Change from baseline in 6MWT parameters at 
Weeks 26 and 52. 
To evaluate the safety and tolerability of 
BG00011. 
• The incidence, severity, outcome, and 
relationship to study treatment of AEs and 
SAEs. 
• Change from baseline in clinical 
laboratory test results, vital signs, ECG, 
PFT results, and HRCT findings.  
• Immunogenicity (antibodies to BG00011). 
To evaluate the serum concentration of 
BG00011. 
Measurement of BG00011 serum 
concentrations using sparse PK sample 
collection at select timepoints during the 
study.  
Exploratory Objectives 
Exploratory Endpoints 
 
 
 
 
 
 
 
 
 
 


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Statistical Analysis Plan 
 
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Statistical Analysis Plan 
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3 STUDY DESIGN 
This is a Phase 2b randomized, double-blind, placebo-controlled study designed to evaluate the 
efficacy, safety, PK, and tolerability of BG00011 in subjects with IPF. Approximately 290 
subjects who meet inclusion/exclusion criteria will be stratified by background therapy status 
(subjects receiving background therapy and subjects not receiving background therapy) and 
randomized in a 1:1 ratio of BG00011 to placebo (Error! Reference source not found. of the 
protocol).   
Subjects will receive weekly injections of BG00011 or placebo for 52 consecutive weeks (a total 
of 52 doses).  Study duration for an individual subject is approximately 65 weeks, including a 
Screening Visit up to 5 weeks prior to the first dose of study treatment, a Placebo-Controlled 
Treatment Period of 52 weeks, and a Safety Follow-Up Visit 8 weeks after the end of the 
Treatment Period. 
A schematic of the study design is provided in Figure 1. Additional details on the study design 
and the schedule of study assessment is provided in the full protocol. Due to the early 
termination of the study, no interim analysis will be performed. This change supersedes the 
interim analysis planned in the schematic of the study design in the protocol. 
Figure 1: Schematic for Study 203PF203 
 
 
 
   Week 52 
       Placebo-Controlled Treatment Period 
         Week 60 
Safety 
Follow-Up 
Visit 
 
Screening 
Period 
≤35 days 
prior to 
Baseline 
Baseline
End of Study 
 
Stratification by use or non-use of background therapy and 
Randomization 1:1 to BG00011 or placebo:  
 
Stratum 1 – Not on background therapy (~145 subjects) 

Placebo (~50% of stratum) 

BG00011 (~50% of stratum) 
 
Stratum 2 – On background therapy (~145 subjects) 

Placebo (~50% of stratum) 

BG00011 (~50% of stratum) 
 
         
Safety 
Follow Up 
Period 
Interim Analysis 
To be performed when 
50% of subjects have 
reached Week 52 
(~122 subjects, 
accounting for 
estimated dropouts) 


 
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Statistical Analysis Plan 
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4 SAMPLE SIZE JUSTIFICATION 
The sample size calculation is based on the annual declining rate in FVC (mL/year).  With 145 
subjects randomized per arm, and assuming a 15% dropout rate over a 1-year treatment period, 
the study has approximately 80% power to show that the BG00011 treatment arms differentiate 
from the arm without BG00011 at a 2-sided 15% α level, given a treatment effect of 
82.5 mL/year with a common standard deviation of 280 mL.  The calculation is based on the 
assumption that the FVC decline rate in subjects receiving placebo and no background therapy is 
220 mL/year, and in subjects receiving background but no BG00011 therapy it is assumed to be 
110 mL/year.  A 60% reduction in the FVC decline rate in the subjects receiving placebo would 
be a treatment effect of 132 mL/year.  A 30% reduction in the FVC decline rate in subjects 
receiving background therapy would be a treatment effect of 33 mL/year.  With the assumption 
that 50% of each type of subject are randomized in the study, the combined treatment effect is 
approximately 82.5 mL/year.  The 15% dropout rate for this study was estimated based on prior 
experience for the placebo arms in the Phase 3 studies for nintedanib and pirfenidone [King 
2014; Richeldi 2014]. 


 
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5 ANALYSIS POPULATIONS  
5.1 Modified Intent-to-Treat (MITT) Population  
The modified intent-to-treatment (MITT) population will include all subjects who are 
randomized and receive at least 1 dose of study treatment (BG00011 or placebo). Subject will be 
analyzed by randomized treatment, even if the subject did not receive the assigned treatment or 
did not follow the protocol until completion. The definition of MITT population is same as the 
intent-to-treat (ITT) population stated in the protocol.  
5.2 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. 
5.3 Immunogenicity population  
The analysis population for immunogenicity is defined as all MITT subjects who have at least 1 
postdose immunogenicity sample evaluated for anti-BG00011 antibodies and whose pre-dose 
anti-BG00011 samples are screened negative at baseline (Day 0) visit. 
5.4 Pharmacokinetic (PK) population  
The pharmacokinetic (PK) population will include all safety subjects who have at least one PK 
concentration measurement. Subjects will be analyzed by the actual treatment received.  


 
Statistical Analysis Plan 
 
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Statistical Analysis Plan 
Version No.: 1.0 
 
6 General Analysis 
6.1 General Consideration  
Data listings will be provided by treatment group, subjects and visits, if applicable. Summary 
statistics and statistical analyses will only be presented for data where detailed in this SAP and 
will generally only be performed for subjects included in the relevant analysis population. Unless 
otherwise specified, all variables will be summarized for the MITT population. 
Summary statistics will be presented throughout for all endpoints at all visits including follow-up 
visits. For continuous variables, summary statistics will generally include number of subjects 
with data, mean, standard deviation (SD), median, minimum and maximum. In addition, the 95% 
confidence interval (CI) for the mean will be presented. For log-normal data the geometric mean and 
geometric coefficient of variation (CV) will also be presented. For categorical endpoints, 
summary statistics will generally include number and percentage of subjects with data in each 
category. 
The statistical software, SAS®, will be used for all summaries and statistical analyses.  
6.1.1 Analysis Visit and Study Day Definition 
6.1.1.1 Baseline 
Unless stated otherwise, baseline value is defined as the data collected prior to the time and/or on 
the date of first dose, which is usually the same day as the Baseline visit (Day 0). If there is more 
than one value on/before the date of the first dose, the non-missing value closest to the first dose 
will be used as the baseline value. 
6.1.1.2 Analysis Visit 
Observations that are collected after the first randomized dose as scheduled visit will be used to 
the corresponding analysis week. 
6.1.1.3 Study/Treatment Day 
To facilitate the analysis of the data in the treatment period (TP), study/treatment day 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 study/treatment day 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 study/treatment day is a negative value and will be calculated as (date of 
study day – date of the first randomized dose). The study starts at study/treatment day 1. 
6.1.1.4 Early Termination or Unscheduled Visits for Acute Exacerbation of IPF 
In general, when data are summarized by analysis visit, the Early Termination Visit or 
Unscheduled Visits for Acute Exacerbation of IPF will be assigned to an appropriate scheduled 
analysis visit by using a window scheme provided in Table 1.  


 
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Statistical Analysis Plan 
Version No.: 1.0 
 
Table 1: Visit Windows for Early Termination or Unscheduled Visits 
Scheduled 
Visit Time 
Target 
study  
day 
Analysis visit window (days) 
Efficacy & Safety 
Data 
PK Data 
Baseline (Day 
0) 
1 
Most recent non-missing value on/before the date of first dose 
Day 5* 
6 
N/A 
[6,7] 
Week 4 
29 
[2,43] 
[8,43] 
Week 8 
57 
[44,71] 
Week 12 
85 
[72,99] 
Week 16 
113 
[100,127] 
Week 20 
141 
[128,162] 
Week 26 
183 
[163,203] 
Week 32 
225 
[204,246] 
Week 38 
267 
[247,288] 
Week 44 
309 
[289,337] 
Week 52 
365 
[338,393] 
Safety 
Follow-up 
(Week 60) 
421 
• If subject who discontinued treatment due to reasons other 
than study termination by sponsor:  
> min (393, study day of each subject’s week 52/EOT visit in 
treatment period) **  
• If subject who discontinued treatment due to study early 
termination by sponsor:  
> min (393, study day of each subject’s last dose)  
*The Day 5 Visit is for blood collection only (for PK analysis) and may be done in the clinic or at home (by appropriate 
personnel). Sample collection should occur on Day 5 (not sooner), with a +1 day window allowed (i.e., collection should occur  
on Day 5 but may occur on Day 6). 
** For subjects who discontinued the treatment due to reasons other than study termination by sponsor will go on to complete all 
scheduled visits until either week 52 or the study was terminated by sponsor due to the urgent safety measure whichever occurs 
first. The Week 52/ EOT visit in treatment period is defined as the last visit scheduled for either week 52 or study termination due 
to the urgent safety measure.  
 


 
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The lower bound and the upper bound for the visit windows are defined as the midpoints of the 
scheduled visits. If the date and time from early termination visit or unscheduled visit for acute 
exacerbation 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/earliest assessment will be used. 
6.2 Subject Disposition 
The number and percentage of subjects who were randomized, dosed, randomized but not dosed, 
completed the study, discontinued study treatment (including reasons for discontinuation, 
specified in Sections 7.2.4) and withdrew from the study (including reasons for withdrawal, 
specified in Sections 7.2.5) will be summarized by treatment group and overall. The subject 
disposition will be summarized for the MITT and safety populations. If the safety population is 
the same as MITT population (i.e. all subjects receive their randomized treatment), the subject 
disposition will be summarized for MITT population only.  
Additionally, a listing of subjects who discontinued treatment and/or withdrew from study and 
the associated reasons for discontinuation/withdrawal will be provided. 
The number and percentage of subjects in each background stratum, treatment group and overall 
will be summarized for the MITT and safety populations. If the safety population is the same as 
MITT population, summary will only be presented for MITT population.  
6.3 Demography and Baseline Disease Characteristic 
6.3.1 Summary of Demographic information 
The demographic information of age, gender, ethnicity, race, height, weight, and body mass 
index (BMI) at baseline will be summarized by treatment group and overall. In addition, the 
associated listing will be provided. The demographic 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. 
6.3.2 Baseline Disease Characteristics 
6.3.2.1 GAP score 
As a disease characteristic, GAP score [Ley 2012] is an 8-point score (0-8) and calculated from 
age, gender, baseline percent predicted FVC and percent predicted DLco corrected for 
hemoglobin (DLco/Hb) at baseline visit. The calculation is described in Table 2 as follows.  
Table 2: GAP Score Calculation 
 
Calculation 
Gender 
• If female, add 0 point.  


 
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• If male, add 1 point. 
Age 
• If Age ≤60, add 0 point 
• If 61 ≤Age ≤65, add 1 point 
• If Age > 65, add 2 points 
Baseline percent (%) 
predicted FVC 
• If % predicted FVC > 75, add 0 point 
• If 50≤ % predicted FVC ≤75, add 1 point 
• If % predicted FVC < 50, add 2 points 
Percent (%) predicted 
DLco/Hb at baseline visit 
• If % predicted DLco/Hb > 55, add 0 point 
• If 36≤ % predicted DLco/Hb ≤55, add 1 point 
• If % predicted DLco/Hb ≤35, add 2 points 
• If DLCO cannot be performed at baseline visit, add 3 
points. If the % predicted DLco/Hb is missing due to 
the unacceptable values through the ERT best test 
review (BTR) quality control process or hemoglobin 
missing, the defined baseline % predicted DLco/Hb, 
the latest non-missing % predicted DLco/Hb before 
first dosing, will be applied.  
6.3.2.2  Summary of Baseline Disease Characteristics  
Baseline disease characteristics information of ex-smoker status, randomization stratum (on/off 
background therapy), region, GAP score, GAP score category (0-3, 4-5 and 6-8), FVC (mL), 
percent predicted FVC (%), forced expiratory volume over 1 second (FEV1 , L),  FEV1/FVC, 
absolute DLco corrected for hemoglobin (DLco/Hb, mL/min/mmHG), percent Predicted DLco/Hb 
(%), total lung capacity (TLC, L), residual volume (RV, L) will be summarized by treatment 
group and overall. 
The baseline characteristics will be summarized for the MITT population only – note that if the 
safety population differs from the MITT population, then the summaries will be repeated for the 
safety population. 
6.4 Concomitant Therapy 
A concomitant therapy is any drug or substance administered between the time a subject is 
screened for the study and the final study visit. 
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, then the therapy will be 
considered concomitant; 
• If the start date is missing and the stop date of the therapy falls on/after the screening 
visit, then the therapy will be considered concomitant; 


 
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• If the start date of a therapy is prior to the date of the screening and the stop date of the 
therapy is missing and the therapy is listed as ongoing, that therapy will be considered 
concomitant; 
• If the start date of a therapy is prior to the date of screening and the stop date of that 
therapy is missing and the therapy is not listed as ongoing, that therapy will be considered 
non-concomitant. 
For a record with a partial start/end date, the year/month of the partial date will be compared to 
screening to determine whether it is concomitant. 
All concomitant medications will be coded using the World Health Organization (WHO) 
medication dictionary. All concomitant non-drug treatments will be coded using the MedDRA 
dictionary.   
The number and percent of subjects taking concomitant medication, non-drug treatments will be 
summarized by treatment group.  
6.5 Study Drug Exposure and Study Drug Compliance 
Number of weeks on study treatment (BG00011 or placebo), calculated as  
Duration of treatment exposure (weeks) = (date of the last dose – date of the first dose +1)/7, 
will be summarized as a categorical variable with the following cumulative duration of exposure 
categories: at least 4, 8, 12, 16, 20, 26, 32, 38, 44, 52 weeks.  
In addition, the duration of treatment exposure (weeks) will be summarized as continuous 
variable with summary statistics. 
The first dose of BG00011 or placebo (study treatment) will be administered at the study site 
during the Baseline Visit. All subsequent doses should be administered by the subject or the 
subject’s caregiver. Compliance with study treatment dosing is to be documented by the subject 
or the subject’s caregiver in the electronic study diary and monitored at each study visit by study 
site personnel. 
Overall compliance for each subject will be assessed based on the dosing recorded in the 
electronic study diary along with the first dose recorded in the eCRF. The compliance will be 
calculated and summarized as a continuous variable for each treatment group and background 
status. The compliance will be calculated using the following formula:  
Percent Compliance = (actual number of doses administered)/(number of doses expected to be 
administered) *100 
For all subjects who did not reach week 52 visits whether due to the study early termination 
and/or treatment discontinuation, “number of doses expected” will be relative to the time of 
discontinuation. 
6.6 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 


 
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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 by background therapy status and treatment group.  
6.7 Multiplicity Adjustment  
No multiple comparison adjustments are planned and all inferential analyses performed will be 
interpreted nominally. 
 


 
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7 Efficacy Analysis 
7.1 General considerations 
All efficacy analyses will be performed on the MITT population, unless otherwise specified. For 
each endpoint, additional conditions may apply to the definition of the population for the 
analysis. Subjects will be analyzed in the groups to which they were randomized.  
7.2 Analysis of Primary Endpoint 
7.2.1 Primary Analysis 
The estimand of the primary analysis is the mean difference of the change from baseline in FVC 
(expressed in mL, at each week 26 or week 38) between treatment and placebo group in the 
MITT population [ICH E9 (R1) Addendum 2014, 2017]. Data will be censored when subject 
experienced intercurrent event (i.e. death and/or lung transplantation and/or treatment 
discontinuation) and prematurely discontinue the study treatment. The estimate of this analysis 
reflects the treatment effect of BG00011 if the drug were taken as directed [de jure efficacy 
estimand].  
Due to the study early termination, the estimand will assess the mean difference of the change 
from baseline in FVC (mL) at week 26 and 38 based on the data availability and visit times of 
interest. Both change from baseline in FVC (mL) at weeks 26 and 38 are the continuous 
secondary efficacy endpoints. If less than 20 subjects (i.e. <20 subjects) had non-missing 
measurements at either visit time of interest, the mean difference comparison will not be 
performed at that visit time due to the insufficient data.   
A random coefficients linear regression model will be used as the primary analysis where the 
change from baseline in FVC (mL) is the outcome variable assuming linear decline in lung 
function over time. The model will include random coefficients for intercept and slope (time), 
and fixed-effect terms for treatment, randomization stratum (background therapy), age, and 
baseline FVC along with treatment-by-time interaction and background therapy status-by-time 
interaction. In this model, time is considered as a continuous variable. 
An unstructured variance covariance structure will be used to model the within-patient 
measurements variability. If the unstructured covariance structure matrix results in a lack of 
convergence, first-order autoregressive, AR(1), covariance structure will be used. The Kenward-
Roger approximation will be used to estimate the denominator degrees of freedom.  
If a subject who experiences unscheduled visit(s) for acute exacerbation of IPF and has non-
missing FVC measurement(s), those unscheduled FVC measurement(s) will be included in the 
primary analysis.   
In the primary analysis, missing data are assumed to be missing at random (MAR) [Rubin 1976]. 
For subjects who experienced intercurrent event (i.e. death and/or lung transplantation and/or 
treatment discontinuation), subject’s post intercurrent event data will be censored and then 
imputed based on individual’s estimated rate of worsening of lung function prior to treatment 
discontinuation, similar to linear extrapolation because of the linear assumption of the statistical 
model.  


 
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7.2.2 Supplementary Analysis 
A mixed model of repeated measures (MMRM) model will be used as supplementary analyses to 
analyse the change from baseline in FVC using the same fixed effects, for treatment, 
randomization stratum (background therapy), age, and baseline FVC along with treatment-by-
time interaction and background therapy status-by-time interaction, as in the random coefficients 
linear regression model. MMRM assume a nonlinear decline in lung function over time. An 
unstructured variance covariance structure, same as used in the primary analysis, will be used to 
model the within-patient measurements variability. If the unstructured covariance structure 
matrix results in a lack of convergence, first-order autoregressive, AR(1), covariance structure 
will be used. The Kenward-Roger approximation will be used to estimate the denominator 
degrees of freedom.  
The comparison will be conducted to evaluate the treatment difference in absolute FVC at week 
26 and 38 between BG00011 cohort versus placebo cohort, respectively.  
• If a subject who experiences unscheduled visit(s) for acute exacerbation of IPF and has 
non-missing FVC measurement(s), such unscheduled FVC measurement(s) may be 
included in the analysis by using the follow rule. 
• If the unscheduled FVC measurement is between 2 consecutives post-baseline scheduled 
visits with both FVC measurements non-missing, the unscheduled FVC measurement(s) 
will not be included in the model. If more than one unscheduled FVC measurements are 
between the same visit window (between the same 2 consecutives post-baseline 
scheduled visits), all unscheduled FVC measurements will not be included in the model.    
• If the unscheduled FVC measurement is between 2 consecutives post-baseline scheduled 
visits with one of the two FVC measurements missing, the unscheduled FVC 
measurement will be included in the model and imputed as the schedule visit with 
missing FVC value. If more than one unscheduled FVC measurements are between the 
same visit window, the unscheduled FVC measurement which is closest to the scheduled 
visit with missing FVC measurement will be included in the model and imputed as the 
schedule visit with missing FVC value.  
• If the unscheduled FVC measurement is between 2 consecutives post-baseline scheduled 
visits with FVC measurements missing at both visits, the unscheduled FVC measurement 
will be included in the model and imputed to the scheduled visit which is closer to the 
unscheduled visit. If the unscheduled visit is in the middle of the 2 schedule visits, the 
unscheduled FVC measurement will be included in the model and imputed to the earlier 
scheduled visit. If more than one unscheduled FVC measurements are between the same 
visit window, the earliest unscheduled FVC measurement and the latest unscheduled 
FVC in the same visit window will be included in the model and the earliest unscheduled 
FVC measurement will be imputed to the earlier scheduled visit and the latest 
unscheduled FVC measurement will be imputed to the later scheduled visit. 
Since the study stops early, Table 1 will be applied to define the visit window for FVC 
measurement at the early termination visit.   


 
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7.2.3 Complementary Analysis 
The estimand of this complementary analysis is the mean difference of the change from baseline 
in FVC (expressed in mL over 52 weeks, i.e. mL/year) between treatment and placebo group in 
the MITT. All observed on-treatment and the retrieved dropout data including those collected 
after experienced intercurrent event (i.e. death and/or lung transplantation and/or treatment 
discontinuation) and prematurely discontinue the study treatment will be applied as observed, no 
imputation will be implemented  [ICH E9 (R1) Addendum 2017]. The estimate of this analysis 
reflects the treatment effect of BG00011 seen as actually taken [de facto effectiveness estimand]. 
All data after intercurrent events are included, the same random coefficients linear regression 
model described in Section 7.2.1 will be applied. In this complementary analysis, missing data 
are assumed to be missing at random [Rubin 1976] and no imputation will be applied. 
Similar to the primary analysis, the complementary analysis will be evaluated at week 26 and 
week 38, respectively.  
7.3 Analysis of Secondary Efficacy Endpoints 
7.3.1 Analysis of Continuous Endpoints 
7.3.1.1 Pulmonary Function Tests  
The continuous secondary efficacy endpoint of change from baseline in percent predicted FVC, 
at week 26 and week 38 will be applied using the primary analysis, supplementary analysis and 
complementary analysis described in Section 7.2.   
The continuous secondary efficacy endpoints listed as follows will be applied using MMRM 
model described in Section 7.2.2. Similarly, if less than 20 subjects (i.e. <20 subjects) had non-
missing measurements for any endpoint at a given visit time of interest, the mean difference 
comparison will not be performed at that visit time for that endpoint due to the insufficient data.   
• Change from baseline in DLco, corrected for hemoglobin (DLco/Hb) at weeks 26 and 38, 
respectively.  
• Change from baseline in percent (%) predicted DLco /Hb at weeks 26 and 38, 
respectively. 
• Change from baseline in TLC at weeks 26 
• Change from baseline in percent (%) predicted TLC at weeks 26 
Because the study stopped early, the following continuous secondary efficacy endpoints could 
not be evaluated with insufficient data. 
• Changes from baseline in percent (%) predicted FVC over 52 weeks 
• Changes from baseline in DLco/Hb absolute over 52 weeks. 
• Changes from baseline in percent (%) predict DLco/Hb over 52 weeks.  
• Changes from baseline in total lung capacity (TLC), as measured by plethysmography, 
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• Changes from baseline in percent (%) predicted TLC over 52 weeks. 
All the continuous secondary endpoints listed below will be summarized by descriptive statistics 
at each scheduled visit time. The measurement and change from baseline will be presented. Plots 
of mean value with standard error for each of the following continuous secondary endpoints at 
each visit will also be presented. 
• FVC 
• Percent (%) predicted FVC 
• DLco/Hb 
• Percent (%) predicted DLco/Hb 
• Total lung capacity (TLC), as measured by plethysmography 
• Percent (%) predicted TLC 
7.3.1.2 6-Minute Walk Test (6MWT)  
6MWT distance and change from baseline in 6MWT distance will be summarized and presented 
by descriptive statistics at each scheduled visit time.  
7.3.2 Analyses of Binary Endpoints 
The non-responder imputation (NRI) approach will be applied for all binary endpoints, unless 
otherwise specified. Subjects who discontinued treatment will be classified as non-responders for 
all the visits following treatment discontinuation. 
The odds ratio (OR), relative risk (RR) and absolute risk reduction (ARR) with their confidence 
interval and associated p-value for BG00011 compared to placebo will be presented. 
7.3.2.1 IPF Acute Exacerbation  
The secondary efficacy endpoint, proportion of subjects with at least 1 acute exacerbation (using 
modified diagnostic criteria for acute IPF exacerbation derived from [Collar 2007]) during the 52 
weeks on study, will be analyzed using the binary endpoint analyses described in Section 7.3.2.  
7.3.2.2 Pulmonary Function Tests 
The secondary efficacy endpoint, number of subjects with absolute decline of 10% predicted in 
FVC (i.e. FVC percent predictedbaseline −FVC percent predictedprogression ≥10%) over 52 
weeks will be analyzed using the binary endpoint analyses described in Section 7.3.2. Subject 
with absolute decline of 10% predicted in FVC at any scheduled visits will be considered as 
subject with absolute decline of 10% predicted in FVC regardless whether the percent predicted 
FVC decline is less than 10% afterward and before the study early termination.  
7.3.3 Analysis of Time-to-Event Endpoints 


 
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The time-to-event endpoints will be analyzed using survival analyses methods. The Kaplan-
Meier curve and number of subjects at risk at each visit will be presented. The proportion of 
subjects who progressed in each treatment group will be summarized.   
Time to event will be analyzed by a cox proportional hazards model with terms for treatment 
(BG00011 vs. placebo) and randomization stratification factor. A stratified log-rank test will be 
used to compare the 2 treatment groups using randomization stratus as the stratification factor. 
The progression will be summarized descriptively for each stratum.     
Censoring rules will be applied for all time-to-event endpoints, unless otherwise specified. 
Subjects who do not experience an event by 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. If a subject who was not on background therapy at randomization 
initiate treatment with background therapy during the study, the study will be censored at the 
time of new background therapy initiation. If a subject who was on background therapy at 
randomization stop background therapy during the study, the study will be censored at the time 
of the background therapy stopped. 
7.3.3.1 Composite endpoint 
The secondary efficacy endpoint, time to progression defined as a composite endpoint will be 
analyzed using the method described in Section 7.3.3. The composite endpoint is defined by 
including any of the following events.  
• Absolute decline of 10% predicted in FVC (i.e. FVC percent predictedbaseline −
FVC percent predictedprogression ≥10%) 
• Nonelective hospitalization for respiratory events 
• Lung transplantation or death 
7.3.3.2 Other Time-to-Event endpoints 
The time-to-event types secondary efficacy endpoints listed as follows will be applied only by 
the Kaplan-Meier curve method where number of subjects at risk at each visit and the proportion 
of subjects who progressed in each treatment group will be summarized and presented.   
• Time to first acute exacerbation (using modified diagnostic criteria for acute IPF 
exacerbation derived from [Collar 2007]), measured in days. 
• Time to death or lung transplantation measured in days. 
• Time to all nonelective hospitalizations, measured in days. 
• Time to all nonelective respiratory hospitalizations, measured in days. 
7.3.4  Analysis of Other Endpoints 
7.3.4.1 Number of Occurrences 


 
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The secondary efficacy endpoint, number of exacerbations during 52 weeks, defined by using the 
2007 modified diagnostic criteria [Collard 2007], a listing will be provided if less than 4 subjects 
in each treatment group in which each subject experiences more than one exacerbation during the 
study period. If no fewer than 4 subjects in either treatment group in which each subject 
experience more than one exacerbation during the study period, a table of summary descriptive 
statistics will be provided with its associated listing.  
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8 Safety Analysis 
8.1 General Consideration 
All safety analyses will be performed for the safety population unless otherwise specified. No 
statistical testing will be performed on the safety data.  
8.2 Analysis of Adverse Events (AEs) 
All AEs will be coded by system organ class and preferred term using the Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary (Version 22.0). In this study, all AEs will be 
analyzed based on the principle of treatment emergence. Therefore, whenever an analysis of 
summary of AEs is mentioned, it is intended that this is in reference to treatment emergence AEs 
(TEAEs). A TEAE is defined as an AE that has an onset date on or after the date of first dosing, 
or if it was present prior to the first dose and subsequently worsened until last follow up visit.   
To define treatment emergence for AEs with missing start or stop date or time the following 
additional criteria will be used: 
• if both the start and stop dates for an AE are missing, then this AE is considered 
treatment emergent; 
• if the start date for an AE is missing and the stop date/time falls after the first dose 
date/time, then this AE is considered treatment emergent; 
• if the start date for an AE was the same as the first dose date, and the start time was 
missing, then that event is considered treatment emergent. 
For AEs with a partial start date, the year/month of the event date will be compared to that of the 
first dosing date to determine whether the event is treatment emergent. 
Overall TEAE summary table will include the number of subjects with any TEAE, the number of 
subjects with any TEAE by maximum severity (mild, moderate, severe), the number of subjects 
with any related TEAE, the number of subjects with Serious adverse events (SAE), the number 
of subjects with related SAE, the number of subjects with TEAE leading to withdrawal of study 
drug, the number of subjects with TEAE leading to study withdrawal, and the number of deaths. 
The overall TEAE summary table will be provided for all subjects in the safety population and 
for subjects in each randomization stratification factor.   
Incidence is defined as the number of subjects who experienced an event and each subject will be 
counted only once within each category. Therefore, to count the number of subjects who 
experience TEAEs within each preferred term (PT), a subject experiencing the same TEAE 
multiple times will only be counted once for that PT. Similarly, if a subject experience multiple 
TEAEs within the same system organ class (SOC), that subject will be counted only once for that 
SOC category. For subjects experiencing the same AE more than once within a same SOC and 
PT, that subject will be counted only once at the maximum severity in the calculation of 
incidence by severity.  
Incidence proportion (i.e. percentage, %) is defined as the number of subjects who experienced 
an event divided by total number of subjects in the analysis population times 100. 


 
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The following incidence tables of TEAEs will be presented. The Incidence and incidence 
proportion will be provided in the incidence tables. The sorting order for TEAE incidence tables, 
unless otherwise specified, will be by decreasing frequency order of total column within each 
category. For the table of TEAEs by SOC and PT sorted by decreasing frequency presented by 
treatment group, SOCs will be presented in decreasing frequency order of total column, and 
within each SOC, PTs will be presented in decreasing frequency order of total column.  
• TEAEs by SOC and PT sorted by decreasing frequency  
• TEAEs by SOC and PT sorted by alphabetical order 
• TEAEs at least 5% higher in incidence by SOC and PT for BG00011 compared to 
placebo 
• TEAEs by PT 
• TEAEs by PT with an incidence of 5% or more in any treatment group 
• Severe TEAEs by SOC and PT 
• Severe TEAEs by PT 
• TEAEs by maximum severity by SOC and PT 
• TEAEs by maximum severity by PT 
• Related TEAEs by SOC and PT 
• SAE by SOC and PT 
• SAE by PT 
• Related SAE by SOC and PT 
• TEAEs that led to discontinuation of study drug by SOC and PT 
• TEAEs that led to withdrawal from study by SOC and PT 
• Incidence rates of TEAEs by SOC and PT 
• Suspected unexpected serious adverse reactions (SUSAR) by SOC and PT 
The following listings will be provided: 
• Listing of all TEAEs 
• Listing of SAEs 
• Listing of TEAEs that led to discontinuation of study drug 
• Listing of TEAEs that led to withdrawal from study 
• Listing of deaths 
8.2.1 Subgroup Analysis of AE 
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• Regions (Australia, Asia, Europe, North America, South America) 
• Usage of background therapy: Nintedanib or Pirfenidone.  
The following incidence tables will be presented by pre-defined subgroups using the same 
methods as mentioned in Section 8.2.   
• SAE by SOC and PT by region 
• SAE by PT by region 
• SAE by SOC and PT by usage of background therapy 
• SAE by PT by usage of background therapy 
The region and background therapy (Nintedanib or Pirfenidone) will also be including in the 
following listings. 
• Listing of SAEs  
• Listing of AE of exacerbation 
8.3 Analysis of Laboratory Tests 
The following laboratory safety assessments will be conducted: 
• Hematology: complete blood count (CBC) including red blood cell count, white blood 
cell counts with differentials (neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils), hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular 
hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC). 
• Serum chemistry: albumin, alkaline phosphatase, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), blood urea nitrogen (BUN), calcium, chloride, carbon 
dioxide, creatinine, direct bilirubin, gamma-glutamyl transpeptidase, glucose, lactate 
dehydrogenase (LDH), phosphorus, potassium, sodium, total bilirubin, total protein  
• Urinalysis: including urine protein, glucose, ketones, occult blood, and white blood cells 
by dipstick, with microscopic examination if indicated  
The clinical laboratory parameters include safety assessment listed above will be summarized by 
treatment group and visit. Descriptive statistics will be presented for continuous variables at each 
visit by treatment group, including number of subjects, mean, standard deviation, median, 25%, 
75% quartiles, minimum, and maximum values. Plots of mean value with standard error for 
numeric laboratory parameters at each visit will be presented. For categorical endpoints, 
summary statistics will be presented at each visit by treatment group include number and 
percentage of subjects with data in each category. 
Changes from baseline and percent changes from baseline in quantitative laboratory values will 
be summarized using descriptive statistics by treatment group and visit.  
The clinical laboratory parameters by worst post-baseline grade will be provided for all safety 
assessment. The worst post-baseline cumulative grade will be provided for the safety 
assessments for Hematology and Urinalysis.  


 
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Individual subject listings of clinical laboratory parameters at each visit will be provided. Values 
for hematology, serum chemistry, and urinalysis values outside the central laboratory reference 
ranges will be flagged on the individual subject data listings. 
8.3.1 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’.  
8.3.2 Analysis of Clinically Significant Abnormalities  
The number and percentage of subjects with clinically significant abnormal values for laboratory 
parameters will be summarized. A listing of clinically significant abnormal values will also be 
presented. Clinical significance will be determined for selected parameters based on the criteria 
listed below in Table 3. 
Table 3: Criteria for clinically significant abnormal laboratory value 
Parameter name  
Unit 
Low 
High 
Hematology 
White blood cells  
x109 cells/L 
<3.0   
>16  
Lymphocytes  
x109 cells/L 
<0.8  
>12   
Neutrophils  
x109 cells/L 
<1.5  
>13.5  
Monocytes  
x109 cells/L 
N/A  
>2.5  
Eosinophils  
x109 cells/L 
N/A  
>1.6  
Basophils  
x109 cells/L 
N/A  
>1.6  
Red blood cells (RBC) 
x1012 cells/L 
≤ 3.5  
≥ 6.4  
Hemoglobin - Females 
                     - Males 
g/L 
≤ 95  
≥ 175  
≤ 115  
≥ 190 
Hematocrit - Females  
                   - Males  
% 
≤ 32 
≥ 54 
≤ 37  
≥ 60 
Platelet count  
x109 cells/L 
≤ 75 
≥ 700 
Blood Chemistry 


 
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Parameter name  
Unit 
Low 
High 
Alanine aminotransferase 
(ALT)  
 
N/A  
> 3 x ULN  
Aspartate aminotransferase 
(AST)  
 
N/A  
> 3 x ULN  
Alkaline phosphatase (ALP) 
 
N/A  
>3 x ULN  
Total bilirubin  
 
N/A  
>2 x ULN  
Blood urea nitrogen (BUN)  
 
N/A  
≥10.7 mmol/L  
Creatinine  
 
N/A  
≥176.8 umol/L  
Sodium  
mmol/L 
≤ 126  
≥ 156 
Potassium  
mmol/L 
≤ 3 
≥ 6  
Chloride  
mmol/L 
≤ 90   
≥ 118  
Bicarbonate  
mmol/L 
≤ 16  
≥ 35  
Glucose (non-fasting) 
mmol/L 
≤ 2.2  
≥ 9.7   
HbA1C 
% 
N/A 
≥ 6.5% 
Calcium  
mmol/L 
≤ 2  
≥ 3  
Phosphorus  
mmol/L 
≤ 0.5491  
≥ 1.7119  
Albumin  
g/L 
≤ 25  
≥ 100 
Total protein  
g/L 
≤ 45  
≥ 100  
8.4 Vital Signs 
Vital sign parameters include oral temperature, systolic blood pressure, diastolic blood pressure, 
pulse rate, respiration rate and weight. Subjects evaluated will be safety subjects with a baseline 
and at least one post-baseline assessment for that vital sign. The descriptive statistics for actual 
values and change from baseline will be summarized at each visit. Plots of mean vital sign values 
over time will be provided. 
The analysis of vital signs will also focus on the incidence of clinically relevant outliers based on 
the following criteria. The incidence as described in Section 8.2 and percentage of clinically 
relevant outliers determined by each criterion will be summarized. A listing of all vital sign 
values will be presented for subjects with any vital sign abnormalities. Clinically relevant 
abnormal vital signs will be flagged in the listing. 
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  


 
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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  
8.5 Electrocardiogram (ECG) 
The ECG data will be obtained directly from the 12-lead ECG traces. These data include the PR 
interval (milliseconds), QTcB interval (milliseconds), QRS duration (milliseconds), and heart 
rate (beats/min).  
Descriptive statistics will be used to summarize ECG measurements at each visit for each 
treatment group. Individual subject listings of ECG parameters at each timepoint will also be 
provided by treatment group. 
A shift table of ECG interpretation results (i.e. normal; abnormal, not adverse event; abnormal, 
adverse event from baseline to post-baseline will be presented at each visit by treatment group. 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. 
8.6 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.  
8.7 Immunogenicity (Anti-BG00011 Antibodies) 
Blood samples for the presence and titer of anti-BG00011 antibodies will be collected at 
scheduled visits of baseline, weeks 4, 12, 26, 38 and 60 (safety follow-up). The analysis visit 
should be defined using window in the table below in Table 4.  Each blood sample will initially 
be tested for the presence of anti-BG00011 antibodies using a validated 
electrochemiluminescence (ECL) method. Confirmed positive samples using the screening assay 
will be titered and subsequently tested using a validated neutralization assay.  
Table 4: Visit Windows for Anti-BG00011 Antibodies 
Analysis Visit 
Target visit day 
Analysis visit window 
Baseline (Day 0) 
1 
Most recent non-missing pre-dose value 
Week 4 
29 
[2,57] 
Week 12 
85 
[58,134] 
Week 26 
183 
[135,225] 
Week 38 
267 
[226,344] 


 
Statistical Analysis Plan 
 
Study Number: 203PF203   
Statistical Analysis Plan 
Version No.: 1.0 
 
Safety Follow-up 
(Week 60) 
421 
• If subject who discontinued treatment due 
to reasons other than study termination by 
sponsor:  
> min (393, study day of each subject’s 
week 52/EOT visit in treatment period) *  
• If subject who discontinued treatment due 
to study early termination by sponsor:  
> min (393, study day of each subject’s last 
dose) 
* For subjects who discontinued the treatment due to reasons other than study termination by sponsor will go on to complete all 
scheduled visits until either week 52 or the study was terminated by sponsor due to the urgent safety measure whichever occur s 
first. The Week 52/ EOT visit in treatment period is defined as the last visit scheduled for either week 52 or study termination due 
to the urgent safety measure.  
 
Antibody results will be presented by treatment group and subject in listings. The incidence of 
antibodies to BG00011 will be summarized over time by treatment group using descriptive 
statistics.  
Since the study early termination, the antibody results will not be included in the Part 1 data of 
the two-part database lock. The antibody data will be included in the Part 2 data. In order to keep 
the data integrity, the reconciliation of the antibody samples will be conducted prior to the Part 1 
data being cleaned and finalized.   
 


 
Statistical Analysis Plan 
 
Study Number: 203PF203   
Statistical Analysis Plan 
Version No.: 1.0 
 
9 Pharmacokinetics (PK) Analysis 
BG00011 concentrations in serum will be summarized for PK population using descriptive 
statistics at the scheduled PK sample collection visits. Number of evaluable subjects, arithmetic 
mean, standard deviation, median, 25% and 75% quartiles, minimum, maximum, geometric 
mean, and CV will be presented at each visit.  
This study will collect only sparse PK samples; thus, no noncompartmental or compartmental 
methods will be used to analyze the PK data for presentation in the clinical study report. The 
mean serum concentrations (+/- SD) will be plotted over time by treatment group on the linear 
and log linear scale.  
No dose-proportionality assessments will be conducted because of the sparse PK data sampling. 
Atypical drug concentrations (e.g., very low or very high) will be excluded from the analysis, if 
no apparent explanation exists. Concentration observations will also be removed from the data 
set if corresponding dosing or sampling times are missing or cannot be reconstructed. 
Measurements that are below the level of quantification (BLQ) will be set to missing and 
removed from analysis before statistics are calculated, if the BLQ occurs before the first 
measurable concentration (such as pre-dose), it should be set to zero. If the value of the 
concentration is "Non-Determinable", then the concentration value will be set to missing.   
A listing of individual serum concentration data will be provided. The BLQ and all atypical drug 
concentration excluded from the analysis will be flagged in the listing.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


 
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11 Reference  
Berry, J. D., Miller, R., Moore, D. H., Cudkowicz, M. E., Van Den Berg, L. H., Kerr, D. A., 
Dong, Y., Ingersoll, E. W., and Archibald, D. The combined assessment of function and survival 
(CAFS): A new endpoint for ALS clinical trials. Amyotrophic Lateral Sclerosis and 
Frontotemporal Degeneration. 2013; 14(3):162-168. 
 
 
 
 
Finkelstein DM, Schoenfeld DA. Combining mortality and longitudinal measures in clinical 
trials. Stat Med. 1999; 18:1341–54 
 
ICH E9 (R1): Addendum to statistical principles for clinical trials on choosing appropriate 
estimands and defining sensitivity analyses in clinical trials. Endorsed by the ICH Steering 
Committee. 2014. 
 
ICH E9 (R1): Addendum on Estimands and Sensitivity Analysis in Clinical Trials to the 
Guideline on Statistical Principles for Clinical Trials. European Medicines Agency. 2017. 
 
Ley B, Ryerson CJ, Vittinghoff E, et al.  A multidimensional index and staging system for 
idiopathic pulmonary fibrosis.  Ann Intern Med. 2012;156(10):684-69122586007 
 
Rubin, D. B. (1976) “Inference and missing data.” Biometrika, 63(3), 581-592. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Study Number: 203PF203   
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Statistical Analysis Plan 
 
Study Number: 203PF203   
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Statistical Analysis Plan 
 
Study Number: 203PF203   
Statistical Analysis Plan 
Version No.: 1.0