Clinical trial NCT03955146
Conditions: Idiopathic Pulmonary Fibrosis
Keywords: Idiopathic Pulmonary Fibrosis, IPF, Idiopathic Interstitial Pneumonia, Interstitial Lung Disease, Lung Fibrosis
Sponsor: FibroGen
Start date: 2019-06-18; Completion date: 2023-08-28
Enrollment: 393 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 3 trial to evaluate the efficacy and safety of 30 milligrams (mg)/kilogram (kg) intravenous (IV) infusions of pamrevlumab administered every 3 weeks as compared to placebo in participants with IPF.

Detailed description:
This is a Phase 3, randomized, double-blind, placebo-controlled, multi-center trial to evaluate the efficacy and safety of pamrevlumab in participants with IPF.

Participants who are not being treated with approved IPF therapies (that is, nintedanib or pirfenidone) may be eligible for screening. Examples of reasons participants may not be treated with approved IPF therapies include but are not limited to:

* Intolerant or not responsive to approved IPF therapies
* Ineligible to receive these therapies
* Participant voluntarily declines to receive approved IPF therapies after being fully informed of the potential benefits/risks

NOTE: No participant should discontinue an approved IPF therapy for the purpose of enrolling in this study.

The study consists of the following study periods:

* Main (double blind, placebo-controlled) phase:

  * Screening period: Up to 6 weeks
  * Treatment period: 48 weeks
* Optional, open-label extension (OLE) phase of pamrevlumab:

  o Access to pamrevlumab will be available until the last participant completes 48 weeks of treatment in the OLE phase, or pamrevlumab is commercially available for the indication of IPF, or the Sponsor decides to end the OLE phase, whichever occurs first.
* Follow-up period/final safety assessments:

  * 28 days after last dose
  * 60 days after last dose: follow-up phone call, for a final safety assessment

During the treatment period, co-administration of an approved IPF therapy (that is, pirfenidone or nintedanib) is acceptable if clinically indicated in the Investigator's opinion, provided that the Investigator assesses the potential risks/benefits of combining approved IPF therapies with blinded study treatment.

Participants who discontinue study treatment for any reason should be encouraged to remain in the study and be followed for all study visits and assessments.

Participants who complete the Week 48 visit of the main study (regardless of the number of study drug infusions received) will be eligible to participate in the optional OLE phase of the study that offers continuing access to pamrevlumab regardless of randomization assignment in the main study.

Arms: arm 1: Participants will receive pamrevlumab 30 milligrams (mg)/kilogram (kg) by intravenous (IV) infusion every 3 weeks for up to 48 weeks in the DB period. arm 2: Participants will receive placebo matching to pamrevlumab by IV infusion every 3 weeks for up to 48 weeks in the DB period. arm 3: Participants will receive pamrevlumab 30 mg/kg by IV infusion every 3 weeks for up to 48 weeks. arm 4: Participants will receive placebo matching to pamrevlumab by IV infusion every 3 weeks for up to 48 weeks. arm 5: Participants who receive pamrevlumab in the DB period will continue to receive the same dose of pamrevlumab for up to 48 weeks in the OLE period or until pamrevlumab is commercially available for the indication of IPF, or the sponsor decides to end the OLE period, whichever occurrs first. arm 6: Participants who receive placebo matching to pamrevlumab in the DB period, will receive pamrevlumab 30 mg/kg by IV infusion every 3 weeks for up to 48 weeks in the OLE period or until pamrevlumab is commercially available for the indication of IPF, or the sponsor decides to end the OLE period, whichever occurrs first.
Interventions: intervention 1: Pamrevlumab intervention 2: Placebo
Intervention descriptions: intervention 1: Pamrevlumab will be administered per dose and schedule specified in the arm description. intervention 2: Placebo matching to pamrevlumab will be administered per schedule specified in the arm description.

Protocol documents:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL 
STUDY TITLE: 
A Phase 3, Randomized, Double-Blind, 
Placebo-Controlled Efficacy and Safety Study 
of Pamrevlumab in Subjects with Idiopathic 
Pulmonary Fibrosis (IPF) 
PROTOCOL NUMBER: 
FGCL-3019-091 
PHASE: 
Phase 3 
STUDY SPONSOR: 
FibroGen, Inc. 
409 Illinois Street 
San Francisco, California 94158 USA 
KEY SPONSOR CONTACT(S): 
 
 
 
Mobile:  
 
E-mail Address: 
Name: 
Title:
Mobile:  
E-mail Address: 
IND NUMBER: 
011212 
STUDY DRUG: 
Pamrevlumab (FG-3019) 
Original Protocol: 
17 December 2018 
Amendment 1.0: 
Amendment 2.0: 
Amendment 3.0: 
Amendment 4.0: 
Amendment 5.0: 
Amendment 6.0: 
17 March 2019 
25 September 2019 
19 February 2020 
26 May 2020 
04 November 2020 
31 October 2022 
CONFIDENTIALITY STATEMENT 
The information contained in this document is confidential and proprietary to FibroGen, Inc. No part 
of this document or any of the information contained herein may be transmitted, disclosed, shared, 
reproduced, published or utilized by any persons without prior written authorization by FibroGen, 
Inc. 
NCT #: NCT03955146


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INVESTIGATOR SIGNATURE PAGE 
 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of 
Pamrevlumab in Subjects with Idiopathic Pulmonary Fibrosis (IPF) 
 
FGCL-3019-091 
Original: 17 December 2018 
Amendment 1.0: 17 March 2019 
Amendment 2.0: 25 September 2019 
Amendment 3.0: 19 February 2020 
Amendment 4.0: 26 May 2020 
Amendment 5.0: 04 November 2020 
Amendment 6.0: 31 October 2022 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and the current Investigator’s Brochure (IB), and I 
agree that it contains all necessary details for me and my staff to conduct this study as described. I 
will conduct this study as outlined herein and will make a reasonable effort to complete the study 
within the time designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by FibroGen, Inc. I will discuss this material with them to ensure that they are 
fully informed about the drugs and the study. 
I will conduct the trial in accordance with the guidelines of Good Clinical Practice (GCP) including 
the archiving of essential documents, the Declaration of Helsinki, and any applicable local health 
authority, and Institutional Review Board (IRB)/Independent Ethics Committee (IEC) requirements. 
 
 
 
 
Investigator Name (Printed) 
 
Institution 
 
 
 
Signature 
 
Date 
 
Please return a copy of this signature page to FibroGen (or designee). Please retain the original 
for your study files. 
 


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CONFIRMATION OF PROTOCOL APPROVAL 
 
 
Original Protocol Date: 17 December 2018 
Amendment 1.0: 17 March 2019 
Amendment 2.0: 25 September 2019 
Amendment 3.0: 19 February 2020 
Amendment 4.0: 26 May 2020 
Amendment 5.0: 04 November 2020 
Amendment 6.0: 31 October 2022 
 
This protocol is approved by FibroGen. 
 
 
 
 
 
FibroGen, Inc. 
*See appended final page for 21 CFR 
part 11 compliant approval 
Date 


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AMENDMENT 6.0: KEY CHANGES 
The protocol has been edited for clarity, consistency, and quality of content (typos, grammatical 
errors, flow, etc.). A redline version documenting all changes from the previous version of this 
document is available upon request. 
 
Description of Key Change 
Rationale for Change 
Section(s) Affected 
Removed outdated IB language. 
To remove outdated IB language. 
Section 2.5, Section 
2.6.3 
Updated and clarified primary, secondary 
and exploratory endpoints. 
Endpoints clarified and updated 
to optimize for clinical 
relevance. 
Synopsis, Section 3.2, 
Section 8.3.4 
Added when early termination visits should 
occur. 
To clarify timing of early 
termination visits. 
Section 3.3.1, Section 
4.4, Appendix 1. 
Appendix 6 
Clarified required procedures/assessments at 
early termination visits. 
To further clarify the required 
procedures/assessments for early 
termination visits. 
Section 4.4 
Added Open-label Extension language. 
To further clarified the infusion 
rate and post-infusion observation 
periods for Open-label Extension 
visits. 
Table 1 
Added recommendation for COVID-19 
vaccine and study drug administration. 
To clarify the recommendation for 
COVID-19 vaccine and study drug 
administration timing. 
Section 5.1.6 
Clarified requirement for medications 
and supplies for Home Health Care. 
To further clarify the 
requirement for medication and 
supplies for suspected 
hypersensitivity/analytical 
events for Home Health Care 
Section 5.1.7 
Added preliminary non-clinical study 
results 
Preliminary results of rabbit 
embryo-fetal development study 
available to inform 
contraception recommendations. 
Section 5.2.3 
Added language regarding pregnancy 
testing 
To align with the CTFG v1.1. 
embryo-fetal risk contraception 
recommendations regarding 
pregnancy testing in the event 
of delayed menstruation. 
Section 5.2.3, 
Appendix 1, 
Appendix 2 
Added PK, HAHA and, HAHA-NA, 
CTGF and tryptase scheduled blood 
draws and at the time of any suspected 
hypersensitivity/anaphylactic reactions. 
To meet Regulatory 
recommendations for 
immunogenicity testing. 
Section 6.2.4.2, 
Appendix 2 
Clarified the order of Patient Reported 
Outcome questionnaire administration. 
To further clarify the order in 
which Patient Report Outcome 
Section 6.2.6 


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questionnaires should be 
administered.  
Added visit window for EX Day 1 
To clarify the visit window for 
EX Day 1 
Appendix 6 
Clarified main study procedures and 
AEs. 
To clarify main study 
procedures and AEs versus 
OLE. 
Appendix 6 
In addition to the changes listed above, 
minor editorial changes were made 
throughout the document to improve 
consistency and clarity. 
To correct typographical errors, 
and to improve consistency and 
clarity. 
Throughout the 
document  


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1. 
PROTOCOL SYNOPSIS 
 
 
PROTOCOL SYNOPSIS 
Study Title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled 
Efficacy and Safety Study of Pamrevlumab in Subjects with 
Idiopathic Pulmonary Fibrosis (IPF) 
Protocol Number: 
FGCL-3019-091 
Investigational Product: 
Pamrevlumab (FG-3019) 
Study Phase: 
Phase 3 
Indication: 
Idiopathic Pulmonary Fibrosis 
Number of 
Subjects Planned: 
Approximately 340 
Number of Sites Planned: 
Approximately 120 
OBJECTIVES 
The overall objective of this trial is to evaluate the efficacy and safety of pamrevlumab as 
compared to placebo in subjects with idiopathic pulmonary fibrosis.   


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ENDPOINTS 
Primary Endpoint: 
• Change in FVC (L) from baseline at Week 48   
Secondary Endpoints: 
• Time to disease progression, defined as absolute FVCpp decline of ≥10% or death, 
whichever occurs first   
• Change in Quantitative Lung Fibrosis (QLF) volume from baseline at Week 48 
• Time to any component of the clinical composite endpoint, whichever occurs first: acute 
IPF exacerbation, respiratory hospitalization, or death 
• Time to first acute IPF exacerbation during study 
• Time to all-cause mortality during study 
• Time to first respiratory hospitalization during study 
Exploratory Endpoints: 
• Time to composite of: respiratory hospitalization, absolute FVCpp decline ≥10%, or 
death, whichever occurs first 
• Change in absolute FVCpp from baseline at Week 48 
• Change in relative FVCpp from baseline at Week 48 
• Change in St. George’s Respiratory Questionnaire (SGRQ) score from baseline at Week 
48 
• Change in University of California San Diego – Shortness of Breath Questionnaire 
(UCSD-SOBQ) score from baseline at Week 48 
• Change in Leicester Cough Questionnaire (LCQ) from baseline at Week 48 
• Exploratory biomarkers 
 Safety Assessments: 
Adverse events (including serious adverse events), clinical laboratory parameters, vital signs, 
immunogenicity (Human Anti-Human Antibody [HAHA] formation), and 
hypersensitivity/anaphylactic reactions. 
STUDY DESIGN 
This is a Phase 3, randomized, double-blind, placebo-controlled, multi-center trial to evaluate 
the efficacy and safety of pamrevlumab in subjects with idiopathic pulmonary fibrosis (IPF). 
Subjects who are not being treated with approved IPF therapies (i.e., nintedanib or pirfenidone) 
may be eligible for screening. Examples of reasons subjects may not be treated with approved 
IPF therapies include but are not limited to: 


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• Intolerant or not responsive to approved IPF therapies 
• Ineligible to receive these therapies 
• Subject voluntarily declines to receive approved IPF therapies after being fully 
informed of the potential benefits/risks 
NOTE: No subject should discontinue an approved IPF therapy for the purpose of enrolling in 
this study. 
Approximately 340 eligible subjects will be randomized at a 1:1 ratio to Arm A or Arm B, 
respectively:   
• Arm A: Pamrevlumab, 30 mg/kg IV, Day 1 and every 3 weeks thereafter 
• Arm B: Matching placebo IV, Day 1 and every 3 weeks thereafter 
Randomization will be stratified by: 
• Prior treatment with an approved IPF therapy (Yes/No) 
• GAP stage (I, II, III) derived from GAP score obtained at screening (See Appendix 5). 
 NOTE:  For calculation of the GAP score: Use the Best-Test Review (BTR) 
assessment provided by the spirometry vendor over-reader of the screening value (see 
Section 6.2.5 and Appendix 5). 
The intent of this study is to evaluate the efficacy and safety profile of pamrevlumab as 
monotherapy in subjects with IPF who were either treated with an approved therapy in the past, 
but discontinued that therapy (possible reasons for discontinuation of approved therapy could 
include, but are not limited to, intolerance or disease progression); or who decided voluntarily 
to forego such treatment, after being fully informed of the potential benefits/risks. 
During the treatment period, co-administration of an approved IPF therapy (i.e., pirfenidone or 
nintedanib) is acceptable if clinically indicated in the Investigator’s opinion, provided that the 
Investigator assesses the potential risks/benefits of combining approved IPF therapies with 
blinded study treatment.  
Subjects who complete the Week 48 visit of the main study (regardless of the number of study 
drug infusions received) will be eligible to participate in the optional, open-label, extension 
(OLE) phase of the study that offers continuing access to pamrevlumab regardless of 
randomization assignment in the main study.  Details of this OLE phase are outlined in 
Appendix 6. 
Subjects who discontinue study treatment for any reason should be encouraged to remain in the 
study and be followed for all study visits and assessments.  
The following assessments will be assessed centrally:  
• Pulmonary function tests (PFTs) 
• High-resolution computed tomography (HRCT)  
• Acute IPF exacerbations and respiratory hospitalizations    


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STUDY PERIODS 
The study consists of the following study periods: 
• Main (double blind, placebo-controlled) phase:  
o Screening period: Up to 6 weeks 
o Treatment period: 48 weeks  
• Optional, open label extension (OLE) phase of pamrevlumab:  
o Access to pamrevlumab will be available until the last subject completes 48 
weeks of treatment in the OLE phase, or pamrevlumab is commercially available 
for the indication of IPF, or the Sponsor decides to end the OLE phase, 
whichever occurs first.  
• Follow-up period/final safety assessments:   
o 28 days after last dose 
o 60 days after last dose: follow-up phone call, for a final safety assessment   
 
SUBJECT ELIGIBILITY CRITERIA 
Inclusion Criteria: 
1. Age 40 to 85 years, inclusive, at screening initiation. 
2. Diagnosis of IPF as defined by ATS/ERS/JRS/ALAT guidelines (Raghu 2018).  
3. IPF diagnosis within the past 7 years, with onset defined as the date of the first recorded 
diagnosis of IPF by HRCT and/or surgical biopsy (SLB) or other appropriate tissue 
sample (e.g., cryobiopsy) in the medical history. 
4. Interstitial pulmonary fibrosis defined by HRCT scan at screening, with evidence of 
≥10% to <50% parenchymal fibrosis (reticulation) and <25% honeycombing, within the 
whole lung. NOTE: this requires confirmation by an Independent Radiology Imaging 
Review Group, prior to randomization. If a recent HRCT scan (within 3 months prior to 
screening) is available, it can be utilized for screening purposes, provided it is submitted 
and evaluated by the Independent Radiology Imaging Review Group, is adhering to the 
imaging parameters detailed in the Imaging Core Manual (ICM), and is using the same 
accredited scanner as the on-study HRCT scans. 
5. FVCpp value >45% and <95% at screening and Day 1 (prior to randomization).   
6. Diffusing capacity of the lungs for carbon monoxide (DLCO) percent predicted and 
corrected by Hb value ≥25% and ≤90% at screening (determined locally). If a DLCO is 
available within 3 months prior to screening, it can be utilized for screening purposes.  
7. Both FVC and DLCO testing must be representative of the IPF underlying disease (i.e., 
have been obtained in absence of an acute respiratory event [e.g., lung infection, cold] 


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or other events that are known to affect PFT testing results (e.g., broken rib, chest pain, 
other). 
8. Not currently receiving treatment for IPF with an approved therapy (i.e., pirfenidone or 
nintedanib) for any reason, including prior intolerance or lack of response to an 
approved IPF therapy, or choice to forego treatment with an approved IPF therapy after 
a full discussion with the Investigator regarding risks/benefits of such therapy. NOTE: 
no subject should discontinue approved therapy for the purpose of enrolling in this 
study. 
9. Male subjects with partners of childbearing potential and female subjects of 
childbearing potential (including those <1 year postmenopausal) must use a highly 
effective method of contraception per Clinical Trial Facilitation Group (CTFG) 
recommendation (see protocol section 5.2.3 for details) during the conduct of the study, 
and for 3 months after the last dose of study drug.  Women not of childbearing potential 
are defined as: 
a. Post-menopausal women (defined as at least 12 months with no menses without an 
alternative medical cause); in women < 45 years of age, a high follicle stimulating 
hormone (FSH) level in the post-menopausal range may be used to confirm a post-
menopausal state in women not using hormonal contraception or hormonal 
replacement therapy; OR 
b. Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; OR 
c. Have a congenital or acquired condition that prevents childbearing. 
10. Able to understand and sign a written informed consent form. 
Exclusion Criteria: 
1. Previous exposure to pamrevlumab. 
2. Evidence of significant obstructive lung disease by any of the following criteria: (1) 
forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio <0.70, or 
(2) extent of emphysema greater than the extent of fibrosis on HRCT. NOTE: this 
requires confirmation by an Independent Radiology Imaging Review Group, prior to 
randomization. 
3. Female subjects who are pregnant or nursing. 
4. Smoking within 3 months of screening and/or unwilling to avoid smoking throughout 
the study. 
5. Interstitial lung disease (ILD) other than IPF, including but not limited to any of the 
other types of idiopathic interstitial pneumonias; lung diseases related to exposure to 
fibrogenic agents or other environmental toxins or drugs; other types of occupational 
lung diseases; granulomatous lung diseases; pulmonary vascular diseases; systemic 
diseases, including vasculitis, infectious diseases and connective tissue diseases. In 
cases of uncertain diagnosis, serological testing and/or review by multi-disciplinary 
team should be performed to confirm diagnosis of IPF vs. other types of ILD. 


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6. Sustained improvement in the severity of IPF during the 12 months prior to screening, 
based on changes in FVC, DLCO, and/or HRCT scans of the chest. 
7. History of other types of respiratory diseases, including diseases or disorders of the 
airways, lung parenchyma, pleural space, mediastinum, diaphragm, or chest wall that, in 
the opinion of the Investigator, would impact the primary protocol endpoint or 
otherwise preclude the subject’s participation in the study. 
8. Medical conditions (e.g., MI/stroke within the past 6 month), or logistical challenges 
that in the opinion of the Investigator preclude the subject’s adequate participation in the 
study. 
9. Poorly controlled chronic heart failure (NYHA Class 3 or above); clinical diagnosis of 
cor pulmonale requiring specific treatment; or severe pulmonary arterial hypertension 
requiring specific treatment that, in the opinion of the Investigator, would preclude the 
subject’s participation in the study.  
10. Clinically important abnormal laboratory tests (including serum creatinine ≥1.5 x upper 
limit of normal [ULN], hemoglobin (Hb) <10 g/dL, white blood cells <3,000/mm3, 
platelets less than 100,000/mm3, serum total bilirubin >1.5 x ULN, serum alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) ≥2 x ULN, or serum 
alkaline phosphatase ≥2 x ULN. 
11. Ongoing acute IPF exacerbation, or suspicion of such process during screening or 
randomization, including hospitalization due to acute IPF exacerbation within 4 weeks 
prior to or during screening. 
12. High likelihood of lung transplantation (in the opinion of the Investigator) within 6 
months after Day 1. 
13. Use of any investigational drugs or unapproved therapies, or participation in a clinical 
trial with an investigational new drug, within 30 days prior to screening. Or use of 
approved IPF therapies (i.e., pirfenidone or nintedanib) within 1 week prior to 
screening. 
14. Daily use of PDE-5 inhibitor drugs (e.g., sildenafil, tadalafil) except for treatment of 
severe pulmonary artery hypertension. 
15. Any current malignancy (this does not include localized cancer such as basal or 
squamous cell carcinoma of skin). Any history of malignancy likely to result in 
mortality, or requiring significant medical or surgical intervention within the next year. 
16. History of allergic or anaphylactic reaction to human, humanized, chimeric or murine 
monoclonal antibodies, or to any component of the excipient. 
17. Any condition (other than IPF) that is likely to result in the death of the patient within 
the next year. 
18. The Investigator judges that the subject will be unable to fully participate in the study 
and complete it for any reason, including inability to comply with study procedures and 
treatment, addiction, or any other relevant medical or psychiatric conditions. 


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STUDY TREATMENT 
Dose and Mode of Administration: 
Main Phase (Double-Blind, Placebo-Controlled):  
Pamrevlumab or placebo, 30 mg/kg, IV, Day 1 and every 3 weeks thereafter, up to Week 48, 
for a total of up to 17 infusions.  
Optional, Open Label Extension (OLE) Phase of Pamrevlumab: 
Pamrevlumab (30 mg/kg) every 3 weeks  
Other Important Information: 
Other medications and therapies intended to treat IPF, other than approved IPF therapies 
(pirfenidone or nintedanib), will not be allowed during the study except for some protocol-
specified exceptions. 
Study drug should not be administered to subjects with a history of allergic or anaphylactic 
reaction to human, humanized, or chimeric monoclonal antibodies, or to any of the components 
of the excipient. 
 
STATISTICAL METHODS 
Sample Size Calculations: 
This study will enroll approximately 340 subjects with a 1:1 randomization ratio to either 
pamrevlumab or placebo.  
A sample size of 340 subjects will have at least 90% power, based on a two-sided alpha level of 
0.05 for a two-sample t-test, to detect a treatment difference of 120 mL in the primary efficacy 
endpoint, change from baseline in FVC (L), assuming a standard deviation of 300 mL. 
 
Statistical Analysis Methods: 
The primary efficacy endpoint, change from baseline to Week 48 in FVC (L), will be analyzed 
using a random coefficient model (RCM) with treatment, visit, visit-by-treatment interaction, 
randomization stratification, baseline FVC volume, age, sex, height as fixed effects; the 
intercept and linear slope of visit are random effects.  
For the other efficacy endpoints, unless stated otherwise, the RCM model will be used for 
pulmonary function test variables; the Mixed Model for Repeated Measure (MMRM) model 
will be used for patient reported outcome questionnaires and other continuous variables; and the 
Cox regression model will be used in time-to-event variables. The analysis models will include 
the stratification factors and appropriate baseline factors.   
 
 


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Safety Analyses:  
All subjects who received any dose of study treatment will be included in the safety analyses. 
Treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events 
(TESAEs) will be summarized by treatment arm.  
Clinically significant changes from baseline in vital signs and laboratory tests will be identified 
and summarized by treatment arm. Additionally, hypersensitivity/anaphylactic and 
immunogenicity reactions will be monitored and assessed. 
Safety data collected during the OLE phase will be summarized descriptively. 
OPTIONAL BLOOD DRAWS 
Optional Pharmacokinetics (PK) and Genomic Analyses:  
Two optional sub-studies, one for PK assessment, and one for genomic analyses, will be 
performed in a subset of subjects at select sites. Such subjects will provide their consent to 
these optional sub studies prior to their participation in these sub-studies. PK assessments will 
continue to be optional except in the case of suspected hypersensitivity/anaphylactic reactions 
(see Section 6.2.4.2.3 for more detail). 
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) and 
the applicable regulatory requirement(s), including the archiving of essential documents. 


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TABLE OF CONTENTS 
INVESTIGATOR SIGNATURE PAGE .........................................................................................2 
CONFIRMATION OF PROTOCOL APPROVAL.........................................................................3 
AMENDMENT 6.0: KEY CHANGES ...........................................................................................4 
1. 
PROTOCOL SYNOPSIS .............................................................................................6 
2. 
INTRODUCTION ......................................................................................................19 
2.1. 
Description of Pamrevlumab ......................................................................................19 
2.2. 
Idiopathic Pulmonary Fibrosis ....................................................................................19 
2.3. 
Connective Tissue Growth Factor ..............................................................................22 
2.4. 
Connective Tissue Growth Factor in Idiopathic Pulmonary Fibrosis ........................23 
2.5. 
Clinical Trial Experience with Pamrevlumab .............................................................23 
2.6. 
Rationale for Pamrevlumab in Idiopathic Pulmonary Fibrosis ..................................24 
2.6.1. 
Clinical Studies in IPF ................................................................................................24 
2.6.2. 
Dose Rationale ............................................................................................................25 
2.6.3. 
Safety Summary and Benefit/Risk Assessment ..........................................................26 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................28 
3.1. 
Objective .....................................................................................................................28 
3.2. 
Endpoints ....................................................................................................................28 
3.2.1. 
Primary Endpoint: .......................................................................................................28 
3.2.2. 
Secondary Endpoints ..................................................................................................28 
3.2.3. 
Exploratory Endpoints ................................................................................................28 
3.2.4. 
Safety Assessment ......................................................................................................29 
3.3. 
Overall Study Design ..................................................................................................29 
3.3.1. 
Study Duration ............................................................................................................30 
3.3.2. 
Placebo Control Group ...............................................................................................31 
3.4. 
Randomization and Treatment Assignment ................................................................31 
3.4.1. 
Randomization ............................................................................................................31 
3.4.2. 
Treatment Assignment ................................................................................................31 
3.5. 
Blinding ......................................................................................................................31 
3.5.1. 
Maintenance of Blinding ............................................................................................32 
3.5.2. 
Request for Unblinding of Treatment Assignment .....................................................32 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................33 


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4.1. 
Subject Inclusion Criteria ...........................................................................................33 
4.2. 
Subject Exclusion Criteria ..........................................................................................34 
4.3. 
Subject Study Withdrawal Criteria .............................................................................35 
4.4. 
Subject Study Withdrawal Procedures/Assessments ..................................................36 
4.5. 
Replacement of Study Subjects ..................................................................................36 
4.6. 
Study Closure..............................................................................................................36 
5. 
TREATMENT OF SUBJECTS ..................................................................................37 
5.1. 
Study Treatment ..........................................................................................................37 
5.1.1. 
Pamrevlumab or Placebo ............................................................................................37 
5.1.2. 
Formulation .................................................................................................................37 
5.1.3. 
Study Drug Packaging and Labeling ..........................................................................37 
5.1.4. 
Study Drug Storage .....................................................................................................37 
5.1.5. 
Study Drug Preparation ..............................................................................................37 
5.1.6. 
Study Drug Administration.........................................................................................38 
5.1.7. 
Home Health Care ......................................................................................................39 
5.1.8. 
Missed Dose ................................................................................................................40 
5.1.9. 
Study Drug Handling and Disposal ............................................................................40 
5.1.10. 
Co-Administration of an Approved IPF Therapy .......................................................40 
5.1.11. 
Treatment Compliance ................................................................................................40 
5.2. 
Concomitant Medications ...........................................................................................41 
5.2.1. 
Permitted Concomitant Medications ..........................................................................41 
5.2.2. 
Prohibited Concomitant Medications .........................................................................41 
5.2.3. 
Contraception Requirements ......................................................................................42 
6. 
ASSESSMENTS OF EFFICACY ..............................................................................44 
6.1. 
Study Assessments......................................................................................................44 
6.1.1. 
Screening Period .........................................................................................................44 
6.1.2. 
Treatment Period ........................................................................................................44 
6.1.3. 
Safety Follow-Up ........................................................................................................44 
6.1.4. 
Missed Visits ..............................................................................................................44 
6.1.5. 
Unscheduled Visits .....................................................................................................45 
6.2. 
Assessments ................................................................................................................45 
6.2.1. 
Vital Signs (including Weight and Height) ................................................................45 
6.2.2. 
Physical Exam ............................................................................................................46 


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6.2.3. 
Electrocardiogram (ECG or EKG) .............................................................................46 
6.2.4. 
Laboratory Evaluations ...............................................................................................46 
6.2.5. 
High Resolution Computerized Tomography (HRCT) Scans and Spirometry ..........49 
6.2.6. 
Patient Reported Outcomes (PROs) ...........................................................................50 
7. 
ASSESSMENTS OF SAFETY ..................................................................................52 
7.1. 
Background .................................................................................................................52 
7.2. 
Definitions ..................................................................................................................52 
7.2.1. 
Definition of an Adverse Event (AE) .........................................................................52 
7.2.2. 
Definition of a Serious Adverse Event (SAE) ............................................................52 
7.3. 
Procedures for Eliciting, Recording, and Reporting Adverse Events ........................53 
7.3.1. 
Adverse Event Reporting Period ................................................................................53 
7.3.2. 
Adverse Event Eliciting/Reporting .............................................................................53 
7.3.3. 
Assessing Adverse Event Severity .............................................................................54 
7.3.4. 
Assessing the Adverse Event’s Relationship to Study Drug ......................................54 
7.3.5. 
Reporting Serious Adverse Events (SAEs) ................................................................55 
7.3.6. 
Pregnancies: Reporting and Follow-up of Subjects and Female Partners of 
Subjects .......................................................................................................................56 
7.3.7. 
Laboratory or other Test Abnormalities/ Findings .....................................................57 
7.3.8. 
Hypersensitivity/Anaphylactic Reactions: ..................................................................57 
7.3.9. 
Safety Monitoring .......................................................................................................58 
8. 
STATISTICS ..............................................................................................................59 
8.1. 
Sample Size Determination ........................................................................................59 
8.2. 
Analysis Populations ..................................................................................................59 
8.2.1. 
Intent to Treat (ITT) Population .................................................................................59 
8.2.2. 
Safety Population ........................................................................................................59 
8.3. 
Statistical Analysis ......................................................................................................59 
8.3.1. 
General Considerations ...............................................................................................59 
8.3.2. 
Subject Enrollment and Disposition ...........................................................................60 
8.3.3. 
Demographics and Baseline Characteristics ...............................................................60 
8.3.4. 
Efficacy Analyses .......................................................................................................60 
8.3.5. 
Pharmacokinetic Analyses ..........................................................................................62 
8.3.6. 
Safety Analyses ..........................................................................................................62 
8.4. 
Interim Analysis ..........................................................................................................62 


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8.5. 
Statistical Analysis Plan .............................................................................................62 
9. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................63 
9.1. 
Data Quality Assurance ..............................................................................................63 
9.2. 
Audit and Inspection ...................................................................................................63 
10. 
ETHICS ......................................................................................................................64 
10.1. 
Ethical Considerations ................................................................................................64 
10.2. 
Communication with the Institutional Review Board or Independent Ethics 
Committee ...................................................................................................................64 
10.3. 
Subject Information and Consent ...............................................................................64 
10.4. 
Subject Confidentiality ...............................................................................................65 
11. 
DATA HANDLING AND RECORD KEEPING ......................................................66 
11.1. 
Source Documents ......................................................................................................66 
11.2. 
Direct Access to Source Documents...........................................................................66 
11.3. 
Data Collection, Handling, and Verification ..............................................................66 
11.4. 
Protocol Deviations ....................................................................................................66 
11.5. 
Retention of Data ........................................................................................................67 
11.6. 
Financial Disclosure ...................................................................................................67 
12. 
PUBLICATION POLICY ..........................................................................................68 
13. 
REFERENCES ...........................................................................................................69 
14. 
APPENDICES ............................................................................................................76 
APPENDIX 1. MAIN STUDY SCHEDULE OF ASSESSMENTS ..........................................77 
APPENDIX 2. PHARMACOKINETIC, BIOMARKER, IMMUNOGENICITY AND 
GENOMICS SAMPLING ..........................................................................................80 
APPENDIX 3. HRCT CRITERIA AND HISTOPATHOLOGICAL CRITERIA FOR 
UIP PATTERN ...........................................................................................................81 
APPENDIX 4. RADIATION RISK ASSESSMENT .................................................................82 
APPENDIX 5. GAP SCORE CALCULATION .........................................................................84 
APPENDIX 6. OPTIONAL, OPEN LABEL EXTENSION (OLE) PHASE OF 
PAMREVLUMAB .....................................................................................................85 
 
 
 
 
 


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LIST OF TABLES 
Table 1 
Pamrevlumab (or placebo): Dose, Route, and Administration ...................................38 
Table 2: 
Laboratory Tests .........................................................................................................47 
 
LIST OF FIGURES 
Figure 1: 
FGCL-3019-091 Study Schema .................................................................................30 
 
 


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2. 
INTRODUCTION 
2.1. 
Description of Pamrevlumab 
Pamrevlumab is a recombinant fully human immunoglobulin G1 (IgG) kappa monoclonal 
antibody that binds to connective tissue growth factor (CTGF) and is being developed for 
treatment of diseases in which tissue fibrosis has a major pathogenic role, as hepatitis induced 
liver fibrosis, idiopathic pulmonary fibrosis, certain fibrotic cancers and Duchenne muscular 
dystrophy (DMD). Pamrevlumab (MW ~150 kDa) is produced by mammalian Chinese hamster 
ovary (CHO) fed-batch cell culture system. Pamrevlumab contains 1,326 amino acids and binds 
with high affinity to domain 2 of CTGF (dissociation constant: Kd=0.1–0.2 nM). 
2.2. 
Idiopathic Pulmonary Fibrosis 
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fatal lung disease of unknown 
etiology characterized by fibrotic interstitial infiltrates that are consistent with the 
histopathologic pattern of usual interstitial pneumonia (Gross, 2001, Raghu, 2018). IPF is the 
most common of seven recognized types of idiopathic interstitial pneumonia (Kim, 2006, Travis, 
2013). 
The pathogenesis of IPF has not been clearly defined. The long-held view that fibrosis in IPF is 
triggered by chronic inflammation (alveolitis) has given way to the current belief that IPF is a 
disorder caused by repetitive epithelial injury (Selman, 2001, Selman, 2006, Wilson, 2009). The 
recurrent, subclinical epithelial injury superimposed on accelerated epithelial aging leads to 
aberrant repair of the injured alveolus and deposition of interstitial fibrosis by myofibroblasts 
(Lederer 2018).  According to this hypothesis, alveolar cell injury and activation initiate a 
dysregulated, exaggerated fibrotic healing process characterized by myofibroblast proliferation 
and progressive deposition of extracellular matrix (ECM) in genetically susceptible individuals 
(Agostini, 2006, Gross, 2001, Selman, 2004, Selman, 2006, Willis, 2006). ECM deposition and 
other pathologic processes in IPF, including epithelial basement membrane disruption, 
angiogenesis, smooth muscle cell proliferation, infiltration of mononuclear cells, accumulation 
of loose connective tissue, and cyst formation, eventually remodel the normal lung architecture 
and impair the lung’s ability to perform gas exchange. 
Exogenous and endogenous insults to the alveolar epithelium have been proposed as possible 
stimuli of the fibrotic process in IPF, but conclusive associations have not been established. The 
most commonly cited exogenous triggers of alveolar injury are exposure to cigarette smoke 
(Baumgartner, 1997, Flaherty, 2004) and environmental and occupational dusts (Hubbard, 2001, 
Taskar, 2006), viral infection (Kelly, 2002, Tang, 2003), and gastroesophageal reflux (Raghu, 
2006). Alveolar epithelial cell apoptosis and failure of alveolar re-epithelialization (Barbas-Filho, 
2001, Li, 2004, Selman, 2001, Selman, 2006), resistance of myofibroblasts to apoptosis 
(Thannickal, 2006), shortened telomeres, oxidative injury, proteostatic dysregulation and 
endoplasmic reticulum stress, and mitochondrial dysfunction lead to decreased alveolar 
epithelial-cell proliferation and secretion of profibrotic mediators (Beeh, 2002, Cantin, 1987, 
Daniil, 2008, Hunninghake, 2005, Waghray, 2005, Alder 2008, Selman 2014). Additionally, 
activation of the coagulation cascade (Chambers, 2008, Selman, 2001), and circulating bone 
marrow-derived fibroblast precursors (fibrocytes) (Andersson-Sjoland, 2008, Hashimoto, 2004) 
have also been implicated in the pathogenesis of IPF. Genetic factors may play a role, as gene 


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mutations account for some cases of familial IPF (Lawson, 2006), including mutations in the 
gene encoding surfactant protein C and telomerase genes that are responsible for telomere length 
shortening (Armanios, 2007, Loyd, 2008, Tsakiri, 2007). 
Transforming growth factor-beta (TGF-β) is considered a key cytokine that is thought to drive 
the fibrotic process in IPF (Agostini, 2006, Bergeron, 2003). However, many other proteins have 
been implicated in regulation of the complex process of cellular interactions among activated 
epithelial cells, myofibroblasts, fibroblasts, macrophages, endothelial cells, and lymphocytes, 
including connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), tumor 
necrosis factor-alpha (TNF-α), endothelin-1, interleukin (IL)-1β, IL-4, IL-10, IL-13, IL-17, 
osteopontin, matrix metalloproteases, and multiple chemokines (Agostini, 2006, Ask, 2006, 
Pardo, 2006, Selman, 2004, Selman, 2006, Strieter, 2007, Wilson, 2009). The roles of epithelial-
mesenchymal transition (EMT) and circulating fibrocytes and other extrapulmonary fibroblast 
progenitor cells in expanding the myofibroblast population within the lung have been the subject 
of active debate (Lama, 2006, Strieter, 2009, Willis, 2006, Kage 2012). Connective tissue growth 
factor is a central mediator of tissue remodeling and fibrosis and has been reported to be essential 
for the fibrotic activity of TGF- β (Blom, 2002, Grotendorst, 1997, Wang 2011, Lipson, 2012). 
The epidemiology of IPF is not clearly defined. A report of a population-based study of adults 
with IPF in Olmstead County, Minnesota, from 1997 to 2005, revealed a prevalence of IPF of 
27.9 to 63 cases per 100,000, and an incidence of 8.8 to 17.4 cases per 100,000, again depending 
on the diagnostic criteria (Fernandez Perez, 2010). In the United States, the prevalence of IPF 
has been reported to range from 10 to 60 cases per 100,000, although in one study, the 
prevalence was 494 cases per 100,000 in 2011 among adults over the age of 65 years, which was 
twice as high as the prevalence recorded 10 years earlier (Lederer, 2018). The prevalence of IPF 
increases with age, and most IPF patients are age 60 or older at the time of diagnosis, although it 
is unclear whether this reflects increased recognition or a true increase in incidence (Lederer, 
2018) The disease is more common in men than in women (Fernandez Perez, 2010). Most 
patients are current or former smokers. A familial form of IPF may account for as many as 20% 
of cases of IPF (Loyd, 2008). 
Patients with IPF suffer from progressive dyspnea and cough, and most have been symptomatic 
for several years by the time of their initial presentation. Delayed diagnosis is therefore common. 
Physical examination often reveals bibasilar inspiratory crackles, but it may be normal. Digital 
clubbing is observed in about one quarter of IPF patients (King, Jr., 2001). The chest radiograph 
reveals non-specific bilateral, reticular infiltrates in the periphery of the lower lung zones, often 
with findings suggestive of pulmonary hypertension. Pulmonary function tests demonstrate 
reduced lung volumes, proportionate reduction in the pulmonary diffusing capacity, and a normal 
to increased FEV1/FVC ratio (Martinez, 2006). Arterial hypoxemia, oxyhemoglobin 
desaturation, and an increased alveolar-arterial oxygen gradient that worsens with exercise are 
typically observed in patients with IPF (Idiopathic pulmonary fibrosis: diagnosis and treatment. 
International consensus statement. American Thoracic Society (ATS), and the European 
Respiratory Society (ERS), 2000, King, Jr., 2001). High resolution computed tomography 
(HRCT) scans display subpleural reticular abnormalities and honeycombing, especially in the 
lung bases (Kim, 2006). Traction bronchiectasis is a common finding. The presence of extensive 
ground glass opacities, peribronchial and perivascular predominance of infiltrates, discrete lung 
cysts, small nodules, air trapping, mosaic attenuation, and consolidation suggest alternative 


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diagnoses (Misumi, 2006). The sensitivity and specificity of HRCT for the diagnosis of IPF in 
the hands of expert radiologists approach 90% and 80%, respectively (Kim, 2006, Raghu, 1999). 
Acute exacerbations of IPF, defined as an acute, clinically significant respiratory deterioration 
(acute worsening or development of dyspnea typically <1 mo duration) characterized by 
evidence of new widespread alveolar abnormality (computed tomography with new bilateral 
ground-glass opacity and/or consolidation superimposed on a background pattern consistent with 
usual interstitial pneumonia pattern), not fully explained by cardiac failure or fluid overload 
(Collard, 2016). These exacerbations are the leading cause of hospitalization and death in 
patients with IPF (Kondoh, 2010, Daniels 2008, Kim, 2015). The etiology of acute exacerbations 
of IPF remains uncertain, and its pathobiology may be related to intrinsic biological dysfunction 
of the lung that makes individuals with IPF more susceptible to external insults than individuals 
without IPF (Collard, 2016). A meta-analysis of six clinical trials in patients with IPF revealed a 
weighted average of 4.1 acute exacerbations per 100 patient-years (Atkins, 2014).  A less 
common, rapidly progressive form of IPF, which is common in actively smoking males, has been 
described (Selman, 2007). 
The diagnosis of IPF is suspected when the clinical and radiographic features described above 
occur in a patient with no known risk factors for interstitial disease and after other types of 
idiopathic interstitial pneumonias have been excluded. Transbronchial lung biopsy and 
bronchoalveolar lavage are occasionally performed to rule other causes of lung infiltrates. The 
diagnosis of IPF is confirmed when HRCT demonstrates definite features of “usual interstitial 
pneumonia” (UIP) (Subpleural and basal predominant reticular infiltrates; distribution is often 
heterogeneous, Honeycombing with or without peripheral traction bronchiectasis or 
bronchiolectasis) in the appropriate clinical setting. For patients with newly detected Interstitial 
lung disease (ILD) of apparently unknown cause who are clinically suspected of having IPF and 
have an HRCT pattern of UIP, the current recommendation is to not perform Surgical Lung 
Biopsy (SLB) (strong recommendation). On the other hand, patients with an HRCT pattern of 
probable UIP, indeterminate, or an alternative diagnosis, SLB is recommended (conditional 
recommendation) (Raghu, 2018).  
The histopathologic pattern of UIP is a dense fibrosis with architectural distortion (i.e., 
destructive scarring and/or honeycombing), predominant subpleural and/or paraseptal 
distribution of fibrosis, patchy involvement of lung parenchyma by fibrosis, fibroblast foci, and 
the absence of features to suggest an alternate diagnosis (Raghu, 2018). These histopathologic 
features are more commonly found in subpleural regions in the lower lung zones. Interstitial 
infiltrates of lymphocytes and plasma cells are usually not prominent (Visscher, 2006). 
Pirfenidone and nintedanib are approved drugs for the treatment of IPF. In addition to these 
drugs, IPF patients are usually managed with supportive measures such as symptomatic 
treatment of cough and dyspnea, supplemental oxygen for hypoxemia, smoking cessation, 
pulmonary rehabilitation, and prophylaxis and control of respiratory tract infections (Idiopathic 
pulmonary fibrosis: diagnosis and treatment. International consensus statement. American 
Thoracic Society (ATS), and the European Respiratory Society (ERS), 2000, (Collard, 2004, 
Walter, 2006, Wuyts, 2009). Corticosteroids and the immunosuppressive drugs 
cyclophosphamide and azathioprine were commonly prescribed for IPF in the past, but there is 
no evidence that these drugs improve patient outcomes or alter the natural course of the disease 
(Collard, 2004, Walter, 2006). Furthermore, IPF subjects taking a combination of prednisone, 


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azathioprine, and N-acetylcysteine (NAC) in one arm of a three-arm multicenter Phase 3 clinical 
trial experienced increased risks of hospitalization and death compared with those taking NAC 
only or placebo only (Raghu, 2012). A multicenter Phase 3 randomized trial of warfarin in 
patients with progressive IPF was stopped because of increased mortality in subjects taking 
warfarin compared with those taking placebo (Noth, 2012). Lung transplantation is the only 
treatment that improves survival (Noth, 2007, Walter, 2006, Lancaster 2019), but most IPF 
patients are not eligible for transplantation because of their age or comorbid conditions. 
In two Phase 3 clinical trials examining the safety and efficacy of pirfenidone in patients with 
IPF, the mean decline in percent predicted FVC (FVCpp) from baseline to 72 weeks was 12.4% 
in one group receiving placebo and 9.6% in the other placebo group (Karimi-Shah, B., 2010). As 
the interstitial fibrosis and architectural distortion advance in IPF, the lung becomes more 
noncompliant, and the work of breathing and dyspnea increase. Progressive pulmonary 
hypertension and cor pulmonale often characterize the late course of the disease.  
Several retrospective studies suggest that the median survival time from diagnosis is 2–3 years 
(Raghu, 2011). The 5-year survival rate of patients with IPF is approximately 20% to 40% (Kim, 
2006), which is worse than that of all major cancers except cancer of the lung, pancreas, and 
esophagus (Siegel, 2012). Mortality from IPF was reported to have increased 28% in men and 
41% in women between 1992 and 2003 (Olson, 2007). The majority of IPF patients die from 
complications of the disease, such as respiratory failure, pulmonary hypertension, and 
pneumonia, or from coronary artery disease (Daniels, 2008, Gross, 2001, Martinez, 2005, Olson, 
2007).  
2.3. 
Connective Tissue Growth Factor 
Connective tissue growth factor is a 38 kDa secreted matricellular glycoprotein of the cysteine-
rich 61/CTGF/nephroblastoma overexpression (CCN) family (Perbal, 2004, Rachfal, 2005) 
which was recently renamed cellular communication network family (Perbal 2018). It is 
produced by many cells, including fibroblasts, myofibroblasts, endothelial cells, mesangial cells, 
and stellate cells. 
The name “connective tissue growth factor” implies a mechanism of action akin to that of 
classical growth factors, which signal through specific cell-surface receptors. However, 
experimental evidence does not support this concept. Instead, CTGF and the other members of 
the CCN family have activities associated with matricellular proteins that function in a more 
subtle modulatory fashion. Matricellular proteins, with prototypical representatives including 
secreted protein acidic and rich in cysteine (SPARC), osteopontin, and thrombospondins, are a 
subclass of ECM proteins that modulate cellular functions and signaling pathways through 
multiple mechanisms depending on cell type and the cellular context (Bornstein, 2002). These 
proteins are generally expressed at high levels during development and in response to injury; 
they typically bind to multiple cell-surface receptors, ECM components, growth factors, and 
cytokines. Connective tissue growth factor fits squarely within this definition (Chen, 2009). The 
cellular functions that can be modulated by CTGF include secretion and/or organization of ECM, 
cell proliferation, survival, adhesion, migration and EMT. Modulation of cellular signaling 
appears to occur through interactions of CTGF with 1) cell surface components such as integrins 
or the low density lipoprotein receptor-related protein (LRP)-1 (a multifunctional endocytic and 
signaling receptor), 2) cytokines and cytokine inhibitors, and 3) matrix components such as 


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heparin sulfate proteoglycans (HSPGs) and fibronectin. Interactions with HSPGs may displace 
other HSPG-binding proteins such as vascular endothelial growth factor (VEGF) and bone 
morphogenetic proteins (BMPs). It is believed that binding of cytokines to CTGF may either 
sequester them in an inactive conformation, or help to present cytokine binding partners to their 
receptors. 
Connective tissue growth factor is a central mediator of tissue remodeling and fibrosis (Lipson, 
2012). Connective tissue growth factor is essential for the fibrotic activity of TGF-β (Mori, 1999, 
Wang, 2011) but it may also act independently of TGF-β. While much has been made of the role 
of TGF-β in fibrosis, studies of the role of fibronectin in pulmonary fibrosis showed that the 
activity of TGF-β is dependent on cellular fibronectin to induce myofibroblast differentiation and 
that cellular fibronectin may have a fundamental role in activation of latent TGF-β (Muro, 2008). 
Shi-wen and colleagues showed that critical activities of TGF-β in the fibrotic process are 
dependent on CTGF expression, including EMT and ECM deposition, supporting the idea that 
CTGF over-expression is critical for activities attributed to TGF-β (Shi-wen, 2006). 
Connective tissue growth factor has been shown to be an important mediator of pulmonary 
fibrosis in a mouse model of bleomycin-induced pulmonary fibrosis (Bonniaud, 2004). Lasky 
and coworkers observed upregulation of CTGF messenger ribonucleic acid (mRNA) gene 
expression in a mouse model of bleomycin-induced pulmonary fibrosis, suggesting a possible 
role of CTGF in the pathogenesis of lung fibrosis (Lasky, 1998). 
2.4. 
Connective Tissue Growth Factor in Idiopathic Pulmonary Fibrosis 
Transcripts of genes for TGF-β1 and CTGF were reported to be approximately 7-fold and 4-fold 
higher, respectively, in transbronchial lung biopsy specimens of patients with IPF compared with 
normal (Ziesche, 1999). TGF-β is expressed at fibrogenic foci in IPF (Broekelmann, 1991). 
Increased CTGF gene expression has been described in transbronchial biopsy specimens and in 
bronchoalveolar lavage fluid in patients with IPF (Allen, 1999, Pan, 2001). Allen and coworkers 
also reported that CTGF mRNA expression is increased 10-fold in bronchoalveolar lavage fluid 
in patients with IPF, compared with healthy control subjects (Allen, 1999). Connective tissue 
growth factor in plasma was reported to be elevated in IPF patients and the abundance correlated 
with change in FVC (Kono, 2011). These observations suggest that CTGF may have a role in the 
pathogenesis of IPF. 
2.5. 
Clinical Trial Experience with Pamrevlumab 
The clinical trial experience with pamrevlumab is presented in the current Investigator’s 
Brochure (IB). 
Overall, pamrevlumab has been well-tolerated. Adverse events (AEs) have been generally mild 
or moderate in severity and transient in duration. The AEs have been typical of the subjects’ 
underlying medical condition(s) and, in placebo-controlled studies, were equally distributed 
between the placebo and pamrevlumab treatment groups. Infusions of pamrevlumab have been 
well tolerated.  
Duration of exposure to pamrevlumab by indication is described in the IB.  
See the IB for additional information. 


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2.6. 
Rationale for Pamrevlumab in Idiopathic Pulmonary Fibrosis 
The observations that CTGF is a central mediator in the process of fibrosis suggest a potential 
role for pamrevlumab in interfering with the activity of CTGF and thereby preventing or 
reversing fibrotic lung damage in IPF. Connective tissue growth factor is considered a potential 
target for therapeutic intervention in pulmonary fibrosis (Antoniou, 2007, Ask, 2006, Blom, 
2002, Bonniaud, 2004, Grotendorst, 1997). 
In a mouse model of radiation-induced pulmonary fibrosis (Bickelhaupt et al, 2017), 
pamrevlumab at 10 mg/kg or placebo was administered by IP injection 3 times a week for 8 
weeks starting before or up to 16 weeks after the irradiation. Pamrevlumab-treated mice 
demonstrated better survival compared with untreated irradiated mice. Pamrevlumab attenuated 
lung remodeling, improved pulmonary function, and improved lung density in a schedule 
dependent manner. Additional observations in gene-expression changes in the lungs also 
indicated that pamrevlumab can disrupt physiological tissue remodeling after the process has 
begun.  In particular, pamrevlumab appears to disrupt a CTGF autocrine loop in mesenchymal 
cells like myofibroblasts that reduces their recruitment of leukocytes like macrophages, mast and 
dendritic cells via chemokine secretion.  This disruption results in collapse of the cellular 
crosstalk that drives tissue remodeling (Sternlicht et al, 2018). 
In another study, administration of pamrevlumab to mice with bleomycin-induced pulmonary 
fibrosis significantly inhibited lung hydroxyproline content, a marker of lung collagen content 
(FibroGen, 2003, data on file). 
These preclinical findings are supported by preliminary efficacy data in the FGCL-3019-049 
study, which suggest that treatment of subjects with IPF with pamrevlumab 15 mg/kg and 30 
mg/kg IV every 3 weeks is associated with improvement or stability in quantified scores of 
whole lung fibrosis in approximately 45 percent of subjects at 24 weeks (Raghu, 2012). Changes 
from baseline in these scores were significantly correlated with changes in FVCpp value (Raghu, 
2012).  
In 2012, the Food and Drug Administration (FDA) granted Orphan Drug Designation to 
pamrevlumab for the treatment of IPF. Additionally, results from the Phase 2, randomized, 
double-blind, placebo-controlled trial of pamrevlumab in IPF (Study 067) has shown a 
statistically significant difference from placebo for the primary efficacy endpoint of FVCpp 
change from baseline to week 48 favoring pamrevlumab. Other important efficacy endpoints 
favoring pamrevlumab include: proportion of subjects with disease progression, time to disease 
progression, change from baseline in lung fibrosis (QLF, FIB) score to Week 48 measured by 
quantitative HRCT, patient-reported quality of life measurements using the SGRQ (positive 
trends) and the UCSD-SOBQ, as well as favorable trend in all-cause mortality.  
These results of an open-label Phase 2 study and a randomized placebo-controlled Phase 2 study 
suggest pamrevlumab slows the progression of IPF as measured by change in FVCpp, 
quantitative analysis of fibrosis, and time to disease progression or death. 
2.6.1. 
Clinical Studies in IPF 
FibroGen has sponsored 5 studies in idiopathic pulmonary fibrosis (IPF), three Phase 1 / 2 
studies that are completed, and two Phase 3 studies that are ongoing. 


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Study FGCL-MC3019-002, was a Phase 1 open-label, dose-escalation study to determine the 
safety, pharmacokinetics, immunogenicity, and bioactivity of escalating single doses of 
pamrevlumab in subjects with IPF; a total of 21 subjects were treated with pamrevlumab. 
Study FGCL-3019-049, was an open-label, Phase 2 study to evaluate the safety, tolerability, and 
efficacy of pamrevlumab in subjects with IPF; subjects were treated with 2 doses of 
pamrevlumab every 3 weeks: 15mg/kg and 30mg/kg. Subjects who met extension criteria 
continued to receive pamrevlumab treatment every 3 weeks until disease progression. Results of 
the 049 study were published (Raghu et al. 2016, Clukers et al. 2018). 
Study FGCL 3019-067 (PRAISE Study), was a Phase 2, randomized, double-blind, placebo-
controlled study in subjects with IPF to evaluate the safety and efficacy of pamrevlumab 
administered at 30 mg/kg by IV infusion every 3 weeks for 45 weeks for a total of 16 infusions. 
Following the double-blind randomized treatment period, qualifying subjects had the option to 
enter an open-label extended treatment period to receive pamrevlumab 30 mg/kg every 3 weeks. 
Fifty subjects were randomized to pamrevlumab and fifty-three were randomized to placebo in 
the main study. The study was amended to include an additional subset of subjects (called “sub-
study” to differentiate from the “main” study) receiving background IPF approved therapy with 
pirfenidone or with nintedanib in a stratified manner. For the sub-study, the randomized double-
blind placebo-controlled treatment period was 24 weeks with no extended treatment period. 
For details on studies 049 and 067 (main study, extended treatment period, and the sub-study) 
see Section 2.6.3 below, and the current version of the IB. Results of the PRAISE study were 
published (Richeldi et al, 2019). 
2.6.2. 
Dose Rationale 
Pamrevlumab has been tested in a Phase 1 single-ascending dose study (FGCL-MC3019-002) 
and two repeat-dose Phase 2 studies (Study 049 and Study 067) in IPF patients. The single-dose 
study utilized intravenous infusions of 1, 3, or 10 mg/kg. Study 049 was an open-label study 
testing 15 mg/kg and 30 mg/kg every 3 weeks for 45 weeks as monotherapy. Study 067 was a 
placebo-controlled study testing 30 mg/kg every 3 weeks for 45 weeks as monotherapy. All 
studies collected safety and tolerability data, samples for pharmacokinetic analyses and 
pulmonary function test measurements. 
Prior to studying IPF, pamrevlumab was tested in a Phase 1 multiple ascending dose study in 
combination with gemcitabine and erlotinib in advanced pancreatic cancer patients using IV 
doses of 3 mg/kg up to 45 mg/kg every 2 weeks, and weekly doses up to 22.5 mg/kg. The Phase 
1 study in pancreatic cancer included assessments of safety and tolerability, samples for 
pharmacokinetic analyses and measures of disease progression.  
Collectively these studies have investigated repeat doses up to 30 mg/kg every three weeks in 
IPF and up to 45 mg/kg every 2 weeks in pancreatic cancer. The doses in all studies were found 
to be safe and tolerable and active doses were identified in each indication.   
The combined data were analyzed via population pharmacokinetics (PopPK) to determine if the 
PK for the two indications were similar. The combined PopPK model was used to derive steady 
state trough exposures of pamrevlumab leading to exposure-response relationships for the two 
Phase 2 IPF studies. The efficacy measure was forced vital capacity FVCpp. Clinical trial 
simulations of FVCpp were also performed to evaluate the probability of success of 


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pamrevlumab versus placebo at different doses. Safety data for the two Phase 2 IPF studies were 
tabulated by dose group, and exposure-response relationships were explored for selected adverse 
events. These analyses form the basis for the Phase 3 dose in IPF patients and shows that an IV 
administration of 30 mg/kg of pamrevlumab every three weeks to IPF patients achieves better 
efficacy than placebo for FVCpp, and reaches the mean pamrevlumab trough where efficacy 
begins to plateau (approximately 150 µg/mL). 
2.6.3. 
Safety Summary and Benefit/Risk Assessment 
Overall, pamrevlumab has been well-tolerated. Three Phase 1/2 studies were completed in IPF: 
Study FGCL-MC3019-002 (N=21); Study FGCL-3019-049 (N=89; 53 receiving 15mg/kg and 
36 receiving 30mg/kg pamrevlumab); and Study FGCL 3019-067 (N=103; 50 randomized to 
pamrevlumab 30mg/kg, 53 randomized to placebo). The majority of TEAEs reported were of 
respiratory nature and consistent with those reported for historical, comparable IPF populations 
(Richeldi, 2014). Across the IPF studies, the most common treatment emergent adverse event 
(TEAEs) by subject have been cough, fatigue, dyspnea, upper respiratory tract infection, 
bronchitis, and nasopharyngitis. 
In study FGCL-MC3019-002, pamrevlumab was well tolerated across the range of doses studied; 
there were no dose-limiting toxicities, and adverse events were generally mild or moderate. A 
single TESAE, interstitial lung disease in the 10 mg/kg dose cohort, was reported during the 
study. No subject withdrew due to a TEAE.  
During a post-PK long term follow up three subjects died: approximately two, six, and 11 
months after the administration of pamrevlumab, respectively, due to disease progression. None 
of the deaths were considered related to pamrevlumab. 
In study FGCL-3019-049, the most frequent TEAEs were cough, fatigue, dyspnea, upper 
respiratory tract infection and bronchitis, which are consistent with those AEs reported for 
historical, untreated controls in IPF populations in randomized, placebo-controlled studies (King 
2009; Raghu et al, 2004; Zisman et al, 2010; King et al, 2014; Richeldi et al, 2014). 
TEAEs were similar across cohorts and also similar when comparing these observed during the 
initial 48 weeks and during the extension. Approximately one-third of study subjects experienced 
TEAEs Grade ≥3 and these were of respiratory nature, related to IPF or its complications. 
TESAEs were reported in about one-third of subjects, mainly related to IPF or its complications. 
Treatment or study discontinuation was reported for 16 subjects, the most frequent cause being 
IPF progression. A total of 13 deaths have been reported during the entire study duration 
(including the first 48 weeks and the extension periods), 12 of them from respiratory causes. The 
mortality rate observed in this study is below the calculated expected mortality rate as per the 
GAP system (Ley et al, 2012). 
In Study FGCL-3019-067, pamrevlumab was well tolerated, with a safety profile similar to that 
of placebo: 48 (96%) patients in the pamrevlumab group compared to 52 (98%) patients in the 
placebo group had at least one TEAE. TESAEs were observed in 12 patients (24%) in the 
pamrevlumab group and 8 (15%) in the placebo-group and were mostly respiratory-related; 
however, fewer patients in the pamrevlumab group discontinued study treatment because of a 
TESAE than did those in the placebo group: three (6%) versus seven (13%), and fewer patients 
in the pamrevlumab group (five [10%]) compared to placebo (seven [13%]) were hospitalized 


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following a respiratory-related TESAE. Nine patients died during the study: three (6%) in the 
pamrevlumab group and six (11%) in the placebo group. No safety concerns were identified in 
the analysis of clinical laboratory results or ECG parameters.  
Regarding efficacy results in study 067, subjects receiving pamrevlumab showed a statistically 
significant difference from placebo for the primary efficacy endpoint of FVCpp change from 
baseline to week 48 favoring pamrevlumab. In addition, other efficacy results showed that 
pamrevlumab slowed the progression of IPF as measured by change in HRCT quantitative lung 
fibrosis, and time to disease progression as measured by 10% categorical decline in FVCpp or 
death. 
In summary, across all completed phase 2 IPF studies, the observed TEAEs have been generally 
mild or moderate in severity and transient in duration, have been typical of the patients’ 
underlying medical condition(s) and, in the placebo-controlled study, were equally distributed 
between the placebo and pamrevlumab treatment groups.  
Therefore, based on the cumulative safety data and the potential benefit of pamrevlumab in IPF, 
the benefit/risk profile is considered overall favorable (Wells, 2019). 


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3. 
OBJECTIVES AND ENDPOINTS 
3.1. 
Objective 
The overall objective of this trial is to evaluate the efficacy and safety of 30 mg/kg IV infusions 
of pamrevlumab as compared to placebo in subjects with idiopathic pulmonary fibrosis.   
3.2. 
Endpoints 
3.2.1. 
Primary Endpoint: 
• Change in FVC (L) from baseline at Week 48  
3.2.2. 
Secondary Endpoints 
Endpoints: 
• Time to disease progression, defined as absolute FVCpp decline of ≥10% or death, 
whichever occurs first 
• Change in Quantitative Lung Fibrosis (QLF) volume from baseline at Week 48 
• Time to any component of the clinical composite endpoint, whichever occurs first: 
acute IPF exacerbation, respiratory hospitalization, or death 
• Time to first acute IPF exacerbation during study 
• Time to all-cause mortality during study 
• Time to first respiratory hospitalizations during study 
3.2.3. 
Exploratory Endpoints 
Exploratory endpoints include: 
• Time to composite of: respiratory hospitalization or death or absolute FVCpp decline 
≥10%, whichever occurs first 
• Change in absolute FVCpp from baseline at Week 48 
• Change in relative FVCpp from baseline at Week 48 
• Change in St. George’s Respiratory Questionnaire (SGRQ) score from baseline at 
Week 48 
• Change in University of California San Diego – Shortness of Breath Questionnaire 
(UCSD-SOBQ) score from baseline at Week 48 
• Change in Leicester Cough Questionnaire (LCQ) from baseline at Week 48 
• Exploratory biomarkers 


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3.2.4. 
Safety Assessment  
Treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events 
(TESAEs), clinical laboratory parameters, vital signs, immunogenicity (Human Anti-Human 
Antibody [HAHA] formation), and hypersensitivity/anaphylactic reactions.  
3.3. 
Overall Study Design 
This is a Phase 3, randomized, double-blind, placebo-controlled multi-center trial to evaluate the 
efficacy and safety of pamrevlumab in subjects with IPF. Approximately 340 subjects will be 
enrolled in this trial.   
Subjects must be fully informed of the potential benefits of approved products and make an 
informed decision that they prefer to participate in a clinical trial in which they could be 
randomized to placebo. 
NOTE: Plans to re-screen a subject must be discussed with and approved by the Medical 
Monitor, prior to re-screening 
Subjects will be randomized in a 1:1 ratio to one of the two study treatment arms:  
• Arm A: pamrevlumab, 30 mg/kg IV, Day 1 and every 3 weeks thereafter 
• Arm B: Matching placebo IV, Day 1 and every 3 weeks thereafter  
Subjects will be stratified by: 
• Prior treatment with an approved IPF therapy (Yes/No) 
• GAP stage (I, II, III) derived from GAP score obtained at screening (See Appendix 5). 
NOTE:  For calculation of the GAP score: Use the Best-Test Review (BTR) assessment 
provided by the spirometry vendor over-reader of the screening value (See Section 6.2.5 and 
Appendix 5). 
This study consists of the following study periods: 
• Main (double blind, placebo-controlled) phase:  
 Screening period: Up to 6 weeks 
 Treatment period: 48 weeks  
• Optional, open label extension phase:  
 Access to pamrevlumab will be available until the last subject completes 48 
weeks of treatment in the OLE phase, or pamrevlumab is commercially 
available for the indication of IPF, or the Sponsor decides to end the OLE 
phase, whichever occurs first.  
• Follow-up period/final safety assessment:  
 28 days after last dose 
 60 days after last dose: follow-up phone call, for a final safety assessment   


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The intent of this study is to evaluate the efficacy and safety profile of pamrevlumab as 
monotherapy in subjects with IPF who were either treated with an approved therapy in the past, 
but discontinued that therapy (possible reasons for discontinuation of approved therapy could 
include, but are not limited to, intolerance or disease progression); or who decided voluntarily to 
forego such treatment, after being fully informed of the potential benefits/risks. 
NOTE: No subject should discontinue an approved therapy for the purpose of enrolling in this 
study. 
During the treatment period, co-administration of one of the two approved IPF therapies, 
pirfenidone or nintedanib, is acceptable if clinically indicated in the Investigator’s opinion, after 
assessment of potential risks / benefits of such combination with blinded study treatment. See 
also Section 5.1.10. 
A schematic overview of the study is provided in Figure 1.  A detailed overview of assessments 
and the timing of assessments is provided in Appendix 1.  A detailed overview of the OLE 
assessments and procedures is provided in Appendix 6. 
3.3.1. 
Study Duration 
Subjects are encouraged to receive all 17 study drug doses in the main study. Subjects who do 
not receive all doses are encouraged to continue with study visits and assessments. 
Subjects who complete the Week 48 visit (regardless of the number of study drug doses 
received) will be eligible for an open-label extension (OLE) phase, which will provide 
continuing access to pamrevlumab until the last subject completes 48 weeks of treatment in the 
OLE phase, or pamrevlumab is commercially available for the indication of IPF, or the Sponsor 
decides to end the OLE phase, whichever occurs first.  
Subjects who withdraw from the main study early, for any reason, will need to return for an early 
termination (ET) visit as soon as feasible and 28 days after the last dose, with a follow-up phone 
call 60 days after the last dose for a final safety assessment. Such subjects should also be 
contacted by phone at weeks 24 and 48, to check the subject’s vital status; such subjects will not 
be eligible for the OLE phase.  
See also Section 4.3 for mandatory Study Withdrawal reasons, and Section 4.4 for procedures 
related to Early Study Withdrawal. 
Figure 1: 
FGCL-3019-091 Study Schema 
 


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3.3.2. 
Placebo Control Group 
In order to evaluate the effect of treatment with pamrevlumab on the endpoints described in 
Section 3.2, 50% of subjects will be randomized to placebo treatment. 
A placebo control is appropriate and ethical for this trial given the intended population of 
participating subjects: those who have not responded to or are intolerant of approved IPF 
therapies, or who decided voluntarily to forego such treatment, after being fully informed of the 
potential benefits/risks. For these subjects the best treatment option is supportive care, which is 
available to them within this protocol. In addition, they have the option of receiving treatment 
with an approved IPF therapy any time after randomization, if clinically indicated in the 
Investigators opinion, without the need to end study participation. All study subjects who 
complete Week 48 visit (regardless of the number of study drug infusions received) will be 
offered participation in the optional OLE phase which provides continuing access to 
pamrevlumab treatment (Appendix 6).  
 NOTE: No unblinding of subject’s treatment assignment in the main study will occur for 
purposes of OLE participation.  
3.4. 
Randomization and Treatment Assignment 
3.4.1. 
Randomization  
Approximately 340 subjects will be randomized 1:1 to receive either pamrevlumab or placebo, 
resulting in approximately 170 subjects per treatment arm. Each subject will receive a unique 
study ID number during screening.   
Subjects will be stratified by: 
• Prior treatment with an approved IPF therapy (Yes/No) 
• GAP stages (I, II, III), derived from the GAP scores obtained at screening (See Section 
6.2.5 and Appendix 5).     
  
Automated randomization and treatment assignments will be performed by an Interactive 
Response System (IXRS or IRT).   
3.4.2. 
Treatment Assignment 
Subjects will be randomized 1:1 to one of two treatment arms: 
• Arm A: Pamrevlumab 
• Arm B: Placebo 
3.5. 
Blinding 
This is a double-blind, placebo-controlled study. The Investigator, study site staff, subjects, 
selected Sponsor clinical team and designees are blinded to study drug assignment. Blinded 


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treatment with a placebo control is the gold standard method for obtaining unbiased assessments 
of safety and efficacy in clinical trials of investigational drugs such as pamrevlumab. 
3.5.1. 
Maintenance of Blinding 
The study blind will be maintained for all parties specified above throughout the study with the 
exception of the scenarios outlined in Section 3.5.2. Pamrevlumab and placebo are identical in 
appearance, packaging, and labeling in order to maintain the study blind.   
3.5.2. 
Request for Unblinding of Treatment Assignment 
 
Breaking the blind during the study (for a single subject) should be considered only when 
knowledge of the treatment assignment is deemed essential by the Investigator due to immediate 
safety concerns, or is considered essential for the immediate subject management.  The 
responsibility to break the blind (for a single subject) in emergency situations resides solely with 
the Investigator. It is the Investigator’s responsibility to promptly document and explain any 
unblinding to the Sponsor.   
Such emergency unblinding will be done by the Investigator using the automated Interactive 
Response System (IXRS or IRT) which ensures rapid unblinding in emergency situations. 
 
 


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4. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1. 
Subject Inclusion Criteria 
In order to be eligible for inclusion in this trial, a subject must meet all of the following: 
1. Age 40 to 85 years, inclusive, at screening initiation. 
2. Diagnosis of IPF as defined by ATS/ERS/JRS/ALAT guidelines (Raghu 2018).  
3. IPF diagnosis within the past 7 years, with onset defined as the date of the first recorded 
diagnosis of IPF by HRCT and/or surgical lung biopsy (SLB), or other appropriate tissue 
sample (e.g., cryobiopsy) in the medical history. 
4. Interstitial pulmonary fibrosis defined by HRCT scan at screening, with evidence of 
≥10% to <50% parenchymal fibrosis (reticulation) and <25% honeycombing, within the 
whole lung. NOTE: this requires confirmation by an Independent Radiology Imaging 
Review Group, prior to randomization. If a recent HRCT scan (within 3 months prior to 
screening) is available, it can be utilized for screening purposes, provided it is submitted 
and evaluated by the Independent Radiology Imaging Review Group, is adhering to the 
imaging parameters detailed in the Imaging Core Manual (ICM), and is using the same 
accredited scanner as the on-study HRCT scans. 
5. FVCpp value >45% and <95% at Screening and Day 1 (prior to randomization).  
6. Diffusing capacity of the lungs for carbon monoxide (DLCO) percent predicted and 
corrected by Hb value ≥25% and ≤90% at screening (determined locally). If a DLCO is 
available within 3 months prior to screening, it can be utilized for screening purposes.  
7. Both FVC and DLCO testing must be representative of the IPF underlying disease (i.e., 
have been obtained in absence of an acute respiratory event [e.g., lung infection, cold] or 
other events that are known to affect PFT testing results. [e.g., broken rib, chest pain, 
other]). 
8. Not currently receiving treatment for IPF with an approved therapy for IPF (i.e., 
pirfenidone or nintedanib) for any reason, including prior intolerance or lack of response 
to an approved IPF therapy, or choice to forego treatment with an approved IPF therapy 
after a full discussion with the Investigator regarding risks/benefits of such therapy. 
NOTE: no subject should discontinue approved therapy for the purpose of enrolling in 
this study. 
9. Male subjects with partners of childbearing potential and female subjects of childbearing 
potential (including those <1 year postmenopausal) must use a highly effective method of 
contraception per Clinical Trial Facilitation Group (CTFG) recommendation (see 
protocol section 5.2.3 for details) during the conduct of the study, and for 3 months after 
the last dose of study drug.  Women not of childbearing potential are defined as: 
a. Post-menopausal women (defined as at least 12 months with no menses without an 
alternative medical cause); in women < 45 years of age, a high follicle stimulating 
hormone (FSH) level in the post-menopausal range may be used to confirm a post-
menopausal state in women not using hormonal contraception or hormonal 
replacement therapy. OR 


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b. Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; OR 
c. Have a congenital or acquired condition that prevents childbearing. 
10. Able to understand and sign a written informed consent form. 
4.2. 
Subject Exclusion Criteria 
Subjects will be ineligible for and excluded from this trial if any of the following apply:  
1. Previous exposure to pamrevlumab. 
2. Evidence of significant obstructive lung disease by any of the following criteria: (1) 
forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio <0.70, or 
(2) extent of emphysema greater than the extent of fibrosis on HRCT. NOTE: this 
requires confirmation by an Independent Radiology Imaging Review Group, prior to 
randomization. 
3. Female subjects who are pregnant or nursing. 
4. Smoking within 3 months of screening and/or unwilling to avoid smoking throughout the 
study. 
5. Interstitial lung disease (ILD) other than IPF, including but not limited to any of the other 
types of idiopathic interstitial pneumonias; lung diseases related to exposure to fibrogenic 
agents or other environmental toxins or drugs; other types of occupational lung diseases; 
granulomatous lung diseases; pulmonary vascular diseases; systemic diseases, including 
vasculitis, infectious diseases and connective tissue diseases. In cases of uncertain 
diagnosis serological testing and/or review by multi-disciplinary team should be 
performed to confirm diagnosis of IPF vs. other types of ILD. 
6. Sustained improvement in the severity of IPF during the 12 months prior to screening, 
based on changes in FVC, DLCO, and/or HRCT scans of the chest. 
7. History of other types of respiratory diseases, including diseases or disorders of the 
airways, lung parenchyma, pleural space, mediastinum, diaphragm, or chest wall that, in 
the opinion of the Investigator, would impact the primary protocol endpoint or otherwise 
preclude the subject’s participation in the study. 
8. Medical conditions (e.g., MI/stroke within the past 6 month), or logistical challenges that 
in the opinion of the Investigator preclude the subject’s adequate participation in the 
study. 
9. Poorly controlled chronic heart failure (NYHA Class 3 or above); clinical diagnosis of 
cor pulmonale requiring specific treatment; or severe pulmonary arterial hypertension 
requiring specific treatment that, in the opinion of the Investigator, would preclude the 
subject’s participation in the study.  
10. Clinically important abnormal laboratory tests (including serum creatinine ≥1.5 x upper 
limit of normal [ULN], hemoglobin (Hb) <10 g/dL, white blood cells <3,000/mm3, 
platelets less than 100,000/mm3, serum total bilirubin >1.5 x ULN, serum alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) ≥2 x ULN, or serum 
alkaline phosphatase ≥2 x ULN. 


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11. Ongoing acute IPF exacerbation, or suspicion of such process, during screening or 
randomization, including hospitalization due to acute IPF exacerbation within 4 weeks 
prior to or during screening. 
12. High likelihood of lung transplantation (in the opinion of the Investigator) within 6 
months after Day 1. 
13. Use of any investigational drugs or unapproved therapies, or participation in any clinical 
trial with an investigational new drug within 30 days prior to screening. Or use of 
approved IPF therapies (i.e., pirfenidone or nintedanib) within 1 week prior to screening. 
14. Daily use of PDE-5 inhibitor drugs (e.g., sildenafil, tadalafil), except for treatment of 
severe pulmonary artery hypertension. 
15. Any current malignancy (this does not include localized cancer such as basal or 
squamous cell carcinoma of skin).  Any history of malignancy likely to result in 
mortality, or requiring significant medical or surgical intervention within the next year.  
16. History of allergic or anaphylactic reaction to human, humanized, chimeric or murine 
monoclonal antibodies, or to any component of the excipient. 
17. Any condition (other than IPF) that is likely to result in the death of the patient within the 
next year. 
18. The Investigator judges that the subject will be unable to fully participate in the study and 
complete it for any reason, including inability to comply with study procedures and 
treatment, addiction, or any other relevant medical or psychiatric conditions. 
4.3. 
Subject Study Withdrawal Criteria 
Subjects who do not receive all study drug doses in the main study are encouraged to remain in 
the study and continue with the regular study visits and assessments. However, subjects may 
withdraw from the study at any time, for any reason. Reasons for discontinuing study drug 
treatment, as well as reasons for withdrawing from study, will be captured on CRF.   
Mandatory reasons for withdrawing the subject from the study include the following:  
• Any safety concern in the Investigator’s opinion, that precludes further study 
participation, including infusion-associated reactions deemed life-threatening by the 
Investigator (see also/ Section 5.1.6) 
• Lung transplant 
• Pregnancy 
• Major protocol deviation that substantially affects subject safety or assessment of 
efficacy endpoints  
• Withdrawal of Consent  


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4.4. 
Subject Study Withdrawal Procedures/Assessments 
Subjects who withdraw from the study early will have an early termination (ET) visit as soon as 
feasible. Subjects will return for a Safety Follow-up Visit 28 days after the last dose and will have 
a final Safety Follow-up Phone call 60 days after last dose for a final assessment of safety.   
In addition, these subjects should also be contacted by phone for vital status at weeks 24 and 48.   
At the Early Study Termination visit, PFTs do not have to be repeated, if the last one (excluding 
the screening visit) was performed within 8 weeks of this visit; HRCT does not have to be 
repeated, if the last one (excluding the screening visit) was performed within 4 months of this 
visit.   
4.5. 
Replacement of Study Subjects 
All randomized subjects will be included in the study. Subjects who terminate the study early 
will not be replaced.  
4.6. 
Study Closure 
FibroGen reserves the right to close any investigational site(s) or terminate the study at any time 
for any reason.  Reasons for the closure of the study site or termination of the study by FibroGen 
may include (but are not limited to): 
• Successful completion of the study at the investigational site 
• The required number of subjects for the study has been recruited 
• Failure of the Investigator to comply with the protocol, GCP guidelines or local 
requirements 
• Safety concerns 
• Inadequate recruitment of subjects by the Investigator  


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5. 
TREATMENT OF SUBJECTS 
5.1. 
Study Treatment 
5.1.1. 
Pamrevlumab or Placebo 
Pamrevlumab is a fully human IgG1 kappa monoclonal antibody that binds to CTGF and is 
formulated as solution for administration by IV infusion. 
Matching placebo is formulated as solution to be administered in a manner that is identical to 
pamrevlumab infusion. 
5.1.2. 
Formulation 
Pamrevlumab is supplied in single-use glass vials containing sterile, preservative-free solution 
(100 mg pamrevlumab/vial or 500 mg pamrevlumab/vial respectively).  The solution is 
composed of 10 mg/mL pamrevlumab, 1.60 mg/mL L-histidine, 3.08 mg/mL L-histidine HCl, 
8.01 mg/mL sodium chloride, and 0.05 mg/mL polysorbate 20, resulting in a solution with a 
tonicity of approximately 290 mmol/kg and a pH of 6.0.   
The placebo formulation is of identical composition as the pamrevlumab formulation, except for 
the absence of pamrevlumab. 
5.1.3. 
Study Drug Packaging and Labeling 
Labels will be prepared and will comply with Good Manufacturing Practice requirements for 
labelling and local regulatory guidelines.   
5.1.4. 
Study Drug Storage 
All Investigational Product (IP) vials must be stored refrigerated (2°C to 8°C), in a temperature- 
controlled and monitored environment, protected from light, and in a securely locked area to 
which access is limited to appropriate study personnel. Documentation of the storage conditions 
must be maintained by the site for the entire period of study participation. Details regarding the 
reporting of temperature excursions can be found in the study Investigational Product (IP) 
Manual. 
5.1.5. 
Study Drug Preparation 
IP is infused undiluted after pooling the contents of the calculated number of vials in an empty 
infusion bag (total volume of fluid must not exceed 410 mL) according to the Dose Preparation 
Instructions in the IP Manual. 
Once prepared, the IP infusion is stable at room temperature for up to 6 hours. However, if prepared 
IP and stored refrigerated at 2 to 8ºC IP is stable for 48 hours. 
IP is administered by IV infusion, using an infusion set with a 0.2 µm in-line filter. 
 


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5.1.6. 
Study Drug Administration 
Dosing is based on the weight obtained on Day 1 and every 12-weeks thereafter. The total dose 
is not to exceed 4.1g. The total volume of fluid is not to exceed 410 mL. Study Drug is 
administered by IV infusion, using an infusion set with a sterile, nonpyrogenic, low-protein-
binding in-line filter (0.2-micron pore size). The infusion and post-infusion observation periods 
are provided in Table 1 below: 
Table 1 
Pamrevlumab (or placebo): Dose, Route, and Administration 
Agent 
Dose 
Route 
Infusion Rate 
Frequency 
Pamrevlumab/ 
matching placebo 
30 mg/kg 
IV 
• 
First Infusion (including first infusion in 
OLE): Infuse over approximately 2 hours.   
• 
Second Infusion (including second 
infusion in OLE): If first infusion is well 
tolerated, infuse over approximately 1 
hour.  
• 
Subsequent Infusions: If 1 hour infusion(s) 
are well tolerated, infuse over 
approximately 30 minutes. 
 
For ALL infusions: A Post-infusion 
observation period has to be included 
throughout the study: It is 1 hour for at least 
the first 3 infusions (including in OLE); this 
may be reduced to 30 minutes if there were 
no infusion-related AEs after the first 3 
infusions. 
Day 1 and 
Every 3 
weeks 
thereafter 
 
NOTE: 
Infusions 
must be AT 
LEAST 10 
days apart  
NOTE:  DO NOT ADMINSITER STUDY DRUG AS AN IV PUSH OR BOLUS INJECTION, OR 
CONCURRENTLY IN THE IV LINE WITH OTHER AGENTS. 
 
The first infusion should be completed in approximately 2 hours. If the first infusion is well 
tolerated and no infusion-associated AEs are observed during the infusion and observation 
periods, the second infusion should be completed in approximately 1 hour. The subsequent 
infusion periods may be shortened to approximately 30 minutes if no infusion-associated AEs 
were observed during the initial two infusions.   
If an infusion-associated AE occurs during any of the subsequent infusions, study drug will be 
administered over approximately 1 hour for the next three infusions. If no infusion-associated 
AEs are observed in any of these three infusions, the infusion may be decreased again, to 
approximately 30 minutes. 
The Investigator or other qualified personnel must be either present, or immediately available, 
during all infusions and observation periods for each subject. If a subject has a significant 
infusion-associated AE, the infusion rate may be slowed or temporarily stopped, depending on 
the severity of symptoms. If such a subject continues study drug dosing, a physician should be 
immediately available during all subsequent infusions and observation periods at the site.  
Subjects who experience an infusion-associated AE will not be allowed to participate in Home 
Health Care (HHC). In addition, if a subject experiences a life-threatening (per Section 7.3.3) 
infusion-associated AE, study drug treatment must be permanently discontinued (see Section 
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The Investigator has the option to use premedication ( e.g., antihistamines, nonsteroidal anti-
inflammatory drugs (NSAIDs)) for a subsequent infusion; this may be discussed with the 
FibroGen Medical Monitor.  
Infusions are to be continued until the total volume has been administered. Subjects will remain 
at the study site for 1 hour after the end of the infusion for clinical observation. This post-
infusion observation period may be reduced to 30 minutes if the subject has had no infusion-
associated AEs during the first three infusions.  
Study drug will be administered at a hospital or ambulatory setting with adequate facilities for 
managing medical emergencies. Medications for the treatment of acute reactions, including 
anaphylaxis, must be available to study site staff for immediate use. There is no specific 
treatment for a pamrevlumab overdose or infusion-associated AEs. Signs and symptoms should 
be managed with appropriate standard of care treatment. 
The Sponsor may consider the use of properly trained home health care staff to administer the 
infusions of study drugs at the subject’s home and corresponding study assessments during the 
conduct of the study (after the completion of at least three 30 minute infusions without safety 
concerns), consistent with institutional regulations and policies. See Section 5.1.7 for details. 
COVID-19 Vaccine and Study Drug Administration  
If a subject receives a COVID-19 vaccine during the study, it is recommended that a time 
separation of at least 48 hours is maintained between administration of the COVID-19 vaccine 
(single/multiple dose) and study drug infusion. The time separation may allow for better 
interpretation of any adverse events and their relationship to the vaccine or study drug. 
The following procedures must be performed prior to each infusion: 
• Vital signs (blood pressure [BP], pulse, and temperature) within 30 minutes before 
starting the infusion 
• Query subject and assess AEs and SAEs 
• Record concomitant medications 
The following procedures must be performed after each infusion: 
• Vital signs (BP, pulse, and temperature) within 30 minutes after completion of the 
infusion  
• Query subject and assess AEs and SAE’s 
5.1.7. 
Home Health Care 
The Sponsor may consider the use of properly trained and qualified home health care staff in 
specific regions/countries, depending on local acceptance and adoption of home visits, to 
administer study drug at the subject’s home, after completion of at least the first 3 infusions 
without safety concerns. Home Health Care (HHC) is optional and the decision to utilize this 
service is determined by the site, consistent with institutional regulations and policies. 
NOTE: Subjects who experience a significant infusion-associated AE may not receive HHC. In 
addition, if a new safety concern arises during a home infusion, the subject has to attend an on-
site visit for an Investigator assessment as soon as feasible.  HHC support will only be on weeks 


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with study drug infusions and no scheduled study assessments. Visits that include collection of 
PFT, ePRO, safety labs or HRCT must be performed on-site. Medications and supplies to treat 
suspected hypersensitivity/anaphylactic reactions must be available for immediate use for all 
study drug infusion visits. 
5.1.8. 
Missed Dose 
Every attempt should be made to complete all study visits within the windows as outlined in the 
Schedule of Assessment (SOA) (Appendix 1).  
Scheduled visit dates are determined from the time of the first dose, which is defined as Day 1. A 
visit schedule is provided in Section 6.1.2 and the SOA (Appendix 1). Visits conducted outside 
the visit windows will be recorded as a protocol deviation. Missed doses are not to be made up 
through extra visits. If a subject misses more than two infusions in any 18-week period 
throughout the study, or two sequential infusions, the FibroGen Medical Monitor should be 
notified.  The reason for missed doses must be documented in the subject’s clinical record. 
If a dose is missed due to a missed visit see section 6.1.4 and 6.1.5. 
Refer to the case report form (CRF) completion guidelines for additional information on CRF 
completion requirements for missed visits.  
5.1.9. 
Study Drug Handling and Disposal 
All study drug provided by the Sponsor should be retained at the site until otherwise instructed in 
writing by the Sponsor (or designee). If local/regional/institutional policies do not allow the site 
to retain study drug, the site must provide the Sponsor (or designee) their drug destruction 
SOP/process for review and approval. The Sponsor (or designee) will perform drug 
accountability and reconciliation for all study drug received at the site prior to approving study 
drug return/destruction. Upon completion of accountability/reconciliation or upon completion of 
the study or termination of the investigational site, all used, unused, partially used study drug, 
and all study drug that was not dispensed will be shipped to a destruction site designated by the 
Sponsor (or designee) for destruction. IV bags used to infuse study drug can be disposed of per 
institutional policy. Please refer to the IP Manual for additional information on study drug 
materials, management and accountability.   
5.1.10. 
Co-Administration of an Approved IPF Therapy  
During the treatment period, co-administration of an approved IPF therapy (i.e., pirfenidone or 
nintedanib) is acceptable if clinically indicated in the Investigator’s opinion, provided that the 
Investigator assesses the potential risks/benefits of combining approved IPF therapies with 
blinded study treatment. 
Dosing of approved IPF therapy, and safety monitoring while receiving such therapy, must be in 
accordance with the approved therapy’s local label.  
5.1.11. 
Treatment Compliance 
All treatments are administered at the investigational site by qualified personnel and documented 
in the corresponding case report form (CRF). 


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5.2. 
Concomitant Medications 
5.2.1. 
Permitted Concomitant Medications 
Concomitant medications (any prescription and/or over-the-counter [OTC] preparation) and 
procedures or nondrug therapies (e.g., physical therapy, acupuncture, continuous positive airway 
pressure [CPAP]) used by a subject while participating in this clinical trial must be recorded 
from the Screening Visit through the Safety Follow-Up Visits. 
Other than the restrictions that follow, concomitant medications may be given at the discretion of 
the Investigator. It is expected that Investigators will provide optimal medical care for the 
subject’s various co-existing medical conditions. The Investigator should ensure optimal medical 
care is provided during the course of the study. 
Oral prednisone or equivalent oral corticosteroid: up to 10 mg daily for chronic use is permitted, 
as long as such use is for a condition other than IPF, and has to be documented accordingly. 
Higher doses for acute conditions are permitted.  N-acetylcysteine (NAC): up to 1800 mg daily, 
is also permitted during the study. 
5.2.2. 
Prohibited Concomitant Medications 
Pirfenidone and nintedanib are permitted as approved IPF therapies, if clinically indicated during 
the study. For details, see Section 5.1.10. 
Prohibited medications include any other (off-label or investigational) agents for the treatment of 
interstitial lung diseases including IPF. The list of prohibited concomitant medications for 
treatment of IPF includes, but is not limited to, the following:  
• sildenafil: if used for erectile dysfunction the frequency of administration should be 
no more than two times a week,  
• azathioprine,  
• cyclophosphamide,  
• cyclosporine,  
• interferon gamma 1b,  
• D penicillamine,  
• methotrexate,  
• leflunomide,  
• colchicine,  
• bosentan,  
• ambrisentan,  
• aminobenzoate,  
• mycophenolate mofetil, 
• imatinib,  


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• relaxin,  
• etanercept,  
• adalimumab,  
• infliximab,  
• anakinra,  
• abatacept,  
• rituximab  
If any of these treatments are prescribed for their approved indications, for other co-existing 
medical conditions such as systemic inflammatory disease (e.g., rheumatoid arthritis), severe 
pulmonary hypertension, etc.), such uses are allowed. All indication needs to be clearly 
documented in the subject’s clinical record. 
Questions about concomitant medications should be discussed with the FibroGen Medical 
Monitor. 
5.2.3. 
Contraception Requirements  
A non-clinical study evaluating the potential effects of pamrevlumab on embryo-fetal 
development has been conducted (rabbit embryo-fetal development study 352021017). The 
pamrevlumab systemic exposure levels at 200 mg/kg to the pregnant female rabbits which 
resulted in fetal external and skeletal abnormalities are approximately 20-fold greater than the 
systemic exposure levels in humans at doses of 30mg/kg or 35 mg/kg in our current protocols. 
No adverse effects of pamrevlumab administration were observed in a study of rat male and 
female fertility. 
Therefore, female subjects of childbearing potential and male subjects who have partners with 
reproductive potential are required to use a highly effective method of contraception per Clinical 
Trial Facilitation Group (CTFG) recommendation (for reference see section 13) during the study 
and for 3 months after the last dose of study drug as follows: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1:  
- oral  
- intravaginal  
- transdermal  
• Progestogen-only hormonal contraception associated with inhibition of ovulation1:  
- oral  
- injectable  
- implantable2  
• Intrauterine device (IUD)2  
• Intrauterine hormone-releasing system (IUS)2  


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• Bilateral tubal occlusion2  
• Vasectomised partner2,3  
• Sexual abstinence4  
In each case of delayed menstrual period (over one month between menstruations) confirmation 
of absence of pregnancy is strongly recommended. This recommendation also applies to women 
of childbearing potential with infrequent or irregular menstrual cycles. 
1Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method (see section 4.3 of the CTGF guidance document).  
2 Contraception methods that in the context of the CTGF guidance are considered to have low user dependency.  
3 Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of 
the WOCBP trial participant and that the vasectomised partner has received medical assessment of the surgical 
success.  
4 In the context of the CTGF guidance sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred 
and usual lifestyle of the subject. 


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6. 
ASSESSMENTS OF EFFICACY 
6.1. 
Study Assessments 
A signed and dated IRB/IEC-approved informed consent must be obtained before any study-
specific assessments are performed. Assessments that are part of routine care are not considered 
study-specific and may be used at screening to determine eligibility. All subjects will be 
screened for eligibility before randomization. Only eligible subjects will be randomized into the 
study.  
6.1.1. 
Screening Period 
All screening procedures must be performed within 6 weeks.  Plans to rescreen a subject should 
be discussed with the medical monitor. Study procedures to be performed during the screening 
period can be found in the SOA (Appendix 1).   
6.1.2. 
Treatment Period 
The study procedures and assessments are presented for the Treatment phase in Appendix 1.  
The treatment period begins on Day 1 (first study drug infusion) and continues through Week 48. 
Visit windows are within ±7 days of the scheduled visit date for Weeks 3 through 48; however, 
visits should be at least 10 days apart, to ensure intervals of at least 10 days between study drug 
infusions.  
Subjects who complete the Week 48 visit may be eligible to participate in an optional OLE 
period where all subjects are offered continuing access to pamrevlumab treatment. The details of 
procedures and assessments, including visit window for OLE are described in Appendix 6.   
6.1.3. 
Safety Follow-Up 
Safety assessments will be performed at the following two time points: 
• 28 days after last dose  
• 60 days after last dose: follow-up phone call, for a final safety assessment   
 The visit windows for the safety assessments are: 28 days +7 days and 60 days +7 days (phone 
call) after the last dose. 
After this protocol-required reporting period, the Investigator does not need to actively monitor 
subjects for SAEs.  However, if the Investigator becomes aware of an SAE/death that may be 
possibly related to study treatment after the protocol-required reporting period, the Investigator 
may report the event to FibroGen as outlined in Section 7. SAEs reported outside of the protocol-
required reporting period will be captured within the safety database only as clinical trial cases 
for the purposes of expedited reporting. 
6.1.4. 
Missed Visits 
Scheduled visit dates are determined from the time of the first dose, which is defined as Day 1. 
Protocol-defined visits conducted outside the study visit window (see Section 6.1.2) will be 
recorded as a protocol deviation unless there is an AE/SAE/intercurrent illness or other 


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extenuating circumstance (such as during the COVID-19 pandemic), resulting in missed visit(s). 
Refer to Section 5.1.8 for additional details. For missed visits, the subject will be asked to 
resume the planned visit schedule at the next scheduled visit.  
NOTE: In accordance with FDA Guidance: During the COVID-19 pandemic, the visit modality 
(e.g.: in-person versus remotely) and scheduling maybe adjusted and conducted at the discretion 
of the Investigator, in accordance with the site’s rules and recommendations, and using all 
necessary precautions. If a visit has to be done remotely, it can be conducted with any 
technology available to the site and study subjects, such as via tele-health visits, phone calls, etc.   
Subjects who do not receive all study drug doses, but complete the Week 48 visit, are considered 
study completers, and may be considered for participation in the OLE of pamrevlumab (see also 
Appendix. 6). 
6.1.5. 
Unscheduled Visits 
Unscheduled visits/assessments may be scheduled as needed.  Unscheduled visit data will be 
captured accordingly in the clinical database. 
Unscheduled PFTs: Subjects who are unable to perform a PFT on a scheduled visit, or are 
missing a visit with a scheduled PFT, need to do an unscheduled PFT assessment at the next 
scheduled visit.  
If the subject is unable to perform PFT at the Week 48 visit, the subject must have an 
unscheduled visit at the nearest possible date to perform the end of treatment (EOT) PFT 
assessment. 
NOTE: In accordance with FDA Guidance: During the COVID-19 pandemic, the visit modality 
(e.g.: in-person versus remotely) and scheduling maybe adjusted and conducted at the discretion 
of the Investigator, in accordance with the site’s rules and recommendations, and using all 
necessary precautions. If a visit has to be done remotely, it can be conducted with any 
technology available to the site and study subjects.   
 
6.2. 
Assessments 
Refer to the SOA (Appendix 1) for details regarding the timing and frequency of study 
assessments.  Spirometry, laboratory evaluations and patient reported outcomes assessments 
should be performed prior to infusions.   
6.2.1. 
Vital Signs (including Weight and Height) 
Vital signs to be collected include; heart rate, blood pressure and temperature:   
• Heart rate should be collected as beats/min 
• Systolic and diastolic blood pressure should be collected from subjects in seated 
position (mmHg) 
• Temperature should be taken as oral or tympanic and captured as °F or °C 


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Weight is collected during screening, Day 1 and every 12 weeks thereafter.  Height is collected 
during screening only. 
6.2.2. 
Physical Exam 
Full physical exams (PEs) will be performed according to the SOA (Appendix 1). In addition, 
PEs may be performed throughout the study as needed, if clinically indicated.  
6.2.3. 
Electrocardiogram (ECG or EKG) 
12-lead ECGs will be performed in accordance with institutional standards and according to the 
SOA (Appendix 1). In addition, ECGs may be performed throughout the study as needed, if 
clinically indicated. 
6.2.4. 
Laboratory Evaluations 
Details regarding sample collection, preparation and transport can be found in the central lab 
manual.   
6.2.4.1. 
Central Laboratory Evaluations 
The following labs will be evaluated by a central laboratory in accordance with the SOA 
(Appendix 1): 


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Table 2: 
Laboratory Tests 
CBC: 
Chemistry Panel: 
Absolute neutrophil count (ANC) 
Bicarbonate  
Eosinophils 
BUN 
Erythrocyte count (RBC) 
Calcium 
Hematocrit % 
Creatinine 
INR 
Chloride 
PT/PTT 
Magnesium 
Hemoglobin 
Glucose 
WBCs (Leukocyte count) 
   ALP 
Lymphocytes 
ALT 
Mean corpuscular volume  
AST  
Monocytes 
Bilirubin, total  
Neutrophils 
Albumin 
Platelets 
Phosphorous 
Basophils  
   Potassium 
   Sodium 
 
   Cholesterol  
 
Total Protein  
 
GGT 
 
Triglycerides  
Pregnancy Test: Urine; Serum hCG at screening and to confirm a positive urine test  
Abbreviations:         ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = 
Gamma-glutamyltransferase; BUN = blood urea nitrogen; CBC = complete blood count; INR = international 
normalized ratio; PT/PTT = prothrombin time/partial thromboplastin time; RBC = red blood cell; 
WBCs = white blood cells; hCG =Human chorionic gonadotropin. 
 
Central lab results obtained during the screening period will be used to determine subject 
eligibility for participation in the trial.  Central lab results will be reviewed by the Investigator 
for clinical significance and to determine appropriate reporting of adverse events (see Section 
7.3).  A Central Laboratory Manual with instructions on specimen collection, processing, storing, 
and shipping to the central laboratory will be provided to all participating sites. 
Local laboratory assessments are not required for this study, but the results of any local 
laboratory assessments may be used to assess subject safety.  If a local lab abnormality is 
reflective of an AE, report the etiology, if known, as per section 7.3.7.  Local laboratory results 
will not be captured in the clinical database.   
NOTE: Local laboratory assessments may also be used in case of Central Laboratory supply 
shortages or shipment delays. If local laboratory assessments are used instead of central labs, the 
following points need to be considered: 
• In case of local screening labs, the Investigator needs to review the results with respect to 
Exclusion #10. 


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• For on-study laboratory assessments, only laboratory abnormalities that are considered 
clinically significant in the Investigator’s assessment need to be reported as TEAEs, as 
per Protocol Section 7.3.7. In such a case, if possible, the etiology of a lab abnormality 
should be reported as TEAE, not the abnormal lab value.  
6.2.4.2. 
Pharmacokinetics (PK) and Pharmacodynamics 
Additional samples will be collected to evaluate PK, HAHA, HAHA-NA, CTGF, exploratory 
biomarkers and genomics in accordance with the SOA in Appendix 2. The central laboratory will 
manage the storage of these samples while analysis will be performed at a specialty lab. 
6.2.4.2.1. Pharmacokinetics (Optional) 
An optional PK assessment will be performed in a subset of subjects at select sites. PK 
assessments will continue to be optional except in the case of suspected 
hypersensitivity/anaphylactic reactions (see Section 6.2.4.2.3 for more detail). Plasma samples 
will be collected for estimates of PK parameters using population PK and exposure-response 
analysis, if possible, according to the SOA in Appendix 2. A specialty laboratory will measure 
plasma pamrevlumab levels using a validated assay.  For the population PK analysis, it is critical 
to accurately record the dosing time and date in addition to the sampling collection time and 
date. Both pre-dose and post-dose samples are required for PK.  The pre-dose PK sample should 
be taken within 2 hours prior to dosing, the post-dose PK sample should be between 1-4 hours 
after the end of dosing.    
6.2.4.2.2. Human Anti-Human Antibodies (HAHA)  
Plasma samples will be collected for evaluation of human anti-human antibodies (HAHA) in all 
subjects according to the SOA in Appendix 2. A specialty laboratory will measure HAHA titers 
using a validated assay.   
Samples with positive HAHA results will be tested for neutralizing antibody (HAHA-NA). The 
prevalence and duration of binding and neutralizing antibodies and the effect of these antibodies 
on the pharmacokinetics, pharmacodynamics markers, efficacy, and safety of pamrevlumab will 
be assessed. 
 
6.2.4.2.3. Suspected Hypersensitivity or Anaphylactic Reactions 
Any immunogenic reactions, including drug-related hypersensitivity or anaphylaxis, should have 
PK, HAHA, HAHA-NA, CTGF and tryptase drawn within 24 hours of a suspected reaction from 
pamrevlumab (see Appendix 2 for more detail). This is in addition to timepoints in which PK, 
HAHA, and HAHA-NA and CTGF were drawn pre-infusion and post-infusion.   
This will not be considered optional for the subject unless there is local institutional guideline 
consideration for total blood volume collection on the same day as a standard blood draw 
timepoint, which could preclude the subject from having this collection take place within 24 
hours. The Tryptase sample should be drawn within 1 to 6 hours of immunogenic reaction, and 
all other samples should be collected within 24 hours of the immunogenic reaction.  See 
Appendix 2 for more detail. 
 


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6.2.4.2.4. Exploratory Biomarkers  
Serum and plasma samples will be collected in subjects according to the SOA in Appendix 2. 
These samples will be stored and used to explore additional biomarkers of pamrevlumab’s 
effects in the context of the current clinical trial.  
Exploratory biomarkers to be analyzed may include markers of inflammation such as CRP, TNF, 
IL-6, IL-8 and CCL18; markers of fibrosis and collagen synthesis such as TGF-beta, PINP and 
PIIINP, as well as other markers of tissue remodeling and angiogenesis such as angiopoietins, 
VEGF, MMP7 and KL-6. 
NOTE: Biomarker samples will be collected for subjects, except in countries where the 
Regulatory Agencies do not allow collection of these markers.  
6.2.4.2.5. DNA for Genomic Analysis (Optional) 
A genome-wide association study was performed in subjects with fibrotic idiopathic interstitial 
pneumonias (N = 1616) and controls (N = 4683) (Fingerlin, 2013) and determined an association 
of disease with TERT and MUC5B on chromosomes 5p15 and 11p15, respectively, the 
chromosome 3q26 region near TERC, and identified 7 novel chromosome loci. The novel loci 
include FAM13A (4q22), DSP (6p24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19p13), and 
chromosomal regions 7q22 and 15q14-15. Their findings indicate that genes involved in host 
defense, cell-cell adhesion, and DNA repair contribute to the risk of fibrotic pulmonary disease. 
In this study, we plan to collect whole blood samples to isolate patient DNA and evaluate the 
relationship between clinical response to pamrevlumab and variants in loci such as those 
described above. 
A whole blood sample will be collected for DNA analysis on Day 1 before dosing for all subjects 
who agree to DNA analysis. This testing is optional, requires specific consent by participating 
subjects and subjects may refuse DNA testing. Only tests for genetic loci associated with ILD, 
fibrosis or CTGF biology will be performed, and all samples will be destroyed after testing is 
completed. 
NOTE: DNA samples for genomics analysis will be collected for subjects who consent, except 
in countries where the Regulatory Agencies do not allow collection of these samples. 
6.2.5. 
High Resolution Computerized Tomography (HRCT) Scans and Spirometry 
The key study procedures that measure efficacy are serial spirometries to assess lung function 
(refer to the PFT Procedure Manual for additional details) and serial HRCT assessments to 
evaluate fibrosis. These measurements will be performed in all patients according to the SOA in 
Appendix 1.  
HRCT: 
An Independent Radiology Review Group is assessing all HRCTs for: 
- 
Quantitation of fibrosis, a secondary efficacy measure, and 
- 
Confirmation of HRCT-related eligibility, specifically:  
o Inclusion # 4 and Exclusion # 2 
o Assessment of UIP pattern.  


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For the screening HRCT, the Independent Radiology Review Group is providing their 
assessment to study sites, in accordance with the Independent Radiology Review Imaging 
Charter. It is the responsibility of the Investigator to review this assessment prior to 
randomization, to make sure all HRCT-related eligibility criteria are met. 
For the screening HRCT: if a recent scan, i.e., within 3 months prior to screening, is available, it 
can be utilized as the screening HRCT, provided it is submitted and evaluated by the 
Independent Radiology Imaging Review Group, is adhering to the imaging parameters detailed 
in the Imaging Core Manual (ICM), and is using the same accredited scanner as the on-study 
HRCT scans. 
Spirometry:  
Subjects must have an FVCpp value >45% and <95% at screening and Day 1 (prior to 
randomization), in order to be eligible for the study. 
For the screening FVCpp value and GAP score calculation: the quality-controlled, Best-Test 
Review (BTR) assessment provided by the spirometry vendor over-reader, which is provided to 
sites within 48 hours after uploading the test, is to be used for eligibility assessment and GAP 
score calculation.  
For the Day 1 (pre-randomization) FVCpp value: the real-time value obtained from the device is 
to be used for eligibility confirmation, without the need to wait for the BTR assessment.  
BTR assessments of all spirometries are conducted for statistical purposes, and will be provided 
to the site, for quality feedback. 
NOTE: For spirometries deemed “unacceptable” by the spirometry vendor over-reader, the test 
has to be repeated. 
6.2.6. 
Patient Reported Outcomes (PROs) 
Patient reported outcome (PRO) data will be collected in all subjects to evaluate specific patient 
reported symptoms, treatment related symptoms and functional impacts that may be responsive 
to treatment.  All questionnaires will be administered as specified in the SOA (see Appendix 1) 
in the same order at Week 48 as was done at baseline. On weeks where both questionnaires and 
spirometry are performed, the PFT should be completed prior to administering the PRO.   
6.2.6.1. 
St. Georges Respiratory Questionnaire (SGRQ) 
The St. Georges Respiratory Questionnaire is a disease-specific instrument designed to measure 
impact on overall health, daily life, and perceived well-being in patients with obstructive airways 
disease. 
6.2.6.2. 
University of California, San Diego – Shortness of Breath Questionnaire (UCSD-
SOBQ) 
The UCSD-SOBQ is a self-administered rating of dyspnea associated with activities of daily 
living (ADLs).  The questionnaire is designed to assess severity of shortness of breath during 
specific ADLs and to assess the limitations due to shortness of breath, fear of harm from 
overexertion and fear of shortness of breath. 


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6.2.6.3. 
Leicester Cough Questionnaire (LCQ) 
The Leicester Cough Questionnaire is a self-administered instrument designed to monitor 
individual patients cough, assess different aspects of health affected in patients and detect 
changes in health status within an adult chronic cough population (Birring, 2003).   


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7. 
ASSESSMENTS OF SAFETY 
7.1. 
Background 
Adverse event reports from Investigators are the critical building blocks to the development of 
the safety profile of the Study Drug. Subjects will be asked non-leading questions in general 
terms to determine the occurrence of AEs, according to the schedule outlined in Appendix 1. In 
addition, all AEs reported spontaneously during the course of the study will be recorded. The 
Investigator must immediately (within 24 hours of awareness) report to the Sponsor or 
designated safety management vendor all SAEs, regardless of whether the Investigator believes 
they are related to the study drug. 
7.2. 
Definitions 
7.2.1. 
Definition of an Adverse Event (AE) 
An adverse event is defined as any untoward medical occurrence in a clinical trial subject. The 
event does not necessarily have a causal relationship with study treatment. The Investigator is 
responsible for ensuring that any adverse events observed by the Investigator or reported by the 
subject as defined in the study protocol are recorded in the subject’s medical record. The 
definition of adverse events includes worsening of a pre-existing medical condition. Worsening 
indicates that the pre-existing medical condition (e.g., diabetes, migraine headaches and gout) 
has increased in severity, frequency, and/or duration, and/or has an association with a 
significantly worse outcome. A pre-existing condition that has not worsened during the study or 
involves an intervention, such as elective cosmetic surgery, or a medical procedure while on 
study, is not considered an adverse event. 
7.2.2. 
Definition of a Serious Adverse Event (SAE) 
A serious adverse event is any adverse event or suspected adverse reaction that results in any of 
the following outcomes: 
• Death, 
• A life-threatening AEs (i.e., if in the view of the Investigator or Sponsor, the subject 
was at immediate risk of death at the time of the event). Life-threatening does not 
refer to an event which hypothetically might have caused death if it were more 
severe, 
• Inpatient hospitalization or prolongation of existing hospitalization, 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, 
• A congenital anomaly or birth defect, or 
• Is considered a medically important event not meeting the above criteria, but which 
may jeopardize a subject or may require medical or surgical intervention to prevent 
one of the other criteria listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or 


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at home, and blood dyscrasias or convulsions that do not result in inpatient 
hospitalization. 
Please note that death is an outcome, not an event; the primary cause of death would be the 
adverse event. 
Surgical procedures, per se, are not SAEs. The condition requiring the surgical procedure, 
however, may be a SAE. 
Scheduled or pre-planned hospitalization or prolongation of a hospitalization due to standard of 
care assessments and procedures (including elective procedures) do not warrant reporting as 
adverse events unless resulting observations are deemed by the Investigator to meet the 
definition of an adverse event. 
7.3. 
Procedures for Eliciting, Recording, and Reporting Adverse Events 
7.3.1. 
Adverse Event Reporting Period 
The safety reporting period begins after the subject has signed the informed consent and ends 60 
days after the last dose of study drug.  It is only required that SAEs be reported prior to first 
dose, while all AEs (serious and non-serious) be reported thereafter.  The Investigator should 
notify FibroGen of any death or other SAEs occurring after a subject has discontinued or 
terminated study participation that may reasonably be related to this study (Section 7.3.5). 
Pregnancy reporting requirements are outlined in Section 7.3.6. 
Adverse events will be followed until resolved, stable, or until the subject’s last study visit or 
subject is lost to follow-up. 
7.3.2. 
Adverse Event Eliciting/Reporting 
During the AE reporting period, study site personnel will actively seek information from each 
subject at each visit to collect any AEs occurring since the previous visit. All AEs will be 
collected in response to a general question about the subject’s well-being and any possible 
changes from the BL or previous visit. There will be no directed questioning for any specific AE. 
This does not deter the site from collecting and recording any AEs reported by the subject to site 
personnel at any other time. 
Whenever possible, diagnoses should be recorded when signs and symptoms are due to a 
common etiology, as determined by qualified medical study staff. The Investigator is responsible 
for reviewing laboratory test results and determining whether an abnormal value in an individual 
study subject represents a clinically significant change from the subject’s baseline values. In 
general, abnormal laboratory findings without clinical significance (based on the Investigator's 
judgment) are not to be recorded as adverse events. However, laboratory value changes that 
require treatment or adjustment in current therapy are considered adverse events. Where 
applicable, clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. The Investigator is expected to follow reported adverse events until stabilization or 
reversibility. 
The following attributes must be assigned to each AE: 
• Description (Investigator’s verbatim term describing the event) 


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• Dates of onset and resolution 
• Severity 
 
• Relationship to study drug 
• Outcome 
• Action taken regarding study drug 
• Other treatment required 
• Determination of “seriousness” 
7.3.3. 
Assessing Adverse Event Severity 
AEs, including abnormal clinical laboratory values, should be graded using the most current 
National Cancer Institute (NCI) Common Terminology Criteria for AE (CTCAE) guidelines. For 
terms not specified as part of NCI CTCAE, the following guidelines should be used to determine 
grade: 
All AEs will be assessed for severity using the following criteria: 
• Grade 1, Mild: Asymptomatic or mild symptoms which the subject finds easily 
tolerated. The event is of little concern to the subject and/or of little-or-no clinical 
significance; intervention not indicated. 
• Grade 2, Moderate: The subject has enough discomfort to cause interference with or 
change in some of their age-appropriate instrumental activities of daily living (e.g., 
preparing meals, shopping for groceries or clothes, using the telephone, managing 
money); local or noninvasive intervention indicated. 
• Grade 3, Severe: The subject is incapacitated and unable to work or participate in 
many or all usual activities. The event is of definite concern to the subject and/or 
poses substantial risk to the subject’s health or well-being; likely to require medical 
intervention and/or close follow-up, including but not limited to hospitalization or 
prolongation of hospitalization. 
• Grade 4, Life-threatening:  The subject was at immediate risk of death from the 
event as it occurred. 
• Grade 5, Death: Fatal AE. 
7.3.4. 
Assessing the Adverse Event’s Relationship to Study Drug 
Most of the information about the safety of a drug prior to marketing comes from clinical trials; 
therefore, AE reports from Investigators are critically important. The assessment of whether an 
AE is causally related to the study drug(s) using an evidence-based approach is critical in order 
to appropriately describe the safety profile of the study drug(s). Default reporting of individual 
events as possibly related is uninformative and does not meaningfully contribute to the 
development of the study drug’s safety profile. 


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The Investigator must provide an evidence-based assessment of the relationship of the AE to 
study drug in accordance with the guidance below. Absence of an alternative cause would not 
normally be considered sufficient evidence to assess an event as related to study drug. 
• Related: 
− Any event for which there is sufficient evidence to suggest that the study drug 
may have caused the event. For example, an unanticipated medical condition 
occurs which resolves with study drug interruption and re-occurs with re-
administration of study drug; another example is a typical drug-related medical 
condition such as a rash that occurred shortly after first dose of study drug. 
• Not Related: 
− The event represents a pre-existing underlying disease that has not worsened on 
study 
− The event has the same characteristics of a known side-effect associated with a 
co-medication 
− The event is an anticipated medical condition of anticipated severity for the study 
population 
− The most plausible explanation for the event is a factor that is independent of 
exposure to study drug 
7.3.5. 
Reporting Serious Adverse Events (SAEs) 
The Investigator is responsible for ensuring that all SAEs observed by the Investigator or 
reported by the subject that occur after signing of the informed consent/assent through 60 days 
after the last dose of pamrevlumab are recorded in the subject’s medical record and are submitted 
to FibroGen. All SAEs must be submitted to FibroGen within 24 hours following the 
Investigator’s knowledge of the event via the SAE report form. Additionally, pamrevlumab 
related SAEs (including deaths) that occur after the Safety Follow-Up visits will be reported. 
If a subject is permanently withdrawn from protocol required therapies because of a serious 
adverse event, this information must be submitted to FibroGen. FibroGen will report serious 
adverse events and/or suspected unexpected serious adverse reactions as required to regulatory 
authorities, Investigators/institutions, and central IRBs/IECs in compliance with all reporting 
requirements according to local regulations and Good Clinical Practice (GCP). 
There is no requirement to monitor study subjects for serious adverse events following the 
protocol-required reporting period or after end of study. However, these serious adverse events 
can be reported to FibroGen if the Investigator becomes aware of them. If serious adverse events 
are reported, the Investigator is to report them to FibroGen within 24 hours following the 
Investigator’s knowledge of the event. Serious adverse events reported outside of the protocol-
required reporting period will be captured within the safety database as clinical trial cases for the 
purposes of expedited reporting; these cases will not be included in the clinical study report. 
To report an SAE, the Investigator must complete an SAE Report Form and fax or email the 
completed form to the Sponsor or its designated safety management vendor. 


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Full details of the SAE should also be recorded on the medical records and in the CRF. The 
following minimum information is required: 
• Subject number, sex and age 
• The date of report 
• A description of the SAE (event, seriousness of the event) 
• Causal relationship to the study drug 
Follow-up information for the event should be sent promptly. 
For each SAE observed, the Investigator should obtain all of the information available about the 
event, including (but not limited to): hospital discharge diagnoses, hospital discharge note, death 
certificate, appropriate laboratory findings (including autopsies and biopsy results), and clinical 
examinations (including radiological examinations and clinical consultations). 
7.3.5.1. 
Reporting Serious Adverse Events to the Institutional Review Board / 
Independent Ethics Committee 
The Investigator is responsible for notifying his/her Institutional Review Board (IRB) or Ethics 
Committee (EC) of SAEs in accordance with local regulations. The Sponsor, or its designated 
safety vendor, will provide a copy of expedited safety reports to the Investigator that it intends to 
submit to global regulatory authorities. 
7.3.5.2. 
Deaths 
The Investigator will report the fatal event to the Sponsor’s medical monitor. The Investigator 
must provide a causal assessment of the relationship of the event to the study drug according to 
the guidance in Section 7.3.4. 
If the death occurred within the AE collection and reporting period (signed ICF to 60 days after 
last dose) and meets the reporting criteria, the Investigator must submit the SAE Report Form in 
the same manner as described above in Section 7.3.5. If the Investigator becomes aware of a 
death occurring after the AE reporting period and considers it related to pamrevlumab, it will be 
reported as an SAE.  
7.3.6. 
Pregnancies: Reporting and Follow-up of Subjects and Female Partners of 
Subjects  
The outcome of all pregnancies for female subjects or female partners of male subjects should be 
followed up and documented as described. If a female subject or a female partner of a male 
subject becomes pregnant while the subject is receiving study treatment or within 12 weeks after 
the last dose of study treatment, a Pregnancy Report Form must be completed and submitted to 
the Sponsor or designated safety management vendor within 24 hours of the Investigator 
becoming aware of the pregnancy. The Investigator must follow-up to completion of the 
pregnancy to ascertain its outcome (e.g., spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth or congenital abnormality) and whether any AEs occur during the 
pregnancy or birth. The outcome of the pregnancy must be reported by the Investigator on a 
Pregnancy Outcome Report Form, which should be sent to the Sponsor and/or its designated 
safety vendor within 24 hours of the Investigator becoming aware of the outcome.  


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Pregnancy itself is not an AE unless there is a suspicion that the investigational product under 
study may have interfered with the effectiveness of a contraceptive medication. Pregnancies are 
followed up to outcome even if the subject was discontinued from the study. Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs. Elective abortions without complications should not be handled as AEs.  
If a lactation case occurs while the female subject is taking protocol-required therapies, or within 
60 days after the last dose of study treatment, report the lactation case to FibroGen. In addition to 
reporting a lactation case during the study, investigators should monitor for lactation cases that 
occur after the last dose of protocol-required therapies through 60 days after the last dose of 
pamrevlumab.  Any lactation case should be reported to FibroGen’s Safety within 24 hours of 
the investigator’s knowledge of event.  
7.3.7. 
Laboratory or other Test Abnormalities/ Findings 
A laboratory or other test abnormality (e.g., spirometry, HRCT) in the absence of any signs or 
symptoms is not necessarily an AE. The Investigator must review and assess all test results 
provided by the central laboratory or other vendors throughout the study in a timely manner, and 
determine whether any abnormal values/test results are clinically significant (CS) or not 
clinically significant (NCS), and whether there are associated signs and symptoms. Such 
abnormalities should be considered CS if they are associated with new signs or symptoms, if 
they occur after taking study medication, reflect a meaningful change from the screening 
value(s), or require active management (e.g., requiring treatment, additional testing, study 
treatment dose modification, discontinuation, more frequent follow-up assessments, etc.).  
Clinically significant laboratory abnormalities will be reported as AEs. If the abnormal 
laboratory finding is accompanied by signs or symptoms, report the signs and symptoms as the 
AE in lieu of the abnormal laboratory value. If a diagnosis is available, report the diagnosis. 
7.3.8. 
Hypersensitivity/Anaphylactic Reactions: 
Hypersensitivity and anaphylactic reactions will be monitored throughout the study, using the 
criteria below as defined per Sampson et al. 2006 (Sampson, 2006). 
Anaphylaxis is highly likely when the following criteria is fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-
uvula). 
And at least one of the following criteria: 
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia) 
b. Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia 
[collapse], syncope, incontinence) 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours):  
 a. Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen 
lips-tongue-uvula)  


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 b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia)  
 c. Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence) 
 d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
      3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):  
 a. Systolic BP of less than 90 mm Hg or greater than 30% decrease from that person's 
baseline 
7.3.9. 
Safety Monitoring  
Safety will be assessed throughout the study. A medically complete baseline profile of each 
subject will be established through medical history, a complete physical examination including 
vital signs, laboratory tests, PFTs, and a 12-lead ECG. During the course of the study, vital signs, 
laboratory tests, and PFTs will be performed at frequent intervals as described in Appendix 1 and 
Appendix 2. Any medically significant changes from baseline will be monitored throughout the 
study and appropriate interventions will be taken accordingly. Safety and tolerability will be 
monitored closely by FibroGen. 
7.3.9.1. 
Special Reporting Situations 
Special Reporting Situations on FibroGen investigational product pamrevlumab (or placebo) that 
require safety evaluation include: 
• Overdose (any dose greater than 4.1g) 
• Suspected abuse/misuse 
• Inadvertent or accidental exposure 
• Medication error (e.g., incorrect dose administered) 
• Drug-drug interactions 
Report special situations to FibroGen’s Safety within 24 hours of the investigator’s knowledge of 
the event. See Study Reference Manual for detailed reporting instructions. 
7.3.9.2. 
Data Monitoring Committee (DMC) 
A Data Monitoring Committee (DMC) will be utilized and will be composed of external experts. 
Composition and responsibilities of the DMC will be defined in a separate DMC charter. The 
DMC responsibilities will include review of the safety data.  


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8. 
STATISTICS 
8.1. 
Sample Size Determination 
This study will enroll approximately 340 subjects with a 1:1 randomization ratio to pamrevlumab 
or placebo, respectively.  
A sample size of 340 subjects will have at least 90% power, based on a two-sided alpha level of 
0.05 for a two-sample t-test, to detect a treatment difference of 120 mL in the primary efficacy 
endpoint, change from baseline in FVC (L), assuming a common standard deviation of 300 mL.    
The rationale for these sample size assumptions are as follows. In the phase 2 study FGCL-3019-
067, a treatment difference of 178 mL was observed in change from baseline in FVC to Week 
48. For this study, a conservative treatment difference of 120 mL is assumed. The standard 
deviation is estimated based on published results from other IPF studies.  
8.2. 
Analysis Populations 
8.2.1. 
Intent to Treat (ITT) Population 
The ITT population is defined as all randomized subjects. Subjects will be analyzed according to 
the treatment as randomized. 
8.2.2. 
Safety Population 
The safety population is defined as all subjects who have received the study medication.  
Subjects will be analyzed according to the treatment as received. 
8.3. 
Statistical Analysis 
8.3.1. 
General Considerations 
The primary efficacy endpoint will be tested at the significance level of 0.05.  Upon observing a 
significant treatment difference in the primary endpoint, the secondary endpoints will be tested 
sequentially in a fixed sequence according to the order listed in section 3.2.2, taking into 
consideration the adjustment for the family-wise error-rate of 0.05. The testing will continue 
with the significance level of 0.05 in sequential fashion until the test fails to show statistical 
significance for a secondary endpoint. 
Baseline characteristics, safety, efficacy, and biomarker data will be summarized by treatment 
arm, based on available data in the ITT and/or Safety Population.  
All study parameters will be presented in the data listings and summarized descriptively by visit. 
Descriptive statistics for continuous variables include: n, mean, standard deviation or standard 
error (SE), median, minimum, and maximum. Categorical variables will be presented by 
frequency count of subjects and percentage. Two-sided 95% confidence intervals will be 
provided. 
Efficacy and safety analyses for formal treatment arm (pamrevlumab vs placebo) comparisons 
will only be based on data observed during the main study that is double-blind and placebo-
controlled.  Data from the OLE period will be summarized descriptively. 


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8.3.2. 
Subject Enrollment and Disposition 
The number (%) of subjects who completed or discontinued the study, and reasons for early 
discontinuation, will be summarized by treatment for subjects in the ITT population. 
8.3.3. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for subjects in the ITT 
population. 
8.3.4. 
Efficacy Analyses 
Unless stated otherwise, analyses performed using the random coefficient model (RCM), mixed 
model for repeated measurements (MMRM), and time to event model are under the same set of 
estimand and estimator descriptions as the primary endpoint.  The analysis population is all 
randomized subjects to reflect the intent-to-treat (ITT) principle for all analyses. 
8.3.4.1. 
Primary Endpoint Analysis 
The primary estimand is intended to provide a population level estimate of the treatment effects 
of the pamrevlumab on a continuous endpoint, regardless of participants compliance with the IP 
dosing. Under estimand framework, the analysis of primary endpoint includes the following 
components: 
Population: Male and female patients aged 40 to 85 years, inclusive at screening initiation with 
IPF diagnosis made with 7 years prior to screening under American Thoracic Society/European 
Respiratory Society (ATS/ERS) criteria (Raghu 2018), and not currently receiving treatment 
with the 2 approved antifibrotic standard of care medications. All subjects in ITT population will 
be included. 
Endpoint: Change from baseline in FVC (L) assessments at Week 48. 
Treatment of interest: The randomization study treatment (pamrevlumab or placebo). 
Handling of intercurrent events: The treatment policy strategy will be adopted for primary 
analysis. Details on handling missing values will be defined in SAP. 
Population-level summary for the endpoint: Absolute LSMeans difference between 
pamrevlumab and placebo in change from baseline to Week 48 in FVC (L) estimated from a 
random coefficient model (RCM), the primary analysis approach. RCM model includes 
treatment, visit (as a continuous variable), visit-by-treatment interaction, randomization 
stratification factors, baseline FVC volume, age, sex, height as fixed effects, and the intercept 
and linear slope of visit as random effects. Details of RCM model will be defined in SAP. 
Additional sensitivity and supplemental analyses on primary endpoint will be defined in SAP. 
The following analysis will be performed including, but not limited to: 
1. With alternative model using quadratic assumption of FVC decline 
2. Alternative assumptions for missing data (imputation method): 
a. Missing not at random: Pattern mixture model (e.g., control-based imputation) 
b. Missing not at random: Tipping point analysis (e.g., delta-adjusting pattern 
imputation)  


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8.3.4.2. 
Secondary Endpoint Analysis 
The secondary estimands are intended to provide a population level estimate of the treatment 
effect of the pamrevlumab on time-to-event endpoints and continuous endpoint, regardless of 
participants compliance with the IP dosing. Under estimand framework, the analysis of 
secondary endpoint includes the following components: 
Population: Same as primary estimand. 
Endpoints: 
• Time to disease progression, defined as absolute FVCpp decline of ≥10% or death, 
whichever occurs first 
• Change in Quantitative Lung Fibrosis (QLF) volume from baseline at Week 48 
• Time to any component of clinical composite endpoint, whichever occurs first: acute 
IPF exacerbation, respiratory hospitalization, or death 
• Time to first acute IPF exacerbation during study 
• Time to all-cause mortality during study 
• Time to first respiratory hospitalizations during study 
Treatment of interest: Same as primary estimand.  
Handling of intercurrent events: 
For time-to-event endpoints, treatment policy strategy will be adopted. For death, composite 
strategy will be used if death is a component of the endpoint. Censoring rules will be defined in 
SAP. 
For QLF, the same strategy as primary estimand will be applied.  
Population-level summary for the endpoint:  
For time-to-event endpoints: The hazard ratio and corresponding 95% CI from Cox proportional 
hazard model will be presented. P-value from stratified Log-rank test will also be reported. 
Details will be defined in SAP. 
For QLF endpoint: treatment difference of Least-square mean (LSMean) and SE at week 48 
between pamrevlumab and placebo and the corresponding 95% CI derived from a Mixed Model 
for Repeated Measure (MMRM) will be presented. The MMRM model includes treatment, visit, 
treatment-visit interaction, randomization stratification, and baseline endpoint value as fixed 
effects. 
8.3.4.3. 
Exploratory Analyses 
Patient reported outcomes (PROs) including SGRQ, UCSD-SOBQ and LCQ will be analyzed 
using same MMRM model as QLF. Absolute and relative FVCpp will be analyzed with similar 
RCM model as FVC excluding the covariates adjusted for FVCpp. Time to composite of 
respiratory hospitalization, absolute FVCpp decline ≥10%, or death will be analyzed similar to 
other secondary time-to-event endpoints. Biomarkers will be summarized.  
  


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8.3.5. 
Pharmacokinetic Analyses 
A plan for population PK analysis will be provided in the SAP. 
8.3.6. 
Safety Analyses 
Safety data will be summarized based on the Safety population. TEAEs and TESAEs will be 
summarized by treatment arm.  
Clinically significant changes from baseline in vital signs and laboratory tests will be identified 
and summarized by treatment arm. Additionally, hypersensitivity/anaphylactic reactions will be 
monitored and immunogenicity reactions, including neutralizing HAHA formation, will be 
assessed by treatment arm. 
8.4. 
Interim Analysis 
No interim analysis is planned for this study. 
8.5. 
Statistical Analysis Plan 
The Statistical Analysis Plan (SAP) will include detailed analysis methods, statistical models, 
definitions, missing data handling as well as other data handling rules. It will document detailed 
analyses of the primary, secondary, and additional exploratory endpoints that are not otherwise 
specified in the protocol.  The SAP will be finalized prior to database lock and treatment 
unblinding. 
 


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9. 
QUALITY CONTROL AND QUALITY ASSURANCE 
9.1. 
Data Quality Assurance 
Quality assurance and quality control systems will be implemented and maintained with 
Standard Operating Procedures by FibroGen and its designee(s), as appropriate, to ensure that 
this clinical study is conducted and data are generated, documented (recorded) and reported in 
compliance with the protocol, ICH E6 (GCP), and other applicable regulations. 
This study will be monitored by FibroGen or designee in accordance with GCP, and may be 
audited or reviewed by an independent Quality Assurance department, IRB/IEC, and/or 
regulatory authorities.  This implies that monitors and auditors/inspectors will have the right to 
inspect the study sites at any time during and/or after completion of the study and will have 
direct access to data/source documents, including the subject's file.  By participating in this 
study, Investigators agree to this requirement. 
The purpose of trial monitoring is to verify the following: 
• The rights and well-being of human subjects are protected. 
• The reported data are accurate, complete, and verifiable from source documents. 
• All data are collected, tracked, and submitted by the site to FibroGen or designee, 
including unscheduled and missed assessments 
• The reported data are reconciled across all data sources (e.g., laboratory, safety, IRT, 
clinical databases). 
• The conduct of the trial is in compliance with the currently approved 
protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s). 
Measures will be undertaken to protect the confidentiality of records that could identify subjects, 
respecting the privacy and confidentiality rules in accordance with applicable regulatory 
requirements. 
9.2. 
Audit and Inspection 
Authorized representatives of the Sponsor, a regulatory authority, and/or an IRB/IEC may visit 
the Investigator site to perform audits or inspections, including source data verification and 
source documentation review. The Investigator will allow the Sponsor auditor (or designee), 
regulatory authority or ethics committee representative to inspect the drug storage area, study 
drug stocks, drug accountability records, subject charts (e.g., medical records) and study source 
documents, and other records relative to study conduct. 
The purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents to determine whether these activities were conducted, and data 
were recorded, analyzed, and accurately reported according to the protocol, ICH GCP guidelines, 
and any applicable regulatory requirements. 
The Investigator must contact the Sponsor, or its third party representative (CRO), immediately 
if notified by a regulatory authority of an inspection pertaining to this study. 


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10. 
ETHICS 
10.1. 
Ethical Considerations 
The study will be conducted in accordance with applicable regulatory requirements, the 
International Conference on Harmonisation (ICH) E6 Guideline for Good Clinical Practice 
(GCP), the Declaration of Helsinki, any other applicable regulatory requirements, and 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) requirements. 
10.2. 
Communication with the Institutional Review Board or Independent 
Ethics Committee 
This protocol, the Informed Consent Form, the IB, and any information to be given to the subject 
must be submitted to a properly constituted IRB/IEC by the Investigator for review and approved 
by the IRB/IEC before the study is initiated and before any investigational product is shipped to 
the investigator. In addition, any subject recruitment materials must be approved by the IRB/IEC 
before the material is used for subject recruitment. 
The Investigator is responsible for obtaining reapproval by the IRB/IEC annually or as required 
by the policies and procedures established by the IRB/IEC. Copies of the investigator’s annual 
report and other required reports submitted to the IRB/IEC and copies of the IRB/IEC 
continuance of approval must be furnished to FibroGen or designee. A copy of the signed FDA 
Form 1572 or other qualified Investigator statement (as required) must also accompany the 
above approval letter provided to FibroGen. 
Investigators are also responsible for promptly informing the IRB/IEC of any protocol changes 
or amendments, changes to the IB, and other safety-related communications from FibroGen or its 
designee. Written documentation of IRB/IEC approval must be received before the amendment 
is implemented. 
Investigators must maintain a list of appropriate qualified persons to whom the Investigator has 
delegated significant trial-related duties and update the list as staff and their delegated 
responsibilities change.    
10.3. 
Subject Information and Consent 
Prior to participation in any study-specific procedures, the subject must sign (note: all references 
to “subject” in this section refers to the study subject or his/her legally acceptable representative) 
an IRB/IEC-approved written Informed Consent Form (ICF) in his/her native language.  The 
approved written informed consent must adhere to all applicable laws in regards to the safety and 
confidentiality of the subjects.  To obtain and document informed consent, the Investigator 
should comply with applicable regulations, and adhere to ICH GCP standards and the ethical 
principles in the Declaration of Helsinki (October 2008). 
The language in the written information about the study should be as non-technical as practical 
and should be understandable to the subject.  Before informed consent is obtained, the 
Investigator should provide the subject ample time and opportunity to inquire about the study 
and to decide whether or not to participate. 


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All questions about the study should be answered to the satisfaction of the subject.  The written 
ICF should be signed and personally dated by the subject and the person who conducted the 
informed consent discussion, with any additional signatures obtained as required by applicable 
local regulations and IRB/IEC requirements.  Each subject will be informed that participation is 
voluntary and that he/she can withdraw from the study at any time.  All subjects will receive a 
copy of the signed and dated ICF. 
If there are any changes to the IRB/IEC approved ICF during the subjects’ participation in the 
study, the revised ICF must receive the IRB/IEC’s written approval before use and subjects must 
be re-consented to the revised version of the ICF, if/as required by the IRB/IEC. 
Each subject must provide his or her consent for the use and disclosure of personal health 
information in accordance with applicable regulatory requirements. 
10.4. 
Subject Confidentiality 
The confidentiality of records that could identify subjects should be protected, respecting the 
privacy and confidentiality rules in accordance with applicable regulatory requirements.  
Subject medical information obtained as part of this study is confidential and may only be 
disclosed to third parties as permitted by the Informed Consent or other disclosure authorization 
documents signed by the subject, unless permitted or required by applicable law. 


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11. 
DATA HANDLING AND RECORD KEEPING 
11.1. 
Source Documents 
Source documents are original documents, data, and records necessary for the reconstruction and 
evaluation of the clinical study. The Investigator or designee will prepare and maintain adequate 
and accurate source documents. These documents are designed to record all observations and 
other pertinent data for each subject enrolled in this clinical study. Source documents must be 
adequate to reconstruct all data transcribed onto the Case Report Forms (CRFs) and resolved 
queries. 
11.2. 
Direct Access to Source Documents 
The Investigator must provide direct access to source data and source documents for trial-related 
monitoring, audits, IRB/IEC review, and regulatory authority inspection.  Direct access includes 
examining, analyzing, verifying, and reproducing any records and reports that are important to 
the evaluation of the study.  The Investigator is obligated to inform and obtain the consent of the 
subject to permit such individuals to have access to his/her study-related records, including 
personal information and medical records. 
11.3. 
Data Collection, Handling, and Verification 
All required data will either be entered onto CRFs by authorized site personnel or will be 
provided as a data transfer from authorized service providers (such as laboratory results from a 
central laboratory). Data will be entered or uploaded into a validated, clinical database compliant 
with 21 CFR Part 11 regulations.  
All subject data will be reviewed by Sponsor and/or designee. Data that appear inconsistent, 
incomplete or inaccurate will be queried for site clarification. 
Medical history, adverse events and medications will be coded using industry standard 
dictionaries (e.g., MedDRA and World Health Organization Drug [WHODrug]) Dictionary. 
The Investigator is responsible for reviewing, verifying, and approving all subject data (i.e., 
CRFs and queries) throughout the duration of the study and prior to study completion, ensuring 
that all data are verifiable with source documents. 
11.4. 
Protocol Deviations 
Unless there is a safety concern, there should be no deviations or violations of the study protocol.  
In the event of a safety concern, the Investigator or designee must document and explain the 
reason for any deviation from the approved protocol.  The Investigator may implement a 
deviation from, or a change to, the protocol to eliminate an immediate hazard to study 
participants without prior IRB/IEC approval.  Immediately after the implemented deviation or 
change, the Investigator must submit a report explaining the reasons for the protocol violation or 
deviation to the IRB/IEC, FibroGen, and to the regulatory authorities, if required. 


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11.5. 
Retention of Data 
A FibroGen representative will inform the Investigator in writing when it is acceptable to dispose 
of any study records.  To enable evaluation and/or audits from regulatory authorities or FibroGen 
or designee, the Investigator agrees to keep records, including the identity of all participating 
subjects (e.g., subject identification code list and all source documents), all original signed ICFs, 
copies of all CRFs, original laboratory reports, detailed records of drug disposition and all 
essential documents for the conduct of a clinical study.  To comply with international 
regulations, the records should be retained by the Investigator for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
However, the Investigator may need to retain these documents for a longer period if required by 
applicable law, regulatory requirements or by an agreement with FibroGen whichever is longer. 
11.6. 
Financial Disclosure 
The Investigator’s disclosable financial interests must be obtained prior to initiation of the study 
site, at completion of the study at the investigational site, and 1 year following study completion.  
The Investigator should promptly update this information if any relevant changes occur during 
the above described period.  
Disclosable financial interests will be recorded on the Investigator Financial Disclosure Form.  
Any Investigator(s) added as investigational staff to the form FDA 1572 or other qualified 
investigator statement must complete the Investigator Financial Disclosure Form at the 
beginning of his/her participation in the study.  The Investigator Financial Disclosure Form for 
any Investigator(s) leaving the clinical site prior to study completion will be obtained prior to 
study completion. 


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12. 
PUBLICATION POLICY 
The data and results of the study will be owned solely by FibroGen and shall be confidential 
information of FibroGen, subject to the Investigator's publication rights, described below and if 
any outlined in the Clinical Trial Agreement.  It is understood by the Investigator that FibroGen 
may use the information developed in this clinical study in connection with the development of 
its compounds and therefore, may disclose it as required to other clinical investigators, the 
Licensing Authority or to regulatory agencies of other governments.  To allow for the use of the 
information derived from this clinical study, the Investigator understands that he/she has an 
obligation to provide and disclose test results and all data developed during this study to 
FibroGen. 
Any publication or presentation of the results of this clinical study by the Investigator may only 
be made in strict compliance with the provisions of the Clinical Trial Agreement.  Any 
publication relating to the study shall be made in collaboration with FibroGen. The Investigator 
should understand that it is not FibroGen’s intention to prevent publication of the data generated 
in the clinical study.  However, FibroGen reserves the right to control the form and timing of 
such publication for commercial reasons.  The Study Center and Investigator shall adhere to the 
publication language as outlined in both Clinical Trial Agreement and the protocol to the extent 
that if there is any conflict or ambiguity between Clinical Trial Agreement and the protocol, the 
publication terms in the Clinical Trial Agreement shall prevail. 


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13. 
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10.1056/NEJMoa1402582 


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Martinez FJ, Safrin S, Weycker D, et al. (2005) The clinical course of patients with idiopathic 
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Wilson MS, Wynn TA (2009) Pulmonary fibrosis: pathogenesis, etiology and regulation. 
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Wuyts, W. A., Ryan, S., and Egan, JJ (2009) Pulmonary Fibrosis. Lung Transplantation. 
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controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. New England Journal of 
Medicine 363: (7):620-628 


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14. 
APPENDICES 


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APPENDIX 1. MAIN STUDY SCHEDULE OF ASSESSMENTS 
 
 
Screening 
Period 
(Up to 6 
Weeks) a 
Dosing Period b, c (48 Weeks) 
Safety Follow-Up Period  
 
Study Week 
 
Day 1 
(First dose) 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
39 
42 
45 
48/ 
last 
dose/ 
ET 
28 days  
after last 
dose r 
60 days  
after last 
dose (phone 
call) r  
Assessment 
  
Pre-
dose 
Post-
dose 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Sign and date ICF 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Xs 
  
  
Eligibility Assessment 
(Inclusion/Exclusion) 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demographics 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical History 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Labs  
X 
X 
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
X 
 
Vital Signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Exam d, e 
X d  
X d  
  
  
  
  
Xd 
  
  
  
Xd 
  
  
  
Xd 
  
  
  
Xd 
 
 
ECG f 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
 
Randomization 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Infusions g, h 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Screening 
Period 
(Up to 6 
Weeks) a 
Dosing Period b, c (48 Weeks) 
Safety Follow-Up Period  
 


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Study Week 
 
Day 1 
(First dose) 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
39 
42 
45 
48 
/last 
dose/ 
ET 
28 days  
after last 
dose r 
60 days  
after last 
dose 
(phone 
call) r  
Adverse Events i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Procedures and Nondrug 
Therapies j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DLCO 
X k  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PFTs 
X 
Xl 
  
  
Xl 
  
Xl 
  
Xl 
  
Xl 
  
  
  
Xl 
  
  
  
Xl, t 
 
 
HRCT of Chest 
Xm 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
X t 
 
 
SGRQ n 
  
X 
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
X 
 
UCSD-SOBQ n 
  
X 
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
X 
 
Leicester Cough Q n 
  
X 
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
X 
 
Pregnancy Test o 
(WOCBP) 
X 
X 
  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Xp 
X 
X 
Assess vital status (in 
subject who terminate 
study early)  
  
  
  
  
  
  
  
  
  
  
Xq 
  
  
  
  
  
  
  
 Xq 
 
  
Abbreviations: AE = adverse event; CBC = complete blood count; DLCO = diffusing capacity of the lungs for carbon monoxide; ECG = electrocardiogram; ET = early 
termination; hCG = human chorionic gonadotropin; HRCT = high resolution computed tomography; ICF = Informed Consent Form; PFTs = Pulmonary Function Test; SGRQ = 
Saint George’s Respiratory Questionnaire; UCSD-SOBQ = University of California San Diego – Shortness of Breath Questionnaire;  
WOCBP = Women of childbearing potential 
 
a.) Plans to re-screen a subject must be discussed with, and approved by, the Medical Monitor prior to re-screening 
b.) Visit window of ±7 days, Week 3 through Week 48. Missed visits are not to be made up between scheduled visits, subject is to return for the next scheduled visit 
c.) Unscheduled visit assessments (procedures) performed as necessary. During the COVID 19 pandemic, the visit modality (e.g.: in-person versus remotely) and scheduling 
maybe adjusted and conducted at the discretion of the Investigator, in accordance with the site’s rules and recommendations, and using all necessary precautions. If a visit has to be 
done remotely it can be conducted with any technology available to the site and study subjects.    
d.) Height is measured only at screening. Weight is measured at screening, Day 1 (to calculate the starting dose), and every 12 weeks thereafter to determine the need for dose 
adjustment. 
e.) Additional PE’s may be performed as needed, if clinically indicated.    
f.) Additional ECGs may be performed as needed, if clinically indicated. 


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g.) Study drug infusions are Q3W starting on Day 1. NOTE: infusions must be at least 10 days apart; missed doses are not to be made up between scheduled visits, subject is to 
return for the next scheduled visit/dose. Vital signs (blood pressure, pulse, and temperature) must be recorded prior to, and after each infusion, according to Section 5.1.6. 
h.) If during a home infusion a new safety concern arises, the subject has to attend an on-site visit for an Investigator assessment as soon as feasible. 
i.) See Section 7 for details on safety assessments and AE/SAE reporting. 
j.) Concomitant medications and nondrug therapies must be reported starting with signing of informed consent and ending 28 days after the last dose. If the subject experiences an 
AE/SAE before the end of the final safety phone call (60 days after last dose), concomitant medications and nondrug therapies may also be collected, if part of the treatment of the 
AE/SAE. 
k.) If a DLCO is available within 3 months prior to screening, it can be utilized for screening purposes. 
l.) On-treatment PFTs, should be collected pre-dose. 
m.) If a recent HRCT scan (within 3 months prior to screening) is available, it can be utilized for screening purposes, provided it is submitted and evaluated by the Independent 
Radiology Imaging Review Group, is adhering to the imaging parameters detailed in the Imaging Core Manual (ICM), and is using the same accredited scanner as the on-study 
HRCT scans. 
n.) Questionnaires are obtained pre-dose. On weeks where both questionnaires and PFTs are obtained, PFT should be completed first.  
o.) Pregnancy tests for women of childbearing potential (WOCBP) only: serum pregnancy test at Screening; urine pregnancy tests (pre-dose) during study visits. A positive urine 
pregnancy test must be confirmed by serum hCG. In each case of delayed menstrual period (over one month between menstruations) confirmation of absence of pregnancy is 
strongly recommended. This recommendation also applies to WOCBP with infrequent or irregular menstrual cycles. 
p.) Urine pregnancy test to be done at Week 48 visit for women of childbearing potential only who consent to OLE. A positive urine pregnancy test must be confirmed by serum 
hCG. 
q.) ET subjects will be contacted by phone at weeks 24 and 48 to check the subject’s vital status. 
r.) All subjects will attend a visit 28 days after the last dose for all the marked assessments, and will be contacted by phone 60 days after the last dose, for a final safety assessment. 
If the subject experiences an SAE during these 60 days, it must be reported within 24 hours of awareness (see Section 7.3 for details).  
s.) Subjects eligible for the OLE are to be consented for the OLE at or before the Week 48 visit  
t.) ET subjects: PFTs do not have to be repeated if the last one was performed within 8 weeks (excluding the screening visit) of the ET visit. HRCT does not have to be repeated if 
the last one performed was within 4 months (excluding the screening visit) 
 


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APPENDIX 2. PHARMACOKINETIC, BIOMARKER, 
IMMUNOGENICITY AND GENOMICS SAMPLING 
Timepoint a 
PK g 
(Plasma) 
Biomarkers 
b, f 
(Serum and 
plasma) 
CTGF b 
(Plasma) 
HAHA/HAH
A-NAe 
(Plasma) 
Genomic
s b,g 
(Whole 
blood) 
Tryptas
e 
(serum) 
Day 1 
Xc 
X 
X 
Xb 
X 
 
Day 8 
Xd 
  
 
  
  
 
Day 15 
Xd 
  
 
  
  
 
Week 
3 
Xc 
  
 
  
  
 
Week 12 
Xc 
  
 
  
  
 
Week 24 
Xc 
X  
 X  
Xb  
  
 
Week 36 
Xc 
  
 X  
 Xb  
  
 
Week 48/Last Dose 
/ ET 
Xc, 
X  
X 
Xb 
  
 
28 Days after Last 
Dose  
Xd,  
X 
X 
Xb 
  
 
Suspected 
Hypersensitivity/ 
Anaphylactic 
Reaction 
Xh 
 
Xh 
Xh 
 
Xh 
Abbreviations: PK = Pharmacokinetic; CTGF = connective tissue growth factor; HAHA = human anti-human 
antibody; HAHA-NA = human anti-human antibody neutralizing antibody 
 
a.) For all time points, the actual date and time of sample collection must be recorded, in addition to date and time 
of study treatment administration. 
b.) Sample should be collected within 2 hours prior to dosing start. 
c.) Both pre-dose and post-dose samples are required for PK.  Pre-dose sample collection should be within 2 
hours prior to dosing and post-dose should be between 1-4 hours after dosing end.   
d.) Only one sample is required.  A ±2 day window may be applied to the Day 8 and 15 sample. 
e.) Samples with positive HAHA results will be tested for neutralizing antibody (HAHA-NA). 
f.) Biomarkers will be collected for subjects in countries where the Regulatory Agencies allow collection of these 
samples  
g.) PK and DNA samples will be collected for subjects who consent, except in countries where the Regulatory 
Agencies do not allow collection of these samples 
h.) In the event of a suspected hypersensitivity/anaphylactic reaction, PK, HAHA, HAHA-NA, CTGF and 
tryptase. The Tryptase sample should be drawn within 1 to 6 hours of immunogenic reaction, and all other 
samples should be collected within 24 hours of the immunogenic reaction. 


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APPENDIX 3. HRCT CRITERIA AND HISTOPATHOLOGICAL 
CRITERIA FOR UIP PATTERN 
 
HRCT Criteria for UIP Pattern 
UIP Pattern 
• Subpleural and basal predominant; distribution is often heterogeneous¹ 
• Honeycombing with or without peripheral traction bronchiectasis or bronchiolectasis² 
Probable UIP Pattern 
• Subpleural and basal predominant; distribution is often heterogeneous 
• Reticular pattern with peripheral traction bronchiectasis or bronchiolectasis 
• May have mild ground-glass opacities (GGO) 
Indeterminate for UIP 
• Subpleural and basal predominant• Subtle reticulation; may have mild GGO or 
distortion (“early UIP pattern”) 
• CT features and/or distribution of lung fibrosis that do not suggest any specific 
etiology (“truly indeterminate for UIP”) 
 
Histopathological Criteria for UIP Pattern 
UIP Pattern  
• Dense fibrosis with architectural distortion (i.e., destructive scarring and/or 
honeycombing) 
• Predominant subpleural and/or paraseptal distribution of fibrosis 
• Patchy involvement of lung parenchyma by fibrosis 
• Fibroblast foci 
• Absence of features to suggest an alternate diagnosis 
Probable UIP Pattern 
• Some histologic features from column 1 are present but to an extent that precludes a 
definite diagnosis of UIP/IPF AND 
• Absence of features to suggest an alternative diagnosis OR 
• Honeycombing only 
Indeterminate for UIP Pattern 
• Fibrosis with or without architectural distortion, with features favoring either a 
pattern other than UIP or features favoring UIP secondary to another cause³ 
• Some histologic features from column 1, but with other features suggesting an 
alternative diagnosis⁴ 
 
¹ Variants of distribution: occasionally diffuse, may be asymmetrical. 
² Superimposed CT features: mild GGO, reticular pattern, pulmonary ossification. 
³ Granulomas, hyaline membranes (other than when associated with acute exacerbation of IPF, which may be the 
presenting manifestation in some patients), prominent airway-centered changes, areas of interstitial inflammation 
lacking associated fibrosis, marked chronic fibrous pleuritis, organizing pneumonia. Such features may not be overt 
or easily seen to the untrained eye and often need to be specifically sought. 
⁴ Features that should raise concerns about the likelihood of an alternative diagnosis include a cellular inflammatory 
infiltrate away from areas of honeycombing, prominent lymphoid hyperplasia including secondary germinal centers, 
and a distinctly bronchiolocentric distribution that could include extensive peribronchiolar metaplasia. 


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APPENDIX 4. RADIATION RISK ASSESSMENT 
The estimated radiation dose that results from participation in this study is based on an estimate 
is for a “standard patient” such as the MIRD phantom used in the ImPACT dose calculator 
spreadsheet. However, the ImPACT spreadsheet does not have a model for all CT platforms and 
for these the DLP*k method is used. For this method we assume a “standard sized” patient 
model, scan length is 25 cm (the length of the lungs for the MIRD Phantom) and a k factor of 
0.014 mSv/mGy*cm for a thoracic scan (AAPM report 96 and European Guidelines 2000). For 
this study the expected doses are summarized in the table below. 
Please NOTE that for each visit, one CT exam will be performed. That exam will consist of a 
required scan per imaging manual. Effective dose estimates provided: (For this study, visits 
occur at Baseline, Week 24 and Week 48 (i.e., 3 visits).  Early Term scan is not required if a 
previous scan was completed within 4 months.    
Summary 
 
TLC scan – CTDIvol 
6.1 mGy 
TLC scan – DLP (25 cm scan) 
153 mGy*cm 
TLC scan only – DLP 
153 mGy*cm 
Effective Dose per CT exam (TLC only) 
2.14 mSv per exam 
Effective Dose per year (TLC only) (assume 2 studies each 
calendar year) 
4.28 mSv per year 
Effective Dose over entire study (TLC only) (3 studies) 
6.42 mSv over entire study 
Average background radiation (excluding medical exposure to population): 
 
For a comparison, the average annual exposure from background radiation: 
Based on National Average: 
 
United States 
3.0 mSv per year 
Canada 
1.8 mSv per year 
United Kingdom 
2.5 mSv per year 
Australia 
2.0 mSv per year 
Germany 
2.0 mSv per year 
India 
2-2.5 mSv per year 
 


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References: 
ImPACT http://www.impactscan.org/ctdosimetry.htm 
AAPM - American Association of Physicists in Medicine (2008). The measurement, Reporting and Management of 
Radiation Dose in CT. Report No. 96 of AAP M Task Group 23, (2008) 
European Commission (2000). European guidelines on quality criteria for computed tomography. EUR 16262 EN. 
Luxembourg, Office for Official Publications of the European Communities. 
U.S. NRC Fact Sheet on Biological Effects of Radiation 


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APPENDIX 5.  GAP SCORE CALCULATION  
 NOTE:  For the screening FVCpp value and GAP score calculation: the quality-controlled, 
Best-Test Review (BTR) assessment provided by the spirometry vendor over-reader, which is 
provided to sites within 48 hours after uploading the test, is to be used for eligibility assessment 
and GAP score calculation.  
 
Use the FVCpp and DLCOpp that qualifies the subject for the study entry at screening 
https://www.mdcalc.com/gap-index-idiopathic-pulmonary-fibrosis-ipf-mortality 
 
 
 
 
 
 
 
GAP STAGE CALCULATION  
(GAP Stage is derived from the GAP Score taken at screening) 
 
 
 
  
  
Points 
Gender  
Female 
0 
Male 
1 
Age  
≤ 60 years 
0 
61-65 years 
1 
> 65 years 
2 
Predicted Forced Vital 
Capacity (FVCpp)  
> 75 % 
0 
50-75% 
1 
< 50% 
2 
Predicted Diffusing Capacity 
of the Lung for Carbon 
Monoxide (DLCOpp)  
> 55% 
0 
36-55% 
1 
≤ 35% 
2 
Unable to 
perform 
3 
Total possible points 
  
8 
Stage 
Points 
Stage I 
0-3 
Stage II 
4-5 
Stage III 
6-8 


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APPENDIX 6. OPTIONAL, OPEN LABEL EXTENSION (OLE) PHASE 
OF PAMREVLUMAB 
 
Objective: 
This is an optional, open-label, single arm extension phase to provide continued access to 
pamrevlumab in subjects with IPF who completed the Week 48 visit of the main study and wish 
to participate in this OLE. 
 
Efficacy Assessment: 
The following efficacy assessments will be collected only as standard-of-care per each 
investigational site’s real world practice and descriptively presented during the OLE period: 
• FVC (L) 
• FVC percent predicted (pp) 
• Absolute FVCpp decline of ≥10%  
• All-cause mortality 
• Respiratory hospitalizations 
• Acute IPF exacerbations  
• Change in HRCT Quantitative Lung Fibrosis (QLF) volume (if HRCT is performed 
as part of routine patient care) 
 
Safety Assessments: 
Treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events 
(TESAEs; including hypersensitivity/anaphylactic reactions) will be collected for 60 days after 
the last dose.  
 
Design 
This is a multi-center, single-arm, open-label extension (OLE) phase in which subjects who 
complete the Week 48 visit of the main study are eligible to participate, as per Eligibility 
Assessments below.   
All subjects will receive pamrevlumab in an open-label manner. NOTE: No unblinding of 
subject’s treatment assignment in the main study will occur for purposes of OLE participation.  
During the OLE treatment period, co-administration of an approved IPF therapy (i.e., pirfenidone 
or nintedanib) is acceptable if clinically indicated in the Investigator’s opinion, provided that the 
Investigator assesses the potential risks/benefits of combining approved IPF therapies with 
pamrevlumab. See also Section 5.1.10 of the main study for details. 
 
 


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Eligibility Assessments: 
All subjects participating in the OLE phase must have completed the Week 48 visit of the main 
study. In addition, the Investigator must consider the subject to be suitable for continued 
participation in this phase, including ability to comply with study visits every 3 weeks for 
pamrevlumab infusions.  
A signed and dated IRB/IEC-approved informed consent must be obtained before dosing start, 
and preferably at the Week 48 visit of the main study.   
Male subjects with partners of childbearing potential and female subjects of childbearing 
potential (including those <1 year postmenopausal) must continue to use highly effective 
contraception methods (per Section 5.2.3) until 3 months after the last dose of study drug in the 
OLE phase.  
 
Additional consideration for participation in the OLE 
The following conditions are excluded for continued participation in this OLE phase: 
• Female subjects who are pregnant or nursing. 
• Use of any investigational drugs, or participation in a clinical trial with an investigational 
new drug, other than participation in the main study. 
• History of allergic or anaphylactic reaction to human, humanized, chimeric or murine 
monoclonal antibodies, or experienced an allergic or anaphylactic reaction to study drug 
or to any component of the excipient while participating in the main study. 
• Subjects who withdrew informed consent while participating in the main study. 
• The Investigator judges that the subject is not suitable for participation, or is unable to 
fully participate in the OLE phase and complete it for any reason, including inability to 
comply with study procedures and treatment, or any other relevant medical or psychiatric 
conditions 
 
Study Duration 
The OLE phase will end either after the last subject completes 48 weeks of treatment, or 
pamrevlumab is commercially for the indication of IPF, or the Sponsor decides to end the OLE 
phase, whichever occurs first. 
Subjects may withdraw from the OLE at any time, for any reason; such subjects will have an 
early termination visits (EX ET) as soon as feasible. Subjects will have a Safety Follow-Up Visit 
28 days after the last dose and have a final Safety Follow-Up Phone Call 60 days after the last 
dose. 
Any assessments repeated as a part of main study, and all AEs prior to first dose in OLE are 
considered as a part of the main study. 
 
Study Drug Dosing instructions and Visit Schedule 
Each subject will receive pamrevlumab (30 mg/kg) every 3 weeks, using the weight obtained on  
Day 1 of the OLE phase (=EX Day 1), and every 24 weeks thereafter, for assessment of the 


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proper weight-based dosing regimen. EX Day 1 is expected to be scheduled 3 weeks (+7 days) 
after the Week 48 visit of the main study.  
See Protocol Section 5 for detailed information on study drug infusions.  Home infusions via 
home health care may be available during the OLE phase of the study at the discretion of the 
Investigator but such home infusions services will not be reimbursed by the Sponsor. 
Important NOTE: The infusion durations and post-infusion observations periods have to be 
followed per Table 1 in Protocol Section 5.1.6, including the initial dosing and observations 
periods. 
Visit windows are within ±7 days of the scheduled visit date from EX Week 3 through EX End 
of Treatment; however, visits should be at least 10 days apart, to ensure intervals of at least 10 
days between study drug infusions. 
All study visits will be performed in accordance with the OLE Schedule of Assessments 
presented in Appendix 6. 
 
Missed Visits/Missed Doses 
Scheduled visit dates are determined from the time of the first dose in OLE, which is defined as 
EX Day 1. If a subject misses a visit, the subject should resume the regular visit schedule at the 
next scheduled visit.  
Missed doses are not to be made up through extra visits. If a subject misses more than two 
infusions in any 18-week period, or two sequential infusions, the FibroGen Medical Monitor 
should be notified.  The reason for missed doses must be documented in the subject’s clinical 
record. 
NOTE: In accordance with FDA Guidance: During the COVID-19 pandemic, the visit modality 
(e.g.: in-person versus remotely) and scheduling maybe adjusted and conducted at the discretion 
of the Investigator, in accordance with the site’s rules and recommendations, and using all 
necessary precautions. If a visit has to be done remotely, it can be conducted with any 
technology available to the site and study subjects.   
 
Unscheduled Visits 
Unscheduled visits/assessments will be captured accordingly in the clinical database 
 
Subject Study Withdrawal Criteria 
Subjects may withdraw from the OLE at any time, for any reason. Such subjects will have an early 
termination visit (EX ET) as soon as feasible. Study procedures to be performed during the EX ET 
visit can be found in the OLE Schedule of Assessments (SOA) presented in Appendix 6. Reasons for 
withdrawal will be captured on CRF.   
Mandatory reasons for withdrawing from the OLE phase include:  
• Any safety concern in the Investigator’s opinion, that precludes further study 
participation 
• Lung transplant 


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• Pregnancy 
• Withdrawal of Consent  
 
Safety Follow-Up 
All subjects  will have two  Safety Follow-Up Visits: 
• 28 days  after the last dose 
• 60 days after last dose: follow-up phone call, for a final safety assessment   
The visit windows for the safety assessments are: 28 days +7 days and 60 days +7 days (phone 
call) after the last dose. 
See OLE SOA in Appendix 6. 
After the protocol-required reporting period (60 days after the last dose), the Investigator does 
not need to actively monitor subjects for SAEs.  However, if the Investigator becomes aware of 
an SAE/death that may be possibly related to study treatment after the protocol-required 
reporting period, the Investigator may report the event to FibroGen as outlined in Section 7 of 
the main study. SAEs reported outside of the protocol-required reporting period will be captured 
within the safety database only as clinical trial cases for the purposes of expedited reporting. 
 
Study Assessments: 
All study assessments are done per the local standard of care with the exception of weight, pre 
and post infusion vital signs and pregnancy test. Refer to OLE SOA for details. 
 
Vital Signs (including Weight) – Pre and Post pamrevlumab infusion 
Vital signs to be collected include heart rate, blood pressure and temperature:   
• Heart rate should be collected as beats/min 
• Systolic and diastolic blood pressure should be collected from subjects in seated 
position (mmHg) 
• Temperature should be taken as oral or tympanic and captured as °F or °C 
Weight is collected at EX Day 1 and every 24 weeks thereafter for purposes of adjusting the 
weight-based dose if necessary. 
 
Laboratory Evaluations 
Local lab results, done as part of local standard-of-care, will not be recorded on CRF; local lab 
results will be reviewed by the Investigator for clinical significance and to determine appropriate 
reporting of adverse events (see Section 7.3.7 of the main study).  
Pregnancy tests (performed pre-dose EX Day 1, and pre-dose at other times) for women of 
childbearing potential (WOCBP) only, via urine pregnancy test should be done by the site using 
site supplies. A positive urine pregnancy test must be confirmed by serum hCG using the site 
local labs for testing 


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PFTs and HRCT 
PFTs and HRCTs are performed locally, and at a frequency according to local SOC, as 
determined by the Investigator. These tests will not be reimbursed by Sponsor. 
All local spirometry results are entered into EDC. 
If HRCT scans are done, they should be uploaded to the same Independent Radiology Review 
Group as for the main study.  
 
Human Anti-Human Antibodies (HAHA) 
Plasma samples will be collected for evaluation of human anti-human antibodies (HAHA), 
specific to the impact of neutralizing anti-drug antibodies (ADA) and the impact on 
immunogenicity, in all subjects participating in the OLE at the 28 days after last dose Safety 
Follow-Up Visit. A specialty laboratory will measure HAHA titers using a validated assay.   
Samples with positive HAHA results will be tested for neutralizing antibody (HAHA-NA). The 
prevalence and duration of binding and neutralizing antibodies and the effect of these antibodies 
on the pharmacokinetics, pharmacodynamics markers, efficacy, and safety of pamrevlumab will 
be assessed. 
 
Statistical Considerations: 
Data collected during the extension period will be summarized descriptively. 
 
 


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OLE Schedule of Assessments 
 
Abbreviations: AE = adverse event; SAE = serious adverse event; ET = early termination; hCG = human chorionic 
gonadotropin; HRCT = high resolution computed tomography; PFTs = Pulmonary Function Test; (SOC)  = not 
required at time-points noted above, but assessed per timing of local standard of care; EX = Extension; WOCBP = 
Women of childbearing potential; HAHA = human anti-human antibody ; HAHA-NA = human anti-human antibody 
neutralizing antibody 
 
a.) Pamrevlumab is dosed Q3W starting with EX-Day 1. Visit windows of ±7 days, EX Week 3 through EX Follow-
Up Period. Missed visits are not to be made up between scheduled visits, subject is to return for the next scheduled 
visit 
b.) Unscheduled visit assessments (procedures) will be determined by the investigator.  During the COVID-19 
pandemic, the visit modality (e.g.: in-person versus remotely) and scheduling maybe adjusted and conducted at the 
discretion of the Investigator, in accordance with the site’s rules and recommendations, and using all necessary 
precautions. If a visit has to be done remotely it can be conducted with any technology available to the site and study 
subjects.    
c.) Ensure subject has signed the informed consent at or before Week 48 visit of the main study and eligibility 
considerations have been assessed prior to EX Day 1 infusion. 
d.) Weight will be measured at EX Day 1 and every 24 weeks thereafter to determine dose for the subsequent 24-
week interval. 
e.) Infusions must be at least 10 days apart. Vital signs (blood pressure, pulse, and temperature) must be recorded 
prior to, and after each infusion. 
f.) See Section 7 of the main protocol for safety assessments. 
g.) Concomitant medications and nondrug therapies are recorded after signing of informed consent and ending 28 
days after the last dose. Subjects will also be contacted by phone for a follow-up at 60 days after the last dose for a 
final safety assessment. If the subject experiences an SAE, it must be reported within 24 hours of awareness (see 
Section 7.3 for details).  If an AE/SAE occurs during this timeframe, concomitant medications and nondrug 
therapies if used to treat the AE/SAE, are also collected. 
h.) Local Labs and PFTs are performed pre-dose. 
i.) Collected according to local standard of care.  
 
Dosing Period a, b 
Follow-Up Period o 
Study Week 
EX-Day 
1c 
Q3 
Weeks 
Q24 
Weeks / 
Last Dose 
/ EX ET 
28 Days after 
Last Doseo   
60 Days 
after Last 
Dose (phone 
call)o 
Assessment 
 
 
 
 
 
Weight  
X d 
 
X d 
 
 
Vital Signs e 
X 
X 
 
X 
 
Infusions e 
X 
X 
 
 
 
AEs/SAEs f 
X 
X 
 
X 
X 
Concomitant 
Medications g 
X 
X 
 
X 
X 
Procedures and 
Nondrug Therapies g 
X 
X 
 
X 
X 
PFTs (local) h, i, j  
SOC 
 
SOC 
 
 
Labs (local) h, i, k 
SOC 
 
SOC 
SOC 
 
HRCT of Chest i, l 
SOC 
 
SOC 
SOC 
 
Pregnancy Test (urine) 
(WOCBP) m 
X 
 
X 
X 
X 
HAHA/HAHA-NA n 
(Plasma) 
 
 
 
X 
 


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j.) PFT will be done locally, and at a frequency per local SOC, and recorded on CRF whenever they are performed 
locally.  
k.) Labs will be done locally and at a frequency per local SOC. Lab data will NOT be recorded on CRF. Clinically 
significant laboratory abnormalities will be reported in the context of AE reporting; do not report non-clinically 
significant lab abnormalities as AE 
l.) HRCT scans will be performed at a frequency per local SOC. Any HRCT scan will be uploaded to central HRCT 
radiology vendor  
m.) Pregnancy tests (performed pre-dose EX Day 1, and pre-dose at other times) for WOCBP only, via urine 
pregnancy test. A positive urine pregnancy test must be confirmed by serum hCG. In each case of delayed menstrual 
period (over one month between menstruations) confirmation of absence of pregnancy is strongly recommended. 
This recommendation also applies to WOCBP with infrequent or irregular menstrual cycles. 
n.) All subjects participating in the OLE will have a HAHA sample taken 28 days after the last dose. Samples with 
positive HAHA results will be tested for neutralizing antibody (HAHA-NA). 
o.) Subjects who withdraw from the study, for any reason, should attend a Follow-Up Period visit 28 days after the 
last dose. These subjects will also be contacted by phone for a follow-up at 60 days after the last dose for a final 
safety assessment. Such subjects will have an early termination visit (EX ET) as soon as feasible. If the subject 
experiences an SAE, it must be reported within 24 hours of awareness (see Section 7.3 for details).  
 
 
 

SAP_001.pdf: 
S T A TI S TI C A L A N A L Y SI S P L A N  
TI T L E P A G E  
S T U D Y TI T L E:  
A P hase 3, Ra n d o mize d, D o u ble- Bli n d, Place b o-
C o ntr olle d Efficac y a n d Safet y St u d y of Pa mre vl u ma b i n 
S u bjects wit h I di o pat hic P ul m o nar y Fi br osis (I P F) 
P R O T O C O L N U M B E R:  
F G C L - 3 0 1 9- 0 9 1 (Z E P H Y R U S  1) 
S T U D Y S P O N S O R:  
Fi br o Ge n, I nc.  
4 0 9 Illi n ois Street 
Sa n Fra n cisc o, Calif or nia 9 4 1 5 8 U S A  
S T U D Y D R U G: 
Pa mre vl u ma b  
I N DI C A TI O N: 
I di o pat hic P ul m o nar y Fi br osis (I P F) 
P R O T O C O L V E R SI O N:  
Versi o n 6. 0 
S A P V E R SI O N  
Fi nal Versi o n  1. 0 ( D o u ble- Bli n d Peri o d) 
R E L E A S E D A T E : 
1 2 Ma y 2 0 2 3 
C O N FI D E N TI A LI T Y S T A T E M E N T  
T he i nf or mati o n c o ntai ne d i n t his d oc u me nt is c o nfi de ntial a n d pr o priet ar y t o Fi br o Ge n, 
I n c. N o part of t his d oc u me nt or a n y of t he i nf or mati o n c o ntai ne d herei n ma y be 
tra ns mitte d, discl ose d, s hare d, r e pr o d uce d, p u blis he d, or utilize d b y a n y pers o ns wit h o ut 
pri or writte n a ut h orizati o n b y Fi br o Ge n, I nc.  
C o nfi de ntial
Pa ge 1 of 5 5
N C T #: N C T 0 3 9 5 5 1 4 6


F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S  1)    
   
               Statistical A nal ysis Pla n  ( v 1. 0, D o u ble -Bli n d Peri o d ) 
 
SI G N A T U R E P A G E  
A p pr o v als 
I h a ve r e vie w e d a n d acce pte d t he i nf or mati o n i n t his d oc u me nt t o be a tr ue a n d acc urate 
re pres e ntati o n of t he Statistical A nal ysis Pla n.  
* Si g nat ure: see a p p e n de d fi nal pa ge f or 2 1 C F R Part 1 1 c o m plia nt a p pr o val  
I niti at or: 
 
, Fi br o Ge n, I n c.  
Re vie we d b y:  
 
 Fi br o Ge n, I nc.  
 
, Fi br o G e n, I nc.  
 
, Fi br o G e n, I nc.  
 
, Fi br o Ge n, I nc.  
  
, Fi br o Ge n, I n c.  
 
, Fi br o G e n, I n c.  
 
, Fi br o G e n, I n c.  
 
, Fi br o Ge n, I n c.  
Si g n at ure Si g nific a nce  
T he f oll o wi n g si g nifica n ce is le nt t o t he si g nat ures o n t he A p pr o vals pa g e of t his d oc u me nt. 
Si g n at or y 
Si g nific a nce  
I niti at or 
B y si g ni n g, t he a ut h or is attesti n g t hat t he c o nte nt of t he d oc u me nt is c o m pl ete 
a n d acc urate.  
Re vie wer  B y si g ni n g, t he re vie wer is attesti n g t hat t he d oc u me nt’s a p pr oac h  a n d c o nte nts 
are c o m plia nt wit h t he st u d y pr ot oc ol, all a p pr o pri ate, re g ulat or y re q uire me nts, 
a n d ot her si g nifica nt g ui deli nes. T his i n di vi d ual(s) has re vie we d t he d o c u me nt f or 
acc ur ac y a n d c o m plete n ess.  
C o nfi de ntial
Pa ge 2 of 5 5


F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S  1)    
   
               Statistical A nal ysis Pla n  ( v 1. 0, D o u ble -Bli n d Peri o d ) 
 
C H A N G E HI S T O R Y  
Versi o n  
D ate  
Descri pti o n  
1. 0  
1 2 Ma y 2 0 2 3  
Fi nal A p pr o v e d Versi o n  
 
 
C o nfi de ntial
Pa ge 3 of 5 5


F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S  1) 
      Statistic al A nal ysis Pla n  ( v 1. 0, D o u ble -Bli n d Peri o d ) 
T A B L E O F C O N T E N T S  
TI T L E P A G E  ................................................................................................................................... 1 
C H A N G E HI S T O R Y ....................................................................................................................... 3 
T A B L E  O F CO N T E N T S  ................................................................................................................. 4 
LI S T O F T A B L E S  ........................................................................................................................... 7 
LI S T O F FI G U R E S  ......................................................................................................................... 7 
LI S T O F A B B R E VI A TI O N S  .......................................................................................................... 8 
1.  
I N T R OD U C TI O N  ...................................................................................................... 1 1 
2.  
S T U D Y O BJ E C TI V E  ................................................................................................. 1 1 
3.  
S T U D Y D E SI G N  ....................................................................................................... 1 1 
3. 1.  
O ver vie w ..................................................................................................................... 1 1  
3. 2.  
Sa m ple Size  ................................................................................................................ 1 1 
3. 3.  
Ra n d o mizati o n a n d Treat me nt Assi g n me nt ................................................................ 1 2  
3. 4.  
St u d y Peri o ds .............................................................................................................. 1 2  
3. 4. 1.  
Mai n St u d y C o h ort ..................................................................................................... 1 2  
3. 4. 2.  
Ja pa n E xte nsi o n C o h ort .............................................................................................. 1 3 
4.  
S T U D Y E N D P OI N T S  ................................................................................................ 1 4 
4. 1.  
Pri mar y E n d p oi nt ........................................................................................................ 1 4  
4. 2.  
Sec o n dar y E n d p oi nts .................................................................................................. 1 4  
4. 3.  
E x pl orat or y E n d p oi nts ................................................................................................ 1 4  
4. 4.  
Safet y Assess me nts  ..................................................................................................... 1 4 
4. 5.  
E x pl orat or y Bi o mar ker E n d p oi nts .............................................................................. 1 4  
5.  
G E N E R A L S T A TI S TI C A L C O N SI D E R A TI O N S  .................................................... 1 5 
5. 1.  
Ge ner al C o n ve nti o ns .................................................................................................. 1 5  
5. 1. 1.  
A nal ysis of Cate g orical E n d p oi nts ............................................................................. 1 5  
5. 1. 2.  
A nal ysis of C o nti n u o us E n d p oi nts ............................................................................. 1 5  
5. 1. 3.  
A nal ysis of Ti me -t o- E ve nt E n d p oi nts ........................................................................ 1 5 
5. 1. 4.  
A nal ysis of S pir o metr y Data ...................................................................................... 1 5  
5. 1. 5.  
A nal ysis of H R C T Data  .............................................................................................. 1 6 
5. 2.  
A nal ysis Sets  ............................................................................................................... 1 6 
5. 2. 1.  
I nte nt-t o- Treat P o p ulati o n (I T T) ................................................................................. 1 6 
5. 2. 2.  
Per -Pr ot oc ol Set ( P P S)  ................................................................................................ 1 6 
C o nfi de ntial
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F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S  1)    
   
               Statistical A nal ysis Pla n  ( v 1. 0, D o u ble -Bli n d Peri o d ) 
 
5. 2. 3.  
Safet y A nal ysis Set ( S A F)  .......................................................................................... 1 6 
5. 2. 4.  
I m m u n o ge nicit y A n al ysis Set (I G S) ........................................................................... 1 7 
5. 3.  
Ge ner al Data H a n dli n g R ules a n d Prese ntati o n S pecificati o ns  .................................. 1 7 
5. 3. 1.  
A nal ysis Peri o d ........................................................................................................... 1 7  
5. 3. 1. 1.  
O n - St u d y Peri o d ......................................................................................................... 1 7 
5. 3. 1. 2.  
O n -Treat me nt Peri o d  .................................................................................................. 1 7 
5. 3. 2.  
Baseli ne Defi niti o ns  .................................................................................................... 1 7 
5. 3. 3.  
F or m ulas ..................................................................................................................... 1 7  
5. 3. 4.  
Ge ner al I nstr ucti o ns of T L F ....................................................................................... 1 8  
5. 3. 5.  
Ha n dli n g of Dr o p o uts or Missi n g Data ...................................................................... 1 8  
5. 4.  
I nteri m A nal yses a n d Data M o nit ori n g C o m mittee .................................................... 1 8 
5. 5.  
A nal ysis Visit Wi n d o w  ............................................................................................... 1 8 
6.  
S T A TI S TI C A L A N A L Y SI S  ...................................................................................... 1 9 
6. 1.  
S u bject E nr oll me nt a n d Dis p ositi o n ........................................................................... 1 9  
6. 1. 1.  
Eli gi bilit y Criteria  ....................................................................................................... 1 9 
6. 1. 2.  
S u bject Acc o u nta bilit y a n d Dis p ositi o n ..................................................................... 1 9  
6. 2.  
I m p ort a nt Pr ot oc ol De viati o ns .................................................................................... 1 9 
6. 3.  
De m o gra p hics a n d Baseli ne C haract eristics  ............................................................... 2 0 
6. 3. 1.  
De m o gra p hics a n d Baseli ne C haract eristics  ............................................................... 2 0 
6. 3. 2.  
Me dical Hist or y  .......................................................................................................... 2 0 
6. 4.  
Pri or a n d C o nc o mita nt Me dicati o ns ........................................................................... 2 1  
6. 5.  
Pri or a n d C o nc o mita nt Pr oce d ures a n d N o n- dr u g T hera pies  ..................................... 2 1 
6. 6.  
St u d y Dr u g E x p os ure a n d Treat me nt C o m plia nce  ..................................................... 2 1 
6. 6. 1.  
St u d y Dr u g E x p os ure .................................................................................................. 2 1  
6. 6. 2.  
Treat me nt C o m plia nce  ................................................................................................ 2 2 
6. 7.  
Efficac y A nal ysis  ........................................................................................................ 2 2 
6. 7. 1.  
Pri mar y E n d p oi nt A nal ysis a n d Esti ma n d .................................................................. 2 3  
6. 7. 1. 1.  
Pri mar y A nal ysis wit h Mi xe d M o del f or Re peate d Meas ures ( M M R M) ................... 2 3  
6. 7. 1. 2.  
Se nsiti vit y A nal ysis  .................................................................................................... 2 4 
6. 7. 1. 3.  
S u p ple me ntal A nal ysis ............................................................................................... 2 6  
6. 7. 1. 4.  
S u b gr o u p A nal ysis ...................................................................................................... 2 6  
6. 7. 2.  
Sec o n dar y a n d E x pl orat or y E n d p oi nts A nal ysis a n d Esti ma n ds ................................ 2 6  
6. 7. 2. 1.  
Ti me -t o- E ve nt E n d p oi nts ............................................................................................ 2 6 
C o nfi de ntial
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F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S  1)    
   
               Statistical A nal ysis Pla n  ( v 1. 0, D o u ble -Bli n d Peri o d ) 
 
6. 7. 2. 2.  
C o nti n u o us E n d p oi nts wit h M M R M M o del ............................................................... 2 8  
6. 7. 2. 3.  
S u b gr o u p A nal ysis f or Sec o n dar y Efficac y E n d p oi nts .............................................. 3 0  
6. 8.  
Safet y A nal ysis  ........................................................................................................... 3 0 
6. 8. 1.  
A d verse E v e nts ( A Es)  ................................................................................................. 3 0 
6. 8. 2.  
S pecial Safet y E ve nts  ................................................................................................. 3 1 
6. 8. 3.  
Cli nical La b orat or y Par a meters  .................................................................................. 3 1 
6. 8. 4.  
Li ver F u n cti o n Tests ................................................................................................... 3 2  
6. 8. 5.  
Vital Si g ns  .................................................................................................................. 3 2 
6. 8. 6.  
Electr ocar di o gra m ( E C G)  ........................................................................................... 3 3 
6. 8. 7.  
P h ysical E xa mi nati o n ( P E) ......................................................................................... 3 3  
6. 8. 8.  
Pre g na nc y T est  ............................................................................................................ 3 3 
6. 9.  
Bi o mar ker E n d p oi nt A nal ysis ..................................................................................... 3 3  
6. 1 0.  
I m m u n o ge nicit y A n al ysis a n d P K .............................................................................. 3 3 
6. 1 0. 1.  
Ter ms a n d Defi niti o ns ................................................................................................ 3 4  
6. 1 0. 1. 1.  
Sa m ple A D A Stat us  .................................................................................................... 3 4 
6. 1 0. 1. 2.  
S u bject A D A Stat us  .................................................................................................... 3 4 
6. 1 0. 2.  
Statistical A nal ysis f or C haract erizati o n of A D A I m m u ne Res p o nse  ........................ 3 4 
6. 1 0. 2. 1.  
I n ci de nce of A D A ....................................................................................................... 3 4 
6. 1 0. 2. 2.  
A D A Titer Ki netics  ..................................................................................................... 3 5 
6. 1 0. 3.  
Cli nical I m plicati o n of A D A I m m u ne Res p o nse  ........................................................ 3 5 
6. 1 0. 3. 1.  
P K  ............................................................................................................................... 3 5 
6. 1 0. 3. 2.  
Safet y a n d Efficac y  ..................................................................................................... 3 6 
7.  
C H A N G E S F R O M P R O T O C O L  ............................................................................... 3 6 
8.  
R E F E R E N C E  ............................................................................................................. 3 6 
A P P E N DI X  1. H A N D LI N G MI S SI N G/I N C O M P L E T E D A T E S  ............................................. 3 8 
A p pe n di x 1. 1  Missi n g/I nc o m plete A E O nset Date  ..................................................................... 3 8 
A p pe n di x 1. 2.  Missi n g/I nc o m plete A E St o p Date  ...................................................................... 3 8 
A p pe n di x 1. 3.  Missi n g/I nc o m plete Pri or or C o nc o mita nt Me dicati o n Start Date  ...................... 3 9 
A p pe n di x 1. 4.  Missi n g/I nc o m plete Pri or or C o nc o mita nt Me dicati o n St o p Date  ...................... 3 9 
A p pe n di x 1. 5.  Missi n g Date I m p utati o n f or Last D ose Date  ...................................................... 3 9 
A P P E N DI X  2. A N A L Y SI S VI SI T WI N D O W S  ........................................................................ 4 0 
A P P E N DI X  3. S G R Q  ................................................................................................................. 4 4 
A P P E N DI X  4. U C S D -S O B Q  ..................................................................................................... 4 9 
C o nfi de ntial
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F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S  1)    
   
               Statistical A nal ysis Pla n  ( v 1. 0, D o u ble -Bli n d Peri o d ) 
 
A P P E N DI X  5. L C Q  .................................................................................................................... 5 0 
A P P E N DI X  6. G A P S C O R E A N D S T A G E  ............................................................................... 5 1 
A P P E N DI X  7. E X A M P L E S A S C O D E  ..................................................................................... 5 2 
A p pe n di x 7. 1. M M R M .................................................................................................................. 5 2  
A p pe n di x 7. 2. J u m p- t o- C o ntr ol ..................................................................................................... 5 2 
A p pe n di x 7. 3. Delta- A dj usti n g ( Ti p pi n g P oi nt) A nal ysis ............................................................. 5 3  
A p pe n di x 7. 4. Ra n ke d A N C O V A ................................................................................................. 5 4  
A P P E N DI X  8. C HI N A C D E R E Q UI R E M E N T S ....................................................................... 5 5 
 
LI S T O F T A B L E S  
Ta ble  1: 
Criteria f or Maj or Pr ot o c ol De viati o ns  ....................................................................... 2 0 
Ta ble  2: 
Classificati o n of Pri or a n d C o nc o mita nt Me dicati o ns  ................................................ 2 1 
Ta ble  3: 
Fi xe d Se q ue n ce Testi n g Or der of Pri mar y a n d Sec o n dar y E n d p oi nts ....................... 2 3  
Ta ble  4: 
La b orat or y T e sts ......................................................................................................... 3 2 
Ta ble  5: 
Criteria f or P ote ntiall y Cli nicall y Si g nifica nt Vital Si g ns  .......................................... 3 3 
Ta ble  6: 
A nal ysis Visit Wi n d o w f or Vital Si g ns  ...................................................................... 4 0 
Ta ble  7: 
A nal ysis Visit Wi n d o w f or P F T ................................................................................. 4 1  
Ta ble  8: 
A nal ysis Visit Wi n d o w f or H R C T ............................................................................. 4 1  
Ta ble  9: 
A nal ysis Visit Wi n d o w f or S G R Q, U C S D- S O B Q, L C Q, a n d La bs .......................... 4 1  
Ta ble  1 0: A nal ysis Visit Wi n d o w f or P E a n d Wei g ht ................................................................ 4 2  
Ta ble  1 1: A nal ysis Visit Wi n d o w f or E C G ................................................................................ 4 2  
Ta ble  1 2: A nal ysis Visit Wi n d o w f or Bi o mar kers ( Ser u m a n d Plas ma)  .................................... 4 2 
Ta ble  1 3: A nal ysis Visit Wi n d o w f or C T G F a n d A D A ( Plas ma) .............................................. 4 2  
Ta ble  1 4: A nal ysis Visit Wi n d o w f or P har mac o ki netic C o nce ntrati o n ( Plas ma) ...................... 4 3  
 
LI S T O F FI G U R E S  
Fi g ure 1:  
St u d y Sc he ma ............................................................................................................. 1 3  
C o nfi de ntial
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F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S  1)    
   
               Statistical A nal ysis Pla n  ( v 1. 0, D o u ble -Bli n d Peri o d ) 
 
L I S T O F A B B R E VI A TI O N S 
A b bre vi ati o n  
E x pl a n ati o n  
A D A  
A nti -Dr u g A nti b o d y  
A E  
A d verse E v e nt  
A L P  
Al kali ne P h os p hatase  
A L T  
Ala ni ne A mi n otra nsferas e  
A N C  
A bs ol ute Ne utr o p hil C o u nt  
A N C O V A  
A nal ysis of C o varia nce  
A N O V A  
A nal ysis of Varia n ce  
a P T T/ P T T 
Acti vate d P artial T hr o m b o plasti n T i me 
A S T  
As partate A mi n otra nsferase  
A T C  
A nat o mical T her a pe utic Class  
A T S  
A merica n T h oraci c S ociet y  
B MI  
B o d y Mass I n d e x  
B T R  
Best -Test Re vie w  
B U N  
Bl o o d Urea Nitr o ge n  
C C L 1 8  
C he m o ki ne ( C -C M otif) Li ga n d 1 8  
C D E  
Ce nter f or Dr u g E val uati o n  
CI  
C o nfi de nce I nter val  
C R F  
Case Re p ort F or m  
C R P  
C -Reacti ve Pr otei n  
C S R  
Cli nical St u d y Re p ort  
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d vers e E ve nts  
C T G F  
C o n necti ve Tiss ue Gr o wt h Fact or  
C Y P  
C yt oc hr o me P 4 5 0  
D B L  
Data base L oc k  
D L C O  
Diff usi o n ca p acit y of t he L u n gs for Car b o n M o n o xi de  
D M C  
Data M o nit ori n g C o m mittee  
E C G  
Electr ocar di o gra m  
E D C  
Electr o nic D ata Ca pt ure  
E O S  
E n d of St u d y  
E O T  
E n d of Treat me nt  
E R S  
E ur o pea n Res pir at or y S ociet y  
F V C  
F orce d Vital Ca pacit y  
F V C p p  
F orce d Vital Ca pacit y perce nta g e pre di cte d  
G A P  
G A P i n de x a n d sta gi n g s yste m f or I P F: ge n d er ( G), a ge ( A), a n d t w o 
p ul m o nar y p h ysi ol o gical para meters ( P) - p erce nta ge pre dicte d F V C [ %], a n d 
perce nt a ge pr e dicte d D L C O [ %]  
G G T  
Ga m ma -G l uta m yltra nsferase 
H A H A  
H u ma n A nti -Pa mre vl u m a b A nti b o d y  
H R C T  
Hi g h -Res ol uti o n C o m p ute d T o m o gra p h y  
I C F 
I nf or me d C o nse nt F or m 
I C H E 9 
I nter nati o nal C o nfere nce o n Har m o nizati o n Statistical Pri nci ples f or Cli nical 
Trials  
I G S 
I m m u n o ge nicit y A n al ysis Set 
C o nfi de ntial
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F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S  1)    
   
               Statistical A nal ysis Pla n  ( v 1. 0, D o u ble -Bli n d Peri o d ) 
 
A b bre vi ati o n  
E x pl a n ati o n  
I L-6  
I nterle u ki n-6  
I L-8  
I nterle u ki n-8  
I N R 
I nter nati o nal N or m alise d R ati o 
I P 
I n v esti gati o nal Pr o d uct 
I P D 
I m p ort a nt Pr ot oc ol De viati o ns 
I P F 
I di o pat hic P ul m o nar y Fi br osis  
I R T 
I nteracti ve Res p o nse S yste m 
I T T 
I nte nt-T o -Tr eat  
I V 
I ntr a ve n o us 
K L -6  
Kre bs v o n de n L u n g e n 6  
L  
Liter  
L C Q  
Leicester C o u g h Q u esti o n naire  
L S Mea n(s)  
Least -S q uar e Mea n(s)  
M A R  
Missi n g At Ra n d o m  
M C M C  
Mar k o v C hai n M o nte Carl o  
Me d D R A  
Me dical Dicti o nar y f or R e g ulat or y Acti vities  
MI  
M ulti ple I m p utati o n  
m L  
milli liter 
M M P 7  
Matri x Metall o Pr otei nase -7  
M M R M  
Mi xe d M o del f or Re peate d Meas ures  
M N A R  
Missi n g N ot at Ra n d o m  
N M P A  
Nati o nal Me dical Pr o d ucts A d mi nistrati o n  
O L E  
O pe n La bel E xt e nsi o n  
P C S  
P ote ntiall y Cli nicall y Si g nifica nt  
P E  
P h ysical E xa mi nati o n  
P F T  
P ul m o nar y F u ncti o n Test s 
PIII N P  
T y pe III c olla ge n  
PI N P  
Pr oc olla ge n t y pe I N -ter mi nal Pr o pe pti de 
P K  
P har mac o ki netic(s)  
P o p P K  
P o p ulati o n p har mac o ki netic(s)  
P P S  
Per -Pr ot oc ol Set  
P R Os  
Patie nt Re p orte d O utc o m es  
P T  
Prefer T er m  
Q 3 W  
E ver y 3 Wee ks  
Q L F  
Q ua ntitati ve L u n g Fi br osis  
R B C  
Re d Bl o o d Cell, or Er yt hr oc yte  
R C M  
Ra n d o m C oefficie nt M o del  
S A E  
Seri o us A d verse E v e nt  
S A F  
Safet y A nal ysis Set  
S A P  
Statistical A nal ysis Pla n  
S D  
Sta n dar d De viati o n  
S E  
Sta n dar d Err or  
S G R Q  
St. Ge or ge’s Res pirat or y Q uesti o n naire  
S O C  
S yste m Or ga n Class  
T E A E  
Treat me nt -E mer ge nt A d verse E ve nt  
C o nfi de ntial
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F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S  1)    
   
               Statistical A nal ysis Pla n  ( v 1. 0, D o u ble -Bli n d Peri o d ) 
 
A b bre vi ati o n  
E x pl a n ati o n  
T E S A E  
Treat me nt -E mer ge nt Seri o us A d verse E v e nt  
T G F -b eta  
Tra nsf or mi n g Gr o wt h Fact or beta  
T L C  
T otal L u n g Ca pacit y V ol u me  
T L F  
Ta ble, Listi n g, a n d Fi g ure  
T N F  
T u m or Necr osis Fact or  
U C S D -S O B Q  
U ni versit y of Calif or nia Sa n Die g o –  S h ort ness of Breat h Q uesti o n naire  
U L N  
U p per Li mit of N or mal, val ue pr o vi de d b y t he la b orat or y  
V E G F  
Vasc ular E n d ot helial Gr o wt h Fact or  
W H O D D  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y  
W O C B P  
W o me n Of C hil d beari n g P ote ntial  
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1.  
IN T R O D U C TI O N  
T his statistical a nal ysis pla n ( S A P) is  f or t he pre -s pecifie d re p orti n g of st u d y res ults f or pr ot oc ol 
F G C L - 3 0 1 9- 0 9 1, a me n d me nt 6. 0. S pecificati o ns of ta bles, data listi n gs, a n d fi g ures ( T L F) are 
c o ntai ne d i n a se p arate d oc u me nt. T he statistical a nal yses a n d s u m mar y ta b ulati o ns descri be d i n 
t his S A P will pr o vi de t he basis f or t he res ults secti o n of t he cli nical st u d y re p ort ( C S R). T he S A P 
will be fi nalize d pri or t o u n bli n di n g after t he st u d y Data base L oc k ( D B L). A n y maj or 
m o dificati o n t o  t his S A P after t he si g n off will be d oc u me nte d i n a n S A P a m e n d me nt or i n t he 
C S R.  
T his S A P descri bes t he pla n ne d statistical a nal ys es f or t he d o u ble- bli n d peri o d of t he st u d y. 
Statistical  a nal yses f or  t h e mai n st u d y c o h ort of s u bjects  are pl a n ne d f or i ncl usi o n i n t he b o d y of 
t he C S R. Statistical a nal yses f or a J a pa nes e e xte nsi o n c o h ort of s u bjects ( als o i ncl u di n g o nl y t he 
d o u ble- bli n d peri o d) will be a nal yze d a n d re p orte d i n a s u bse q ue nt C S R a d de n d u m, f oll o wi n g 
t he sa me met h o d ol o g y o ut li ne d i n t his S A P , wit h t he e xce pti o ns t hat s u b gr o u p a nal yses will n ot 
be perf or me d d ue t o t he s mall sa m ple size a n d race will be e xcl u de d fr o m t he c o vari ates f or a n y 
a p plica ble statistical m o deli n g . 
T he o pe n-la b el e xte nsi o n peri o d ( O L E) of t he st u d y will ha ve a se parate S A P . A d diti o nall y, a 
p o p ulati o n p har mac o ki netic ( P o p P K ) a nal ysis as well as a n e x p os ure -res p o nse a nal ysis will be 
defi ne d i n a se p arat e P K a nal ysis pla n.  
Base d o n re gi o nal r e g ulat or y fili n g nee ds, re gi o n- s pecific s u bset a n al yses  ma y  be perf or me d 
f oll o wi n g t he met h o d ol o g y o utli ne d i n t his S A P.  Refer t o A p pe n di x 8  if re g ulat or y s u b missi o n i n 
C hi na is p urs ue d. 
2.  
S T U D Y O B J E C TI V E  
T he o ver all o bjecti ve of t his P hase 3 re gistrati o n-e na bli n g st u d y is t o e val uate t h e effi cac y a n d 
safet y of 3 0 m g/ k g i ntra v e n o us (I V) i nf usi o ns of pa mre vl u ma b as c o m pare d t o place b o i n 
s u bjects wit h I di o pat hic P ul m o nar y Fi br osis (I P F). 
3.  
S T U D Y D E SI G N  
3. 1.  
O ver vie w  
T his is a P hase 3, ra n d o mize d, d o u ble- bli n d, place b o- c o ntr olle d m ulti -ce nt er trial t o e val uat e t he 
efficac y a n d s afet y of p a mre vl u ma b i n s u bjects wit h I P F. A p pr o xi matel y 3 4 0 s u bjects will be 
e nr olle d i n t his trial . 
3. 2.  
S a m ple Size  
A sa m ple size of 3 4 0 s u bjects  will ha ve at least 9 0 % p o wer, b ase d o n a t w o -si de d al p ha le v el of 
0. 0 5 f or a t w o- s a m ple t-test, t o detect a treat me nt differe n ce of 1 2 0 m L i n t he pri mar y efficac y 
e n d p oi nt, c ha n ge fr o m baseli ne i n f orce d vital ca p acit y (F V C , i n Liter: L), ass u mi n g a c o m m o n 
sta n dar d de viati o n of 3 0 0 m L (all o wi n g a b o ut 2 0 % dr o p o ut rate). 
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T he rati o nale f or t hese s a m ple size ass u m pti o ns is as f oll o ws. I n t he p has e 2 st u d y F G C L- 3 0 1 9-
0 6 7, a treat me nt diff er e n ce of 1 7 8 m L w as o bser v e d i n c ha n ge fr o m baseli ne i n F V C t o 
Wee k  4 8. F o r t his st u d y, a c o nser v ati ve treat me nt differe n ce of 1 2 0 m L is ass u me d. T he sta n dar d 
de viati o n is esti mate d base d o n p u blis he d res ults fr o m ot her I P F st u dies. 
O nce t he c o m pleti o n of mai n st u d y c o h ort e nr oll me nt is reac h e d, Ja pa n es e  sites will c o nti n ue 
e nr oll me nt i n a n e xte nsi o n c o h ort u ntil t he pla n ne d n u m ber of s u bjects i n J a pa n ( N = 3 6) is 
ac hie ve d. T h ese a d diti o nal s u bjects will n ot be a n al yze d f or efficac y  or safet y i n t he mai n st u d y 
C S R . 
3. 3.  
R a n d o miz ati o n  a n d Tre at me nt Assi g n me nt  
S u bjects will be ra n d o mize d i n a 1: 1 rati o t o o ne of t he t w o st u d y treat me nt ar ms as f oll o ws: 
•  Ar m A: pa mre vl u ma b, 3 0 m g/ k g I V, Q 3 W (e v er y 3 wee ks) 
•  Ar m B: matc hi n g place b o I V, Q 3 W 
Ra n d o mizati o n is stratifie d b y t he f oll o wi n g fact ors: 
•  Pri or treat me nt wit h a n a p pr o ve d I P F t hera p y ( Yes/ N o) 
•  G A P sta ge (I, II, III) deri ve d fr o m t he G A P sc ore o btai ne d at scree ni n g ( Refer t o 
A p pe n di x 6 ). Calc ulati o n of t he G A P sc ore f or ra n d o mizati o n is base d o n t he Best-Test 
Re vie w ( B T R) assess me nt pr o vi de d b y t he i n de pe n de nt ce ntral s pir o metr y ve n d or rea der. 
3. 4.  
St u d y Peri o ds  
3. 4. 1.  
M ai n St u d y C o h ort  
T he mai n st u d y c o h ort c o nsists of t he f oll o wi n g st u d y peri o ds ( Fi g ure 1 ): 
•  Mai n ( d o u ble- bli n d, place b o-c o ntr olle d) st u d y p eri o d: 
− Scree ni n g peri o d: U p t o 6 wee ks 
− Treat me nt peri o d: 4 8 wee ks 
•  O pti o nal, o pe n la bel e xte nsi o n ( O L E) peri o d 
Access t o pa mre vl u ma b d uri n g t he O L E peri o d will be a vaila ble u ntil t he last e nr olle d s u bject 
c o m pletes 4 8 wee ks of tr eat me nt i n t he O L E  peri o d, or pa mre vl u ma b is c o m merciall y a vaila ble 
f or t he i n dicati o n of I P F, or t he S p o ns or deci des t o e n d t he O L E peri o d, w hic he ver o cc urs first. 
•  F oll o w- u p peri o d/fi nal s afet y assess me nt: 
− 2 8 da ys after t h e last d ose: sc he d ule d visit 
− 6 0 da ys after t h e last d ose: f oll o w- u p p h o ne call, f or a fi nal safet y assess me nt 
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Fi g ure  1: 
St u d y Sc he m a  
 
T he i nte nt of t his st u d y is t o e val uate t he efficac y a n d safet y pr ofile of pa mre vl u ma b as 
m o n ot hera p y vs. place b o i n s u bjects wit h I P F w h o were eit her treate d wit h a n a p pr o ve d a nti-
fi br otic I P F t her a p y (e. g., pirfe ni d o ne or ni nte d a ni b) t hera p y i n t he p ast b ut disc o nti n ue d t hat 
t hera p y pri or t o e nr oll me nt ( p ossi ble reas o ns f or disc o nti n uati o n of a p pr o ve d t hera p y c o ul d 
i ncl u de, b ut are n ot li mite d t o, i nt olera nce or disease pr o gressi o n); or w h o v ol u ntaril y deci de d t o 
f ore g o s uc h tr eat me nt after bei n g f ull y i nf or me d of t he p ote ntial be nefits/ris ks. 
After r a n d o mizati o n a n d d uri n g t he treat me nt peri o d, c o-a d mi nistrati o n of a n a p pr o ve d I P F 
t hera p y (i.e., pirfe ni d o ne or ni nte da ni b) is per mitte d if cli nicall y i n dicate d i n t he I n v esti gat or’s 
o pi ni o n, pr o vi de d t hat t he I n vesti gat or ass esses t h e p ote ntial ris ks/ be nefits of c o m bi ni n g 
a p pr o ve d I P F t her a pies wit h bli n de d st u d y treat me nt. 
S u bjects w h o c o m plete t he Wee k 4 8 visit of t he mai n st u d y (re gar dl ess of t he n u m ber of st u d y 
dr u g i nf usi o ns recei ve d a n d or treat me nt gr o u p assi g ne d i n t he d o u ble- bli n d peri o d ) will be 
eli gi ble t o partici pate i n t he o pti o nal O L E peri o d of t he st u d y t hat offers c o nti n ui n g access t o 
pa mre vl u ma b r e gar dless of ra n d o mizati o n assi g n me nt i n t he mai n st u d y. 
S u bjects w h o disc o nti n ue st u d y treat me nt f or a n y reas o n are e n c o ura g e d t o re mai n i n t he st u d y 
a n d be f oll o we d f or all st u d y visits a n d assess me nts. 
T he f oll o wi n g assess me nts will be assesse d ce ntrall y  b y i n de pe n de nt e xter n al ve n d ors or st u d y 
c o m mittees : 
•  P ul m o nar y f u ncti o n tests ( P F Ts) 
•  Hi g h -res ol uti o n c o m p ute d t o m o gra p h y ( H R C T) 
•  Ac ute I P F e xacer b ati o ns a n d res pirat or y h os pitalizati o ns 
I n a d diti o n, a n i n de pe n de nt Data M o nit ori n g C o m mittee ( D M C) will re vie w safet y dat a a n d 
ot her cli nical data  ( wit h t he a ut h orit y t o u n bli n d s uc h data) o n a peri o dic b asis t o m o nit or o verall 
s u bject safet y. 
3. 4. 2.  
J a p a n E xte nsi o n C o h ort 
Ja pa n e xte nsi o n c o h ort will perf or m si milarl y as mai n st u d y c o h ort, e xce pt wit h o ut t he O L E 
peri o d. 
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4.  
S T U D Y E N D P OI N T S  
4. 1.  
Pri m ar y E n d p oi nt  
•  C ha n ge i n F or ce d Vital Ca pacit y (F V C) fr o m bas eli ne at Wee k 4 8  
4. 2.  
Sec o n d ar y E n d p oi nts  
•  Ti me t o disease pr o gr essi o n, defi ne d as a bs ol ute F orce d Vital Ca p acit y perce nta ge 
pre dicte d  (F V C p p ) d ecli ne of ≥1 0 % or d eat h, w hi c he ver o cc urs first 
•  Ti me t o t he first occ urre n ce of a n y c o m p o ne nt of cli nical c o m p osite e n d p oi nt: ac ute 
I P F e xacer b ati o n, res pirat or y h os pitalizati o n, or deat h, w hic he v er occ urs first 
•  C ha n ge i n Q ua ntitati ve L u n g Fi br osis ( Q L F) v ol u me fr o m baseli ne at Wee k 4 8 
•  Ti me t o first ac ute I P F e xacer b ati o n d uri n g st u d y 
•  Ti me t o all-ca use m ortalit y d uri n g st u d y 
•  Ti me t o first res pirat or y h os pitalizati o n d uri n g st u d y 
4. 3.  
E x pl or at or y E n d p oi nts  
•  Ti me t o c o m p osite of: res pirat or y h os pitalizati o n , a bs ol ute F V C p p decli ne ≥1 0 %, or 
all-ca use d eat h, w hic h e v er occ urs first  
•  C ha n ge i n a bs ol ute F V C p p fr o m baseli ne at Wee k 4 8 
•  C ha n ge i n relati ve F V C p p fr o m baseli ne at Wee k 4 8  
•  C ha n ge i n St. Ge or ge’s Res pirat or y Q uesti o n naire ( S G R Q) sc ore fr o m b aseli ne at 
Wee k 4 8  
•  C ha n ge i n U ni versit y of Calif or nia Sa n Die g o – S h ort ness of Breat h Q u esti o n naire 
( U C S D-S O B Q) sc ore fr o m baseli ne at Wee k 4 8  
•  C ha n ge i n Leicester C o u g h Q uesti o n naire ( L C Q) fr o m baseli ne at Wee k 4 8 
4. 4.  
S afet y Assess me nt s 
•  Treat me nt -e mer ge nt a d v erse e v e nts ( T E A Es) a n d treat me nt -e mer ge nt seri o us a d verse 
e ve nts ( T E S A Es)  
•  C li nical la b orat or y par a meters 
•   Vital si g ns 
•   Hy perse nsiti vit y/a na p h ylactic reacti o ns  
4. 5.  
E x pl or at or y Bi o m ar ker  E n d p oi nts  
E x pl orat or y bi o mar kers t o be a nal yze d ma y i ncl u d e b ut are n ot li mite d t o:  
•  h u ma n a nti- h u ma n a nti b o dies ( H A H A) , als o na m e d as a nti-dr u g a nti b o d y ( A D A)  
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•  C o n necti ve Tiss ue Gr o wt h Fact or ( C T G F ) 
•  mar kers of i nfl a m mati o n s uc h as C- reacti ve pr ot ei n ( C R P), t u m or necr osis fact or 
(T N F ), i nterle u ki n- 6 (I L- 6), i nterle u ki n- 8 (I L- 8), a n d c he m o ki ne ( C-C m otif) li ga n d 
1 8 ( C C L 1 8 ) 
•  mar kers of fi br osis a n d c olla ge n s y nt hesis s uc h as tra nsf or mi n g gr o wt h fact or beta 
(T G F -beta ), pr oc olla ge n t y pe I N -ter mi nal pr o pe pti de (PI N P ), a n d t y pe III c olla ge n 
(PIII N P ) 
•  ot her mar kers of tiss ue re m o deli n g a n d a n gi o ge nesis s uc h as a n gi o p oieti ns, v asc ular 
e n d ot helial gr o wt h fact or ( V E G F ), matri x metall o pr otei nase - 7 (M M P 7 ), a n d Kre bs 
v o n de n L u n ge n 6 ( K L - 6). 
N O T E : Bi o mar ker sa m ples will be c ollecte d f or s u bjects, e xce pt i n c o u ntries w here t he 
Re g ulat or y A ge nci es d o n ot all o w c ollecti o n of t hese mar k ers. 
5.  
G E N E R A L S T A TI S TI C A L C O N SI D E R A TI O N S 
5. 1.  
Ge ner al C o n ve nti o ns  
All data c ollecte d will be i ncl u de d i n t he data listi n gs. All a nal yses will be perf or me d usi n g 
S A S ® Versi o n 9. 3 or hi g her. 
5. 1. 1.  
A n al ysis of C ate g oric al E n d p oi nts  
Fre q u e nc y distri b uti o ns ( n u m ber a n d perce nt a g e of s u bjects) will be pres e nte d f or cate g orical 
varia bles.  
5. 1. 2.  
A n al ysis of C o nti n u o us E n d p oi nts  
F or c o nti n u o us varia bles, d escri pti ve statistics , i ncl u di n g n, mea n, sta n dar d de viati o n ( S D), 
me dia n,  mi ni m u m, a n d ma xi m u m , will be prese nte d. Li ne gra p hs of gr o u p mea n (a n d sta n d ar d 
err or: S E) a n d mea n c h a n ge fr o m baseli ne ( a n d S E) val ues will be pl otte d o ver visits  as 
a p pr o priate. A d diti o nal pl ots s uc h as Least-s q uare mea n ( S E) or b o x pl ot will be pr o vi de d as 
a p pr o priate.  
5. 1. 3.  
A n al ysis of Ti m e -t o-E ve nt E n d p oi nts  
Ka pla n -Mei er c ur ves f or ti me -t o-e ve nt e n d p oi nts will be pl otte d as a p pr o priate. C o m paris o ns of 
t he res pirat or y h os pitalizati o n a n d a c ute I P F ex acer bati o n e n d p oi nts will be  base d o n t he e ve nts 
i de ntifie d b y t he I n de p e n de nt A dj u dicati o n C o m mittee  i n acc or d a nce wit h t he A dj u dicati o n 
C harter . 
5. 1. 4.  
A n al ysis of S pir o m etr y  Dat a  
All s pir o metr y res ults are re vie we d b y t h e i n de pe n de nt s pir o metr y O ver- Rea der gr o u p f or 
q ualit y, d uri n g t heir Best Test Re vie w ( B T R). T he O ver- Rea der d o es a n o v erall q ualit y rati n g of 
t he s pir o metr y data ( “acce pta ble”, “ b or derli ne acce pta ble” or “ u nacce pt a ble”) a n d d eter mi nes 
w hic h is t he “ Best” F V C ( L) val ue a n d c orres p o n di n g F V C p p f or eac h test. 
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F or eac h visit, o nl y o ne F V C val ue a n d c orres p o n di n g F V C p p t hat is i de ntifie d b y t he O ver-
Rea der as t he “ Best” F V C val ue, wit h a n o verall q ualit y rati n g of “acce pta ble” or “ b or derli ne 
acce pta ble” will be use d f or a nal yses.  
N O T E: I n t he sit uati o n w here at a visit m ulti ple s pir o metries were perf or me d, a B T R is 
perf or me d f or eac h s pir o metr y. T he res ul t c o nsi dere d f or t he a nal yses will be selecte d as f oll o ws: 
Defi niti o n of “ Best” p ost- B T R F V C val ue (a n d c orrelate d F V C p p val ue): T he “ Best” val u e will 
be defi ne d as t hat w hic h meets t he f oll o wi n g criteria: ( 1) F V C val ue w as selecte d after B T R b y 
o ver- r ea der as t he b est test res ult; a n d ( 2) Res ult recei ve d a n acce pta bl e or b or derli ne acce pta ble 
B T R rati n g. 
•  F or t he D a y 1 assess me nt ( Baseli ne), t he “ Best” p ost -B T R F V C val ue (a n d c orrel ate d 
F V C p p val ue) as defi n e d a b o ve w hic h als o meets t he f oll o wi n g criteria will be use d: ( 1) 
P F T was perf or me d o n or pri or t o Da y 1; a n d ( 2) Res ult met eli gi bilit y criteria, t hat is, 
c orrel ate d F V C p p val ue was wit hi n t he ra n ge of > 4 5 % a n d < 9 5 %. T he q ualif yi n g Da y 1 
val ue will be use d w he n e ver a q ualif yi n g D a y 1 val ue is a vaila ble; ot her wis e, t he 
q ualif yi n g val ue o n t he last visit pri or t o Da y 1 will be use d. I n cases w here t here is m ore 
t ha n o ne set of P F Ts p erf or me d o n t he sa me d a y, t he hi g hest of t he m ulti ple 
q ualif yi n g val ues will be use d. 
•  F or all s u bse q u e nt ( p ost- Da y 1) visits, t he “ Best” p ost-B T R F V C val ue (a n d c orrel ate d 
F V C p p val ue) as defi n e d a b o ve w hic h c orrelates wit h t he st u d y visit will be use d f or 
F V C a n d F V C p p a nal yses. 
5. 1. 5.  
A n al ysis of H R C T D at a  
H R C T i ma ges t hat meet t he q ualit y c o ntr ol sta n dar ds as assesse d b y t he i n d e pe n de nt ra di ol o g y 
i ma gi n g gr o u p will be c o nsi dere d f or t h e a nal yses. 
5. 2.  
A n al ysis Set s 
5. 2. 1.  
I nte nt-t o- Tre at P o p ul ati o n (I T T) 
T he i nte nt-t o-treat p o p ul ati o n i ncl u des all ra n d o mize d s u bjects. S u bjects will be a nal yze d 
acc or di n g t o t he ir ra n d o mize d treat me nt ar m re g ar dless of t he act ual st u d y treat me nt recei ve d. 
5. 2. 2.  
Per - P r ot oc ol Set  ( P P S) 
T he per - pr ot oc ol set is defi ne d as all ra n d o mize d s u bjects w h o ha ve c o m pleted at least 3 6 wee ks 
of treat me nt, wit h baseli n e a n d at least o ne p ost- baseli ne P F T assess me nt, a n d  n o maj or pr ot oc ol 
de viati o n ( defi ne d i n T a ble  1) t hat si g nifica ntl y i m pact efficac y a nal yses. 
5. 2. 3.  
S afet y A n al ysis Set ( S A F) 
T he safet y a nal ysis set i ncl u des all s u bjects w h o h a ve recei ve d a n y  st u d y dr u g. S u bjects  will be 
a nal yze d acc or di n g t o t he treat me nt act uall y recei ve d. 
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5. 2. 4.  
I m m u n o ge nicit y A n al ysis Set (I G S) 
T he I G S will i ncl u de all s u bjects w h o are i n  t he S A F a n d h a ve a b aseli ne  e val ua ble 
i m m u n o ge nicit y assess me nt  a n d at least 1  p ost- baseli ne e val ua ble (i.e., p ositi ve, ne gati ve) 
i m m u n o ge nicit y assess me nt. 
5. 3.  
Ge ner al  D at a H a n dli n g R ules a n d Prese nt ati o n S pecific ati o ns  
5. 3. 1.  
A n al ysis Peri o d 
5. 3. 1. 1.  
O n -St u d y Peri o d  
U nless ot her wise s pecifie d , t he efficac y a nal ysis will be base d o n t he o n-st u d y peri o d, w hic h 
i ncl u des all data c ollecte d d uri n g  t he d o u ble- bli n d peri o d. 
F or t he safet y a n al ysis, all safet y assess me nts be y o n d 6 0 da ys of t he last d os e will be e xcl u de d 
fr o m s u m mar y ta bles or fi g ures. 
5. 3. 1. 2.  
O n -Tre at m e nt Peri o d  
T he o n- treat me nt a nal ysis i ncl u des o nl y t he assess me nts t hat are o bser ve d d uri n g o n-st u d y 
peri o d as defi n e d a b o ve ( Secti o n  5. 3. 1. 1 ), b ut wit hi n 3 wee ks aft er t he last st u d y dr u g i nf usi o n i n 
t he d o u ble- bli n d peri o d. 
5. 3. 2.  
B aseli ne Defi niti o n s 
Baseli ne  f or P F T s is defi ne d as t he last “ Best” P F T (fr o m t he O v er-Rea der) bef ore t he first st u d y 
dr u g i nf usi o n ( or ra n d o mizati o n date if n o i nf usi o n is recei ve d) (Secti o n  5. 1. 4 ). 
Baseli ne f or all ot her e n d p oi nts is defi ne d as t he last meas ure me nt  pri or t o t he first st u d y dr u g 
i nf usi o n ( or ra n d o mizati o n date if n o i nf usi o n is recei ve d). U ns c he d ule d visits will be c o nsi dere d 
f or baseli ne. 
5. 3. 3.  
F or m ul as 
•  St u d y Da y Calc ulati o n 
− T he da y w he n a s u bject recei ves t he first d ose of st u d y dr u g after ra n d o mizati o n is 
desi g nate d as D a y 1. F or s u bjects w h o ha ve n ot recei ve d a n y st u d y dr u g i n a n I T T 
a nal ysis, t heir ra n d o mizati o n date will be use d as Da y 1. 
− St u d y da y of a n assess me nt/ pr oce d ure is calc ulate d as f oll o ws. 
 F or ass ess me nts or pr oce d ures o n Da y 1 or later: 
St u dy d ay = assess me nt/ pr oce d ure d ate – D a y 1 d ate + 1 
 F or ass ess me nts or pr oce d ures earlier t ha n D a y 1: 
St u dy d ay = assess me nt/ pr oce d ure d ate – D a y 1 d ate 
•  B o d y Mass I n d e x ( B MI ) =
𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊ℎ𝑡𝑡 (𝑘𝑘𝑊𝑊)
𝐻𝐻𝑊𝑊𝑊𝑊𝑊𝑊ℎ𝑡𝑡 (𝑐𝑐𝑐𝑐)2  
•  B o d y wei g ht, hei g ht, a n d te m perat ure will be c o n v erte d usi n g t he f oll o wi n g f or m ula: 
− k g = l b/ 2. 2 
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− c m = 2. 5 4 × i n 
− 
oC = ( 5/ 9) × ( oF – 3 2) 
•  A bs ol ute C ha n ge fr o m B aseli ne = V al ue at P ost- b aseli ne visit – b aseli ne v al ue  
•  Relati ve c ha n ge fr o m bas eli ne ( %) is deri ve d wit h t he f or m ula bel o w: 
𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑡𝑡 𝑘𝑘𝑊𝑊 𝐻𝐻𝑊𝑊𝑊𝑊𝑊𝑊 𝑡𝑡𝑐𝑐𝑐𝑐𝑉𝑉𝑉𝑉𝑏𝑏𝑏𝑏𝑉𝑉 𝑣𝑣𝑏𝑏𝑃𝑃𝑏𝑏𝑎𝑎−𝐵𝐵𝑉𝑉𝑃𝑃𝑉𝑉𝑉𝑉𝑏𝑏𝑏𝑏𝑉𝑉 𝑣𝑣𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉
𝐵𝐵𝑉𝑉𝑃𝑃𝑉𝑉𝑉𝑉𝑏𝑏𝑏𝑏𝑉𝑉 𝑣𝑣𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉
× 1 0 0  
5. 3. 4.  
Ge ner al I nstr ucti o ns of T L F 
•  F or c o nti n u o us varia bles t hat are rec or d e d as “ < X ” or “ > X ”, t he val ue of “ X ” will be 
use d i n t he calc ulati o n of s u m mar y statistics.  
•  All re p orti n g val ues ( mea n, me dia n, S D, S E, L S Mea n , 9 5 % CI, et c.) f or t he 
c o nti n u o us varia bles will ha ve 1 a d diti o nal deci mal place t ha n ra w d ata.  Mi n a n d 
Ma x will ha ve t he sa me deci mal place as ra w dat a.  
•  All perce nta g es will be r o u n de d t o o ne deci mal pl ace. T h e perce nta g e will be 
s u p presse d w he n t h e c o u nt is zer o. All d urati o ns of ti me will ha ve 1 deci mal place.  
•  All ta bles a n d listi n gs will ha ve a hea der s h o wi n g “ Fi br o G e n, I nc. ”, t he pr ot oc ol 
n u m ber ( Z E P H Y R U S 1 ), date of data c ut off, a n d Pa ge x of y. A f o oter will s h o w t he 
pr o gra m file pat h/ na m e, o ut p ut f ile pat h/ na me, date of data e xtracti o n, r u n date, a n d 
r u n ti me. 
5. 3. 5.  
H a n dli n g of Dr o p o uts or Missi n g  D at a  
All assess me nts c ollecte d will be c o nsi dere d f or a n al yses re gar dless of w h et her s uc h dat a were 
c ollecte d d uri n g tr eat me nt or after a s u bject disc o nti n ue d treat me nt. All a nal yses ass u me t he 
missi n g data are missi n g at ra n d o m ( M A R), u nless state d  ot her wise. D etaile d missi n g data 
ha n dli n g is descri be d i n t he a nal ysis of s pecific e n d p oi nts. 
5. 4.  
I nteri m A n al yses a n d D at a M o nit ori n g C o m mittee 
I n a d diti o n t o r o uti ne saf et y m o nit ori n g, a n i n de pe n de nt D M C will be esta blis he d t o re vie w 
safet y data o n a n o n g oi n g basis. A D M C c harter will esta blis h t he pr oce d ures, meeti n g 
fre q ue n c y, a n d sc o pe of r es p o nsi bilities of t he c o m mittee. 
T h is st u d y has n o pla n ne d or pre-s p ecifie d i nteri m a nal ysis f or eit her effi cac y or f utilit y. 
5. 5.  
A n al ysis Visit Wi n d o w  
A nal ysis visits , i nstea d of t he n o mi nal visits fr o m case re p ort f or m ( C R F ), deri ve d fr o m visit 
dates a n d visit ti me wi n d o ws will be use d i n t he b y- visit a nal yses. U nsc he d ul e d visits wit hi n a 
visit wi n d o w ( defi ne d i n A p pe n di x 2 ) will be gr o u pe d i nt o t he cl osest sc he d ule d visits base d o n 
t he visit date. F or s u bjects w h o ha ve m ore t h a n o n e meas ure me nt at a certai n a nal ysis visit, t he 
last meas ure me nt will be use d, wit h t he f oll o wi n g e xce pti o ns: 
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•  Li ver f u ncti o n tests, s uc h as Ala ni ne A mi n otra nsferase ( A L T), As partat e 
A mi n otra nsfer ase ( A S T), Ga m ma -Gl uta m yltra nsferase ( G G T), Al kali ne P h os p hatase 
( A L P), a n d t otal bilir u bi n, i n w hic h t he ma xi m u m val ue will be use d. 
•  S pir o metr y data: t he best val ue t o be use d f or a nal ysis as defi ne d i n Secti o n  5. 1. 4 . 
•  Vital si g ns: t he val ues o n t he i nf usi o n da ys will be use d if a p plica ble. 
•  A D A assess me nt: select i n t he or der of 1) last A D A + assess me nt; 2) earlier A D A + 
assess me nt; 3) last A D A - assess me nt .  
6.  
S T A TI S TI C A L A N A L Y SI S  
6. 1.  
S u bject E nr oll me nt  a n d Dis p ositi o n  
6. 1. 1.  
Eli gi bilit y Criteri a  
Eli gi bilit y criteria will be s u m marize d f or all scree ne d s u bjects. T he dat a will be s u m marize d 
wit h res pect t o:  
•  n u m ber of s u bjects scree ne d 
•  n u m ber ( %) of s u bjects s cree n-faile d 
•  n u m ber ( %) of s u bjects f or eac h faile d i ncl usi o n/e xcl usi o n criteri o n 
6. 1. 2.  
S u bject Acc o u nt a bilit y a n d Dis p ositi o n  
S u bject le vel i ncl usi o n criteria n ot met/e xcl usi o n criteria met listi n gs will be pr o vi de d.  
T he n u m ber ( %) of s u bjects ra n d o mize d (I T T), d ose d (S A F ), p er -pr ot oc ol s et ( P P S),  
I m m u n o ge nicit y A n al ysis Set (I G S), c o m plete d t h e mai n st u d y, e ntere d t h e O L E peri o d, a n d 
disc o nti n u e d pre mat urel y fr o m treat me nt a n d st u d y will be prese nte d f or eac h treat me nt gr o u p 
a n d all s u bjects p o ole d.  
Reas o ns f or pr e mat ure disc o nti n uati o n will be s u m marize d b y treat me nt gr o u p f or t he I T T 
p o p ulati o n. 
I n a d diti o n, discre pa n cies bet wee n r a n d o mizati o n stratificati o n fact ors deri ve d fr o m data i n t he 
Electr o nic D ata Ca pt ure S yste m  ( E D C) vs. data  fr o m t he I nteracti ve Res p o nse S yste m (I R T) 
ra n d o mizati o n s yste m will be s u m marize d. A listi n g will s h o w a n y discre p a ncies bet w ee n t he 
t w o s yste ms. If m or e t ha n 5 % discre pa ncies w ere i de ntifie d, E D C ra n d o mi zati o n stratificati o n 
fact ors will be use d as fi xe d eff ects i n the statistical a nal ysis if a p plica ble; ot her wise, I R T 
ra n d o mizati o n stratificati o n fact ors will be use d , u nless ot her wise s pecifie d. 
6. 2.  
I m p ort a nt Pr ot oc ol De vi ati o ns  
T he n u m ber a n d p erce nta ge of s u bjects wit h i m p orta nt pr ot oc ol de viati o ns (I P Ds) will be 
cate g orize d a n d ta b ul ate d as a p pr o priat e f or t he I T T p o p ulati o n. C O VI D- 1 9- relate d i m p orta nt 
pr ot oc ol de viati o ns will be s u m marize d i n a s e parate ta ble. All pr ot oc ol de v iati o ns will be 
fi nalize d pri or t o dat a bas e l oc k a n d u n bli n di n g. 
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A s u bset of I P Ds t hat si g nifica ntl y i m pact effi cac y a nal yses will be c ate g orize d  as maj or pr ot oc ol 
de viati o ns ( P Ds ). S u bjects wit h a n y maj or P D will be e xcl u de d fr o m t he P P S a nal yses. T hese 
m aj or P Ds will be re vie w e d a n d fi nalize d b y f oll o wi n g Fi br o Ge n m e dical re vie w pr ocess pri or t o 
data base l oc k a n d u n bli n di n g. C o nsi derati o ns will be gi ve n acc or di n g t o t he f oll o wi n g ta ble. 
T a ble 1: 
Criteri a f or M aj or P r ot oc ol De vi ati o ns  
N u m ber  
M aj or P r ot oc ol D e vi ati o n  
1  
Vi olati o n of a n y i ncl usi o n or e xcl usi o n criteria t hat ma y affect t he assess me nt of 
efficac y or s afet y of t h e st u d y dr u g *   
2  
Wit h dra wal D e viati o n: S u bject met wit h dra wal criteria d uri n g t he st u d y b ut was 
n ot wit h dra w n *  
3  
D osi n g De viati o n: S u bject recei ve d t he wr o n g treat me nt or i nc orrect d ose , 
i ncl u di n g i nc orrect ti mi n g of a d ose, w hic h m a y affect t he assess me nt of efficac y 
or safet y of t h e st u d y dr u g *  
4  
A d mi nistrati o n of pr o hi bite d c o nc o mita nt me dicati o n t hat ma y i m pact e val uati o n 
of efficac y of t he st u d y dr u g *  
5  
Si g nifica nt n o nc o m plia nce wit h st u d y pr oce d ures t hat ma y i m pact e val uati o n of 
efficac y of t he st u d y dr u g will be e val uate d case b y case *  
* Maj or P Ds will be re vie we d a n d f i nalize d b y f oll o wi n g Fi br o Ge n me dical re vie w pr ocess; t hese fi ve cate g ories 
ma y n ot c o ver all I P Ds.  
6. 3.  
De m o gr a p hics a n d B aseli ne C h ar acteristics  
6. 3. 1.  
De m o gr a p hics a n d B aseli ne C h ar acteristics  
De m o gra p hics a n d i m p orta nt baseli ne c haract eristics will be s u m marize d f or t he I T T b y 
treat me nt ar m a n d all p o ole d. T hese ma y i ncl u d e b ut are n ot li mite d t o a ge, a ge gr o u p ( ≤6 4, 
6 5- 7 4, ≥7 5 years ), se x, et h nicit y, race gr o u p, wei g ht, b o d y mass i n de x ( B MI), s m o ki n g hist or y, 
pri or treat me nt wit h a n a p pr o ve d I P F t hera p y ( Yes/ N o), G A P sta ge (I, II, III), a n d y ears si nce t he 
first dia g n osis of I P F. A g e is defi ne d as t he a ge o n t he da y of si g ni n g t he i nf or me d c o nse nt f or m 
(I C F). Y ears si nce t he first dia g n o sis will be deri ve d usi n g t he f or m ula: dat e of I C F- date of I P F 
dia g n osis + 1. Partial missi n g date of I P F dia g n osis will be i m p ute d as Ja n. 0 1 (if m o nt h is 
missi n g), or 0 1 (if da y is missi n g). 
Baseli ne val ues f or effi cac y assess me nts  will be prese nte d i n baseli ne t a bles as a p pr o priat e. 
C o m para bilit y of baseli ne c har acteristics bet wee n  treat me nt gr o u ps will be assesse d  usi n g 
a nal ysis of varia n ce ( A N O V A) m o del f o r c o nti n u o us varia bles a n d C hi-sq uare d test f or 
cate g orical varia bl es . T h e n o mi nal p -val ues will b e prese nt e d  f or refere n ce o nl y. 
6. 3. 2.  
Me dic al Hist or y  
Me dical Hist or y c o de d b y Me dical Dicti o nar y f or Re g ulat or y Acti vities (Me d D R A , Versi o n 2 5. 0 
or hi g her) will be s u m marize d f or t h e I T T P o p ulati o n. 
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6. 4.  
Pri or a n d C o nc o mit a nt Me dic ati o ns  
T he latest W orl d H ealt h Or ga nizati o n Dr u g Dicti o nar y ( W H O D D Gl o bal B 3 Mar 2 0 2 2, or hi g her 
versi o n) will be use d t o classif y pri or a n d c o n c o mita nt me dicati o ns b y t hera pe utic class a n d 
preferre d t er m . 
Pri or me dicati o n is defi n e d as a n y me dicati o n ta k e n a n d st o p pe d pri or t o t he first d ose of t he 
st u d y dr u g. C o nc o mita nt me dicati o n is defi ne d as a n y me dicati o n ta ke n aft er t he first d ose of t he 
st u d y dr u g a n d bef or e t he last d ose da ys + 6 0 da ys. F or s u bjects w h o are treate d i n t he O L E, 
me dicati o ns t hat starte d after 1st d ose i n t he O L E peri o d ma y be c o nsi d ere d as c o nc o mita nt 
me dicati o n f or t he O L E peri o d, b ut n ot f or t he d o u ble- bli n d peri o d. Partiall y or i nc o m pletel y  
missi n g pri or/c o nc o mita nt me dicati o n start or st o p date s will be i m p ute d (A p pe n di x 1 ). Ta ble  2 
pr o vi des t he classificati o n g ui deli ne w he n me dicati o n starti n g or e n di n g dates are missi n g. 
T a ble 2:  
Cl assific ati o n of Pri or a n d C o nc o mit a nt Me dic ati o ns 
E n d D ate  
St art D ate  
Bef ore st art of st u d y 
dr u g a d mi nistr ati o n  
O n or after st art of st u d y 
dr u g a d mi nistr ati o n  
Missi n g  
Bef ore st art of st u d y dr u g 
a d mi nistr ati o n  
Pri or  
C o nc o mita nt  
C o nc o mita nt  
O n or after st art of st u d y dr u g 
a d mi nistr ati o n  a n d bef ore t he l ast 
d ose d ate + 6 0 d a ys  
- 
C o nc o mita nt  
C o nc o mita nt  
Missi n g  
Pri or  
C o nc o mita nt  
C o nc o mita nt  
B ot h pri or a n d c o nc o mita nt me dicati o n usa ge will be s u m marize d b y t he n u m ber ( %) of s u bjects 
recei vi n g t he dr u g wit hi n eac h t hera pe utic class a n d A T C c o de le vel 3 a n d preferre d t er m f or t he 
S A F . M ulti ple usa ges of t he sa me dr u g b y a p atie nt will be c o u nte d o nl y o nce. 
Se parate s u m mari es ma y be pr o vi de d f or pri or a n d c o nc o mita nt me dicati o ns of s pecial i nterest 
s uc h as t he a p pr o ve d I P F me dicati o ns ( pirfe ni d o n e a n d/ or ni nte da ni b). 
T o e val uate t he us e of c o -a d mi nistere d me dicati o ns t hat are narr o w t hera pe utic C Y P s u bstrates, 
t he c o nc o mita nt me dicati o n f or narr o w t hera pe utic i n de x c yt oc hr o me P 4 5 0 s u bstrates will be 
liste d a n d s u m marize d . T he list f or relate d m e dicati o ns will be fi nalize d pri or t o data base l o c k . 
6. 5.  
Pri or a n d C o nc o mit a nt Pr oce d ures a n d N o n -dr u g T her a pies  
Pr oce d ures a n d n o n- dr u g thera pies w ere c o de d wit h Me d D R A V ersi o n 2 5. 0 or hi g her versi o n. 
Pri or/ C o nc o mita nt pr oce d ures an d n o n- dr u g t hera pies will be  defi ne d  an d  su m marize d  si milarl y 
t o pri or an d  co nc o mita nt  me di cati o ns (Details  i n Secti o n 6. 4 ). Partiall y  or inc o m pletel y  missi n g 
pr oce d ures a n d n o n- d r u g t hera pies  start or st o p dates will be i m pute d  si milarl y t o 
pri or/c o nc o mita nt me dicati o ns  (A p pe n di x 1).  
6. 6.  
St u d y Dr u g E x p os ure a n d Tre at me nt C o m pli a nce  
6. 6. 1.  
St u d y Dr u g E x p os ure  
E x p os ure t o t he st u d y dr u g will be s u m marize d i n ter ms of treat me nt d urati o n  f or t he S A F . 
D urati o n of st u d y treat m e nt i n wee ks is cal c ulate d as: (l ast d ose d ate – first d ose d ate + 1)/ 7. 
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D urati o n of st u d y treat m e nt will be s u m marize d as a c o nti n u o us varia ble a n d be ta b ulate d b y t he 
cate g ories as f oll o ws : 
•  < 6 wee ks  
•  6 t o < 12 wee ks  
•  1 2 t o < 1 8 wee ks  
•  1 8 t o < 2 4  wee ks  
•  2 4 t o < 36 wee ks  
•  ≥3 6 wee ks  
N u m ber ( %) of s u bjects b y t he t otal n u m ber of i nf usi o ns ( 1- 3, 4- 6, 7- 9, 1 0- 1 2, ≥1 3) recei ve d, 
o verall a vera g e i nf usi o n d oses (i n m g/ k g), w het her i nf usi o n was misse d/ i nterr u pte d a n d reas o n 
f or misse d/ i nterr u pti o n, a n d patie nt-e x p os ure y ears ( P E Y) will be s u m marize d f or t h e S A F . 
6. 6. 2.  
Tre at m e nt C o m pli a nce  
T he c o m plia nce will be prese nte d as % of t he act u al d ose  a d mi nistere d o ut of t he t otal pla n ne d 
d ose of i nf usi o ns b y e n d of st u d y ( E O S) or b y dis c o nti n uati o n i n s u bjects w h o disc o nti n ue d. 
𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑡𝑡𝑘𝑘𝑊𝑊𝐻𝐻𝑊𝑊𝑊𝑊 ( %)  =
𝑊𝑊𝑡𝑡𝑐𝑐𝑐𝑐𝑉𝑉𝑉𝑉 𝑏𝑏𝑏𝑏𝑉𝑉𝑣𝑣𝑏𝑏 𝑃𝑃𝑏𝑏𝑎𝑎𝐵𝐵 𝑉𝑉𝑃𝑃𝑉𝑉𝑉𝑉𝑏𝑏𝑏𝑏𝑉𝑉𝑣𝑣
𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝐵𝐵 𝑉𝑉𝑃𝑃𝑉𝑉𝑉𝑉𝑏𝑏𝑏𝑏𝑉𝑉 𝑣𝑣𝑉𝑉𝑉𝑉𝑉𝑉 𝑉𝑉ℎ𝑏𝑏𝑉𝑉𝑉𝑉 𝑉𝑉𝑖𝑖𝑎𝑎𝑏𝑏𝑣𝑣𝑉𝑉𝑉𝑉𝑎𝑎 𝑏𝑏𝑏𝑏 𝑎𝑎𝑟𝑟𝑉𝑉𝑉𝑉𝑎𝑎𝐶𝐶𝑉𝑉𝑏𝑏𝑎𝑎× 1 0 0  
Descri pti ve statistics f or st u d y dr u g c o m plia nce will be prese nte d b y treat me nt gr o u p f or t he 
S A F . Treat me nt c o m plia nce will be s u m marize d as a c o nti n u o us varia ble a n d as a cat e g orical 
varia ble ( < 7 0 %, 7 0 % – < 8 0 %, 8 0 % – < 9 0 %, 9 0 %- 1 1 0 %, a n d > 1 1 0 %).  
6. 7.  
Effic ac y A n al ysis  
T he pri mar y a n d s ec o n d ar y e n d p oi nts will be teste d usi n g a fi xe d se q ue n ce a nal ysis a p pr oac h t o 
preser v e t he st u d y -wi de err or rate of 5 %. U n der t he se q ue ntial a nal ysis, the pri mar y  a n d 
sec o n dar y effi cac y e n d p oi nt s will be teste d i n a defi ne d se q ue n ce acc or di n g t o t he or der liste d i n 
Ta ble  3 eac h at t he us u al al p ha =  0. 0 5 le vel of statistical si g nifica nce. T he testi n g will cease w he n a 
fail ure occ urs i n t he pre-deter mi ne d se q ue ntial h y p ot hesis testi n g  a n d all p- val ues f or t he s u bse q ue nt 
testi n g will be c o nsi dere d n o mi nal. All p - val ues f or e x pl orat or y e n d p oi nts will be c o nsi dere d 
n o mi n al. 
A ll a nal yses f or efficac y e n d p oi nts will be perf or me d f or t he I T T p o p ul ati o n d uri n g t he O n -
St u d y peri o d ( Secti o n  5. 3. 1. 1 ), u nless n ote d ot her wise. T he p lace b o gr o u p will be use d as t he 
refere nce gr o u p f or all tr eat me nt c o m paris o ns. 
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T a ble 3: 
Fi xe d Se q ue nce Testi n g Or der  of Pri m ar y a n d Sec o n dar y E n d p oi nts  
T esti n g 
or der  
E n d p oi nts  
1  
C ha n ge i n F V C ( L) fr o m baseli ne at Wee k 4 8  (P ri m ar y E n d p oi nt ) 
2  
Ti me t o disease pr o gr essi o n, defi ne d as a bs ol ute F V C p p decli ne of ≥1 0 %  
or deat h, w hic h e ver o cc urs first  
3  
Ti me t o t he occ urr e nce of a n y c o m p o ne nt of t h e cli nical c o m p osite e n d p oi nt: 
ac ute I P F e xacer b ati o n, res pirat or y h os pitalizati o n, or deat h ( w hi c he ver occ urs 
first) 
4  
C ha n ge i n Q L F v ol u me fr o m baseli ne at Wee k 4 8  
5  
Ti me t o first ac ute I P F e xacer b ati o n d uri n g st u d y  
6  
Ti me t o all -ca use m ortalit y d uri n g st u d y  
7  
Ti me t o first res pirat or y h os pitalizati o ns d uri n g st u d y   
6. 7. 1.  
Pri m ar y E n d p oi nt  A n al ysis a n d Esti m a n d 
T he pri mar y e n d p oi nt is c ha n ge fr o m baseli ne i n F V C ( L) at Wee k 4 8 . 
T he h y p ot heses t o be test e d f or t he pri mar y efficac y a nal ysis is: 
H 0: C ha n ge fr o m baseli n e i n F V C ( L) at wee k 4 8 f or t he pa mre vl u ma b ar m  = C ha n ge fr o m 
baseli ne i n F V C ( L) at w ee k 4 8 f or t h e place b o ar m  
Vers us:  
H 1: C ha n ge fr o m baseli n e i n F V C ( L) at wee k 4 8 f or t he pa mre vl u ma b ar m  ≠ C ha n ge fr o m 
baseli ne i n F V C ( L) at w ee k 4 8 f or t h e place b o ar m  
6. 7. 1. 1.  
Pri m ar y A n al ysis wit h Mi xe d M o del f or R e pe ate d Me as ures ( M M R M ) 
6. 7. 1. 1. 1.  Esti m a n d Str ate g y  
T he pri mar y esti ma n d is i nte n de d t o pr o vi de a p o p ulati o n le vel esti mate of t he treat me nt effect of 
t he pa mre vl u ma b o n a c o nti n u o us e n d p oi nt, re gar dless of partici pa nt c o m plia nce wit h t he I P 
(i n vesti gati o nal pr o d uct) d osi n g. 
6. 7. 1. 1. 2.  P o p ul ati o n of I nterest 
T he I T T p o p ulati o n i ncl u d es all ra n d o mize d s u bjects d uri n g t he o n-st u d y peri o d as defi n e d i n 
Secti o n  5. 3. 1. 1 . Male a n d fe male patie nts a ge d 4 0  or a b o ve wit h I P F di a g n osis u n der A merica n 
T h oracic S oci et y / E ur o pea n Res pirat or y S ociet y (A T S/ E R S ) criteria (Ra g h u 2 0 1 8 ), a n d n ot 
c urre ntl y r ecei vi n g treat me nt wit h t he 2 a p pr o ve d a ntifi br otic sta n dar d of care me dicati o ns. 
6. 7. 1. 1. 3.  I nterc urre nt E ve nt H a n dli n g Str ate g y 
Treat me nt disc o nti n uati o n d ue t o n o n- deat h reas o n s: T reat me nt p olic y strate g y will be use d. 
Missi n g data are ass u me d t o be missi n g at ra n d o m. 
Deat h : P ost- deat h F V C  val ues  will be set as t he w orst (l o west) p ost- baseli n e F V C val u es acr oss 
all ra n d o mize d s u bjects i n t he d o u ble- bli n d peri o d. Missi n g st u d y da y will be i m p ute d as t he 
tar get da y of eac h a nal ysis visit. 
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6. 7. 1. 1. 4.  A n al ysis V ari a ble 
C ha n ge fr o m bas eli ne i n a ll F V C assess me nts  i n t he d o u ble- bli n d peri o d, i ncl u di n g sc he d ule d, 
u nsc he d ule d, a n d a vaila ble assess me nts after treat me nt disc o nti n uati o n , u p t o wee k 4 8 d uri n g t he 
O n - St u d y peri o d (Secti o n  5. 3. 1. 1 ), will be i ncl u de d i n t he a nal ysis. 
I n t he sit uati o n w h ere a s u bject has m ore t ha n o n e rec or d of F V C wit hi n a n a nal ysis visit, t he 
best val ue will be use d f or M M R M.  
6. 7. 1. 1. 5.  P o p ul ati o n S u m m ar y f or Tre at me nt C o m p aris o n 
T reat me nt diff ere n ce of Least-s q uar e mea n ( L S Mea n) a n d S E  at wee k 4 8 a n d t he c orres p o n di n g 
9 5 % c o nfi de n ce i nter v al  (CI ) will be pres e nte d . 
All p ost- baseli ne visits f or t he s pecifie d p ara meters bel o w d uri n g t he d o u ble- bli n d peri o d will be 
i ncl u de d i n t he a nal ysis. C ha n ge fr o m bas eli ne f or t he s pecifie d e n d p oi nts (e xcl u di n g baseli ne 
visits)  will be a nal yze d usi n g a Mi xe d M o del f or Re peate d Meas ures ( M M R M) a p pr oac h wit h 
fi xe d eff ects f or treat me nt, visit (as a fact or), treat me nt- b y-visit i nteracti o n, ra n d o mizati o n 
stratificati o n fact ors, a n d c o variates (baseli ne v al u es,  se x, a ge, race gr o u p, a n d hei g ht). E xa m ple 
S A S c o de i n A p pe n di x 7. 1 . 
T he f oll o wi n g gra p hical dis pla ys will be pr o vi de d: 
•  T he mea n ( ± S E) F V C o ver ti me b y treat me nt gr o u p  
•  T he mea n ( ± S E) F V C c ha n ge fr o m b aseli ne b y treat me nt gr o u p 
•  T he L S mea n ( ± S E) esti mate d F V C c h a n ge fr o m baseli ne o ver ti me b y treat me nt 
gr o u p (as esti mate d i n t h e pri mar y a n al ysis)  
6. 7. 1. 1. 6.  C o v ari a nce Str uct ure Str ate g y  
T he u nstr uct ure d c o vari a nce patter n m o d el will be use d first. T he b y- treat m e nt- gr o u p o pti o n will 
be a d de d t o t he c o varia n ce patter n t o i m pr o ve t he m o del fit as a p pr o priat e. If t he m o del usi n g t he 
u nstr uct ure d c o v aria n ce patter n d oes n ot c o n v er g e, t he f oll o wi n g c o varia n ce str uct ures will be 
teste d i n se q ue nce: heter o ge ne o us T oe plitz, h o m o ge ne o us T oe plitz, first- or der a ut ore gressi ve, 
c o m p o u n d s y m metr y, a n d varia nce c o m p o ne nt, u ntil t he m o del c o n ver ges. 
If t he m o del d oes n’t c o n ver ge f or all si x c o vari a n ce str uct ures liste d a b o ve, t he n t he f oll o wi n g 
atte m pts will be ma de: 1) sa n d wic h c o v aria nce esti mat or will be use d; 2) s o me least si g nifica nt 
fact ors or i nteracti o n ter ms ( p > 0. 0 5) ca n be dr o p pe d fr o m t he m o del t o ac hie ve c o n ver ge nce. T he 
re vise d m o del wit h fe w er fact ors or i nteracti o n ter ms will be teste d usi n g t he sa me se q u e nce as 
s pecifie d a b o v e. 
T his c o varia nce str uct ur e strate g y will a p pl y t o all a nal yses o n c o nti n u o us pri mar y, sec o n d ar y, 
a n d e x pl orat or y effi cac y e n d p oi nts  if a p pr o priate. 
6. 7. 1. 2.  
Se nsiti vit y A n al ysis  
T he f oll o wi n g se nsiti vit y a nal ysis u n der t he sa m e esti ma n d fra me w or k as t he pri mar y a n al ysis 
defi ne d i n Secti o n  6. 7. 1  will be perf or me d  o n F V C : 
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6. 7. 1. 2. 1.  Li ne ar Sl o pe M o del  ( R C M) 
T he ra n d o m c o effi cie nt li near r e gressi o n m o del ( R C M) wit h a ra n d o m effect f or t he sl o pe of 
ti me will be perf or me d. T he ti me i n t he R C M m o del will be calc ulate d as t he ela pse d w ee ks  
(c o nti n u o us) fr o m t he first i nf usi o n ( or ra n d o mizati o n if n ot d ose d) t o t he assess me nt date. T he 
R C M m o del will als o i ncl u de fi xe d effects of treat me nt, ti me, treat me nt- b y-ti me i nteracti o n, 
ra n d o mizati o n stratificati o n fact ors, bas eli ne F V C v ol u me, a n d c o vari ates  (a ge, se x, race gr o u p, 
a n d hei g ht). Baseli ne visits will be set as 0 a n d i ncl u de d i n t he R C M m o del. I n t he sit uati o n 
w here a s u bject has m or e t ha n o ne rec or d of F V C o n differe nt st u d y da ys wit hi n a n a nal ysis visit, 
t he hi g hest q ualif yi n g F V C o n eac h st u d y da y (Secti o n  5. 1. 4 ) will be use d f or R C M. 
6. 7. 1. 2. 2.  J u m p- t o- C o ntr ol A n al ysis  
T h e g oal of t he j u m p-t o- c o ntr ol a nal ysis is t o a d dress t he p ossi bilit y of data bei n g missi n g n ot at 
ra n d o m ( M N A R). T h e missi n g data patter n f or t he pa mre vl u ma b s u bjects after wit h dra w al fr o m 
t he st u d y ca n be ass u me d t o s witc h t o t he sa me dat a patter n as s u bjects o n t he place b o treat me nt. 
S u bjects t hat disc o nti n ue d fr o m t he place b o ar m are ass u me d t o ha v e t he sa me data patter n as 
place b o s u bjects t hat r e m ai n i n t he st u dy (e xcl u di n g p ost- deat h missi n g val ues defi ne d i n 
Secti o n  6. 7. 1. 1. 3 ). T his is ofte n calle d t he j u m p -t o-c o ntr ol a p pr o ac h .  
T he a nal ysis of c o v aria n ce ( A N C O V A ) m o del will c o ntai n ter ms f or treat me nt , baseli ne F V C 
meas ure me nt s, c o v ariat es (a ge, se x, race gr o u p, a n d hei g ht), a n d t he ra n d o mizati o n stratificati o n 
fact ors ( E x a m ple S A S c o de i n A p pe n di x 7. 2 ). 
6. 7. 1. 2. 3.  Delt a -A dj usti n g ( Ti p pi n g P oi nt) A n al ysis  
A n alter nati ve ass u m pti o n is t hat t he missi n g data f or t he pa mre vl u ma b treate d s u bjects w h o 
disc o nti n ue earl y ha v e a l o wer e x p ecte d v al ue t ha n t he pa mre vl u ma b s u bjects re mai ni n g i n t he 
st u d y, w hile s u bjects w h o disc o nti n ue fr o m t he place b o ar m are ass u me d t o ha ve t he sa me d ata 
patter n as place b o s u bjects re mai ni n g i n t he st u d y (e xcl u di n g p ost- deat h missi n g val ues defi ne d 
i n Secti o n  6. 7. 1. 1. 3 ). T his is  ofte n calle d t he delta -a dj usti n g ( or ti p pi n g p oi nt) a p pr oac h 
( E xa m ple S A S c o de i n A p pe n di x 7. 3 ). 
A N C O V A will  be perf or me d as Secti o n  6. 7. 1. 2. 2 . 
6. 7. 1. 2. 4.  R a n k e d A N C O V A A n al ysis  
A ra n ke d A N C O V A a nal ysis ( a n o n-para metric a n al ysis ) will be perf or m e d o n t he ra n ke d 
c ha n ge fr o m baseli ne v al ues i n  F V C at Wee k 4 8. T he ra n k e d  A N C O V A w as t he pri mar y 
efficac y e n d p oi nt a n al ysis i n t he pirfe ni d o ne p has e 3 trials. 
Missi n g wee k 4 8 val ues will be i m p ute d as t he a v era ge v al ue fr o m t hree s u bjects wit h t he 
s mallest s u m of s q uare d diff ere n ces o v er  t he visits wit h n o n-missi n g data  bet wee n eac h of t he 
t hree s u bjects a n d t h e earl y ter mi nate d s u bject. 
D eat h: S u bjects wit h missi n g data d ue t o deat h w ere ra n k e d w ors e t ha n t h ose w h o re mai n e d 
ali ve. S u bjects w h o die d were ra n ke d acc or di n g t o t he n u m ber of da ys fr o m ra n d o mizati o n u ntil 
deat h, wit h t he s h ortest ti me t o  deat h as t he w orst ra n k.  
T he ra n k e d  A N C O V A wit h ter ms f or se x, a ge, race gr o u p ( w hite vs ot hers), hei g ht, 
ra n d o mizati o n stratificati o n fact ors, a n d sta n dar di ze d ra n k b aseli ne F V C v al ue as a c o vari ate  will 
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be perf or me d o n t he r a n k e d c ha n g e fr o m bas eli ne i n F V C at wee k 4 8  ( E xa m ple S A S c o de 
i n A p pe n di x 7. 4 ). T he p -val ue f or tr eat me nt c o m p aris o n will be prese nt e d.  
6. 7. 1. 3.  
S u p ple m e nt al  A n al ysis 
T he f oll o wi n g s u p ple me ntal a nal ysis u n der t he sa me esti ma n d fra me w or k as t he pri mar y a n al ysis 
defi ne d i n Secti o n  6. 7. 1  will be perf or me d  o n F V C:  
6. 7. 1. 3. 1.  O n - Tre at m e nt Peri o d A n al ysis 
A n a d diti o nal a nal ysis will be perf or me d f or ass ess me nts perf or me d d uri n g t he O n -treat me nt 
peri o d as defi n e d i n Secti o n  5. 3. 1. 2 . F V C assess m e nts be y o n d 3 wee ks after t he last st u d y dr u g 
i nf usi o n will be e xcl u de d fr o m t he a nal ysis. 
6. 7. 1. 3. 2.  Per - P r ot oc ol Set  ( P P S) A n al ysis 
A n a d diti o nal a nal ysis sa me as Secti o n  6. 7. 1. 1. 4  will be perf or me d f or s u bjects i n P P S  ( defi ne d 
i n Secti o n  5. 2. 2 ). E D C ra n d o mizati o n stratificati o n fact ors will be use d f or a nal ysis i n P P S.  
6. 7. 1. 4.  
S u b gr o u p A n al ysis  
T he pri mar y a n al ysis will be re peate d f or rele v a nt a n d a p pr o pri ate s u b gr o u ps. T he L S Mea n of 
treat me nt differe nce a n d c orres p o n di n g 9 5 % CI will be prese nte d i n a f orest pl ot as a p pr o priate. 
T he s u b gr o u ps ma y i ncl u de b ut are n ot li mite d t o se x, a ge gr o u p , race gr o u p ( w hite vs. ot hers), 
pri or use of a p pr o ve d I P F treat me nts ( y es/ n o), a n y use of a p pr o v e d I P F treat me nts d uri n g t he 
st u d y ( yes/ n o), c o u ntr y/ g e o gra p hic re gi o n  (L ati n A merica/ U S/ Asia Pacifi c -i ncl u di n g R ussia a n d 
A ustralia ), c o u ntr y ( C hi na/ N o n - C hi na), G A P sta g e (I, II, III), a n d A D A stat us ( P ositi ve, 
Ne gati ve, or u n k n o w n; details i n Secti o n  6. 1 0 ). 
6. 7. 2.  
Sec o n d ar y a n d E x pl or at or y E n d p oi nts  A n al ysis a n d Esti m a n ds  
T he sec o n d ar y e n d p oi nts d uri n g t he o n-st u d y peri o d (as defi ne d i n Secti o n  5. 3. 1. 1 ) will be 
a nal yze d i n t he or der s p ecifie d i n Ta ble  3. I n a d diti o n, o n-treat me nt a n al ysis a n d s u b gr o u p 
a nal ysis ( b ot h c o nsi dere d as n o minal) will als o be perf or me d f or sec o n dar y efficac y e n d p oi nts. 
All e x pl orat or y e n d p oi nt a nal yses  will be c o nsi dere d n o mi nal. 
6. 7. 2. 1.  
Ti m e -t o-E ve nt E n d p oi nts  
6. 7. 2. 1. 1.  Esti m a n d Str ate g y  
T he sec o n d ar y esti ma n ds are  i nte n de d t o pr o vi de a p o p ulati o n le vel esti mate of t he treat me nt 
effect of t he pa mre vl u ma b o n ti me-t o-e ve nt e n d p oi nts ; re gar dless of partici pa nt c o m plia nce wit h 
t he I P d osi n g. 
6. 7. 2. 1. 2.  P o p ul ati o n of I nterest 
Sa me as Secti o n  6. 7. 1. 1. 2 . 
A n a d diti o nal a nal ysis will be perf or me d f or all sec o n dar y e n d p oi nts d uri n g t he o n-t reat me nt 
peri o d as defi ne d i n Secti o n  5. 3. 1. 2. 
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6. 7. 2. 1. 3.  I nterc urre nt E ve nt H a n dli n g Str ate g y 
Treat me nt disc o nti n uati o n (s uc h as earl y ter mi nati o n d ue t o A Es, L ost t o F oll o w- U p, Wit h dra w al 
b y S u bject, P h ysicia n Decisi o n, Pr ot oc ol De viati o ns, etc.): T reat me nt p olic y strate g y will be 
use d . 
Deat h: C o m p osite strate g y will be use d if deat h is a c o m p o ne nt of t he e n d p oi nt. 
6. 7. 2. 1. 4.  A n al ysis V ari a bles 
6. 7. 2. 1. 4. 1.  Ti m e  ( D a ys) t o dise ase p r o gressi o n  
Ti me ( Da ys) t o diseas e pr o gressi o n is defi ne d as t he n u m ber of d a ys fr o m ra n d o mizati o n t o 
eit her t he first occ urr e nce of a n a bs ol ute ≥1 0 % decli ne fr o m baseli ne i n F V C p p or all-ca use 
deat h base d o n o bs er ve d data, w hic he v er occ urs earlier d uri n g t he o n-st u d y peri o d as des cri be d 
i n Secti o n  5. 3. 1. 1 . S u bjects w h o die d wit h o ut a n y p ost- baseli ne P F T ass ess me nts will be 
c o nsi dere d as a n e v e nt o n t he date of deat h. 
S u bjects wit h o ut a n e ve nt will be  ce ns ore d o n t he date of t he last P F T assess me nt after 
ra n d o mizati o n i n t he d o u ble- bli n d peri o d. Ali ve / Ce ns ore d s u bjects wit h o ut a n y p ost-baseli ne 
P F T assess me nts will be ce ns ore d o n Da y 1. 
6. 7. 2. 1. 4. 2.  Ti m e ( D a ys) t o t he first occ urre nce of a n y c o m p o ne nt of t he cli nic al c o m p osite 
e n d p oi nt: ac ute I P F e x acer b ati o n, res pir at o r y h os pit aliz ati o n, or de at h 
Ti me ( Da ys) t o t he o cc urre nce of a n y c o m p o ne nt of t he cli nical c o m p osite e n d p oi nt is defi ne d as 
t he n u m ber of da ys fr o m ra n d o mizati o n t o eit her t he first occ urre n ce of a dj u dicate d ac ute I P F 
e xacer bati o n  (i ncl u di n g b ot h c o nfir me d a n d s us pecte d cas es), a dj u dicate d res pirat or y 
h os pitalizati o n, or deat h d uri n g t he o n-st u d y peri o d as descri be d i n Secti o n  5. 3. 1. 1 . 
S u bjects wit h o ut a n e ve nt will be ce ns ore d o n t he date of last k n o w n ali ve d uri n g t he d o u ble-
bli n d peri o d. 
6. 7. 2. 1. 4. 3.  Ti m e ( d a ys) fr o m r a n d o miz ati o n t o first ac ute I P F e x acer b ati o n 
Ti me ( Da ys) t o first ac ut e I P F e x acer bati o n is  defi ne d as t he n u m ber of da ys fr o m ra n d o mizati o n 
t o eit her t he first occ urr e nce of a dj u dicate d ac ute I P F e xacer b ati o n (i ncl u di n g b ot h c o nfir me d 
a n d s us pecte d cases) as d escri be d i n Secti o n  5. 3. 1. 1 . 
S u bjects wit h o ut a n e ve nt will be ce ns ore d o n t he date of last k n o w n ali ve d uri n g t he d o u ble-
bli n d peri o d. 
6. 7. 2. 1. 4. 4.  Ti m e ( d a ys) fr o m r a n d o miz ati o n t o all- c a use m ort alit y  
S u bjects wit h o ut a n e ve nt will be ce ns ore d o n t he last date k n o w n ali ve i n t he d o u ble- bli n d 
peri o d. A n y s ur vi val vital stat us will be i ncl u de d f or earl y disc o nti n ue d s u bjects. 
6. 7. 2. 1. 4. 5.  Ti m e ( d a ys) fr o m r a n d o miz ati o n t o first res pir at or y h os pit aliz ati o n 
S u bjects wit h o ut a n e ve nt will be ce ns ore d o n t he date of last k n o w n ali ve d uri n g t he d o u ble-
bli n d peri o d. 
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6. 7. 2. 1. 4. 6.  Ti m e ( D a ys) t o t he first occ urre nce of c o m p osite of res pir at o r y h os pit aliz ati o n, 
a bs ol ute F V C p p decli ne ≥1 0 %, or all- c a use de at h  
Ti me ( da ys) t o t he first o cc urr e nce of c o m p osite is defi ne d as fr o m ra n d o mizati o n t o t he first 
occ urr e nce , w hic h i ncl u d es a dj u dicate d res pirat or y h os pitalizati o n, all-ca use deat h, or a bs ol ute 
F V C p p  decli ne ≥1 0 %. S u bjects w h o die d wit h o ut a n y p ost- baseli ne P F T assess me nts or 
res pirat or y h os pitalizati o n e ve nt will be c o nsi dere d as a n e ve nt o n t he d ate of deat h. 
S u bjects wit h o ut a n e ve nt will be ce ns ore d wit h t h e sa me r ule d efi ne d i n  Secti o n  6. 7. 2. 1. 4. 1 . 
6. 7. 2. 1. 5.  P o p ul ati o n s u m m ar y f or tre at me nt c o m p aris o n 
T he hazar d r ati o  a n d its c orres p o n di n g 9 5 % CI will be prese nte d. P- v al ue fr o m stratifie d L o g -
ra n k test will als o be pres e nte d. 
All ti me -t o-e ve nt anal yses will i ncl u de data c ollect e d i n t he d o u ble- bli n d peri o d. T he stratifie d 
C o x pr o p orti o nal hazar d m o del stratifie d b y ra n d o mizati o n stratificati o n fact ors will be use d t o 
esti mate t he hazar d r ati o a n d its c orres p o n di n g 9 5 % CI. A s tratifie d l o g-ra n k test stratifie d b y 
ra n d o mizati o n stratificati o n fact ors will be use d f or treat me nt c o m paris o n. 
F or ti me fr o m r a n d o mizati o n t o t he first ac ute I P F e xacer bati o n, all e v e nts pre- defi ne d i n t he 
a dj u dicati o n c hart er will be a dj u dicate d b y a n i n de pe n de nt A dj u dicati o n C o m mittee. T he 
a dj u dicate d r es ults will be s u m marize d b y cate g ories of c o nfir me d, s us p ect e d, or n ot ac ute 
res pirat or y e xacer bati o n.  
I n a d diti o n, all a dj u dicate d ac ute r es pirat or y e xacer bati o ns will be f urt her s u m marize d as:   
•  a tri ggere d ac ute res pirat or y e xacer b ati o n  
•  a n i di o pat hic ac ute e xacer bati o n (i.e., n o tri g ger i d e ntifie d). 
6. 7. 2. 2.  
C o nti n u o us E n d p oi nts  wit h M M R M M o del  
6. 7. 2. 2. 1.  Esti m a n d Str ate g y  
Sa me as Secti o n  6. 7. 1. 1. 1  
6. 7. 2. 2. 2.  P o p ul ati o n of I nterest 
Sa me as Secti o n  6. 7. 1. 1. 2  
6. 7. 2. 2. 3.  I nterc urre nt E ve nt H a n dli n g Str ate g y 
Sa me as Secti o n  6. 7. 1. 1. 3  
F or all p ost- deat h a nal ysis visits , t he missi n g val ues will be set as t he w orst o bser ve d p ost-
baseli ne val ues (l o w est F V C p p a n d L C Q sc ore, hi g hest Q L F, U C S D- S O B Q, a n d S G R Q sc ore) 
acr oss all s u bjects i n t he d o u ble- bli n d peri o d. St u d y da y will be i m p ute d as t he tar get da y of t h e 
c orres p o n di n g a nal ysis visit.  
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6. 7. 2. 2. 4.  A n al ysis V ari a bles 
6. 7. 2. 2. 4. 1.  C h a n ge fr o m b aseli ne i n Q L F  v ol u me 
T he Q ua ntitati ve L u n g Fi br osis ( Q L F) v ol u me is calc ulate d as Q L F =t ot al l u n g c a p acity v ol u m e 
( T L C) * % of q u a ntit ative l u n g fi br osis f or fi br osis of t he w h ole l u n g. 
6. 7. 2. 2. 4. 2.  A bs ol ute c h a n ge fr o m b aseli ne i n F V C p p  
T he a bs ol ute c h a n ge fr o m baseli ne i n F V C p p is d eri ve d wit h t he f or m ula b el o w: 
𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑡𝑡 𝑘𝑘𝑊𝑊𝐻𝐻𝑊𝑊𝑊𝑊 𝑊𝑊𝑡𝑡 𝑐𝑐𝑐𝑐𝑉𝑉𝑉𝑉 𝑏𝑏𝑏𝑏𝑉𝑉𝑣𝑣𝑏𝑏𝑃𝑃𝑏𝑏𝑎𝑎 𝐵𝐵𝑉𝑉𝑃𝑃𝑉𝑉𝑉𝑉−𝑏𝑏𝑏𝑏𝑉𝑉𝑣𝑣𝑉𝑉 𝑉𝑉𝑉𝑉𝑉𝑉𝐵𝐵𝑉𝑉 𝑃𝑃𝑉𝑉 𝑉𝑉𝑏𝑏𝑏𝑏𝑉𝑉𝑣𝑣𝑉𝑉𝑉𝑉𝑉𝑉 
6. 7. 2. 2. 4. 3.  Rel at i ve ch a n ge f r o m b aseli ne i n F V C p p  
T he relati ve c ha n ge ( %) fr o m baseli ne i n F V C p p is t he c ha n ge fr o m baseli n e F V C p p val u e as a 
perce nt a ge of t h e  baseli n e F V C p p val u e  a n d is deri ve d wit h t he f or m ula bel o w: 
𝑉𝑉𝑏𝑏𝑉𝑉𝑉𝑉𝑉𝑉 𝑖𝑖𝑎𝑎𝑏𝑏𝑣𝑣𝑉𝑉 𝑉𝑉𝑎𝑎 𝑏𝑏𝑏𝑏𝑎𝑎𝑟𝑟 𝑉𝑉𝑉𝑉𝑎𝑎𝐶𝐶𝑉𝑉𝑏𝑏𝑎𝑎𝑉𝑉 𝑣𝑣𝑏𝑏𝑃𝑃𝑏𝑏𝑎𝑎−𝐹𝐹𝑉𝑉𝐶𝐶𝐶𝐶𝐶𝐶 𝑣𝑣𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉 𝑉𝑉𝑎𝑎 𝐵𝐵𝑉𝑉𝑃𝑃𝑉𝑉𝑉𝑉𝑏𝑏𝑏𝑏𝑉𝑉
𝐵𝐵𝑉𝑉𝑃𝑃𝑉𝑉𝑉𝑉𝑏𝑏𝑏𝑏𝑉𝑉 𝐹𝐹𝑉𝑉𝐶𝐶𝐶𝐶𝐶𝐶 𝑣𝑣𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉
× 1 0 0  
6. 7. 2. 2. 4. 4.  C h a n ge fr o m b aseli ne i n S G R Q  
R efer t o A p pe n di x 3  f or details of sc ores f or St. G e or ge's Res pirat or y Q uesti o n naire ( S G R Q). 
T he t otal sc ore of S G R Q t o get her wit h t he s y m pt o m, acti vit y, a n d i m pact d o mai n sc ores, will be 
i ncl u de d i n t he a nal ysis. 
6. 7. 2. 2. 4. 5.  C h a n ge fr o m b aseli ne i n t he t ot al sc ore of  U C S D -S O B Q  
R efer t o A p pe n di x 4  f or details of sc ores f or U ni v ersit y of Calif or nia, Sa n Die g o – S h ort ness of 
Breat h Q uesti o n nair e ( U C S D- S O B Q) . 
6. 7. 2. 2. 4. 6.  C h a n ge fr o m b aseli ne i n L C Q  
R efer t o A p p e n di x 5 f or details of sc ores f or Lei cester C o u g h Q uesti o n naire ( L C Q). T he t otal 
sc ore of L C Q t o g et her wit h t he p h ysical, ps yc h ol o gical, a n d s ocial d o mai ns sc ores, will be 
i ncl u de d i n t he a nal ysis. 
6. 7. 2. 2. 5.  P o p ul ati o n S u m m ar y f or Tre at me nt C o m p aris o n 
Treat me nt diff ere n ce of L S Mea n s (a n d S E ) at eac h sc he d ule d visit a n d t he c orres p o n di n g 9 5 % 
CI  will be pr ese nte d.  
All p ost- baseli ne visits f or t he s pecifie d p ara meters bel o w d uri n g t he d o u ble- bli n d peri o d will be 
i ncl u de d i n t he a nal ysis. C ha n ge fr o m bas eli ne f or t he s pecifie d e n d p oi nts (e xcl u di n g baseli ne 
visits)  will be a nal yze d usi n g a Mi xe d M o del f or Re peate d Meas ures ( M M R M) a p pr oac h wit h 
fi xe d eff ects f or treat me nt, visit (as a fact or), treat me nt- b y-visit i nteracti o n, ra n d o mizati o n 
stratificati o n fact ors, a n d c o variates (baseli ne v al u es , se x, a ge, race gr o u p, a n d hei g ht). 
C o variates of se x, a ge, r ace gr o u p, a n d hei g ht  will be e xcl u de d fr o m t he m o del f or F V C p p si nce 
t hese varia bl es ha ve alrea d y bee n a dj uste d i n t he defi niti o n of F V C p p. 
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6. 7. 2. 3.  
S u b gr o u p A n al ysis f or Sec o n d ar y Effic ac y E n d p oi nts  
T he sa me s u b gr o u p a nal ysis defi ne d i n  Se cti o n 6. 7. 1. 4  will be perf or me d f or all sec o n dar y 
efficac y e n d p oi nts. 
6. 8.  
S afet y A n al ysis  
T he safet y a nal yses will be perf or me d f or  t h e S A F . 
6. 8. 1.  
A d verse E ve nts  ( A Es) 
A d verse e ve nts will be c o de d usi n g Me d D R A.  
A ne w or w orse ni n g A E occ urri n g o n or after t he first d ose of st u d y dr u g a n d wit hi n  6 0 da ys after 
t he last d ose of st u d y dr u g is defi ne d as a treat me nt-e mer g e nt a d vers e e v e nt ( T E A E). A Es t h at 
starte d after 1st d ose i n t he O L E peri o d will be e xcl u de d fr o m t he mai n st u d y. Partiall y or 
i nc o m pletel y missi n g A E start/st o p date/ti me will be i m p ute d ( A p pe n di x 1 ). 
If m ore t ha n o n e e ve nt o cc urs wit h t he sa me s yste m or ga n class ( S O C) a n d preferre d t er m  ( P T) 
f or t he sa me p atie nt, t he patie nt will be c o u nte d o nl y o nce f or t hat preferre d ter m usi n g t he m ost 
se vere a n d m ost relate d o cc urr e nce f or t he s u m marizati o n b y c o m m o n ter mi n ol o g y criteria f or 
a d verse e ve nts  ( C T C A E) se verit y gra d e  a n d relati o ns hi p t o t he st u d y treat me nt. Relati o ns hi p t o 
st u d y treat me nt will be i m p ute d as “ Relate d ” f or a n y T E A E wit h a missi n g val ue f or 
relati o ns hi p. 
T he c u m ulati ve i nci de n ce of t he f oll o wi n g A E cat e g ories i ncl u di n g t he n u m ber ( %) of s u bjects 
will be pr o d uce d: 
•  S u m mar y of all T E A Es  
•  T E A Es b y P T  
•  T E A Es b y S O C a n d P T  
•  T E A Es b y S O C, P T , a n d ma xi m u m se verit y 
•  T E A Es b y S O C, P T , a n d i n vesti gat or-deter mi ne d relati o ns hi p  
•  T E A Es  wit h  se verit y gra de ≥3 b y S O C a n d P T 
•  T E A Es  relate d t o st u d y tr eat me nt deter mi ne d b y t h e i n vesti gat or b y S O C a n d P T 
•  T E A Es wit h fre q u e nc y ≥ 5 % of s u bjects i n eit her treat me nt ar m b y S O C a n d P T 
•  N o n-seri o us T E A Es  wit h fre q ue n c y ≥ 5 % of s u bjects i n eit her treat me nt ar m b y S O C 
a n d P T ( N ote: t his is re q uire d f or Cli nical Trials. g o v) 
•  T E A E s lea di n g t o disc o nti n uati o n of st u d y treat me nt b y S O C a n d P T 
•  T E A E s lea di n g t o i nterr u pti o n of st u d y treat me nt b y S O C a n d P T 
•  T reat me nt-e mer ge nt s eri o us A Es ( T E S A E s) b y S O C a n d P T  
•  T E S A Es b y P T  
•  T E S A Es b y S O C a n d P T 
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•  T E S A E s b y S O C , P T , a n d ma xi m u m se verit y  
•  T E S A Es relate d t o st u d y treat me nt deter mi ne d b y t he i n vesti gat or b y S O C a n d P T 
•  F atal T E S A Es (i.e., a d verse e ve nts t hat ha v e  a n o utc o me of deat h)  b y S O C a n d P T 
•  A ll-ca use d eat hs  
Listi n gs of all a d verse e v e nts, T E S A Es , T E A Es  lea di n g t o st u d y treat me nt disc o nti n uati o n, 
T E A Es  lea di n g t o deat h,  a n d all-ca us e deat hs  will be pr o vi de d. 
I n a d diti o n, T E A Es a n d T E S A Es  will be prese nte d s u b gr o u ps as descri b e d i n Secti o n  6. 7. 1. 4 , 
al o n g wit h a n a d diti o nal s u b gr o u p assess me nt  b y c o nc o mita nt ster oi d me dicati o n  use. 
6. 8. 2.  
S peci al S afet y E ve nts  
Treat me nt -e mer ge nt s p ecial safet y e v e nts  i ncl u di n g: 
1.  H y perse nsiti vit y  (a n y ti me) 
2.  I nf usi o n reacti o ns (occ urre d o n t he da y o r t he da y after a n y st u d y dr u g i nf usi o n) 
3.  A na p h ylactic r eacti o ns  (occ urr e d o n t he da y or t he da y aft er  a n y st u d y dr u g i nf usi o n) 
Ite ms 1 a n d 2 i ncl u de b ot h h y perse nsiti vit y a n d a n gi oe de ma e v e nts . B ot h ite ms 1 a n d 2 will be 
liste d a n d s u m marize d si milarl y t o T E A Es: 
•  E ve nts b y e ve nt t y pe, S O C, P T, a n d ma xi m u m se verit y 
•  E ve nts b y e ve nt t y pe, S O C, P T, a n d s u b gr o u ps (sa me s u b gr o u ps as T E A Es)  
Ite m 3 will be liste d a n d s u m marize d b y P T o nl y. 
T he pref err e d ter m list f or t hese  s peci al safet y e ve nts will be fi nalize d pri or t o data base l oc k. 
6. 8. 3.  
C li nic al L a b or at or y Par a meters  
Descri pti ve statistics f or la b orat or y val u es (i n SI u nits) a n d c ha n ges fr o m b aseli ne at selecte d 
visit s will be prese nte d f or t he f oll o wi n g la b orat or y para m eters. T he n u m b er ( %) of s u bjects b y 
t o xicit y gra des at selecte d visits will als o be  pr o vi de d f or selecte d la b tests. S hift ta bles f or 
selecte d para meters fr o m baseli ne t o w orst p ost- baseli ne will be pr o vi de d. 
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T a ble 4:  
L a b or at or y Tests 
He m at ol o g y P a nel: 
A bs ol ute ne utr o p hil c o u nt ( A N C), Bas o p hils, 
E osi n o p hils, Er yt hr oc yte c o u nt ( R B C), 
He mat ocrit %, H e m o gl o bi n, W B Cs 
( Le u k oc yte c o u nt), L y m p h oc ytes, Mea n 
c or p usc ular v ol u me, M o n oc ytes, Ne utr o p hils, 
Platelets  
C he mistr y P a nel:  
Bicar b o nate, bl o o d urea nitr o ge n ( B U N ), 
Calci u m, Creati ni ne, C hl ori de, 
Ma g nesi u m, Gl uc ose, A L P, A L T, A S T, 
t otal Bilir u bi n, Al b u mi n, P h os p h or o us , 
P otassi u m, S o di u m, C h olester ol, T otal 
Pr otei n, G G T, Tri gl yceri des 
C o a g ul ati o n  P a nel : 
I nter nati o nal N or m alise d Rati o (I N R),  
partial t hr o m b o plasti n ti me  (a P T T/ P T T) 
 
6. 8. 4.  
Li ver F u ncti o n Tests  
Li ver f u ncti o n test res ults a n d t he n u m ber ( %) of s u bjects a b o ve 2 × U L N or 3 × U L N  will be 
s u m marize d o ver s elect e d visits. 
A matri x scatter pl ot of li ver e nz y m es a n d bilir u bi n s h o wi n g t he ma xi m u m A L T or A S T vs. t otal 
bilir u bi n d uri n g treat me nt o n nat ural -l o g scales wit h a d otte d li ne dra w n at 3 ×U L N f or A L T  or 
A S T  vs. at 2 × U L N f or t otal bilir u bi n  will be pr o vi de d. 
6. 8. 5.  
Vi t al Si g ns 
Heart r ate  ( b eat/ mi n), diast olic a n d s yst olic bl o o d press ure ( m m H g), te m perat ure (°C) , a nd b o d y 
wei g ht ( k g) will be descri pti vel y s u m marize d b y  treat me nt at selecte d visits. 
Vital si g n val ues are p ote ntiall y cli nicall y si g nifica nt ( P C S) if t he y meet b ot h t he o bser ve d v al ue 
criteria a n d t he c ha n g e fr o m baseli ne criteri a liste d i n  Ta ble  5 bel o w. T he n u m ber a n d perce nt a ge 
of s u bjects wit h p ost- bas eli ne P C S val ues will be ta b ulate d b y treat me nt gr o u p. T he perce nta g es 
are t o be calc ulat e d relati ve t o t he n u m ber of s u bjects wit h baseli ne a n d at l east o ne p ost -bas eli ne 
assess me nt. T he n u mer at or is t he t otal n u m ber of s u bjects wit h at least o ne p ost- baseli ne P C S 
vital si g n val ue. A s u p p orti ve listi n g of s u bjects wit h p ost- baseli ne P C S val ues will be pr o vi de d 
i ncl u di n g t he patie nt I D, st u d y ce nter, bas eli ne, a n d p ost- baseli ne val ues. A listi n g of all A Es f or 
s u bjects wit h P C S vital si g ns will als o be pr o vi de d. 
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T a ble 5: 
Criteri a f or P ot e nti all y Cli nic all y Si g nific a nt Vit al Si g ns  
Vital  Si g n  Para meter  
Fla g  
Criteria *  
O bser ve d  Val ue  
C ha n ge  fr o m Baseli ne  
S yst olic  Bl o o d  Press ure  ( m m H g) 
Hi g h  
≥ 1 7 0  
I ncrease of  ≥ 2 0  
L o w  
≤ 9 0  
Decrease  of  ≥ 2 0  
Diast olic  Bl o o d  Press ure  ( m m H g) 
Hi g h  
≥ 1 1 0  
I ncrease of  ≥ 1 5  
L o w  
≤ 4 5  
Decrease  of  ≥ 1 5  
Heart  Rate  ( b p m) 
Hi g h  
≥ 1 2 0  
I ncrease of  ≥ 2 0  
L o w  
≤ 5 0  
Decrease  of  ≥ 2 0  
Wei g ht  ( k g) 
Hi g h  
- 
I ncrease of  ≥ 1 0 %  
L o w  
- 
Decrease  of  ≥ 1 0 %  
* E xce pt f or b o d y wei g ht, a p ost -baseli ne val ue is c o nsi dere d as a P C S val ue if it meets b ot h criteria f or o bser ve d  
val ue a n d c ha n ge fr o m baseli ne.  
6. 8. 6.  
Electr oc a r di o gr a m (E C G ) 
E C G res ults ( n or mal, a b n or mal-cli nicall y si g nifica nt, a n d a b n or mal-n ot cli nicall y  si g nifica nt) 
will be s u m marize d b y tr eat me nt o ver visits. A s hift ta ble f or E C G fr o m baseli ne t o w orst p ost-
baseli ne will be pr o vi de d. 
6. 8. 7.  
P h ysic al E x a mi n ati o n ( P E) 
A b n or mal P E res ults will be s u m marize d b y treat me nt o ver visit s. A s hift ta ble will be pr o vi de d 
if data is a p pr o pri ate. A listi n g of a b n or mal P E res ults will be pr o vi de d. 
6. 8. 8.  
Pre g n a nc y T est  
Pre g na nc y tests f or w o m e n of c hil d beari n g p ote ntial ( W O C B P) o nl y: ser u m pre g na nc y test at 
Scree ni n g; uri ne pr e g na n c y tests ( pre- d ose) d uri n g st u d y visits. 
A listi n g of p ositi ve pre g na nc y test res ults d uri n g st u d y visits will be pr o vi de d. 
6. 9.  
Bi o m ar ker E n d p oi nt  A n al ysis  
All a na l yses f or t he e x pl orat or y bi o mar kers liste d i n Secti o n  4. 5  will be perf or me d f or t he S A F  
base d o n o bser v e d data as a p pr o priate. Descri pti ve s u m maries will be perf or me d f or t he ot her 
e x pl orat or y bi o mar k ers as a p pr o priate. 
A listi n g will be pr o vi de d f or Tr y ptase at t he ti me of a n y s us pect e d h y pers e nsiti vit y/ 
a na p h ylactic reacti o ns , as defi ne d i n t he pr ot oc ol. 
6. 1 0.  
I m m u n o ge nicit y A n al ysis a n d P K  
S u m mar y of i m m u n o ge nicit y data will be base d o n I G S a n d listi n gs will be o n S A F. T he 
anal ysis dataset a n d d ata listi n g will i ncl u de all a vaila ble a nti- dr u g a nti b o d y ( A D A, als o na m e d 
as H A H A ) sa m ples. T he f oll o wi n g ter ms a n d defi niti o ns are i m ple me nte d.  
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6. 1 0. 1.  
Ter ms a n d Defi niti o ns  
6. 1 0. 1. 1.  S a m ple A D A St at us  
•  Baseli ne A D A -p ositi ve s a m ple: A D A is detect e d i n t he last sa m ple bef ore i nitiati o n 
of treat me nt.  
•  Baseli ne A D A -n e gati ve s a m ple: A D A is n ot detect e d i n t he last sa m ple bef ore 
i nitiati o n of treat me nt. 
•  Tre at m e nt -e m er g e nt A D A - P ositi ve: Meets defi niti o n of treat me nt-i n d uce d or 
treat me nt- b o oste d A D A: 
− Tre at m e nt -i n d uce d A D A-P osi ti ve: a p ost-treat me nt p ositi ve A D A is detecte d i n 
a s u bject f or w h o m pre- treat me nt A D A assess me nt is eit her ne gati ve or n ot 
assessa ble  
− Tre at m e nt - b o oste d A D A- P ositi ve: pre-e xisti n g A D A w as b o oste d t o a hi g her 
le vel f oll o wi n g st ud y treat me nt, i.e. pre- treat me nt p ositi ve A D A titer was b o oste d 
b y at least 2 dil uti o n ste ps ( 4-f ol d) f oll o wi n g st u d y treat me nt. 
•  A D A - ne g ati ve s a m ple: After i nitiati o n of treat m e nt, A D A is n ot treat me nt-e mer ge nt 
A D A - p ositi ve. 
Ne xt, usi n g t he sa m ple A D A stat us, t he s u bject’s A D A stat us is defi ne d. 
6. 1 0. 1. 2.  S u bject A D A St at us  
•  Baseli ne A D A -p ositi ve s u bject: A s u bject wit h a baseli ne A D A -p ositi ve sa m ple.  
•  Baseli ne A D A -n e gati ve  s u bject: A s u bject wit h baseli ne A D A-n e gati ve  sa m ple. 
•  A D A - p ositi ve s u bject: A n e val ua ble s u bject wit h at least o ne treat me nt -e m er ge nt 
A D A -p ositi ve sa m ple at a n y ti me d uri n g t he st u d y. 
•  Ne utralizi n g -p ositi ve: At least o ne treat me nt -e mer ge nt A D A -p ositi ve sa m ple wit h 
ne utralizi n g a nti b o dies d etecte d (if a vaila ble).  
•  A D A -ne g ati ve s u bject: A n e val ua ble p atie nt wit h o ut a treat me nt -e m er ge nt A D A 
sa m ple d uri n g t he st u d y. 
•  A D A - u n k n o w n: Patie nts wit h o ut e val ua ble baseli n e a n d/ or p ost- bas eli ne A D A 
sa m ples will be cate g ori ze d as “ A D A- u n k n o w n ”. 
6. 1 0. 2.  
St atistic al A n al ysis f or C h ar acteriz ati o n of A D A I m m u ne Res p o nse 
6. 1 0. 2. 1.  I nci de nce of A D A 
•  Perce nta g e of treat me nt -e mer ge nt A D A patie nts f or t he defi ne d st u d y peri o d, w here 
t he de n o mi nat or is t he n u m ber of A D A e val ua bl e patie nts i n t he res pecti ve treat me nt 
ar m a n d/ or s u b gr o u p. 
•  N u m ber ( %) of s u bjects will be re p orte d f or t he f oll o wi n g para meters b ase d o n 
e val ua ble s u bjects:  
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− Baseli ne A D A - p ositi ve 
− Treat me nt -e mer ge nt  A D A -p ositi ve ( Treat me nt -i n d uce d, Treat me nt- b o oste d) 
− Ne utralizi n g P ositi ve (if a vaila ble)  
− A D A -ne g ati ve  
•
A D A pre v ale nce : Perce nta ge of treat me nt-e mer g e nt A D A patie nts at a n y gi ve n
ti me p oi nt, w here t he de n o mi nat or is t he n u m ber of A D A e v al ua ble p atie nts i n t he
res pecti ve tr eat me nt ar m a n d/ or s u b gr o u p at t hat ti me p oi nt.
•
A listi n g of all A D A assess me nts will be pr o vi de d.
•
A d diti o nall y, a se parat e listi n g of A D A assess me nts f or all ne utralizi n g a nti b o d y
( N A b)-p ositi ve s u bjects will be pr o vi de d (if a v aila ble).
6. 1 0. 2. 2.  A D A Titer Ki netics  
All A D A - p ositi ve s u bjects will be i ncl u de d i n t he a nal ysis. 
•
S u m mar y statistics of s u bject -le vel A D A titers usi n g t he ma xi m u m titer val ue wit hi n
a n A D A- p ositi ve s u bject will be prese nte d f or bas eli ne A D A-n e gati ve s u bj ects a n d
baseli ne A D A - p ositi ve s u bjects. T he me dia n, i nter q uartile ra n g e, a n d ra n g e of t he
ma xi m u m titers will be re p orte d. F or A D A -p ositi ve s u bjects wit h a b aseli n e A D A-
p ositi ve sa m ple, t he me dia n a n d i nter q uartile ra n g e of t he f ol d i ncreas e fr o m baseli ne
i n titer (rati o of ma xi m u m p ost-baseli ne titer t o baseli ne titer) will als o be re p orte d.
Gra p hical prese ntati o n of t he s u m mar y data ma y b e pr o vi de d usi n g b o x pl ots, as
a p pr o priate.
•
F or sa m ple- le vel A D A titers, b o x pl ots of A D A titers at eac h ass ess me nt ti me p oi nt
will be pr o vi de d, as a p pr o priate, t o de m o nstrate w het her t he A D A le vels te n d t o
c ha n ge o v er ti me d uri n g t he treat me nt, al o n g wit h A D A i nci de nce at eac h assess me nt
ti me p oi nt.
•
S pi der pl ots ma y be c o nsi dere d t o s h o w t he tre n d of A D A titer o ver ti me.
6. 1 0. 3.  
Cli nic al I m plic ati o n of A D A  I m m u ne Res p o nse  
6. 1 0. 3. 1.  P K  
•
Effect of A D A  res p o nse o n dr u g e x p os ure will be e x pl ore d b y e x a mi ni n g t he dr u g
e x p os ures usi n g gra p hi cal pl ots or si m ple s u m mar y statistics of o bser ve d dr u g
c o nce ntr ati o n le vels b y A D A stat us a n d  sa m pli n g ti me. C orres p o n di n g n u merical
val ues of ge o metri c mea n, arit h met ic mea n, a n d sta n dar d de viati o n will be dis pla ye d
u n der t he fi g ur es.
•
A listi n g of dr u g c o nce ntrati o ns will be pr o vi de d. Ti me c o urse of o bs er ve d
c o nce ntr ati o ns b y st u d y visit wit h i de ntifiers f or a nti b o d y res p o nse will be pl otte d f or
eac h s u bject se par atel y .
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6. 1 0. 3. 2.  S afet y  a n d Effic ac y  
•
S u b gr o u p a nal ysis f or A Es a n d effi cac y e n d p oi nts will i ncl u de A D A stat us ( details i n
Secti o n  6. 7. 1. 4  a n d Secti o n  6. 8. 1 ).
7.
C H A N G E S F R O M P R O T O C O L
Base d o n fee d bac k fr o m t he F o o d a n d Dr u g A d mi nistrati o n ( F D A), M M R M is defi ne d as t he 
pri mar y a nal ysis f or F V C. R C M will be a se nsiti vit y a nal ysis. S u p ple me ntal a n d s u b gr o u p 
a nal yses f or F V C will als o use M M R M. T he e x pl orat or y efficac y e n d p oi nt F V C p p will als o be 
a nal yze d usi n g M M R M.  
I n a d diti o n, wit h c o nsi derati o n f or F D A rec o m me n dati o ns, t he testi n g or der was s witc he d f or t he 
f oll o wi n g sec o n dar y effi cac y e n d p oi nts: “ Ti me t o t he first occ urre nce of a n y c o m p o ne nt of 
cli nical c o m p osite e n d p oi nt: ac ute I P F e x acer bati o n, res pirat or y h os pitalizati o n, or deat h, 
w hic he ver  o cc urs first”  a n d “ C ha n ge i n Q L F v ol u me fr o m baseli ne at Wee k 4 8” (Ta ble  3). 
8.  
R E F E R E N C E
•
E 9( R 1) Statistical Pri nci ples f or Cli nical Trials: A d de n d u m: Esti ma n ds a n d
Se nsiti vit y A nal ysis i n Cli nical Trials
•
Ea ki n E G, Res ni k off P M, Pre witt L M, Ries A L, Ka pla n R M., Vali dati o n  of a ne w
d ys p nea meas ure: t he U C S D S h ort ness of Breat h Q uesti o n naire. C hest. 1 9 9 8;
1 1 3: 6 1 9- 6 2 4
•
J o nes, P. W., Q uir k, F. H., Ba ve yst oc k, C. M., a n d Littlej o h ns, P. A,  Self-c o m plete
meas ure of h ealt h stat us f or c hr o nic airfl o w li mitat i o n. T he St. Ge or ge's Res pirat or y
Q uesti o n naire. A m Re v Res pir Dis , 1 9 9 2; 1 4 5: 1 3 2 1 – 1 3 2 7
•
J o nes P W, F or d e, Y., St Ge or ge’s Re s pirat or y Q u esti o n naire Ma n ual.
htt p:// w w w. healt hstat us.s g ul.ac. u k/ S G R Q _ d o w nl oa d/ S G R Q % 2 0 Ma n ual % 2 0J u ne % 2
0 2 0 0 9. p df . Accesse d J u n e 2,  2 0 2 0
•
Ric hel di  L, d u B ois R M, Ra g h u G, et al. Effi cac y a n d safet y of ni nte da ni b i n
i di o pat hic p ul m o nar y fi br osis. N E n gl J Me d 2 0 1 4; 3 7 0: 2 0 7 1- 8 2.
•
N o ble P W , Al ber a C, Bra df or d W Z, C osta b el  U, etc.; Pirfe ni d o ne i n patie nts wit h
i di o pat hic p ul m o nar y fi br osis ( C A P A CI T Y): t w o ra n d o mise d trials; La ncet 2 0 1 1;
3 7 7: 1 7 6 0 – 6 9
•
St atistical Re vie w a n d  E val uati o n f or Ofe v ® ( ni nte da ni b) 1 5 0 m g ca ps ules;
I n dicati o n: Treat me nt of I di o pat hic P ul m o nar y Fi br osis (I P F); P D U F A: Ja n uar y 2,
2 0 1 5 
•
Ki n g T E Jr., Bra df or d W Z, Castr o- Ber nar di ni S, etc.; A P hase 3 Trial of Pirfe ni d o ne
i n Patie nts wit h I di o pat hic P ul m o nar y Fi br osis; N E n gl J Me d 2 0 1 4; 3 7 0: 2 0 8 3- 9 2
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      Statistical A nal ysis Pla n  ( v 1. 0, D o u ble -Bli n d Peri o d ) 
•
Pic ozzi  VJ, etc.; F G - 3 0 1 9, a h u ma n m o n ocl o nal a nti b o d y t o c o n necti ve tiss ue gr o wt h
fact or ( C T G F), wit h ge mcita bi ne/erl oti ni b ( G/ E) i n patie nts wit h l ocall y a d va nce d or
metastatic pa ncr eatic d u ctal a de n ocarci n o ma ( P D A C). J. Ca ncer Cli n Trials 2 0 1 7, 2: 1
•
H ui Q ua n: P H A R M A C E U TI C A L S T A TI S TI C S P har mace ut. Statist. 9: 1 0 0 – 1 1 2
( 2 0 1 0)
•
T he Acce pta nce of O v ers eas Dr u g Cli nical Trial D ata . N M P A 2 0 1 8
htt ps:// w w w. n m pa. g o v.c n/z h ua nti/ y p q x g g/ g gz hcf g/ 2 0 1 8 0 7 1 0 1 5 1 4 0 1 4 6 5. ht ml
•
Ra g h u G., et.al. Dia g n osis of I di o pat hic P ul m o nar y Fi br osis. A n Official A T S/ E R S/
J R S/ A L A T Cli nical Practice G ui deli ne. A m J Res pir Crit Care Me d 2 0 1 8 Se p 
1; 1 9 8( 5):e 4 4-e 6 8.
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A P P E N DI X  1.  H A N D LI N G MI S SI N G/I N C O M P L E T E D A T E S 
A p pe n di x 1. 1 
Missi n g/I nc o m plete A E O nset D ate  
T he  f oll o wi n g i m p utati o n r ules a p pl y t o t he case w here  t he start date is i nc o m plete (i.e., partiall y  
missi n g)  f or a d verse e ve nts.  W he n t he start date a n d t he st o p date are b ot h i nc o m plete f or a 
patie nt, i m p ute t he start date first.  
If t he st o p date is c o m plete a n d t he i m p ute d start d ate is after t h e st o p date, t he n t he start date 
will be i m p ute d usi n g t he st o p date. 
•  Missi n g st art ti m e o nl y  
A Es wit h missi n g start ti mes a n d w hic h occ ur o n a st u d y- dr u g- d osi n g da y will be c o nsi dere d as 
occ urr e d aft er t he st u d y treat me nt a d mi nistrati o n o n t hat da y. N o i m p utati o n o n ot her missi n g 
ti me. 
•  Missi n g d a y a n d m o nt h 
If t h e year  is t he sa me as t he year  of t he first da y  o n d o u ble- bli n d st u d y treat me nt, t he n t he da y  
a n d  m o nt h of t he start date  of t h e d o u ble- bli n d  st u d y treat me nt will be  assi g ne d t o t he missi n g 
fiel ds. 
If t h e year  is differe nt fr o m t he year  of t he first da y o n d o u ble- bli n d st u d y treat me nt, t he n 
Ja n uar y 1 will be  assi g ne d  t o t he missi n g  fiel ds. 
•  Missi n g m o nt h o nl y  
Treat  da y  as missi n g  a n d re place b ot h m o nt h a n d da y acc or di n g  t o t he a b o ve pr oce d ure.  
•  Missi n g d a y o nl y  
If t he m o nt h a n d year are t he sa me as t he y ear a n d m o nt h of t he first da y of d o u ble- bli n d st u d y 
treat me nt, t he n t he start d ate of t he d o u ble- bli n d st u d y treat me nt will be assi g ne d t o t he missi n g 
da y. 
If t he m o nt h a n d year are differe nt fr o m  t he year a n d m o nt h of t he first da y of d o u ble- bli n d st u d y 
treat me nt, t he n t he first d a y of t he m o nt h will be assi g ne d t o t he missi n g da y. 
•  Missi n g ye ar 
N o i m p utati o n. 
A p pe n di x 1 . 2. 
Missi n g/I nc o m plete A E St o p D ate  
If nee de d,  t he f oll o wi n g i m p utati o n r ules a p pl y t o t he case w here  t he e n d date is i nc o m plete (i.e., 
partiall y  missi n g) f or a d verse e ve nts. Ot her  partial  e n d dates  will  n ot be i m p ute d. If t he i m p ute d 
st o p date  is bef ore t he start date  (i m p ute d or n o n-i m p ute d start date),  t he n t he i m p ute d st o p date 
will be  re place d wit h t he  start date.  
•  Missi n g d a y a n d m o nt h, or Missi n g m o nt h o nl y 
Dece m ber  3 1 will be  assi g ne d  t o t he missi n g  fiel ds. If i m p ute d st o p date is after d ate of deat h, 
date of deat h will be use d.  
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•  Missi n g d a y o nl y 
If t he m o nt h a n d year of t he i nc o m plete st o p date are t he sa me as t he m o nt h a n d year of t he last 
d ose date of d o u ble- bli n d st u d y treat me nt, t he n t he da y of t he last d ose dat e will be assi g ne d t o 
t he missi n g da y. 
If t he m o nt h a n d year of t he i nc o m plete st o p date are differe nt fr o m t he m o nt h a n d year of t he 
last d ose date of d o u ble- bli n d st u d y treat me nt, t he n t he mi ni m u m of (t he last da y of t he m o nt h, 
e n d of st u d y date, dat e of deat h) will be assi g ne d t o t he missi n g da y. 
•  Missi n g ye ar 
N o i m p utati o n. 
A p pe n di x 1 . 3. 
Missi n g/I nc o m plete Pri or or C o nc o mit a nt Me dic ati o n St art 
D ate  
Sa me i m p utati o n r ules as missi n g/i nc o m plete A E o nset date ( A p p e n di x 1. 1 ).  
A p pe n di x 1 .4.  
Missi n g/I nc o m plete Pri or or C o nc o mit a nt Me dic ati o n St o p 
D ate  
Sa me i m p utati o n r ules as missi n g/i nc o m plete A E st o p date ( A p pe n di x 1. 2 ).  
A p pe n di x 1 . 5. 
Missi n g D ate I m p ut ati o n f or L ast D ose D ate  
I m p ute d last d ose d ate = t he earliest date of (last dr u g dis pe nse date + t he n u m ber of da ys of dr u g 
dis pe nse d, date of d eat h, date of e n d of treat me nt ( E O T)/ E O S visit, a n d ot her dates as 
a p pr o priate). 
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A P P E N DI X  2.  A N A L Y SI S VI SI T WI N D O W S  
A nal ysis visits are defi ne d b y t he wi n d o ws t hat will ha ve t he wi dt hs of t he c orres p o n di n g 
assess me nts  ce ntere d at t he sc he d ule d ti me.  U ns c he d ule d visits wit hi n a visit wi n d o w defi ne d 
bel o w will be gr o u pe d i nt o t he cl osest sc he d ule d visits base d o n t he visit date. 
T a ble 6:  
A n al ysis Visit Wi n d o w f or Vit al Si g ns  
A n al ysis Visit  
T ar get D a y  
St art D a y  
E n d D a y  
Baseli ne  
Last val ue bef ore t he first st u d y dr u g i nf usi o n  
( or ra n d o mizati o n date if n o i nf usi o n recei ve d) 
Da y 1 p ost d ose  
1 
1 
1 
Wee k 3 ( pre d ose a n d p ost d ose)  
2 2  
2 
3 2  
Wee k 6 ( pre d ose a n d p ost d ose)  
4 3  
3 3  
5 3  
Wee k 9 ( pre d ose a n d p ost d ose)  
6 4  
5 4  
7 4  
Wee k 1 2 ( pre d ose a n d p ost d ose)  
8 5  
7 5  
9 5  
Wee k 1 5 ( pre d ose a n d p ost d ose)  
1 0 6  
9 6  
1 1 6  
Wee k 1 8 ( pre d ose a n d p ost d ose)  
1 2 7  
1 1 7  
1 3 7  
Wee k 2 1 ( pre d ose a n d p ost d ose)  
1 4 8  
1 3 8  
1 5 8  
Wee k 2 4 ( pre d ose a n d p ost d ose)  
1 6 9  
1 5 9  
1 7 9  
Wee k 2 7 ( pre d ose a n d p ost d ose)  
1 9 0  
1 8 0  
2 0 0  
Wee k 3 0 ( pre d ose a n d p ost d ose)  
2 1 1  
2 0 1  
2 2 1  
Wee k 3 3 ( pre d ose a n d p ost d ose)  
2 3 2  
2 2 2  
2 4 2  
Wee k 3 6 ( pre d ose a n d p ost d ose)  
2 5 3  
2 4 3  
2 6 3  
Wee k 3 9 ( pre d ose a n d p ost d ose)  
2 7 4  
2 6 4  
2 8 4  
Wee k 4 2 ( pre d ose a n d p ost d ose)  
2 9 5  
2 8 5  
3 0 5  
Wee k 4 5 ( pre d ose a n d p ost d ose)  
3 1 6  
3 0 6  
3 2 6  
Wee k 4 8 ( pre d ose a n d p ost d ose)  
3 3 7  
3 2 7  
 3 5 1  [ $] or *[ @] 
2 8 d a ys p ost last d ose [ $]  
3 6 5  
Date of Last d osi n g + 1 5  [ $] 
* [ $]  
$ F or s u bjects w h o d o n ot e nr oll O L E o nl y . 
* E n d of t he d o u ble -bli n d  peri o d  ( D B P). 
@ F or s u bjects w h o e nr oll O L E.  
N ote: T he st u d y da y wit h i nf usi o ns will be use d f or s u m mar y ta bles w he ne ver p ossi ble.  
N ote: If ra w data s h o ws visit is “ 2 8 Da ys p ost last d ose”, t he n set a nal ysis visit = visit  
N ote: all assess me nts be y o n d 6 0 da ys p ost last i nf usi o n will be e xcl u de d fr o m s u m mar y ta bles  or fi g ures . 
 
 
C o nfi de ntial
Pa ge 4 0 of 5 5


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               Statistical A nal ysis Pla n  ( v 1. 0, D o u ble -Bli n d Peri o d ) 
 
T a ble 7:  
A n al ysis Visit Wi n d o w f or P F T 
A n al ysis Visit  
T ar get D a y  
St art D a y  
E n d D a y  
Baseli ne  
L ast B T R P F T bef ore t he first st u d y dr u g i nf usi o n ( or ra n d o mizati o n date if n o i nf usi o n 
recei ve d) 
Wee k 6  
4 3  
2 
6 4  
Wee k 1 2  
8 5  
6 5  
1 0 6  
Wee k 1 8  
1 2 7  
1 0 7  
1 4 8  
Wee k 2 4  
1 6 9  
1 4 9  
2 1 1  
Wee k 3 6  
2 5 3  
2 1 2  
2 9 5  
Wee k 4 8  
3 3 7  
2 9 6  
E n d of D B P  
 
T a ble 8:  
A n al ysis Visit Wi n d o w f or H R C T  
A n al ysis Visit  
T ar get D a y  
St art D a y  
E n d D a y  
Baseli ne  
Last val ue bef ore t he first st u d y dr u g i nf usi o n ( or ra n d o mizati o n date if n o i nf usi o n 
recei ve d) 
Wee k 2 4  
1 6 9  
2 
2 5 3  
Wee k 4 8  
3 3 7  
2 5 4  
E n d of D B P  
T a ble 9: 
A n al ysis Visit Wi n d o w f or S G R Q, U C S D -S O B Q, L C Q, a n d L a bs  
A n al ysis Visit  
T ar get D a y  
St art D a y  
E n d D a y  
Baseli ne  
Last val ue bef ore t he first st u d y dr u g i nf usi o n  
( or ra n d o mizati o n date if n o i nf usi o n recei ve d) 
Wee k 1 2  
8 5  
2 
1 2 7  
Wee k 2 4  
1 6 9  
1 2 8  
2 1 1  
Wee k 3 6  
2 5 3  
2 1 2  
2 9 5  
Wee k 4 8  
3 3 7  
2 9 6  
 3 5 1 [ $] or *[ @]  
2 8 da ys p ost last d ose [ $]  
3 6 5  
 Date of Last d osi n g + 1 5 [ $]  
* [ $]  
$ F or s u bjects w h o d o n ot e nr oll O L E o nl y.  
* E n d of t he d o u ble -bli n d peri o d.  
@ F or s u bjects w h o e nr oll O L E. 
N ote: If ra w data s h o ws visit is “ 2 8 Da ys p ost last d ose”, t he n set a nal ysis visit = visit . 
N ote: If a s u bject w h o c o m plete d Wee k 4 8 treat me nt d oes n ot  ha ve Wee k 4 8 assess me nt f or Patie nt Re p orte d 
O utc o mes ( P R O ), b ut ha ve assess me nt o n 2 8  da y s p ost last d ose, t he 2 8  da y s p ost last d ose rec or d will als o be  
i m p ute d as Wee k 4 8 assess me nt.  
N ote: all assess me nts be y o n d 6 0 da ys p ost last i nf usi o n will be e xcl u de d fr o m s u m mar y ta bles f or la bs. 
C o nfi de ntial
Pa ge 4 1 of 5 5


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               Statistical A nal ysis Pla n  ( v 1. 0, D o u ble -Bli n d Peri o d ) 
 
T a b le 1 0:  
A n al ysis Visit Wi n d o w f or P E a n d Wei g ht 
A n al ysis Visit  
T ar get D a y  
St art D a y  
E n d D a y  
Baseli ne  
Last val ue bef ore t he first st u d y dr u g i nf usi o n ( or ra n d o mizati o n date if n o i nf usi o n recei ve d)  
Wee k 1 2  
8 5  
2 
1 2 7  
Wee k 2 4  
1 6 9  
1 2 8  
2 1 1  
Wee k 3 6  
2 5 3  
2 1 2  
2 9 5  
Wee k 4 8  
3 3 7  
2 9 6  
E n d of D B P  
N ote: all assess me nts be y o n d 6 0 da ys p ost last i nf usi o n will be e xcl u de d fr o m s u m mar y ta bles f or P E.  
T a ble 1 1:  
A n al ysis Visit Wi n d o w f or E C G 
A n al ysis Visit  
T ar get D a y  
St art D a y  
E n d D a y  
Baseli ne  
Last val ue bef ore t he first st u d y dr u g i nf usi o n ( or ra n d o mizati o n date if n o i nf usi o n recei ve d)  
Wee k 4 8  
3 3 7  
2 
E n d of D B P  
N ote: all assess me nts be y o n d 6 0 da ys p ost last i nf usi o n will be e xcl u de d fr o m s u m mar y ta bles f or E C G.  
 
T a ble 1 2:  
A n al ysis Visit Wi n d o w f or Bi o m ar kers ( Ser u m a n d Pl as m a)  
A nal ysis Visit  
Tar get Da y  
Start Da y  
E n d Da y  
Da y 1  
1 
1 
1 
Wee k 2 4  
1 6 9  
2 
2 5 3  
Wee k 4 8  
3 3 7  
2 5 4  
3 5 1 [ $] or *[ @]  
2 8 da ys p ost last d ose [ $]  
3 6 5  
 Date of Last d osi n g + 1 5 
[ $] 
* [ $]  
$ F or s u bjects w h o d o n ot e nr oll O L E o nl y.  
* E n d of t he d o u ble -bli n d peri o d.  
@ F or s u bjects w h o e nr oll O L E.  
N ote: If ra w data s h o ws visit is “ 2 8 Da ys p ost last d ose”, t he n set a nal ysis visit = visit  
N ote: all assess me nts be y o n d 6 0 da ys p ost last i nf usi o n will be e xcl u de d fr o m s u m mar y ta bles.  
T a ble 1 3:  
A n al ysis Visit Wi n d o w f or C T G F a n d A D A  ( Pl as m a) 
A n al ysis Visit  
T ar get D a y  
St art D a y  
E n d D a y  
Da y 1  
1  
1  
1  
Wee k 2 4  
1 6 9  
2 
2 1 1  
Wee k 3 6  
2 5 3  
2 1 2  
2 9 5  
Wee k 4 8  
3 3 7  
2 9 6  
3 5 1 [ $] or *[ @]  
2 8 da ys p ost last d ose [ $]  
3 6 5  
 Date of Last d osi n g + 1 5 [ $]  
* [ $]  
$ F or s u bjects w h o d o n ot e nr oll O L E o nl y . 
* E n d of t he d o u ble -bli n d peri o d.  
@ F or s u bjects w h o e nr oll O L E.  
N ote: If ra w data s h o ws visit is “ 2 8 Da ys p ost last d ose”, t he n set a nal ysis visit = visit 
N ote: all assess me nts be y o n d 6 0 da ys p ost last i nf usi o n will be i ncl u de d i n s u m mar y ta bles. 
C o nfi de ntial
Pa ge 4 2 of 5 5


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               Statistical A nal ysis Pla n  ( v 1. 0, D o u ble -Bli n d Peri o d ) 
 
T a ble 1 4: 
A n al ysis Visit Wi n d o w f or P h ar m ac o ki netic  C o nce ntr ati o n  ( Pl as m a) 
A n al ysis Visit  
T ar get D a y  
St art D a y  
E n d D a y  
Da y 1  
1  
1  
1  
Da y 8  
8 
2 
1 1  
Da y 1 5  
1 5  
1 2  
1 8  
Wee k 3 
2 2  
1 9  
5 2  
Wee k 1 2  
8 5  
5 3  
1 2 7  
Wee k 2 4  
1 6 9  
1 2 8  
2 1 1  
Wee k 3 6  
2 5 3  
2 1 2  
2 9 5  
Wee k 4 8  
3 3 7  
2 9 6  
3 5 1 [ $] or *[ @]  
2 8 da ys p ost last d ose [ $] 
3 6 5  
 Date of Last d osi n g + 1 5 [ $]  
* [ $]  
$ F or s u bjects w h o d o n ot e nr oll O L E o nl y . 
* E n d of t he d o u ble -bli n d peri o d.  
@ F or s u bjects w h o e nr oll O L E.  
N ote: If ra w data s h o ws visit is “ 2 8 Da ys p ost last d ose”, t he n set a nal ysis visit = visit  
N ote: all assess me nts be y o n d 6 0 da ys p ost last i nf usi o n will be i ncl u de d i n s u m mar y ta bles. 
 
C o nfi de ntial
Pa ge 4 3 of 5 5


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               Statistical A nal ysis Pla n  ( v 1. 0, D o u ble -Bli n d Peri o d ) 
 
A P P E N DI X  3.  S G R Q  
T he S G R Q is desi g ne d t o meas ure h ealt h i m pair me nt i n patie nts wit h as t h ma a n d C O P D. It is 
als o vali d f or use i n br o n c hiectasis a n d h as bee n use d s uccessf ull y i n patie nts wit h  
k y p h osc oli osis a n d sarc oi d osis. It i ncl u des S y m pt o ms sc ores ( q uesti o ns 1- 8) , Acti vit y sc ores 
( q uesti o ns 1 1 a n d 1 5), a n d I m pacts sc ores ( q uesti o ns 9- 1 0, 1 2- 1 4, a n d 1 6- 1 7). A T otal sc ore is 
als o calc ulate d w hic h s u m marizes  t he i m pact of t he disease o n o v erall healt h stat us. Sc ores are 
e x presse d as a perce nt a g e of o ver all i m pair me nt w here 1 0 0  re prese nts t he w orst p ossi ble healt h 
stat us a n d 0 i n dicates t he best p ossi ble healt h stat us. 
Q uesti o ns 1 – 7, 9, 1 0 & 1 7 W here a patie nt has ti c ke d a b o x, a val ue of 1 is e ntere d f or t he 
a p pr o priate q u esti o n. T he e m pt y b o xes are e ntere d as 0. It will be n ote d t hat t he q uesti o n naire 
re q uests a si n gle r es po ns e t o q uesti o ns 1- 7, 9- 1 0, a n d 1 7. If m ulti ple res p o nses are gi ve n t o o ne 
of t hese q uesti o ns, t he n a vera gi n g t he w ei g hts f or t he p ositi ve res p o nses f or t hat q uesti o n is 
acce pta ble.  
Q uesti o n 8  W here a p atie nt has tic ke d ‘ Y es’ t o ha vi n g a w orse w h eeze i n t he m or ni n g, a val ue 
of 1 is e ntere d f or t he a p pr o priate q uesti o n. All ot her res p o ns es are e ntere d as 0. 
Q uesti o ns 1 1 – 1 6  W here a patie nt has tic k e d ‘ Tr ue’ , a val u e of 1 is e ntere d f or t he a p pro priate 
q uesti o n, a n d w her e a patie nt has tic ke d ‘ False’ a  val ue of 0 is e ntere d. W h ere a p atie nt has 
misse d a q uesti o n t he cell o n t he s prea ds heet is left bla n k. I n res p o nse t o q u esti o n 1 4, if a patie nt 
is n ot recei vi n g me dicati o n, t he n t he res p o nse is zer o, ot her wise, t he val ues are missi n g . 
Missi n g Q uesti o ns  
T he missi n g ( bla n ks) i n part 1 ( S y m pt o ms) will be i m p ute d  b y a n a vera ge of t he m ulti ple 
wei g hte d res p o ns es i n part 1 . T his i m p utati o n will a dj ust f or u p t o 2 4 % of missi n g ite ms i n t he 
q uesti o n naire. If m or e t h a n 2 4 % of ite ms are missi n g, t he c o m p o ne nt sc ore will  be ‘ Missi n g’. 
Misse d Ite ms f or  C o m p o ne nt  Sc ores  
It is better n ot t o miss ite ms a n d a n y missi n g ite ms are t he fa ult of t he e x p eri me nter, n ot t he 
patie nt. T he effect of missi n g ite ms a n d rec o m me n dati o ns fr o m t he sc ori n g ma n ual are t h e 
f oll o wi n g: 
S y m pt o ms Sc ore: T he  S y m pt o ms c o m p o ne nt will t olerate a ma xi m u m of 2 misse d ite m s fr o m 
q uesti o ns 1- 8. 
Acti vit y Sc ore: T he  Acti vit y c o m p o ne nt will t olerate a ma xi m u m of 4 misse d ite ms  fr o m 
q uesti o ns 1 1 a n d 1 5. 
I m pacts Sc ore: T h e  I m pacts c o m p o ne nt will t olerate a ma xi m u m of 6 misse d ite ms fr o m 
q uesti o ns 9- 1 0, 1 2- 1 4, a n d 1 6- 1 7. 
T heref ore, if t here are m ore t ha n t he r ec o m me n d e d misse d ite ms descri be d a b o ve t he c o m p o n e nt 
sc ore will be set t o missi n g.  If one of t h e c o m p o n e nt sc ores is missi n g, t he n t he t otal sc ore is 
missi n g.  
O utli ne of Sc ori n g Al g orit h m  
•  Pri nci ple of calc ul ati o n  
C o nfi de ntial
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Eac h q uesti o n nair e res p o nse has a u ni q ue e m piricall y deri ve d ' wei g ht'. T h e l o west p ossi ble 
‘ wei g ht’ is zer o a n d t he hi g hest ‘ wei g ht’ is 1 0 0. 
•  Eac h c o m p o ne nt of t he q uesti o n naire is sc ore d s e paratel y i n t hree ste ps: 
− T he wei g hts f or all ite ms wit h p ositi ve res p o nses are s u m me d.  
− T he wei g hts f or misse d it e ms are d e d ucte d fr o m t he ma xi m u m p ossi ble wei g ht f or 
eac h c o m p o ne nt. T he w ei g hts f or all misse d ite ms are de d u cte d fr o m t he 
ma xi m u m  p ossi ble wei g ht f or t he T otal sc ore. 
S u m of ma xi m u m wei g hts f or eac h c o m p o ne nt a n d T otal: 
C o m p o ne nt  
Q uesti o ns  
# of t olerate d  
ma xi m u m missi n g ite ms  
Ma xi m u m  
Wei g ht  
S y m pt o ms  
1 –  8  
2  
6 6 2. 5  
Acti vit y  
1 1 a n d 1 5  
4  
1 2 0 9. 1  
I m pacts 
9 –  1 0, 1 2 –  1 4, 1 6 –  1 7  
6  
2 1 1 7. 8  
T otal  
All  
 
3 9 8 9. 4  
( N ote: t hese are t he ma xi m u m p ossi ble wei g hts t hat c o ul d be o btai ne d f or t he w orst p ossi ble 
state of t he patie nt). 
− T he sc ore is calc ulate d b y di vi di n g t he s u m me d wei g hts b y t he a dj uste d 
ma xi m u m  wei g ht f or t hat c o m p o ne nt a n d e x pressi n g t he res ult as a perce nta ge:  
Sc ore = 1 0 0 % x ( S u m me d wei g hts fr o m p ositi ve ite ms i n t hat c o m p o ne nt/ S u m of wei g hts f or 
all ite ms i n t hat c o m p o ne nt ) 
T he T otal sc or e is calc ul ate d si milarly: 
Sc ore = 1 0 0 x ( S u m me d wei g hts fr o m p ositi ve ite ms i n t he q uesti o n naire / S u m of wei g hts f or 
all ite ms i n t he q uesti o n naire ) 
Ite m Wei g hts 
T he f oll o wi n g wei g hts will be use d t o sc ore t he a ns wers s i milar t o t he E xcel-base d s yste m a n d 
ot her c o m p uterize d sc ori n g s yste ms. N ote t hat t he w or di n g of t he ite m ma y n ot c orres p o n d 
e xactl y wit h t he w or di n g i n t he c urre nt v ersi o n of t he q uesti o n naire. 
•  P A R T 1  
1) O ver t he p ast 3 m o nt hs , I h a ve c o u g he d: 
 
Res p o nse  
Wei g ht  
al m ost e ver y da y  
8 0. 6  
se veral d a ys a wee k  
6 3. 2  
a fe w d a ys a m o nt h  
2 9. 3  
o nl y wit h res pirat or y i nfecti o ns  
2 8. 1  
n ot  at all 
0. 0  
 
 
2) O ver t he p ast 3 m o nt hs, I h a ve br o u g ht u p p hle g m (s p ut u m):  
Res p o nse  
Wei g ht  
al m ost e ver y da y  
7 6. 8  
se veral d a ys a wee k  
6 0. 0  
C o nfi de ntial
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a fe w d a ys a m o nt h  
3 4. 0  
o nl y wit h res pirat or y i nfecti o ns  
3 0. 2  
n ot  at all 
0. 0  
 
 
3) O ver t he p ast 3 m o nt hs, I h a ve h a d s h ort ness of bre at h : 
 
Res p o nse  
Wei g ht  
al m ost e ver y da y  
8 7. 2  
se veral d a ys a wee k  
7 1. 4  
a fe w d a ys a m o nt h  
4 3. 7  
o nl y wit h res pirat or y i nfecti o ns 
3 5. 7  
n ot  at all 
0. 0  
 
 
4) O ver t he p ast 3 m o nt hs, I h a ve h a d w heezi n g att ac ks:  
Res p o nse  
Wei g ht  
al m ost e ver y da y  
8 6. 2  
se veral d a ys a wee k  
7 1. 0  
a fe w d a ys a m o nt h  
4 5. 6  
o nl y wit h res pirat or y i nfecti o ns  
3 6. 4  
n ot  at all 
0. 0  
 
 
5) H o w m a n y ti m es d uri n g t he p ast 3 m o nt hs h a ve y o u s uffere d fr o m  se vere or ver y 
u n ple as a nt res pir at or y att ac ks ?  
Res p o nse  
Wei g ht  
m ore t ha n 3 ti mes  
8 6. 7  
3 ti mes 
7 3. 5  
2 ti mes  
6 0. 3  
1 ti me  
4 4. 2  
n o ne of t he ti me  
0. 0  
 
 
6) H o w l o n g di d t he w orst att a c k of c hest tr o u ble l ast ?  
Res p o nse  
Wei g ht  
a wee k or m ore  
8 9. 7  
3 or m ore da ys  
7 3. 5  
1 or 2 da ys  
5 8. 8  
less t ha n a da y  
4 1. 9  
 
 
7) O ver t he p ast 3 m o nt hs, i n a t y pic al wee k, h o w m a n y g o o d d a ys ( wit h  fe w res pir at o r y 
pr o ble ms) h a ve y o u h a d ?  
Res p o nse  
Wei g ht  
N o g o o d da ys  
9 3. 3  
1 or 2 g o o d da ys  
7 6. 6  
3 or 4 g o o d da ys  
6 1. 5  
nearl y e v er y da y was g o o d  
1 5. 4  
e ver y da y was g o o d  
0. 0  
 
 
8) If y o u w heeze, is it w orse w he n y o u get u p i n t he m or ni n g ?  
 
Res p o nse  
Wei g ht  
N o  
0. 0  
Yes  
6 2. 0  
C o nfi de ntial
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•  P A R T 2  
9) H o w w o ul d y o u descri be y o ur res pir at or y c o n diti o n ?  
 
Res p o nse  
Wei g ht  
T he m ost i m p orta nt pr o ble m I h a ve  
8 3. 2  
Ca uses me q uite a l ot of pr o ble m  
8 2. 5  
Ca uses me a f e w pr o ble ms  
3 4. 6  
Ca uses n o pr o ble m  
0. 0  
 
 
1 0) If y o u h a ve e ver hel d a j o b: 
 
Res p o nse  
Wei g ht  
M y res pirat or y pr o bl e ms ma de me st o p w or ki n g alt o get her  
8 8. 9  
M y res pirat or y pr o bl e ms  i nterfer e wit h m y j o b or ma de me c h a n ge m y j o b  
7 7. 6  
M y res pirat or y pr o bl e ms d o n ot affect m y j o b  
0. 0  
 
 
1 1) Q uesti o ns a b o ut w h at acti vities us u all y m a ke y o u feel  s h ort of bre at h t hese d a ys. 
Res p o nse  
Wei g ht  
Sitti n g or l yi n g still  
9 0. 6  
Was hi n g or dr essi n g y o urself  
8 2. 8  
Wal ki n g ar o u n d t he h o us e  
8 0. 2  
Wal ki n g o utsi de o n le vel gr o u n d  
8 1. 4  
Wal ki n g u p a fli g ht of stairs  
7 6. 1  
Wal ki n g u p hills  
7 5. 1  
Pla yi n g s p orts or ot her p h ysical acti vities  
7 2. 1  
 
 
1 2) M ore q uesti o ns a b o ut y o ur c o u g h a n d s h ort ness of  bre at h t hese d a ys.  
Res p o nse  
Wei g ht  
C o u g hi n g h urts  
8 1. 1  
C o u g hi n g ma kes me tire d  
7 9. 1  
I a m s h ort of br eat h w he n I tal k 
8 4. 5  
I a m s h ort of br eat h w he n I b e n d o ver 
7 6. 8  
M y c o u g hi n g or breat hi n g dist ur bs m y slee p  
8 7. 9  
I g et e x ha uste d easil y  
8 4. 0  
 
 
1 3) Q uesti o ns a b o ut ot her effects y o ur res pir at or y  pr o ble ms m a y h a ve o n y o u t hese d a ys. 
Res p o nse  
Wei g ht  
M y c o u g h or breat hi n g is e m barr assi n g i n p u blic  
7 4. 1  
M y c hest tr o u ble is a n uisa nce t o m y fa mil y fri e n ds or nei g h b ors  
7 9. 1  
I g et afr ai d or pa ni c w he n I ca n n ot catc h m y breat h 
8 7. 7  
I feel t hat I a m n ot i n c o ntr ol of m y res pirat or y pr o ble ms 
9 0. 1  
I d o n ot e x pect m y r es pir at or y pr o ble ms t o get a n y better 
8 2. 3  
I h a ve bec o me frail or a n i n vali d beca use of m y res pirat or y pr o ble ms 
8 9. 9  
E xercise is n ot saf e f or m e  
7 5. 7  
E ver yt hi n g see ms t o o m uc h of a n eff ort  
8 4. 5  
 
 
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1 4) Q uesti o ns a b o ut y o ur res pir at or y tre at me nt . 
 
Res p o nse  
Wei g ht  
M y treat me nt d oes n ot hel p me ver y m uc h  
8 8. 2  
I g et e m barrasse d usi n g m y me dicati o n i n p u blic  
5 3. 9  
I h a ve u n pleasa nt si de eff ects fr o m m y me dicati o n  
8 1. 1  
M y me dicati o n i nterferes wit h m y life a l ot  
7 0. 3  
 
 
1 5) Q uesti o ns a b o ut h o w acti vities m a y be affecte d b y y o ur bre at hi n g.  
Res p o nse  
Wei g ht  
I ta k e a l o n g ti me t o get was he d or dresse d  
7 4. 2  
I ca n n ot ta ke a bat h or s h o wer, or I ta ke a l o n g ti m e t o d o it 
8 1. 0  
I wal k sl o wer t h a n ot her pe o ple m y a ge, or I st o p t o rest  
7 1. 7  
J o bs s uc h as h o use h ol d c h ores ta ke a l o n g ti me, or I h a ve t o st o p t o rest 
7 0. 6  
If I w al k u p o ne fli g ht of stairs, I h a ve t o g o sl o wl y or st o p  
7 1. 6  
If I h urr y or wal k fast, I h a ve t o st o p or sl o w d o w n  
7 2. 3  
M y breat hi n g ma kes it diffic ult t o d o t hi n gs s uc h as wal k -u p hills, carr y t hi n gs 
u pstairs , li g ht gar de ni n g s uc h as wee di n g , da nce , b o wl or pla y g olf  
7 4. 5 
M y breat hi n g ma kes it diffic ult t o d o t hi n gs s uc h as carr y h ea v y  l oa ds, di g i n t he 
gar de n or s h o v el s n o w, j o g or wal k bris kl y ( 5 miles  per h o ur), pla y te n nis or s wi m  
7 1. 4 
M y breat hi n g ma kes it diffic ult t o d o t hi n gs s uc h as ver y hea v y m a n ual w or k, ri de 
a bi ke, r u n, s wi m fast, or pla y c o m petiti ve s p orts  
6 3. 5 
 
 
1 6) We w o ul d li ke t o k n o w h o w y o ur res pir at or y pr o ble ms us u all y  affect y o ur d ail y life.  
Res p o nse  
Wei g ht  
I ca n n ot pla y s p orts or d o ot her p h ysical acti vities   
6 4. 8  
I ca n n ot g o o ut f or e ntert ai n me nt or recreati o n  
7 9. 8  
I ca n n ot g o o ut of t he h o use t o d o t he s h o p pi n g  
8 1. 0  
I ca n n ot d o h o use w or k c h ores  
7 9. 1  
I ca n n ot m o ve f ar fr o m m y be d or c hair  
9 4. 0  
 
1 7) Tic k t he st ate m e nt w hic h y o u t hi n k best descri bes h o w y o ur c hest affects y o u.  
Res p o nse  
Wei g ht  
It d oes n ot st o p me fr o m d oi n g a n yt hi n g I w o ul d li ke t o d o  
0. 0  
It st o ps me fr o m d oi n g o ne or t w o t hi n gs I w o ul d li ke t o d o  
4 2. 0  
It st o ps me fr o m d oi n g m ost of t he t hi n gs I w o ul d li ke t o d o  
8 4. 2  
It st o ps me fr o m d oi n g e ver yt hi n g I w o ul d li ke t o d o  
9 6. 7  
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A P P E N DI X  4.  U C S D - S O B Q 
T he S O B Q as ks s u bjects t o i n dicate t he se verit y of s h ort ness of breat h o n a 6-p oi nt scale ( 0 = 
N ot at all, t o 5 = Ma xi mall y or u na ble t o d o beca use of breat hless ness) d uri n g 2 1 acti vities of 
dail y li vi n g ass ociate d wit h var yi n g le vels of e x erti o n. T hree a d diti o nal q uesti o ns as k a b o ut fear 
of har m fr o m o v ere x erti o n, li mitat i o ns, a n d fear ca use d b y s h ort ness of breat h, f or a t otal of 2 4 
ite ms. If p atie nts d o n ot r o uti nel y perf or m a n acti vit y, t he y are as k e d t o esti mate t heir a ntici pate d 
s h ort ness of breat h. The S O B Q is sc ore d b y s u m mi n g n o n- missi n g res p o nses acr oss all 2 4 
ite ms t o f or m a t otal sc or e. A t otal s u m sc ore ra n g es fr o m 0 t o 1 2 0, wit h hi g her sc ores i n dicati n g 
greater d ys p nea.  
If 2 2- 2 3 q uesti o ns were a ns were d, t he t otal S O B Q sc ore will t he s u m of n o n-missi n g 
q uesti o ns * 2 4/ n u m ber of q uesti o ns a ns were d ass u mi n g missi n g ite ms is ne utral. If 2 1 or fe w er 
q uesti o ns were a ns wer e d, t he S O B Q  sc ore will be set t o missi n g. 
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A P P E N DI X  5.  L C Q 
T he L C Q is a 1 9 Res p o nse q uesti o n naire t hat ass esses c o u g h-relate d Q O L . It has 3 d o m ai ns 
( p h ysical, ps yc h ol o gical, a n d s ocial): 
•  P h ysical: Q uesti o ns 1, 2, 3, 9, 1 0, 1 1, 1 4, 1 5 
•  Ps yc h ol o gical: Q uesti o ns 4, 5, 6, 1 2, 1 3, 1 6, 1 7  
•  S ocial: Q uesti o ns 7, 8, 1 8, 1 9 
T he t otal sc ore ra n ge is 3  t o 2 1 a n d d o mai n sc ores ra n ge fr o m 1 t o 7; a hi g her sc ore i n dicates a 
better q ualit y of life . Sc ores ar e cal c ulate d as a mea n of eac h d o mai n a n d t h e t otal sc ore is 
calc ulate d b y a d di n g e ver y d o mai n sc ore. O nl y n o n- missi n g sc ores are c o nsi dere d i n t he mea n 
d o mai n sc o re calc ulati o n. T w o missi n g val ues are all o we d f or P h ysical, a n d 1 missi n g val ue is 
all o we d f or S ocial  a n d Ps yc h ol o gical d o mai ns. T otal sc ores re q uire n o n- missi n g sc ores f or 3 
d o mai ns. 
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A P P E N DI X  6.  G A P S C O R E A N D S T A G E  
G A P i n de x a n d sta gi n g s yste m f or I P F: ge n d er ( G), a ge ( A), a n d t w o p ul m o nar y p h ysi ol o gical 
para meters ( P) — perce nt a ge pre di cte d F V C [ %], a n d perce nta ge pre dicte d D L C O [ %] . 
G A P S ta ge I: 0- 3 p oi nts; Sta ge II: 4- 5 p oi nts; Sta ge III: 6- 8 p oi nts. 
 
Pre dict or  
P oi nts  
G: Ge n der  
Fe male  
0  
Male  
1  
A: A ge ( ye ars) 
≤6 0  years  
0  
6 1 -6 5  years  
1  
> 6 5  years  
2  
P: F orce d Vit al C a p acit y Perce nt Pre dicte d 
( F V C p p) 
> 7 5 %  
0  
5 0 -7 5 %  
1  
< 5 0 %  
2  
P: Pre dicte d Diff usi n g C a p acit y of t he L u n g f or 
C ar b o n M o n o xi de ( D L C O p p)  
> 5 5 %  
0  
3 6 -5 5 %  
1  
≤3 5 % *  
2  
Ca n n ot perf or m  
3  
T ot al P ossi ble P oi nts  
8  
* Val ue < 3 5. 5 is r o u n de d d o w n t o 3 5; val ue > = 3 5. 5 is r o u n de d u p t o 3 6.  
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A P P E N DI X  7.  E X A M P L E S A S C O D E  
A p pe n di x 7. 1. M M R M  
Sa m ple S A S c o de f or M M R M:  
P R O C  M I X E D  D A T A = m m r m ;  
 
C L A S S  t r t p  r a n d o m i z a t i o n _ f a c t o r s  a v i s i t  s u b j i d ;  
M O D E L  c h g  =  t r t p  a v i s i t  t r t p * a v i s i t  c o v a r i a t e s  r a n d o m i z a t i o n _ f a c t o r s / D D F M = k r ;  
 
R E P E A T E D  a v i s i t / S U B J E C T = s u b j i d  T Y P E = U N  G R O U P = t r t p ;  
 
L S M E A N S  t r t p / P D I F F  C L ;  
 
L S M E A N S  t r t p * a v i s i t / P D I F F  C L ;  
R U N ;  
A p pe n di x 7. 2. J u m p -t o-C o ntr ol  
U n der t he j u m p- t o-c o ntr ol ass u m pti o n, t he a nal ysis will be carrie d o ut i n 3 ste ps.  
Ste p 1 - t he missi n g F V C  data will be i m p ute d  t o deri ve 20 0 i m p ute d datasets wit h n o n- missi n g 
data  acc or di n g t o t he j u m p-t o-c o ntr ol data p atter n . 
Sa m ple S A S c o de:  
/ * g e n e r a t e  a  m o n o t o n e  m i s s i n g  d a t a  p a t t e r n * /  
P R O C  M I  D A T A = a v a l  O U T = x x 1  S E E D = 9 9 7 8  N I M P U T E = 2 0 0  R O U N D = 0 . 0 0 1  M I N I M U M = 0 . 5  M A X I M U M = 7 ;  
 
B Y  t r t p ;  
 
V A R  b a s e  w e e k 6  w e e k 1 2  w e e k 1 8  w e e k 2 4  w e e k 3 6  w e e k 4 8 ;  
 
M C M C  C H A I N = m u l t i p l e  I M P U T E = m o n o t o n e ;  
R U N ;  
 
P R O C  S O R T  D A T A = x x 1 ;  
 
B Y  _ i m p u t a t i o n _  s u b j i d ;  
R U N ;  
 
/ * G e n e r a t e  M I  d a t a s e t s  w i t h  n o n - m i s s i n g  d a t a  v i a  a  J u m p - t o - C o n t r o l  a p p r o a c h * /  
P R O C  M I  D A T A = x x 1  S E E D = 1 4 8 2  N I M P U T E = 1  O U T = m n a r ;  
 
C L A S S  t r t p ;  
 
B Y  _ I M P U T A T I O N _ ;  
 
V A R  b a s e  w e e k 6  w e e k 1 2  w e e k 1 8  w e e k 2 4  w e e k 3 6  w e e k 4 8 ;  
M O N O T O N E  R E G  ( t r t p  b a s e  w e e k 6  w e e k 1 2  w e e k 1 8  w e e k 2 4  w e e k 3 6  w e e k 4 8 ) ;  
M N A R  m o d e l  ( w e e k 6  w e e k 1 2  w e e k 1 8  w e e k 2 4  w e e k 3 6  W e e k 4 8 /  
M O D E L O B S = ( t r t p = ' P l a c e b o ' ) ) ;  
R U N ;  
Ste p 2 - T he 2 0 0 m ulti ple -i m p utati o n datasets wit h i m p ute d a n d o bser ve d F V C data at Wee k 4 8 
will b e a nal yze d s e par atel y f or eac h i m p utati o n usi n g t he A N C O V A met h o d. T he A N C O V A 
m o del will c o ntai n ter ms f or treat me nt , b aseli ne F V C meas ure me nts, c o v ariates (a ge, s e x, race 
gr o u p, a n d hei g ht), a n d t he ra n d o mizati o n stratifi cati o n fact ors. T he  L S Mea n  a n d c orres p o n di n g 
S E f or t he c ha n g e fr o m b aseli ne i n F V C at W ee k 4 8 will be esti mate d.  
Sa m ple S A S c o de:  
P R O C  M I X E D  d a t a = m n a r ;  
 
B Y  _ i m p u t a t i o n _ ;  
 
C L A S S  t r t p  r a n d o m i z a t i o n _ f a c t o r s ;  
M O D E L  c h g _ w k 4 8  =  t r t p  b a s e  c o v a r i a t e s  r a n d o m i z a t i o n _ f a c t o r s / S O L U T I O N  D D F M = k r ;  
 
L S M E A N S  t r t p  /  P D I F F  C L ;  
 
O D S  O U T P U T  D I F F S = l s d i f f s  L S M E A N S = l s m  S O L U T I O N F = p a r m s ;  
R U N ;  
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Ste p 3 - T he S A S P R O C MI A N A L Y Z E will be use d t o deri ve t he fi nal esti mates a n d test 
statistics s u m marizi n g t hese 2 0 0 a nal ysis res ults. 
Sa m ple S A S c o de:  
P R O C  S O R T  D A T A = l s m ;  
 
B Y  t r t p ;  
R U N ;  
 
P R O C  M I A N A L Y Z E  D A T A = l s m ;  
 
B Y  t r t p ;  
 
M O D E L E F F E C T S  e s t i m a t e ;  
 
S T D E R R ;  
 
O D S  O U T P U T  P a r a m e t e r E s t i m a t e s = l s m 2 ;  
R U N ;  
 
P R O C  M I A N A L Y Z E  D A T A = l s d i f f s ;  
 
M O D E L E F F E C T S  e s t i m a t e ;  
 
S T D E R R ;  
 
O D S  O U T P U T  P a r a m e t e r E s t i m a t e s = l s d i f f s 2 ;  
R U N ;  
A p pe n di x 7. 3. Delt a -A dj usti n g ( Ti p pi n g P oi nt) A n al ysis  
T he m ulti ple i m p utati o n s f or ti p pi n g p oi nt a nal ysis will be perf or me d as f oll o ws. 
Ste p 1 - t he missi n g F V C  data will be i m p ute d  t o deri ve 20 0 i m p ute d datasets wit h n o n- missi n g 
data  acc or di n g t o t he delt a-a dj usti n g data a p pr oac h. 
Sa m ple S A S c o de:  
/ * g e n e r a t e  a  m o n o t o n e  m i s s i n g  d a t a  p a t t e r n * /  
P R O C  M I  D A T A = a v a l  O U T = x x 1  S E E D = 9 9 7 8  N I M P U T E = 2 0 0  R O U N D = 0 . 0 0 1  M I N I M U M = 0 . 5  M A X I M U M = 7 ;  
 
B Y  t r t p ;  
 
V A R  b a s e  w e e k 6  w e e k 1 2  w e e k 1 8  w e e k 2 4  w e e k 3 6  w e e k 4 8 ;  
 
M C M C  C H A I N = m u l t i p l e  I M P U T E = m o n o t o n e ;  
R U N ;  
 
P R O C  S O R T  D A T A = x x 1 ;  
 
B Y  _ i m p u t a t i o n _  s u b j i d ;  
R U N ;  
 
% l e t  s f t = - 0 . 3 ; / * D e f i n e  a  m a c r o  f o r  s h i f t  v a l u e ,  a d j u s t  t h e  v a l u e  i n  S A S  c o d e * /  
 
/ * G e n e r a t e  M I  d a t a s e t s  w i t h  n o n - m i s s i n g  v a l u e s  u s i n g  t h e  t i p p i n g  p o i n t  a p p r o a c h * /  
P R O C  M I  D A T A = x x 1  S E E D = 1 4 8 2  N I M P U T E = 1  O U T = t i p p i n g ;  
 
C L A S S  t r t p ;  
 
B Y  _ I M P U T A T I O N _ ;  
 
V A R  t r t p  b a s e  w e e k 6  w e e k 1 2  w e e k 1 8  w e e k 2 4  w e e k 3 6  w e e k 4 8 ;  
 
M O N O T O N E  R E G  ( b a s e  w e e k 6  w e e k 1 2  w e e k 1 8  w e e k 2 4  w e e k 3 6  w e e k 4 8 ) ;  
 
M N A R  A D J U S T ( w e e k 6  /  S H I F T = & s f t  A D J U S T O B S = ( t r t p = ' P a m r e v l u m a b ' ) ) ;  
 
M N A R  A D J U S T ( w e e k 1 2  /  S H I F T = & s f t  A D J U S T O B S = ( t r t p = ' P a m r e v l u m a b ' ) ) ;  
M N A R  A D J U S T ( w e e k 1 8  /  S H I F T = & s f t  A D J U S T O B S = ( t r t p = ' P a m r e v l u m a b ' ) ) ;  
 
M N A R  A D J U S T ( w e e k 2 4  /  S H I F T = & s f t  A D J U S T O B S = ( t r t p = ' P a m r e v l u m a b ' ) ) ;  
 
M N A R  A D J U S T ( w e e k 3 6  /  S H I F T = & s f t  A D J U S T O B S = ( t r t p = ' P a m r e v l u m a b ' ) ) ;  
 
M N A R  A D J U S T ( w e e k 4 8  /  S H I F T = & s f t  A D J U S T O B S = ( t r t p = ' P a m r e v l u m a b ' ) ) ;  
R U N ;  
Ste p 2 – T he 2 0 0 m ulti ple i m p utati o n datasets will b e a nal yze d se paratel y usi n g t he sa me 
A N C O V A m o del as Ste p 2 i n  A p pe n di x 7. 2 .  
Ste p 3 – Sa me as Ste p 3 i n  A p pe n di x 7. 2 . 
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A p pe n di x 7. 4. R a n k e d A N C O V A  
Sa m ple S A S c o de f or Ra n ke d A N C O V A:  
P R O C  R A N K  O U T = r a n k e d  T I E S = m e a n ;  
 
W H E R E  a v i s i t = ’ W e e k  4 8 ’ ;  
 
V A R  b a s e  c h g ; / * M i s s i n g  c h g  w a s  i m p u t e d * /  
R U N ;  
 
P R O C  M I X E D  D A T A = r a n k e d ;  
 
C L A S S  s e x  r a n d o m i z a t i o n _ f a c t o r s ;  
 
M O D E L  c h g =  b a s e  a g e  h e i g h t  r a c e  s e x  r a n d o m i z a t i o n _ f a c t o r s / O U T P = r e s i d u a l ;  
R U N ;  
 
P R O C  F R E Q  D A T A = r e s i d u a l ;  
 
T A B L E S  t r t p * r e s i d  /  N O P R I N T  C M H 2 ;  
 
O U T P U T  O U T = r a n c o v a  C M H 2 ;  
R U N ;  
 
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A P P E N DI X  8.  C HI N A C D E R E Q UI R E M E N T S 
Efficac y data, mai nl y i ncl u di n g o verseas ke y cli nical trial data a n d cli nical trial data c o n d uct e d 
i n C hi na, s h o ul d n ot o nl y c o nfir m t he efficac y of t he st u d y dr u g as a w h ol e, b ut als o a nal yze t he 
c o nsiste nc y bet wee n C hi nese s u b gr o u ps a n d t he o verall p o p ulati o n.  
T he p oi nt esti mate of treat me nt eff ect i n C hi na s u b gr o u p di vi de d b y its c o u nter part i n t he o verall 
p o p ulati o n will be use d f or assessi n g efficac y c o nsiste nc y. 
Safet y data, i ncl u di n g all d o mestic a n d f orei g n d ata use d f or s afet y e val uati o n, s h o ul d be 
a nal yze d n ot o nl y f or o verall safet y, b ut als o f or c o nsiste nc y bet wee n C hi nese s u b gr o u p a n d 
o verall p o p ulati o n. 
All T L F i n C hi na ma y be pr o vi de d per C hi na re g ulat or y re q uire m e nts if re g ulat or y s u b missi o n i n 
C hi na is p urs ue d ( N M P A g ui da nce ). 
 
C o nfi de ntial
Pa ge 5 5 of 5 5


Si g nat ure Pa ge f or V V- C LI N- 0 1 3 5 8 6 v 2. 0
Si g nat ure Pa ge f or V V- C LI N- 0 1 3 5 8 6 v 2. 0
A p pr o val Tas k
1 9- Ma y- 2 0 2 3 1 8: 4 1: 4 4 G M T + 0 0 0 0
A p pr o val Tas k
1 9- Ma y- 2 0 2 3 1 8: 5 0: 5 8 G M T + 0 0 0 0
A p pr o val Tas k
1 9- Ma y- 2 0 2 3 1 9: 0 7: 5 0 G M T + 0 0 0 0
A p pr o val Tas k
1 9- Ma y- 2 0 2 3 1 9: 1 1: 1 9 G M T + 0 0 0 0
A p pr o val Tas k
1 9- Ma y- 2 0 2 3 1 9: 5 8: 0 4 G M T + 0 0 0 0
A p pr o val Tas k
1 9- Ma y- 2 0 2 3 2 0: 4 4: 5 0 G M T + 0 0 0 0
A p pr o val Tas k
1 9- Ma y- 2 0 2 3 2 1: 0 9: 4 2 G M T + 0 0 0 0
A p pr o val Tas k
1 9- Ma y- 2 0 2 3 2 2: 0 0: 5 6 G M T + 0 0 0 0


Si g nat ure Pa ge f or V V- C LI N- 0 1 3 5 8 6 v 2. 0
Si g nat ure Pa ge f or V V- C LI N- 0 1 3 5 8 6 v 2. 0
A p pr o val Tas k
1 9- Ma y- 2 0 2 3 2 2: 5 1: 2 7 G M T + 0 0 0 0


 
 
 
Fi br o Ge n, I nc.  
C o nfi de ntial a n d Pr o prietar y  
Pa ge 1 of 1 7  
S T A TI S TI C A L A N A L Y SI S P L A N  
 
S T U D Y TI T L E:  
A P hase 3, Ra n d o mize d, D o u ble -Bli n d, Place b o -
C o ntr olle d Efficac y a n d Safet y St u d y of 
Pa mre vl u ma b i n S u bjects wit h I di o pat hic 
P ul m o nar y Fi br osis (I P F)  
P R O T O C O L N U M B E R:  
F G C L - 3 0 1 9- 0 9 1 (Z E P H Y R U S  1) 
 
 
A M E N D M E N T V E R SI O N:  
6 . 0 
 
 
 
 
 
 
 
 
 
 
S A P V E R SI O N:  
Fi nal V 1. 0  ( O L E Peri o d) 
R E L E A S E D A T E : 
2 5 Ma y 2 0 2 3  
C O N FI D E N TI A LI T Y S T A T E M E N T  
T he i nf or mati o n c o ntai ne d i n t his d oc u me nt is c o nfi de ntial a n d pr o prietar y t o Fi br o Ge n, I nc. N o 
part of t his d oc u me nt or a n y of t he i nf or mati o n c o ntai ne d herei n ma y be tra ns mitte d, discl ose d, 
s hare d, re pr o d uce d, p u blis he d, or utilize d b y a n y pers o ns wit h o ut pri or writte n a ut h orizati o n b y 
Fi br o Ge n, I nc. 


F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S 1)  
Statistical A nal ysis Pla n  
Fi nal V 1. 0  ( O L E Peri o d) 
 
Fi br o Ge n, I nc.  
C o nfi de ntial a n d Pr o prietar y  
Pa ge 2 of 1 7  
SI G N A T U R E P A G E  
A p pr o v als 
I h a ve r e vie w e d a n d acce pte d t he i nf or mati o n i n t his d oc u me nt t o be a tr ue a n d acc urate 
re pres e ntati o n of t he Statistical A nal ysis Pla n.  
* Si g nat ure: see a p p e n de d fi nal pa ge f or 2 1 C F R Part 1 1 c o m plia nt a p pr o val  
I niti at or: 
 
, Fi br o Ge n, I n c.  
Re vie we d b y:  
 
 Fi br o Ge n, I nc.  
 
, Fi br o G e n, I nc.  
 
, Fi br o G e n, I nc.  
 
, Fi br o Ge n, I nc.  
  
, Fi br o Ge n, I n c. 
 
, Fi br o Ge n, I n c.   
 
, Fi br o G e n, I n c.  
 
 Fi br o Ge n, I n c.  
Si g n at ure Si g nific a nce  
T he f oll o wi n g si g nifica n ce is le nt t o t he si g nat ures o n t he A p pr o vals pa g e of t his d oc u me nt. 
Si g n at or y 
Si g nific a nce  
I niti at or 
B y si g ni n g, t he a ut h or is attesti n g t hat t he c o nte nt of t he d oc u me nt is 
c o m plete a n d acc urate.  
Re vie wer  
B y si g ni n g, t he re vie wer is attesti n g t hat t he d oc u me nt’s a p pr oac h a n d 
c o nte nts are c o m plia nt wit h t he st u d y pr ot oc ol, all a p pr o priate, re g ulat or y 
re q uire me nts, a n d ot h er si g nifica nt g ui deli nes. T his i n di vi d ual(s) has 
re vie we d t h e d oc u me nt f or acc urac y a n d c o m plet e ness. 
 
 
 


F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S 1)  
Statistical A nal ysis Pla n  
Fi nal V 1. 0  ( O L E Peri o d) 
 
Fi br o Ge n, I nc.  
C o nfi de ntial a n d Pr o prietar y  
Pa ge 3 of 1 7  
C H A N G E HI S T O R Y  
Vers i o n 
D ate  
Descri pti o n  
1. 0  
2 5  Ma y 2 0 2 3  
F i nal A p pr o v e d Versi o n  
 
 
 
 
 
 
 
 
 
 


F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S 1)  
Statistical A nal ysis Pla n  
Fi nal V 1. 0  ( O L E Peri o d) 
 
Fi br o Ge n, I nc.  
C o nfi de ntial a n d Pr o prietar y  
Pa ge 4 of 1 7  
T A B L E O F C O N T E N T S  
S T A TI S TI C A L A N A L Y SI S P L A N  ................................................................................................ 1 
SI G N A T U R E P A G E  ....................................................................................................................... 2 
C H A N G E HI S T O R Y ....................................................................................................................... 3 
T A B L E O F C O N T E N T S  ................................................................................................................. 4 
LI S T O F T A B L E S  ........................................................................................................................... 6 
LI S T O F A B B R E VI A TI O N S  .......................................................................................................... 7 
1.  
I N T R O D U C TI O N ........................................................................................................ 9 
2.  
S T U D Y O BJ E C TI V E  ................................................................................................... 9 
3.  
S T U D Y D E SI G N ( O L E P E RI O D)  .............................................................................. 9 
3. 1.  
E nr oll me nt t o O L E Peri o d  ............................................................................................ 9 
3. 2.  
Ra n d o mizati o n .............................................................................................................. 9  
3. 3.  
St u d y Peri o ds ................................................................................................................ 9  
4.  
S T U D Y E N D P OI N T S ( O L E)  .................................................................................... 1 0 
5.  
G E N E R A L S T A TI S TI C A L C O N SI D E R A TI O N S  .................................................... 1 0 
5. 1.  
Statistica l Met h o d ol o g y .............................................................................................. 1 0 
5. 1. 1.  
A nal ysis of Cate g orical E n d p oi nts ............................................................................. 1 0  
5. 1. 2.  
A nal ysis of C o nti n u o us E n d p oi nts ............................................................................. 1 0  
5. 1. 3.  
A nal ysis of S pir o metr y Data ...................................................................................... 1 0  
5. 1. 4.  
A nal ysis of H R C T Data  .............................................................................................. 1 0 
5. 2.  
A nal ysis Set  ................................................................................................................ 1 0 
5. 2. 1.  
Safet y A nal ysis Set - O L E  .......................................................................................... 1 0 
5. 2. 2.  
I m m u n o ge nicit y A n al ysis Set -O L E (I G S -O L E)  ....................................................... 1 0 
5. 3.  
Ge ner al Data H a n dli n g R ules a n d Prese ntati o n S pecificati o ns  .................................. 1 1 
5. 3. 1.  
A nal ysis Peri o d ........................................................................................................... 1 1  
5. 3. 2.  
Baseli ne Defi niti o ns  .................................................................................................... 1 1 
5. 3. 3.  
F or m ulas ..................................................................................................................... 1 1  
5. 3. 4.  
Ge ner al I nstr ucti o ns f or Ta bles, Listi n gs, a n d Fi g ures ( T L Fs) .................................. 1 1  
5. 3. 5.  
Ha n dli n g Dr o p o uts a n d Missi n g Data ........................................................................ 1 2  
5. 4.  
I nteri m A nal ysis a n d Dat a M o nit ori n g C o m mittee .................................................... 1 2 
6.  
S T A TI S TI C A L A N A L Y SI S  ...................................................................................... 1 2 
6. 1.  
S u bject Acc o u nta bilit y a n d Dis p ositi o n ..................................................................... 1 2  


F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S 1)  
Statistical A nal ysis Pla n  
Fi nal V 1. 0  ( O L E Peri o d) 
 
Fi br o Ge n, I nc.  
C o nfi de ntial a n d Pr o prietar y  
Pa ge 5 of 1 7  
6. 2.  
Pr ot oc ol De viati o ns .................................................................................................... 1 2  
6. 3.  
De m o gra p hics ............................................................................................................. 1 2  
6. 4.  
C o nc o mita nt Me dicati o ns ........................................................................................... 1 2  
6. 5.  
Treat me nts a n d M e dicati o ns  ....................................................................................... 1 2 
6. 5. 1.  
St u d y Dr u g E x p os ure .................................................................................................. 1 2  
6. 5. 2.  
Treat me nt C o m plia nce  ................................................................................................ 1 3 
6. 6.  
Efficac y A nal ysis  ........................................................................................................ 1 3 
6. 6. 1.  
Efficac y E n d p oi nt A nal ysis a n d Esti ma n d  ................................................................. 1 3 
6. 6. 1. 1.  
Esti ma n d Strate g y  ....................................................................................................... 1 3 
6. 6. 1. 2.  
P o p ulati o n of I nter est .................................................................................................. 1 3  
6. 6. 1. 3.  
I nterc urre nt E ve nt H a n dli n g Strate g y ......................................................................... 1 3 
6. 6. 1. 4.  
A nal ysis Varia ble  ........................................................................................................ 1 3 
6. 6. 1. 5.  
P o p ulati o n S u m mar y .................................................................................................. 1 4  
6. 7.  
Safet y A nal ysis  ........................................................................................................... 1 4 
6. 7. 1.  
A d verse E v e nts ( A E)  .................................................................................................. 1 4 
6. 7. 2.  
Vital Si g ns  .................................................................................................................. 1 4 
6. 8.  
A D A ( A nti - Dr u g A nti b o d y) A nal ysis ........................................................................ 1 4 
6. 9.  
P K A nal ysi s ................................................................................................................ 1 4 
7.  
C H A N G E S F R O M P R O T O C O L  ............................................................................... 1 4 
8.  
R E F E R E N C E  ............................................................................................................. 1 4 
A p pe n di x 1.  A nal ysis Visit Wi n d o ws  ......................................................................................... 1 6 
A p pe n di x 2.  A nal ysis of Ass ociati o n bet wee n Q L F a n d O S ...................................................... 1 7  
 


F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S 1) 
Statistical A nal ysis Pla n 
Fi na l V 1. 0 ( O L E Peri o d) 
Fi br o Ge n, I nc.  
C o nfi de ntial a n d Pr o prietar y  
Pa ge 6 of 1 7  
LI S T O F T A B L E S  
Ta ble  1: 
A nal ysis Visit Wi n d o w f or Vital Si g ns  ...................................................................... 1 6 
Ta ble  2: 
A nal ysis Visit Wi n d o w f or P F T a n d Wei g ht .... ........................................................ 1 6 
Ta ble  3: 
A nal ysis Visit Wi n d o w f or H R C T ............................................................................. 1 6  


F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S 1)  
Statistical A nal ysis Pla n  
Fi nal V 1. 0  ( O L E Peri o d) 
 
Fi br o Ge n, I nc.  
C o nfi de ntial a n d Pr o prietar y  
Pa ge 7 of 1 7  
L I S T O F A B B R E VI A TI O N S 
A b bre vi ati o n  
E x pl a n ati o n  
A D A  
A nti -Dr u g A nti b o d y  
A E  
A d verse E v e nt  
A N C  
A bs ol ute Ne utr o p hil C o u nt  
A N O V A  
A nal ysis of Varia n ce  
A S T  
As partate A mi n otra nsferase  
A T C  
A nat o mical T her a pe utic Class  
A T S  
A merica n T h oraci c S ociet y  
B MI  
B o d y Mass I n d e x  
B T R  
Best -Test Re vie w  
CI  
C o nfi de nce I nter val  
C R F  
Case Re p ort F or m  
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d vers e E ve nts  
C T G F  
C o n necti ve Tiss ue Gr o wt h Fact or  
D B L  
Data base L oc k  
D L C O  
Diff usi o n ca p acit y of t he L u n gs for Car b o n M o n o xi de  
D M C  
Data M o nit ori n g C o m mittee  
E C G  
Electr ocar di o gra m  
E D C  
Electr o nic D ata Ca pt ure  
E O S  
E n d of St u d y  
E O T  
E n d of Treat me nt  
E R S  
E ur o pea n Res pir at or y S ociet y  
F V C  
F orce d Vital Ca pacit y  
F V C p p  
F orce d Vital Ca pacit y perce nta g e pre di cte d  
H A H A  
H u ma n A nti -Pa mre vl u m a b A nti b o d y  
H R C T  
Hi g h -Res ol uti o n C o m p ute d T o m o gra p h y  
I C F 
I nf or me d C o nse nt F or m 
I C H E 9 
I nter nati o nal C o nfere nce o n Har m o nizati o n Statistical Pri nci ples f or Cli nical 
Trials  
I P F 
I di o pat hic P ul m o nar y Fi br osis 
I V 
I ntr a ve n o us 
L  
Liter  
Me d D R A  
Me dical Dicti o nar y f or R e g ulat or y Acti vities  
m L  
milli liter 
O L E  
O pe n La bel E xt e nsi o n  
P C S  
P ote ntiall y Cli nicall y Si g nifica nt  
P E  
P h ysical E xa mi nati o n  
P F T  
P ul m o nar y F u ncti o n Test  
P T  
Prefer T er m  
Q 3 W  
E ver y 3 Wee ks  
Q L F  
Q ua ntitati ve L u n g Fi br osis  
S A E  
Seri o us A d verse E v e nt  
S A F  
Safet y A nal ysis Set  


F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S 1)  
Statistical A nal ysis Pla n  
Fi nal V 1. 0  ( O L E Peri o d) 
 
Fi br o Ge n, I nc.  
C o nfi de ntial a n d Pr o prietar y  
Pa ge 8 of 1 7  
A b bre vi ati o n  
E x pl a n ati o n  
S A P  
Statistical A nal ysis Pla n  
S D  
Sta n dar d De viati o n  
S E  
Sta n dar d Err or  
S O C  
S yste m Or ga n Class  
T E A E  
Treat me nt -E mer ge nt A d verse E ve nt  
T E S A E  
Treat me nt -E mer ge nt Seri o us A d verse E v e nt  
T L C  
T otal L u n g Ca pacit y V ol u me  
T L F  
Ta ble, Listi n g, a n d Fi g ure  
U L N  
U p per Li mit of N or mal, val ue pr o vi de d b y t he la b orat or y 
V E G F  
Vasc ular E n d ot helial Gr o wt h Fact or  
W H O D D  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y  
W O C B P  
W o me n Of C hil d beari n g P ote ntial  


F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S 1)  
Statistical A nal ysis Pla n  
Fi nal V 1. 0  ( O L E Peri o d) 
 
Fi br o Ge n, I nc.  
C o nfi de ntial a n d Pr o prietar y  
Pa ge 9 of 1 7  
1.  
IN T R O D U C TI O N  
T his statistical a nal ysis pla n ( S A P) is  f or t he pre -s pecifie d re p orti n g of st u d y res ults f or pr ot oc ol 
F G C L - 3 0 1 9- 0 9 1, a me n d me nt 6. 0. T his is part 2 of t he S A P, w hic h d oc u m e nts t he pla n ne d 
a nal yses f or t h e o pe n- la b el e xte nsi o n ( O L E) p eri o d. S pecificati o ns of ta bles, data listi n gs, a n d 
fi g ures ( T L F) are c ontai n e d i n a se parate d o c u me nt.  A se parat e S A P details t he statistical 
a nal yses a n d met h o ds f or t he d o u ble- bli n d peri o d of F G C L- 3 0 1 9- 0 9 1. 
I n t his d oc u me nt, o nl y ne w defi niti o ns a n d r ules will be descri be d. Cr oss -refere n ce t o t he 
d o u ble- bli n d S A P ( Part 1) will be ma de f or d efi niti o ns a n d r ules t hat will f oll o w t he  sa me 
met h o d ol o g y use d f or t he d o u ble- bli n d peri o d of t he trial.    
2.  
S T U D Y O B J E C TI V E  
T he o ver all o bjecti ve of t his P hase 3 re gistrati o n-e na bli n g st u d y is t o e val uate t he effi cac y a n d 
safet y of 3 0 m g/ k g i ntra v e n o us (I V) i nf usi o ns of pa mre vl u ma b as c o m pare d t o place b o i n 
s u bjects wit h I di o pat hic P ul m o nar y Fi br osis (I P F). T he O L E  peri o d will mai nl y f oc us o n t he 
safet y of 3 0 m g/ k g I V i nf usi o ns of pa mre vl u ma b, t h o u g h efficac y ass ess me nts  are i ncl u de d . 
3.  
S T U D Y D E SI G N ( O L E P E RI O D)  
3. 1.  
E nr oll me nt t o O L E Peri o d  
S u bjects w h o c o m plete t he Wee k 4 8 visit of t he mai n st u d y (re gar dl ess of t he n u m ber of st u d y 
dr u g i nf usi o ns recei ve d) will be eli gi ble t o partici pate i n t he o pti o nal O L E  peri o d of t he st u d y. 
T he O L E peri o d  offers c o nti n ui n g access t o pa mre vl u ma b re gar dless of ra n d o mizati o n 
assi g n me nt ( pa mre vl u ma b or place b o) i n t he d o u ble- bli n d peri o d of t he st u d y. S u bjects will be 
c o nsi dere d as ha vi n g e nt ere d t he O L E st u d y if t he y ha ve recei ve d at least o ne d ose of t he st u d y 
dr u g d uri n g t he O L E peri o d. 
3. 2.  
R a n d o miz ati o n  
Ra n d o mizati o n is n ot a p plica ble f or t he O L E peri o d. 
3. 3.  
St u d y Peri o ds  
•  O pti o nal, O L E peri o d of p a mre vl u ma b : 
− Access  t o pa mre vl u ma b will be a vaila ble u ntil t he last s u bject c o m pletes 
4 8 wee ks of tr eat me nt i n t he O L E peri o d , or p a mre vl u ma b is c o m merciall y 
a vaila ble f or t he i n dicati o n of I P F, or t he S p o ns or deci des t o e n d t he O L E peri o d, 
w hic he ver o cc urs first . 
•  F oll o w- u p peri o d/fi nal s afet y assess me nts: 
− 2 8 da ys after t h e last d ose 
− 6 0 da ys after t h e last d ose: f oll o w- u p p h o ne call, f or a fi nal safet y assess me nt 


F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S 1) 
Statistical A nal ysis Pla n 
Fi na l V 1. 0 ( O L E Peri o d) 
Fi br o Ge n, I nc.  
C o nfi de ntial a n d Pr o prietar y  
Pa ge 1 0  of 1 7  
4.
S T U D Y E N D P OI N T S  ( O L E)
T he f oll o wi n g effi cac y assess me nts will be c ollecte d o nl y as sta n dar d- of -care per eac h 
i n vesti gati o nal site’s real- w orl d practice a n d d escri pti vel y prese nte d d uri n g t he O L E peri o d: 
•
F V C ( L)
•
F V C per ce nt pr e dicte d ( F V C p p)
•
A bs ol ute F V C p p decli ne of ≥1 0 %
•
All -ca use m ortalit y
•
C ha n ge i n H R C T Q ua ntitati ve L u n g Fi br osis ( Q L F) v ol u me (if H R C T is perf or me d
as part of r o uti ne p atie nt care)
5.
G E N E R A L S T A TI S TI C A L C O N SI D E R A TI O N S
5. 1.  
St atistic al Met h o d ol o g y
All data c ollecte d will be i ncl u de d i n t he data listi n gs. All a nal yses will be perf or me d usi n g 
S A S ® Versi o n 9. 3 or hi g her. 
5. 1. 1.  
A n al ysis of C ate g oric al E n d p oi nt s 
F oll o w t he sa me g ui deli n es as descri be d i n S A P Part 1 f or t he d o u ble- bli n d peri o d. 
5. 1. 2.  
A n al ysis of C o nti n u o us E n d p oi nts  
F oll o w t he sa me g ui deli n es as descri be d i n S A P Part 1 f or t he d o u ble- bli n d peri o d. 
5. 1. 3.  
A n al ysis of S pir o m etr y  Dat a  
F oll o w t he sa me g ui deli n es as descri be d i n S A P Part 1 f or t he d o u ble- bli n d peri o d. 
5. 1. 4.  
A n al ysis of H R C T D at a  
F oll o w t he sa me g ui deli n es as descri be d i n S A P Part 1 f or t he d o u ble- bli n d peri o d. 
5. 2.  
A n al ysis Set  
5. 2. 1.  
S afet y A n al ysis Set - O L E  
T he S afet y A n al ysis Set - O L E  (S A F -O L E)  i ncl u des all s u bjects w h o ha ve recei v e d at least o ne 
st u d y me dicati o n i n t he O L E peri o d. S u bjects will be a nal yze d acc or di n g t o t he pre vi o us 
treat me nt act u all y recei ve d i n t he d o u ble- bli n d peri o d. 
All a nal ysis i n O L E will be perf or me d o n S A F -O L E  u nless ot her wise s pecifie d. 
5. 2. 2.  
I m m u n o ge nicit y A n al ysis Set - O L E  (I G S- OL E ) 
T he I G S-O L E will i ncl u de all s u bjects w h o are i n S A F -O L E, h a ve bas eli ne A D A ass ess me nt i n 
t he d o u ble- bli n d peri o d, a n d ha ve at least o ne e v al ua ble A D A ass ess me nt i n t he O L E peri o d. 


F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S 1)  
Statistical A nal ysis Pla n  
Fi nal V 1. 0  ( O L E Peri o d) 
 
Fi br o Ge n, I nc.  
C o nfi de ntial a n d Pr o prietar y  
Pa ge 1 1  of 1 7  
5. 3.  
Ge ner al  D at a H a n dli n g R ules a n d Prese nt ati o n S pecific ati o ns  
5. 3. 1.  
A n al ysis Peri o d 
T he pri mar y a n al ysis will be base d o n t he o n-st u d y peri o d w hic h is defi ne d as fr o m Da y 1 i n t he 
O L E peri o d u p t o t he e n d of t he e ntire st u d y, re gar dless of patie nts’ treat me nt stat us. 
5. 3. 2.  
B aseli ne Defi niti o n s 
Baseli ne is defi ne d as t he last assess me nt pri or t o t he first d osi n g i n t he O L E peri o d wit h 2 
e xce pti o ns bel o w: 
•  Baseli ne i n t he d o u ble- bli n d peri o d a n d O L E will be a p plie d f or assess me nts of F V C  
a n d Q L F ; a n d  
•  Baseli ne i n t he d o u ble- bli n d peri o d will be a p plie d f or assess me nts of A D A ( A nti -
Dr u g A nti b o d y). 
5. 3. 3.  
F or m ul as 
•  St u d y Da y Calc ulati o n 
− T he da y w he n a s u bject recei ves t he first d ose of st u d y dr u g i n t he O L E peri o d is 
desi g nate d as D a y 1  i n O L E. 
− St u d y da y of a n assess me nt/ pr oce d ure is calc ulate d as f oll o ws. 
 F or ass ess me nts or pr oce d ures o n Da y 1 or later, 
St u dy d ay = assess me nt/ pr oce d ure d ate – D a y 1 d ate + 1. 
 F or ass ess me nts or pr oce d ures earlier t ha n D a y 1, 
St u dy d ay = assess me nt/ pr oce d ure d ate – D a y 1 d ate. 
•  F oll o w t he sa me f or m ulas as descri be d i n S A P Part 1 f or t he d o u ble- bli n d peri o d : 
− B o d y Mass I n d e x ( B MI) 
− B o d y wei g ht, hei g ht, a n d te m perat ure  
− ( A bs ol ute) C ha n ge fr o m Baseli ne 
− Relati ve c ha n ge fr o m bas eli ne ( %)  
5. 3. 4.  
Ge ner al I nstr ucti o ns f or T a bles, Listi n gs, a n d Fi g ures ( T L Fs) 
T he T L Fs will f oll o w t he sa me g ui deli nes as des cri be d i n S A P Part 1 f or t he d o u ble- bli n d peri o d. 
S u m mar y ta bles will be prese nte d f or eac h pre vi o us act ual treat me nt gr o u p i n t he d o u ble- bli n d 
peri o d a n d all s u bjects p o ole d i n t he O L E peri o d. 
Efficac y a n d safet y data will be s u m marize d descri pti vel y f or s u bjects w h o e ntere d  t he O L E. N o 
f or mal statistical i nfere n ce will be perf or me d. 


F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S 1)  
Statistical A nal ysis Pla n  
Fi nal V 1. 0  ( O L E Peri o d) 
 
Fi br o Ge n, I nc.  
C o nfi de ntial a n d Pr o prietar y  
Pa ge 1 2  of 1 7  
5. 3. 5.  
H a n dli n g Dr o p o uts a n d Missi n g D at a 
F or ha n dli n g dr o p o uts a n d missi n g data , the sa me g ui deli nes  will be f oll o we d  as descri be d i n 
S A P f or t he d o u ble- bli n d peri o d. N o i m p utati o ns will be perf or me d missi n g val ues o n p ost- deat h 
a nal ysis visits. 
5. 4.  
I nteri m A n al ysis  a n d D at a M o nit ori n g C o m mittee  
I n a d diti o n t o r o uti ne saf et y m o nit ori n g, a n i n de pe n de nt Data M o nit ori n g C o m mittee ( D M C) 
was  esta blis he d t o re vi e w safet y dat a o n a n o n g oi n g basis. A D M C c harter will esta blis h t he 
pr oce d ur es, meeti n g fr e q ue nc y, a n d s c o pe of res p o nsi bilities of t he c o m mittee.  
T h is st u d y has n o pla n ne d or pre-s p ecifie d i nteri m a nal ysis f or eit her effi cac y or f utilit y. 
6.  
S T A TI S TI C A L A N A L Y SI S  
6. 1.  
S u bject Acc o u nt a bilit y a n d Dis p ositi o n  
T he n u m ber ( %) of s u bjects w h o e nter e d t he O L E peri o d , disc o nti n u e d pre mat ure l y fr o m 
treat me nt, disc o nti n ue d pre mat ure l y fr o m st u d y, a n d reas o ns f or pre mat ure disc o nti n uati o n will 
be prese nt e d f or eac h pre vi o us treatme nt gr o u p i n t he d o u ble- bli n d peri o d a n d all s u bjects 
p o ole d. 
E nr oll me nt will als o be s u m marize d b y st u d y site. 
6. 2.  
Pr ot oc ol De vi ati o ns  
T he n u m ber a n d p erce nta ge of s u bjects wit h i m p orta nt pr ot oc ol de viati o ns will be cate g orize d 
a n d ta b ulate d as a p pr o pri ate. C O VI D- 1 9 relat e d i m p orta nt pr ot oc ol de viati o ns w ill be 
s u m marize d i n a se p arat e ta ble. All pr ot oc ol de viati o ns will be fi nalize d pri or t o t he O L E 
data base l oc k.  
6. 3.  
De m o gr a p hics  
De m o gra p hic s u m mari es will f oll o w t he sa me g ui deli nes as descri be d i n S A P f or t he d o u ble-
bli n d peri o d. 
6. 4.  
C o nc o mit a nt Me dic ati o ns  
C o nc o mita nt me dicati o n  s u m maries will foll o w t he sa me g ui deli nes as d escri be d i n S A P f or t he 
d o u ble- bli n d peri o d. 
6. 5.  
Tre at me nts a n d Me dic ati o ns  
6. 5. 1.  
St u d y Dr u g E x p os ure  
St u d y treat me nt will be s u m marize d f or t h e O L E peri o d  f or S AF- O L E.  
•  D urati o n of e x p os ur e i n t he O L E peri o d = date last n o n -zer o d os e i n t he O L E peri o d - 
date of t he first d ose i n t h e O L E peri o d + 1.  


F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S 1)  
Statistical A nal ysis Pla n  
Fi nal V 1. 0  ( O L E Peri o d) 
 
Fi br o Ge n, I nc.  
C o nfi de ntial a n d Pr o prietar y  
Pa ge 1 3  of 1 7  
D urati o n of st u d y treat m e nt i n t he O L E peri o d will be s u m marize d as a c o nti n u o us varia ble a n d 
be ta b ulate d b y t he cate g ories as f oll o ws:  
•  < 1 2 wee ks  
•  1 2 t o < 2 4 wee ks 
•  2 4 t o < 4 8 wee ks 
•  4 8 t o < 7 2 wee ks 
•  7 2 t o < 9 6 wee ks 
•  > = 9 6 Wee ks  
N u m ber of i nf usi o ns is defi ne d as t he n u m b er of n o n-zer o d os e i nf usi o ns. 
T he f oll o wi n g d ose a d mi nistrati o n para meters: 
•  T otal n u m ber of i nf usi o ns i n t he O L E peri o d ( 1- 4, 5- 8, 9- 1 6, 1 7- 2 4, 2 5- 3 2, ≥3 3) 
•  O verall a v era g e i nf usi o n d oses (i n m g/ k g) i n t he O L E peri o d 
•  W het her i nf usi o n w as i nterr u pte d a n d reas o n f or i nterr u pti o n i n t he O L E p eri o d 
6. 5. 2.  
Tre at m e nt C o m pli a nce  
F oll o w t he sa me g ui deli n es as descri be d i n S A P Part 1 f or t he d o u ble- bli n d peri o d. 
6. 6.  
Effic ac y A n al ysis  
A ll a nal yses f or efficac y e n d p oi nts will be perf or me d f or t he S A F -O L E  d uri n g t he o n-st u d y 
peri o d u nless n ote d ot her wise. 
6. 6. 1.  
Effic ac y E n d p oi nt  A n al ysis a n d Esti m a n d 
6. 6. 1. 1.  
Esti m a n d Str ate g y  
T he pri mar y esti ma n d is i nte n de d t o pr o vi de a p o p ulati o n-level assess me nt  of t he pa mre vl u ma b 
o n a c o nti n u o us e n d p oi nt, re gar dl ess of partici p a nt c o m plia nce wit h t he I P d osi n g. 
6. 6. 1. 2.  
P o p ul ati o n of I nterest  
All s u bjects i n S A F -O L E.  
6. 6. 1. 3.  
I nterc urre nt E ve nt H a n dli n g Str ate g y  
Treat me nt p olic y strate g y will be use d f or a n y i nt erc urre nt e v e nt. N o i m p utati o n o n missi n g data. 
6. 6. 1. 4.  
A n al ysis V ari a ble 
F oll o w t he g ui deli nes i n S A P f or t he d o u ble- bli n d peri o d. 


F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S 1)  
Statistical A nal ysis Pla n  
Fi nal V 1. 0  ( O L E Peri o d) 
 
Fi br o Ge n, I nc.  
C o nfi de ntial a n d Pr o prietar y  
Pa ge 1 4  of 1 7  
6. 6. 1. 5.  
P o p ul ati o n S u m m ar y  
Efficac y par a meters, i ncl u di n g c ha n ge fr o m baseli ne i n F V C ( L), F V C p p, a n d H R C T fi br osis 
sc ore will be  s u m marize d descri pti vel y at eac h sc he d ule d visit as defi ne d i n  A p pe n di x 1 . 
A d diti o nal e x pl orat or y a nal ysis o n t he ass ociati o n bet wee n Q L F a n d o verall s ur vi val ( O S) is 
descri be d i n A p p e n di x 2 . 
6. 7.  
S afet y A n al ysis  
T he safet y a nal yses will be perf or me d f or  t h e S A F -O L E  i n t he O L E peri o d. 
6. 7. 1.  
A d verse E ve nts  ( A E) 
F oll o w t he sa me g ui deli n es as descri be d i n S A P Part 1 f or t he d o u ble- bli n d peri o d. 
6. 7. 2.  
Vi t al Si g ns 
F oll o w t he sa me g ui deli n es as descri be d i n S A P Part 1 f or t he d o u ble- bli n d peri o d. T he a n al ysis 
visit wi n d o w is defi ne d i n A p pe n di x 1 . 
6. 8.  
A D A ( A nti -Dr u g A nti b o d y)  A n al ysis  
A D A anal ys es f oll o w t he sa me g ui deli nes as des cri be d i n S A P Part 1 f or t he d o u ble- bli n d peri o d. 
C o nsi deri n g A D A assess me nt was c ollecte d o nl y o n 2 8 da ys after last d ose i n t he O L E peri o d, 
A D A i nci de nce will be s u m marize d  on I G S -O L E  ( N o pre v ale nce b y visit will be perf or me d). A 
listi n g w it h details will be pr o vi de d f or S A F-O L E . 
N o s u b gr o u p a nal ysis will be perf or m e d b y A D A stat us. 
6. 9.  
P K A n al ysis  
N ot a p plica ble f or t he O L E peri o d. 
7.  
C H A N G E S F R O M P R O T O C O L  
Res pirat or y h os pitalizati o n a n d ac ute I P F e x acer b ati o n e n d p oi nts ha ve bee n re m o ve d i n t his 
0 9 1 O L E S A P, as a dj u dicati o n of t hese e ve nts was o nl y perf or me d f or t he d o u ble- bli n d peri o d of 
t he st u d y. 
8.  
R E F E R E N C E  
•  E 9( R 1) Statistical Pri nci ples f or Cli nical Trials: A d de n d u m: Esti ma n ds a n d 
Se nsiti vit y A nal ysis i n Cli nical Trials  
•  J o nes P W, F or d e, Y., St Ge or ge’s Re s pirat or y Q u esti o n naire Ma n ual. 
htt p:// w w w. healt hstat us.s g ul.ac. u k/ S G R Q _ d o w nl oa d/ S G R Q % 2 0 Ma n ual % 2 0J u ne % 2
0 2 0 0 9. p df . Accesse d J u n e 2,  2 0 2 0 


F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S 1)  
Statistical A nal ysis Pla n  
Fi nal V 1. 0  ( O L E Peri o d) 
 
Fi br o Ge n, I nc.  
C o nfi de ntial a n d Pr o prietar y  
Pa ge 1 5  of 1 7  
•  Ric hel di L, d u B ois R M, Ra g h u G, et al. Effi cac y a n d safet y of ni nte da ni b i n 
i di o pat hic p ul m o nar y fi br osis. N E n gl J Me d 2 0 1 4; 3 7 0: 2 0 7 1- 8 2. 
•  N o ble P W , Al ber a C, Bra df or d W Z, C osta b el  U, etc.; Pirfe ni d o ne i n patie nts wit h 
i di o pat hic p ul m o nar y fi br osis ( C A P A CI T Y): t w o ra n d o mise d trials; La ncet 2 0 1 1; 
3 7 7: 1 7 6 0 – 6 9 
•  S tatistical Re vie w a n d  E val uati o n f or Ofe v ® ( ni nte da ni b) 1 5 0 m g ca ps ules; 
I n dicati o n: Treat me nt of I di o pat hic P ul m o nar y Fi br osis (I P F); P D U F A: Ja n uar y 2, 
2 0 1 5 
•  Ki n g T E Jr., Bra df or d W Z, Castr o- Ber nar di ni S, etc.; A P hase 3 Trial of Pirfe ni d o ne 
i n Patie nts wit h I di o pat hic P ul m o nar y Fi br osis; N E n gl J Me d 2 0 1 4; 3 7 0: 2 0 8 3- 9 2.  
•  Ra g h u G., et.al. Dia g n osis of I di o pat hic P ul m o nar y Fi br osis. A n Official A T S/ E R S/ 
J R S/ A L A T Cli nical Practice G ui deli ne. A m J Res pir Crit Care Me d 2 0 1 8 Se p 
1; 1 9 8( 5):e 4 4-e 6 8.  
 
 


F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S 1)  
Statistical A nal ysis Pla n  
Fi nal V 1. 0  ( O L E Peri o d) 
 
Fi br o Ge n, I nc.  
C o nfi de ntial a n d Pr o prietar y  
Pa ge 1 6  of 1 7  
A P P E N DI X  1.  A N A L Y SI S VI SI T WI N D O W S  
A nal ysis visits are defi ne d b y t he wi n d o ws t hat will ha ve t he wi dt hs of t he c orres p o n di n g 
assess me nts  ce ntere d at t he sc he d ule d ti me.  U ns c he d ule d visits wit hi n a visit wi n d o w defi ne d 
bel o w will be gr o u pe d i nt o t he cl osest sc he d ule d visits base d o n t he visit date. 
T a ble 1: 
A n al ysis Visit Wi n d o w f or Vit al Si g ns   
A n al ysis Visit  
T ar get D a y  i n O L E 
St art D a y  
E n d D a y  
Baseli ne   
See Secti o n  5. 3. 2   
E X -Da y 1 (p ost d ose ) [ #] 
1  
1  
1  
E X -Wee k 3 ( pr e d ose a n d p ost d ose)  
2 2  
2  
3 2  
E X -Wee k 3 * n  ( pr e d ose a n d p ost d ose) 
2 1 * n + 1  
2 1 * n -9  
2 1 * n + 1 1  
E X -2 8 Da ys p ost last d os e  [ @] 
 
 
* *  
* * E n d of t he O L E peri o d  
[ $] n is 2, 3, 4, etc. 
[ @] Sa me as visit c ollecte d o n C R F. 
 
T a ble 2:  
A n al ysis Visit Wi n d o w f or P F T a n d Wei g ht [ #] 
A n al ysis Visit  
T ar get D a y  
St art D a y  
E n d D a y  
Baseli ne   
See Secti o n  5. 3. 2  
E X -Wee k 2 4  
1 6 9  
2  
2 5 3  
E X -Wee k 2 4 * n  [ $] 
2 4 * n + 1  
2 4 * 7 * n -8 2  
2 4 * 7 * n + 8 5  
[ $] n is 2, 3, 4, etc. 
N ote: T he ti mi n g of P F T is de pe n de nt o n l ocal sc he d ules. 
[ #] Wei g ht baseli nes  f oll o w t he sa me r ules as vital si g ns. 
 
T a ble 3: 
A n al ysis Visit Wi n d o w f or H R C T  
A n al ysis Visit  
T ar get D a y  
St art D a y  
E n d D a y  
Baseli ne  
See Secti o n  5. 3. 2  
E X -Wee k 2 4  
1 6 9  
2  
2 5 3  
E X -Wee k 2 4 * n [ $]  
2 4 * n + 1  
2 4 * 7 * n -8 2  
2 4 * 7 * n + 8 5  
E X -2 8 da ys P ost last d ose  [ @] 
 
 
* *  
* * E n d of O L E peri o d  
[ $] n is 2, 3, 4, etc.  
[ @] Sa me as visit c ollecte d o n C R F. 
N ote: T he t i mi n g of H R C T is de pe n de nt o n l ocal sc he d ules. 
 


F G C L -3 0 1 9 -0 9 1 ( Z E P H Y R U S 1)  
Statistical A nal ysis Pla n  
Fi nal V 1. 0  ( O L E Peri o d) 
 
Fi br o Ge n, I nc.  
C o nfi de ntial a n d Pr o prietar y  
Pa ge 1 7  of 1 7  
A P P E N DI X  2.  A N A L Y SI S O F A S S O CI A TI O N B E T W E E N Q L F A N D O S  
C o x pr o p orti o nal hazar d ( P H) a nal yses o n t he ass ociati o n bet wee n Q L F a n d o verall s ur vi val 
( O S) will be perf or me d f or t he I T T p o p ulati o n i ncl u di n g b ot h mai n st u d y c o h ort ( d o u ble- bli n d 
a n d O L E peri o ds) a n d Ja pa n e xte nsi o n c o h ort. T h e hazar d rati o a n d its c or res p o n di n g 9 5 % CI 
bet wee n Q L F T est Gr o u p vs Q L F Ref ere n ce Gr o u p. A stratifie d l o g -ra n k t est stratifie d b y E D C 
ra n d o mizati o n stratificati o n fact ors will be use d f or treat me nt c o m paris o n. 
N o i m p utati o n will be perf or me d o n missi n g data. O n- treat me nt a nal ysis will be o pti o nal.  
•  Q L F as a pre di ct or:  
1.  T o i n vesti gate w het her b aseli ne Q L F is a si g nifica nt pre dict or of m ortalit y, a C o x P H 
m o del will i ncl u de E D C G A P sta ge (I/ II/III), a n d pri or I P F treat me nt ( Yes/ N o) as 
c o variates, b aseli ne Q L F % (c ut off s u c h as 1 5 %, 2 0 %, 2 5 % , etc.) as t he pre dict or 
varia ble.  
2.  Si milar a nal ysis o n baseli ne Q L F v ol u me ( ml) will be perf or m e d as i n 1), usi n g baseli ne 
Q L F v ol u me ( ml) ( c ut off s uc h as 3 0 0 ml, 4 0 0 ml, 5 0 0 ml , etc.) as t he pre dict or varia ble. 
3.  I n a d diti o n, t he C o x P H m o del i ncl u di n g E D C G A P sta ge (I/II/III), a n d pri or I P F 
treat me nt ( Y es/ N o) as c o variates, bas eli ne Q L F % or Q L F v ol u me ( ml) (as a c o nti n u o us 
varia ble) as t he pr e dict or varia ble, will be perf or m e d. 
•  C ha n ge fr o m bas eli ne i n Q L F at Wee k 2 4 as a pre dict or 
4.  I n a d diti o n, t o i n vesti gate t he ass ociati o n bet wee n c ha n ge fr o m baseli ne i n Q L F % 
( baseli ne t o Wee k 2 4) a n d O S, t he C o x P H m o del will i ncl u de E D C G A P sta ge (I/II/III), 
pri or I P F treat me nt ( Yes/ N o), a n d bas eli ne Q L F % (as a c o nti n u o us varia ble) as 
c o variates, a n d cate g or y i n c ha n ge fr o m baseli ne i n Q L F % (e. g., ≥2 % vs < 2 % , etc.) as 
t he pre dict or v aria ble. 
5.  Si milar a nal ysis o n Q L F v ol u me ( ml) c ha n ge fr o m baseli ne will be perf or me d as i n 4) 
wit h baseli ne Q L F % re pl ace d wit h bas eli ne Q L F v ol u me as a c o nti n u o us c o variate, a n d 
c ha n ge fr o m baseli ne i n Q L F v ol u me ( ml) as t h e pre dict or varia ble wit h a c ut off (e. g., 
≥4 0 m L vs < 4 0 m L , etc.) will be perf or me d. 
 


Si g nat ure Pa ge f or V V- C LI N- 0 1 3 7 2 8 v 1. 0
Si g nat ure Pa ge f or V V- C LI N- 0 1 3 7 2 8 v 1. 0
A p pr o val Tas k
0 8-J u n- 2 0 2 3 0 1: 1 8: 1 4 G M T + 0 0 0 0
A p pr o val Tas k
0 8-J u n- 2 0 2 3 0 1: 1 9: 1 7 G M T + 0 0 0 0
A p pr o val Tas k
0 8-J u n- 2 0 2 3 1 6: 5 0: 0 7 G M T + 0 0 0 0
A p pr o val Tas k
0 8-J u n- 2 0 2 3 1 9: 4 4: 1 0 G M T + 0 0 0 0
A p pr o val Tas k
0 8-J u n- 2 0 2 3 2 0: 1 3: 4 2 G M T + 0 0 0 0
A p pr o val Tas k
0 8-J u n- 2 0 2 3 2 1: 0 0: 0 5 G M T + 0 0 0 0
A p pr o val Tas k
0 8-J u n- 2 0 2 3 2 1: 4 6: 5 4 G M T + 0 0 0 0
A p pr o val Tas k
0 8-J u n- 2 0 2 3 2 2: 0 4: 5 1 G M T + 0 0 0 0


Si g nat ure Pa ge f or V V- C LI N- 0 1 3 7 2 8 v 1. 0
Si g nat ure Pa ge f or V V- C LI N- 0 1 3 7 2 8 v 1. 0
A p pr o val Tas k
0 8-J u n- 2 0 2 3 2 2: 1 1: 2 6 G M T + 0 0 0 0