Clinical trial NCT01890265
Conditions: Idiopathic Pulmonary Fibrosis
Keywords: Idiopathic Pulmonary Fibrosis IPF Idiopathic Interstitial Pneumonia Interstitial Lung Disease Lung Fibrosis
Sponsor: FibroGen
Start date: 2013-07-30; Completion date: 2017-11-16
Enrollment: 160 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the safety and tolerability of pamrevlumab in participants with IPF, and the efficacy of pamrevlumab in slowing the loss of forced vital capacity (FVC) and the progression of IPF in these participants.

Detailed description:
The study has been amended in February 2016 to further allow for the enrollment of a subgroup of participants (N=60) who will be allowed to receive treatment with approved IPF therapy with pirfenidone or with nintedanib as concomitant therapy.

These additional participants will be stratified by background therapy, randomized to pamrevlumab or placebo, and followed up for 24 weeks. The main objective of the study remains safety. Pharmacokinetic (PK) samples to assess drug concentrations will also be collected.

This sub-study portion only applies to a select United States centers.

Enrollment for the main study was completed on 29 June 2016. Enrollment for the sub-study was completed on 16 December 2016.

Arms: arm 1: Participants will receive pamrevlumab 30 milligram/kilogram (mg/kg) by intravenous (IV) infusion every 3 weeks for a total of 16 infusions over 45 weeks. arm 2: Participants will receive placebo matching pamrevlumab by IV infusion every 3 weeks for a total of 16 infusions over 45 weeks. arm 3: Participants will receive pamrevlumab by IV infusion every 3 weeks for a total of 8 infusions over 21 weeks. Initial treatment with pamrevlumab in all active comparator participants will be administered at a dose of 15 mg/kg for the first 2 dose administrations. If these are well tolerated, all following study drug administrations will be at 30 mg/kg.

Pirfenidone or nintedanib will be dosed according to the instructions in their respective labels and the prescribing physician. arm 4: Participants will receive placebo matching pamrevlumab by IV infusion every 3 weeks for a total of 8 infusions over 21 weeks. Initial treatment with placebo in all active comparator participants will be administered at a dose of 15 mg/kg for the first 2 dose administrations. If these are well tolerated, all following study drug administrations will be at 30 mg/kg.

Pirfenidone or nintedanib will be dosed according to the instructions in their respective labels and the prescribing physician.
Interventions: intervention 1: Pamrevlumab intervention 2: Placebo intervention 3: Sub-Study: Pirfenidone intervention 4: Sub-Study: Nintedanib
Intervention descriptions: intervention 1: Solution for infusion intervention 2: Solution for infusion intervention 3: Pirfenidone concomitant therapy will not be provided by the Sponsor. intervention 4: Nintedanib concomitant therapy will not be provided by the Sponsor.

Protocol documents:
SAP_002.pdf: 
STATISTICAL ANALYSIS PLAN 
STUDY TITLE: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Safety and Efficacy of FG-3019 in 
Patients with Idiopathic Pulmonary Fibrosis 
PROTOCOL NUMBER: 
Protocol FGCL-3019-067, Amendment 5.0 
SPONSOR: 
FibroGen, Inc. 
409 Illinois Street 
San Francisco, California  94158 USA 
Version 
Part 2 (Treatment Extension)   Final 
Release Date: 
March 14, 2018 
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 #: NCT01890265


 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Approvals 
I have reviewed and accepted the information in this document to be a true and accurate 
representation of the Statistical Analysis Plan for analysis of extension data for Study FGCL-
3019-067 (Part 2), Extended Treatment Period. 
Initiator: 
Signature:  
Date: 
 
 
  
Project Statistician, 
 
FibroGen, Inc. 
 
 
Reviewed by: 
Signature:  
Date: 
 
 
 
  
FibroGen, Inc. 
 
 
 
Signature: 
 
Date: 
 
 
   
 
FibroGen, Inc. 
 
 
Signature:  
Date: 
 
 
 
  
FibroGen, Inc. 
 
 
Signature Significance 
The following significance is lent to the signatures on the Approvals page of this document. 
Signatory 
Significance 
Initiator 
By signing, the author is attesting that the content of the 
document is complete and accurate. 
Reviewer 
By signing, the reviewer is attesting that the document’s 
approach and contents are compliant with the study 
protocol, all appropriate, regulatory requirements, and 
other significant guidelines. This individual(s) has 
reviewed the document for accuracy and completeness. 


 
 
Table of Contents 
1 
INTRODUCTION ...................................................................................................... 6 
2 
Study Design (Extended Treatment Period) ............................................................... 7 
2.1 
Enrollment to Extended Treatment ..................................................................... 7 
2.2 
Assessments in Extended Treatment Period ....................................................... 7 
3 
Study Endpoints and Definitions (Extended Treatment Period) ................................. 9 
3.1 
Study Endpoints .................................................................................................. 9 
3.2 
Definitions of Endpoints in Extended Treatment Period .................................... 9 
3.2.1 Efficacy Endpoints .......................................................................................... 9 
3.2.2 Study Drug Exposure and Treatment Compliance ......................................... 9 
3.2.3 Adverse Events ............................................................................................... 9 
3.2.4 Patient-Exposure-Years ................................................................................ 10 
3.2.5 TEAE and Mortality ..................................................................................... 11 
4 
General Statistical Considerations ............................................................................ 12 
4.1 
Analysis Populations ......................................................................................... 12 
4.2 
Handling Dropouts and Missing Data............................................................... 12 
4.3 
Definition of Baseline ....................................................................................... 12 
4.4 
Efficacy Analysis Visit Window ...................................................................... 12 
4.5 
General Layout.................................................................................................. 12 
5 
Statistical Analyses ................................................................................................... 13 
5.1 
Subject Disposition ........................................................................................... 13 
5.2 
Protocol Deviations ........................................................................................... 13 
5.3 
Demographic and Baseline Characteristics ...................................................... 13 
5.4 
Summary of Prior and Concomitant Medications ............................................ 13 
5.5 
Summary of Study Drug Exposure and Treatment Compliance ...................... 13 
5.6 
Summary of the Efficacy Data in the Extension Period ................................... 13 
5.7 
Summary of Safety Data in the Extension Period and Overall Study .............. 13 
5.7.1 Summary of Treatment Emergent Adverse Events and Mortality ................ 13 
5.7.2 Summary of Other Safety Data ..................................................................... 13 
6 
Changes from the Protocol........................................................................................ 14 
Appendix. General Specifications for Submission Data................................................... 15 
1. Study Data Tabulation Model (SDTM) .................................................................... 15 


 
 
2 Analysis Data Model (ADaM) ................................................................................... 18 
 


 
 
List of Abbreviations 
ADaM 
Analysis Data Model 
AE 
Adverse event 
CM 
Concomitant medication 
CTGF 
Connective tissue growth factor 
ECG 
Electrocardiogram 
EOS 
End of study 
EOT 
End of treatment 
EX 
Extension 
FG-3019 
FibroGen-3019 (recombinant human monoclonal antibody) 
FVC 
Forced vital capacity 
FVC (L) 
FVC in litre 
FVCpp 
FVC % predicted 
HAHA 
Human anti-human antibody 
HRCT 
High resolution computed tomography 
HRQoL 
health-related quality of life 
ICF 
Informed consent form 
IPF 
Idiopathic pulmonary fibrosis 
PEY 
Patient exposure years 
PK 
Pharmacokinetic 
PRO 
Patient reported outcome 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SGRQ 
Saint Georges Respiratory Questionnaire 
SDTM 
Study Data Tabulation Model 
TEAE 
Treatment emergent adverse event 


 
 
1 
INTRODUCTION 
The planned analyses for the Randomized Treatment Period are documented in Part 1 of the 
Statistical Analysis Plan (SAP) for study FGCL-3019-067: A Phase 2, Randomized, Double-
Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of FG 3019 in Patients 
with Idiopathic Pulmonary Fibrosis. This is the part 2 of the SAP, which documents the 
planned analyses for the Extended Treatment Period. This document is based on the protocol 
Amendment 5.0 dated 12DEC2016.  
In this document, only new definitions and rules will be described; the same defintions and 
rules described in the Part 1 of the SAP will not be repeated. 


 
 
2 
STUDY DESIGN (EXTENDED TREATMENT PERIOD) 
2.1 
Enrollment to Extended Treatment  
Subjects Enrolled under the Original Protocol and Randomized to FG-3019 
All subjects in Arm A whose FVC percent predicted value shows less than 3% absolute decrease 
from baseline in the Randomized Treatment Period will be offered participation in an Extended 
Treatment Period. These subjects may continue treatment until FVC percent predicted decreases 
3% or more on two consecutive scheduled evaluations compared to the original pre-treatment 
baseline. 
Subjects Enrolled Under Protocol Amendments and Randomized to FG-3019 
All subjects in Arm A whose FVC percent predicted value is greater than the original pre-
treatment baseline in the Randomized Treatment Period will be offered participation in an 
Extended Treatment Period and may continue treatment until FVC percent predicted is equal to 
or less than the pre-treatment baseline on two consecutive scheduled evaluations. 
Subjects Randomized to Placebo 
All subjects randomized to Placebo (Arm B) will be offered participation in the Extended 
Treatment Phase for 45 weeks. Placebo subjects in the extension study are treated identically to 
subjects randomized to FG-3019 in Amendment 1, except for the fact that the baseline for these 
patients is the time at which they are enrolled into the extension phase (Baseline for Placebo 
subjects is Week 48 value). Change in FVC percent predicted during the extended treatment 
phase will be compared to this new baseline. Those subjects whose FVC percent predicted value  
is either equal to or greater than the new baseline may continue treatment with FG-3019 until 
FVC percent predicted is equal to or less than the baseline on two consecutive scheduled 
evaluations.  
Subjects in Substudy 
Subjects in substudy are not eligible to enroll into the extended treatment. 
2.2 
Assessments in Extended Treatment Period 
• FVC and FEV1 are assessed at 12-week intervals.  
• HRCT scan of the chest is performed at 24-week interval during extension period.  
• SGRQ questionnaire is administered at 12-week intervals.   
• Electrocardiogram (ECG) is assessed at 24-week intervals.   
• Laboratory samples for safety assessments are collected at 6-week intervals. 
• Serum and plasma samples for biomarker tests (including CTGF) are collected at 24-
week intervals. 
• Plasma samples for assessing HAHA are collected prior to dosing on Day 1 of Extension 
Period and at the End of Study (EOS) safety follow-up.  
• Adverse events, concomitant medications, procedures, non-drug therapies, oxygen use 
are collected from signing ICF through End of Study (EOS).  


 
 
• Vital signs are measured at every clinical visit. On dosing days, vital signs are measured 
at pre-, intra-, and post-infusion. 
• Physical examination is performed at 6-week intervals.   


 
 
3 
STUDY ENDPOINTS AND DEFINITIONS (EXTENDED TREATMENT PERIOD) 
3.1 
Study Endpoints 
• Change from baseline in FVC (L) and FVC (% predicted) at each assessed time point  
• Change from baseline in fibrosis score by quantitative HRCT at each assessed time point  
• Change from baseline in HRQoL at each assessed time point. 
3.2 
Definitions of Endpoints in Extended Treatment Period 
3.2.1 Efficacy Endpoints 
For subjects who were originally randomized to FG-3019, efficacy endpoints are defined as 
change from the original baseline at study entry. These summaries will enable evaluation of 
long-term effect. 
For subjects who were originally randomized to placebo and rolled over to active in extension, 
efficacy endpoints are defined as change from baseline as defined as the final assessment during 
the Randomized Treatment Period. These summaries will enable separate evaluation of effect of 
active treatment from placebo.  
3.2.2 Study Drug Exposure and Treatment Compliance 
Duration of year 1 exposure = date of last non-zero dose in year 1– date of first dose + 1.  
Duration of extended treatment exposure = date last non-zero dose in extension – date of first 
dose in extension + 1. 
Duration of entire study treatment exposure = date last non-zero dose in study – date of first dose 
in study + 1. 
Number of infusions is defined as the number of non-zero dose infusions. 
Compliance in each treatment year = (# of actual doses administered)/ (# of expected doses) * 
100, where # of expected doses = (last dosing week)/3 + 1. All components in the formula are 
winthin each treatment year from Day 1 – EX year k to Weeks 45 or EOT in year k. 
Overall compliance in entire study = (sum of # of actual doses administered in each treatment 
year)/ (sum of # of expected doses in each treatment year) * 100. 
3.2.3 Adverse Events 
In this SAP Part 2, treatment emergent AE (TEAE) will be defined for (a) the entire study, (b) 
the Randomized Treatment Period, and (c) the Extended Treatment Period.  
TEAE in the Entire Study (TEAE)  
TEAEs in the study are defined as new or worsening AEs that occurred in the window of first 
infusion and within 28 days of the last infusion of study drug, regardless of large gaps of 
treatment interruption. 
TEAE in the Randomized Treatment Period (TEAE-R)  
TEAEs during the randomized treatment period are defined as new or worsening AEs that 
occurred in the window of first dose of infusion of the blinded study drug (FG-3019 or placebo) 


 
 
(Day 1) and within 28 days of the last infusion of FG-3019/placebo or before the first FG-3019 
infusion in the extended treatment period, whichever occurs first. 
TEAE in the Extended Treatment Period (TEAE-EX)  
TEAEs-EX are defined as new or worsening AEs that occurred in the window of first infusion in 
Extension and within 28 days of the last infusion in Extension.  
Below is an example of the three definitions of TEAE for multiple records of the same AE. 
 
3.2.4 Patient-Exposure-Years 
Patient-Exposure-Years (PEY) is defined as the sum of all subjects’ duration of follow-up in 
years, on FG-3019 or placebo respectively, for the entire study. A subject’s duration of follow-up 
is defined as time from the first dose to the last follow-up recorded in the database. For those 
AE # 
Period 
Onset 
AE 
Severity 
Serious
-ness 
Related to 
study drug? 
TEAE 
TEAE-R TEAE-EX 
1 
Year 1 
Screening 
Headache 
2 
N 
N 
N 
N 
N 
2 
Year 1 
Day 2 
Headache 
1 
N 
N 
N 
N 
N 
3 
Year 1 
Last Year 1 
dose 
Headache 
2 
N 
Y 
N 
N 
N 
4 
Year 1 
10 days post 
last dose 
Headache 
3 
Y 
N 
Y 
Y 
N 
5 
Year 1 
45 days post 
last dose 
Headache 
4 
Y 
N 
Y 
Y 
N 
6 
EX 
Day 2-EX 
Headache 
2 
N 
Y 
N 
N 
N 
7 
EX-2 
Day  10 EX-
2 
Headache 
1 
N 
N 
N 
N 
N 
Consoli-
dated for 
Entire 
study 
summary 
 
 
Headache 
4 
Y 
Y 
Y 
 
 
Consoli-
dated for 
Year 1 
summary 
 
 
Headache 
4 
Y 
Y 
 
Y 
 
Consoli-
dated for 
Extension 
summary 
 
 
{none} 
NA 
NA 
NA 
 
 
N 


 
 
who died, their date of death is the date of last follow-up. For subjects who are randomized to 
placebo and treated in extension, their last follow-up on placebo is defined as the date prior to 
Day 1-EX. For other subjects, date recorded on End-of-Study Disposition is the date of last 
follow-up.  
3.2.5 TEAE and Mortality  
TEAE and mortality will be reported in percentage per total number of subjects exposed.    


 
 
4 
GENERAL STATISTICAL CONSIDERATIONS  
Efficacy and safety data will be summarized descriptive for subjects who entered extension and 
for all subjects who have been treated in the study. No formal statistical inference will be 
performed. 
4.1 
Analysis Populations 
Extension Safety Population (Safety-EX) and Safety Population are the same defined as in the 
SAP Part 1. 
4.2 
Handling Dropouts and Missing Data 
Missing values in the efficacy and safety parameters will not be imputed. All efficacy and safety 
will be summarized based on available observed data. Imputation will only be performed on 
missing or incomplete AE onset date or CM start/stop date. The same imputation algorithm 
described in SAP Part 1 will be used.  
4.3 
Definition of Baseline 
For subjects who were randomized to FG-3019 arm, the original baseline defined in the 
Randomized Treatment Period as described in SAP Part 1 will be used. This definition will 
enable evaluation of long term treatment effect in safety and efficacy parameters.  
For subjects who were randomized to placebo arm, baseline in Extension Period will be re-
defined as last assessment prior to first dose in Extension on Day 1-EX. This will separate the 
effect of FG-3019 from placebo.  
4.4 
Efficacy Analysis Visit Window 
The assessment intervals for the efficacy parameters (PFT, HRCT, and PRO) are the same in the 
Randomized Treatament Period and Extened Treatment Period, the same windowing rules 
described in SAP Part 1 will be used.   
4.5 
General Layout 
For subjects who have been treated in extension, all safety and efficacy data, including both 
the Randomized Treatment Period and Extended Treatment Period, will be summarized 
descriptively by scheduled visit. All data will be presented in data listings. 
 
 


 
 
5 
STATISTICAL ANALYSES 
5.1 
Subject Disposition 
The number of subjects in each study population will be summarized.  The number of subjects 
who completed or discontinued the study as well as the reasons for early discontinuation will be 
summarized for subjects entered extension. 
Subject who discontinued the study prematurely and the reasons will be listed.  
5.2 
Protocol Deviations 
Protocol deviations occurred in the extension period will be summarized and presented in data 
listing for subjects treated in extension. 
5.3 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized and presented in data listing as 
described in Section 4.5. 
5.4 
Summary of Prior and Concomitant Medications 
Concomitant medications and non-drug therapies administered during the study will be 
summarized by study period. 
All medications and non-drug therapies will be presented in data listings for subjects treated in 
extension. 
5.5 
Summary of Study Drug Exposure and Treatment Compliance 
Duration in days from first dose to last dose, number of doses, and dose amount in mg will be 
summarized and presented in data listing as described in Section 4.5. 
5.6 
Summary of the Efficacy Data in the Extension Period 
Efficacy parameters, including change from baseline in FVCpp, FVC (L), HRCT fibrosis score, 
and SGRQ total and domain scores, are summarized descriptively at each scheduled visit for 
subjects who have been treated in extension.  
5.7 
Summary of Safety Data in the Extension Period and Overall Study 
5.7.1 Summary of Treatment Emergent Adverse Events and Mortality 
TEAE and mortality will be summarized for subjects who entered extension.  
5.7.2 Summary of Other Safety Data 
Other safety data including central laboratory data, vital signs, ECG, and physical examination 
will be summarized descriptively by visit for subjects who have received extended treatment.  


 
 
6 
CHANGES FROM THE PROTOCOL 
• As documented in Note-To-File dated 05DEC2017 biomarker samples collected at 
Week 24 (pre-dose) and Week 48 at each extension year, are used to evaluate trough 
level of FG-3019 concentraction.  
 


 
 
APPENDIX. GENERAL SPECIFICATIONS FOR SUBMISSION DATA 
1. Study Data Tabulation Model (SDTM) 
A new set of SDTM datasets, containing the entire study data, will be created. The set of 
SDTM datasets created for the Randomized Treatment Period is a subset of this set for 
the entire study. 
Table A. 
Study Data Tabulation Model Datasets (SDTM) 
SDTM 
Domain 
SDTM Domain 
Description 
SDTM Domain 
Structure 
General 
Observation 
Class 
Source 
Data Used 
Key Variables 
AE 
Adverse Events 
One record per 
adverse event per 
subject 
Events 
AE 
STUDYID, 
USUBJID, 
AESTDTC, 
AEDECOD, 
AESPID 
CM 
Concomitant 
Medications 
One record per 
recorded medication 
occurrence per 
subject 
Interventions 
CM, CMIPF 
STUDYID, 
USUBJID, 
CMCAT, 
CMSPID, 
CMTRT, 
CMSTDTC 
DD 
Death Details 
One record per 
subject 
Findings 
DTH 
STUDYID, 
USUBJID, 
DDTESTCD 
DM 
Demographics 
One record per 
subject 
Special 
Purpose 
Domains 
DM, EX, 
ICF, DTH,  
SITE_INV 
STUDYID, 
USUBJID 
DS 
Disposition 
One record per 
disposition status or 
protocol milestone 
per subject 
Events 
DS, ICF, 
DTH, EX 
STUDYID, 
USUBJID, 
DSSTDTC, 
DSDECOD, 
DSSPID, 
EPOCH 
DV 
Protocol 
Deviations 
One record per 
protocol deviations 
per subject 
Events 
DV 
STUDYID, 
USUBJID, 
DVTERM 
EC 
Exposure as 
Collected 
One record per 
protocol-specified 
study treatment per 
collected-dosing 
interval  per subject 
Interventions 
EX 
STUDYID, 
USUBJID, 
ECTRT, 
ECSTDTC, 
ECGRPID 
EG 
ECG Test Results 
One record per ECG 
Findings 
EG 
STUDYID, 


 
 
observation per visit 
per subject 
USUBJID, 
EGTESTCD, 
VISITNUM 
EX 
Exposure 
One record per 
constant dosing 
interval per subject 
Interventions 
EX 
STUDYID, 
USUBJID, 
EXTRT, 
EXSTDTC 
IE 
Inclusion/Exclusi
on Criteria Not 
Met 
One record per 
inclusion/exclusion 
criterion not met per 
subject 
Findings 
IE 
STUDYID, 
USUBJID, 
IETESTCD 
LB 
Laboratory Test 
Results 
One record per lab 
test per specimen 
per method per 
LOINC code per 
reason not done per 
visit per subject 
Findings 
eDT LB, 
RAND, 
LBC, 
LBPREG 
STUDYID, 
USUBJID, 
LBCAT, 
LBTESTCD, 
VISITNUM, 
LBMETHOD, 
LBREASND, 
LBLOINC 
MH 
Medical History 
One record per 
medical history 
event per time 
interval per subject 
Events 
MH 
STUDYID, 
USUBJID, 
MHSPID, 
MHDECOD, 
MHSTDTC, 
MHENDTC 
PC 
Pharmacokinetic 
Concentrations 
One record per time-
point concentration 
or sample 
characteristic per 
analyte per subject 
Findings 
Source 
documents, 
PKC 
STUDYID, 
USUBJID, 
PCTESTCD, 
VISITNUM, 
PCTPTNUM 
PE 
Physical 
Examination 
One record per body 
system or 
abnormality per visit 
per subject 
Findings 
PE 
STUDYID, 
USUBJID, 
PETESTCD, 
VISITNUM 
PP 
Pharmacokinetic 
Parameters 
One record per PK 
parameter per time-
concentration profile 
per modeling 
method per subject 
Findings 
Source 
documents 
STUDYID, 
USUBJID, 
PPTESTCD, 
PPCAT, 
VISITNUM, 
PPTPTREF 
PR 
Procedures 
One record per 
recorded procedure 
per occurrence per 
subject 
Interventions 
NDT, OU 
STUDYID, 
USUBJID, 
PRCAT, 
PRTRT, 
PRSPID 


 
 
QS 
Questionnaires 
One record per 
question per 
questionnaire per 
visit per subject 
Findings 
SGRQ, 
UCSD 
STUDYID, 
USUBJID, 
QSTESTCD, 
VISITNUM 
SC 
Subject 
Characteristics 
One record per 
characteristic per 
subject 
Findings 
DM 
STUDYID, 
USUBJID, 
SCTESTCD 
SE 
Subject Elements 
One record per 
actual Element per 
subject 
Special 
Purpose 
Domains 
SDTM.DM, 
SDTM.EX, 
SDTM.DS, 
SDTM.SV 
STUDYID, 
USUBJID, 
TAETORD, 
SESTDTC 
SU 
Substance Use 
One record per 
substance type per 
subject 
Intervention 
SUTOB 
STUDYID, 
USUBJID, 
SUTRT 
SV 
Subject Visits 
One record per 
actual visit per 
subject 
Special 
Purpose 
Domains 
All datasets 
including 
visits 
STUDYID, 
USUBJID, 
VISITNUM 
TA 
Trial Arms 
One record per 
planned Element per 
Arm 
Trial Design 
N/A 
STUDYID, 
ARMCD, 
TAETORD 
TE 
Trial Elements 
One record per 
planned Element 
Trial Design 
N/A 
STUDYID, 
ETCD 
TI 
Trial 
Inclusion/Exclusi
on Criteria 
One record per I/E 
criterion per 
protocol criteria 
version 
Trial Design 
N/A 
STUDYID, 
TIVERS, 
IETESTCD 
TS 
Trial Summary 
One record per Trial 
Summary parameter 
per occurrence 
Trial Design 
N/A 
STUDYID, 
TSPARMCD, 
TSSEQ 
TV 
Trial Visits 
One record per 
planned Visit per 
Arm 
Trial Design 
N/A 
STUDYID, 
VISITNUM, 
ARMCD 
VS 
Vital Signs 
One record per vital 
sign measurement 
per time point per 
visit per subject 
Findings 
VS, SC 
STUDYID, 
USUBJID, 
VSTESTCD, 
VISITNUM, 
VSDTC 
ZH 
High Resolution 
Computed 
Tomography 
One record per 
examination per 
location per time 
point per visit per 
subject 
Findings 
 HRCT, 
TEXTCAD, 
TEXTVIS, 
IMQUAL 
STUDYID, 
USUBJID, 
ZHCAT, 
ZHTESTCD, 
VISITNUM, 
ZHDTC, 


 
 
ZHLOC, 
ZHEVAL 
ZI 
IPF Confirmation 
One record per IPF 
Confirmation per 
test per subject 
Findings 
IPFD 
STUDYID, 
USUBJID, 
ZITESTCD 
ZP 
Pulmonary 
Function Tests 
One record per test 
per time point per 
visit per result per 
subject 
Findings 
eDT PFT, 
RAND, ZP, 
MHPFT 
STUDYID, 
USUBJID, 
ZPCAT, 
ZPTESTCD, 
VISITNUM, 
ZPDTC, 
ZPORRES 
 
2 Analysis Data Model (ADaM) 
A new set of ADaM datasets will be created to fit the required analyses for SAP Part 2.  
Table B. 
Analysis Data Model (ADaM) 
Dataset 
Description 
Structure 
Keys 
ADSL 
Subject-Level 
Analysis Dataset 
One record per subject 
STUDYID, SUBJID  
ADAE 
Analysis Dataset 
Adverse Events 
One record per subject 
per adverse event 
STUDYID, SUBJID, 
AESTDTC, 
AEDECOD, AESPID 
ADCM 
Analysis Dataset 
Concomitant 
Medications 
One record per subject 
per recorded medication 
occurrence 
STUDYID, SUBJID, 
CMCAT, CMSPID, 
CMTRT, CMSTDTC 
ADDD 
Analysis Dataset 
Death 
One record per subject 
per paramter 
STUDYID SUBJID 
PARAMCD  
ADEG 
Analysis Dataset for 
ECG Test Results 
One record per subject 
per visit 
STUDYID, SUBJID, 
PARAMCD, 
AVISITN, ADT  
ADEX 
Analysis Dataset 
Exposure 
One record per subject 
per parameter per visit 
STUDYID, SUBJID, 
PARAMCD, AVISITN 
ADHRCT Analysis Dataset 
HRCT 
One record per subject 
per measurement method 
per Lung Lobe per 
parameter per visit 
STUDYID, SUBJID, 
PARAMCD, 
AVISITN, 
DTYPE ALOC 
ADLB 
Analysis Dataset 
Laboratory Test 
One record per subject 
per category per 
STUDYID, SUBJID, 
PARCAT1, 


 
 
Results 
parameter per visit per 
normal range per result 
PARCAT2, 
PARAMCD, 
AVISITN, ANRHI, 
AVAL  
ADMH 
Analysis Dataset 
Medical History 
One record per subject 
per medical history per 
time interval of medical 
history 
STUDYID, SUBJID,  
MHSPID, 
MHDECOD, 
MHSTDTC, 
MHENDTC  
ADPC 
Analysis Dataset 
PK Concentrations 
One record per subject 
per visit per time point 
per parameter 
STUDYID, SUBJID, 
AVISITN, ATPTN, 
PARAMCD  
ADPE 
Analysis Dataset 
Physical 
Examination 
One record per subject  
per parameter per visit 
STUDYID, SUBJID, 
AVISITN, PARAMCD 
ADPF 
Analysis Dataset 
Pulmonary Function 
Tests 
One record per subject 
per parameter per time 
point per visit 
USUBJID, SUBJID, 
PARAMCD, 
AVISITN, DTYPE, 
ADT, ATM 
ADPP 
Analysis Dataset 
Pharmacokinetic 
Parameters 
One record per subject 
per parameter per visit 
STUDYID, SUBJID, 
AVISITN, 
PARAMCD  
ADPR 
Analysis Dataset 
Procedures 
One record per recorded 
procedure per occurrence 
per subject 
STUDYID, SUBJID, 
PRTRT, PRSPID  
ADQS 
Analysis Dataset for 
Questionnaire 
One record per subject 
per category per 
parameter per visit 
STUDYID, SUBJID, 
PARCAT1, 
PARAMCD, 
AVISITN, VISITNUM 
ADTTE 
Analysis Dataset 
Time-to-Event 
One record per subject 
per parameter 
STUDYID, SUBJID, 
PARAMCD  
ADVS 
Analysis Dataset 
Vital Signs 
One record per subject 
per parameter per time 
point per visit 
STUDYID, SUBJID, 
PARAMCD, 
AVISITN, DTYPE, 
ADT, ATM, ATPTN 
 
 

Prot_000.pdf: 
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 from 
FibroGen, Inc. 
CLINICAL STUDY PROTOCOL 
STUDY TITLE: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study 
to Evaluate the Safety and Efficacy of FG-3019 in Patients with 
Idiopathic Pulmonary Fibrosis 
PROTOCOL NUMBER: 
FGCL-3019-067 
SPONSOR: 
FibroGen, Inc. 
409 Illinois Street 
San Francisco, California  94158 USA 
IND NUMBER: 
11212 
EudraCT NUMBER: 
2014-005658-20 
INVESTIGATIONAL 
PRODUCT: 
FG-3019 
INDICATION: 
Idiopathic Pulmonary Fibrosis 
FIBROGEN MEDICAL 
MONITOR: 
Name: 
 
Title: 
 
Work Phone: 
 
Cell Phone: 
  
E-mail Address: 
ORIGINAL PROTOCOL / 
DATE: 
AMENDMENT 1.0: 
AMENDMENT 2.0: 
15 January 2013
09 December 2014 
09 March 2015 
AMENDMENT 3.0: 
28 May 2015 
AMENDMENT 5.1: 
12 December 2016  (Regional: Australia, Bulgaria, India, New 
Zealand and South Africa)  
NCT #: NCT01890265


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STUDY ACKNOWLEDGEMENT 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and 
Efficacy of FG-3019 in Patients with Idiopathic Pulmonary Fibrosis  
FGCL-3019-067 
Original:  15 January 2013 
Amendment 1.0: 09 December 2014 
 
Amendment 2.0: 09 March 2015 
Amendment 3.0: 28 May 2015 
Amendment 5.1: 12 December 2016 (Regional: (Regional: Australia, Bulgaria, India, New Zealand 
and South Africa)   
 
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 drug and the study. 
I will conduct the trial in accordance with the guidelines of GCP including the archiving of essential 
documents, the Declaration of Helsinki, the International Conference on Harmonisation (ICH) E6 
Guideline for GCP, the FDA, any applicable local health authority, and Institutional Review Board (IRB) 
requirements. 
 
 
 
Investigator Name (Printed) 
 
Institution 
 
 
 
Signature 
 
Date 
 


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CONFIRMATION OF PROTOCOL APPROVAL 
Original:  15 January 2013 
Amendment 1.0: 09 December 2014 
Amendment 2.0: 09 March 2015 
Amendment 3.0: 28 May 2015 
Amendment 5.1: 12 December 2016 
 
This protocol is approved by FibroGen. 
 
 
 
 
 
  
FibroGen Inc. 
 
Date 
 
 
 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ............................................................................................................. 11 
1 
Introduction ........................................................................................................................... 19 
1.1 
Idiopathic Pulmonary Fibrosis ...................................................................................... 19 
1.2 
Connective Tissue Growth Factor ................................................................................ 22 
1.3 
Connective Tissue Growth Factor in Idiopathic Pulmonary Fibrosis ........................... 23 
1.4 
Investigational Product FG-3019 .................................................................................. 23 
1.5 
Clinical Trial Experience with FG-3019....................................................................... 23 
1.6 
Rationale for FG-3019 in Idiopathic Pulmonary Fibrosis ............................................ 24 
2 
Objectives ............................................................................................................................. 25 
2.1 
Primary Safety Objective .............................................................................................. 25 
2.2 
Primary Efficacy Objective ........................................................................................... 25 
2.3 
Secondary Efficacy Objectives ..................................................................................... 25 
2.4 
Exploratory Efficacy Objectives ................................................................................... 25 
3 
Endpoints and Assessments .................................................................................................. 26 
3.1 
Safety Endpoints and Assessments ............................................................................... 26 
3.2 
Efficacy Endpoints and Assessments............................................................................ 26 
3.2.1 Primary Efficacy Endpoint ....................................................................................... 26 
3.2.2 Secondary Efficacy Endpoints. ................................................................................. 26 
3.2.3 Exploratory Efficacy Endpoints ................................................................................ 26 
4 
Study Design ......................................................................................................................... 27 
4.1 
Study Population ........................................................................................................... 27 
4.2 
Description of the Study ............................................................................................... 27 
4.2.1 Study Periods ............................................................................................................ 27 
4.2.2 Randomized Treatment Phase................................................................................... 28 
4.2.3 Extended Treatment Period (Weeks Identified with –EX Suffix) ............................ 28 
4.2.4 End of Treatment and Follow-up .............................................................................. 29 
4.2.5 Extended Treatment Phase ........................................................................................ 29 
4.2.6 Placebo Control Group ............................................................................................. 30 
4.3 
Treatment Assignment .................................................................................................. 30 
4.4 
Blinding......................................................................................................................... 30 


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4.4.1 Rationale for Blinding............................................................................................... 30 
4.4.2 Maintenance of Blinding........................................................................................... 30 
4.4.3 Unblinding of Treatment Assignment ...................................................................... 30 
4.5 
Study Treatment with FG-3019 .................................................................................... 31 
4.6 
Concomitant Medications, Procedures and Nondrug Therapies ................................... 31 
4.6.1 Concomitant Medications ......................................................................................... 31 
4.6.2 Contraception ............................................................................................................ 31 
4.7 
Safety Plan .................................................................................................................... 32 
4.8 
Independent Data Monitoring Committee .................................................................... 32 
4.8.1 Safety Monitoring ..................................................................................................... 32 
5 
Eligibility Criteria ................................................................................................................. 33 
5.1 
Inclusion Criteria .......................................................................................................... 33 
5.2 
Exclusion Criteria ......................................................................................................... 33 
6 
Study Drug/Treatment Supply .............................................................................................. 36 
6.1 
FibroGen Investigational Product ................................................................................. 36 
6.1.1 Formulation ............................................................................................................... 36 
6.2 
Reference Therapy (Placebo) ........................................................................................ 36 
6.2.1 Formulation ............................................................................................................... 36 
6.3 
Preparation of Dose and Administration....................................................................... 36 
6.4 
Storage .......................................................................................................................... 37 
7 
Study Procedures-All Cohorts Unless Otherwise Specified ................................................. 38 
7.1 
Study Procedures .......................................................................................................... 38 
7.2 
Serial PFT and HRCT ................................................................................................... 38 
7.3 
Blood Volume ............................................................................................................... 38 
7.4 
Missed Visits ................................................................................................................. 38 
7.5 
Unscheduled Visits ....................................................................................................... 39 
7.6 
Assessments .................................................................................................................. 39 
7.6.1 Central Laboratory .................................................................................................... 39 
7.6.2 Local Laboratory(s) .................................................................................................. 39 
7.6.3 Other Reference Laboratories ................................................................................... 39 
7.6.4 Exploratory Biomarkers ............................................................................................ 39 
7.6.5 DNA for Genomic Analysis...................................................................................... 39 
8 
Subject Discontinuation ........................................................................................................ 41 


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8.1 
Replacement of Subjects ............................................................................................... 41 
9 
Study Termination by FibroGen ........................................................................................... 42 
10 Statistics ................................................................................................................................ 43 
10.1 
Sample Size Determination........................................................................................... 43 
10.2 
Analysis Populations ..................................................................................................... 43 
10.2.1 
Safety Population .................................................................................................. 43 
10.2.2 
Full Analysis Set Population ................................................................................. 43 
10.2.3 
HRCT Evaluable Population................................................................................. 43 
10.3 
Statistical Analysis ........................................................................................................ 44 
10.3.1 
General Analysis Methods .................................................................................... 44 
10.3.2 
Subject Enrollment and Disposition ..................................................................... 44 
10.3.3 
Demographics and Baseline Characteristics ......................................................... 44 
10.3.4 
Efficacy Analyses ................................................................................................. 44 
10.3.5 
Safety Analyses ..................................................................................................... 45 
10.3.6 
Interim Analyses ................................................................................................... 45 
10.4 
Statistical Analysis Plan ................................................................................................ 46 
11 Assessment of Safety ............................................................................................................ 47 
11.1 
Background ................................................................................................................... 47 
11.2 
Definitions..................................................................................................................... 47 
11.2.1 
Definition of an Adverse Event (AE) ................................................................... 47 
11.2.2 
Definition of a Serious Adverse Event (SAE) ...................................................... 47 
11.2.3 
Definition of a Suspected Adverse Reaction ........................................................ 48 
11.2.4 
Definition of an Adverse Reaction ....................................................................... 48 
11.2.5 
Special Situations .................................................................................................. 48 
11.3 
Procedures for Eliciting, Recording, and Reporting Adverse Events ........................... 48 
11.3.1 
Adverse Event Reporting Period .......................................................................... 48 
11.3.2 
Adverse Event Eliciting/Reporting ....................................................................... 49 
11.3.3 
Assessing Adverse Event Severity........................................................................ 49 
11.3.4 
Assessing the Adverse Event’s Relationship to Study Drug ................................ 50 
11.3.5 
Reporting Serious Adverse Events on the SAE Report Form .............................. 51 
11.3.6 
Pregnancies: Reporting and Follow-up of Subjects .............................................. 52 
11.3.7 
Abnormal Laboratory Findings............................................................................. 52 
12 Study Monitoring .................................................................................................................. 54 


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12.1 
Data Quality Assurance ................................................................................................ 54 
12.2 
Compliance with Laws and Regulations....................................................................... 54 
12.3 
Audit and Inspection ..................................................................................................... 54 
12.4 
Data Collection and Handling ....................................................................................... 55 
12.4.1 
Source Documents ................................................................................................ 55 
12.4.2 
Data Collection, Handling, and Verification ........................................................ 55 
13 Human Subjects .................................................................................................................... 56 
13.1 
Ethical Considerations .................................................................................................. 56 
13.2 
Communication with the Institutional Review Board .................................................. 56 
13.3 
Informed Consent Form ................................................................................................ 56 
13.4 
Subject Confidentiality ................................................................................................. 56 
14 Investigator Requirements .................................................................................................... 57 
14.1 
Study Medication Accountability ................................................................................. 57 
14.2 
Disclosure of Data......................................................................................................... 57 
14.3 
Study Files and Retention of Records ........................................................................... 57 
15 Publication Policy ................................................................................................................. 58 
16 References ............................................................................................................................. 59 
17 Appendices ............................................................................................................................ 66 
 
LIST OF FIGURES 
Figure 1. 
Study Schema............................................................................................................ 28 
LIST OF APPENDICES 
Appendix 1. 
Schedule of Assessments ─ Randomized Treatment Phase ................................. 67 
Appendix 2. 
Schedule of Assessments ─ Extended Treatment Phase ...................................... 69 
Appendix 3. 
Schedule of Assessments ─ End of Treatment and Follow-up ............................. 71 
Appendix 4. 
HRCT Criteria and Histopathological Criteria for UIP Pattern* .......................... 72 
Appendix 5. 
Radiation Risk Assesment .................................................................................... 73 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AEs 
adverse events 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATS 
American Thoracic Society 
BMPs 
bone morphogenetic proteins 
BP 
blood pressure 
CCN 
cysteine-rich 61/CTGF/nephroblastoma overexpression 
CFR 
Code of Federal Regulations 
CPAP 
continuous positive airway pressure 
CRF 
case report form 
CTGF 
connective tissue growth factor 
DLCO 
diffusing capacity of the lung for carbon monoxide 
DNA 
deoxyribonucleic acid 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
ECM 
extracellular matrix 
EMT 
epithelial-mesenchymal transition 
EOS 
end of study 
FDA 
US Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
FG-3019 
FibroGen-3019 (recombinant human monoclonal antibody) 
FVC 
forced vital capacity  
GCP 
Good Clinical Practice 
HAHA 
human anti-human antibody 
HRQoL 
health-related quality of life 
Hb 
hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act  
HRCT 
high resolution computed tomography 
HSPG 
heparin sulfate proteoglycans 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug  


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INR 
international normalized ratio 
IL-1β 
interleukin-1 beta 
IL-4 
interleukin-4 
IL-10 
interleukin-10 
IL-13 
interleukin-13 
IL-17 
interleukin-17 
IPF 
idiopathic pulmonary fibrosis 
IRB 
Institutional Review Board 
IV 
intravenous, intravenously 
kDa 
kilodalton 
LRP 
lipoprotein receptor-related protein 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
messenger ribonucleic acid 
NAC 
N-acetylcysteine 
NCI 
National Cancer Institute 
NCI CTCAE, v4.0 
NCI Common Terminology Criteria for Adverse Events, Version 4.0 
NSAIDs 
non-steroidal anti-inflammatory drugs 
NYHA 
New York Heart Association 
OTC 
over-the-counter 
PDGF 
platelet-derived growth factor 
PFTs 
pulmonary function tests 
PP 
per protocol 
SAEs 
serious adverse event(s) 
SaO2 
oxyhemoglobin saturation 
SAP 
statistical analysis plan 
SGRQ 
Saint George’s Respiratory Questionnaire 
SPARC 
secreted protein acidic and rich in cysteine 
TE-AE 
treatment-emergent adverse event 
TE-SAE 
treatment-emergent serious adverse event 
TGF-β 
transforming growth factor-β 
TLC 
total lung capacity 
TNF-α 
tumor necrosis factor-α 
UIP 
usual interstitial pneumonia 
ULN 
upper limit of normal 
VEGF 
vascular endothelial growth factor 
WHODrug 
World Health Organization Drug Dictionary 


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AMENDMENT 5.1: KEY CHANGES FROM AMENDMENT 3.0 
The protocol has been edited for clarity, consistency, and quality of content (typos, grammatical 
errors, etc.). A redline version documenting all changes from the previous version of this 
document is available upon request.  
Key Change 
Rationale 
Sections Affected 
The Follow Up / End of Study 
Visit is now scheduled at 4 
weeks after the last dose of 
study drug (instead of 10 
weeks). 
 
The change in the schedule of 
the  Follow Up/End of Study 
Visit is supported by 
pamrevlumab’s drug PK 
characteristics and available 
safety data. 
 
Protocol Synopsis, Sections 4 
and 11, Appendix 2 and 
Appendix 3. 
 
 


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PROTOCOL SYNOPSIS 
Study Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Safety and Efficacy of FG-3019 in Patients with Idiopathic 
Pulmonary Fibrosis 
Protocol Number: 
FGCL-3019-067, Amendment 5.1 
Investigational Product: 
FG-3019 
Target Population: 
Male or female subjects, 40 to 80, years old who have IPF 
diagnosed in accordance with criteria published in the 2011 
international consensus guidelines. Subjects who have failed or are 
intolerant of products approved for treating IPF are eligible.  
 
IND Number: 
011212 
Study Phase: 
Phase 2 
Study Centers Planned: 
Approximately 60 centers in the United States and other countries 
Number of Subjects 
Planned: 
Approximately 136 
Objective: 
The overall objective of this study is to evaluate the safety, 
tolerability, and efficacy of FG-3019 in subjects with IPF 
Primary Safety 
Objective: 
• To determine the safety and tolerability of FG-3019 
administered at a dose of 30 mg/kg by intravenous (IV) infusion 
every 3 weeks  
Primary Efficacy 
Objective: 
• To determine the effect of FG-3019 on forced vital capacity 
(FVC) (percent of predicted value) in the target population  
Secondary Efficacy 
Objectives: 
• To evaluate the effect of FG-3019 on the extent of pulmonary 
fibrosis as measured by high resolution computed tomography 
(HRCT) scans of the chest 
• To evaluate the relationship between changes in quantified 
scores of pulmonary fibrosis and clinical outcomes 
• To evaluate the effect of FG-3019 on progression of IPF and the 
frequency of respiratory-related hospitalizations and respiratory-
related mortality  
• To evaluate the effect of FG-3019 on health-related quality of 
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Exploratory Efficacy 
Objectives: 
• To evaluate the effect of FG-3019 on FVC (liters) 
• To evaluate the effect of FG-3019 on a panel of serum and 
plasma biomarkers 
• To evaluate the relationship between known chromosomal loci 
associated with IPF and the response to FG-3019 
Study Design: 
This is a Phase 2, randomized, double-blind, placebo-controlled 
multicenter study. Subjects who have failed or are intolerant of 
products approved for treating IPF are eligible. Other 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 may be randomized to placebo. 
Randomized Treatment Period 
Subjects who sign informed consent will undergo screening visits to 
determine their eligibility. Eligible subjects who provide written 
informed consent will be stratified based on prior therapy with 
nintedanib and/or pirfenidone (yes/no) and randomized (1:1) to one 
of two treatment arms: 
 
Arm A: FG-3019, 30 mg/kg  
 
Arm B: Matching placebo 
Treatment should begin within 42 days of the first screening visit. 
Study Drug (FG-3019 [30 mg/kg] or placebo) will be administered 
by IV infusion every 3 weeks for a total of 16 infusions over 
48 weeks. At the time of roll over into the Extended Treatment 
Period, the study subject treatment assignment will be unblinded 
only to designated personnel not associated with the study at 
FibroGen Inc. 
Extended Treatment Period 
Subjects Enrolled under the Original Protocol and Assigned to Arm 
A: FG-3019 
All subjects in Arm A whose FVC percent predicted value shows 
less than 3% absolute decrease from baseline in the Randomized 
Treatment Period will be offered participation in an Extended 
Treatment Period. These subjects may continue treatment until FVC 
percent predicted decreases 3% or more on two consecutive 
scheduled evaluations compared to the original pre-treatment 
baseline. 
 
Subjects Enrolled Under Amendment 1 or Subsequent Amendments 
and Assigned to Arm A: FG-3019 
All subjects in Arm A whose FVC percent predicted value is greater 
than the original pre-treatment baseline in the Randomized 


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Treatment Period will be offered participation in an Extended 
Treatment Period and may continue treatment until FVC percent 
predicted is equal to or less than the pre-treatment baseline on two 
consecutive scheduled evaluations. 
 
Subjects Enrolled Under the Original Protocol,  Amendment 1 or 
Subsequent Amendments Assigned to Arm B: Placebo 
All subjects assigned to Placebo (Arm B) will be offered 
participation in the Extended Treatment Phase for 45 weeks. 
Placebo subjects in the extension study are treated identically to 
subjects randomized to FG-3019 in Amendment 1, except for the 
fact that the baseline for these patients is the time at which they are 
enrolled into the extension phase (Baseline for Placebo subjects is 
Week 48 value). Change in FVC percent predicted during the 
extended treatment phase will be compared to this new baseline. 
Those subjects whose FVC percent predicted value at Week 48 of 
the Extension Period  is greater than the new baseline may continue 
treatment with FG-3019 until FVC percent predicted is equal to or 
less than the  baseline on two consecutive scheduled evaluations. 
See Section 4.2.3 for details regarding the Extended Treatment 
Period. 
Study Periods 
Screening Period (up to 6 weeks) 
Randomized Treatment Period (48 weeks) 
Extended Treatment Period (sub-set of subjects [see definition 
above]; duration based on changes in FVC (Section 4.2.3) 
Follow-Up Period (all subjects will undergo a final safety 
assessment at 4 weeks after last dose of study drug.) 
Study Population 
Male or female subjects 40 to 80 years old who have IPF diagnosed 
in accordance with criteria published in the 2011 international 
consensus guidelines.  
Diagnosis and Main 
Eligibility Criteria 
Inclusion Criteria:  
1. Age 40 to 80 years, inclusive. 
2. Diagnosis of IPF as defined by current international guidelines 
(Raghu, 2011). Each subject must have one of the following: (1) 
Usual Interstitial Pneumonia (UIP) Pattern on an available 
HRCT scan; or (2) Possible UIP Pattern on an available HRCT 
scan and surgical lung biopsy within 4 years of Screening 
showing UIP Pattern (HRCT criteria for UIP Pattern and 
Possible UIP Pattern and histopathological criteria for UIP 
Pattern are described in Appendix 4). 
3. History of IPF of ≤5 years duration with onset defined as the 
date of the first diagnosis of IPF by HRCT or surgical lung 


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biopsy. 
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, as determined by the HRCT central reader.  
5. FVC percent of predicted value ≥55% at Screening. 
6. Female subjects of childbearing potential and male subjects with 
female partners of childbearing potential are required to use 
double barrier contraception methods during the conduct of the 
study and for 3 months after the last dose of study drug.  
Exclusion Criteria:   
1. Female subjects who are pregnant or nursing. 
2. Infiltrative lung disease other than IPF, including any of the 
other types of idiopathic interstitial pneumonias (Travis, 2013); 
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 and connective 
tissue diseases.  
3. HRCT scan findings at Screening are inconsistent with UIP 
Pattern, as determined by the HRCT central reader (a definition 
of “Inconsistent with UIP Pattern” is provided in Appendix 4). 
4. Pathology diagnosis on surgical lung biopsy is anything other 
than UIP Pattern, as determined by the local pathologist 
(Appendix 4). 
5. The Investigator judges that there has been sustained 
improvement in the severity of IPF during the 12 months prior to 
Screening, based on changes in FVC, diffusing capacity of the 
lung for carbon monoxide (DLCO), and/or HRCT scans of the 
chest. 
6. 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 endpoints in the protocol or 
otherwise preclude the subject’s participation in the study. 
7. History of any other respiratory, cardiovascular, renal, hepatic, 
metabolic, neurologic, hematologic, or other medical conditions 
that, in the opinion of the Investigator, would preclude the 
subject’s participation in the study. 
8. 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 


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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. 
9. Upper or lower respiratory tract infection of any type within 
4 weeks of Screening. 
10. Acute exacerbation of IPF within 3 months of Screening. 
11. Evidence of obstructive lung disease by any of the following 
criteria: forced expiratory volume in 1 second/forced vital 
capacity (FEV1/FVC) ratio <0.70 or extent of emphysema on 
HRCT greater than the extent of fibrosis on HRCT. 
12. DLCO <30% of predicted value. 
13. High likelihood of lung transplantation (in the opinion of the 
Investigator) within 6 months after Day 1. 
14. Poorly controlled chronic heart failure; clinical diagnosis of cor 
pulmonale requiring specific treatment; or severe pulmonary 
hypertension requiring specific treatment that, in the opinion of 
the Investigator, would preclude the subject’s participation in the 
study.  
15. Use of medications to treat IPF within 5 half-lives of Day 1 
dosing. If monoclonal antibodies were used, the last dose of the 
antibody must be at least 4 weeks before Day 1 dosing. 
16. Use of any investigational drugs, including any investigational 
drugs for IPF, within 4 weeks prior to Day 1 dosing. 
17. History of cancer diagnosis of any type in the 3 years preceding 
Screening, excluding non-melanomatous skin cancer, localized 
bladder cancer, or in situ cancers.  
18. Clinically significant trauma or surgical procedures within 
4 weeks prior to dosing. 
19. Planned elective surgery during the study including 4 weeks 
following the final dose of Study Drug. 
20. History of allergic or anaphylactic reaction to human, 
humanized, chimeric or murine monoclonal antibodies. 
21. 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. 
22. Body weight >130 kg. 
23. Previous treatment with FG-3019. 
24. Inadequate IV access.  


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Concomitant 
Medications/Therapies 
Oral prednisone or equivalent oral corticosteroid (up to 10 mg daily) 
and N-acetylcysteine (NAC) (up to 1800 mg daily) are allowed. 
Medications that, in the opinion of the Investigator, are required for 
the treatment of acute exacerbations of IPF during the Treatment 
Period are acceptable. 
Female subjects of childbearing potential and male subjects with 
female partners of childbearing potential are required to use double 
barrier contraception methods during the conduct of the study and 
for 3 months after the last dose of study drug.  
Investigational Product, 
Dose, and Mode of 
Administration 
FG-3019 is a fully human IgG1 kappa monoclonal antibody that 
binds to connective tissue growth factor (CTGF). It will be 
administered at a dose of 30 mg/kg by IV infusion in a total volume 
of 250 mL (up to 400 mL if necessary) normal saline every 3 weeks.  
Reference Therapy 
(and/or Placebo), Dose, 
and Mode of 
Administration 
Placebo (identical to the FG-3019 vehicle) will be handled and 
administered in a manner that is identical to FG-3019. 
Safety Endpoints and 
Assessments 
• Adverse events and serious adverse events (SAEs) 
• Laboratory test abnormalities  
• 12-lead ECGs 
• Physical examinations 
• Human anti-human antibodies (HAHA) 
Efficacy Endpoints and 
Assessments 
Primary efficacy endpoint 
• Change from baseline in FVC (percent of predicted value) at 
Week 48. 
Secondary efficacy endpoints  
• Change in pulmonary fibrosis score by quantitative HRCT at 
Week 24, Week 48, and later time points. 
• Change from baseline in HRQoL at Week 24, Week 48, and 
later time points. 
• Progression of IPF, defined as time from Day 1 to any one of the 
following: 
o Death from any cause 
o Absolute decline FVC percent of predicted value of ≥10% 
not due to intercurrent illness, confirmed by repeat 
spirometry 


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o Clinical diagnosis of IPF progression. 
• Proportion of subjects with at least one respiratory-related 
hospitalization. 
• Proportion of subjects with respiratory-related death, censored at 
Week 52. 
• Categorical assessment of absolute change from baseline in FVC 
percent of predicted value at Week 48. 
Exploratory efficacy endpoints  
• Change from baseline to Week 24 and from baseline to Week 48 
in FVC (liters). 
• Change from Day 1 to Week 48 in a panel of serum and plasma 
biomarkers that will be determined by FibroGen. 
• Relationship between known chromosomal loci associated with 
IPF and the response to FG-3019. 
Statistical Methods: 
This study is planned to enroll approximately 136 subjects, who will 
include a target of 110 subjects who are seeking first-line therapy 
and approximately 26 subjects who failed pirfenidone and/or 
nintedanib treatment. First line therapy is defined as no prior therapy 
with pirfenidone and/or nintedanib or <10% relative decrease in 
FVC % predicted while receiving either pirfenidone or nintedanib. 
Pirfenidone and/or nintedanib failure is defined as having ≥10% 
relative decrease in FVC % predicted during prior pirfenidone 
and/or nintedanib treatment. The effect of first-line treatment is the 
primary interest of the study and is the basis for sample size 
estimates. Assuming a 10% dropout rate and a common standard 
deviation of 7.3, a sample size of 55 subjects per arm in the primary 
analysis population provides approximately 80% power to detect a 
treatment difference of 4.2 in change from baseline to Week 48 in 
percent predicted FVC, using a two-sample t-test at the two-sided 
significance level of 0.05. If the treatment effect in the pirfenidone 
and/or nintedanib treatment failure group is similar to that in the 
general population, the two subgroups will be combined to achieve 
higher power. 
The primary efficacy analysis is to compare the treatment arms in 
change from baseline to Week 48 in FVC % predicted. A rank 
ANCOVA model will be used. A repeated measures model utilizing 
all observed data will be used for sensitivity analyses. Logistic 
regression and Fisher’s exact test will be used to compare 
categorical endpoints. The Cox regression model will be used in 
time-to-event endpoints. All efficacy and safety data will be 
summarized descriptively by treatment arm. 


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Treatment effect will be evaluated in various subgroups of interest. 
Unblinded analyses will be performed after all subjects have either 
completed the Week 48 assessments or discontinued the study. 
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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1 
INTRODUCTION 
1.1 
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, 2011). 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). 
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). Extracellular matrix 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, 2006a). 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), oxidant stress (Beeh, 2002, Cantin, 1987, 
Daniil, 2008, Hunninghake, 2005, Waghray, 2005), 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 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 a key cytokine thought to drive the fibrotic process 
in IPF (Agostini, 2006, Bergeron, 2003). Other cytokines, 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 have been implicated in this complex process of 
cellular interactions among activated epithelial cells, myofibroblasts, fibroblasts, macrophages, 
endothelial cells, and lymphocytes (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 are gaining increased attention 


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(Lama, 2006, Strieter, 2009, Willis, 2006). Connective tissue growth factor has been shown to be 
a central mediator of tissue remodeling and fibrosis and has been reported to be a downstream 
mediator that is essential for the fibrotic activity of TGF- β (Blom, 2002, Grotendorst, 1997). 
The epidemiology of IPF is not clearly defined. Retrospective data from a large health care 
claims database suggest that the prevalence of IPF ranges from 14.0 to 42.7 per 100,000 and the 
annual incidence ranges from 6.8 to 16.3 per 100,000, depending on the strictness of the 
diagnostic criteria employed (Raghu, 2006b). Among persons aged 18 and older in the United 
States, as many as 89,000 people have been diagnosed with IPF, and as many as 34,000 are 
newly diagnosed each year (Raghu, 2006b). A recent 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). The prevalence of IPF increases with age, and 
most IPF patients are age 60 or older at the time of diagnosis. 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 forced expiratory volume in 1 second (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 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, characterized by worsening dyspnea over one month or less, new 
diffuse lung infiltrates and ground-glass opacities on HRCT, and worsening hypoxemia in the 
absence of pulmonary infection or other identifiable causes, punctuate the natural course of the 
disease, especially in its pre-terminal phase (Collard, 2007, Hyzy, 2007, Kim, 2006, Walter, 
2006). These exacerbations are often fatal events (Hyzy, 2007, Kim, 2006, Martinez, 2005). The 
etiology of acute exacerbations of IPF is unknown, and its pathogenesis is not well understood 
(Collard, 2007). IPF-related exacerbations occurred at a rate of 0.13 per person-year in the 
Olmstead County population-based study reported above (Fernandez Perez, 2010). A less 
common, rapidly progressive form of IPF, which is common in actively smoking males, has been 
described (Selman, 2007).  


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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, reticular infiltrates with basal predominance, honeycombing, and 
absence of the features suggesting a different diagnosis) in the appropriate clinical setting 
(Raghu, 2011). Surgical lung biopsy, long considered the gold standard for diagnosis of IPF, is 
now performed in a minority of cases because of the morbidity associated with the procedure and 
increasing acceptance of diagnosis by HRCT (Raghu, 1999). Nevertheless, combined clinical, 
radiologic, and pathologic correlation is recommended as the optimal approach to diagnosis.  
The histopathologic pattern of UIP is a heterogeneous, patchy involvement of lung parenchyma 
with areas of relatively normal lung tissue adjacent to areas that display architectural distortion 
(“spatial heterogeneity”), infiltrates of fibroblasts and myofibroblasts, collagen deposition, 
honeycombing, Type II pneumocyte hyperplasia, smooth muscle hyperplasia, and buds of young 
proliferating fibroblasts adjacent to alveoli called “fibroblastic foci” (Raghu, 2011, 
Selman, 2006, Visscher, 2006). 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, 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, 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 recent 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), but most IPF patients are not eligible for transplantation 
because of their age or comorbid conditions. 
The natural course of IPF is variable. Patients with IPF typically experience slowly progressive 
worsening of lung function over time, but some experience rapid declines and frequent 
hospitalizations in the late stage of the disease (Martinez, 2005). In two Phase 3 clinical trials 
examining the safety and efficacy of pirfenidone in patients with IPF, the mean decline in 
percent predicted FVC 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. The median survival is about 7 years after the onset of 


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symptoms and 3 years after the initial clinic visit (King, Jr., 2001). In patients over the age of 70, 
the median survival is about 15 months after the initial clinic visit (King, Jr., 2001). 
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). The high mortality rate of IPF and the modest efficacy of approved drugs to treat 
IPF underscore the need to explore new pharmacologic approaches to manage this devastating 
disease. 
1.2 
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). 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 
heparin sulfate proteoglycans (HSPGs) and fibronectin. Interactions with HSPGs may displace 
other HSPG-binding proteins such as 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, 


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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). 
1.3 
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. 
1.4 
Investigational Product FG-3019    
FG-3019 is a fully human, recombinant DNA-derived, IgG1 kappa monoclonal antibody that 
binds to CTGF in the N-terminal domain 2, with high affinity (Kd = 0.1–0.2 nM). The antibody, 
which has a molecular weight of approximately 150 kDa and contains 1326 amino acids, has 
been shown to interfere with the activity of CTGF. For additional information on FG-3019, 
please refer to the current Investigator’s Brochure.  
1.5 
Clinical Trial Experience with FG-3019 
The clinical trial experience with FG-3019 includes seven clinical studies that are described in 
the Investigator’s Brochure (Version 13, 18 December 2014). Overall safety experience with 
FG-3019 has been favorable in studies involving subjects with IPF, pancreatic cancer, liver 
fibrosis due to hepatitis B, and diabetic kidney disease.  
In the Investigator Brochure, exposure of subjects to FG-3019 is displayed in Table 1. Twenty 
one subjects with IPF received a single dose of FG-3019, 89 subjects with IPF received multiple 
doses in an open label trial, and 27 subjects with IPF have received multiple doses of blinded 
study drug (FG-3019 or placebo) in the current trial Overall, FG-3019 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 FG-3019 treatment groups. 
Infusions of FG-3019 have been well tolerated. No infusion has been stopped due to AEs. There 
is no apparent pattern to the SAEs observed during clinical trials, and all SAEs, except one case 
of pain in extremity, were considered by the Sponsor as unrelated to study drug. See the 
Investigator Brochure for additional information. 


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1.6 
Rationale for FG-3019 in Idiopathic Pulmonary Fibrosis 
The observations that CTGF is a central mediator in the process of fibrosis suggest a potential 
role for FG-3019 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).  
A murine model of chronic lung fibrosis demonstrated that FG-3019 attenuated 
radiation-induced lung remodeling (Huber, 2010). In mice treated with FG-3019 for 8 weeks 
starting 3 or 16 weeks after irradiation, no tissue remodeling or fibrosis was observed 30 weeks 
after irradiation, and lung function, as measured by partial pressure of oxygen in arterial blood, 
was normalized compared with mice in the irradiated control groups. Mice treated with FG-3019 
starting 16 weeks after irradiation displayed a significant reversal of lung density, which was 
measured by computed tomography. FG-3019 also improved survival in most groups that 
received FG-3019. Mice that received FG-3019 starting 3 weeks after irradiation had a survival 
rate of 70% at the end of the study (48 weeks after irradiation) compared with 0% survival in the 
irradiated controls (Huber, 2010). In another study, administration of FG-3019 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 FG-3019 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 FVC percent of predicted 
value (Raghu, 2012). In 2012, the FDA granted Orphan Drug Designation to FG-3019 for the 
treatment of IPF. A randomized, double-blind, placebo-controlled trial of FG-3019 30 mg/kg is 
warranted at this time to further assess safety, tolerability, and efficacy in subjects with IPF.  


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2 
OBJECTIVES  
The overall objective of this study is to evaluate the safety and tolerability of FG-3019 in 
subjects with IPF, and the efficacy of FG-3019 for attenuating fibrosis and loss of FVC in these 
subjects. 
2.1 
Primary Safety Objective 
To determine the safety and tolerability of FG-3019 administered at a dose of 30 mg/kg by IV 
infusion every 3 weeks. 
2.2 
Primary Efficacy Objective 
To determine the effect of FG-3019 on FVC (percent of predicted value) when administered at a 
dose of 30 mg/kg by IV infusion every 3 weeks for 45 weeks in the target population. 
2.3 
Secondary Efficacy Objectives 
1. To evaluate the effect of FG-3019 on the extent of pulmonary fibrosis as measured by 
HRCT scans of the chest. 
2. To evaluate the relationship between changes in quantified scores of pulmonary fibrosis 
and clinical outcomes. 
3. To evaluate the effect of FG-3019 on progression of IPF and the frequency of 
respiratory-related hospitalizations and respiratory-related mortality. 
4. To evaluate the effect of FG-3019 on health-related quality of life (HRQoL).  
2.4 
Exploratory Efficacy Objectives 
1. To evaluate the effect of FG-3019 on FVC (liters). 
2. To evaluate the effect of FG-3019 on a panel of serum and plasma biomarkers. 
3. To evaluate the relationship between known chromosomal loci associated with IPF and 
the response to FG-3019. 


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3 
ENDPOINTS AND ASSESSMENTS 
3.1 
Safety Endpoints and Assessments 
• AEs and SAEs 
• Laboratory test abnormalities (graded by NCI Common Terminology Criteria for 
Adverse Events [NCI CTCAE, v4.0]) 
• 12-lead electrocardiograms (ECGs) 
• Physical examinations 
• Human anti-human antibody (HAHA) 
3.2 
Efficacy Endpoints and Assessments 
3.2.1 Primary Efficacy Endpoint 
• Change from baseline in FVC (percent of predicted value) at Week 48. 
3.2.2 Secondary Efficacy Endpoints. 
• Change in pulmonary fibrosis score by quantitative HRCT at Week 24, Week 48, and 
later time points. 
• Change from baseline in HRQoL at Week 24, Week 48, and later time points. 
• Progression of IPF, defined as time from Day 1 to any one of the following: 
o Death from any cause 
o Absolute decline in FVC % of predicted value of ≥10% not due to intercurrent illness, 
confirmed by repeat spirometry.  
o Clinical diagnosis of IPF progression. 
• Proportion of subjects with at least one respiratory-related hospitalization. 
• Proportion of subjects with respiratory-related death, censored at Week 52. 
• Categorical assessment of absolute change from baseline in FVC percent of predicted 
value at Week 48. 
3.2.3 Exploratory Efficacy Endpoints  
• Change from baseline to Week 24 and from baseline to Week 48 in FVC (liters). 
• Change from Day 1 to Week 48 in a panel of serum and plasma biomarkers that will be 
determined by FibroGen. 
• Relationship between known chromosomal loci associated with IPF and the response to 
FG-3019. 


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4 
STUDY DESIGN 
4.1 
Study Population 
Male or female subjects, 40 to 80, years old who have IPF diagnosed in accordance with criteria 
published in the 2011 international consensus guidelines. Subjects who have failed or are 
intolerant of products approved for treating IPF are eligible. 
4.2 
Description of the Study 
This is a Phase 2, randomized, double-blind, placebo-controlled multicenter study. Subjects who 
have failed or are intolerant of products approved for treating IPF are eligible. Other 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 may be randomized to 
placebo. 
Subjects who sign informed consent will undergo screening visits to determine their eligibility. 
Eligible subjects will be stratified based on prior therapy with nintedanib and/or pirfenidone 
(yes/no) and randomized (1:1) to one of two treatment arms: 
 
Arm A: FG-3019, 30 mg/kg  
 
Arm B: Matching placebo 
Approximately 60 centers in the United States and other countries will participate in this clinical 
trial. 
4.2.1 Study Periods 
There are four study periods: 
• Screening Period (up to 6 weeks) 
• Randomized Treatment Period (48 weeks) 
• Extended Treatment Period (sub-set of subjects [see definition above]; duration based on 
changes in FVC (Section 4.2.3) 
• Follow-Up Period (all subjects will undergo a final safety assessment at 4 weeks after last 
dose of study drug.) 
A schematic overview of the trial is provided in Figure 1.  
 
 
 
 
 
 
 
 


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Figure 1. 
Study Schema 
 
4.2.2 Randomized Treatment Phase 
Treatment should begin within 42 days of the first screening visit. Study Drug (FG-3019 
[30 mg/kg] or placebo) will be administered by IV infusion every 3 weeks for a total of 
16 infusions over 48 weeks.  
The schedule of assessments of safety and efficacy are provided in Appendix 1 and Appendix 2. 
Safety and tolerability will be monitored closely by FibroGen. Cumulative safety experience will 
be evaluated by FibroGen on a regular basis. Final efficacy assessment is in Week 48. Subjects 
who do not enter the Extended Treatment Phase will undergo end-of-study (EOS) assessment 
(Appendix 3) on Week 49 (4 weeks after last dose of study drug). 
After all subjects complete Week 48 evaluations or prematurely discontinue the study, data will 
be cleaned and locked for the primary analysis of efficacy and safety.  
4.2.3 Extended Treatment Period (Weeks Identified with –EX Suffix) 
At the time of roll over into the Extended Treatment Period, the study subject treatment 
assignment will be unblinded only to designated personnel not associated with the study at 
FibroGen Inc. To continue to maintain the study blind, the first dose for all subjects in the 
Extended Treatment Period will be administered over approximately 2 hours. 
 
4.2.3.1 Subjects Enrolled under the Original Protocol and Assigned to Arm A: FG-3019 
All subjects in Arm A whose FVC percent predicted value shows less than 3% absolute decrease 
from baseline in the Randomized Treatment Period will be offered participation in an Extended 
Treatment Period. These subjects may continue treatment until FVC percent predicted decreases 
3% or more on two consecutive scheduled evaluations compared to the original pre-treatment 
baseline. 
 
Screening 
Period 
Randomize 
1:1
FG- 3019 
48 - Week 
Blinded 
Treatment 
Phase 
Extended 
Treatment Phase 
Assessment at 
Wk 48 (or early 
termination) 
Placebo 
All FG-3019 
Subjects
Week 49 End-of-
study visit  
All Placebo 
Subjects 
Yes
No
≥ 
l≤0% change 
FVC% predicted 


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4.2.3.2 Subjects Enrolled Under Amendment 1 or Subsequent Amendments and Assigned 
to Arm A: FG-3019 
All subjects in Arm A whose FVC percent predicted value is greater than the original pre-
treatment baseline in the Randomized Treatment Period will be offered participation in an 
Extended Treatment Period and may continue treatment until FVC percent predicted is equal to 
or less than the pre-treatment baseline on two consecutive scheduled evaluations. 
 
4.2.3.3 Subjects Enrolled Under the Original Protocol or Amendment 1 and Subsequent 
Amendments Assigned to Arm B: Placebo 
All subjects assigned to Placebo (Arm B) will be offered participation in the Extended Treatment 
Phase for 45 weeks. Placebo subjects in the extension study are treated identically to subjects 
randomized to FG-3019 in Amendment 1, except for the fact that the baseline for these patients 
is the time at which they are enrolled into the extension phase (Baseline for Placebo subjects is 
Week 48 value). Change in FVC percent predicted during the extended treatment phase will be 
compared to this new baseline. Those subjects whose FVC percent predicted value  is either 
equal to or greater than the new baseline may continue treatment with FG-3019 until FVC 
percent predicted is equal to or less than the baseline on two consecutive scheduled evaluations. 
See Section 4.2.3 for details regarding the Extended Treatment Period. 
4.2.4 End of Treatment and Follow-up 
4.2.4.1 Randomized Treatment Phase 
• Subjects assigned to either FG-3019 or placebo who discontinue treatment before week 
48 should undergo end of treatment and safety assessment visits (Appendix 3). 
• Subjects who were assigned to FG-3019 complete 48 weeks of treatment and are not 
going on to the Extended Treatment Period should undergo a Safety Assessment visit 
(Appendix 3); Week 48 evaluation is identical to End of Treatment visit. Thus, subjects 
who complete Week 48 and are not eligible for the extension study only need the final 
safety assessment. Subjects who enter the Extended Treatment Period do not need a final 
safety assessment because they are continuing treatment). 
• Subjects who were assigned to placebo who complete 48 weeks of treatment but do not 
enter the Extended Treatment Period should undergo a safety assessment as described in 
Appendix 3. 
4.2.5 Extended Treatment Phase 
• Subjects who were assigned to FG-3019 and continue in the Extended Treatment Period 
will undergo early termination and safety assessment visits (Appendix 3) at the time they 
discontinue treatment unless they discontinue treatment at Week 48 EX. In this case, they 
only undergo the safety assessment visit. This is applicable whether subjects stop before 
or after week 48 EX.  
• Subjects who were assigned to placebo, and receive FG-3019 in the Extended Treatment 
Phase and then discontinue treatment at Week 48 of the Extended Treatment Period 
should undergo a Safety Assessment visit (Appendix 3).  
 


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• Subjects who were assigned to placebo, and receive FG-3019 in the Extended Treatment 
Phase who discontinue treatment prior to Week 48 of the extended treatment period will 
undergo early termination and safety assessment visits (Appendix 3) at the time they 
discontinue treatment.  
4.2.6 Placebo Control Group 
In order to evaluate the effect of treatment with FG-3019 on the endpoints described in 
Section 3, approximately 50% of subjects will be randomized to placebo treatment (Arm B). 
The placebo control is appropriate for this trial given the population of participating subjects. 
Enrolled subjects are those who have failed or are intolerant of approved therapies and who 
refuse to receive approved therapies. For these subjects the only treatment option is best 
supportive care, which is available to them within this protocol, and optionally experimental 
treatment. Therefore, placebo control, which provides for the best supportive care, is appropriate 
and ethical. Additionally, subjects who are randomized to placebo will be offered crossover 
treatment to the active arm after completion of the initial 48-week treatment period. 
4.3 
Treatment Assignment 
Subjects are stratified by prior therapy with pirfenidone and/or nintedanib (yes/no) and 
randomized 1:1 to FG-3019 or placebo using an Interactive Web Response System (IWRS). 
4.4 
Blinding 
4.4.1 Rationale for Blinding 
Blinded 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 FG-3019. 
4.4.2 Maintenance of Blinding 
A statistician who is not otherwise affiliated with the study prepared the randomization code and 
the code is not available to study staff. The subjects, clinical site staff, and the FibroGen Medical 
Monitor and Clinical Operations staff will be blinded to whether a subject is randomized to 
FG-3019 or placebo. Study drug (FG-3019 or placebo) are provided in coded vials that are 
identified by serial number only. 
4.4.3 Unblinding of Treatment Assignment 
Treatment assignment of individual subjects will be unblinded during the study if this 
information is required to manage a SAE. Study documentation provides details on the 
procedures for unblinding treatment assignment by investigators. For planned assessments of 
efficacy, treatment assignment by groups will be unblinded but individual subject treatment 
assignments will not be unblinded. Treatment will be unblinded for each subject after completion 
of the Week 48 evaluations by unblinded FibroGen personnel. Subject eligibility for the 
Extended Treatment Phase will be communicated to the site. 
Unblinding will also occur at the time of enrollment of subjects into the at Extended Treatment 
Period, after all week 48 assessments are complete only for designated individuals at FibroGen 
Inc. who are not associated with the conduct of this study. The Investigators, subjects and study 
teams will remain blinded till the study is complete. 


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4.5 
Study Treatment with FG-3019 
Subjects will receive FG-3019 at a dose of 30 mg/kg by IV infusion in normal saline  (unless 
volume is >250mL in which case the study drug can be administered undiluted)  every 3 weeks. 
The maximum dose of FG-3019 at any infusion will be capped at 3,900 mg. 
4.6 
Concomitant Medications, Procedures and Nondrug Therapies 
4.6.1 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 Screening Visit 1 through the End-of-Study (EOS) Visit.  
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 management of 
idiopathic pulmonary fibrosis and that subjects may be treated with concomitant medications for 
their various medical conditions. Optimal medical care must be provided, and Investigators 
should ensure, for example, that subjects maintain stable vital signs and laboratory test values 
during the course of the study. 
Oral prednisone or equivalent oral corticosteroid (up to 10 mg daily) and NAC (up to 1800 mg 
daily) will be allowed during the study. 
Prohibited medications include approved 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, pirfenidone, nintedanib, azathioprine, 
cyclophosphamide, cyclosporine, interferon gamma 1b, D penicillamine, methotrexate, 
leflunomide, colchicine, bosentan, ambrisentan, aminobenzoate, mycophenolate mofetil, 
imatinib, relaxin, etanercept, adalimumab, infliximab, anakinra, abatacept, and rituximab. If 
sildenafil is used for erectile dysfunction the dosage regimen should be no more than three times 
a week. Immunosuppressives and monoclonal antibodies used for other diseases such as 
rheumatoid arthritis are allowed but the indication should be clearly documented. Indications for 
concomitant medications should be clearly documented in the subjects clinical record (use for 
IPF or other diseases). 
Any medications to treat IPF should be terminated within 5 half-lives of Day 1 dosing. If 
monoclonal antibodies are used the last dose must be at least 4 weeks before Day 1 dosing 
(Exclusion criterion 15). 
Questions about concomitant medications should be addressed to the attention of the FibroGen 
Medical Monitor or designee. 
4.6.2 Contraception 
Female subjects of childbearing potential and male subjects with female partners of childbearing 
potential are required to use double barrier contraception methods during the conduct of the 
study and for 3 months after the last dose of study drug.  
Pregnancy, spontaneous or therapeutic abortion, or events related to pregnancy must be reported 
(Section 11.3.6). 


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4.7 
Safety Plan 
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, 
complete and focused physical examinations, 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.  
4.8 
Independent Data Monitoring Committee 
4.8.1 Safety Monitoring 
Safety data in this double-blind placebo-controlled study will be monitored on a regular basis by 
a Data Monitoring Committee (DMC) that is independent of the FibroGen Medical Monitor and 
Clinical Operations staff. FibroGen is responsible for the establishment of this DMC, the 
development of a DMC charter, and supporting DMC meetings. 


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5 
ELIGIBILITY CRITERIA 
FibroGen will not grant waivers to Inclusion Criteria and Exclusion Criteria in this protocol. 
5.1 
Inclusion Criteria 
1. Age 40 to 80 years, inclusive. 
2. Diagnosis of IPF as defined by current international guidelines (Raghu, 2011). Each 
subject must have one of the following: (1) Usual Interstitial Pneumonia (UIP) Pattern 
on an available HRCT scan; or (2) Possible UIP Pattern on an available HRCT scan and 
surgical lung biopsy within 4 years of Screening showing UIP Pattern (HRCT criteria for 
UIP Pattern and Possible UIP Pattern and histopathological criteria for UIP Pattern 
described in Appendix 4). 
3. History of IPF of ≤5 years duration with onset defined as the date of the first diagnosis of 
IPF by HRCT or surgical lung biopsy. 
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, as determined by the HRCT central reader. 
5. FVC percent of predicted value ≥55% at Screening. 
6. Female subjects of childbearing potential (including those <1 year postmenopausal) and 
male subjects with female partners of childbearing potential, must use double barrier 
contraception methods during the conduct of the study, and for 3 months after the last 
dose of study drug.  
5.2 
Exclusion Criteria 
1. Female subjects who are pregnant or nursing. 
2. Infiltrative lung disease other than IPF, including any of the other types of idiopathic 
interstitial pneumonias (Travis, 2013); 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 and connective tissue diseases.  
3. HRCT scan findings at Screening are inconsistent with UIP Pattern, as determined by the 
HRCT central reader (a definition of Inconsistent with UIP Pattern is provided in in 
Appendix 4). 
4. Pathology diagnosis on surgical lung biopsy is anything other than UIP Pattern, as 
determined by the local pathologist (Appendix 4). 
5. The Investigator judges that there has been sustained improvement in the severity of IPF 
during the 12 months prior to Screening, based on changes in FVC, diffusing capacity of 
the lung for carbon monoxide (DLCO), and/or HRCT scans of the chest. 


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6. 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 endpoints in the protocol or otherwise 
preclude the subject’s participation in the study. 
7. History of any other respiratory, cardiovascular, renal, hepatic, metabolic, neurologic, 
hematologic, or other medical conditions that, in the opinion of the Investigator, would 
preclude the subject’s participation in the study. 
8. 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. 
9. Upper or lower respiratory tract infection of any type within 4 weeks of Screening. 
10. Acute exacerbation of IPF within 3 months of Screening (a definition of acute 
exacerbation of IPF is provided in Section 8. 
11. Evidence of obstructive lung disease by any of the following criteria: forced expiratory 
volume in 1 second/forced vital capacity (FEV1/FVC) ratio <0.70, or extent of 
emphysema on HRCT greater than the extent of fibrosis on HRCT. 
12. DLCO <30% of the predicted value. 
13. High likelihood of lung transplantation (in the opinion of the Investigator) within 6 
months after Day 1. 
14. Poorly controlled chronic heart failure; clinical diagnosis of cor pulmonale requiring 
specific treatment; or severe pulmonary hypertension requiring specific treatment that, in 
the opinion of the Investigator, would preclude the subject’s participation in the study.  
15. Use of medications to treat IPF within 5 half-lives of Day 1 dosing. If monoclonal 
antibodies were used, the last dose of the antibody must be at least 4 weeks before Day 1 
dosing. 
16. Use of any investigational drugs, including any investigational drugs for IPF, within 
4 weeks prior to Day 1 dosing. 
17. History of cancer diagnosis of any type in the 3 years preceding Screening, excluding 
non-melanomatous skin cancer, localized bladder cancer, or in situ cancers.  
18. Clinically significant trauma or surgical procedures within 4 weeks prior to dosing. 
19. Planned elective surgery during the study including 4 weeks following the final dose of 
Study Drug. 
20. History of allergic or anaphylactic reaction to human, humanized, chimeric or murine 
monoclonal antibodies. 
21. 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. 
22. Body weight >130 kg. 


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23. Previous treatment with FG-3019. 
24. Inadequate IV access. 


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6 
STUDY DRUG/TREATMENT SUPPLY 
6.1 
FibroGen Investigational Product 
FG-3019 is a fully human IgG1 kappa monoclonal antibody that binds to CTGF. It will be 
administered at a dose of 30 mg/kg by IV infusion in a total volume of 250 mL (up to 400 mL if 
necessary) normal saline every 3 weeks. The maximum dose of FG-3019 will be capped at 
3,900 mg. Labels will be prepared in accordance with Good Manufacturing Practice and local 
regulatory guidelines. The labels will fulfil Good Manufacturing Practice Annex 13 requirements 
for labelling. Label text will be translated into local language. 
The patient emergency contact details will not be on the label, but can be found in the informed 
consent.  
6.1.1 Formulation 
FG-3019 is supplied in single-use glass vials containing 10 mL of a sterile, preservative-free 
solution. The solution is composed of 10 mg/mL FG-3019, 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.  
6.2 
Reference Therapy (Placebo) 
Placebo (identical to the FG-3019 vehicle) is handled and administered in a manner that is 
identical to FG-3019.  
6.2.1 Formulation 
Placebo is a sterile, aqueous solution of pH 6.0 for dilution into 0.9% serum chloride injection 
USP prior to IV infusion. The solution formulation contains 8.01 mg/mL sodium chloride, 
3.08 mg/mL L-histidine HCL, 1.60 mg/mL L-histidine, and 0.05 mg/mL polysorbate 20. The 
solution is free of preservatives as the content of each vial is intended for single use. Each vial 
delivers a nominal volume of 10 mL.  
6.3 
Preparation of Dose and Administration  
The dose of Study Drug (FG-3019 [30 mg/kg] or placebo) for each infusion will be based on the 
Day 1 weight for the first 12 weeks. Total volumes of <250 mL must be diluted in 0.9% Sodium 
Chloride Injection according to the Dose Preparation Instructions in the Study Reference 
Manual. Total volumes of >250 mL FG-3019 can be infused undiluted. The dose should be 
prepared in a volume of fluid that does not exceed 400 mL. Study Drug will be administered as 
soon as possible after release from the site’s pharmacy and within 8 hours of preparation. Study 
Drug will be administered by IV infusion, using an infusion set with a sterile, nonpyrogenic, 
low-protein-binding in-line filter (0.2-micron pore size).  
The first administration of Study Drug in any given subject in the Randomized Treatment Period 
as well as the Extended Treatment Period shall be completed in approximately 2 hours. If the 
first administration is well tolerated and no drug-related AEs are observed during the infusion or 
subsequent 1-hour observation period, the second administration of Study Drug shall be 
completed in approximately 1 hour. All subsequent infusion periods, including those in the 
Extended Treatment Phase, may be shortened to approximately half an hour. If a drug-related AE 
occurs during the first or a subsequent infusion, Study Drug will be administered over 


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approximately 1 hour for the next three infusions. If no drug-related AEs are observed in any of 
these three infusions, the duration of infusion may be decreased to approximately half an hour.  
A physician must be immediately available during the first Study Drug infusion and observation 
period for each subject. If a subject has a significant infusion reaction, the infusion rate may be 
slowed or temporarily stopped, depending on the severity of symptoms. If a subject experiences 
a significant infusion reaction and continues Study Drug dosing, a physician should be 
immediately available during all subsequent infusions and observation periods. If the 
Investigator wishes to use premedication, e.g., antihistamines, nonsteroidal anti-inflammatory 
drugs (NSAIDs) for a subsequent infusion, this should be discussed with the FibroGen Medical 
Monitor or designee. Infusions are to be continued until the total volume of the infusion has been 
administered. Subjects will remain at the study site for 1 hour after the end of the infusion for 
clinical observation. The post-infusion observation period may be reduced to 30 minutes if the 
subject has had no infusion-related AEs after three infusions. The IV line should remain in place 
and maintained per site procedures until the end of this post-treatment observation period.  
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 an FG-3019 overdose or infusion reaction. Signs and symptoms should be managed 
with appropriate standard of care treatment.  
The following procedures must be performed during each infusion: 
Vital signs (blood pressure [BP], pulse, respiration rate, and temperature) every 30 minutes 
(± 10 minutes) 
Query subject and assess AEs and SAEs  
Record concomitant medications, including any pre-medication pre-approved by the FibroGen 
medical monitor or designee 
The following procedures must be performed after each infusion: 
Vital signs (BP, pulse, respiration rate, and temperature) every 30 minutes (± 10 minutes) for a 
minimum of 30 minutes after completion of the infusion (see above) 
Query subject and assess AEs and SAEs 
Record concomitant medications 
6.4 
Storage  
Vials of Study Drug must be stored refrigerated (2°C to 8°C), temperature-controlled and 
monitored, 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. 


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7 
STUDY PROCEDURES-ALL COHORTS UNLESS OTHERWISE SPECIFIED 
7.1 
Study Procedures 
The study procedures and assessments are presented for the Randomized Treatment phase in 
Appendix 1, for the Extended Treatment phase in Appendix 2, and for End-of-Treatment and 
Follow-up periods in Appendix 3. See the Study Reference Manual for additional details. 
The treatment period in the Randomized Treatment Phase begins on Day 1 (first infusion of 
Study Drug) and continues through Week 48. Visit windows are within ± 3 days of the scheduled 
visit date for Weeks 3 through 48. 
After completion of Week 48 assessments and reporting of all AEs, subjects may be eligible to 
continue to open label treatment in the Extended Treatment Phase. All other subjects undergo the 
EOS assessments. 
Eligible subjects from the Randomized Treatment Phase of the study are offered participation in 
the Extended Treatment Phase as described under Section 4.2.3 and illustrated in Figure 1. A 
Transition Period of up to 3 weeks between the Week 48 Visit in the Randomized Treatment 
Period and Day 1-EX in the Extended Treatment Phase is provided in order to determine subject 
eligibility for the Extended Treatment Phase and to arrange scheduling of the Day 1-EX Visit. 
The total interval between the Week 45 Visit in the Randomized Treatment Phase and the Day 
1-EX Visit in the Extended Treatment Phase should not exceed 6 weeks. If necessary, an 
unscheduled visit should be performed to obtain repeat pulmonary function tests (FVC) if the 
interval between the Week 45 Visit in the Randomized Treatment Phase and the Day 1-EX Visit 
in the Extended Treatment Phase is expected to exceed 6 weeks.  
The treatment period in the Extended Treatment Phase begins on Day 1-EX (first infusion of 
FG-3019) and continues until progression or withdrawal. Visit windows are within ± 3 days of 
the scheduled visit date.  
7.2 
Serial PFT and HRCT 
The key study procedures that measure efficacy are serial PFT measurements to look at 
spirometry (see Procedure Manual for PTF for additional details) and serial HRCT assessments 
to look for fibrosis (see Site Manual for HRCT and Appendix 5). 
7.3 
Blood Volume 
The total amount of blood taken is approximately 13 tablespoons (195 ml) in the Randomized 
Treatment Phase and 10 tablespoons (150 ml) per year in the Extended Treatment Phase (total 23 
tablespoons (345ml) for two years. Subjects who continue Extended Treatment beyond one year 
will give approximately 150 mL of blood per year.  
7.4 
Missed Visits 
Every attempt should be made to complete all study visits within window as outlined in the 
Schedule of Assessments (Appendix 1, Appendix 2, and Appendix 3).  
Scheduled visit dates are determined from the time of the first dose, which is defined as Day 1. 
Protocol-defined visits conducted outside the ± 3 day study visit window will be recorded as a 
protocol deviation unless there is an AE/SAE/intercurrent illness. If a dose is delayed due to an 
AE/SAE/illness, the next dose should occur as soon as possible when the patient is stable so that 


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the dosing interval is close to 3 weeks. No subject should receive more than one dose in any 
7-day period. Missed doses are not to be made up through undertaking 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. Subjects who miss three sequential 
doses or more than one instance of two sequential doses will not be allowed to continue in the 
study and will be terminated early. The reason for missed doses should be documented in the 
subject’s clinical record. 
For missed visits without an AE/SAE/intercurrent illness, the subject will be asked to resume the 
planned visit schedule and return for the next scheduled visit. If the subject is unable to perform 
PFTs at a scheduled visit the PFT can be performed at the next scheduled visit. 
Refer to the case report form (CRF) completion guidelines in the Study Reference Manual for 
additional information on CRF completion requirements for missed visits.  
7.5 
Unscheduled Visits 
Unscheduled Visit assessments may be required at the discretion of the Investigator. These 
should be recorded on the appropriate CRF. 
Subjects who, in the judgment of the PFT technician or investigator, are unable to perform PFTs 
adequately on a scheduled visit should undergo PFT assessment at the next scheduled visit or 
sooner if feasible. 
7.6 
Assessments 
7.6.1 Central Laboratory 
All laboratory tests of blood and/or urine specimens will be performed by a central laboratory or 
FibroGen, as appropriate. A Central Laboratory Manual with instructions on specimen 
collection, processing, storing, and shipping to the central laboratory will be provided to all 
participating sites. 
7.6.2 Local Laboratory(s) 
A local laboratory will analyze urine (and blood, if necessary) samples for pregnancy testing 
only. 
7.6.3 Other Reference Laboratories 
Human anti-human antibody plasma level measurement will be performed at a specialty 
laboratory. 
7.6.4 Exploratory Biomarkers 
Serum and plasma samples will be stored and used to explore additional biomarkers of 
FG-3019’s effects. The final selection of these biomarkers will be made by FibroGen, based 
upon the best scientific data available at that time. 
7.6.5 DNA for Genomic Analysis 
Fingerlin et al performed a genome-wide association study 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), 


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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 FG-3019 and variants in these specific chromosomal 
loci. 
A whole blood sample will be collected for DNA analysis on Day 1 before dosing or at 
subsequent visits for subjects already enrolled in the study 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 IPF will be performed and all samples 
will be destroyed after testing is completed. 


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8 
SUBJECT DISCONTINUATION 
Subjects who discontinue the study early should be strongly encouraged to complete the 
End-of-Treatment and Follow-up Visit (Appendix 3).  
Subjects may withdraw from the study at any time for any reason, whether during the Screening, 
Treatment, or Follow-up Periods. Completion of efficacy assessments as outlined in Appendix 3 
is discretionary and must be discussed in advance with the FibroGen Medical Monitor.  
The Investigator must remove a subject from study treatment for the reasons below. Removing a 
subject from study treatment is based on the judgment of the Investigator in consultation with the 
FibroGen Medical Monitor. 
• Pregnancy in a female subject 
• AEs, SAEs, repeated hospitalizations, or medical conditions that make further 
participation in the study a risk to the subject.  
• Clear evidence of progression of IPF and or absolute decline in FVC % of predicted 
value of ≥10%  in the absence of an intercurrent illness, documented by two consecutive 
spirometry tests. 
• Receipt of a prohibited medication that cannot be discontinued. 
Dosing may be temporarily suspended up to 4 weeks for:  
• Acute exacerbation of IPF, defined as (1) worsening or newly developed dyspnea as 
reported by the subject (≤30 days); (2) new bilateral ground-glass opacities on HRCT 
superimposed on the UIP abnormalities that defined subject eligibility for the study 
(Section 5.1); and (3) worsening hypoxemia (in the judgment of the Investigator), in the 
absence of pulmonary infection, heart failure, or other identifiable causes for this finding. 
• Any other intercurrent illness that temporarily precludes the subject receiving the study 
drug infusion. 
The reasons for suspension of treatment should be clearly documented in the subject’s clinical 
record. 
8.1 
Replacement of Subjects  
At the Sponsor’s discretion, the number of subjects who are enrolled may be increased to 
account for early dropouts if the dropout rate is projected to be greater than 10%. 


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9 
STUDY TERMINATION BY FIBROGEN 
FibroGen has the right to terminate this study or to close any site at any time.  
FibroGen may also suspend enrollment temporarily at any time for business or other reasons. 
If the planned interim analysis indicates a lack of efficacy, FibroGen will terminate the Extended 
Treatment Period and dosing will cease for all subjects.  


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10 STATISTICS 
10.1 Sample Size Determination 
This study is planned to enroll approximately 136 subjects, which will include a target of 
110 subjects who are seeking first-line therapy and 26 subjects who failed pirfenidone and/or 
nintedanib treatment. First-line therapy is defined as no prior therapy with pirfenidone/nintedanib 
or <10% relative decrease in FVC % predicted while receiving either pirfenidone or nintedanib. 
Failure of pirfenidone and or nintedanib treatment is defined as having ≥10% relative decrease in 
FVC % predicted during prior pirfenidone/nintedanib treatment. The effect of first-line treatment 
is the primary interest of the study, and is the basis for sample size determination. Assuming a 
10% dropout rate and a common standard deviation of 7.3, a sample size of 55 subjects per arm 
in the primary analysis population provides approximately 80% power to detect a treatment 
difference of 4.2 in change from baseline to Week 48 in percent predicted FVC, using a 
two-sample t-test at the two-sided significance level of 0.05. The expected treatment difference 
is estimated using data from study FG-3019-049 and placebo data from published studies. In 
Study FG-3019-049, a mean decline of 2.8 in % predicted FVC from baseline to Week 48 was 
observed. The expected decline of 7.0 % predicted FVC in the placebo arm is estimated based on 
the weighted average of published studies (Azuma, 2005, Daniels, 2010, Demedts, 2005, King, 
Jr., 2008, King, Jr., 2009, King, Jr., 2011, Meier-Kriesche, 2004, Noble, 2011, Noth, 2012, 
Raghu, 2004, Raghu, 2008, Raghu, 2012, Richeldi, 2011, Taniguchi, 2010, Zisman, 2010).  
Second line therapy patients are evaluated in an exploratory fashion. If the treatment effect in the 
pirfenidone/nintedanib failure group is similar to that in the general population, the two 
subgroups will be combined to achieve higher power.  
10.2 Analysis Populations 
10.2.1 Safety Population 
The Safety Population will consist of all randomized subjects who received any dose of study 
medication. If actual treatment received differs from the randomized treatment arm, the actual 
treatment arm will be used for safety data analysis. 
10.2.2 Full Analysis Set Population 
The Full Analysis Set (FAS) Population will consist of randomized subjects who received at 
least one dose of study drug and have evaluable FVC assessments at baseline and at least one 
evaluable post baseline. The FAS population will be used in the primary analyses of the PFT 
endpoints and other efficacy endpoints except for PFS. 
10.2.3 HRCT Evaluable Population 
The HRCT Evaluable (HE) Population will consist of randomized subjects who have evaluable 
HRCT fibrosis scores at baseline and at Week 24 or at a later time point. The HE population will 
be used in the analyses related to HRCT fibrosis scores. 


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10.3 Statistical Analysis 
10.3.1 General Analysis Methods 
Unless the planned interim analysis at the end of the Randomized Treatment Phase indicates a 
lack of efficacy, the study is completed when the last subject completes the last visit in the 
Extended Treatment Phase. 
Baseline characteristics, safety, and biomarker data will be summarized based on available data 
in the Safety Population, except for the parameters indicated otherwise. The primary efficacy 
analyses will be based on the FAS population, except for the analysis of PFS, which will be 
based on the Safety Population. All safety, efficacy, and exploratory endpoints will be 
summarized by group of actual treatment received. 
All randomized subjects will be included in the data listings. 
Continuous variables will be presented by descriptive statistics: n, mean, standard deviation, or 
standard error, median, minimum, and maximum. Categorical variables will be presented by 
counts of subjects and percentage.  
10.3.2 Subject Enrollment and Disposition 
The total number of subjects who completed or discontinued the study, and reasons for early 
discontinuation will be summarized for all randomized subjects. 
10.3.3 Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for subjects in different analysis 
populations and subgroups. Baseline data related to safety and efficacy assessments will be 
summarized with the post-baseline data in the corresponding safety and efficacy sections. 
10.3.4 Efficacy Analyses 
The primary efficacy analyses will be performed in subjects in the FAS population except for 
analyses of PFS, which will be based on the Safety Population. Rules of missing data imputation 
will be described in the SAP. Analyses based on observed data will be used for sensitivity 
analyses. 
10.3.4.1  Primary Efficacy Analysis 
The primary analysis will be to compare the treatment arms in change from baseline to Week 48 
in FVC % predicted based on the FAS Population. A rank ANCOVA model will be used, with 
baseline FVC % predicted value as covariate, treatment group, stratification, and treatment by 
stratification interaction as fixed effects. Factors may be eliminated from the model if they are 
insignificant. If the interaction term is significant, the primary analysis will be based on the 
subgroup of subjects on first-line therapy.  
The ranks of the primary endpoint will be based on observed data and on imputed data if 
observed data are not available. A detailed description of the rank assessment will be described 
in the statistical analysis plan. A repeated measures model utilizing all observed data will be used 
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Descriptive summaries of the primary efficacy parameter will include the following: 
1. Median change from baseline by treatment and visit 
2. % of subjects with no decline by treatment and visit 
3. % of subjects with decline ≥10% by treatment and visit 
10.3.4.2 Analyses of Secondary Efficacy Endpoints 
Similar models to those described above will be applied to analyzing changes in other PFT 
parameters, HRCT fibrosis score, and patient-reported outcome.  
10.3.4.3 Analysis of Progression Free Survival 
PFS is defined as the time from randomization to the first occurrence of the following events 
during the study (whichever occurs first): 
1. Death from any cause 
2. Absolute decline FVC percent of predicted value of ≥10% not due to intercurrent illness 
confirmed by repeat spiromeetry 
3.  Clinical diagnosis of progression of IPF 
The analysis of PFS will be based on the Safety Population. If no PFS event is observed during 
the study, then PFS is censored at the last PFT assessment. 
Comparison between treatment arms in PFS will be performed using the Cox regression model 
with adjustment for baseline FVC % predicted value as well as stratification and stratification by 
treatment interaction. 
10.3.4.4 Analysis of IPF DNA Markers 
Exploratory analyses will be performed to evaluate the relationship between clinical response to 
FG-3019 and variants in the chromosomal loci listed in Section 7.6.5 
10.3.5 Safety Analyses 
Treatment-emergent adverse events (TEAEs), defined as new or worsening AEs that occur after 
the first dose of study drug and within 4 weeks of last dose of study drug, will be tabulated to 
examine their frequency, severity, organ systems affected and relationship to study treatment. 
Treatment emergent SAEs and TEAEs leading to study or treatment discontinuation will be 
listed or tabulated separately.  
Clinically significant changes from baseline in vital signs, laboratory tests, physical 
examinations, and ECGs will be identified.  
Human anti-human antibody data will be summarized in a separate report. 
10.3.6 Interim Analyses 
Unblinded analysis of changes in pulmonary function and in pulmonary fibrosis will be 
performed after all subjects have either completed Week 48 assessments or discontinued the 
study early (prior to week 48 of the Randomized Treatment Phase). This analysis may be 
performed before data lock for the primary analysis of safety and efficacy provided the relevant 
pulmonary function and pulmonary fibrosis data are cleaned. If there is a substantial gap in 
completion of enrollment between subjects on first-line therapy and the pirfenidone and or 
nintedanib treatment failures, unblinded subgroup analysis may be performed at different times.  


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10.4 Statistical Analysis Plan 
The SAP will include detailed plans for presenting and analyzing study data, as well as 
documentation of changes in protocol-specified analysis plans.  
 


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11 ASSESSMENT OF SAFETY 
11.1 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 outlines in Appendix 1, 
Appendix 2, and Appendix 3. 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 all SAEs, regardless of whether the Investigator believes they are related to 
the study drug. 
The definitions of an AE, suspected adverse reaction, adverse reaction, and SAE are describe 
below in accordance with the FDA Final Rule Vol 75, No 188, September 29, 2010, and/or 
Article 18 of Directive 2001/20/EC of the European Parliament and of the Council of 4 April 
2001 and the International Conference on Harmonisation (ICH) E2A guidance.  
11.2 Definitions 
11.2.1 Definition of an Adverse Event (AE) 
An AE can be any unfavorable and unintended sign (e.g., an abnormal and clinically significant 
laboratory finding), symptom, or disease temporally associated with the use of a drug, without 
any judgment about causality. This includes any occurrence that is new in onset or aggravated in 
severity or frequency from the baseline condition, or abnormal results of diagnostic procedures, 
including laboratory test abnormalities. An AE can arise from any use of the drug (e.g., off-label 
use, use in combination with another drug) and from any route of administration, formulation, or 
dose, including an overdose.  
An AE includes medical conditions, signs, and symptoms not previously observed in the subject 
that emerge during the protocol-specified AE reporting period, including signs or symptoms 
associated with an underlying condition that were not present prior to the AE reporting period 
(Section 11.3.1). 
11.2.2 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 
• Other medically important events 


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Based upon appropriate medical judgment, important medical events that may not result 
in death, be life-threatening, or require hospitalization may be considered serious when, 
they may jeopardize the subject or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. These 
events must be reported to the sponsor similar to SAEs. 
• A clinical diagnosis of IPF progression and surgical procedures such as lung 
transplantation are expected in this patient population. Data for IPF progression is being 
collected an efficacy endpoint (Sections 3.2.2, 10.3.4.3). However, as these events are 
medically significant and may be associated with hospitalization, so they should be 
reported as SAEs.  
• Other elective surgeries (example knee replacement, haemorroidectomy, mole removal 
etc.) may occur during the study period. They should not be reported as SAEs, but the 
diagnosis that warranted these procedures should be reported (especially if this is a 
worsening of a pre-existing medical history condition). Any complications of such 
procedures should be reported as AE/SAE based on seriousness criteria listed above. 
11.2.3 Definition of a Suspected Adverse Reaction 
Suspected adverse reaction means any AE for which there is a reasonable possibility that the 
drug caused the AE. The term “reasonable possibility” means there is evidence to suggest a 
causal relationship between the drug and the AE. A suspected adverse reaction implies a lesser 
degree of certainty about causality than the term “adverse reaction”. 
11.2.4 Definition of an Adverse Reaction 
An adverse reaction means any AE caused by a drug. 
11.2.5 Special Situations 
Safety events of interest (“Special Situations”) on the medicinal products administered to the 
subject as part of the study (e.g., study drug, comparator, and background therapy) that may 
require expedited reporting and/or safety evaluation include, but are not limited to: 
• Overdose of the medicinal product 
• Suspected abuse/misuse of the medicinal product 
• Inadvertent or accidental exposure to the medicinal product 
• Medication error involving the medicinal product (with or without subject exposure to the 
Sponsor medicinal product, e.g., name confusion) 
• Drug-drug interaction  
11.3 Procedures for Eliciting, Recording, and Reporting Adverse Events 
11.3.1 Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be collected begins after informed 
consent is obtained and ends 4 weeks after the last dose of study drug, except for pregnancy 


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reporting (Section 11.3.6). In addition, all AEs reported spontaneously by the subject to site 
personnel, outside the study period, may be recorded. 
Adverse events will be followed until resolved, stable, or until the subject’s last study visit or lost 
to follow-up. If an AE is not resolved or stabilized at the subject’s last visit, it is up to the 
discretion of the Investigator and study Medical Monitor to determine if further monitoring of 
the event is warranted. 
Adverse events collected prior to dosing of study drug will be considered “non-treatment 
emergent” while those reported after the first dose of study drug and up to 4 weeks after the last 
dose of study drug will be considered “treatment emergent” and will be assessed for relationship 
to study drug. 
11.3.2 Adverse Event Eliciting/Reporting 
During the AE reporting period, study site personnel will query each subject at each visit to 
actively solicit any AE 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 baseline 
or previous visit, but shall not be specifically solicited. There will be no directed questioning for 
any specific AE. This does not preclude 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. New indications for 
medications started after informed consent is obtained until 4 weeks after the last dose of study 
drug will be recorded as AEs; recurrence or worsening of medical history problems requiring 
new or changes in concomitant medication, will also be recorded as AEs. Abnormal, clinically 
significant laboratory results, physical examination findings, and ECGs will be recorded as AEs 
if they are deemed by the Investigator to meet criteria. 
The following attributes must be assigned to each AE: 
• Description (Investigator’s verbatim term describing the event) 
• Dates of onset and resolution 
• Severity 
• Relationship to study drug  
• Outcome 
• Action taken regarding study drug 
• Other treatment required 
• Determination of “seriousness” 
11.3.3 Assessing Adverse Event Severity 
Adverse Events, including abnormal clinical laboratory values, should be graded using the 
National Cancer Institute (NCI) Common Terminology Criteria for AE (CTCAE) guidelines 
(Version 4.03; http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf). For terms not specified as part of NCI CTCAE, the following 
guidelines should be used to determine grade: 


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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; clinical or diagnostic observations only; 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: Death related to AE.  
11.3.4 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. Moreover, appropriately 
deciding whether the AE meets the definition of a suspected adverse reaction is usually the most 
difficult determination, but it is critical to avoid the miscategorization of the product’s safety 
profile.  
Due to the historical tendency for assessment of relationship to default as possibly related, the 
FDA has issued new guidance that clarifies the intent of the phrase “reasonable possibility” in 
the definition of “associated with the use of the drug.”  Default reporting of individual events as 
possibly related is uninformative and does not meaningfully contribute to the development of the 
product safety profile.  
The Investigator must provide an 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 enough evidence to assess an event as possibly related or related to study drug.  
• Related (Adverse Reaction): 
o Any event for which there is evidence to conclude that the study drug caused the 
event 
• Possibly Related (Suspected Adverse Reaction): 
o A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure, such as angioedema, anaphylaxis, 
rhabdomyolysis, Stevens-Johnson syndrome, etc. 
o One or more occurrences of an event that is not commonly associated with drug 
exposure but is otherwise uncommon in the population exposed to the drug, such 
as tendon rupture 


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• Not Related: 
o The event represents the underlying disease (e.g., disease-related symptoms, 
disease progression) 
o The event represents a comorbid condition present at the time the subject entered 
the study that has not worsened 
o The event represents a known adverse reaction associated with a co-medication 
received by the study subject 
o The event is common for the study population (e.g., cardiovascular events in an 
elderly population) 
The Investigator must provide an assessment of the relationship of the event to study drug, as 
this information is very important to monitor the real-time safety of the study drug. However, as 
the manufacturer of the study drug, Beijing FibroGen is responsible for making the final 
causality assessment for individual reports, and for reporting suspected adverse reactions and 
adverse reactions to Health Authorities. 
11.3.5 Reporting Serious Adverse Events on the SAE Report Form 
All SAEs must be reported immediately to the Sponsor and/or its designated safety management 
vendor. 
To report an SAE, the Investigator must fax an SAE Report Form to the Sponsor’s designated 
safety management vendor within 24 hours of becoming aware of the serious event. In case of 
emergency or doubt, the Investigator shall call the Sponsor’s Medical Monitor for guidance. 
Follow-up reports must be submitted in a timely fashion as additional information becomes 
available.  
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 (within 7 days) as necessary. 
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). 
11.3.5.1 Reporting Serious Adverse Events to the Institutional Review Board/ Independent 
Ethics Committee 
The Investigator is responsible for notifying his/her Institutional Review Board/Independent 
Ethics Committee (IRB/IEC) of SAEs in accordance with local regulations. Sponsor, or its safety 
representative, will provide to the Investigator a copy of any expedited safety reports that it 
intends to file with a regulatory authority.  


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11.3.5.2 Deaths  
For any death or life-threatening event occurring during the subject’s study participation 
regardless of attribution, the Investigator will report the death or life-threatening event 
immediately to the Sponsor’s Medical Monitor. The Investigator must provide an assessment of 
the relationship of the event to the study drug according to the guidance in Section 11.3.4. 
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.  
If the death occurred within the SAE collection and reporting period (signed ICF to 28 days after 
last dose), the Investigator must submit the SAE Report Form in the same manner as described 
above in Section 11.3.5. Additionally, the site must complete the appropriate CRF page. This 
includes death attributed to progression of the subject’s underlying disease. 
11.3.6 Pregnancies: Reporting and Follow-up of Subjects 
A pregnancy in a female subject must be confirmed by a positive serum β-HCG test. If a female 
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 (by way of its designated safety management vendor) within 24 hours of the 
Investigator learning of the pregnancy. If applicable, a pregnant subject is immediately 
withdrawn from receiving study treatment. The Investigator must follow the pregnancy to 
completion to ascertain both its outcome (e.g., spontaneous miscarriage, elective termination, 
ectopic pregnancy, normal birth or congenital abnormality) and whether any AEs occur.  
Pregnancy itself is not an AE. However, the Investigator should report the information to the 
Sponsor on the designated forms. Pregnancies are followed up to outcome even if the subject 
was discontinued from the study. 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 management vendor within 24 hours of the Investigator learning of the 
outcome. 
Pregnancy of the subject’s partners is not considered to be an AE. However, the outcome of all 
pregnancies should if possible be followed up and documented as described. To capture 
information about a pregnancy from the partner of a male subject, the male subject’s partner 
consent must be obtained to collect information related to the pregnancy and outcome (will be 
handled on a case-by-case basis with IRB/IEC approval).  
11.3.7 Abnormal Laboratory Findings 
Laboratory values will be collected throughout the study to assess for safety. The Investigator 
must review and assess all laboratory results in a timely manner, and determine whether the 
abnormal laboratory values, if any, are clinically significant (CS) or not clinically significant 
(NCS), and whether there are associated signs and symptoms. Clinically significant laboratory 
abnormalities will be reported as AEs.  
An abnormal laboratory finding in absence of any other signs or symptoms is not necessarily an 
AE. 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, 
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Clinically significant laboratory abnormalities after taking study medication that reflect a 
meaningful change from the screening value(s) and that require active management are to be 
considered by the Investigator as AEs (e.g., abnormalities that require study treatment dose 
modification, discontinuation, more frequent follow-up assessments, etc.).  


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12 STUDY MONITORING 
A site must have had a previous pre-qualification site visit conducted to have a combined 
pre-qualification site visit and site initiation visit. Following site pre-qualification and/or 
initiation of the study site, periodic monitoring visits and site closeout visits will be made by 
FibroGen or its designee. The Investigator must provide direct access to, and allocate sufficient 
space and time for, the monitor to inspect subject source records, CRFs, queries, collection of 
local laboratory normal ranges (if applicable), investigational product accountability records, and 
regulatory documents in accordance with GCP and the ICH E6 guideline. 
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 Investigator must also permit the FDA or other applicable regulatory authorities to inspect 
facilities and records pertaining to this study if so requested. If the Investigator is notified of an 
inspection pertaining to this study by the FDA or other applicable regulatory authorities, the 
Investigator must notify FibroGen immediately. 
12.1 Data Quality Assurance 
The following steps will be taken to ensure that the study is conducted by the study site in 
compliance with the study protocol, GCP, and other applicable regulatory requirements:  
• Investigator meeting and/or Investigator site initiation 
• Routine study site monitoring 
• Documented study and system training 
• CRF and query review against source documents 
• Collection of local laboratory normal ranges 
The study site may be audited by FibroGen’s Quality Assurance department or designee. The 
Investigator agrees to make available to the auditor all necessary study personnel (including 
himself/herself), all source documentation, and study subject records related to this trial. The 
Investigator agrees to follow-up to address and/or correct any audit observations promptly. 
12.2 Compliance with Laws and Regulations 
This study will be conducted in accordance with the FDA regulations, the ICH E6 guideline for 
GCP, the Declaration of Helsinki, and applicable local, state, and federal laws, as well as other 
applicable country laws. 
12.3 Audit and Inspection 
Authorized representatives of the Sponsor, a regulatory authority, an IEC may visit the 
investigator site to perform audits or inspections, including source data verification. The 
Investigator will allow the sponsor auditor, regulatory authority or ethics committee 


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representative to inspect the drug storage area, study drug stocks, drug accountability records, 
subject charts 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 should contact the 
Sponsor immediately if contacted by a regulatory agency about an inspection. 
12.4 Data Collection and Handling 
12.4.1 Source Documents 
Source records are original documents, data, and records that are relevant to the clinical trial. The 
Investigator 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 trial. Source records must be adequate to reconstruct all data transcribed 
onto the CRFs and resolved queries. 
12.4.2 Data Collection, Handling, and Verification 
All required data will be entered onto CRFs by authorized site personnel. Data will be entered 
into a validated, clinical database compliant with 21 CFR Part 11 regulations. The database will 
be a secured, password-protected system with full audit trail. 
All subject data will be reviewed by FibroGen and/or designee. Data that appear inconsistent, 
incomplete or inaccurate will be queried for site clarification.  
Adverse events and concomitant medications will be coded using industry standard dictionaries 
(e.g., Medical Dictionary for Regulatory Activities [MedDRA] and World Health Organization 
Drug (WHODrug) dictionaries). 
The Investigator is responsible for reviewing, verifying, and approving all subject data, i.e., 
CRFs and queries prior to study completion. 


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13 HUMAN SUBJECTS 
13.1 Ethical Considerations 
The study will be conducted in accordance with FDA regulations, the ICH E6 guideline for GCP, 
the Declaration of Helsinki, any other applicable regulatory requirements, and IRB requirements. 
13.2 Communication with the Institutional Review Board 
This protocol, the Informed Consent Form, the Investigator’s Brochure, and any information to 
be given to the subject (e.g., subject information sheet, questionnaires) must be submitted to a 
properly constituted IRB by the Investigator for review and approved by the IRB 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 before the material is 
used for subject recruitment.  
The Investigator is responsible for obtaining reapproval by the IRB annually or more frequently 
in accordance with the regulatory requirements and policies and procedures established by the 
IRB. Copies of the Investigator’s annual report and other required report to the IRB and copies 
of the IRB continuance of approval must be furnished to FibroGen. A copy of the signed form 
FDA 1572 must also accompany the above approval letter provided to FibroGen. 
Investigators are also responsible for promptly informing the IRB of any protocol changes or 
amendments, changes to the Investigator’s Brochure, and other safety-related communications 
from FibroGen. Investigators also are responsible for promptly informing the IRB of protocol 
deviations/violations, as required by their IRB. Written documentation of IRB approval must be 
received before the amendment is implemented. 
Investigators must also enter the names of the staff that are involved in the study on the 
Delegation of the Authority form and sign the form (including their responsibilities). This form 
must be updated when responsibilities of the staff change. 
13.3 Informed Consent Form 
No study procedure may be implemented prior to obtaining a signed and dated written Informed 
Consent Form (ICF) from the subject or the subjects legally authorized representative. IRB 
review and approval are required for the ICF. The final IRB-approved ICF must be provided to 
FibroGen for regulatory purposes. 
If there are any changes to the Sample ICF during the subjects’ participation in the study, the 
revised ICF must receive the IRB’s written approval before use and subjects must be 
re-consented to the revised version of the ICF.  
13.4 Subject Confidentiality 
Release of research results should preserve the privacy of medical information and must be 
carried out in accordance with Department of Health and Human Services Standards for Privacy 
of Individually Identifiable Health information, 45 CFR Parts 160 and 164, and the HIPAA. 
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 and HIPAA Authorization Form 
signed by the subject, or unless permitted or required by law. The subject may request in writing 
that medical information be given to his/her personal physician. 


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14 INVESTIGATOR REQUIREMENTS 
The Investigator must be medically qualified to directly supervise the conduct of the trial at his 
or her site. The Investigator agrees to employ qualified staff to participate in the trial. The 
Investigator will permit trial-related monitoring, audits, IRB review, and regulatory 
inspection(s), providing direct access to source data/documents. 
14.1 Study Medication Accountability 
All Study Drug required for completion of this study will be provided by FibroGen. The 
recipient will acknowledge receipt of the drug by returning the appropriate documentation form 
indicating shipment content and condition. Damaged supplies will be replaced. 
Accurate records of all Study Drug received, dispensed, returned, and disposed of by the study 
site according to the Study Reference Manual should be recorded using the Drug Inventory Log. 
14.2 Disclosure of Data 
Data records generated by this study must be available for inspection upon request by 
representatives of the FDA or other regulatory agencies, national and local health authorities, 
FibroGen monitors/representatives and collaborators, auditors, and the IRB for each study site. 
14.3 Study Files and Retention of Records 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories:  
(1) Investigator’s Study Files, and (2) Subject Clinical Source Documents. 
The Investigator’s Study File commonly contains essential documents, which are defined as 
those documents that individually and collectively permit evaluation of the conduct of the study 
and the quality of the data produced. Examples of such essential documents are as follows: the 
protocol, amendments, CRFs and query forms, IRB approvals correspondence, informed 
consents, drug records, staff curriculum vitae, laboratory accreditation, authorization forms, and 
other appropriate documents and correspondence.  
Subject clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the CRFs) would include (although not be limited to) 
the following:  subject hospitalization records, physician’s and nurse’s (or other study staff’s) 
notes, appointment book, original laboratory reports, ECGs, x-rays, pathology and special 
assessment reports, consultant letters, screening and enrollment eligibility documentation, 
screening and enrollment logs, etc. 
The Investigator shall retain records required to be maintained under 21 CFR 312.62(c) for a 
period of 2 years following the date a marketing application is approved for the drug for the 
indication for which it is being investigated. If no application is to be filed or if the application is 
not approved for such indication, the Investigator shall retain these records until 2 years after the 
investigation is discontinued and the FDA is notified. 
If the Investigator moves or retires, he or she should identify in writing, the designee who will be 
responsible for record keeping. Archived data may be retained on electronic records or similar 
medium provided that a back-up exists and a hard copy is obtainable if required. No records will 
be destroyed without the prior written consent of FibroGen. 


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15 PUBLICATION POLICY 
A detailed explanation of FibroGen’ s publication policy is described in the Clinical Trial 
Agreement. 


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16 REFERENCES 
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17 APPENDICES


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Appendix 1. Schedule of Assessments ─ Randomized Treatment Phase 
Study Period 
Screening 
Period (up to 
6 weeks) 
Treatment Period 
Visit Number 
1 
2a 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
Study Days 
 
Day 1 
pre 
dose 
Day 1 
post 
dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Week (± 3 day 
window for Week 3 to 
Week 48) 
Scr 
1 
Scr 
2a 
0 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
39 
42 
45 
48 
Signed and Dated Written 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SGRQ 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Height and Weightb 
Xb 
 
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 
Complete Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Focused Physical Examc 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Pulmonary Function Tests 
Xd 
 
Xe 
 
 
 
 
Xe 
 
 
 
Xe 
 
 
 
Xe 
 
 
 
Xe 
CBC with Differential 
X 
 
X 
  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Serum Chemistry 
X 
 
X  
  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Spot Urine for Urinalysis 
X 
 
X 
  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
  
X 
Pregnancy Testf 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HRCT of Chest 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Serum and Plasma 
Biomarkers 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Plasma HAHA 
 
 
X 
  
  
  
  
  
  
  
  
  
  
 
 
 
 
  
  
  
Whole Blood for DNA 
 
 
X 
  
  
  
  
  
  
  
  
  
  
 
 
 
 
  
  
  
AEs and SAEsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
Concomitant Medicationsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Procedures and Nondrug 
Therapies 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug infusioni 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Study Period 
Screening 
Period (up to 
6 weeks) 
Treatment Period 
Visit Number 
1 
2a 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
Study Days 
 
Day 1 
pre 
dose 
Day 1 
post 
dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Week (± 3 day 
window for Week 3 to 
Week 48) 
Scr 
1 
Scr 
2a 
0 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
39 
42 
45 
48 
Subject Disposition 
 
 
Xj 
 
Abbreviations: 
AE = adverse event; CBC = complete blood count; DLCO = diffusing capacity of the lungs for carbon monoxide; ECG = electrocardiogram; EX = extended 
(treatment); HAHA = human anti-human antibody; HCG = human chorionic gonadotropin; HRCT = high resolution computed tomography; SAE = serious 
adverse event; Scr = screening visit; SGRQ = Saint George’s Respiratory Questionnaire 
a 
Screening Visit 2 may be combined with Screening Visit 1. 
b 
Height will be measured only once at Screening Visit 1. Weight will be measured every 12 weeks to determine dose for the subsequent 12-week interval. 
c 
Including chest auscultation  
d 
Spirometry (DLCO at first screening test only). 
e 
Spirometry  
f 
Pregnancy tests (performed at Screening Visit 1, pre-dose Day 1, and pre-dose at other times) for women of childbearing potential only:  serum pregnancy test at 
Screening Visit 1; urine pregnancy tests at other visits. A positive urine pregnancy test must be confirmed by serum HCG. 
g 
See Section 11.3.1 for follow-up of AEs. 
h 
Refer to Section 4.6.1 for prohibited concomitant medications. 
i 
Vital signs (blood pressure, pulse, respiration rate, and temperature) must be recorded prior to each FG-3019 infusion. Intra-infusion and post-infusion assessments will 
be performed according to Section 6.3.  
j 
Subjects who do not complete all visits in the Treatment Period will be encouraged to return for the assessments listed in Appendix 3. 
 


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Appendix 2. Schedule of Assessments ─ Extended Treatment Phase 
Study Period 
Treatment Perioda 
Visit Number 
1-EX 2-EX 3-EX 4-EX 5-EX 6-EX 7-EX 8-EX 9-EX 10-EX 11-EX 12EX 13-EX 14-EX 15-EX 16-EX 17-EX 
Study Week (± 3 d 
window for Week 3-EX to 
Week 48-EX) 
0- 
(Day 
1-EX) 3-EX 6-EX 9-EX 12-EX 15-EX 18-EX 21-EX 24-EX 27-EX 30-EX 33-EX 36-EX 39-EX 42-EX 45-EX 48-EX 
SGRQ 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Weightb  
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Physical Exam 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Focused Physical Examc  
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Spirometry 
 
 
 
 
Xd 
 
 
 
Xd 
 
 
 
Xd 
 
 
 
Xd 
CBC with Differential 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Serum Chemistry 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Spot Urine for Urinalysis 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Pregnancy Teste  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HRCT of Chest 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
12-Lead ECG 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Serum and Plasma 
Biomarkers 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
AEs and SAEsf  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medicationsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Procedures and Nondrug 
Therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FG-3019 Infusionh 
X 
X  
X  
X  
X  
X  
X  
X  
X 
X  
X  
X  
X  
X  
X  
X  
X 
Subject Disposition 
Xi 
 
FOOTNOTES ARE ON THE FOLLOWING PAGE 


FG-3019 
Protocol FGCL-3019-067 Amendment 5.1 
FibroGen, Inc. 
Confidential and Proprietary 
Page 70 of 74 
Abbreviations: 
AE = adverse event; CBC = complete blood count; ECG = electrocardiogram; EX = extended (treatment); FVC = forced vital capacity; HAHA = human anti-
human antibody; HCG = human chorionic gonadotropin; HRCT = high resolution computed tomography; SAE = serious adverse event; SGRQ = Saint 
George’s Respiratory Questionnaire. 
a 
The total duration of the study for subjects is indeterminate because subjects in the extension period may continue treatment until they meet stopping criteria 
(Section 4.2.3). Subjects who complete 48 weeks of treatment extension may continue treatment according to this table (beginning in Week 1Ex).  
b 
Weight will be measured every 12 weeks to determine dose for the subsequent 12-week interval. 
c 
Including chest auscultation  
d 
Spirometry  
e 
Pregnancy tests (performed pre-dose Day 1-EX and at other times) for women of childbearing potential only:  urine pregnancy tests at all Extended Treatment Period 
visits. A positive urine pregnancy test must be confirmed by serum HCG. 
f 
See Section 11.3.1 for follow-up of AEs. 
g 
Refer to Section 4.6.1 for prohibited concomitant medications. 
h 
Vital signs (blood pressure, pulse, respiration rate, and temperature) must be recorded prior to each FG-3019 infusion. Intra-infusion and post-infusion assessments will 
be performed according to Section 6.3.  
i 
Subjects who do not complete all visits in the Treatment Period will be encouraged to return for the assessments listed in Appendix 3. 


FG-3019 
Protocol FGCL-3019-067 Amendment 5.1 
FibroGen, Inc. 
Confidential and Proprietary 
Page 71 of 74 
Appendix 3. Schedule of Assessments ─ Early Termination/End of Treatment and Follow-
up Visit 
Assessment 
Early Termination/End of 
Treatmenta 
End of Study 
1. SGRQ 
Xb 
 
2. Vital Signs 
Xb 
X 
3. Complete Physical Exam 
Xb 
 
4. Spirometry 
Xb,c 
 
5. CBC with Differential 
Xb 
 
6. Serum Chemistry 
Xb 
 
7. Spot Urine for Urinalysis 
Xb 
 
8. Pregnancy Testd 
Xb 
X 
9. HRCT of Chest 
Xb 
 
10. 12-Lead ECG 
Xb 
 
11. Serum and Plasma Biomarkers 
Xb 
 
12. Plasma HAHA 
 
X 
13. AEs and SAEse  
Xb,e 
Xb,e 
14. Concomitant Medicationsf 
Xb 
X 
15. Procedures and Nondrug 
Therapies 
Xb 
X 
16. Subject Disposition 
X 
X 
Abbreviations: 
AE = adverse event; CBC = complete blood count; ECG = electrocardiogram; HAHA = human 
anti-human antibody; HCG = human chorionic gonadotropin; HRCT = high resolution computed 
tomography; PFT = pulmonary function test; SAE = serious adverse event; SGRQ = Saint 
George’s Respiratory Questionnaire. 
a 
End of treatment, including due to withdrawal/progression evaluation preferably 3 weeks after last dose of 
study drug for all subjects who have received more than 4 doses of FG-3019. The End of Study, final safety 
assessment should be 4 weeks after last dose of study drug. Study windows are ± 3 days 
b 
Subjects who completed the withdrawal/progression evaluations at Week 48 or for early withdrawal do not 
need to repeat them. Study endpoint evaluations do not require repetition if performed within 8 weeks, 
HRCT does not require repetition if performed within 4 months, and safety assessments, such as clinical 
laboratory tests, do not require repetition if performed within 2 weeks. 
c 
Spirometry . 
d 
Pregnancy tests for women of childbearing potential only: urine pregnancy tests at all Extended Treatment 
Period visits. A positive urine pregnancy test must be confirmed by serum HCG. 
e 
See Sections 4.7 and 11.3.1 for follow-up of AEs. 
f 
Refer to Section 4.6.1 for prohibited concomitant medications. 
 
 


FG-3019 
Protocol FGCL-3019-067 Amendment 5.1 
FibroGen, Inc. 
Confidential and Proprietary 
Page 72 of 74 
Appendix 4. HRCT Criteria and Histopathological Criteria for UIP Pattern* 
HRCT Criteria for UIP Pattern 
UIP Pattern (All Four Features)  
• Subpleural, basal predominance 
• Reticular abnormality 
• Honeycombing with or without traction bronchiectasis 
• Absence of features listed (below) as Inconsistent with UIP Pattern 
 
Possible UIP Pattern (All Three Features) 
• Subpleural, basal predominance 
• Reticular abnormality 
• Absence of features listed (below) as Inconsistent with UIP Pattern 
 
Inconsistent with UIP Pattern (Any of the Seven Features) 
• Upper or mid-lung predominance 
• Peribronchovascular predominance 
• Extensive ground glass abnormality (extent > reticular abnormality) 
• Profuse micronodules (bilateral, predominately upper lobes) 
• Discrete cysts (multiple, bilateral away from areas of honeycombing) 
• Diffuse mosaic attenuation/air trapping (bilateral, in three or more lobes) 
• Consolidation in bronchopulmonary segment(s)/lobe(s) 
 
Histopathological Criteria for UIP Pattern 
UIP Pattern (All Four Criteria) 
• Evidence of marked fibrosis/architectural distortion, ± honeycombing in a predominantly 
subpleural/paraseptal distribution 
• Presence of patchy involvement of lung parenchyma by fibrosis 
• Presence of fibroblast foci 
• Absence of features against a diagnosis of UIP suggesting an alternate diagnosis (hyaline 
membranes, organizing pneumonia, granulomas, marked interstitial inflammatory cell 
infiltrate away from honeycombing, predominant airway centered changes, other features 
suggestive of an alternate diagnosis) 
 
*Raghu, 2011 
 
 
 


FG-3019 
Protocol FGCL-3019-067 Amendment 5.1 
FibroGen, Inc. 
Confidential and Proprietary 
Page 73 of 74 
Appendix 5. 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 TLC scan. RV scans are not required for the quantitative image analysis data being 
collected for this study. Effective dose estimates provided: (For this study, visits occur at 
Baseline, 6 months, 1 year, 18 months and 2 years (i.e. 5 studies).  
 
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) (5 studies) 
10.7  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 


FG-3019 
Protocol FGCL-3019-067 Amendment 5.1 
FibroGen, Inc. 
Confidential and Proprietary 
Page 74 of 74 
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 AAPM 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 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
STUDY TITLE: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Safety and Efficacy of FG-3019 in 
Patients with Idiopathic Pulmonary Fibrosis  
PROTOCOL NUMBER: 
Protocol FGCL-3019-067, Amendment 5.0 
SPONSOR: 
FibroGen, Inc. 
409 Illinois Street 
San Francisco, California  94158 USA 
Version 
FINAL 
Release Date: 
July 26, 2017 
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 #: NCT01890265


 
 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Approvals 
I have reviewed and accepted the information in this document to be a true and accurate 
representation of the Statistical Analysis Plan for Study FGCL-3019-067 (Amendment 
5.0). 
Initiator: 
Signature:  
Date: 
 
 
 
  
Project Statistician, 
 
FibroGen, Inc. 
 
 
Reviewed by: 
Signature: 
 
Date: 
 
 
   
 
 
 
Signature: 
 
Date: 
 
 
   
 
 
 
Signature:  
Date: 
 
 
 
Project Statistician  
Q-square Business Intelligence 
 
 
Signature:  
Date: 
 
 
 
 
 
 
 
Signature Significance 
The following significance is lent to the signatures on the Approvals page of this 
document. 
Signatory 
Significance 
Initiator 
By signing, the author is attesting that the content of the 
document is complete and accurate. 
Reviewer 
By signing, the reviewer is attesting that the document’s 
approach and contents are compliant with the study protocol, 
all appropriate, regulatory requirements, and other significant 
guidelines. This individual(s) has reviewed the document for 
accuracy and completeness. 


 
 
CHANGE HISTORY 
 
Version 
Date 
Description 
0.1 
July 6, 2015 
Draft for the AE summaries for the 2015 IND 
Update 
0.2 
January 11, 2016 
Safety data summaries  
0.3 
February 4, 2016 
Add summaries of FVC data 
0.4 
March 1, 2016 
First draft to study team 
0.5 
April 29, 2016 
Add more details 
0.6 
October 31, 2016 
Add more details 
0.7 
January 9, 2017 
Add multiple imputation procedure to key 
efficacy endpoints. 
0.8 
January 31, 2017 
Add more details 
0.9 
June 7, 2017 
Revise imputation methods and efficacy 
analysis models, per discussion with 
 
 and 
 
1.0 
July 17, 2017 
Add references and justifications of the 
statistical methods; pre-final 
1.1 
July 21, 2017 
Incorporated comments from the previous 
version 
FINAL 
July 26, 2017 
Sign off 
 
 
 


 
 
Table of Contents 
1 
Introduction ............................................................................................................... 13 
2 
Study Objectives ....................................................................................................... 14 
2.1 
Primary Safety Objective .................................................................................. 14 
2.2 
Primary Efficacy Objective ............................................................................... 14 
2.3 
Secondary objectives ........................................................................................ 14 
2.4 
Exploratory Objectives ..................................................................................... 14 
2.5 
Objectives of the Substudy (Amendment 4.0) .................................................. 14 
3 
Study Design ............................................................................................................. 15 
3.1 
Overview ........................................................................................................... 15 
3.2 
Study Population ............................................................................................... 15 
3.3 
Study Assessments ............................................................................................ 16 
3.4 
Sample Size Determination............................................................................... 16 
3.5 
Randomization .................................................................................................. 17 
3.6 
Treatment Blinding ........................................................................................... 17 
3.7 
Protocol Amendments ....................................................................................... 18 
3.8 
Changes from the Protocol................................................................................ 18 
4 
Study Endpoints and Definitions .............................................................................. 19 
4.1 
Study Endpoints ................................................................................................ 19 
4.1.1 Efficacy Endpoints ........................................................................................ 19 
4.1.2 PK Parameters and Biomarker Endpoints..................................................... 19 
4.1.3 Safety Endpoints ........................................................................................... 19 
4.2 
Detailed Definitions of the Study Endpoints .................................................... 20 
4.2.1 Change from baseline in FVC (% predicted) at Week 48 ............................ 20 
4.2.2 Change in Fibrosis Score by Quantitative HRCT at Weeks 24 and 48 ........ 20 
4.2.3 Change from baseline in HRQoL at Weeks 24 and 48 ................................. 21 
4.2.4 Time to Progression of IPF ........................................................................... 21 
4.2.5 Proportion of Subjects with Respiratory-Related Hospitalization ................ 22 
4.2.6 Proportion of Subjects with Respiratory-Related Death ............................... 22 
4.2.7 Categorical Assessment of ΔFVCpp48......................................................... 22 
4.2.8 Prior and Concomitant Medication ............................................................... 23 
4.2.9 Study Drug Exposure and Treatment Compliance ....................................... 23 
4.2.10 
FG-3019 Pharmacokinetic (PK) Parameters ............................................. 23 


 
 
4.2.11 
Pirfenidone and Nintedanib Pharmacokinetic (PK) Parameters ............... 23 
4.2.12 
AEs and SAEs ........................................................................................... 23 
4.2.13 
Laboratory Abnormalities Central Laboratory Evaluations ..................... 26 
4.2.14 
Vital Signs ................................................................................................. 27 
4.2.15 
Electrocardiogram ..................................................................................... 27 
4.2.16 
Physical Examination................................................................................ 27 
4.2.17 
DNA Analysis ........................................................................................... 27 
4.2.18 
Connective Tissue Growth Factor (CTGF)............................................... 28 
4.2.19 
Human Anti-Human Antibodies to FG-3019 (HAHA) ............................ 28 
4.3 
Definitions of Additional Endpoints ................................................................. 28 
4.3.1 Change from Baseline in FVC (L) at Week 48............................................. 28 
4.3.2 Other Endpoints Related to Change from Baseline in FVC (L) and FVC (% 
predicted) .................................................................................................................. 28 
4.3.3 Other PFT Parameters ................................................................................... 28 
4.3.4 HRCT Visual Assessment............................................................................. 29 
4.3.5 Other Quantitative HRCT Reading Scores ................................................... 29 
4.3.6 Rate of Change in FVC and DLCO Prior to Enrollment .............................. 29 
5 
General Statistical Considerations ............................................................................ 30 
5.1 
Analysis Populations ......................................................................................... 30 
5.1.1 Randomized Population ................................................................................ 30 
5.1.2 Safety Population .......................................................................................... 30 
5.1.3 Full Analysis Set Population ......................................................................... 30 
5.1.4 Substudy Population ..................................................................................... 30 
5.1.5 Substudy PK Population ............................................................................... 30 
5.1.6 Extension Safety Population ......................................................................... 30 
5.2 
Hypotheses and Decision Rules ........................................................................ 30 
5.3 
Adjustment for Multiple Comparisons ............................................................. 30 
5.4 
Handling Dropouts and Missing Data............................................................... 31 
5.4.1 Imputation for Missing Data in ΔFVCpp48 and ΔFVC48 ........................... 31 
5.4.2 Imputation for Missing HRCT Fibrosis Scores ............................................ 34 
5.4.3 Rules for Handling Missing Data in Individual Questions in SGRQ Scoring
 
35 
5.4.4 Handling Missing/Incomplete AE Onset Date ............................................. 35 


 
 
5.4.5 Handling Missing/Incomplete CM Start/Stop Dates .................................... 36 
5.4.6 Handling Missing/Incomplete Dates for PFT Prior to Enrollment ............... 36 
5.5 
Adjustment for Covariates ................................................................................ 36 
5.6 
Definition of Baseline ....................................................................................... 36 
5.7 
Efficacy Analysis Visit Window ...................................................................... 36 
5.8 
Interim Analyses and Data Monitoring............................................................. 37 
5.9 
Pooling Data of Study Sites .............................................................................. 37 
5.10 
General Layout.................................................................................................. 37 
5.11 
Data Errata and Hard-Coding ........................................................................... 38 
6 
Statistical Analyses ................................................................................................... 39 
6.1 
Subject Enrollment and Disposition ................................................................. 39 
6.2 
Protocol Deviations ........................................................................................... 39 
6.3 
Demographic and Baseline Characteristics ...................................................... 39 
6.3.1 Subject Demographics and Other Baseline Characteristics .......................... 39 
6.3.2 Medical History ............................................................................................ 40 
6.3.3 Baseline Disease Characteristics ................................................................... 40 
6.3.4 Baseline GAP Score and Staging .................................................................. 40 
6.3.5 Annualized Rate of Change in FVC and DLCO Prior to Study Treatment .. 41 
6.3.6 Comparison between Treatment Arms in Baseline Parameters .................... 42 
6.4 
Summary of Prior and Concomitant Medications ............................................ 42 
6.5 
Summary of Study Drug Exposure and Treatment Compliance ...................... 42 
6.6 
Efficacy Analyses ............................................................................................. 42 
6.6.1 Analyses of the Primary Efficacy Endpoint (ΔFVCpp48)............................ 43 
6.6.2 Analyses of Quantative HRCT Fibrosis Score ............................................. 46 
6.6.3 Analysis of Change from Baseline in HRQoL Score ................................... 48 
6.6.4 Analysis of Time to Progression of IPF ........................................................ 48 
6.6.5 Analysis of Respiratory-Related Hospitalization and Respiratory-Related 
Death 49 
6.7 
Exploratory Analyses ........................................................................................ 49 
6.7.1 Sensitivity Analyses of the Primary Efficacy Endpoint ............................... 49 
6.7.2 Analyses of Other PFT Parameters ............................................................... 51 
6.7.3 Analyses of Other Quantitative HRCT Parameters ...................................... 52 
6.7.4 Analysis of HRCT Visual Reading Scores ................................................... 52 


 
 
6.7.5 Examination of Subgroups (Main Study) ..................................................... 52 
6.7.6 Other Exploratory Analyses .......................................................................... 53 
6.8 
Safety Analyses ................................................................................................. 53 
6.8.1 Adverse Events ............................................................................................. 53 
6.8.2 Mortality ....................................................................................................... 54 
6.8.3 Summary of Central Laboratory Data........................................................... 54 
6.8.4 Vital Signs ..................................................................................................... 55 
6.8.5 ECG Data ...................................................................................................... 55 
6.8.6 Physical Exams ............................................................................................. 55 
6.9 
PK, CTGF, HAHA, and Biomarkers ................................................................ 55 
6.10 
Changes from the Protocol Specified Analysis Methods ................................. 55 
6.10.1 
Change of the Primary Analysis Method for ΔFVCpp48 ......................... 55 
6.10.2 
Change in the Analysis Population for HRCT Parameters ....................... 56 
6.10.3 
Definition of Final Analysis of the Randomized Treatment Period ......... 56 
7 
Validation and Quality Assurance ............................................................................ 57 
8 
References ................................................................................................................. 58 
9 
Planned Tables, Listings, and Figures ...................................................................... 60 
9.1 
List of Tables and Figures................................................................................. 60 
9.2 
List of Listings .................................................................................................. 69 
Appendices ........................................................................................................................ 73 
Appendix I   Computation Formulae for Predicted PFT Parameters ............................ 73 
1   Predicted FVC and FEV1 .................................................................................... 73 
2   Predicted DLCO Corrected for Hb ...................................................................... 74 
3    Predicted TLC and FRC...................................................................................... 75 
Appendix II    Scoring of the SGRQ Domain and Total Scores ................................... 77 
1   Overview of SGRQ .............................................................................................. 77 
2   SGRQ Scoring Algorithm .................................................................................... 77 
3   Weight of Each Question ..................................................................................... 78 
Appendix III General Specifications for Submission Data ............................................... 82 
1. Study Data Tabulation Model (SDTM) .................................................................... 82 
2 Analysis Data Model (ADaM) ................................................................................... 85 
Appendix IV  General Specifications for Tables, Listings, Figures ................................. 88 
1 Software Used ............................................................................................................ 88 


 
 
2 General ....................................................................................................................... 88 
3 Table/Listing/Figure Output File Type and Organization ......................................... 88 
4 Page Layout ............................................................................................................... 88 
5 Titles and Footnotes ................................................................................................... 89 
6 Table, Listing, Figure Metadata ................................................................................. 90 
7 Significant Digits of Summary Statistics ................................................................... 90 
8  Figure Specifications ................................................................................................ 92 
9  Unit Conversion ........................................................................................................ 92 


 
 
List of Abbreviations 
Δ 
Change from baseline 
ΔFVCpp48 
Change from baseline to Week 48 in FVC % predicted (this abbreviation rule is 
applied in other parameters) 
ADaM 
Analysis Data Model 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the curve 
BL 
Baseline 
BP 
Blood pressure 
BPM 
Beats per minute 
CAD 
Computer assisted diagnosis 
CBC 
Complete blood count 
CM 
Concomitant medication 
Cmax 
maximal concentration 
Cmin 
minimal concentration 
CRF 
Case report form 
CS 
Clinically significant 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTGF 
Connective tissue growth factor 
DLCO 
Diffusing capacity of the lung for carbon monoxide 
DLCOpp 
DLCO % predicted 
DLCOpp-hb 
DLCO % predicted corrected for hemoglobin 
EMA 
European Medicines Agency 


 
 
ECG 
Electrocardiogram 
EE 
Efficacy evaluable 
EOS 
End of study 
EOT 
End of treatment 
EX 
Extension 
FAS 
Full analysis set 
FEV1 
Forced expiratory volume in 1 second 
FG-3019 
FibroGen-3019 (recombinant human monoclonal antibody) 
FIB 
HRCT fibrosis score 
FIB-WZ 
Fibrosis at worst zone 
FRC 
Functional residual capacity 
FVC 
Forced vital capacity 
FVC (L) 
FVC in litre 
FVCpp 
FVC % predicted 
GG 
HRCT ground glass score 
HAHA 
Human anti-human antibody 
Hb 
Hemoglobin 
HC 
HRCT honeycombing score 
HRCT 
High resolution computed tomography 
HRQoL 
health-related quality of life 
IPF 
Idiopathic pulmonary fibrosis 
ITT 
Intent-to-treat 
IV 
Intravenous 
kg 
Kilogram 
LOCF 
Last observation carried forward 
LS Means 
Least squares means 
MedDRA 
Medical Dictionary for Regulatory Activities 


 
 
mg 
Milligram 
MAR 
Missing at random 
MCMC 
Markov chain Monte Carlo 
MI 
Multiple Imputation 
MI Imputed 
Average imputed value from multiple imputations 
MMRM 
Mixed effect Model Repeated Measures 
MNAR 
Missing not at random 
NCI 
National Cancer Institute 
NCS 
Not clinically significant 
OC 
Observed cases 
PD 
Progressive disease 
PFT  
Pulmonary Function Test 
PINP 
Procollagen type I N-peptide 
PIIINP 
Procollagen type III N-peptide 
PK 
Pharmacokinetic 
PMM 
Pattern-mixture model 
PRO 
Patient reported outcome 
PT 
Prothrombin time, Preferred Term 
PTT 
Partial prothrombin time 
QILD 
HRCT quantitative interstitial lung disease 
QoL 
Quality of life 
RPM 
Respirations per minute 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
S.D. 
Standard deviation 
S.E. or s.e. 
Standard error 
SGRQ 
Saint Georges Respiratory Questionnaire 


 
 
SOBQ 
Shortness of Breath Questionnaire 
SOC 
System organ class 
SDTM 
Study Data Tabulation Model 
TEAE 
Treatment emergent adverse event 
TLC 
Total lung capacity 
TLFs 
Tables, listings and figures 
UCSD-SOBQ 
University of California, San Diego Shortness of Breath Questionnaire 
ULN 
Upper limit of normal 
WHODrug 
World Health Organization Drug Dictionary 
 


 
 
1 
INTRODUCTION 
This Statistical Analysis Plan (SAP), Part 1, documents planned analyses for the blinded 
Randomized Treatment Period for Study FGCL-3019-067 based on the study protocol dated 
12DEC2016 (Amendment 5.0):  A Phase 2, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Safety and Efficacy of FG-3019 in Patients with Idiopathic Pulmonary 
Fibrosis.   
This study allows for subjects who complete the Blinded Randomized Treatment Period to 
continue receiving open-label treatment in an Extended Treatment Period, if they qualify. After 
all subjects have completed the Randomized Treatment Period, the database will be locked. Data 
from this study period will be summarized as a stand-alone package as Part 1 of the study 
summaries.  Tables, listings, and figures (TLFs) in this package will include all data from 
subjects who did not enter the extended treatment period, and all data up to the date prior to the 
first extended treatment dosing date for subjects who entered the extended treatment period. Data 
from subjects participating in the Open-Label Extended Treatment Period will be summarized 
and analyzed separately in a Part 2 report.  Summaries of pharmacokinetics, CTGF (post-
treatment), HAHA, and biomarker (post-treatment) data will be conducted after treatment 
unblinding.    
After the completion of the Extended Treatment Period, all data for subjects treated in extension 
will be summarized in Part 2 of the study summaries. Part 2 summaries will also include the 
overall safety profile for all subjects in the entire study. Additional analysis methods and data 
handling rules for Part 2 summaries will be documented in a separate SAP (Part 2).  
This SAP includes statistical analysis methods, models, definitions, and data handling rules.  It 
supersedes the statistical sections in the protocol in case of differences. 


 
 
2 
STUDY OBJECTIVES 
The overall objective of this study is to evaluate the safety, tolerability, and efficacy of FG 3019 
in subjects with IPF. 
2.1 
Primary Safety Objective 
To determine the safety and tolerability of FG-3019 administered at a dose of 30 mg/kg by 
intravenous (IV) infusion every 3 weeks. 
2.2 
Primary Efficacy Objective 
To determine the effect of FG-3019 on forced vital capacity (FVC) (percent of predicted value) 
in the target population. 
2.3 
Secondary objectives 
• To evaluate the effect of FG-3019 on the extent of pulmonary fibrosis as measured by high 
resolution computed tomography (HRCT) scans of the chest 
• To evaluate the relationship between changes in quantified scores of pulmonary fibrosis and 
clinical outcomes 
• To evaluate the effect of FG-3019 on progression of IPF and the frequency of respiratory-
related hospitalizations and respiratory-related mortality  
• To evaluate the effect of FG-3019 on health-related quality of life (HRQoL) 
2.4 
Exploratory Objectives 
• To evaluate the effect of FG-3019 on FVC (liters) 
• To evaluate the effect of FG-3019 on a panel of serum and plasma biomarkers 
• To evaluate the relationship between known chromosomal loci associated with IPF and the 
response to FG-3019 
2.5 
Objectives of the Substudy (Amendment 4.0) 
To assess the safety, pharmacokinetics (PK), and efficacy of FG-3019 when given with standard 
of care (pirfenidone or nintedanib) IPF background medication. 


 
 
3 
STUDY DESIGN 
3.1 
Overview 
This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter study to evaluate 
the safety, tolerability, and efficacy of FG-3019 30 mg/kg comparing with placebo.  The study 
includes two components: the main study which includes subjects not receiving other IPF 
treatment and the Substudy which includes subjects receiving either pirfenidone or nintedanib. 
Below is a brief description of the study components. 
Table 1. 
Overview of the Main and Substudy 
 
Main Study 
Substudy 
Planned sample size 
136 Total 
110 first-line treatment 
26 prior treatment failure 
30 on pirfenidone 
30 on nintedanib 
Randomization ratio 
(FG-3019 : placebo) 
1:1 
2:1 
Dosing  
Day 1 -- Week 45;  
Every 3 weeks;  
16 infusions  
Day 1 – Week 21; Every 3 
weeks; 
8 infusions 
Dose level 
30 mg/kg 
15 mg/kg at first 2 infusions; 30 
mg/kg the next 6 infusions 
Last FVC and HRCT 
assessment 
Week 48 
Week 24 
PK 
None 
PK of FG-3019 and PK of 
background medication 
Extended treatment 
Subjects meet protocol defined 
criteria 
Not offered  
3.2 
Study Population 
Subjects 40 to 80 years old who have IPF diagnosed in accordance with criteria published in the 
2011 international consensus guidelines.  
Subjects who have failed or are intolerant of products approved for treating IPF are eligible 
under amendment 1. No subjects are enrolled in this category. 


 
 
Subjects who are on pirfenidone or nintedanib are eligible for substudy under amendment 4. 
3.3 
Study Assessments 
This section includes a brief summary of the study assessments in the Randomized Treatment 
Period. More detailed descriptions can be found in the protocol.  
• Spirometry (FVC and FEV1) is performed at Screening, Day 1, and every 12 weeks.  
• HRCT scans of the chest are performed at Screening and every 24 weeks.   
• Saint Georges Respiratory Questionnaire (SGRQ) is administered on Day 1 and every 12 
weeks.  
• Serum samples for central lab tests (CBC with differentials and serum chemistry) are 
collected at Screening, Day 1, and every 12 weeks. Spot urine samples for urinalysis are 
collected with the same schedule. 
• Serum and plasma samples for biomarker tests (including CTGF) are collected on Day 1 
and every 24 weeks. 
• Blood sample for DNA testing is collected on Day 1. 
• Plasma samples for assessing HAHA are collected on Day 1 and at the End of Study 
(EOS) safety follow-up.  
• Adverse events, concomitant medications, procedures, non-drug therapies, oxygen use 
are collected from signing ICF through End of Study (EOS).  
• Vital signs are measured at every clinical visit. On dosing days, vital signs are measured 
at pre-, intra-, and post-infusion. 
• Electrocardiograms (ECG) are performed at Screening and every 24 weeks.  
• A complete physical examination is performed at Screening and at Week 48.  Focused 
physical examinations are performed every 6 weeks from Day 1 to Weeks 42.   
• For subjects enrolled in the substudy, blood samples for assessing FG-3019 PK and PK 
for pirfenidone or nintedanib are collected on Day 1, Week 9, and Week 21.  
• DLCO is measured at Screening to assess entry eligibility for all subjects. For subjects 
who enrolled prior to Amendement 2, DLCO is measured on Day 1 prior to first dose and 
every 12 weeks during the randomized treatment period.  
• For subjects enrolled under Amendment 2 and subsequent amendments, post-treatment 
DLCO, lung volumes (TLC and FRC), UCSD questionnaire are not evaluated.  
Assessments and sample collections on Day 1 are all performed prior to first infusion. For 
subjects who discontinue the study early, evaluations scheduled for Week 48 are performed at 
the visit of early termination.  
3.4 
Sample Size Determination 
This study is planned to enroll approximately 136 subjects with no background therapy and 60 
subjects with background therapy. 


 
 
Among those who are not receiving background therapy, it is planned to enroll 110 subjects who 
are seeking first-line therapy and 26 subjects who failed pirfenidone and/or nintedanib treatment. 
First-line therapy is defined as no prior therapy with pirfenidone/nintedanib or <10% relative 
decrease in FVC % predicted while receiving either pirfenidone or nintedanib. Failure of 
pirfenidone and or nintedanib treatment is defined as having ≥10% relative decrease in FVC % 
predicted during prior pirfenidone/nintedanib treatment. The effect of first-line treatment is the 
primary interest of the study, and is the basis for sample size determination. Assuming a 10% 
dropout rate and a common standard deviation of 7.3, a sample size of 55 subjects per arm in the 
primary analysis population provides approximately 80% power to detect a treatment difference 
of 4.2 in change from baseline to Week 48 in percent predicted FVC, using a two sample t-test at 
the two sided significance level of 0.05. The expected treatment difference is estimated using 
data from study FG-3019-049 and historical placebo data from published studies. In Study FG-
3019-049, a mean decline of 2.8 in % predicted FVC from baseline to Week 48 was observed. 
The expected decline of 7.0 % predicted FVC in the placebo arm is estimated based on the 
weighted average of published studies (Azuma, 2005, Daniels, 2010, Demedts, 2005, King, Jr., 
2008, King, Jr., 2009, King, Jr., 2011, Meier-Kriesche, 2004, Noble, 2011, Noth, 2012, Raghu, 
2004, Raghu, 2008, Raghu, 2012, Richeldi, 2011, Taniguchi, 2010, Zisman, 2010).   
No subject is enrolled in the category of pirfenidone/nintedanib failure. 
3.5 
Randomization 
Subjects are randomized in a 1:1 ratio to receive FG-3019 or placebo under the original protocol. 
(main study) 
Subjects are randomized in a 1:1 ratio, stratifying by prior therapy of pirfenidone/nintedanib 
(yes/no), under protocol amendment 1. (No subjects enrolled in this category) 
Subjects in substudy under amendment 4 are randomized in a 2:1 ratio to FG-3019 + background 
therapy or background therapy alone, stratifying by background therapy (pirfenidone or 
nintedanib). 
Subject randomization and drug dispense are performed by an interactive responsive technology 
(IRT) system developed by Endpoint Clinical Inc. (San Francisco, CA). The randomization 
specifications are documented in different versions of Randomization Specification Forms 
developed for the original protocol and subsequent amendments.  
3.6 
Treatment Blinding 
After a subject completes the Randomized Treatment Period and assessments at Week 48, his/her 
treatment assignment will be unblinded only to designated personnel not associated with the 
study conduct to determine eligibility to enter the Extended Treatment Period. The treatment 
assignment is only used (by the mentioned designated personnel) with the purposes to assess 
eligibility into the Extension Period.  Study subjects, investigators and site staff, as well as the 
operation team members at Fibrogen and contract organizations remain blinded to treatment 
assignment throughout the study. The study treatment unblinding for final analyses will occur 
after all subjects have completed the Randomized Treatment Period and the 4-week Follow-up, 
and the database has been cleaned and locked. Data modules that are not included in the database 
lock prior to unblinding are: PK, CTGF (post-treatment), HAHA, biomarkers (post-treatment), 
and HRCT visual reading data.    


 
 
3.7 
Protocol Amendments  
Below is a brief description of changes from the original protocol that affect data analyses. 
• In Amendment 1 (09 December 2014), the study sample size was increased to enroll a 
total of 136 subjects., of which up to 26 subjects with ≥10% relative decrease in forced 
vital capacity (FVC) % predicted during pirfenidone/nintedanib treatment will be 
enrolled to explore whether subjects who progress on pirfenidone and/or nintedanib may 
respond to FG-3019.   
o Randomization is stratified by subjects who received prior IPF treatment or not. 
The eligibility criterion for subjects in the FG-3019 arm to receive extended 
treatment is changed from <3% decrease from baseline in FVC % predicted value 
to no decrease. 
o DLCO is only assessed at Screening to evaluate entry eligibility; post-treatment 
assessments are not performed for subjects enrolled under Amendment 1 and later 
amendments. 
o UCSD questionnaire and Lung volume parameters (TLC and FRC) are not 
assessed in subjects enrolled under Amendment 1 and subsequent amendments. 
o Eligibility of receiving extended treatment for subjects who are randomized in 
FG-3019 is changed from no more than 3% decline from baseline to no decline 
from baseline. 
• Amendment 2 (09 March 2015) includes only clarifications of the previous amendment. 
• Protocol amendment 3 (28 May 2015), safety follow-up is changed from 7 to 10 weeks 
after the last dose of study medication. 
• In protocol amendment 4 (04 January 2016, US and Canada sites only): a substudy is 
added to assess the safety, pharmacokinetics (PK), and efficacy of FG-3019 when given 
with standard of care IPF background medication (pirfenidone or nintedanib). A total of 
60 subjects (30 with background therapy of pirfenidone and 30 with nintedanib) is 
planned to be enrolled into the substudy with randomization ratio of 2:1 to FG-3019 + 
background therapy or background therapy alone, stratifying by the type of background 
therapy. 
• In Amendments 5 and 5.1 (12 December 2016): safety follow-up is changed from 10 
weeks to 4 weeks after the last dose.  
3.8 
Changes from the Protocol 
• The study is planned to enroll approximately 136 subjects, who will include a target of 
110 subjects who are seeking first-line therapy and approximately 26 subjects who failed 
pirfenidone and/or nintedanib treatment. Due to lack of availability of subjects who failed 
pirfenidone and/or nintedanib treatment during the enrollment period, it was decided not 
to further pursue enrolling this category of subjects, as documented in Note-to-File dated 
05 FEB 2016.  
 
 


 
 
4 
STUDY ENDPOINTS AND DEFINITIONS 
4.1 
Study Endpoints 
4.1.1 Efficacy Endpoints  
4.1.1.1 Primary Efficacy Endpoint 
• Change from baseline in FVC (percent of predicted value) at Week 48  
4.1.1.2 Other Efficacy Endpoints 
• Change in pulmonary fibrosis score by quantitative HRCT at Week 24, Week 48, and 
later time points. (Note that efficacy endpoints after Week 48 are described in Part 2 of 
SAP.) 
• Change from baseline in HRQoL at Week 24, Week 48, and later time points. 
• Progression of IPF, defined as time from Day 1 to any one of the following: 
- 
Death from any cause 
- 
Absolute decline in FVC % of predicted value of ≥10% not due to intercurrent illness, 
confirmed by repeat spirometry 
- 
Clinical diagnosis of IPF progression 
• Proportion of subjects with at least one respiratory-related hospitalization 
• Proportion of subjects with respiratory-related death, censored at Week 52 
• Categorical assessment of absolute change from baseline in FVC percent of predicted 
value at Week 48 
4.1.2 PK Parameters and Biomarker Endpoints 
• Change from baseline to Week 24 and from baseline to Week 48 in FVC (liters). 
• Change from Day 1 to Week 48 in a panel of serum and plasma biomarkers that will be 
determined by FibroGen. 
• Relationship between known chromosomal loci associated with IPF and the response to 
FG-3019. 
• Population pharmacokinetics in all subjects to assess trough and peak drug concentrations 
(Substudy) 
- 
FG-3019 Cmax of 1st, 4th 8th dose  
- 
Pirfenidone blood concentration before the first morning dose and one hour after 
study drug dosing completion on Day 1, Week 9 and Week 21.  
- 
Nintedanib blood concentration before the first morning dose and two hours after 
study drug dosing completion on Day 1, Week 9 and Week 21.  
4.1.3 Safety Endpoints 
• AEs and SAEs 


 
 
• Laboratory test abnormalities (graded by NCI Common Terminology Criteria for 
Adverse Events [NCI CTCAE] v4.0) 
• Vital signs 
• 12-lead electrocardiograms (ECGs) 
• Physical examinations 
• Human anti-human antibody (HAHA) 
4.2 
Detailed Definitions of the Study Endpoints 
4.2.1 Change from baseline in FVC (% predicted) at Week 48  
FVC in litres is measured at Screening, Day 1, and every 12 weeks during the randomized 
treatment period. Unscheduled assessments may be performed if subjects are experiencing 
respiratory conditions that are un-related to IPF and that affect PFT performance. The percent 
predicted FVC value (FVC % predicted) is calculated using the algorithm provided by 
Hankinson et al. (1999) for the corresponding gender-age group (Appendix I).   
This primary efficacy endpoint, change from baseline to Week 48 in FVC % predicted 
(ΔFVCpp48), is defined only for subjects in the Full Analysis Set population (see definition in 
Section 5.1.3) in the main study. Baseline is defined as the mean of the last Screening visit and 
the Day 1 visit. Week 48 window is target day (Day 337) ± 6 weeks (see Section 5.7). 
ΔFVCpp48 will be characterized in mean, median, proportion of subjects with no decline 
(change >=0), and proportion of subjects with absolute decline ≥ 10% (change ≤-10%). The 
categorical parameters are described in Section 4.2.7. 
The primary analysis of ΔFVCpp48 will be using a random coefficients linear regression model, 
assuming missing data to be missing at random (see Section 6.6.1.1). Only the observed cases 
will be included in the model. No imputation is needed for the primary analysis.  
ΔFVCpp48 will be characterized in mean, median, categorical responses such as no decline 
(change >=0) and decline ≥ 10% (change ≤-10%), as well as empirical distribution. For these 
summaries,  missing data will be imputed using the algorithm described in Section 5.4.1. Other 
imputation methods will be used for sensitivity analyses. 
4.2.2 Change in Fibrosis Score by Quantitative HRCT at Weeks 24 and 48 
HRCT scan is performed at Screening, Weeks 24 and 48 weeks during the randomized treatment 
period. HRCT images are sent to MedQIA, LLC, the central reading center, for quantification of 
disease severity. 
Each lung is divided into five lobes (right upper, right middle, right lower, left upper, left lower).  
A computer algorithm takes samples of pixels; classifies each pixel in the sample into fibrotic 
reticulation or not; and calculates percent of fibrotic reticulation in each lung lobe. The average 
of the 5 lung lobes is defined to be fibrosis score of the whole lung.  
Change from baseline in HRCT fibrosis score at Weeks 24 and 48 (ΔFIB24 and ΔFIB48) are 
only defined for subjects in the FAS Population. ΔFIB48 is defined for the main study only. The 
fibrosis score at Screening is defined as the baseline. Visit windows are defined as target day 
(day 169 and 337 for Weeks 24 and 48, respectively) ± 12 weeks (see Section 5.7). Missing data 


 
 
are imputed using the MI method for subjects in the FAS Population. Detail imputation 
algorithm is described in Section 5.4.2. This endpoint will be characterized in mean, median, 
proportion of responders which are defined as change from baseline (1) <= 0 (not worsened) and 
(2) < 0 (improved). Responder definition is based on observed + imputed data defined in Section 
5.4.2.  
4.2.3 Change from baseline in HRQoL at Weeks 24 and 48  
Subject’s health-related quality of life (HRQoL) is assessed by the Saint George’s Respiratory 
questionnaire (SGRQ). This instrument was designed to measure health impairment in patients 
with asthma and Chronic Obstructive Pulmonary Disease (COPD).  Its application in IPF patient 
population was evaluated by Swigris et al. (2010). It was used in nintedanib pivotal trials to 
evaluate treatment benefit in IPF patients (Richeldi et al., 2014).  
The questionnaire includes 17 questions covering 3 domains: Symptoms (SYM); Activity 
(ACT); and Impacts (IMP).  The domain and the total (TOT) scores range from 0 to 100, where 0 
indicates the best and 100 the worst possible health status. The scoring algorithm is provided by 
the SGRQ manual which is extracted in Appendix II. The manual includes rules on how to 
handle missing responses to individual questions. Subjects self-administer the questionnaire on 
Day 1 and at Weeks12, 24, 36, and 48. 
Changes from baseline in the 3 domain scores and the total score (abbreviated as ΔSYM, ΔACT, 
ΔIMP, and ΔTOT) are defined only for subjects in the FAS Population. Day 1 assessment is 
defined as the baseline. Change from baseline to Week 48 is defined for the main study only. 
Visit windows are defined as target day ± 6 weeks (see Section 5.7). These endpoints will be 
estimated based on LS means obtained from a mixed effect repeated measures model (MMRM) 
described in Section 6.6.3. Missing data will not be imputed explicitly for these endpoints.  
Detail description of the questionnaire is presented in St. George’s Respiratory Questionnaire 
Manual, Version 2.3 (June 2009), by Jones, Paul, St. George’s, University of London.  A 
summary of the scoring algorithm is presented in Appendix II for reference. 
4.2.4 Time to Progression of IPF 
Time to progression of IPF is defined as the time from Day 1 to the first occurrence of the 
following events: 
- 
Death from any cause 
- 
Absolute decline in FVC % of predicted value of ≥10% not due to intercurrent illness, 
confirmed by repeat spirometry 
- 
 Clinical diagnosis of IPF progression  
If a subject discontinued treatment due to disease progression as recorded on the Disposition 
CRF, it is considered clinical diagnosis of IPF progression. To determine whether a subject’s 
FVC (% predicted) declined ≥10%, it should be either confirmed by a subsequent test or by the 
fact that the subject has discontinued the study. If confirmed, the earlier time is used to define 
this endpoint. Below are some examples. 


 
 
1. If a subject’s FVC declined below the threshold at Week 36 but the assessment increased 
above the threshold at the next test, this subject is not considered to have progressed at 
Week 36. 
2. If a subject’s FVC declined below the threshold at Week 36 and the assessment was 
confirmed at the next test, this subject is defined to have progressed at Week 36. 
3. If a subject’s FVC declined below the threshold at Week 36 and dropped out 
subsequently due to any reason, this subject is defined to have progressed at Week 36. 
If the last assessment is at week 48, no confirmation will be required. Only observed FVC values 
(no imputed values) are used to assess progression. All events collected during year 1 (including 
Day 365) are included.  If no event is observed, PFS is censored on the date of last PFT in the 
Randomized Treatment Period. Mortality events reported after EOS but before or on Day 365 are 
included in this endpoint. 
Table 2. 
Examples of Year 1 Time to Progression and Censoring Rules 
Subject 
Day of 
Last PFT 
PFT result 
Day of 
death or 
acute IPF 
Event or 
Censor 
Days 
Comment 
1 
300 
normal 
320 
event 
320 
 
2 
300 
normal 
370 
censor 
300 
Event beyond day 365. 
Technically the subject’s 
status between days 300-
370 is unknown. It should 
not be marked as censor at 
365.  
3 
300 
normal 
none 
censor 
300 
 
 
4.2.5 Proportion of Subjects with Respiratory-Related Hospitalization 
Respiratory-related hospitalization is recorded on the AE CRF.  
4.2.6 Proportion of Subjects with Respiratory-Related Death 
Respiratory-related and IPF related death is recorded on the Death CRF. 
4.2.7 Categorical Assessment of ΔFVCpp48 
Two categorical endpoints will be summarized: 
- 
Proportion of subjects with no decline (change ≥0)  
- 
Proportion of subjects with absolute decline ≥ 10% (change ≤ -10%). 


 
 
The observed and imputed value of ΔFVCpp48 (defined in Section 5.4.1) will be used to classify 
these categories.  Dropouts due to deaths and disease progression are classified in the failure 
category by the imputation algorithm.  
4.2.8 Prior and Concomitant Medication 
Medications are coded using The World Health Organization Drug Dictionary (WHODD: March 
1, 2015). The medications are reported by therapeutic class and generic name.  
Prior medications are defined as those that are stopped prior to first infusion of FG-3019. These 
medications are summarized separately from the concomitant medications. If the stop date is 
incomplete or missing, the imputation rules are described in Section 5.4.10.  
4.2.9 Study Drug Exposure and Treatment Compliance 
Duration of study drug exposure = date of last non-zero dose – date of first dose + 1. This 
calculation does not account for FG-3019’s half-life and the resulting drug exposure after the last 
dose. 
Number of infusions is defined as the number of non-zero dose infusions. 
The calculated dose amount of FG-3019 = nominal dose * body weight. 
The latest measurement of body weight is used in calculating the dose for each infusion. The 
calculated dose amount is used to verify the actual amount administered.  
Treatment compliance is defined as: 
Compliance = (# of actual doses administered)/ (# of expected doses) * 100, where # of expected 
doses  =  (last dosing week)/3 + 1. 
4.2.10 FG-3019 Pharmacokinetic (PK) Parameters 
For subjects in the substudy, six FG-3019 plasma samples are collected: pre-any study 
medication and 0-1 hour from end of infusion on Day 1 and at Weeks 9 and 21. Post-dose 
samples are collected within 1 hour after the end of infusion. PK parameters include peak and 
trough concentrations, approximated by pre- and post-dose samples.  Population PK (/PD) 
analysis may be performed separately with details described in the CSR (if applicable). 
4.2.11 Pirfenidone and Nintedanib Pharmacokinetic (PK) Parameters 
For subjects in the substudy, six plasma samples are collected for each subject to assess the 
pirfenidone and nintedanib concentration level: pre-dose and post-dose on Day 1 and at Weeks 9 
and 21. Post-dose samples are collected at 3 hours after dosing for pirfenidone, and at 4 hours 
after dosing for nintedanib. Trough and peak concentration level, estimated by pre- and post-
dosing samples, are evaluated. Metabolite-to-parent ratio will also be calculated  in the post-dose 
samples  for both pirfenidone and nintedanib.  
4.2.12 AEs and SAEs 
AEs and SAEs are collected on the AE CRFs. SAEs are special cases of AEs. In this document 
the more general terms such as AE and TEAE are used to cover both cases of AEs and SAEs. 


 
 
The definitions of AEs, SAEs, severity, and relationship to study medication are described in 
Section 11of the protocol. Adverse events are coded using the Medical Dictionary for Regulatory 
Activities (MedDRA: 18.0) for system organ class (SOC) and preferred term for summary.   
Treatment Emergent Adverse Event in the Study (TEAE) – Randomized Treatment Period 
TEAEs during the randomized treatment period are defined as new or worsening AEs that 
occurred in the window of first dose of infusion of the blinded study drug (FG-3019 or placebo) 
(Day 1) and within 28 days of the last infusion of FG-3019/placebo or before the first FG-3019 
infusion in the extended treatment period, whichever occurs first.  
Table 3 
Definition of TEAE and Study Period When AE Occurred 
AE Onset Date Relative to Dosing*  
AEPRIOR 
TEAE  
Study Period 
(EPOCH) 
AE onset date < Day 1 
Any 
No 
screen 
AE onset date = Day 1 
Yes**  
No 
screen 
No**  
Yes 
treatment 
Day 1 < AE onset date ≤ date of last dose in 
randomized treatment period 
Any 
Yes 
treatment 
Date of last year 1 dose < AE onset date ≤ earlier 
date of {last year 1 dose + 28, Day 1-EX} 
Any  
Yes 
Within 28 days 
from last dose 
follow-up 
AE onset date > date of last year 1 dose + 28 and 
AE onset date < Day 1-EX for subjects entered EX 
Any 
No 
Additional 
Follow-up 
beyond 70 days 
*Dosing refers to FG-3019 or placebo infusion 
** If AE onset time is known, TEAE will be determined by AE onset date/time; AEPRIOR will 
not be used. 
AEs may be recorded in multiple records due to changes of characteristics such as seriousness, 
severity, frequency, treatment, and other aspects. These records will be linked together for 
summary purposes. The most severe grade, seriousness, relatedness to study drug, and AE 
frequency will be used in AE summary tables. Below are the rules: 
(1) Multiple AE records are linked as one AE if they have the same preferred term and onset 
date of a later record is the same as stop date or stop date + 1 of the previous record.  
(2) If the linked AE starts in the TEAE window as shown in Table 3, it is a TEAE.  
(3) If the linked AE starts in screening, then the worst seriousness, severity grade, and AE 
frequency of the screening records will be used as the reference. A post-dose AE is 


 
 
considered TEAE if it is worsened comparing to the reference. ‘Worsened’ is defined as 
increased grade in seriousness, severity, and frequency. 
(4) Once an AE record is determined to be a TEAE, all subsequent records of the linked AE, 
including the records past 28 days after last dose of the randomization treatment period, 
are considered TEAE. The highest grade of severity and seriousness of the linked TEAE 
will be included in the AE summary tables. 
The hypothetic example below illustrates the algorithm. Of note, AE #1 occurred in Screening; 
AE #2 and #3 were not worse than AE #1; these 3 AEs are not TEAEs. AE#4 worsened during 
the TEAE window; the subsequent AE #5 is also a TEAE by the algorithm.   
Table 4 
Example of Definition of TEAE for Multiple Records of the Same AE 
                                   
AE Severity Rating 
AEs are rated by the investigators as “Grade 1 - mild”, “Grade 2 - moderate”, “Grade 3 - severe”, 
“Grade 4 - life threatening”, or “Grade 5 - fatal” based on the CTCAE v4.0 grading system as 
described in Section 11.3.3 of the protocol. If a subject reports multiple occurrences of an AE 
within one system organ class or preferred term, the most severe occurrence will be presented in 
the summary by severity rating. Missing severity rating will not be imputed and it is ranked the 
lowest in summary by severity rating.                         
AEs Related to FG-3019 
Investigators determine the relationship of AEs with the study medication. For summary 
purposes, ‘Possibly related’ AEs are grouped with the ‘Related’ AEs. If related and unrelated 
occurrences of an AE within one system organ class or preferred term are reported in a subject, 
the related occurrence will be presented in the summary by relationship. Missing relationship 
evaluation will not be imputed and it is ranked the lowest in summary by relationship. 
AE # 
Onset 
AE 
Severity Seriousness 
Related to 
study drug? TEAE 
1 
Screening 
Headache 
2 
N 
N 
N 
2 
Day 2 
Headache 
1 
N 
N 
N 
3 
Last dose 
Headache 
2 
N 
Y 
N 
4 
10 days post last 
dose 
Headache 
3 
Y 
N 
Y 
5 
45 days post last 
dose 
Headache 
5 
Y 
N 
Y 
Consolidated 
for summary 
 
Headache 
5 
Y 
Y 
Y 


 
 
Infusion-associated AE 
TEAEs are considered possible infusion reactions if they occurred during a FG-3019 infusion or 
within 12 hours from the end of a FG-3019 infusion regardless of causality assessment. In 
addition, TEAEs reported by investigators as possible infusion reactions and TEAEs with 
verbatim containing the word ‘infusion’, regardless of timing, are classified as possible infusion 
reactions. 
4.2.13 Laboratory Abnormalities Central Laboratory Evaluations 
Safety lab tests are evaluated at Screening to assess entry eligibility and on Day 1 prior to first 
dose. The last assessment prior to the first dose is defined as baseline. Post-treatment 
assessments are performed every 12 weeks to monitor subject safety. Lab test abnormality 
grading defined by CTCAE v4.0 is provided by ICON Central Laboratories, Inc. (see reference). 
Complete Blood Count with Differentials 
Hemoglobin, hematocrit, red blood cell (RBC) count, mean corpuscular volume (MCV), mean 
corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), white 
blood cell (WBC) count, neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet 
count and calculated absolute neutrophil count (ANC).  
Serum Chemistry 
Sodium, potassium, chloride, bicarbonate, creatinine, blood urea nitrogen, glucose, calcium, 
phosphorus, uric acid, albumin, aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), alkaline phosphatase, and total bilirubin.  
Coagulation 
Prothrombin time (PT) and activated partial thromboplastin time (aPTT).  
Urinalysis  
Specific gravity, pH, protein, glucose, ketones, bilirubin, leukocyte esterase, nitrite, 
urobilinogen, blood, clarity, color, and microscopic examinations if any of the preceding 
urinalysis tests (other than glucose or ketones) are abnormal. 
Serum Pregnancy Test 
Human chorionic gonadotropin (HCG) for females of child-bearing potential only.  
The CTCAE grading of lab test results is provided in Appendix I. Potentially clinically 
significant lab test results are those that are CTCAE grade 3 or higher. 
In addition to using CTCAE grading, normal ranges for each numeric laboratory variable are 
provided by the central lab.  Numeric variable values are compared to the normal range and are 
flagged as low, normal, or high.   
Baseline for lab tests is defined as the last assessment prior to the first dose.  


 
 
4.2.14 Vital Signs 
Vital signs parameters include systolic/diastolic blood pressures, pulse rate, respiratory rate, and 
body temperature. Baseline for vital signs is defined as the average of the last Screening value 
and the Day 1 pre-infusion measurement. .  
Potentially clinically significant vital sign changes are those which meet both criteria in Table 
5a.  
Table 5a. 
Potentially Clinically Significant Changes in Vital Signs 
Parameter 
Observed Values  
Change from 
Baseline 
Systolic BP (mm Hg) 
<90 or>140 mm Hg 
>20 mm Hg 
Diastolic BP (mm Hg) 
<50 or>90 mm Hg 
>15 mm Hg 
Pulse Rate (bpm) 
<50 or>100 bpm 
>20 bpm 
BP=blood pressure; bpm=beats per minute;  
 
4.2.15 Electrocardiogram 
ECG is evaluated qualitatively by investigator as: 
Normal, 
Abnormal, clinically significant, or 
Abnormal, not clinically significant. 
Abnormal findings are described. 
Table 5b. 
Criteria for Potentially Clinically Significant ECG 
Parameter 
Criteria  
PR interval (msec) 
<120 or  >200 
QT interval (msec)* 
≤300 or  > 450 
RR interval (msec) 
<600 or  >1200 
*(Uncorrected for heart rate. For QTc use >450 for males and >470 for females) 
4.2.16 Physical Examination 
Body systems are evaluated as normal or abnormal based on investigator assessment. For 
abnormal cases, descriptions are provided. 
4.2.17 DNA Analysis 
Fingerlin et al. (2013) performed a genome-wide association study in subjects with fibrotic 
idiopathic interstitial pneumonias (N = 1616) and controls (N = 4683) 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.  
Patient DNA is isolated from whole blood samples. We will evaluate the relationship between 
clinical response to FG-3019 or placebo, in terms of changes in pulmonary function and fibrosis, 
and the specific identified variants in these chromosomal loci. A categorical analysis for each 
response [FVC (% predicted) change ≤ -10% or change >0%] will be provided for each gene 
variant of interest in terms of relative expression in active and placebo patients, similar to Figure 
4A in Fingerlin. 
4.2.18 Connective Tissue Growth Factor (CTGF) 
Plasma samples are collected to measure the levels of whole CTGF and whole + N-terminal 
fragment CTGF. Concentration level at each time point will be summarized descriptively. 
4.2.19 Human Anti-Human Antibodies to FG-3019 (HAHA) 
Blood samples are collected at the end of study visit which is between 4 – 10 weeks from the last 
dose. HAHA level is evaluated. A sample is considered reactive and specific for antibodies to 
FG-3019 if the unspiked sample signal is greater than the cut-point.  
4.3 
Definitions of Additional Endpoints 
4.3.1 Change from Baseline in FVC (L) at Week 48 
Change from Baseline in FVC (L) at Week 48 (abbreviated as ΔFVC48) is the same measure of 
lung function as ΔFVCpp48 in the unit of volume. It is similarily defined as ΔFVCpp48. For 
subjects with missing assessments at Week 48, missing data will be imputed following the 
imputation rules are described in Section 5.4.2.  
4.3.2 Other Endpoints Related to Change from Baseline in FVC (L) and FVC (% 
predicted) 
• Proportion of subjects with change in FVC % predicted > 0 at all assessment time points 
• Change from baseline in FVC (L) at all assessment time points 
• Categorical assessment of change from baseline in FVC(% predicted) at all assessment 
time points 
• Percent of relative change from baseline in FVC (L) at all assessment time points 
Percent of relative change from baseline is defined as [FVC (L) at a post-baseline visit – 
baselined FVC (L)] / baseline FVC (L) * 100. Observed and imputed values (see Section 
5.4.1) will be used in defining % relative change at Week 48.  
•  
4.3.3 Other PFT Parameters 
Other PFT parameters include FEV1 (% predicted) and FEV1/FVC ratio. DLCO, TLC, and FRC 
are not measured in subjects enrolled under protocol amendment 2.0 and subsequent 
amendments.  Predicted value of FEV1is calculated using the formula presented in Appendix II.  
For summaries by visit, assessments are grouped based on windowing rules described in Section 
5.6. Baseline is defined as the mean values of the last Screening visit and Day 1. 


 
 
4.3.4 HRCT Visual Assessment 
Each lung is divided into five lobes (right upper, right middle, right lower, left upper, left lower).  
For baseline, the extent of pulmonary abnormality in each lobe is scored using the following 6-
point scale: none, 1 to 5%, 6 to 25%, 26 to 50%, 51-75% and more than 75%.  The score of the 
worst lung lobe is defined as the highest score of the five lobes. Three types of abnormality are 
assessed: pure ground glass (GG, increased lung attenuation in the absence of reticular interstitial 
thickening or architectural distortion), fibrosis (FIB, reticular inter and intra-lobular interstitial 
thickening, traction bronchiectasis, and bronchiolectasis), and honeycomb cysts (HC, clustered 
air-filled lung cysts with contiguous walls). In addition, the airways are assessed for presence or 
absence of bronchiectasis per lobe.  If ANY lung lobe shows presence or bronchiectasis, then 
whole lung will be considered having presence of bronchiectasis. For follow-up, the change in 
the extent of pulmonary abnormality in each lung lobe is scored using the following 3-point 
scale: better, same, worse, comparing to Baseline.  To avoid bias in comparing follow-up with 
baseline images, readers are presented with two sets of HRCT scans (Baseline and Follow-up) in 
a randomized order and in a blinded fashion. 
HRCT images are assessed by two independent thoracic radiologists.  Any discrepancies are 
reviewed by a third independent reader for a consensus read. Only the final assessments will be 
used in analyses. 
4.3.5 Other Quantitative HRCT Reading Scores 
In addition to the fibrosis score described in Section 4.2.2, ground glass (GG) and honeycombing 
(HC) scores are included as part of the quantitative HRCT reading. An overall score (QILD) is 
defined as the sum of FIB, GG, and HC.    
The worst lung zone is defined as the lung zone with the highest fibrosis score. If there are two 
or more lung zones with the same highest fibrosis score, these lung zones are combined and the 
average scores of these zones will be used in the follow-up visits.  
4.3.6 Rate of Change in FVC and DLCO Prior to Enrollment 
The rate of change in FVC and DLCO prior to enrollment is define as the linear regression slope 
based on the data collected up to day 1 prior to enrollment. This parameter is summarized as 
baseline characteristics. These two parameters may be evaluated whether they are prognostic 
factors to the clinical outcomes and change in FVC over time. 


 
 
5 
GENERAL STATISTICAL CONSIDERATIONS  
5.1 
Analysis Populations 
Summaries of baseline characteristics, safety, study drug exposure, and biomarker are based on 
available data in the Safety population.  Efficacy analyses are based on the FAS population.  
Pharmacokinetic parameters are summarized based on the PK population.  All subjects in the 
Safety population are included in the data listings. 
5.1.1 Randomized Population 
The Randomized Population consists of all subjects who have received a randomized treatment 
assignment, regardless of whether they received study treatment. 
5.1.2 Safety Population 
The Safety Population consists of all randomized subjects who have received any amount of 
study medication. If actual treatment received differs from the randomized treatment arm, the 
actual treatment arm will be used in safety data analysis. 
5.1.3 Full Analysis Set Population 
The Full Analysis Set (FAS) Population consists of randomized subjects who have received any 
amount of study medication and have evaluable FVC assessments at baseline and at least one 
evaluable post baseline. Subjects who are mis-diagnosed as IPF will be excluded from FAS. The 
FAS population will be used in the primary analyses of the PFT endpoints and other efficacy 
endpoints. If actual treatment received differs from the randomized treatment arm, the actual 
treatment arm will be used in efficacy data analysis. 
5.1.4 Substudy Population 
The Safety Population consists of randomized subjects who have received any amount of study 
medication. If actual treatment received differs from the randomized treatment arm, the actual 
treatment arm will be used for safety data analysis. 
5.1.5 Substudy PK Population 
Substudy PK population includes subjects in substudy who have received at least one dose of 
study medication and have corresponding PK concentration data. 
5.1.6 Extension Safety Population 
Extension Safety Population (Safety-EX) includes subjects who have received any amount of 
study medication during the extension period. 
5.2 
Hypotheses and Decision Rules 
The hypothesis of the study is whether treatment of FG-3019 is superior to placebo in attenuating 
the decline of FVC from baseline to Week 48 in patients with IPF. It will be tested based on the 
primary endpoint, change from baseline to Week 48 in FVC (% predicted), using the ANCOVA 
model described in Section 6.6.1, at a two-sided significance level of 0.05.  
5.3 
Adjustment for Multiple Comparisons 
Using a gatekeeping procedure, if the primary endpoint achieves the statistical significance level, 
the secondary hypothesis of whether treatment of FG-3019 is superior to placebo in change of 


 
 
lung fibrosis score at Week 48 will be tested at the significance level of 0.05 (two-sided).  The 
model of testing this secondary endpoint is described in Section 6.6.2.  
If both the primary and the first secondary endpoint achieve the statistical significance level, 
analyses of all other secondary endpoints will be performed at the significance level of α=0.05, 
using two-sided tests. No adjustments will be made for multiple tests on secondary endpoints 
except for change in fibrosis score at week 48. 
5.4 
Handling Dropouts and Missing Data 
Patients with IPF have relatively short median survival time. Disease progression (PD) is the 
most frequent reason of early treatment discontinuation in the current study. Missing data are 
primarily caused by discontinuation due to PD. Other infrequent causes of missing data include 
discontinuation due to AE or withdrawal of consent, technical failures, and incompleteness in 
patient reported outcome.  As recommended by regulators, appropriate methods based on 
plausible assumptions on the nature of the data and the mechanism of missing data should be 
used in analysis with missing data. This section presents the missing data handling methods for 
different efficacy parameters and the rationale of the associated assumptions. In addition, 
imputation of missing or incomplete start or stop date of AE and concomitant medication is also 
included in this section.   
5.4.1 Imputation for Missing Data in ΔFVCpp48 and ΔFVC48 
5.4.1.1 Assumptions and Rationales 
The primary analysis of ΔFVCpp48 will be using a random coefficient linear regression model 
based on the missing at random (MAR) assumption (section 6.6.1.1). Only observed cases will 
be included in the model; no imputation will be performed. However, in order to characterize 
ΔFVCpp48 and ΔFVC48 in mean, median, categorical responses such as no decline (change 
>=0) and decline ≥ 10% (change ≤-10%), as well as empirical distribution, it is necessary to 
impute the missing data. Based on clinical experience, FVC rate of decline in IPF patients is 
gradual in the absence of IPF exacerbation but can be drastic after an IPF exacerbation or disease 
progression. Therefore, it seems realistic to model the missing data in subjects who discontinued 
due to PD/death utilizing the trend in a subgroup with similar characterics, and model other types 
of missing data utilizing the trend of the overall study population.  
This imputation strategy is conformed to the recommendations of the EMA Guideline on 
Missing Data in Confirmatory Clinical Trials (2011)  
- 
“An attractive approach for imputing missing data may be to employ a different pre-
specified imputation technique for each different reason for withdrawal, rather than the 
same technique for all patients. While this would represent a relatively novel approach, 
there is no objection to this in principle. The strategy has more flexibility in handling 
different reasons for and timings of withdrawal and consequently the possible 
relationship between missing data and the outcome of interest. If used appropriately, it 
may better address the question of primary regulatory interest. The method also offers an 
intuitive framework for conducting a range of sensitivity analyses.”  
- 
“A combined strategy incorporating several methods for handling missingness (e.g. 
assume dropouts due to lack of efficacy and adverse events are MNAR and lost to follow-
up are MAR) may also be considered.” 


 
 
5.4.1.2 Imputation Procedure 
Missing data in ΔFVCpp48 and ΔFVC48 are classified into 2 categories:  
(A) missing due to discontinuation for PD or death;  
(B) missing due to other reasons.  
Step 1: Missing data in Category B are imputed as the average of the multiple imputed values 
from the MI procedure. The model specifications are provided in the next two subsections. All 
subjects in FAS are included in the models.  
Step 2a: Missing data in Category A are imputed using a linear slope random coefficient model. 
Subjects in FAS who are classified as having PD, including dropouts due to PD/death and 
completers whose FVCpp declined ≥10 at Week 48, are included in this model.   
Step 2b: If the regression projected decline in Step 2a is higher than the maximum observed 
decline in the study population, truncate the linear projected value to the maximum observed 
decline in the main study.  
Step 2c: If the projected decline in FVCpp48 in Step 2a is less than 10 (ΔFVCpp48>-10), then 
assign imputed ΔFVCpp48 a value of -10. For FVC (L), the cutoff point corresponding to 
ΔFVCpp48 = -10 is determined as (-10) * mean [predicted FVC (L) at baseline in FAS] /100. 
In theory, the same MI model used to impute missing data in Category B can be applied to 
subjects who are classified as PD to impute missing data in Category A. However, due to limited 
available observed data in the PD subset, the MI model cannot be implemented. The linear slope 
random coefficient model requires only 2 or more data points per subjects. 
The rationales of including steps 2b and 2c are as follows: a large decline of FVC may occur 
when a subject is experiencing an IPF exacerbation. Such decline usually subsides after the 
subject’s condition is stabilized. Truncating the linear projection in step 2b is more likely to 
mimic the actual outcome than without truncation. For step 2c, if a subject discontinues 
treatment due to progressive disease, his or her FVC value is likely to have declined 
substantially, although only moderate changes are observed prior to the subject’s 
discontinuation.    
5.4.1.3 Statistical Models Used in Imputing Missing Data ΔFVCpp48 
(a) For subjects in FAS, generate a monotone missing pattern by Monte Carlo Markov Chain 
(MCMC) procedure: 
Model – FVCpp_MI1 
PROC MI data=FVCpp_main   nimpute = 100 round = .01 minimum = 30 
maximum=130  seed=303019067 out=FVCpp_MI1; 
BY  trt; 
MCMC impute=monotone; 
VAR age sex DLCOPP-hb0 FVCpp0 FVCpp12 FVCpp24 FVCpp36 FVCpp48; 
run; 
Input dataset FVCpp includes FAS subjects except those who were mis-diagnosed as IPF. 


 
 
(b) Use a monotone MAR-based multiple imputation approach from PROC MI to impute 
missing data from monotone missing data pattern generated by Model – ΔFVCpp_MI1.  
Model – FVCpp_MI2 
PROC MI data=fvc_mi1 nimpute = 1 round = .01 minimum =30 maximum = 130  
seed=313019067 out=FVCpp_MI2; 
BY   _imputation_  trt; 
      VAR age sex DLCOPP-hb0 FVCpp0 FVCpp12 FVCpp24 FVCpp36 FVCpp48; 
MONOTONE REGRESSION (FVCpp48 =  age sex DLCOPP-hb0 FVCpp0 FVCpp12 
FVCpp24 FVCpp36);    
run; 
(c)  For subjects who dropped out due to death or PD and subjects whose FVCpp declined 
≥10 at Week 48, fit the following random coefficient model: 
Model – Random_coeff 
proc mixed data=PD/Deaths;  
  class subjid; 
  model chg = visitn/ noint outp=pred_data; 
  random visitn /subject=subjid type=UN; 
run; 
If the iterations do not converge, other variance structure will be used. Baseline records with chg 
= 0 are include in the model.  
5.4.1.4 Statistical Models Used in Imputing Missing Data FVC (L) 
(d) For subjects in FAS except those who are mis-diagnosed as IPF, generate a monotone 
missing pattern by Monte Carlo Markov Chain (MCMC) procedure: 
Model – MI_FVC1 
PROC MI data=fvc_main   nimpute = 100 round=.001 minimum=1 maximum=5  
seed=203019067 out=fvc_mi1; 
BY  trt; 
MCMC impute=monotone; 
VAR age sex DLCOPP-hb0 fvc0 fvc12 fvc24 fvc36 fvc48; 
run; 
(e) Use a monotone MAR-based multiple imputation approach from PROC MI to impute 
missing data from monotone missing data pattern generated by Model-FVC1.  
Model – MI_FVC2 
PROC MI data=fvc_mi1 nimpute = 1 round=.001 minimum=1 maximum=5  
seed=213019067 out=fvc_mi2; 


 
 
BY   _imputation_  trt; 
VAR age sex DLCOPP-hb0 fvc0 fvc12 fvc24 fvc36 fvc48; 
MONOTONE REGRESSION (fvc48 = age sex DLCOPP-hb0 fvc0 fvc12 fvc24 fvc36);    
run; 
(f) The same random coefficient model (Model Random_coeff) in (c) above is used to obtain 
the projection coefficient for ΔFVC. 
5.4.2 Imputation for Missing HRCT Fibrosis Scores 
HRCT fibrosis score is a measure of physiological condition of lung tissue. Unlike functional 
measures such as FVC, physiological changes are gradual and are in general predictable from the 
pattern of prior measurements and the pattern of the study population. Based on this 
understanding, missing HRCT fibrosis score will be imputed by regression model that includes 
prior assessments as predictive effects. The multiple imputation (MI) procedure, which can 
impute missing data for subjects with no post-baseline assessment, is an appropriate procedure in 
this situation.   
Since HRCT is a required procedure to evaluate subject eligibility, baseline values are in general 
available except a few cases of which the quality of the HRCT images is inadequate for 
quantitative scoring. Missing post-baseline data are mostly due to subjects discontinuing the 
study.  Therefore, missing data at weeks 24 and 48 are in general in a monotone pattern with a 
few exceptions. A multi-step multiple imputation method, as shown below, will be used to 
perform missing data imputation as well as data analysis. Subjects with missing baseline value 
will not be included in the imputation and analysis models. Imputation and analysis procedure 
will be performed for main study and substudy separately.   
5.4.2.1 Main Study 
1) Use Monte Carlo Markov Chain (MCMC) methodology from PROC MI by treatment group 
to generate a monotone missing pattern; 
Model - FIB1 
PROC MI data=fib_obs_main   nimpute = 100 round=.1 minimum=0 maximum=100  
seed=103019067 out=fib_mi1main; 
 
BY  trt; 
 
MCMC impute=monotone; 
VAR fib0 fib24 fib48; 
run; 
2) Use a monotone MAR-based multiple imputation approach from PROC MI to impute 
missing data from monotone missing data pattern generated by Model-FIB1.  
Model - FIB2 
PROC MI data=fib_mi1main nimpute = 1 round=.1 minimum=0 maximum=100  
seed=113019067 out=fib_mi2main; 
BY  _imputation_ trt; 


 
 
VAR fib0 fib24 fib48; 
MONOTONE REGRESSION (fib24= fib0);    
MONOTONE REGRESSION (fib48= fib0 fib24);    
run; 
A regression method is preferred over the predictive mean matching method because those 
who drop out of the study are likely to be sicker than those who complete the study. 
If the final missing data pattern is monotone, then Model – FIB1 will not be needed and 
NIMPUTE in Model – FIB2 will be changed to 100. 
Change from baseline at Week 24 is: ΔFIB24 = FIB24 – FIB0; 
Change from baseline at Week 48 is: ΔFIB48 = FIB48 – FIB0. 
5.4.2.2 Substudy 
Since the substudy is relatively small and there is only one post-baseline assessment, the two 
background therapies are combined in MI procedure in order for it to perform properly. The 
following MI model will be used for the substudy: 
Model – FIB3: 
PROC MI data= fib_obs_sub  nimpute = 100 round=.1 minimum=0 maximum=100  
seed=133019067 out= fib_mi2sub; 
BY  trt  ; 
VAR fib0 fib24; 
MONOTONE REGRESSION (fib24= fib0);    
run; 
If at the final data analysis there are not enough observed data points to perform the imputation 
in Models FIB3, variable trt will be moved from the ‘BY’ statement to the ‘MONOTONE 
REGRESSION’ statement.  
5.4.3 Rules for Handling Missing Data in Individual Questions in SGRQ Scoring  
Rules of handling missing data in individual questions in SGRQ questionnaire are presented in 
Appendix III.2. Missing data in the SGRQ domain and total scores will not be imputed. Analysis 
of these endpoints will be based on observed data using a MMRM model.  
5.4.4 Handling Missing/Incomplete AE Onset Date 
If the AE onset date is incomplete or missing, the following rules will be applied to obtain 
imputed AE onset date before applying Table 3 in Section 4.2.12.  
• If year and month are present, only day is missing, 
a) If AE onset Year/month = Day 1 Year/month, assign onset date = date of Day 1; 
b) If AE onset Year/month ≠ Day 1 Year/month, assign onset Day = 1; 
• If year is present, month and day are missing, 


 
 
a) If onset year = year of Day 1, assign onset date = date of Day 1; 
b) If onset year ≠ year of Day 1, assign January 1st to onset month and day. 
• If onset date is completely missing, assign onset date = date of Day 1. 
If the stop date is complete and the imputed start date as above is after the stop date, the start 
date will be imputed by the stop date. 
5.4.5 Handling Missing/Incomplete CM Start/Stop Dates 
For the purpose of grouping medications in different study period, the following rules will be 
used to impute incomplete CM start and end date: 
• Incomplete CM start date: assign 1 to missing Day, January to missing Month.  
• Incomplete CM end date: assign 30 to missing Day, December to missing Month. Impute 
CM end date only if ‘ONGOING’ is not checked. 
If the imputed stop date is before the start date (imputed or non-imputed start date), then the 
imputed stop date will be replaced with the start date. 
No imputation will be performed for the following cases: 
• CM end date will not be imputed if ‘ONGOING’ is checked. 
• Year of CM start or end is missing. If CM end year is missing, the CM will be grouped in 
the ‘Concomitant Medication’ category. 
5.4.6 Handling Missing/Incomplete Dates for PFT Prior to Enrollment 
For the purpose of estimating the rate of change in PFT parameters prior to enrollment, the 
following rules will be used to impute incomplete PFT performance date: 
• If year and month are present, only day is missing, assign day = 15; 
• If year or month is missing, then the corresponding PFT assessment is not evaluable for 
evaluating rate of change.  
5.5 
Adjustment for Covariates 
Comparisons between treatment arms will be adjusted for baseline value of the parameter being 
analyzed.  
5.6 
Definition of Baseline 
Baseline is defined in Section 4.2 for each parameter separately.  
5.7 
Efficacy Analysis Visit Window 
Efficacy parameters (PFT, HRCT, and PRO) will be summarized by analysis visit defined by the 
following assessment windows in Tables 6 and 7.  
Table 6.  Assessments with 12-week interval (PFT and SGRQ) 
Analysis Visit 
Window 
Baseline 
Prior to first dose on Day 1 


 
 
Week X 
X = 12, 24, 36, 48 
Target day = 7 * X + 1 
Window = [Target day – 42, Target day + 41] 
Table 7. 
Year 1 assessments with 24-week interval (HRCT) 
Analysis Visit 
Window 
Baseline 
Prior to first dose on Day 1  
Week X 
X = 24, 48 
Target day = 7 * X + 1 
Window = [Target day – 84, Target day + 83] 
All scheduled and unscheduled assessments are included. If multiple FVC assessments are 
available in the same window, the highest value will be used in the analysis. If multiple HRCT 
assessments or SGRQ assessments are in the same window, the one closest to the scheduled visit 
will be used in the analysis. If two assessments with equal distance to the target day, the later 
assessment will be used in analysis. Assessments that do not fall in any windows are considered 
not evaluable and will not be included in analyses. 
Safety data (lab tests, vital signs, ECG, physical exams) are summarized by nominal clinic visit. 
Data collected during the unscheduled visits are not included in the summary tables, but are 
included in data listings and in evaluations for clinically significant abnormal changes. 
The upper bound of the Week 48 window is at the earlier time point of Target day +41 (or +83 
for HRCT) days or Day 1-EX. 
5.8 
Interim Analyses and Data Monitoring 
Unblinded safety data summaries are performed by an independent vendor and are reviewed an 
independent Data Monitoring Committee periodically. DMC recommendations are documented 
in the DMC meeting minutes.  
5.9 
Pooling Data of Study Sites 
All study sites are pooled in all analyses due to the small number of subjects enrolled at each 
site. Effect of a region, or country, or site will be evaluated as part of exploratory analyses.  
5.10 General Layout 
All study parameters, including baseline characteristics, efficacy, safety, PK and biomarker, will 
be summarized descriptively. Descriptive statistics including the number of subjects (n), mean, 
standard deviation (SD) for baseline variables or standard error (SE) for efficacy parameters, 
median, minimum and maximum will be presented for continuous variables. For continuous PK 
parameters, coefficient (CV) and geometric mean may also be presented. Number (n) and 
percentage (%) of subjects in each category will be summarized for categorical variables.  


 
 
Efficacy parameters will be summarized analytically. Analytical statistics include LS mean and 
standard error, 95% CI for the mean or median, p-value, treatment difference expressed in 
absolute difference, odds ratio, or hazard ratio depending on the nature of the parameter.  
All summaries will be presented by treatment group as well as a combined group (FG-3019, 
Placebo, Overall), unless specified otherwise. Subjects who are enrolled in the substudy will be 
summarized separately from those who are enrolled in the main study. Only data collected 
during the Randomized Treatment Period are included in this set of analyses and summaries. 
Data collected during the extension period will be summarized in a separate package. 
Data listings are sorted by patient sub-group: main study, substudy pirfenidone, and substudy 
nintedanib. Within each sub-group, subjects are sorted by treatment arm (FG-3019 first) and 
finally by subject ID.  
Figures, such as line-chart, bar-chart, box-plot, scatter plot, forest plot, or waterfall plot, are in 
general included to facilitate comparison between treatment arms and evaluation of trend.  
5.11 Data Errata and Hard-Coding 
Data errors identified after database lock are documented in an errata log. Under special 
circumstances, hard-coding in SAS programs is necessary to correct data errors in order to avoid 
obscure study results. Only limited cases deemed necessary and are approved by study team will 
be hard-coded. The changed values as well as approval from the study team will be documented. 


 
 
6 
STATISTICAL ANALYSES 
6.1 
Subject Enrollment and Disposition 
The number of subjects enrolled in each study site will be summarized. 
The number of subjects in each study population (Randomized, Safety, FAS, Substudy, and 
Extension) will be summarized by treatment group for main and substudy separately.  The 
number of subjects who completed or discontinued the study as well as the reasons for early 
discontinuation will be summarized. Treatment completion rate will be compared between the 
two treatment arms. 
Subject who discontinued the study prematurely and the reasons will be listed.  
6.2 
Protocol Deviations 
Protocol deviations will be categorized as follows: 
• Entry Deviation: Subject entered study, but did not satisfy eligibility criteria.  
• Withdrawal Deviation: Subject met withdrawal criteria during the study but was not 
withdrawn. 
• Dosing Deviation: Subject received the wrong treatment or incorrect dose; including 
incorrect timing of a dose. 
• Prohibited Medication Deviation: Subject received an excluded concomitant treatment. 
• Operational Deviation:  All other deviations; including, but not limited to: informed 
consent form-related deviations other than consent not obtained, IRB/IEC approval 
expired, study drug not stored under protocol-specified conditions, missing laboratory 
report, out-of window visit, etc.; includes missed visits, and subject refusal of a study 
procedure or procedures.  
Important deviations are defined as those that are likely to affect a) the safety or physical or 
mental integrity of the subject, b) the scientific value of the trial. 
Deviations are summarized by subject count and by event count, by treatment group and by 
study site. All recorded protocol deviations are listed. Reported items that are not considered as 
protocol deviations are not included in summary tables and data listings, but remain in the 
database for reference.  
6.3 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for subjects in the Safety 
population using descriptive statistics.   
6.3.1 Subject Demographics and Other Baseline Characteristics  
Demographic variables will include age in years, gender, race, and ethnicity.  Age is defined as 
the age on the day of signing inform consent: 
age = INTCK( ‘YEAR’, Birth Date, Date of Informed Consent, ‘C’)  
where INTCK is a SAS function. 


 
 
Height and weighted collected at Screening are defined as baseline. Screening characteristics 
include height, weight, body surface area (BSA), body mass index (BMI), IPF confirmation, 
smoking history, rate of decline in FVC and DLCO prior to enrollment, medications used for 
treatment of IPF and medical history.  Computation formulas: 
BSA = [Weight 0.425 (kg) * Height 0.725 (cm)] x 0.007184   
BMI = Weight (kg) / (Height (m))2  
Time since the first IPF diagnosis (<1 year, 1 – 3 years, > 3years) is derived from of the onset 
date documented on the Medical History CRF to Day 1. If the day of first IPF diagnosis is 
missing, substitute it by 15; if month is missing, substitute by July 1st. 
6.3.2 Medical History  
Medical conditions, including allergies and surgeries, are coded in system organ class (SOC) and 
preferred term (PT) using MedDRA (version 18.0).  
The medical conditions will be tabulated by SOC and PT.  A subject with multiple medical 
conditions within an SOC is only counted once in this SOC. Similarly, a subject with multiple 
medical conditions within a PT is only counted once in this PT. The tabulation will be sorted 
alphabetically by SOC and by decreasing order of frequency of PT within each SOC based on 
the Safety Population. 
6.3.3 Baseline Disease Characteristics   
Baseline disease characteristics include FVC, DLCO, and other PFT parameters, lung fibrosis 
scores as well as other HRCT reading scores, and SGRQ scores. These baseline characteristics 
will be summarized based on the Safety Population. 
Baseline assessments for safety evaluations (lab, vital signs, ECG, physical exam) are 
summarized along with the post-baseline evaluations. 
 
6.3.4 Baseline GAP Score and Staging 
The GAP score and staging were developed by Ley et al. (2012) as composite prognostic factors 
that can be used to predict expected survival in IPF patients. Four variables are included in the 
GAP score: gender (G), age (A), and 2 lung physiology variables (P) (FVC and DLCO). It is 
defined as the sum of the points of the 4 variables defined in Table 8. The range is 0 – 8. Staging 
is defined based on GAP score as shown in Table 9. 
Table 8. Scoring of GAP Variables 
 
Predictor 
Points 
G (Gender) 
Female 
0 
 
Male 
1 
A (Age) 
<=60 
0 


 
 
 
61 - 65 
1 
 
>65 
2 
P (Physiology) 
FVC, % predicted 
 
 
>75 
0 
 
50 - 75 
1 
 
< 50 
2 
 
DLCO, % predicted 
Hb corrected 
 
 
>55 
0 
 
36 -55 
1 
 
<=35* 
2 
 
Cannot perform 
3 
*Value < 35.5 is rounded down to 35; value>=35.5 is rounded up to 36. 
Table 9. GAP Staging 
GAP Stage 
GAP Score 
I  
0 – 3  
II  
4 – 5  
III  
6 – 8  
6.3.5 Annualized Rate of Change in FVC and DLCO Prior to Study Treatment   
Annualized rate of change in FVC (L) and DLCO (ml/min/mmHg) (without correction for Hb) 
prior to study treatment is estimated via linear random coefficient model historic data in the past 
2 years as well as values at Screening and Day 1.   
proc mixed; 
   class subjid; 
   model chg = time earliest_value  /noint s outp=pred_data; 
   random time /subject=subjid type=UN; 
run; 


 
 
CHG in the model = Day 1 value - historical value;  
Time in years = (Date of Day 1 - Date of historical assessment)/365.25.  
All observed values prior to and on Day 1 will be included in the model. If the Day 1 value is 
missing, the last Screening value will be used to calculate the change. If the day portion of the 
historical assessment date is missing, day = 15 is assigned, Missing year or month will not be 
imputed. For multiple values on the same day, the highest value will be used. 
6.3.6 Comparison between Treatment Arms in Baseline Parameters 
Balance between the two treatment arms in baseline parameters is evaluated using the two 
sample t-test for continuous variables and the chi-square test for categorical variables. The p-
values are used for evaluation of balance of randomization.  
6.4 
Summary of Prior and Concomitant Medications 
The historical use of the medications listed on the Screening CRF is summarized using 
descriptive statistics for the Safety population. 
Medications recorded on the Concomitant Medication CRF are classified in the analysis dataset 
in the following categories: 
1. Medications that were stopped prior to the first infusion (PRIOR).  
2. Medications that are used concomitantly with the study drug, which are defined as 
medications that were not stoped before the first infusion.   
Prior and concomitant medications are summarized by ATC class and preferred term for the 
safety population. Subjects reporting more than one use of the same medication will be counted 
only once in the summary tables.  
All medications captured in screening Medication CRF and Concomitant Medication CRF, as 
well as Non-Drug Therapies CRF are presented in data listings. Oxygen use will also be 
presented in data listing. 
6.5 
Summary of Study Drug Exposure and Treatment Compliance 
Duration in days from first dose to last dose, number of doses, dose amount in mg, and 
compliance as defined in Section 4.2.9 will be summarized descriptively for the Safety 
population.  Proportion of subjects being treated by study week will also be summarized. Study 
drug administration log will be listed. Dose amount prepared that differs from the intended 
amount (30 mg/kg times body weight except the first 2 doses which are 15 mg/kg for subjects in 
the substudy) by more than 10% will be flagged. 
6.6 
Efficacy Analyses 
Analyses of efficacy parameters will be performed on the FAS population. Comparison between 
FG-3019 and placebo will be performed separately for main study, substudy pirfenidone 
background and substudy nintedanib background.  


 
 
A primary analysis will be identified for each key efficacy parameter. Sensitivity analyses using 
different missing data handling rules and different analysis methods are also performed.  
6.6.1 Analyses of the Primary Efficacy Endpoint (ΔFVCpp48) 
For the primary analysis of ΔFVCpp48, missing data will be assumed to be MAR. The MAR 
assumption implies that the missing data can be reasonably predicted from the observed 
variables, and therefore can be estimated without bias using exclusively the observed data. As 
noted in the EMA Guideline on Missing Data in Confirmatory Clinical Trials (2011), the MAR 
assumption implies that the behavior of the post dropout observations can be predicted from the 
observed variables, and therefore that response can be estimated without bias using exclusively 
the observed data. For example, when a patient drops out due to lack of efficacy reflected by a 
series of poor efficacy outcomes that have been observed, it would be appropriate to impute or 
model poor efficacy outcomes subsequently for this patient.  In the current study evaluating 
treatment effect in the IPF patient population, the random coefficient linear regression model 
based on the MAR assumption is an acceptable method,  “since estimated slope based on 
available data from an individual patient before treatment discontinuation conservatively predicts 
the annual decline in lung function similar to linear extrapolation” (Nintedanib Statistical 
Review, page 42). This method will be defined as the primary analysis of ΔFVCpp48. 
6.6.1.1 Analysis of ΔFVCpp48 Using a Random Coefficients Linear Regression Model 
(Main Study Only) 
The random coefficient linear regression model includes treatment, visit (as a continuous 
variable), visit-by-treatment interaction, and baseline FVCpp as fixed effects and linear slope of 
visit as random effect. Observed data in all visits (including baseline visit with change = 0) from 
subjects in FAS will be included in the model. ΔFVCpp48 is compared between the treatment at 
visit = 48. An annual decline rate is projected at visit = 52. In addition to statistical significance 
level (p-value) of testing the treatment difference, least squares (LS) means (s.e.) and 95% 
confidence intervals (CIs) of ΔFVCpp48 for both treatment arms as well as the treatment 
difference are obtained from the model.  
Model – LinearSlope (FVCpp) 
proc mixed data = OC-main; 
class trt subjid; 
model ΔFVCpp = trt  visitn  trt*visitn  FVCpp0 /solution covb; 
random visitn  /subject=subjid type=UN  (option ‘group=trt’ will be used if it provides a better 
fit of the model at final analysis); 
lsmeans trt  / at visitn=48 diff CL; 
lsmeans trt  / at visitn=52 diff CL; 
ods output lsmeans=mixlsmeans diffs=mixdiffs; 
run; 
Subject’s age, sex, and height are not included in this model since the FVC (% predicted) value 
has been adjusted for these factors.  
Relative treatment difference is defined as (Active – Placebo) / Placebo * 100.  


 
 
6.6.1.2 ANCOVA Analysis of ΔFVCpp48 (Main Study only)  
This analysis is to use the ANCOVA model to test whether the two treatment arms are different 
and estimate the treatment difference in ΔFVCpp48, under a different missing data mechnism. 
All subjects in the FAS population are included; missing data are imputed following the 
algorithm described in Section 5.4.1. From the ANCOVA model, LS mean (s.e.) of each 
treatment group as well as LS mean (s.e.) of treatment difference, p-value, and 95% confidence 
interval will be obtained. 
Model – ANCOVA (FVCpp): 
proc mixed data=ΔFVCpp48_imputed; 
  class trt; 
  model ΔFVCpp48  = trt  FVCpp0; 
  lsmeans  trt / pdiff  CL alpha=0.05; 
run; 
 
6.6.1.3 Analysis of Categorical Endpoints of ΔFVCpp48 (Main Study Only) 
The categorical endpoints of ΔFVCpp48, subjects with no decline (change ≥0) and subjects with 
decline more than 10% (including deaths and disease progression), are defined in Section 4.2.7.  
These two endpoints will be compared between treatment arms using logistic regression 
controlling for FVCpp0. Odds ratio and its 95% CI will be estimated from this model. 
Model – Logistic  
proc logistic data = Event_of_interest; 
   class TRT; 
   model Event = TRT FVCpp0; 
   oddsratio  TRT / CL = PL; 
run; 
Absolute treatment differences in the proportions are also estimated. 95% CIs for the absolute 
differences are obtained from PROC FREQ using asymptotic approximation. Relative difference 
is defined as (FG-3019 – Placebo) / Placebo * 100. 
6.6.1.4 MMRM Analysis of ΔFVCpp by Visit (Main and Substudy, Observed Cases Only)  
Observed data in all post-baseline visits from subjects in FAS will be included in the model. 
From the MMRM model, LS means (s.e.) of each treatment group, as well as LS mean (s.e.) of 
treatment difference, p-value, and 95% confidence interval are obtained at each visit.  The same 
MMRM model will be applied to the main study and the 2 subgroups in the substudy separately.  
Model – MMRM (FVCpp) 
proc mixed data = OC; 
class trt subjid visitn; 


 
 
model ΔFVCpp = trt  visitn  trt*visitn  FVCpp0  FVCpp0*visitn /solution covb; 
repeated  avisit /subject=subjid type=UN; (option ‘group=trt’ will be used if it provides a better 
fit of the model at final analysis) 
lsmeans trt*visitn  / diff CL alpha=0.05 ; 
ods output lsmeans=mixlsmeans diffs=mixdiffs; 
run; 
6.6.1.5 Categorical Summary of ΔFVCpp by Visit (Main and Substudy) 
ΔFVCpp will be summarized by visit based on observed cases for subjects in the FAS 
population, in the following categories: ≤-10, (-10, -5], (-5, 0), [0, 5), [5, 10), and ≥10. Missing 
data will be included in a separate category. 
6.6.1.6 Analysis of ΔFVC48 Using a Random Coefficients Linear Regression Model (Main 
Study Only) 
For analysis of change from baseline in FVC (L), subject’s age, sex, and height will be included 
as fixed effects in the random coefficient model, in addition to other factors specified in the 
random coefficient model for analysis of ΔFVCpp48. 
Model – LinearSlope (FVC) 
proc mixed data = OC-main; 
class trt subjid; 
model ΔFVC = trt  visitn  trt*visitn  FVC0 age sex height /solution covb; 
random visitn  /subject=subjid type=UN  (option ‘group=trt’ will be used if it provides a better 
fit of the model at final analysis); 
lsmeans trt  / at visitn=48 diff CL; 
lsmeans trt  / at visitn=52 diff CL; 
ods output lsmeans=mixlsmeans diffs=mixdiffs; 
run; 
6.6.1.7 ANCOVA Analysis of ΔFVC48 (Main Study only)  
For analysis of change from baseline in FVC (L) to week 48 with observed and imputed data, 
subject’s age, sex, and height will be included, in addition to other factors specified in the in the 
ANCOVA model for analysis of ΔFVCpp48.  
Model – ANCOVA (FVC): 
proc mixed data=ΔFVC48_imputed; 
  class trt; 
  model ΔFVC48  = trt  FVC0 age sex height; 
  lsmeans  trt / pdiff  CL alpha=0.05; 
run; 


 
 
6.6.1.8 MMRM Analysis of ΔFVC by Visit (Main and Substudy, Observed Cases Only)  
Same method described for MMRM analysis of ΔFVCpp will be applied to MMRM analysis of 
ΔFVC, except that subject’s age, sex, and height are additionally added in the model as fixed 
effects 
Model – MMRM (FVC) 
proc mixed data = OC; 
class trt subjid visitn; 
model ΔFVC = trt  visitn  trt*visitn  FVC0  FVC0*visitn age sex height /solution covb; 
repeated  avisit /subject=subjid type=UN; (option ‘group=trt’ will be used if it provides a better 
fit of the model at final analysis) 
lsmeans trt*visitn  / diff CL alpha=0.05 ; 
ods output lsmeans=mixlsmeans diffs=mixdiffs; 
run; 
6.6.1.9 Analysis of Percent Relative Change in FVC (L) by Visit (Main and Substudy)  
The percent relative change in FVC (L) will be summarized descriptively in mean (s.e.), median, 
range, and frequencies in the following categories: <-20%, -20% -< -10%, -10% -< 0, >=0. 
Observed and imputed values will be used in analysis of 
6.6.1.10 Data Listing  
Data listing will include observed FVC (L) and FVCpp as well as the change from baseline for 
all randomized subjects. Imputed data at Week 48 will also be included. 
6.6.2 Analyses of Quantative HRCT Fibrosis Score 
6.6.2.1 Analysis of Change from Baseline to Week 48 in HRCT Fibrosis Score (Main 
Study)  
Change from baseline to Week 48 in quantitative HRCT fibrosis score (ΔFIB48) is defined in 
Section 4.2.2. Imputation for missing data is described in Section 5.4.2. The ANCOVA model 
will be used to analyze treatment difference based on the output datasets from the MI procedures. 
MIANALYZE procedure will be used to obtain the final estimates of LS mean (s.e.) and 95% CI 
as well as p-values.   
Model – ANCOVA (ΔFIB – main): 
proc mixed data= fib_mi2main;  
  by _imputation_; 
  class trt; 
  model ΔFIB48  = trt  fib0/solution covb; 
  lsmeans trt / diff CL alpha=0.05 ; 
  ods output lsmeans=mixlsmeans diffs=mixdiffs; 
run; 


 
 
LS mean (s.e.), 95% CI, and p-value of treatment difference are obtained using the following 
MIANALYZE procedure: 
proc mianalyze data=mixdiffs; 
      modeleffects estimate; 
      stderr stderr; 
ods output parameterEstimates = MIest; 
run; 
LS mean (s.e.) and 95% CI of each treatment are obtained using the similar MIANALYZE 
procedure based on the MIXLSMEANS output dataset from the ANCOVA model.  
6.6.2.2 Responder Analysis of ΔFIB48 (Main Study)  
For each imputation from the MI procedure, responders of are defined as ΔFIB48 < 0 (improved) 
or ΔFIB48 ≤ 0 (improved or stable) based on the observed + imputed data. Proportion of 
responders and 95% CI for the each treatment arm are obtained from the following PROC FREQ 
procedure followed by MIANALYZE.  
PROC FREQ data = fib_mi2main; 
TABLES responder48  / CL binomial; 
BY trt _Imputation_; 
ODS OUTPUT BINOMIAL=prop; 
run; 
PROC MIANALYZE DATA=propest (transpose of dataset PROP); 
MODELEFFECTS _bin_; 
STDERR e_bin; 
BY trt; 
ODS OUTPUT PARAMETERESTIMATES=prop_trt; 
RUN; 
Treatment difference and 95% CI are estimated using the MIANALYZE procedure with 
ModelEffects being (p1 – p2) and StdErr being sqrt (se1^2 + se2^2). 
Model – Logistic  
proc logistic data= fib_mi2main; 
   model responder48 =  trt  fib0 / covb; 
   by _Imputation_; 
   ods output ParameterEstimates=fibparms 
              CovB=fibcovb; 
run; 


 
 
proc mianalyze parms=fibparms 
               covb(effectvar=stacking)=fibcovb; 
   modeleffects intercept trt  fib0; 
run; 
6.6.2.3 Analysis of ΔFIB24 (Main and SubStudy) 
The same MI – ANCOVA – MIANALYZE procedures described in the previous section are 
applied to analysis of ΔFIB24 in the main study.  
For the substudy, the two subgroups are analyzed in the same model with subgroup and 
treatment-by-subgroup interaction.   
Model – ANCOVA (ΔFIB – sub): 
proc mixed data= fib_mi2sub;  
  by _imputation_; 
  class trt  sub; 
  model ΔFIB24  = trt  sub  trt*sub  fib0/solution covb; 
  lsmeans trt*sub / diff CL alpha=0.05 ; 
  ods output lsmeans=mixlsmeans diffs=mixdiffs; 
run; 
Other ΔFIB24 parameters are similarly estimated as the ΔFIB48 parameters. 
6.6.2.4 Data Listing of Quantitative Fibrosis Score 
The average of the imputed values from Models – FIB2 and – FIB4 are presented in the data 
listing for each subject.  
6.6.3 Analysis of Change from Baseline in HRQoL Score  
Change from baseline in SGRQ total and domain scores (ΔTOT, ΔSYM, ΔACT, and ΔIMP) are 
defined in Section 4.2.3. Missing data data in the total or domain scores are not imputed. Models 
MMRM (main) and MMRM (sub) described in Section 6.6.1.4 for analysis of the main and 
substudy, respectively, are used to estimate LS means (s.e.) of each treatment group, as well as 
LS mean (s.e.) of treatment difference, p-value, and 95% confidence interval at each visit for 
ΔTOT, ΔSYM, ΔACT, and ΔIMP.  
Proportion of subjects with improved SGRQ domain or total score (change <0) will be compared 
between treatment arms using same logistic regression described in Section 6.6.1.5, controlling 
for BL_score. Odds ratio and its 95% CI will be estimated from the same model. 
6.6.4 Analysis of Time to Progression of IPF  
Time to progression (TTP) of IPF is defined in Section 4.2.4. Comparison between treatment 
arms as well as estimation of hazard ratio and its 95% CI will be performed using Cox regression 
model. Analysis will be performed on both Safety population and FAS poulation.   
Model – Cox 


 
 
proc phreg data = TTP; 
   class TRT; 
   model TTP * Censor(0) = TRT; 
   hazardratio TRT / CL = PL; 
run 
Kaplan-Meier curves are plotted by treatment arm, without adjustment for other factors.  
The rate of event at the end of year 1 and the rate of each component are tabulated. The 
corresponding exact 95% confidence interval will also be presented. Comparison between 
treatments is performed using logistic regression model based on subjects in the Safety 
population and FAS population. 
Model – Logistic 
proc logistic data = Event_of_interest; 
   class TRT; 
   model Event = TRT; 
   oddsratio  TRT / CL = PL; 
run; 
Time to event and type of event will be presented in listing. 
6.6.5 Analysis of Respiratory-Related Hospitalization and Respiratory-Related Death 
Comparison between treatment arms as well as estimation of odds ratio and 95% CI will be 
performed using logistic regression (Model – Logistic in Section 6.6.4) based on subjects in the 
Safety population. 
6.7 
Exploratory Analyses 
6.7.1 Sensitivity Analyses of the Primary Efficacy Endpoint 
Sensitivity analyses are recommended by regulatory agencies. Different analyses based on 
different missing data assumptions will be performed. 
6.7.1.1 Rank ANCOVA (Ranking Based on Time to Treatment Discontinuation) 
Based on the study design, it is reasonable to assume that subjects who discontinued treatment 
due to death or progressive disease (PD) have worse clinical outcomes than those who are able to 
complete the study. Time to treatment discontinuation in the current context can be treated as a 
surrogate of time to clinical progression.  Therefore, subjects who discontinued treatment due to 
death or PD (subset A) should be ranked lower than other subjects (Subset B), with ranking 
based on time to discontinuation and the lowest rank assigning to the earliest dropout. Time to 
treatment discontinuation is recorded on the EOT Disposition CRF. Subjects in subset B are 
ranked based on ΔFVCpp48, starting from adding 1 to the highest rank in subset A. Imputed data 
described in Section 5.4.1, Step 1, are included in ranking subjects in subset B, assuming missing 


 
 
data in this subset is missing at random. Ranks for tied observations will be assigned based on 
the average of the corresponding ranks if there had been no ties.  
The rank ANCOVA procedure is described by Stokes, Davis, and Koch (2012). The first step of 
the procedure is to fit a linear regression of the rank of the primary endpoint described above 
against the rank of baseline FVCpp. The residuals from this model are compared between 
treatment arms using the Mantel-Haenszel mean score chi-square test. The two SAS procedures 
are provided below. 
PROC REG data=ranks noprint; 
model R_ ΔFVCpp48 = R_ FVCpp0; 
output out=res 
            r=resid; 
run; 
PROC FREQ data=res; 
tables TRT * resid/noprint cmh2; 
run; 
6.7.1.2 ANCOVA with Rank-based Imputation  
The above rank ANCOVA procedure is used to evaluate qualitatively whether there is treatment 
difference between the two treatment groups. To evaluate quantitatively the magnitude of the 
treatment difference, missing data need to be imputed with quantative values. Following the 
ranking rationale described in the previous section, missing data in subset A can be imputed by 
adding additional declined value on top of the lowest ΔFVCpp48 in subset B. The amount of 
additional decline value is determined by the rank – the lower the rank, the larger decline value is 
added. The maximum additional decline (corresponding to the subject with the lowest rank) can 
be determined by clinical judgment. For this sensitivity analysis, an additional 10 points of 
decline (-10) is added to the earliest dropout from the lowest ΔFVCpp48 in subset B. Evenly 
distributed increment is added to ΔFVCpp48 for each increment of rank in subjects in subset A.  
The ANCOVA Model described in Section 6.6.1.1 is applied to rank-based imputed dataset.   
6.7.1.3 ANCOVA with MI Imputation 
In this approach there is no differentiation of subsets A and B. Missing values are imputed 
following MAR assumption for all subjects in FAS, using the MI models in Section 5.4.1.3. 
Model ANCOVA is used in conjunction with MYANALYZE to evaluate treatment difference. 
Based on the output dataset FVCpp_MI2 from Model in Section 5.4.1.3, the following 
ANCOVA model and MIANALYZE procedure are used.  
Model – ANCOVA_MI 
proc mixed data=FVCpp_MI2; 
class trt; 
model ΔFVCpp48 = trt  FVCpp0 /solution covb; 
lsmeans trt / diff CL; 


 
 
by _Imputation_; 
ods output lsmeans=mixlsmeans diffs=mixdiffs; 
run; 
Treatment difference in ΔFVCpp48 is presented in LS mean (s.e.) and 95% CI using the 
following MIANALYZE procedure: 
proc mianalyze data=mixdiffs; 
      modeleffects estimate; 
      stderr stderr; 
ods output parameterEstimates = MIest; 
run; 
LS mean (s.e.) and 95% CI of ΔFVCpp48 in each treatment arm are obtained from the following 
MIANALYZE procedure: 
proc mianalyze data=mixlsmeans; 
      by trt; 
      modeleffects estimate; 
      stderr stderr;       
   run; 
Categorical analyses for categories of ‘no decline’ and ‘decline 10 or more’ using 
MI/MIANALYZE procedure to handle missing data will also be performed. Detailed procedure 
is the same as that described in Section 6.6.2.2. 
6.7.1.4 ANCOVA with All Randomized Subjects 
The same imputation algorithm described in Section 5.4.1 is applied to subjects in the FAS 
population. For subjects who are not in the FAS population, missing data are imputed as follows: 
- 
For subjects who discontinued due to reasons other than death or PD, their missing data 
are imputed following Step 1 in Section 5.4.1, with all randomized subjects in the MI 
model; 
- 
For subjects who discontinued due to death or PD, their missing data are imputed as the 
largest observed decline of FVCpp48. 
Same Model – ANCOVA in Section 6.6.1.1 is used in analyzing treatment effect in the all 
randomized population. 
6.7.2 Analyses of Other PFT Parameters  
Other PFT parameters include change from baseline to scheduled visits in FEV1 (% predicted) 
and FEV1/FVC ratio. The MMRM (main) and MMRM (sub) models described in Section 
6.6.1.4 will be used to obtain LS means (s.e.) of each treatment group, as well as LS mean (s.e.) 
of treatment difference, p-value, and 95% confidence interval at each visit. 


 
 
6.7.3 Analyses of Other Quantitative HRCT Parameters 
Other quantitative HRCT parameters include change from baseline to Weeks 24 or 48 in fibrosis 
score at the worst lung zone, the QILD score, GG, and HC scores. 
The same analysis procedure described in Section 6.6.2 will be applied to analyzing change from 
baseline in fibrosis score at the worst lung zone and the QILD score. For GG and HC, descriptive 
summary based on observed cases will be provided at each visit. 
6.7.4 Analysis of HRCT Visual Reading Scores 
Baseline visual assessments will be summarized by lung lobe. A baseline whole lung score is 
defined as the average of the mid-point of the five lung lobes.  Mid-points are:  0= none, 3 = 1-5, 
15 = 6-25, 38 = 26-50, 63 = 51-75, 87 = ‘>75’.  The average whole lung score (rounded to whole 
number) is summarized in the same categories as the individual lung lobes.   
The whole lung average score in the follow-up visits is defined as the average of the five lung 
lobes. Categorical assessments at the follow-up visits are coded as: 1 = better, 0 = same; -1 = 
worse.  The average score will be re-mapped to ‘better’ if average is positive, ‘same’ if average 
is zero, and ‘worse’ if average is negative. Responders will be defined based on the derived 
whole lung score 
1. Better,  
2. Better or no change. 
The proportion of responders will be summarized at Weeks 24 and 48 for subjects who are in the 
FAS population.  Analysis will be based on observed data ignoring missing data.  
HRCT visual readings at each lung lobe are presented in a data listing. 
 
6.7.5 Examination of Subgroups (Main Study) 
Treatment effect on ΔFVCpp48 and ΔFIB48 will be examined in the following subgroups: 
Baseline GAP staging (I vs. II+III) 
Age (<65 vs. >=65) 
Sex (male vs. female) 
US sites versus ex-US sites 
Time since IPF diagnosis (< 1 year vs. ≥1 year) 
Baseline FVCpp (below vs. ≥  median) 
Baseline FIB (below vs.  ≥ median) 
Baseline DLCOpp-hb (below vs. ≥ median) 
Baseline FEV1/FVC (below vs.  ≥ median) 
Smoking status (never smoked vs. current/former). 


 
 
The following ANCOVA model will be used to evaluate the effect of each subgroup 
individually. 
Model – ANCOVA (subgroup): 
proc mixed; 
  class trt subgroup; 
  model endpt  = trt subgroup trt * subgroup BL; 
  lsmeans trt * subgroup / pdiff  CL alpha=0.05; 
run; 
The dependent variable endpt is ΔFVCpp48 and ΔFIB48; BL is the baseline value FVCpp0 or 
FIB0 corresponding to the dependent variable. When evaluating the baseline FVCpp subgroups, 
FVCpp0 will not be included in the model; same for evaluating baseline FIB subgroups, FIB0 
will not be included. Subjects in FAS in the main study will be included in the model. Observed 
and imputed values are used. For ΔFIB48, the average of the imputed values from the MI 
procedure is used. (MIANALYZE is not used.) 
Forest plot of the LS mean +/- standard error of the treatment difference in each subgroup will be 
presented. 
6.7.6 Other Exploratory Analyses 
Analysis plan for further exploratory analyses will be documented in a separate document. 
6.8 
Safety Analyses 
Safety analyses will include summary of adverse events (including treatment emergent AEs, 
treatment emergent serious AEs, deaths, and infusion-associated AEs), prior and concomitant 
medication use, lab test results, vital signs, ECGs, and physical exams. In general, safety data 
will only be summarized descriptively and no rigorous inferential statistical procedures will be 
applied. 
6.8.1 Adverse Events 
All reported AEs are presented in listings. Treatment emergent adverse events (TEAEs), as 
defined in Section 4.2.13, are summarized by treatment arm, system organ class (SOC) and 
preferred term (PT). 
An overall summary of TEAEs is provided.  The summary includes the number (%) of subjects 
with at least one TEAE, at least one serious TEAE, deaths, TEAEs leading to study 
discontinuation, at least one TEAE related to study drug and TEAEs by severity.  
The number and percent of subjects experiencing TEAEs will be tabulated by system organ class 
and preferred term and will be sorted alphabetically by SOC and by decreasing order of 
frequency of PT within each SOC.  The decreasing order of frequency of preferred terms will be 
based on the overall population.  A subject with multiple adverse events within a system organ 
class is only counted once in this system organ class. Similarly, a subject with multiple adverse 
events within a preferred term is only counted once in this preferred term.  


 
 
TEAE will also be tabulated by severity grade. In the case of multiple events within the same 
preferred term, the event with the highest severity grade is included. Missing data in the severity 
grade will not be imputed and is ranked the lowest severity grade in the case of multiple events.   
In addition to summary of all TEAEs, the following subgroups of AEs are summarized and listed 
separately: 
- 
SAEs  
- 
SAEs that are possibly related to FG-3019  (as assessed by investigators) 
- 
SAEs that are IPF related or respiratory-related hospitalization 
- 
AEs leading to study or treatment discontinuation 
- 
TEAE with incidence >10% in either treatment arm  within the main study or within each 
sub-group in the substudy 
- 
AEs with severity grade >= 3  
- 
AEs that are possibly related to FG-3019 (as assessed by investigators) 
- 
AEs with severity grade >=3 that are possibly related to FG-3019 (as assessed by 
investigators) 
- 
Possible infusion-associated AEs  
The following events are presented in data listings. 
- 
Deaths  
- 
AEs that are possibly related to study procedure (as assessed by investigators) 
- 
Possible infusion reactions   
All reported adverse events will be presented in a data listing which will also include reference 
information such as the time (days) from the last prior infusion and from the first infusion to the 
onset of the event. 
6.8.2 Mortality 
Year 1 mortality rate will be summarized by GAP staging at baseline. 
Respiratory-related and IPF related death will be identified in the data listing. 
6.8.3 Summary of Central Laboratory Data 
Central laboratory results and change from baseline are summarized descriptively by visit.  
CTCAE grade 3 or higher lab test results will be considered potentially clinically significant. 
These results are presented in a data listing. 
Shift tables to summarize changes from baseline to each visit in CTCAE categories are tabulated. 
Shift from baseline to most severe CTCAE category during the study is also summarized. In 
addition, shift-tables based on normal ranges provided by the central lab are also included. 
Box-plots for selected lab tests by visit are presented to evaluate trend. 


 
 
Lab data are summarized by nominal clinic visit. Data collected during the unscheduled visits are 
not included in the summary tables, but are included in data listings and in evaluations for 
potentially clinically significant abnormal changes. 
6.8.4 Vital Signs 
Vital sign observed values and change from baseline are summarized using descriptive statistics 
by cohort by visit for the Safety population.   Pre-infusion and post-infusion assessments are 
summarized separately. In addition to summarizing the measurements by time point, the average 
measurement after the start of an infusion is defined as the post-infusion measurement. 
In addition, potentially clinically significant changes from baseline are tabulated for each visit. 
Reference range limits for vital signs are provided in Table 5a.  
All measurements and change from baseline are presented in data listings. Potential clinically 
significant changes from baseline are flagged. 
Box-plots of vital sign measurements by visit, pre- and post-infusion separately, are presented to 
evaluate trend. 
6.8.5 ECG Data 
ECG findings are summarized in shift tables that include cross-tabulation of ‘Normal’, 
‘Abnormal NCS’, ‘Abnormal CS’ at Weeks 24 or 48 versus Screening.  
Detailed findings are presented in the data listing. 
ECG parameters measured at each visit as well as change from baseline are summarized 
descriptively. 
6.8.6 Physical Exams 
The number and percent of subjects with “Normal”, “Abnormal”, “Not Done”, and “Missing” 
physical examination results are summarized by body system, cohort, and visit. Shift table of 
changes from baseline will also be summarized by visit. 
The data listing includes abnormal physical examination data. 
6.9 
PK, CTGF, HAHA, and Biomarkers 
PK parameters defined in Sections 4.2.10 and 4.2.11 will be summarized descriptively at each 
sampling time. Parameters include peak and trough level of FG-3019, pirfenidone, and 
nintedanib as well as metabolite-to-parent ratio at the peak level of pirfenidone and nintedanib. 
Descriptive statistics include arithmetic mean (S.D.), 95% CI of the mean, CV, geometric mean, 
median, 25th and 75th percentiles, minimum and maximum.  
Comparison of pirfenidone / nintedanib PK when given with FG-3019 vs placebo will be 
performed. 
Analysis of CTGF, HAHA, DNA and other biomarker data will be documented in a separate 
report. 
6.10 Changes from the Protocol Specified Analysis Methods 
6.10.1 Change of the Primary Analysis Method for ΔFVCpp48 


 
 
In the protocol rank ANCOVA is specified as the primary analysis method to test the hypothesis 
of whether FG-3019 is superior to placebo in the primary endpoint. This method was determined 
prior to FDA’s marketing approval of pirfenidone and nintedanib. In FDA’s statistical review, it 
was pointed out that the random coefficient linear regression model assuming missing data to be 
MAR is an acceptable method,  “since estimated slope based on available data from an 
individual patient before treatment discontinuation conservatively predicts the annual decline in 
lung function similar to linear extrapolation” (Nintedanib Statistical Review, page 42). Based on 
this reason, the primary analysis is changed rank ANCOVA to random linear coefficient model. 
Rank ANCOVA will be performed as one of the sensitivity analyses to support the primary 
analysis.  
6.10.2 Change in the Analysis Population for HRCT Parameters 
In the protocol HRCT parameters are to be analyzed using the HRCT Evaluable population, 
which is defined as randomized subjects who have evaluable HRCT fibrosis scores at baseline 
and at Week 24 or at a later time point. Since the MI procedure can impute missing data for 
subjects who do not have post-baseline data when the fraction of missing data is relatively small 
comparing to the available, the MI procedure is used to analyze the HRCT fibrosis score based 
on FAS, which is a larger set than the HRCT Evaluable population and is the same population 
for analyzing other efficacy parameters. 
6.10.3 Definition of Final Analysis of the Randomized Treatment Period 
In the protocol, unblinded analysis after all subjects have completed the Randomized Treatment 
Period is defined as an interim analysis of the entire study including the Extended Treatment 
Period. It should be noted that, after all subjects (main and substudy) have completed the 
Randomized Treatment Period, the database for the Randomized Treatment Period portion will 
be locked and all analyses described in this document based on the locked database are 
considered final analyses for the Randomized Treatment Period.       


 
 
7 
VALIDATION AND QUALITY ASSURANCE 
All datasets (SDTM, ADaM), tables, listings, figures are programmed by two 
programmers independently.  The results must be 100% match.  
Both primary and validation programmers will develop programs independently based on 
the specifications and/or SAP. If the outputs are datasets, the final outputs are compared. 
If the outputs are TLFs, benchmark results are generated and compared. The validation 
findings and resolutions are documented on a Validation Worksheet. 
The detail process for validation and quality assurance is documented in the Standard 
Operating Procedures of Q2, Inc.  


 
 
8 
REFERENCES 
EMA 2011, Guideline on Missing Data in Confirmatory Clinical Trials. 
Fingerlin TE, et al. Genome-wide association study identifies multiple susceptibility loci 
for pulmonary fibrosis. Nat Genet. 2013 June ; 45(6): 613–620. doi:10.1038/ng.2609. 
Goldman HI, Becklake MR. Respiratory function tests: normal values at median altitudes 
and the prediction of normal results.  Am Rev Tuberculosis 1959; 79:457-471. 
Hankinson JL, Odencrantz JR, Fedan KB, Spirometric reference values from a sample of 
the general U.S. population. Am J Respir Crit Care Med 1999; 159:179 – 187.  
Jones P.  St. George’s Respiratory Questionnaire Manual, Version 2.3.  St. George’s, 
University of London, June 2009. 
King TE, et al. A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary 
Fibrosis. (2014) N Engl J Med 
Kupferberg DH, Kaplan RM, Slymen DJ, Ries AL. Minimal Clinically Important 
Difference for the UCSD Shortness of Breath Questionnaire. J Cardiopulm Rehabil. 
2005, 25(6):370-7.        
Ley B., et al. (2012) A Multidimensional Index and Staging System for Idiopathic 
Pulmonary Fibrosis. Ann Intern Med. 2012;156:684-691. 
Little RJ (2008) Selection and Pattern-Mixture Models. Chapter 18 in Advances in 
Longitudinal Data Analysis, G. Fitzmaurice, M. Davidian, G. Verbeke, & G. 
Molenberghs, eds., pp. 409-431,  London: CRC Press. 
Mallinckrod CH, et al. (2008) Recommendations for the Primary Analysis of Continuous 
Endpoints in Longitudinal Clinical Trials. Therapeutic Innovation & Regulatory Science, 
Vol 42, Issue 4, pp. 303 - 31 
Maruish ME (Ed.). User’s Manual for the SF-36v2 Health Survey (3rd Edition). Lincoln, 
RI: QualityMetric Incorporated. 
Miller A, Thornton JC, Warshaw R, et al. Single breath diffusing capacity in a 
representative sample of the population of Michigan, a large industrial state.  Predicted 
values, lower limits of normal, and frequencies of abnormality by smoking history.  Am 
Rev Respir Dis 1983; 127: 270 – 277. 
Nintedanib FDA Statistical Review for Basis of Approval (2015). 
Pirfenidone FDA Statistical Review for Basis of Approval (2015). 
 
Richeldi, L, et al. Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis 
(2014). N Engl J Med 
SF-36v2 Administration Guide, version 2009, provided by QualifyMetric Inc. 
SF-36v2 Manual and Interpretation Guide (Ware et al., 1993). 
Stokes M, Davis C, Koch G, Categorical Data Analysis Using SAS, third edition, 2012. 


 
 
Swigris JJ, et al. The UCSD shortness of breath questionnaire has longitudinal construct 
validity in idiopathic pulmonary fibrosis.  Respiratory Medicine (2012) 106, 1447 -  
1455        
Swigris JJ, et al. The SF-36 and SGRQ: validity and first look at minimum 
important differences in IPF. Respir Med. 2010 February ; 104(2): 296–304. 
 
Quanjer PH, et al. Multi-ethnic reference values for spirometry for the 3–95-yr age range: 
the global lung function 2012 equations. Eur Respir J 2012; 40: 1324–1343. 
 
Witek TJ, Mahler DA. Minimal important difference of the transition dyspnoea index in a 
multinational clinical trial. Eur Respir J 2003, 21: 267–272) 
 
Toxicity Grade Report for Set: CTCAE ver 4.03, ICON Central Laboratories, Inc. 


 
 
9 
PLANNED TABLES, LISTINGS, AND FIGURES 
9.1 
List of Tables and Figures 
TLF Number 
Title 
Analysis Population 
14.1 
Demographic Data Summary figures and tables 
 
14.1-1 
Subject Enrollment by Site 
Randomized 
14.1-2 
Subject Disposition  
Randomized 
Figure 14.1-1 
Time to Early Withdrawal from Study Treatment  
Randomized 
14.1-3 
Subject Demographics and Subject Characteristics 
Safety 
14.1.4-1 
Baseline Data: Pulmonary Function Test 
Safety 
14.1.4-2 
Baseline Gap Score and Staging 
Safety 
14.1.4-3 
Annualized Rate of Change in FVC and DLCO Prior to 
Study Treatment 
Safety 
14.1-5 
Baseline Data: HRCT CAD Reading 
Safety 
14.1.5-1 
Baseline Visual Fibrosis Assessment by Lung Zone 
Safety 
14.1.5-2 
Baseline Visual Ground Glass Assessment by Lung Zone  Safety 
14.1.5-3 
Baseline Visual Honeycomb Assessment by Lung Zone  
Safety 
14.1-6 
Baseline Data: SGRQ Domain and Total Scores 
Safety 
14.1-7 
Medical History 
Safety 
14.1.8-1a 
Medications for IPF Used and Stopped 4 Weeks Prior to 
Screening 
Safety 
14.1.8-1b 
Medications for IPF Continued Into Study 
Safety 
14.1.8-2 
Medications Stopped Prior to the First Infusion 
Safety 
14.1.8-3 
Concomitant Medications Used After the First Infusion 
Safety 
14.1.8-4 
Oxygen Use  
Safety 
14.1.9-1a 
Summary of Protocol Deviations by Event and by Site 
Safety 
14.1.9-1b 
Summary of Protocol Deviations by Event and by 
Treatment 
Safety 


 
 
14.1.9-2a 
Summary of Protocol Deviations by Subject and by Site 
Safety 
14.1.9-2b 
Summary of Protocol Deviations by Subject and by 
Treatment 
Safety 
 
 
 
14.2 
Efficacy Data Summary Figures and Tables 
 
14.2.1 
Analysis of Change from Baseline in FVC (% predicted) 
and FVC (L) 
 
T14.2.1-1 
Analysis of Change from Baseline to Week 48 in FVC 
(% predicted): Random Coefficients Linear Regression 
Model based on Observed Cases 
FAS - Main 
T14.2.1-2 
Analysis of Change from Baseline to Week 48 in FVC 
(% predicted): ANCOVA based on Observed and 
Imputed values 
FAS - Main 
T14.2.1-3 
Analysis of Categorical Endpoints of Change from 
Baseline to Week 48 in FVC (% predicted): 
Classification based on Observed and Imputed Values 
FAS-Main 
T14.2.1-4 
Analysis of Change from Baseline in FVC (% predicted) 
by Visit: MMRM based on Observed Cases 
FAS 
T14.2.1-5 
Categorical Summary of Change from Baseline in FVC 
(% predicted) by Visit: Classification based on Observed 
Cases Only 
FAS 
F14.2.1-1 
Analysis of Change from Baseline to Week 48 in FVC 
(% predicted):   Random Coefficient Model based on 
Observed Cases 
FAS - Main 
F14.2.1-2 
LS Mean (s.e.) of Change from Baseline to Week 48 in 
FVC (% predicted):  ANCOVA based on Observed and 
Imputed Values 
FAS - Main 
F14.2.1-3 
Analysis of Categorical Endpoints of Change from 
Baseline to Week 48 in FVC (% predicted): 
Classification based on Observed and Imputed Values 
FAS - Main   
F14.2.1-4 
Cummulative Distribution of Change from Baseline to 
Week 48 in FVC (% predicted) (Observed and Imputed 
Values Included) 
FAS - Main  
F14.2.1-5 
LS Mean (s.e.) of Change from Baseline in FVC (% 
predicted) by Visit: MMRM based on Observed Cases 
FAS 
 
 
 
T14.2.1-11 
Analysis of Change from Baseline to Week 48 in FVC 
(L): Random Coefficients Linear Regression Model 
FAS - Main 


 
 
based on Observed Cases 
T14.2.1-12 
Analysis of Change from Baseline to Week 48 in FVC 
(L):  ANCOVA based on Observed and Imputed values 
FAS - Main 
T14.2.1-13 
Analysis of Change from Baseline in FVC (L) by Visit: 
MMRM based on Observed Cases 
FAS 
F14.2.1-11 
Linear Slope Analysis of Rate of Decline in FVC (L): 
Random Coefficient Model based on Observed Cases 
FAS - Main 
F14.2.1-12 
LS Mean (s.e.) of Change from Baseline to Week 48 in 
FVC (L): ANCOVA based on  Observed and Imputed 
values  
FAS - Main 
F14.2.1-13 
Cummulative Distribution of Change from Baseline to 
Week 48 in FVC (L) (Observed and Imputed Values 
Included) 
FAS - Main  
F14.2.1-14 
LS Mean (s.e.) of Change from Baseline in FVC (L) by 
Visit: MMRM based on Observed Cases 
FAS 
 
 
 
14.2.1-21 
Descriptive Summary of Percent Relative Change from 
Baseline in FVC (L) by Visit (Observed and Imputed 
Values Included) 
FAS  
F14.2.1-21 
Cumulative Distribution of Percent Relative Change from 
Baseline to Week 48 in FVC (L) (Observed and Imputed 
Values Included) 
FAS - Main 
 
 
 
14.2.2 
Analysis of Change in Quantitative HRCT Fibrosis Score   
T14.2.2-1 
Analysis of Change from Baseline to Week 48 in 
Quantitative HRCT Fibrosis Score: ANCOVA with 
MI/MIANALYZE  
FAS – Main  
T14.2.2-2 
Analysis of Change from Baseline to Week 24 in 
Quantitative HRCT Fibrosis Score: ANCOVA with 
MI/MIANALYZE 
FAS  
F14.2.2-1 
LS Mean (s.e.) of Change from Baseline in Quantitative 
HRCT Fibrosis Score by Visit: ANCOVA with 
MI/MIANALYZE 
FAS   
F14.2.2-2 
% of Subjects with Improved Quantitative HRCT CAD 
Fibrosis Score by Visit: ANCOVA with 
MI/MIANALYZE 
FAS   
F14.2.2-3 
Waterfall Plot of Change from Baseline in Quantitative 
HRCT Fibrosis Score by Visit (Observed and Imputed 
Values Included) 
FAS   


 
 
F14.2.2-4 
Cummulative Distribution of Change from Baseline to 
Week 48 in HRCT Fibrosis Score (Observed and 
Imputed Values Included) 
FAS - Main 
 
 
 
14.2.3 
Analysis of Change from Baseline in SGRQ Domain and 
Total Scores 
 
T14.2.3-1 
Analysis of Change from Baseline in SGRQ Domain and 
Total Scores by Visit: MMRM based on Observed Cases  
FAS  
T14.2.3-2 
Summary of Proportion of Subjects with Improved 
SGRQ Domain and Total Scores: Classification based on 
Observed Cases  
FAS 
F14.2.3-1 
LS Mean (s.e.) of Change from Baseline in SGRQ 
Domain and Total Scores by Visit: MMRM Model on 
Observed Cases 
FAS 
 
 
 
14.2.4 
Analysis of Progression of IPF 
 
14.2.4a 
Analysis of Time to Progression of IPF, Respiratory-
Related Hospitalization, and Respiratory-Related Death 
FAS 
14.2.4b 
Analysis of Time to Progression of IPF, Respiratory-
Related Hospitalization, and Respiratory-Related Death 
Safety 
 
F14.2.4-1a 
Kaplan-Meier Curve of Time to Progression of IPF 
FAS 
F14.2.4-1b 
Kaplan-Meier Curve of Time to Progression of IPF 
Safety 
 
 
 
14.2.10 
Sensitivity Analyses of the Primary Endpoint 
 
14.2.10-1 
Sensitivity Analysis of Change from Baseline to Week 48 
in FVC (% predicted): Rank ANCOVA 
FAS – Main  
14.2.10-2 
Sensitivity Analysis of Change from Baseline to Week 48 
in FVC (% predicted): ANCOVA with Rank-based 
Imputation 
FAS – Main  
14.2.10-3 
Sensitivity Analysis of Change from Baseline to Week 48 
in FVC (% predicted): ANCOVA with 
MI/MIANALYZE 
FAS – Main  
14.2.10-4 
Sensitivity Analysis of Change from Baseline to Week 48 
in FVC (% predicted): ANCOVA with All Randomized 
Subjects 
Safety – Main  
 
 
 
14.2.11 
Additional PFT Parameters 
 


 
 
T14.2.11-1 
Analysis of Change from Baseline in FEV1 (% predicted) 
by Visit: MMRM based on Observed Cases 
FAS 
F14.2.11-1 
LS Mean (s.e.) of Change from Baseline in FEV1 (% 
predicted) by Visit: MMRM based on Observed Cases 
FAS 
T14.2.11-2 
Analysis of Change from Baseline in FEV1/FVC (%) by 
Visit: MMRM based on Observed Cases 
FAS 
F14.2.11-2 
LS Mean (s.e.) of Change from Baseline in FEV1/FVC 
(%) by Visit: MMRM based on Observed Cases 
FAS 
 
 
 
14.2.12 
Additional Quantitative HRCT Parameters 
 
T14.2.12-1 
Analysis of Change from Baseline in Quantitative HRCT 
Fibrosis Score at the Worst Lung Zone by Visit: 
ANCOVA with MI/MIANALYZE 
FAS 
F14.2.12-1 
Analysis of Change from Baseline in Quantitative HRCT 
Fibrosis Score at the Worst Lung Zone by Visit: 
ANCOVA with MI/MIANALYZE 
FAS 
T14.2.12-2 
LS Mean (s.e.) of Change from Baseline in Quantitative 
HRCT QILD Score by Visit: ANCOVA with 
MI/MIANALYZE 
FAS 
F14.2.12-2 
LS Mean (s.e.) of Change from Baseline in Quantitative 
HRCT QILD Score by Visit: ANCOVA with 
MI/MIANALYZE 
FAS 
T14.2.12-3 
Analysis of Change from Baseline in Quantitative HRCT 
Ground Glass Score by Visit: MMRM based on 
Observed Cases 
FAS 
T14.2.12-4 
Analysis of Change from Baseline in Quantitative HRCT 
Honeycomb Score by Visit: MMRM based on Observed 
Cases 
FAS 
 
 
 
14.2.13 
Summary of HRCT Visual Reading Scores 
 
14.2.13-1 
Change from Baseline in Visual Fibrosis Assessment by 
Lung Zone and Visit 
FAS 
14.2.13-2 
Change from Baseline in Visual Ground Glass 
Assessment by Lung Zone and Visit 
FAS 
14.2.13-3 
Change from Baseline in Visual Honeycomb Assessment 
by Lung Zone and Visit 
FAS 
F14.2.13-4 
% of Subjects with Improved HRCT Fibrosis Visual 
Score in Whole Lung by Visit 
FAS   


 
 
 
 
 
14.2.14 
Examination of Subgroups 
 
14.2.14.1 
Analysis of ΔFVCpp48 by Subgroup: ANCOVA based 
on Observed and Imputed values 
FAS - Main 
14.2.14.2 
Analysis of ΔFIB48 by Subgroup: ANCOVA based on 
Observed and Imputed values 
FAS - Main 
F14.2.14.1 
Forest Plot of LS Means (s.e.) of ΔFVCpp48 by 
Subgroup: ANCOVA based on Observed and Imputed 
values 
FAS - Main 
F14.2.14.2 
Forest Plot of LS Means (s.e.) of ΔFIB48 by Subgroup: 
ANCOVA based on Observed and Imputed values 
FAS - Main 
 
 
 
14.2.15 
Other Exploratory Analyses 
 
14.2.15.1 
Pearson Correlation between Change from Baseline to 
Week 48 in FVC (% predicted) and HRCT Fibrosis Score 
(Observed + MI Imputed for Both Measures) 
FAS 
 
14.2.15.2 
Pearson Correlation between Change from Baseline to 
Week 48 in FVC (% predicted) and SGRQ Domain/Total 
Scores (Observed Cases Only) 
FAS 
 
 
 
 
14.3.1 
Summary of Adverse Events 
 
14.3.1-1 
Overall Summary of Treatment Emergent Adverse 
Events  
Safety 
14.3.1-2 
Summary of Treatment Emergent Adverse Events by 
System Organ Class and Preferred Term  
Safety 
14.3.1-2a 
Summary of Treatment-Emergent Adverse Event 
Incidence > 10% by System Organ Class and Preferred 
Term 
Safety 
14.3.1-3 
Summary of Treatment-Emergent Adverse Events 
Leading to Treatment/Study  Discontinuation by System 
Organ Class and Preferred Term 
Safety 
14.3.1-4 
Summary of Treatment Emergent Adverse Events by 
System Organ Class, Preferred Term, and Maximum 
Severity  
Safety 
14.3.1-5 
Summary of Treatment Emergent Adverse Events with 
Severity Grade ≥ 3 by System Organ Class and Preferred 
Term  
Safety 


 
 
14.3.1-6 
Summary of Treatment Emergent Adverse Events 
Assessed as At Least Possibly Related to FG-
3019/Placebo  by System Organ Class and Preferred 
Term  
Safety 
14.3.1-6a 
Summary of Treatment Emergent Adverse Events 
Assessed as At Least Possibly Related to FG-
3019/Placebo  or Background Therapies by System 
Organ Class and Preferred Term  
Substudy Safety 
14.3.1-7 
Summary of Infusion-Associated Treatment Emergent 
Adverse Events by System Organ Class and Preferred 
Term  
Safety 
14.3.2-1 
Listing of Deaths 
Safety 
14.3.2-1a 
Summary of Mortality Rate 
Safety 
14.3.2-1b 
Summary of Mortality Rate by Baseline GAP Staging  
Safety 
14.3.2-2a 
Listing of Serious Adverse Events 
Safety 
14.3.2-2b 
Summary of Treatment Emergent Serious Adverse 
Events by System Organ Class and Preferred Term  
Safety 
14.3.2-3a 
Listing of Serious Adverse Events Assessed as At Least 
Possibly Related to FG-3019/Placebo 
Safety 
14.3.2-3b 
Summary of Treatment Emergent Serious Adverse 
Events as At Least Possibly Related to FG-3019/Placebo 
by System Organ Class and Preferred Term 
Safety 
14.3.2-4a 
Listing of IPF Related or Respiratory Related 
Hospitalization Serious Adverse Events  
Safety 
14.3.2-4b 
Summary of Treatment Emergent IPF Related or 
Respiratory Related Hospitalization Serious Adverse 
Events by System Organ Class and Preferred Term  
Safety 
14.3.2-4c 
Summary of Treatment Emergent Serious Adverse 
Events Not Related to IPF or Respiratory Related 
Hospitalization by System Organ Class and Preferred 
Term  
Safety 
14.3.2-5a 
Listing of Serious Adverse Events Assessed as At Least 
Possibly Related to Background Therapy 
Safety 
14.3.2-5b 
Summary of Treatment Emergent Serious Adverse 
Events Assessed as At Least Possibly Related to 
Background Therapy by System Organ Class and 
Preferred Term 
Safety 
14.3.3 
Narratives (not part of TLFs) 
 


 
 
14.3.4 
Listing of Clinically Significant Abnormal Laboratory 
Values (CTCAE Grade >= 3) 
Safety 
F14.3.4 
Lab Test Over Time for Subjects with Clinically 
Significant Abnormal Laboratory Values (CTCAE Grade 
>= 3) 
Safety 
 
 
 
14.3.5.1-1 
Laboratory Value and Change from Baseline in 
Complete Blood Count 
Safety 
14.3.5.1-2 
Laboratory Value and Change from Baseline in 
Complete Blood Count: Absolute 
Safety 
14.3.5.1-3 
Laboratory Value and Change from Baseline in 
Complete Blood Count: WBC Differential 
Safety 
14.3.5.1-4 
Summary of CTCAE Grades by Visit in CBC Tests 
Safety 
14.3.5.1-5 
Shift Table Summary of CTCAE Grade in Baseline 
versus Post-baseline Visits in CBC Tests 
Safety 
14.3.5.1-6 
Shift Table Summary of CTCAE Grade in Baseline 
versus Maximum Grade During Study in CBC Tests 
Safety 
 
 
 
14.3.5.2-1 
Laboratory Value and Change from Baseline in Serum 
Chemistry Results: Liver Function Tests 
Safety 
14.3.5.2-2 
Laboratory Value and Change from Baseline in Serum 
Chemistry Results: Kidney Function and Metabolic Tests 
Safety 
14.3.5.2-3 
Laboratory Value and Change from Baseline in Serum 
Chemistry Results: Coagulation 
Safety 
14.3.5.2-4 
Laboratory Value and Change from Baseline in Serum 
Chemistry Results: Electrolytes 
Safety 
14.3.5.2-5 
Laboratory Value and Change from Baseline in Other 
Serum Chemistry Results 
Safety 
14.3.5.1-6 
Summary of CTCAE Grades by Visit in Serum 
Chemistry Tests 
Safety 
14.3.5.1-7 
Shift Table Summary of CTCAE Grade in Baseline 
versus Post-baseline Visits in Serum Chemistry Tests 
Safety 
14.3.5.1-8 
Shift Table Summary of CTCAE Grade in Baseline 
versus Maximum Grade During Study in Serum 
Chemistry Tests 
Safety 
 
 
 


 
 
14.3.5.3-1 
Shift Table Summary of Complete Blood Count 
Safety 
14.3.5.3-2 
Shift Table Summary of Complete Blood Count: 
Absolute 
Safety 
14.3.5.3-3 
Shift Table Summary of Complete Blood Count: WBC 
Differential 
Safety 
14.3.5.4-1 
Shift Table Summary of Serum Chemistry Results: Liver 
Function Test 
Safety 
14.3.5.4-2 
Shift Table Summary of Serum Chemistry Results: 
Kidney Function and Metabolic 
Safety 
14.3.5.4-3 
Shift Table Summary of Serum Chemistry Results: 
Coagulation 
Safety 
14.3.5.4-4 
Shift Table Summary of Serum Chemistry Results: 
Electrolytes 
Safety 
14.3.5.4-5 
Shift Table Summary of Other Serum Chemistry Results 
Safety 
 
 
 
F14.3.5-1a 
Box Plot of CBC Tests by Treatment and Visit  
Safety  
F14.3.5-1 
Box Plot of Change from Baseline in CBC Tests by 
Treatment and Visit  
Safety  
F14.3.5-2a 
Box Plot of Serum Chemistry Tests by Treatment and 
Visit 
Safety  
F14.3.5-2 
Box Plot of Change from Baseline in Serum Chemistry 
Tests by Treatment and Visit  
Safety  
 
 
 
14.3.6 
Vital Signs 
 
14.3.6-1 
Vital Sign Measurements and Change from Baseline 
Safety 
14.3.6-1a 
Vital Sign Measurements and Change from Baseline by 
Time Point 
Safety 
14.3.6-2 
Potentially Clinically Meaningful Changes in Vital Sign 
Measurements 
Safety 
F14.3.6-1a 
Box Plot of Systolic Blood Pressure by Visit 
Safety  
F14.3.6-1b 
Box Plot of Change from Baseline in Systolic Blood 
Pressure by Visit  
Safety  
F14.3.6-2a 
Box Plot of Diastolic Blood Pressure by Visit  
Safety  
F14.3.6-2b 
Box Plot of Change from Baseline in Diastolic Blood 
Safety  


 
 
Pressure by Visit  
F14.3.6-3a 
Box Plot of Pulse Rate by Visit  
Safety  
F14.3.6-3b 
Box Plot of Change from Baseline in Pulse Rate by Visit 
Safety  
F14.3.6-4a 
Box Plot of Respiratory Rate by Visit  
Safety  
F14.3.6-4b 
Box Plot of Change from Baseline in Respiratory Rate by 
Visit  
Safety  
 
 
 
14.3.7-1 
Shift Table Summary of ECG Findings at Weeks 24/48 
versus at Screening  
Safety 
14.3.7-2 
Summary of ECG Parameters 
Safety 
14.3.7-3 
Potentially Clinically Meaningful Changes in ECG 
Parameters 
Safety 
14.3.8 
Shift Table Summary of Physical Examinations  
Safety 
 
 
 
14.4 
Summary of Exposure 
 
14.4-1 
Duration of Treatment                                                   
Safety 
14.4.1a 
Number (%) of Subjects on Treatment by Study Week 
Safety 
14.4-2 
Number of infusions                                                      
Safety 
14.4-3 
FG-3019 Dose Amount (mg) per Infusion         
Safety 
14.4-4 
Summaryof Treatment  Compliance 
Safety 
 
 
 
14.5 
Summary of PK, PD, and Biomarker Parameters 
 
14.5.1 
Summary of Peak and Trough Concentration Level of 
FG-3019, Pirfenidone, Nintedanib and Metabolite-to 
Parent Ratio by Time Point 
Substudy 
9.2 
List of Listings 
16.1.7 
Randomization scheme and codes 
Randomized 
 
 
 
16.2.1 
Discontinued Subjects  
Randomized 
16.2.1a 
Subject Disposition 
Randomized 
16.2.2-1 
Subjects Who Did Not Meet Entry Criteria 
Randomized 
16.2.2-2 
Protocol deviations 
Randomized 


 
 
16.2.3-1 
Subjects Excluded from Efficacy Analysis 
Randomized 
16.2.3-2 
Subjects Included in Efficacy Analysis 
FAS 
16.2.4.1 
Demographic Data 
Randomized 
16.2.4.2 
Medical History 
Randomized 
16.2.4.3 
Baseline Characteristics 
Randomized 
16.2.4.4 
Baseline Gap Score and Staging 
Randomized 
16.2.4.5 
Smoking History 
Randomized 
16.2.4.6 
Previous PFT Values and Estimated Annualized Rate 
of Change 
Randomized 
16.2.4.7 
Medications for IPF in the Past 
Randomized 
16.2.4.8 
Prior Medications 
Randomized 
16.2.4.9 
Concomitant Medications 
Randomized 
16.2.4.10 
Procedures and Non-Drug Therapies 
Randomized 
16.2.4.11 
Oxygen Use 
Randomized 
16.2.4.12 
IPF Confirmation 
Randomized 
 
 
 
16.2.5.1 
Study Drug Administration 
Safety 
16.2.5.1-1 
Treatment Compliance 
Safety 
 
 
 
16.2.6.1-1 
FVC Observed, % predicted, Change from Baseline, 
and Imputation Values 
Safety 
16.2.6.1-2 
DLCO Observed, % predicted, and Change from 
Baseline 
Safety 
16.2.6.1-3 
FEV1 Observed, % predicted, and Change from 
Baseline 
Safety 
16.2.6.1-4 
FRC Observed, % predicted, and Change from 
Baseline 
Safety 
16.2.6.1-5 
TLC Observed, % predicted, and Change from 
Safety 


 
 
Baseline,  
16.2.6.1-6 
FEV1/FVC  and Change from Baseline 
Safety 
 
 
 
16.2.6.2-1 
Time to Progression of IPF  
Safety 
 
 
 
16.2.6.3-1 
HRCT CAD Scores and Change from Baseline 
Safety 
16.2.6.3-2 
HRCT Visual Reading Scores  
Safety 
 
 
 
16.2.6.4-1 
SGRQ Domain and Total Scores and Change from 
Baseline 
Safety 
16.2.6.4-2 
UCSD Shortness of Breath Total Score and Change 
from Baseline 
Safety 
 
 
 
16.2.7-1 
Listing of All Reported Adverse Events 
Safety 
16.2.7-2 
Listing of Adverse Events Assessed as At Least 
Possibly Related to FG-3019/Placebo  
Safety 
16.2.7-2a 
Listing of Adverse Events Assessed as At Least 
Possibly Related to FG-3019/Placebo or Background 
Therapies  
Substudy Safety 
16.2.7-3 
Listing of Adverse Events Leading to 
Treatment/Study Discontinuation 
Safety 
16.2.7-4 
Listing of Adverse Events with Severity Grade ≥ 3 
Safety 
16.2.7-4a 
Listing of Possible Treatment Related Adverse 
Events with Severity Grade ≥ 3 
Safety 
16.2.7-5 
Listing of Possible Infusion Associated Adverse 
Events 
Safety 
16.2.7-5a 
Listing of PI Identified Possible Infusion Associated 
Adverse Events  
Safety 
16.2.7-6 
Listing of Possible Procedure Related Adverse 
Events 
Safety 
16.2.8.1-1 
Complete Blood Count 
Safety 
16.2.8.1-2 
Complete Blood Count: Absolute 
Safety 


 
 
16.2.8.1-3 
Complete Blood Count: WBC Differential 
Safety 
16.2.8.1-4 
Complete Blood Count: Morphology 
Safety 
16.2.8.2-1 
Serum Chemistry Results: Liver Function Test 
Safety 
16.2.8.2-2 
Serum Chemistry Results: Kidney Function and 
Metabolic 
Safety 
16.2.8.2-3 
Serum Chemistry Results: Coagulation 
Safety 
16.2.8.2-4 
Serum Chemistry Results: Electrolytes 
Safety 
16.2.8.2-5 
Serum Chemistry Results: Other 
Safety 
16.2.8.3-1 
Urinalysis Results 
Safety 
16.2.8.3-2 
Urinalysis Results: Casts 
Safety 
16.2.8.3-3 
Urinalysis Results: Cellular 
Safety 
16.2.8.3-4 
Urinalysis Results: Crystals 
Safety 
16.2.8.4 
Pregnancy Results – Females 
Safety 
16.2.9 
Physical Examinations 
Safety 
16.2.10-1 
Vital Signs 
Safety 
16.2.10-2 
Vital Signs (Average over Post-Infusion Time Points) Safety 
16.2.11 
Electrocardiogram 
Safety 
 
 


 
 
APPENDICES 
Appendix I   Computation Formulae for Predicted PFT Parameters 
Predicted PFT values are computed based on Age, Height (Ht), Weight (Wt), and BSA. 
Measurements at Screening will be used in computing the predicted values throughout 
the study. Specifically,   
Aged = (Date when PFT is performed – Date of birth)/365.25   
Ht = height in centimeters measured at Screening 
Wt = weight in kilograms measured at Screening 
BSA = Body Surface area in meter2 calculated by the formula of DuBois and DuBois  = 
(Wt 0.425 x Ht 0.725) x 0.007184 
Note: Aged, without rounding to integer, is used only in calculating predicted values for 
the PFT parameters.   
1   Predicted FVC and FEV1 
The predicted values of FVC and FEV1 are calculated using the following algorithms for 
the corresponding gender-age groups (Hankinson JL, et al.)  
1.1   Predicted FVC 
 
Gender-Race-Age Group 
Intercept 
Aged (yr) 
Aged2 (yr) 
Ht2 (cm) 
Men, Caucasian, Aged≥20 
-0.1933 
0.00064 
-0.000269 
0.00018642 
Men, African American, Aged ≥20 
-0.1517 
-0.01821 
0 
0.00016643 
Women, Caucasian, Aged ≥18 
-0.3560 
0.01870 
-0.000382 
0.00014815 
Women, African American,  
Aged ≥18 
-0.3039 
0.00536 
-0.000265 
0.00013606 
 
Men, Caucasian , Aged ≥20 
Predicted FVC (L) = -0.1933 + 0.00064* Aged -0.000269* Aged 2 + 0.00018642*Ht2 
Men, African American, Aged ≥20 
Predicted FVC (L) = -0.1517 - 0.01821* Aged + 0.00016643*Ht2 
Women, Caucasian , Aged ≥18 
Predicted FVC (L) = -0.3560 + 0.01870* Aged  - 0.000382* Aged 2 + 0.00014815*Ht2 
Women, African American, Aged ≥18 
Predicted FVC (L) = -0.3039 + 0.00536* Aged - 0.000265* Aged 2 + 0.00013606*Ht2 


 
 
Subjects of Southeast Asian ethnicity, as reported by the investigator, were applied a 
correction factor of 0.88 to the Caucasian equations based on more pertinent 
demographic characteristics, as per Quanjer et al. (2012) and the study Pulmonary 
Function Tests experts.  
For all other cases the Caucasian predicted values will be used. 
% predicted FVC = measured FVC (L)/predicted FVC (L) *100. 
 
1.2   Predicted FEV1 
Gender-Race-Age Group 
Intercept 
Aged (yr) 
Aged 2 (yr) 
Ht2 (cm) 
Men, Caucasian, Aged ≥20 
0.5536 
-0.01303 
-0.000172 
0.00014098 
Men, African American, Aged ≥20 
0.3411 
-0.02309 
0 
0.00013194 
Women, Caucasian, Aged ≥18 
0.4333 
-0.00361 
-0.000194 
0.00011496 
Women, African American,  
Aged ≥18 
0.3433 
-0.01283 
-0.000097 
0.00010846 
 
Men, Caucasian and other races, Aged ≥20 
Predicted FEV1 (L) = 0.5536 - 0.01303* Aged - 0.000172* Aged 2 + 0.00014098*Ht2  
Men, African American, Aged ≥20 
Predicted FEV1 (L) = 0.3411 - 0.02309* Aged + 0.00013194*Ht2  
Women, Caucasian and other races, Aged ≥ 18 
Predicted FEV1 (L) = 0.4333 - 0.00361* Aged - 0.000194* Aged 2 + 0.00011496*Ht2  
Women, African America, Aged ≥18 
Predicted FEV1 (L) = 0.3433 - 0.01283* Aged - 0.000097* Aged 2 + 0.00010846*Ht2  
Subjects of Southeast Asian ethnicity, as reported by the investigator, were applied a 
correction factor of 0.88 to the Caucasian equations based on more pertinent 
demographic characteristics, as per Quanjer et al. (2012) and the study Pulmonary 
Function Tests experts.  
For all other cases the Caucasian predicted values will be used. 
% Predicted FEV1 = measured FEV1 (L) / predicted FEV1 (L) 
 
2   Predicted DLCO Corrected for Hb 
Predicted DLCO comes from Miller A, et al. Predicted value for non-smoking (NS) 
status will be used for all calculations in this study.  


 
 
Gender 
Intercept 
Aged (year) 
Ht (cm) 
Men 
12.9113 
-0.2290 
0.4180 / 2.54 
Women 
2.2382 
-0.1111 
0.4068 / 2.54 
 
For men: 
Predicted DLCO (ml/min/mmHg) = 12.9113 - 0.2290* Aged + 0.4180* Ht / 2.54 
For women: 
Predicted DLCO (ml/min/mmHg) = 2.2382 - 0.1111* Aged + 0.4068* Ht / 2.54 
Predicted DLCO Corrected for Hb 
For men: 
Predicted DLCO corrected for Hb (ml/min/mmHg)  
=  DLCO predicted  * 1.7 * Hb / (10.22 + Hb)  
For women,  
Predicted DLCO corrected for Hb (ml/min/mmHg)  
=  DLCO predicted * 1.7 * Hb / (9.38 + Hb)  
where Hb = hemoglobin in g/dL measured at the closest point to the time when DLCO is 
measured. If two Hb values are available with the equal distance, the earlier measurement 
is used.   
For men 
% predicted DLCO (corrected for Hb)  
= measured DLCO / predicted DLCO corrected for Hb *100   
= measured DLCO / {predicted DLCO * 1.7 * Hb /  (10.22 + Hb)} *100 
For women 
% predicted DLCO (corrected for Hb)  
= measured DLCO / predicted DLCO corrected for Hb *100   
= measured DLCO / {predicted DLCO * 1.7 * Hb / (9.38 + Hb)} * 100 
 
3    Predicted TLC and FRC 
Predicted TLC and predicted FRC are based Goldman HI and Becklake MR as shown 
below.  
Gender 
Parameter 
Intercept 
Aged  
(year) 
Ht  
(cm) 
Wt 
 (kg) 
BSA  
(m2) 
Men 
TLC 
-9.167 
-0.015 
+0.094 
0 
0 


 
 
 
FRC 
-7.11 
0 
+0.081 
0 
-1.792 
 
 
 
 
 
 
 
Women 
TLC 
-7.49 
-0.008 
+0.079 
0 
0 
 
FRC 
-4.74 
0 
+0.053 
-0.017 
0 
 
For men: 
Predicted TLC (L) = -9.167 - 0.015* Aged + 0.094*Ht 
Predicted FRC (L) = -7.11 + 0.081*Ht - 1.792*BSA 
For women: 
Predicted TLC (L) = -7.49 - 0.008* Aged + 0.079*Ht 
Predicted FRC (L) = -4.74 + 0.053*Ht - 0.017*Wt 
% predicted TLC = measured TLC (L) / predicted TLC (L) *100. 
% predicted FRC = measured FRC (L) / predicted FRC (L) *100.  
 
 


 
 
Appendix II    Scoring of the SGRQ Domain and Total Scores 
The description in this section is extracted from St. George’s Respiratory Questionnaire 
Manual, Version 2.3 (June 2009), by Jones, Paul,  St. George’s, University of London.  
1   Overview of SGRQ  
The Saint George’s Respiratory questionnaire (SGRQ) is designed to measure health 
impairment in patients with asthma and COPD.  The questionnaire is in two parts. Part 1 
is to assess the patient’s perception of their recent respiratory problems (Symptoms).  Part 
2 is to measure disturbances of patients’ daily physical activity (Activity) and 
disturbances of psycho-social function (Impacts).  The domain and the total scores are 
percentages of sums of weights divided by the maximum possible score in the 
corresponding domain.  The scores range from 0 to 100, where 0 indicates the best and 
100 the worst possible health status.  
The questions covered by each domain and the maximum possible scores are listed 
below. 
Domain 
Questions 
Maximum Possible 
Score 
Symptoms 
1 – 8  
662.5 
Activity 
11 and 15  
1209.1 
Impacts 
9 – 10, 12 – 14, 16 – 17  
2117.8 
Total 
All 
3989.4 
 
2   SGRQ Scoring Algorithm 
The component scores and the total score are derived in the following steps:  
1. The weights for all items with positive responses are summed. 
2. The weights for missed items are deducted from the maximum possible weight for 
each component.  The weights for all missed items are deducted from the 
maximum possible weight for the total score. 
3. The score is calculated by dividing the summed weights by the adjusted 
maximum possible weight for that component and multiplying the result by 100 
(rounded to the nearest integer). 
The questionnaire requests a single response to questions 1-7, 9-10, and 17.  If multiple 
responses are given to one of these questions then averaging the weights for the positive 
responses for that question is acceptable. 
The Symptoms component is calculated from the summed weights for the positive 
responses to questions 1-8.  This component will tolerate a maximum of two missed 
items.  More than two missing items will result in a missing Symptoms score. 
The Activity component is calculated from the summed weights for the positive 
responses to questions 11 and 15.  This component will tolerate a maximum of four 
missed items.  More than four missing items will result in a missing Activity score. 


 
 
The Impacts component is calculated from the summed weights for the positive responses 
to questions 9-10, 12-14, and 16-17.  This component will tolerate a maximum of six 
missed items.  More than six missing items will result in a missing Impacts score. 
The Total score is calculated from the summed weights for the positive responses in the 
questionnaire and expressing the result as a percentage of the total possible weight for the 
non-missing items.  If more than 24% of the items are missing then the Total score will 
be missing.  
3   Weight of Each Question 
PART 1 
1) Over the past 3 months, I have coughed: 
Most  80.6 
Several 63.2 
A few  29.3 
Only  28.1 
Not  
0.0 
2) Over the past 3 months, I have brought up phlegm (sputum): 
Most 76.8 
Several 60.0 
A few 34.0 
Only 30.2 
Not 0.0 
3) Over the past 3 months, I have had shortness of breath: 
Most 87.2 
Several 71.4 
A few 43.7 
Only 35.7 
Not 0.0 
4) Over the past 3 months, I have had attacks of wheezing: 
Most 86.2 
Several 71.0 
A few 45.6 
Only 36.4 
Not 0.0 


 
 
5) During the past 3 months, how many severe or very bad unpleasant attacks of 
chest trouble have you had? 
More than three 86.7 
3 attacks 73.5 
2 attacks 60.3 
1 attack 44.2 
None 0.0 
6) How long did the worst attack of chest trouble last? 
a week or more 89.7 
3 or more days 73.5 
1 or 2 days 58.8 
less than a day 41.9 
7) Over the last year, in an average week, how many good days (with little chest 
trouble) have you had? 
None 93.3 
1 or 2 76.6 
3 or 4 61.5 
nearly every day 15.4 
every day 0.0 
8) If you have a wheeze, is it worse in the morning? 
No 0.0 
Yes 62.0 
PART 2 
9) How would you describe your chest condition? 
The most important problem I have 83 .2 
Causes me quite a lot of problems 82.5 
Causes me a few problems 34.6 
Causes no problem 0.0 
10) If you have ever had paid employment? 
My chest trouble made me stop work 88.9 
My chest trouble interferes with my work or made me change my work 77.6 
My chest trouble does not affect my work 0.0 
11) Questions about what activities usually make you feel breathless. 


 
 
Sitting or lying still 90.6 
Getting washed or dressed 82.8 
Walking around the home 80.2 
Walking outside on the level 81.4 
Walking up a flight of stairs 76.1 
Walking up hills 75.1 
Playing sports or games 72.1 
12) More questions about your cough and breathlessness. 
My cough hurts 81.1 
My cough makes me tired 79.1 
I get breathless when I talk 84.5 
I get breathless when I bend over 76.8 
My cough or breathing disturbs my sleep 87.9 
I get exhausted easily 84.0 
13) Questions about other effects your chest trouble may have on you. 
My cough or breathing is embarrassing in public 74.1 
My chest trouble is a nuisance to my family, friends or neighbours 79.1 
I get afraid or panic when I cannot get my breath 87.7 
I feel that I am not in control of my chest problem 90.1 
I do not expect my chest to get any better 82.3 
I have become frail or an invalid because of my chest 89.9 
Exercise is not safe for me 75.7 
Everything seems too much of an effort 84.5 
14) Questions about your medication. 
My medication does not help me very much 88.2 
I get embarrassed using my medication in public 53.9 
I have unpleasant side effects from my medication 81.1 
My medication interferes with my life a lot 70.3 
15) Questions about how activities may be affected by your breathing. 
I take a long time to get washed or dressed 74.2 
I cannot take a bath or shower, or I take a long time 81.0 
I walk more slowly than other people, or I stop for rests 71.7 
Jobs such as housework take a long time, or I have to stop for rests 70.6 


 
 
If I walk up one flight of stairs, I have to go slowly or stop 71.6 
If I hurry or walk fast, I have to stop or slow down 72.3 
My breathing makes it difficult to do things such as walk up hills, carry things up 
stairs, light gardening such as weeding, dance, play bowls or play golf 74.5 
My breathing makes it difficult to do things such as carry heavy loads, dig the 
garden or shovel snow, jog or walk at 5 miles per hour, play tennis or swim 71.4 
My breathing makes it difficult to do things such as very heavy manual work, run, 
cycle, swim fast or play competitive sports 63.5 
16) We would like to know how your chest trouble usually affects your daily life. 
I cannot play sports or games 64.8 
I cannot go out for entertainment or recreation 79.8 
I cannot go out of the house to do the shopping 81.0 
I cannot do housework 79.1 
I cannot move far from my bed or chair 94.0 
17) Tick the statement which you think best describes how your chest affects you. 
It does not stop me doing anything I would like to do 0.0  
It stops me doing one or two things I would like to do 42.0 
It stops me doing most of the things I would like to do 84.2 
It stops me doing everything I would like to do 96.7 
 
 


 
 
APPENDIX III GENERAL SPECIFICATIONS FOR SUBMISSION DATA 
1. Study Data Tabulation Model (SDTM) 
Raw datasets will be mapped to SDTM datasets following variable names and attributes 
specified in the SDTM Implementation Guide (version 3.2 and subsequent update). Data 
coding is also mapped to the SDTM controlled terminology.  OpenCDISC module will be 
run to confirm compliance to the SDTM guidelines.  Deviations from the guidelines will 
be documented. Variables that exist in different source datasets, such as lab data 
collection date, will be consolidated and included once in the SDTM datasets. 
Unscheduled ‘Not Done’ records are excluded from the SDTM datasets. Detailed 
mapping specifications are documented in Define.xml and annotation CRFs.  
CRF variables that are not included in the SDTM datasets will be marked as ‘Not 
Submitted’, since the SDTM datasets will be submitted as the raw datasets and the raw 
datasets that match the CRFs will not be submitted to regulatory agencies.   
The SDTM datasets are the basis to derive the analysis datasets. Summary tables and 
listings that do not require complex derived variables may be generated directly from 
SDTM datasets. 
Table A contains a list of SDTM datasets to be created for the study. The corresponding 
supplemental datasets are not included. This set of SDTM datasets includes only data for 
the Randomized Treatment Period as described in Section 1.  
Table A. 
Study Data Tabulation Model Datasets (SDTM) 
SDTM 
Domain 
SDTM Domain 
Description 
SDTM Domain 
Structure 
General 
Observation 
Class 
Source 
Data Used 
Key Variables 
AE 
Adverse Events 
One record per 
adverse event per 
subject 
Events 
AE 
STUDYID, 
USUBJID, 
AESTDTC, 
AEDECOD, 
AESPID 
CM 
Concomitant 
Medications 
One record per 
recorded medication 
occurrence per 
subject 
Interventions 
CM, CMIPF 
STUDYID, 
USUBJID, 
CMCAT, 
CMSPID, 
CMTRT, 
CMSTDTC 
DD 
Death Details 
One record per 
subject 
Findings 
DTH 
STUDYID, 
USUBJID, 
DDTESTCD 
DM 
Demographics 
One record per 
subject 
Special 
Purpose 
Domains 
DM, EX, 
ICF, DTH,  
SITE_INV 
STUDYID, 
USUBJID 


 
 
DS 
Disposition 
One record per 
disposition status or 
protocol milestone 
per subject 
Events 
DS, ICF, 
DTH, EX 
STUDYID, 
USUBJID, 
DSSTDTC, 
DSDECOD, 
DSSPID, 
EPOCH 
DV 
Protocol 
Deviations 
One record per 
protocol deviations 
per subject 
Events 
DV 
STUDYID, 
USUBJID, 
DVTERM 
EC 
Exposure as 
Collected 
One record per 
protocol-specified 
study treatment per 
collected-dosing 
interval  per subject 
Interventions 
EX 
STUDYID, 
USUBJID, 
ECTRT, 
ECSTDTC, 
ECGRPID 
EG 
ECG Test Results 
One record per ECG 
observation per visit 
per subject 
Findings 
EG 
STUDYID, 
USUBJID, 
EGTESTCD, 
VISITNUM 
EX 
Exposure 
One record per 
constant dosing 
interval per subject 
Interventions 
EX 
STUDYID, 
USUBJID, 
EXTRT, 
EXSTDTC 
IE 
Inclusion/Exclusi
on Criteria Not 
Met 
One record per 
inclusion/exclusion 
criterion not met per 
subject 
Findings 
IE 
STUDYID, 
USUBJID, 
IETESTCD 
LB 
Laboratory Test 
Results 
One record per lab 
test per specimen 
per method per 
LOINC code per 
reason not done per 
visit per subject 
Findings 
eDT LB, 
RAND, 
LBC, 
LBPREG 
STUDYID, 
USUBJID, 
LBCAT, 
LBTESTCD, 
VISITNUM, 
LBMETHOD, 
LBREASND, 
LBLOINC 
MH 
Medical History 
One record per 
medical history 
event per time 
interval per subject 
Events 
MH 
STUDYID, 
USUBJID, 
MHSPID, 
MHDECOD, 
MHSTDTC, 
MHENDTC 
PC 
Pharmacokinetic 
Concentrations 
One record per time-
point concentration 
or sample 
characteristic per 
analyte per subject 
Findings 
Source 
documents, 
PKC 
STUDYID, 
USUBJID, 
PCTESTCD, 
VISITNUM, 
PCTPTNUM 


 
 
PE 
Physical 
Examination 
One record per body 
system or 
abnormality per visit 
per subject 
Findings 
PE 
STUDYID, 
USUBJID, 
PETESTCD, 
VISITNUM 
PP 
Pharmacokinetic 
Parameters 
One record per PK 
parameter per time-
concentration profile 
per modeling 
method per subject 
Findings 
Source 
documents 
STUDYID, 
USUBJID, 
PPTESTCD, 
PPCAT, 
VISITNUM, 
PPTPTREF 
PR 
Procedures 
One record per 
recorded procedure 
per occurrence per 
subject 
Interventions 
NDT, OU 
STUDYID, 
USUBJID, 
PRCAT, 
PRTRT, 
PRSPID 
QS 
Questionnaires 
One record per 
question per 
questionnaire per 
visit per subject 
Findings 
SGRQ, 
UCSD 
STUDYID, 
USUBJID, 
QSTESTCD, 
VISITNUM 
SC 
Subject 
Characteristics 
One record per 
characteristic per 
subject 
Findings 
DM 
STUDYID, 
USUBJID, 
SCTESTCD 
SE 
Subject Elements 
One record per 
actual Element per 
subject 
Special 
Purpose 
Domains 
SDTM.DM, 
SDTM.EX, 
SDTM.DS, 
SDTM.SV 
STUDYID, 
USUBJID, 
TAETORD, 
SESTDTC 
SU 
Substance Use 
One record per 
substance type per 
subject 
Intervention 
SUTOB 
STUDYID, 
USUBJID, 
SUTRT 
SV 
Subject Visits 
One record per 
actual visit per 
subject 
Special 
Purpose 
Domains 
All datasets 
including 
visits 
STUDYID, 
USUBJID, 
VISITNUM 
TA 
Trial Arms 
One record per 
planned Element per 
Arm 
Trial Design 
N/A 
STUDYID, 
ARMCD, 
TAETORD 
TE 
Trial Elements 
One record per 
planned Element 
Trial Design 
N/A 
STUDYID, 
ETCD 
TI 
Trial 
Inclusion/Exclusi
on Criteria 
One record per I/E 
criterion per 
protocol criteria 
version 
Trial Design 
N/A 
STUDYID, 
TIVERS, 
IETESTCD 
TS 
Trial Summary 
One record per Trial 
Summary parameter 
Trial Design 
N/A 
STUDYID, 
TSPARMCD, 


 
 
per occurrence 
TSSEQ 
TV 
Trial Visits 
One record per 
planned Visit per 
Arm 
Trial Design 
N/A 
STUDYID, 
VISITNUM, 
ARMCD 
VS 
Vital Signs 
One record per vital 
sign measurement 
per time point per 
visit per subject 
Findings 
VS, SC 
STUDYID, 
USUBJID, 
VSTESTCD, 
VISITNUM, 
VSDTC 
ZH 
High Resolution 
Computed 
Tomography 
One record per 
examination per 
location per time 
point per visit per 
subject 
Findings 
 HRCT, 
TEXTCAD, 
TEXTVIS, 
IMQUAL 
STUDYID, 
USUBJID, 
ZHCAT, 
ZHTESTCD, 
VISITNUM, 
ZHDTC, 
ZHLOC, 
ZHEVAL 
ZI 
IPF Confirmation 
One record per IPF 
Confirmation per 
test per subject 
Findings 
IPFD 
STUDYID, 
USUBJID, 
ZITESTCD 
ZP 
Pulmonary 
Function Tests 
One record per test 
per time point per 
visit per result per 
subject 
Findings 
eDT PFT, 
RAND, ZP, 
MHPFT 
STUDYID, 
USUBJID, 
ZPCAT, 
ZPTESTCD, 
VISITNUM, 
ZPDTC, 
ZPORRES 
 
2 Analysis Data Model (ADaM) 
The ADaM datasets are created based on the SDTM datasets following the ADaM 
Implementation Guide (version 1.0 and subsequent update). They include derived 
parameters and flags that are needed to generate tables/listings/figures. ADSL and ADAE 
are created using the specifications provided in the ADaMIG. Study endpoints are 
included in analysis files in ADaM Basic Data Structure (BDS). Horizontal analysis files 
are created for analyses on relationship of multiple endpoints. Variable names and labels 
of the horizontal files are from PARAMCD and PARAM of the corresponding BDS files. 
Detail derivations of each variable in the ADaM datasets are documented in the 
Metadata. 
Table B. 
Analysis Data Model (ADaM) 
Dataset 
Description 
Structure 
Keys 
ADSL 
Subject-Level 
One record per subject 
STUDYID, SUBJID  


 
 
Analysis Dataset 
ADAE 
Analysis Dataset 
Adverse Events 
One record per subject 
per adverse event 
STUDYID, SUBJID, 
AESTDTC, 
AEDECOD, AESPID 
ADCM 
Analysis Dataset 
Concomitant 
Medications 
One record per subject 
per recorded medication 
occurrence 
STUDYID, SUBJID, 
CMCAT, CMSPID, 
CMTRT, CMSTDTC 
ADDD 
Analysis Dataset 
Death  
One record per subject 
per paramter 
STUDYID SUBJID 
PARAMCD  
ADEG 
Analysis Dataset for 
ECG Test Results 
One record per subject 
per visit 
STUDYID, SUBJID, 
PARAMCD, 
AVISITN, ADT  
ADEX 
Analysis Dataset 
Exposure 
One record per subject 
per parameter per visit 
STUDYID, SUBJID, 
PARAMCD, AVISITN 
ADHRCT Analysis Dataset 
HRCT 
One record per subject 
per measurement method 
per Lung Lobe per 
parameter per visit 
STUDYID, SUBJID, 
PARAMCD, 
AVISITN, 
DTYPE ALOC 
ADLB 
Analysis Dataset 
Laboratory Test 
Results 
One record per subject 
per category per 
parameter per visit per 
normal range per result 
STUDYID, SUBJID, 
PARCAT1, 
PARCAT2, 
PARAMCD, 
AVISITN, ANRHI, 
AVAL  
ADMH 
Analysis Dataset 
Medical History 
One record per subject 
per medical history per 
time interval of medical 
history 
STUDYID, SUBJID,  
MHSPID, 
MHDECOD, 
MHSTDTC, 
MHENDTC  
ADPC 
Analysis Dataset 
PK Concentrations 
One record per subject 
per visit per time point 
per parameter 
STUDYID, SUBJID, 
AVISITN, ATPTN, 
PARAMCD  
ADPE 
Analysis Dataset 
Physical 
Examination 
One record per subject  
per parameter per visit 
STUDYID, SUBJID, 
AVISITN, PARAMCD 
ADPF 
Analysis Dataset 
Pulmonary Function 
Tests 
One record per subject 
per parameter per time 
point per visit 
USUBJID, SUBJID, 
PARAMCD, 
AVISITN, DTYPE, 
ADT, ATM 


 
 
ADPP 
Analysis Dataset 
Pharmacokinetic 
Parameters 
One record per subject 
per parameter per visit 
STUDYID, SUBJID, 
AVISITN, 
PARAMCD  
ADPR 
Analysis Dataset 
Procedures 
One record per recorded 
procedure per occurrence 
per subject 
STUDYID, SUBJID, 
PRTRT, PRSPID  
ADQS 
Analysis Dataset for 
Questionnaire 
One record per subject 
per category per 
parameter per visit 
STUDYID, SUBJID, 
PARCAT1, 
PARAMCD, 
AVISITN, VISITNUM 
ADTTE 
Analysis Dataset 
Time-to-Event 
One record per subject 
per parameter 
STUDYID, SUBJID, 
PARAMCD  
ADVS 
Analysis Dataset 
Vital Signs 
One record per subject 
per parameter per time 
point per visit 
STUDYID, SUBJID, 
PARAMCD, 
AVISITN, DTYPE, 
ADT, ATM, ATPTN 
 
 
 
 
 


 
 
APPENDIX IV  GENERAL SPECIFICATIONS FOR TABLES, LISTINGS, 
FIGURES 
1 Software Used 
All programming of tables, listings and figures (TLFs) will be performed using the 
statistical software package SAS version 9.3 or greater. 
2 General  
All TLFs are based on SDTM and/or ADaM datasets. By default, data listings reflect the 
actual values captured in SDTM and ADaM datasets, including date/time variables and 
missing values. Except for concatenation of some variables for compact display purpose, 
data are presented directly with minimum manipulation. In general, the character 
standard result variables, such as –STRESC, are presented in data listings. Date are 
presented in listings in format yyyy-mm-dd. For incomplete date, CDISC presentation 
convension is followed. 
For continuous variables that are recorded as “<X” or “>X”, the value of “X” will be used in 
the calculation of summary statistics. The value “X” is also captured in the numeric variable 
in the SDTM datasets as well as in the ADaM datasets for consistency, although SDTMIG 
recommends capturing missing values in the numeric variables.  
In general, reported verbatim, such as terms of AE, medical history, medication names, 
specifications to the ‘Other’ fields, findings, etc., are presented in upper case. However, when 
reported fields are long, such as comments and protocol deviation descriptions, listing in 
lower case enhances readability.  
3 Table/Listing/Figure Output File Type and Organization 
In general, the final set of TLFs will include both PDF and RTF files. Outputs are combined 
in several large PDF files, eg, all tables, all listings, and all figures, in the order as in the 
planned TLF in Section 12.  A table of content should be included with hyperlinking to 
individual outputs. True RTF files (in-text format) will be created for tables and listings. 
SAS outputs for statistical procedures used in analysis of primary, secondary, and 
exploratory efficacy endpoints will also be included. 
4 Page Layout 
All column headers (consisting of one or several words) will start with uppercase and 
thereafter only lowercase characters, except for acronyms and abbreviations. In case 
values from the database will be displayed in column headers, they may be displayed as 
in the database. Pages will be numbered as ‘Page x of y’, where ‘y’ is the total number of 
pages of the corresponding table or listing. The page specifications are presented in Table 
A.  
Table A. 
Specifications for Page Layout 


 
 
Paper Size 
Letter 
Orientation 
Landscape 
Alignment 
Center 
Font size 
9 
Font type 
Courier New (default) 
Margins 
 
   Top 
0.75” 
   Bottom 
0.38” 
   Left 
0.75” 
   Right 
0.38” 
The margin sizes and font size for listings may be flexible to provide sufficient 
information on a single page to facilitate review and comparison. 
When created using SAS, tables and listings will be created using ODS, and output files 
will be produced in RTF. When RTF files are produced, titles and footnotes will appear 
as document headers/footers. 
5 Titles and Footnotes 
All tables and listings will have a header showing “FibroGen, Inc.”, the protocol number, 
database  cutoff date or ‘Final Database’, and Page x of y. A footer will show the 
program file path/name, output file path/name, run date and time.  
All titles are written in title format, with uppercase at the beginning of each word; 
articles, prepositions, and conjunctions, which are of three characters length or less will 
start with lowercase letters (Mixed Case).  Footnotes are in regular text format. 
Titles 
In total there are up to 10 titles available, defined as following: 
first title 
“FibroGen, Inc.” (left aligned) and “Database extraction date: 
ddMMMyyy” or “Final Database” (right aligned) 
second title 
protocol number + “Clinical Study Report” (left aligned) and 
“Page x of y” (right aligned) 
third title 
blank 
fourth title: 
table/listing/figure number 
fifth title:         table/listing/figure title 


 
 
sixth title:  
population names if provided in SAP, or brief definition of specific 
analysis set 
Footnotes 
Up to 10 footnote lines are available for tables, listings and figures. Footnotes 1, 9 and 10 
are standard. Footnotes 2 to 8 (left aligned) might be used as needed. They are to be 
specified in the Shell.  
first footnote  
is a separating horizontal line. 
second – eighth 
are free text which can be used for explanations. Footnotes 
will be referenced using numbers in square brackets, 
starting with [1], followed by [2] etc.  
ninth footnote 
left blank; in case needed may also be used as for 
explanations. 
tenth footnote 
the program name (left aligned); the date and time in the 
format ddMMMyyyy hh:mm when the output was created;  
the version (e.g. draft or final); and the word 
“Confidential”.  
Footnotes are denoted by [1], [2], and so on.   
If footnotes take more than 30% of the space of a long listing, they may be presented only 
on a standalone first page. 
TLF numbers and titles should be inputted from an external file that can be directly copy-
and-pasted from the SAP planned TLFs, rather than including in the body of the program. 
This is to ensure consistency between the SAP and the actual outputs.  
Footnotes may be inputted from an external file as well for ease of managing changes.  
For summary tables, the corresponding listings with the parameters being summarized 
should be footnoted as reference. For figures, the corresponding summary table should be 
footnoted as reference. 
6 Table, Listing, Figure Metadata 
The table, listing, and figure (TLF) metadata will include the TLF numbers, titles, 
analysis populations, program names, input dataset names. For tables and figures, 
PARAMCD, PARAM, and other conditions will be specified. TLF numbers, titles, and 
footnotes will be imported from this master spreadsheet. In addition, this spreadsheet will 
record the names of the original programmer and the validator/reviewer and the date of 
validation approval. 
7 Significant Digits of Summary Statistics 
- 
All percentages will be rounded to one decimal place and aligned by the decimal 
place.  
- 
If the count is zero, the percentage will be suppressed and only ‘0’ will be 
presented. 


 
 
- 
Any p-values will be rounded to four decimal places and will be presented as 
‘<.0001’ if they are less than 0.0001 after rounding. 
- 
For variables of direct measurements, summary statistics are displayed with the 
following specifications of decimal places in Table B. 
Table B. 
Significant Digits of Summary Statistics 
Description 
Characteristic 
Number of decimal places 
Count 
N 
0 
Mean 
Mean 
As in source + 1 
Standard 
deviation 
Std 
As in source + 1 
Standard error of 
the mean 
SEM 
As in source + 2 
Confidence 
Interval 
CI 
As in source + 1 
Minimum 
Min  
As in source 
Median 
Median 
As in source  
Maximum 
Max 
As in source 
Q1  /  Q3 
Q1/Q3 
As in source  
10%  /  90% 
10%/90% 
As in source  
Percentage 
% 
All percentages will be rounded to one decimal place and lined up 
by the decimal place. The percentage will be suppressed when the 
count is zero 
Coefficient of 
variation 
CV (%) 
1 
p-value 
p-value 
p-values will be rounded to four decimal places and will be 
presented as ‘<.0001’ if they are less than 0.0001 after rounding 
N=number; 
Std=Standard 
deviation; 
CI=Confidence 
Interval; 
Min=minimum; 
Max=maximum; 
CV=Coefficient of variation 
As a general guideline for derived parameters, 3 significant digits may be displayed for a 
parameter with an overall mean less than 100; otherwise, 1 decimal place may be used. If 
a derived parameter is in the same scale as some related measured parameters, such as 
MAP, QTc, the same display format may be used as the measured parameters. 


 
 
Summary Statistics are to be displayed in the following order: Count, Mean, Standard 
Deviation, <Coefficient of Variation, Standard Error of the Mean, Confidence Interval>, 
Minimum, <10%>, <Q1>, Median, <Q3>, <90%>, Maximum. 
For categorical variables the categories will be displayed in the TLFs in the same order 
they appear in the CRF. 
8  Figure Specifications 
- 
In general, figures should include annotation of key summary statistics: n, mean, 
SD or SE, median for continuous variables; n and percent for categorical 
variables; number of subjects at risk and cumulative number of events as well as 
median and 95% CI for time-to-event data. Other statistics such as quartiles, 
ranges may be included depending on need and space.  
- 
P-values should be presented if comparisons are of interest. 
- 
For scatter plots, linear or non-linear trend lines should be included if the 
association of the two variables is of interest. Correlation coefficient or regression 
coefficients as well as corresponding p-values should be presented. 
- 
For box plots, ‘BOXSTYLE=SCHEMATIC’ should be used. The whiskers are 
drawn to the most extreme points in the group that lie within the fences. The 
upper fence is defined as the third quartile (represented by the upper edge of the 
box) plus 1.5 times the interquartile range. The lower fence is defined as the first 
quartile (represented by the lower edge of the box) minus 1.5 times the 
interquartile range. Observations outside the fences are identified with a special 
symbol. 
9  Unit Conversion 
Units Presented in 
TLFs 
Units Reported or 
Derived from CRF 
Conversion Formula 
Kilogram (kg) 
Pound (lb) 
kg = lb/2.2 
Centimeter (cm) 
Inch (in) 
cm = 2.54 * in 
Celsius C° 
Fahrenheit (F°) 
C° = (5/9) * (F° – 32) 
Year 
Day 
1 year = 365.25 days 
Months 
Day 
1 month = 30.4375 days