A Phase 3, Randomized, Double-Blind, Placebo Controlled Study of the Efficacy and Safety of Roxadustat (FG-4592) for the Treatment of Anemia in Chronic Kidney Disease Patients Not on Dialysis
Phase: PHASE3
Conditions: CKD Anemia
Sponsor: Kyntra Bio

1 TITLE 
CLINICAL STUDY PROTOCOL 
STUDY TITLE: 
A Phase 3, Randomized, Double-Blind, Placebo Controlled Study 
of the Efficacy and Safety of Roxadustat (FG-4592) for the 
Treatment of Anemia in Chronic Kidney Disease Patients not on 
Dialysis 
PROTOCOL NUMBER: 
FGCL-4592-060 
SPONSOR: 
FibroGen, Inc. 
409 Illinois Street 
San Francisco, California 94158 USA 
IND NUMBER: 
74,454 
STUDY DRUG: 
Roxadustat (FG-4592) 
INDICATION: 
Anemia associated with chronic kidney disease 
FIBROGEN MEDICAL 
MONITOR 
Name:  
 
Title:  
 
Telephone: 
Mobile/Pager: 
E-mail Address: 
ORIGINAL PROTOCOL 
DATE: 
08 September 2012 
PROTOCOL VERSION 
& DATE: 
Amendment 1: 14 January 2014 
Amendment 2: 10 October 2014 
Amendment 3: 20 September 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 # NCT01750190

Roxadustat 
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INVESTIGATOR SIGNATURE PAGE 
 
STUDY ACKNOWLEDGEMENT 
 
A Phase 3, Randomized, Double-Blind, Placebo Controlled Study of the Efficacy and Safety of 
Roxadustat (FG-4592) for the Treatment of Anemia in Chronic Kidney Disease Patients not on 
Dialysis 
FGCL-4592-060 
Amendment 3 
20 September 2017 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices and the current Investigator’s Brochure (IB), 
and I agree that it contains all necessary details for me and my staff to conduct this study as 
described. I will conduct this study as outlined herein and will make a reasonable effort to 
complete the study within the time designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by FibroGen, Inc. I will discuss this material with them to ensure that they 
are fully informed about the drugs and the study. 
I will conduct the trial in accordance with the guidelines of Good Clinical Practice (GCP) 
including the archiving of essential documents, the Declaration of Helsinki, any applicable local 
health authority, and Institutional Review Board (IRB) requirements. 
 
 
 
 
Investigator Name (Printed) 
 
Institution 
 
 
 
 
Signature 
 
Date 
 
Please retain the original for your study files. 

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SUMMARY OF MAJOR PROTOCOL AMENDMENT CHANGES 
Amendment 3 
In addition to the major changes listed below, minor editorial changes were made throughout the 
document to correct typographical errors, and to improve consistency and clarity.  
Description of Change 
Rationale for Change 
Section(s) Affected a 
The treatment Period for subjects 
enrolled has been clarified. It now 
reads as follows (added text is 
italicized):  
Treatment Period: Variable for 
individual subjects, with a minimum 
treatment duration of 52 weeks and a 
maximum treatment duration of time 
to enroll all subjects plus 52 weeks 
after the last subject is randomized 
• 
The last subject 
randomized will 
complete 52 weeks of 
treatment 
• 
All subjects randomized 
in the trial will continue 
treatment for 52 weeks 
after the final subject is 
randomized 
Amendment 3 Treatment duration is 
variable for individual subjects.  In 
order to complete the Treatment 
Period simultaneously for all study 
subjects, the minimum treatment 
duration may be less than 52 weeks, 
with a maximum treatment duration of  
up to  3 years after the last subject is 
randomized. 
 
This study is part of a phase 3 program 
whose completion is event driven.   This 
amendment will allow this study to 
continue so that it can contribute to the 
larger program’s objectives  
Synopsis, Sections 4.1, 
4.5.1 and 7.1.2 
 

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Description of Change 
Rationale for Change 
Section(s) Affected a 
Protocol Deviation:  
Text has been added to pre-specify 
issues that are not considered protocol 
deviations.  
Added text reads as follows: 
A protocol deviation is generally an 
unplanned excursion from the protocol 
that is not implemented or intended as 
a systematic change. The investigator 
is responsible for ensuring the study is 
conducted in accordance with the 
procedures and evaluations described 
in this protocol and must protect the 
rights, safety, and welfare of subjects. 
The investigator should not implement 
any deviation from, or changes to, the 
protocol, unless it is necessary to 
eliminate an immediate hazard to 
study subjects. 
Due to the complex study design and 
standard of clinical practice, the 
following issues should not be 
captured and reported as protocol 
deviations.  
Given the complexities of the dose 
adjustment algorithm, and the need to 
take into consideration various 
clinical parameters, it is not 
considered a protocol deviation when 
study subjects are dosed based on 
their clinical circumstance, whether or 
not this is concordant with the 
roxadustat dosing algorithm, unless it 
is related to “excessive 
hematopoiesis” (refer to Section 4.5.1) 
or “Overdose”  (prescribed >3.0 
mg/kg per dose). 
ESA administration in during 
hospitalization: Such ESA use is not 
considered a protocol deviation, if 
study subjects have no access to study 
drug while hospitalized. 
. 
 
 
This section was added to align the protocol 
with a new SOP for protocol templates.  
Specifically: 
 
Various factors, such as discrepancies 
between HemoCue Hb and Central lab Hb 
value, Investigator decision etc. can 
influence dose titration decisions at the time 
of the visit or after the visit. As a result, the 
dose prescribed may not exactly match the 
dose per the dose adjustment algorithm.  
However, as the stable dose would be 
achieved through titration, dosing 
discrepancy when subjects are dosed based 
on their clinical status is not considered a 
protocol deviation unless it is related to 
excessive hematopoiesis (≥13.0 g/dL, 
requires a dose-hold) or overdose (>3.0 
mg/kg/dose). 
 
Roxadustat subjects may  receive ESA 
while hospitalized, in part due to lack of 
access to roxadustat while in hospital, 
and/or as part of hospital standard-of-care 
of anemia treatment;  therefore, ESA 
administration in such circumstances is not 
considered a protocol deviation.  
 
 
Section 9.5.1 

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Description of Change 
Rationale for Change 
Section(s) Affected a 
Statistical Analysis Changes: 
1) Primary analysis model is 
changed from MMRM to MI 
ANCOVA 
2) One secondary endpoint is 
removed 
3) Minor wording changes to 
secondary endpoints analyses 
1) Based on FDA feedback  
2) One secondary endpoint is no 
longer relevant due to variable 
duration of treatment in the study 
3) Bring more clarity to the model 
specifications 
Synopsis, Sections 9.4.3.1, 
9.4.3.2, and 9.4.3.3 
]Abbreviations: 
AE = adverse event; BIW = twice a week; BP = blood pressure; CPK = creatine phosphokinase; CSE = 
cardiac safety events; CV = cardiovascular; CTCAE = Common Terminology Criteria for Adverse Events; 
DVT = deep vein thrombosis; ECG = electrocardiogram; EMA = European Medicines Agency; EOS = end of 
study; EPO = erythropoietin; ESA = erythropoiesis stimulating agent; ET = early termination; FDA = US 
Food and Drug Administration; Hb = hemoglobin; HMG-CoA = hydroxymethylglutaryl coenzyme A; 
IV = intravenous; MACE = major adverse cardiac event; N = total number of subjects; NCI = National 
Cancer Institute; PE = pulmonary embolism; QoL = quality of life; QW = once weekly; SAP = Statistical 
Analysis Plan; SmPC = Summary of Product Characteristics; TSAT = transferrin saturation; USPI = United 
States Package Insert; VAT = vascular access thromboses. 
a 
Primary sections listed only; other sections may have been updated accordingly. 

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TABLE OF CONTENTS 
1 
Title ......................................................................................................................................... 1 
2 
Background ........................................................................................................................... 27 
2.1 
Introduction Epidemiology of CKD and ESRD ........................................................... 27 
2.2 
Anemia Associated with Chronic Kidney Disease ....................................................... 27 
2.3 
Treatment of Anemia .................................................................................................... 28 
2.4 
Mechanism of Action of Roxadustat ............................................................................ 28 
2.5 
Clinical Experience with Roxadustat ............................................................................ 31 
2.5.1 Pharmacokinetics and Pharmacodynamics ............................................................... 31 
2.5.2 Efficacy ..................................................................................................................... 32 
2.5.3 Safety ........................................................................................................................ 32 
2.6 
Summary ....................................................................................................................... 33 
2.7 
Roxadustat Dose Rationale ........................................................................................... 33 
2.8 
Risks/Benefits of Roxadustat Treatment ...................................................................... 34 
3 
Objectives ............................................................................................................................. 35 
3.1 
Primary Objectives........................................................................................................ 35 
3.2 
Secondary Objectives.................................................................................................... 35 
4 
Study Design ......................................................................................................................... 36 
4.1 
Description of the Study ............................................................................................... 36 
4.2 
Randomization and Treatment Assignment .................................................................. 37 
4.3 
Replacement of Subjects ............................................................................................... 37 
4.4 
Blinding......................................................................................................................... 37 
4.4.1 Maintenance of Blinding........................................................................................... 37 
4.4.2 Planned and Unplanned Unblinding of Treatment Assignment ............................... 37 
4.5 
Study Treatment ............................................................................................................ 38 
4.5.1 Dose and Schedule Overview ................................................................................... 38 
4.5.2 Dose Adjustment ....................................................................................................... 39 
4.6 
Concomitant Medications, Procedures and Nondrug Therapies ................................... 40 
4.6.1 Concomitant Medications ......................................................................................... 40 
4.6.2 Rescue Therapy Guidelines ...................................................................................... 41 
4.6.3 Therapeutic Phlebotomy ........................................................................................... 42 
4.6.4 Prohibited Medications/Therapies/Substances ......................................................... 42 
4.6.5 Contraception ............................................................................................................ 43 

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4.7 
Safety Monitoring Plan ................................................................................................. 43 
4.8 
Data Safety and Monitoring Board ............................................................................... 43 
5 
Study Enrollment and Discontinuation ................................................................................. 45 
5.1 
Inclusion Criteria .......................................................................................................... 45 
5.2 
Exclusion Criteria ......................................................................................................... 45 
5.3 
Subject Discontinuation ................................................................................................ 47 
6 
Investigational Product ......................................................................................................... 48 
6.1 
Formulation ................................................................................................................... 48 
6.2 
Storage .......................................................................................................................... 48 
6.3 
Study Drug Handling and Disposal .............................................................................. 48 
6.4 
Administration .............................................................................................................. 48 
7 
Study Procedures .................................................................................................................. 50 
7.1 
Study Procedures by Visit ............................................................................................. 50 
7.1.1 Screening Period (Up to 6 Weeks) ............................................................................ 50 
7.1.2 Treatment Period ....................................................................................................... 51 
7.1.3 Post-Treatment Follow-Up Period ............................................................................ 56 
7.2 
Missed Visits ................................................................................................................. 56 
7.3 
Unscheduled Visits ....................................................................................................... 56 
7.4 
Laboratory Assessments ............................................................................................... 56 
7.4.1 HemoCue .................................................................................................................. 57 
7.4.2 Central Laboratory .................................................................................................... 57 
7.4.3 Archival Serum/Plasma Samples .............................................................................. 58 
7.5 
Electrocardiogram ......................................................................................................... 58 
7.6 
Renal Ultrasound .......................................................................................................... 59 
7.7 
Health-Related Quality of Life Questionnaires ............................................................ 59 
7.7.1 36-Item Short Form Health Survey........................................................................... 59 
7.7.2 FACT-An .................................................................................................................. 59 
7.7.3 European Quality of Life Questionnaire in Five Dimensions, Five Levels (EQ-5D-
5L) 
................................................................................................................................... 59 
7.8 
Blood Pressure Measurement ....................................................................................... 60 
8 
Endpoints and Assessments .................................................................................................. 61 
8.1 
Primary Efficacy Endpoint ........................................................................................... 61 
8.2 
Secondary Endpoints .................................................................................................... 61 
8.3 
Additional Evaluation of Efficacy ................................................................................ 62 

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8.4 
Safety Assessments and Endpoints ............................................................................... 63 
9 
Statistical Considerations ...................................................................................................... 65 
9.1 
Sample Size Determination........................................................................................... 65 
9.2 
Analysis Populations ..................................................................................................... 65 
9.3 
Interim Analysis ............................................................................................................ 66 
9.4 
Statistical Analysis ........................................................................................................ 66 
9.4.1 Subject Enrollment, Accountability and Disposition................................................ 66 
9.4.2 Demographics and Baseline Characteristics ............................................................. 66 
9.4.3 Efficacy Analyses ..................................................................................................... 66 
9.4.4 Safety Analyses ......................................................................................................... 69 
9.5 
Statistical Analysis Plan ................................................................................................ 70 
9.5.1 Protocol Deviation .................................................................................................... 70 
10 Safety .................................................................................................................................... 72 
10.1 
Background ................................................................................................................... 72 
10.2 
Definitions..................................................................................................................... 72 
10.2.1 
Definition of an Adverse Event ............................................................................ 72 
10.2.2 
Definition of a Serious Adverse Event ................................................................. 72 
10.2.3 
Definition of a Suspected Adverse Reaction ........................................................ 73 
10.2.4 
Definition of an Adverse Reaction ....................................................................... 73 
10.3 
Procedures for Eliciting, Recording, and Reporting Adverse Events ........................... 73 
10.3.1 
Adverse Event Reporting Period .......................................................................... 73 
10.3.2 
Adverse Event Eliciting/Reporting ....................................................................... 73 
10.3.3 
Assessing Adverse Event Severity........................................................................ 74 
10.3.4 
Assessing the Adverse Event’s Relationship to Study Drug ................................ 74 
10.3.5 
Reporting Serious Adverse Events on the SAE Report Form .............................. 75 
10.3.6 
Pregnancies: Reporting and Follow-up of Subjects .............................................. 76 
10.3.7 
Definition and Reporting of Overdose .................................................................. 77 
10.3.8 
Abnormal Laboratory Findings............................................................................. 77 
11 Direct Access to Source Documents ..................................................................................... 78 
12 Quality Control and Quality Assurance ................................................................................ 79 
12.1 
Data Quality Assurance ................................................................................................ 79 
12.2 
Audit and Inspection ..................................................................................................... 79 
13 Ethics..................................................................................................................................... 80 

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13.1 
Ethical Considerations .................................................................................................. 80 
13.2 
Communication with the Institutional Review Board or Independent Ethics Committee  
 
....................................................................................................................................... 80 
13.3 
Informed Consent Form ................................................................................................ 80 
13.4 
Subject Confidentiality ................................................................................................. 80 
14 Data Handling and Record Keeping ..................................................................................... 82 
14.1 
Source Documents ........................................................................................................ 82 
14.2 
Data Collection, Handling, and Verification ................................................................ 82 
15 Investigator Requirements .................................................................................................... 83 
15.1 
Study Drug Accountability ........................................................................................... 83 
15.2 
Disclosure of Data......................................................................................................... 83 
15.3 
Retention of Records..................................................................................................... 83 
16 Financing and Insurance ....................................................................................................... 84 
17 Publication Policy ................................................................................................................. 85 
18 References ............................................................................................................................. 86 
19 Appendices ............................................................................................................................ 89 
LIST OF TABLES 
Table 1. 
Treatment Arms ........................................................................................................ 36 
Table 2. 
Initial Study Drug (FG-4592 or Placebo) Dosing ..................................................... 37 
Table 3. 
Initial Study Drug (FG-4592 or Placebo) Dosing ..................................................... 38 
Table 4. 
Recommended Maximum Daily Dose of Statins for Subjects in FGCL-4592-060 . 40 
Table 5. 
Laboratory Tests ....................................................................................................... 58 
LIST OF FIGURES 
Figure 1. 
HIF-PHI Mechanism of Action ................................................................................ 29 
LIST OF APPENDICES 
Appendix 1 
Dose Adjustment Algorithm ................................................................................. 90 
Appendix 2 
Schedule of Assessments ...................................................................................... 91 
Appendix 3 
Study Schema........................................................................................................ 92 
Appendix 4 
Liver Safety Monitoring and Assessment Guidelines .......................................... 93 
Appendix 5 
Sponsor Signature(s) ............................................................................................. 94 

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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
BIW 
twice weekly 
BP 
blood pressure 
CBC 
complete blood count 
CFB 
change from baseline 
CFR 
Code of Federal Regulations 
CHOIR 
Correction of Hemoglobin and Outcomes in Renal Insufficiency study 
CHr 
reticulocyte hemoglobin content 
CKD 
chronic kidney disease 
CMH 
Cochran-Mantel-Haenszel 
CRF 
case report form 
CRP 
C-reactive protein 
CS 
clinically significant 
DSMB 
Data and Safety Monitoring Board 
DVT 
deep vein thrombosis 
EC 
Ethics committee 
ECG 
electrocardiogram 
eGFR 
estimated glomerular filtration rate 
ELISA 
enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
EOS 
End of Study 
EPO 
erythropoietin 
EQ-5D-5L 
European Quality Of Life questionnaire in Five dimensions, Five levels  
ESA 
erythropoiesis-stimulating agent 
ESRD 
end-stage renal disease 
EOT 
End of Treatment 
ET 
Early Termination (visit) 
FACT-An 
Functional Assessment of Cancer Therapy – Anemia 
FAS 
Full Analysis Set 

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Abbreviation 
Definition 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
Hb 
hemoglobin 
HbA1C 
hemoglobin A1c 
HbsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HDPE 
high-density polyethylene 
HDL 
high-density lipoprotein 
HIF 
hypoxia-inducible factor 
HIF-PH 
hypoxia-inducible factor prolyl hydroxylase 
HIF-PHI 
hypoxia-inducible factor prolyl hydroxylase inhibitor  
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRQoL 
Health-Related Quality of Life 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug  
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IV 
intravenous 
IWRS 
Interactive or Web Response System) 
KDOQI 
Kidney Disease Outcomes Quality Initiative 
LDL 
low-density lipoprotein 
LFT 
liver function test 
LLN 
lower limit of normal 
LOCF 
last observation carried forward 
MAP 
mean arterial pressure 

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Abbreviation 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDRD 
Modification of diet in renal disease equation 
MI 
myocardial infarction 
MI ANCOVA 
multiple imputation analysis of covariance 
MMRM 
mixed model of repeated measures 
N (or n) 
sample size 
NCS 
not clinically significant 
NKF 
National Kidney Foundation 
PCS 
potentially clinically significant 
PE 
pulmonary embolism 
PEY 
patient-exposure-year 
PF 
physical Functioning subscale component of SF-36 
PH  
Prolyl hydroxylase 
PPS 
Per Protocol Set 
PR 
In an ECG, the interval between the P wave and the beginning of the QRS wave 
complex) 
PK 
pharmacokinetics 
QoL 
Quality of Life 
QRS 
Q wave, R wave, and S wave complex in an ECG 
QT 
In an ECG, the interval between the start of the Q wave and the end of the T wave 
QTc 
QT interval corrected for heart rate 
QW 
once weekly 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SF-36 
The 36-Item Short Form Health Survey 
SOC 
system organ class 
Subcut 
subcutaneous 
sTfR 
soluble transferrin receptor 
Tbili 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TIBC 
total iron binding capacity 

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Abbreviation 
Definition 
TIW 
three times weekly 
TSAT 
transferrin saturation 
ULN 
upper limit of normal 
USRDS 
United States Renal Data System 
VAT 
vascular access thrombosis 
VEGF 
vascular endothelial growth factor 
VHL 
Von Hippel-Lindau 
WBC 
white blood cell 
WHO Drug 
World Health Organization Drug  

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PROTOCOL SYNOPSIS 
Study Title: 
A Phase 3, Randomized, Double-Blind, Placebo Controlled Study 
of the Efficacy and Safety of Roxadustat (FG-4592) for the 
Treatment of Anemia in Chronic Kidney Disease Patients not on 
Dialysis 
Protocol Number: 
FGCL-4592-060 
Investigational 
Product: 
FG-4592 
Target Population: Anemic Stage 3, 4, or 5 chronic kidney disease (CKD) subjects 
IND Number: 
74,454 
Study Phase: 
Phase 3 
Study Centers 
Planned: 
Up to approximately 200 study centers worldwide  
Number of 
Subjects Planned: 
Up to 1200 planned subjects will be randomized in a 2:1 ratio to 
receive either roxadustat (approximately 800 subjects) or placebo 
(approximately 400 subjects) in a double-blind manner. 
Primary 
objectives: 
• Evaluate the efficacy of roxadustat for the treatment of anemia 
(correction and maintenance of hemoglobin [Hb]) in CKD 
subjects not on dialysis. 
• Evaluate the safety of roxadustat administered over a minimum 
of 52 weeks of treatment. 
Secondary 
objectives: 
• Evaluate the effect of roxadustat on serum lipid parameters  
• Evaluate the effect of roxadustat on health-related quality of life 
(HRQoL)  
• Evaluate the effect of roxadustat on blood pressure (BP) 
• Evaluate the need for anemia rescue therapy: red blood cell 
(RBC) transfusion, erythropoiesis-stimulating agent (ESA), or 
intravenous (IV) iron  
• Evaluate time to achieve Hb response 
Study Design: 
This is a Phase 3, multicenter, randomized, double-blind, placebo-
controlled study in anemic subjects with Stage 3, 4, or 5 CKD who 
are not on dialysis. 
This study will consist of three study periods: 
• Screening Period: Up to 6 weeks 

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• Treatment Period: Treatment duration is variable for 
individual subjects.  In order to complete the Treatment Period 
simultaneously for all study subjects, the minimum treatment 
duration may be less than 52 weeks, with a maximum treatment 
duration of up to3 years after the last subject is randomized. 
• Post-Treatment Follow-Up Period*: 4 weeks 
(*or enroll into an Open Label Extension study) 
Following the Screening Period, subjects will be randomized in a 
2:1 ratio to receive either roxadustat or placebo. 
Stratification factors include screening Hb values, 
cardiac/cerebrovascular/thromboembolic medical history, estimated 
glomerular filtration rate (eGFR), and geographic region. 
The Investigator, study site staff, subject, and the Sponsor, are 
blinded to study drug assignment, but not to dose level. 
Additionally, all efforts should be made to keep subjects blinded to 
study Hb values.  
Dosing will be three times weekly (TIW) throughout the study, 
except in subjects who have already converted to twice a week 
(BIW) or once a week (QW) dosing regimens under previous 
FGCL-4592-060 protocol versions. Starting doses of study drug 
will be dose-adjusted according to anemia correction guidelines 
until subjects achieve a Hb value of ≥ 11 g/dL and ≥ 1 g/dL 
increase from baseline, by central lab. Once these criteria are met 
subjects will enter the maintenance phase of anemia treatment and 
will be dose-adjusted according to maintenance guidelines 
(Section 2.1 and Appendix 1).  
Scheduled Visits During Treatment 
During the Treatment Period, subjects will attend consecutive 
weekly study visits for the first 2 weeks of study treatment (from 
Weeks 0 to 2) followed by every other week study visits starting at 
Week 4 through Week 24. After Week 24, subjects will attend 
study visits every 4 weeks until the End of Treatment (EOT) Period 
(Week 28 to EOT). Treatment duration is variable for individual 
subjects.  In order to complete the Treatment Period simultaneously 
for all study subjects, the minimum treatment duration may be less 
than 52 weeks, with a maximum treatment duration of up to 3 years 
after the last subject is randomized.  
After the Treatment Period, study subjects may enter a separate 
Open Label Extension Study or will proceed to the 4-week 
post-treatment Follow-up Period and will attend a final study visit 
at 4 weeks after EOT. 
Subjects who prematurely discontinue study treatment will 
complete the Early Termination (ET) and End of Study (EOS) 

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visits. Such a subject will be considered a non-completer of 
treatment and/or the study. However, these subjects will continue to 
be followed-up for vital status, safety events requiring potential 
adjudication, as well as important concomitant medication use (eg, 
ESA), at periodic intervals of 3 to 6 months until the end of the 
overall study unless the subject withdraws consent for this modified 
follow-up. 
Starting Dose of Study Drug: 
The initial study drug dose (per dose amount) is based on a tiered, 
weight-based dosing scheme shown in Table S1. 
Table S1. 
Initial Study Drug (Roxadustat or Placebo) 
Dosing (TIW) 
Tiered Weight 
Category 
(<70 kg) 
(≥70 kg) 
Initial Tiered 
Weight Dose (TIW) 
70 mg 
100 mg 
Abbreviations: 
TIW = three times weekly. 
Study drug dose will remain constant during the first 4 weeks of the 
Treatment Period, unless a dose reduction is required for excessive 
hematopoiesis.  Dose adjustments are permitted starting at Week 4, 
and at intervals of every 4 weeks thereafter.  In contrast, dose 
frequency conversions may occur at any dosing week (even before 
Week 4), if the criteria for dose frequency conversion are met as 
described in Section 4.5.2. 
Correction Phase of Dosing 
The aim of the Correction Phase is to increase Hb from baseline to 
a level that avoids the need for blood transfusion, using the dosing 
algorithm presented in Appendix 1, and taking into account 
physiologic fluctuations and test variability. This phase is variable 
in length for each subject, depending on when the subject achieves 
a Hb level ≥ 11.0 g/dL and ≥ 1.0 g/dL increase from baseline by 
central lab. 
Maintenance Phase of Dosing 
The aim of the Maintenance Phase is to maintain Hb levels after the 
initial correction, utilizing the dosing algorithm described in 
Appendix 1, and taking into account physiologic fluctuations and 
test variability. 
Supplemental Iron Use 
Oral iron is recommended for dietary supplementation to support 
erythropoiesis and as the first-line for prevention and treatment of 
iron deficiency, unless the patient is intolerant to this route of 

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treatment. The recommended daily oral dose for the treatment of 
iron deficiency is 200 mg of elemental iron. IV iron is restricted as 
rescue therapy, using the Rescue Therapy Guidelines below. 
Rescue Therapy Guidelines 
Rescue therapy guidelines are provided to standardize the use of 
rescue therapy and to ensure safety of study subjects. 
• Red Blood Cell Transfusion 
Red blood cell (RBC) transfusion is allowed if rapid correction of 
anemia is required to stabilize the patient’s condition (eg, acute 
hemorrhage) or the Investigator is of the opinion that the blood 
transfusion is a medical necessity. Study drug treatment may 
continue during or after RBC transfusion administration. 
• Erythropoiesis-Stimulating Agent (ESA)  
Use of more than two courses of an ESA for anemia rescue is a 
withdrawal criterion requiring early termination from study 
treatment. Nevertheless, criteria for use of ESA are provided in 
order to standardize the use of ESA rescue. The Investigator should 
consider initiating the use of an approved ESA only if all of the 
following criteria are met: 
• The subject’s Hb level has not sufficiently responded to two or 
more dose increases or maximum doses (by body weight) of 
study drug; and 
• The subject’s Hb is < 8.0 g/dL; and 
• Reducing the risk of alloimmunization in transplant eligible 
subjects and/or reduction of other RBC transfusion-related risks 
is a goal 
The subject is not allowed to be administered both ESA and study 
drug at the same time. ESA treatment must be stopped after 4 
weeks of use or when Hb ≥ 9 g/dL is reached, whichever occurs 
first. Study drug treatment may be resumed after the following 
intervals: 
• Two days after stopping epoetin  
• One week after stopping darbepoetin alfa  
• Two weeks after stopping methoxy polyethylene glycol-epoetin 
beta (Mircera®) 
After two successful courses of rescue with ESA and return to 
study drug, subjects who again meet the above criteria for ESA 
rescue and receive a third course of ESA must be discontinued 
from the study drug at this point. Such a subject will complete 
procedures for early termination and subsequent modified follow-

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up according to the procedures outlined in Section 7.1.2.6, if 
consent is not withdrawn to do so. 
• Intravenous Iron  
The use of intravenous iron is discouraged in the setting of this 
placebo-controlled trial. In roxadustat phase 2 studies where IV 
iron was restricted, iron repletion was not required for treatment of 
anemia. IV iron is not standard of care in CKD nondialysis patients 
in most regions of the world. Therefore, the subject may receive IV 
iron supplementation only if each of the following criteria are met: 
• The subject’s Hb has not responded adequately to two or more 
dose increases or the maximum dose (by body weight) of study 
drug; and  
• The subject is unresponsive to or does not tolerate oral iron; 
and 
• Ferritin levels are < 100 ng/mL (< 220 pmol/L) OR TSAT is 
< 20% 
If IV iron rescue criteria are met, the dose in a single administration 
(day) should me no more than 250 mg. The selection and dosing of 
the IV iron formulation should be consistent with regional package 
inserts that are applicable to CKD-ND patients. Study drug 
treatment may continue during IV iron administration.  
At 4-8 weeks after the single dose of IV iron, a repeat dose of IV 
iron can be administered if the Hb remains < 9 g/dL AND the 
subject still meets iron deficiency criteria (ferritin < 100 
ng/mL(< 220 pmol/L) or TSAT < 20%). After this 8-week period, 
full IV iron rescue criteria would need to be met again in order to 
qualify a subject for a second course of IV iron at a later point in 
the trial. 
Therapeutic Phlebotomy 
If there are clinical concerns due to excessive elevation in Hb 
levels, the Investigator may decide to perform a therapeutic 
phlebotomy instead of, or in addition to, a dose hold; this should be 
documented and discussed with the study Medical Monitor. 
Inclusion Criteria 
1. Age ≥ 18 years 
2. Subject has been informed of the investigational nature of this 
study and has given written informed consent in accordance 
with institutional, local, and national guidelines 
3. Diagnosis of CKD, with Kidney Disease Outcomes Quality 
Initiative (KDOQI) Stage 3, 4, or 5, not receiving dialysis; with 

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an estimated glomerular filtration rate (eGFR) < 60 
mL/min/1.73 m2 estimated using the abbreviated 4-variable 
Modification of Diet in Renal Disease (MDRD) equation 
4. Mean of the three most recent Hb values during the Screening 
Period, obtained at least 4 days apart, must be ≤ 10.0 g/dL, 
with a difference of ≤ 1.0 g/dL between the highest and the 
lowest values. The last screening Hb value must be within 
10 days prior to randomization 
5. Ferritin ≥ 30 ng/mL ( ≥ 66 pmol/L) 
6. TSAT > 5% 
7. Serum folate level ≥ lower limit of normal (LLN) 
8. Serum vitamin B12 level ≥ LLN 
9. Alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) ≤ 3 x upper limit of normal (ULN), 
and total bilirubin (Tbili) ≤ 1.5 x ULN 
10. Body weight 45 to 160 kg 
Exclusion 
Criteria: 
1. Any ESA treatment within 12 weeks prior to randomization 
2. More than one dose of IV iron within 12 weeks prior to 
randomization 
3. RBC transfusion within 8 weeks prior to randomization 
4. Active, clinically significant infection that could be manifested 
by white blood cell (WBC) count > ULN, and/or fever, in 
conjunction with clinical signs or symptoms of infection 
5. History of chronic liver disease (eg, chronic infectious 
hepatitis, chronic auto-immune liver disease, cirrhosis, or 
fibrosis of the liver) 
6. New York Heart Association Class III or IV congestive heart 
failure 
7. Myocardial infarction, acute coronary syndrome, stroke, 
seizure, or a thromboembolic event (eg, deep vein thrombosis 
or pulmonary embolism) within 12 weeks prior to 
randomization 
8. Systolic BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg 
(confirmed by repeat measurement) within 2 weeks prior to 
randomization 
9. Diagnosis or suspicion (eg, complex kidney cyst of Bosniak 
Category 2F or higher) of renal cell carcinoma on renal 
ultrasound within 12 weeks prior to randomization 
10. History of malignancy, exceptions made for the following 
malignancies: a) those determined to be cured or in remission 

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for ≥ 5 years, b) curatively resected basal cell or squamous cell 
skin cancers, c) cervical cancer in situ, or resected colonic 
polyps 
11. Positive for any of the following: human immunodeficiency 
virus (HIV); hepatitis B surface antigen (HBsAg); or 
antihepatitis C virus antibody (anti-HCV Ab) 
12. Chronic inflammatory disease that could impact erythropoiesis 
or is determined to be the principal cause of anemia (eg, 
systemic lupus erythematosus, rheumatoid arthritis, celiac 
disease) even if it is currently in remission 
13. Known untreated proliferative diabetic retinopathy, diabetic 
macular edema, macular degeneration and retinal vein 
occlusion 
14. Known history of myelodysplastic syndrome or multiple 
myeloma  
15. Known hereditary hematologic disease such as clinically 
apparent thalassemia or sickle cell anemia, pure red cell 
aplasia, or other known causes for anemia other than CKD 
16. Known hemosiderosis, hemochromatosis, coagulation 
disorder, or hypercoagulable condition 
17. Any prior organ transplant (that has not been explanted), or a 
scheduled organ transplantation 
18. Anticipated elective surgery that is expected to lead to 
significant blood loss, or anticipated elective coronary 
revascularization 
19. Known active or chronic gastrointestinal bleeding 
20. Any prior treatment with roxadustat or a hypoxia-inducible 
factor prolyl hydroxylase inhibitor (HIF-PHI) 
21. Use of iron-chelating agents within 4 weeks prior to 
randomization 
22. Use of an investigational drug or treatment, participation in an 
investigational study, or presence of expected carryover effect 
of an investigational treatment, within 4 weeks prior to 
randomization  
23. Anticipated use of dapsone or androgens in any dose amount 
or anticipated chronic use of acetaminophen or paracetamol 
> 2.0 g/day during the treatment or follow-up periods of the 
study 
24. History of alcohol or drug abuse within 2 years prior to 
randomization 

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25. Females of childbearing potential, unless using contraception 
as detailed in the protocol, or sexual abstinence; male subjects 
with sexual partners of childbearing potential who are not on 
birth control unless the male subject agrees to use 
contraception or sexual abstinence 
26. Pregnant or breastfeeding females 
27. Any medical condition that in the opinion of the Investigator 
may pose a safety risk to a subject in this study, which may 
confound efficacy or safety assessment, or may interfere with 
study participation 
Study Procedures 
See Schedule of Assessments (Appendix 2) 
Investigational 
Product, Dose, and 
Mode of 
Administration 
20, 50, and 100 mg roxadustat tablets for oral administration  
Initial Doses 
Subjects will receive tiered, weight-based initial doses (Table S1).  
Dose Adjustment 
Refer to Section 2.1 and Appendix 1. 
Reference 
Therapy (Placebo), 
Dose, and Mode of 
Administration 
20, 50, and 100 mg matching placebo tablets for oral administration 
(control group) 
Initial Doses 
Subjects will receive tiered, weight-based initial doses (Table S1). 
Dose Adjustment  
Refer to Section 2.1 and Appendix 1. 
Efficacy Endpoints 
and Assessments 
Primary 
The primary efficacy endpoint in this study will depend on whether 
the data are being filed to support submission to the US (FDA) or 
to Ex-US Health Authorities. 
• For US (FDA) submission: The change in Hb from baseline 
to the average level during the evaluation period ,defined as 
Week 28 until Week 52  
• For Ex-US submission: The proportion of subjects who 
achieve a Hb response at two consecutive visits during the 
first 24 weeks of treatment, without rescue therapy 
A Hb response is defined, using central laboratory values, as 
the following:  
• Hb ≥ 11 g/dL and Hb increase from baseline by ≥ 1 g/dL 
in subjects with baseline Hb > 8 g/dL, or  
• Increase in Hb by ≥ 2 g/dL in subjects with baseline Hb 
≤ 8.0 g/dL  

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Rescue therapy is defined as RBC transfusion, ESA, or 
IV iron use 
Secondary 
The secondary efficacy endpoints in this study are: 
• For Ex-US submission only: Hb maintenance: Mean change 
from baseline (CFB) in Hb averaged over 8 weeks of treatment 
at Weeks 28 to 36, without rescue therapy within 6 weeks prior 
to and during this 8-week evaluation period 
• Mean CFB in low-density lipoprotein (LDL) cholesterol 
averaged over Weeks 12 to 28 
• Mean CFB in the 36-Item Short Form Health Survey (SF-36) 
Physical Functioning (PF) subscore averaged over Weeks 12 to 
28 in the Intent to Treat (ITT) subjects with baseline PF 
subscore below 35 
• Mean CFB in SF-36 Vitality subscore averaged over Weeks 12 
to 28 in ITT subjects with baseline vitality subscore below 50  
• Blood pressure effect 
a. Mean CFB in mean arterial pressure (MAP) averaged over 
Weeks 20 to 28, measured as the mean of the triplicate 
measurements 5 minutes apart  
b. Time to (and proportion of subjects with) worsened 
hypertension (defined as systolic BP > 170 mmHg or 
diastolic BP > 110 mmHg measured, and an increase from 
baseline of ≥ 20 mmHg [systolic BP] or ≥ 15 mmHg 
[diastolic BP] confirmed by the mean of triplicate 
measurements 5 minutes apart) 
• Time to (and proportion of subjects who received) rescue 
therapy (composite of RBC transfusion, ESA use, and IV iron) 
in the first 24 weeks of treatment 
• Time to (and proportion of subjects who received) rescue 
therapy (composite of RBC transfusion, ESA use, and IV iron) 
in the first 52 weeks of treatment 
Safety 
Assessments: 
Study-specific safety will be assessed by evaluating the following: 
• Adverse events (AEs), serious adverse events (SAEs), and 
clinically significant changes in laboratory values from baseline  
• Vital signs, electrocardiogram (ECG) parameters, and clinical 
laboratory values 
Pooled safety interpretation will also be determined based on 
analyses of composite endpoints derived from adjudicated events 
pooled across multiple studies in the roxadustat Phase 3 program. 
The members of an independent adjudication committee blinded to 

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treatment assignment will adjudicate the following events in 
multiple phase 3 studies: 
All cause death, myocardial infarction (MI), stroke, congestive 
heart failure requiring hospitalization, unstable angina requiring 
hospitalization, hypertensive emergency, deep venous thrombosis, 
pulmonary embolism, and vascular access thrombosis.  
Various region-specific pooled analyses of composites of these 
adjudicated events, pooled across multiple studies, will be 
conducted. The analyses of the adjudicated events will be detailed 
in the region-specific pooled Statistical Analysis Plan (SAP). 
• For US (FDA) Only: The primary safety endpoint in this study 
is the MACE (Major Adverse Cardiac Event) composite 
endpoint, defined as time to first occurrence of death from all 
causes, MI, or stroke, only for the purpose of being pooled 
across multiple similar studies in the Phase 3 program. None of 
the individual studies are powered to meet the MACE primary 
safety endpoint individually. The pooled MACE analysis is only 
for purposes of supporting a US FDA regulatory filing of 
roxadustat. 
• The above adjudicated safety events may also be used to 
support the pooled analyses of additional composite safety 
endpoints across multiple studies in the Phase 3 program, such 
as MACE+ (death, MI, stroke, congestive heart failure 
requiring hospitalization, and unstable angina requiring 
hospitalization), or a composite which consists of all of the 
adjudicated events. 
Statistical 
Methods: 
Sample Size Determination 
The study is sufficiently powered for both primary efficacy 
endpoints. A minimum of 450 subjects are planned to be 
randomized to receive roxadustat or placebo (2:1 with 
approximately 300 subjects randomized to receive roxadustat 
versus 150 subjects randomized to receive placebo) in a double-
blind manner in order to support the primary endpoint(s) of the 
study. 
For US (FDA) Submission Primary Efficacy Endpoint 
A sample size of 450 will have > 99% power to detect a 1 g/dL 
difference in mean Hb values between the two treatment groups, 
assuming that the common standard deviation is 1.2 g/dL, using an 
analysis of variance (ANOVA) test with a 0.05 two-sided 
significance level. 
For comparisons of individual treatment arms versus pooled 
placebo, a sample size of 35 roxadustat and 150 placebo will have 
90% power to detect a 0.75 g/dL difference in mean Hb values 

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between the two treatment groups, assuming that the common 
standard deviation is 1.2 g/dL, using an ANOVA test with a 0.05 
two-sided significance level. 
For Ex-US Submission Primary Efficacy Endpoint 
Based on a two-sided test at the alpha = 0.05 level of significance, 
the study will have > 95% power to demonstrate a statistically 
significant difference between roxadustat and placebo, assuming 
that the proportion of subjects with a Hb response in the roxadustat 
group is at least 65% and the proportion of subjects with a Hb 
response in the placebo group is at most 25%. 
During the course of this Phase 3 study, which is being conducted 
in parallel with other Phase 3 studies, up to 1200 subjects may be 
enrolled in this study to support the overall safety evaluation of 
roxadustat across pooled comparable studies in the Phase 3 
program, using adjudicated composite safety endpoints of interest. 
The study will stop enrollment at the Sponsor’s discretion, if: 
1) the minimum of 450 subjects has been achieved to support 
the primary efficacy endpoint in this study, and  
2) sufficient adjudicated safety events have been accumulated 
across the nondialysis Phase 3 program to support a pooled 
analysis of composite safety events across multiple studies 
in the same population.  
Statistical Analysis 
Intent-to-Treat (ITT): All randomized subjects. 
Safety Population: All subjects who receive any dose of study drug. 
Per Protocol Set (PPS): All randomized subjects who receive at 
least 12 weeks of study treatment, have valid corresponding Hb 
measurements, and are without major protocol violations. Full 
criteria to be defined in the SAP. 
All primary and secondary efficacy analyses will be based on the 
ITT population. The PPS population will be utilized for supportive 
analysis of primary and secondary endpoints. 
Laboratory values from the central laboratory will be used for all 
analyses. The baseline Hb value for efficacy analyses is defined as 
the mean of four central laboratory Hb values: the last three 
screening Hb values prior to randomization plus the predose Hb 
value on Day 1 of the Treatment Period. Hemoglobin values after a 
rescue therapy will not be excluded for the FDA primary efficacy 
analysis. Hemoglobin values within 6 weeks after a rescue therapy 
will be excluded for the Ex-US primary efficacy endpoint as well 
as other sensitivity efficacy analyses. The Mixed Model with 

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Repeated Measures (MMRM) model will be used for missing data 
imputation in the primary analyses. 
The primary efficacy endpoint for the US (FDA) submission will 
be analyzed using the MI ANCOVA model comparing Hb CFB to 
the average of Weeks 28 to 52, stratified by the baseline value and 
randomization stratification factors, in a fixed sequence procedure: 
1) pooled roxadustat (TIW+BIW+QW) vs. pooled placebo, 2) 
roxadustat TIW vs. pooled placebo, 3) roxadustat BIW vs. pooled 
placebo, 4) roxadustat QW vs. pooled placebo. The latter are being 
performed to test the BIW and QW maintenance dosing frequencies 
that are enrolled from earlier versions of the protocol. If a null 
hypothesis is rejected, the claim of the tested roxadustat regimen 
over placebo will be declared successful and the test will progress 
to the next comparison in sequence. The model will contain terms 
for treatment arm, baseline measurement, visit, visit x treatment 
arm, and other stratification factors. The primary efficacy analysis 
will be based on the estimated difference in the overall mean effect 
between the two treatment groups throughout the evaluation period 
based on the MI ANCOVA model.  
The hypothesis to be tested for the primary efficacy analysis is: 
H0: Hb CFB to the average of Weeks 28 to 52  in the 
roxadustat group = Hb CFB to the average of Weeks 28 to 
52 in the placebo group 
Versus 
H1: Hb CFB to the average of Weeks 28 to 52 in the roxadustat 
group ≠ Hb CFB to the average of Weeks 28 to 52 in the 
placebo group  
H0 will be tested at the two-sided alpha=0.05 level of significance 
and will be rejected if the p < 0.05 from the test. 
The primary efficacy endpoint for the Ex-US submission will be 
analyzed using the Cochran-Mantel-Haenszel (CMH) test 
comparing pooled roxadustat (TIW+BIW+QW) to pooled Placebo 
(TIW+BIW+QW) stratified by the randomization stratification 
factors. 
The hypothesis to be tested for the primary efficacy analysis is: 
H0: Hb responder rate in the roxadustat group = Hb 
responder rate in the placebo group 
Versus 
H1: Hb responder rate in the roxadustat group ≠ Hb 
responder rate in the placebo group 
H0 will be tested at the two-sided alpha = 0.05 level of significance 
and will be rejected if the p < 0.05 from the test. 

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Secondary endpoints will be tested using a fixed sequence 
procedure to adjust for multiple endpoints compared between the 
pooled roxadustat group vs. pooled placebo, followed by roxadustat 
TIW vs. pooled placebo. If a null hypothesis is rejected, the claim 
of roxadustat over placebo will be declared successful and the test 
will progress to the next comparison in sequence. 
The secondary endpoints of Hb maintenance will be analyzed using 
the MMRM model with baseline Hb as covariate and other 
randomization stratification factors as fixed effects. Missing values 
will be handled with the MMRM model. The test for these 
endpoints will compare the pooled roxadustat group 
(TIW+BIW+QW) to pooled placebo, followed by roxadustat TIW 
to pooled placebo in a fixed sequence procedure. Separately, 
pairwise comparisons of roxadustat (2A, 1A) to pooled placebo 
(1P+2P+3P) will also be performed as exploratory analyses of the 
BIW and QW maintenance dosing frequencies (from the original 
and amendment 1 versions of the protocol).  
The secondary analyses of mean CFB in LDL cholesterol, SF-36 
PF subscore, SF-36 Vitality, and MAP will use MMRM models 
using baseline value as covariate and randomization stratification 
factors as fixed effects. 
Time to (and proportion of subjects with) protocol-defined 
worsened hypertension for the roxadustat group versus pooled 
placebo will be analyzed using the Cox Proportional Hazards 
model stratified by the randomization stratification factors. A 
hazard ratio and its associated 95% confidence interval (CI) will be 
computed to compare between the roxadustat TIW treatment group 
and pooled placebo. Noninferiority will be declared if the upper 
bound of the 2-sided 95% CI of the hazard ratio does not exceed 
1.3, superiority will be declared if the upper bound of the 2-sided 
95% CI of the hazard ratio does not exceed 1. 
Time to (and proportion of subjects with) rescue therapy over the 
first 24 and 52 weeks of treatment will be analyzed using the same 
method as outlined above. 
All subjects who have received any dose of study treatment will be 
included in the safety analyses. Safety parameters including AEs, 
laboratory parameters, vital signs, and ECG parameters will be 
tabulated using descriptive statistics. The analytical methods for the 
composite safety endpoints of interest will be described in a region-
specific pooled SAP to reflect the nature of the pooling of these 
endpoints across multiple studies in the Phase 3 program and the 
region-specific safety endpoints. 
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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2 BACKGROUND 
Roxadustat is an investigational, novel small molecule drug for oral administration that has not 
been marketed in any country. The drug is in global Phase 3 clinical development. It is being 
developed for the treatment of anemia associated with CKD, including end-stage renal disease 
(ESRD).  
2.1 Introduction Epidemiology of CKD and ESRD 
Chronic kidney disease is a growing worldwide public health challenge associated with 
significant morbidity and mortality, yet it is underdiagnosed and undertreated. It is characterized 
by progressive loss of kidney function, ultimately resulting in premature death or renal 
replacement therapy (kidney transplant or dialysis). In 2007, CKD affected 13% of the US adult 
population (approximately 29 million US adults) and its prevalence is growing rapidly 
(Coresh, 2007). All-cause mortality risk increases exponentially as CKD stages advance 
(Tonelli, 2006).  
The number of patients suffering from ESRD also continues to increase worldwide. The US has 
one of the highest prevalence rates of ESRD in the world: in 2010, the US had over 1700 ESRD 
patients per million population, a 23% increase compared with 10 years prior (USRDS, 2011 Vol 
2, Ch 1, p188). In 2009 (point prevalence Dec 31), there were approximately 570,000 ESRD 
patients in the US, of whom 370,000 were receiving hemodialysis, 27,000 were receiving 
peritoneal dialysis, and 173,000 had a functioning kidney transplant (USRDS, 2011 Vol 2, Ch 1, 
p184). The average expected life expectancy of a dialysis patient is 5.9 years, compared with 
16.4 years for a transplant patient, and 25.2 years for someone of comparable age in the general 
population (USRDS, 2009 Vol 2, Ch 2, p 181). The prevalence of ESRD is projected to grow to 
774,000 by the year 2020 (USRDS, 2009 Vol 2, Ch 2). 
2.2 Anemia Associated with Chronic Kidney Disease 
Anemia is a common complication in patients with CKD, and although its pathogenesis is 
multifactorial, the decreased production of erythropoietin (EPO), a hormone produced primarily 
in the kidneys, is considered an important etiologic factor. The impaired ability of the body to 
absorb and utilize iron is likely a second etiologic factor.  
Anemia may present in early stages of CKD and its prevalence increases as CKD progresses. 
Anemia is present in 17% of patients with late Stage 3 disease; this increases to 25% in patients 
with Stage 4 disease, and to 49% in patients with Stage 5 CKD who have not yet progressed to 
dialysis (Coresh, 2007; Go, 2004). Over 90 % of patients undergoing dialysis are anemic. Half of 
new dialysis patients (50.1%) have hemoglobin (Hb) levels below 10 g/dL and approximately 
28% have Hb below 9 g/dL (USRDS, 2003, Ch 3, Figure 3.11). 
The clinical consequences of anemia in patients with CKD have been studied extensively. 
Because the main impact of anemia on organ function is reduced oxygen delivery to tissues, it 
affects almost every organ system.  
Anemia contributes to the excess morbidity and mortality in CKD and ESRD. In patients with 
CKD, the severity of anemia correlates directly with the risk of hospitalization, cardiovascular 
disease, and death (Collins, 1998). Patients with the lowest Hb have worse outcomes, as was 
discussed in the post hoc analysis of mortality by Hb quintiles for the Normal Hematocrit and 
Correction of Hb and Outcomes in Renal Insufficiency (CHOIR) studies in the FDA briefing 
document for the October 2007 Cardiovascular and Renal Advisory Committee (Unger, 2007). 

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Similar observations are found in USRDS mortality data stratified by Hb. All-cause mortality 
stratified by Hb (1993-1996) showed significantly higher first-year death rates in patients with 
Hb levels < 9, compared with 11 to 12 g/dL. This trend continued to worsen, as reflected in 1998 
to 1999 data, where the death rate rose by ∼75% compared with the 1993 to 1996 period 
[(USRDS, 2000), Ch 8, Fig 8.16; (USRDS,USRDS), Ch 9, Fig 9.14]. This increase coincides 
with the introduction of the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines in 
1997. The relative risk of all-cause mortality for patients with Hb < 9 g/dL is twice that of 
patients with Hb > 12 g/dL [(USRDS, 2002); Ch 9, Table 9b)]. The relative risk of 
cardiovascular hospitalization increases significantly to 1.26 in patients with Hb levels < 9 g/dL 
compared with those with Hb levels at 11 to 12 g/dL [(USRDS,USRDS) Ch 5, Fig 5.27)]. 
Multiple studies have shown that treatment of anemia reduces blood transfusions and improves 
health-related quality of life(HRQoL) (NKF K/DOQI, 2007).  
2.3 Treatment of Anemia 
Today, therapy with erythropoiesis-stimulating agents (ESAs) is a major alternative to 
transfusion in managing anemia associated with CKD. For those not resistant to ESAs, parenteral 
administration of exogenous recombinant human EPO (epoetin alfa or beta) or pegylated 
analogues has been a widely accepted approach for treatment of anemia in patients with CKD 
(Winearls, 1986; Eschbach, 1989; Eschbach 1987), despite the documented safety risks. These 
safety risks include hypertension and thrombosis, and may be associated with the 
supraphysiologic plasma EPO levels frequently observed with ESA therapy. Anemic patients 
with CKD or ESRD will require life-long treatment with these agents.  
Although the treatment of anemia in CKD and ESRD is thought to provide a quality of life 
(QoL) benefit, several studies in ESRD and CKD nondialysis patients have shown higher 
mortality or trends in that direction in the higher-dosed ESA-treated cohorts when the protocol 
objective was to treat to high target Hb levels (Besarab, 1998; Drueke, 2006; Singh, 2006).  
An ESA dose relationship to mortality has been reported in a review of the USRDS database 
(Zhang, 2004) of ESRD patients who received higher ESA doses. Additionally, ESA therapy for 
anemia in ESRD patients on hemodialysis (HD) usually requires concomitant intravenous 
(intravenous [IV]) iron supplementation.  
There is currently an unmet medical need for an oral treatment that can correct anemia in CKD 
nondialysis and dialysis patients while avoiding supraphysiologic levels of circulating plasma 
EPO levels.  
Roxadustat is an oral medication that could potentially deliver effective treatment of CKD-
related anemia with less need for iron supplementation and without producing supraphysiologic 
levels of circulating EPO, which may translate into an improved safety profile.  
2.4 Mechanism of Action of Roxadustat 
Virtually all tissues depend on a sufficient supply of oxygen for survival. Lack of oxygen 
associated with hypoxic, ischemic, and anemic conditions triggers a series of homeostatic 
responses (Figure 1). Hypoxia-inducible factor (HIF) is a transcription factor that is believed to 
be the key element in the body’s oxygen sensing mechanism (Semenza, 2000). HIF regulates 
expression of genes that modulate both the acute and chronic response to hypoxia, and HIF-
responsive genes regulate processes as diverse as erythropoiesis, iron metabolism, oxidation, 
cellular metabolism, glycolysis, vasculogenesis, cell cycle progression, and apoptosis. Chronic 

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hypoxia and intermittent hypoxia induce different sets of genes associated with HIF 
transcriptional activity (Fan, 2005). HIF is a heterodimeric transcription factor family comprising 
three oxygen-sensitive isoforms (HIF-1α, HIF-2α and HIF-3α), and a constitutively expressed 
HIF-1β subunit, with each heterodimeric isoform responsible for the induction of specific sets of 
genes (Greijer, 2005; Hu, 2003). For example, HIF-1α has been shown to regulate vascular 
endothelial growth factor (VEGF) expression (Gray, 2005; Buchler, 2003), while HIF-2α is 
critical for the induction of the EPO gene and erythropoiesis (Warnecke, 2004; 
Scortegagna, 2005).  
Figure 1. 
HIF-PHI Mechanism of Action 
 
Abbreviations: 
DcytB = Duodenal cytochrome B; DMT1 = divalent metal transporter one; EPO = erythropoietin; 
HIF = hypoxia-inducible factor; HIF-PH = hypoxia-inducible factor prolyl hydroxylase; HIF PHI = hypoxia-
inducible factor prolyl hydroxylase inhibitor; mRNA = messenger ribonucleic acid; Tf-R = Transferrin 
receptor; Ub = ubiquitin; VHL = Von Hippel–Lindau protein. 
Source:  Epstein, et al. Cell, 2001 Oct 5; 107(1) 
HIF target genes are expressed when the active heterodimer binds to a conserved 
deoxyribonucleic acid (DNA) motif found within all HIF target genes, termed the hypoxia 
response element, and in cooperation with other coactivators initiates de novo transcription. One 
of the most sensitive and well-studied HIF-responsive genes is the EPO gene. Increased 
transcription of the EPO gene leads to increased circulating levels of EPO, which acts at sites of 
erythropoiesis to enhance the differentiation and proliferation of RBC precursors.  
Although HIF-α isoforms are constitutively produced, their accumulation under normoxic 
conditions is prevented by recruitment and binding by the von Hippel-Lindau (VHL) protein, 
which targets HIF-α isoforms for degradation through the ubiquitin-proteasome pathway. The 
molecular mechanism for oxygen-dependent degradation of HIF-α is based on the hydroxylation 
of specific proline residues, as catalyzed by a family of HIF prolyl hydroxylases (HIF-PH) that 
utilize molecular oxygen as the substrate for hydroxylation. Thus, HIF-PH constitutes the body’s 
main oxygen sensor by regulating the prevalence and activity of nuclear HIF protein. Under 
hypoxic conditions, HIF-PHs are inactive and lead to initiation of the HIF-responsive 
transcriptional cascade (Wang, 1995; Semenza, 1998).  
Roxadustat is a potent and reversible HIF-PH inhibitor (HIF-PHI) that transiently induces HIF 
stabilization and leads to a functional HIF transcriptional response that mimics the erythropoietic 

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response associated with exposure of humans to intermittent hypoxia. HIF induces expression of 
not only EPO, but also the EPO receptor and proteins that promote iron absorption and recycling 
9 (Peyssonnau, 2008). Thus, roxadustat pharmacologically stimulates erythropoiesis via the HIF 
pathway and in a manner consistent with the body’s normal homeostatic response to anemia, but 
under normoxic conditions. In contrast to the classical paradigm, suggesting that anemia in CKD 
patients is caused by the inability of these patients to produce EPO, results of a study of 
roxadustat treatment of CKD subjects not requiring dialysis (Study No. FGCL-SM4592-017) 
suggest that the kidneys and other sites of EPO production in this patient population retain the 
ability to produce sufficient EPO for robust erythropoiesis.  
Roxadustat also has the potential to effectively treat anemias caused by inflammation-induced 
functional iron deficiency, which are typically hyporesponsive to ESAs. In these conditions, iron 
availability for erythropoiesis is reduced due to a number of inflammatory mediators. Because 
HIF-PH inhibitors such as roxadustat alter expression not only of the EPO gene but also of genes 
regulating iron metabolism, it is postulated that roxadustat may be effective in treating these 
anemias as well (Langsetmo, 2005). 
Chronic hypoxia and intermittent hypoxia induce different sets of genes associated with HIF 
transcriptional activity, presumably because intermittent stimulation allows the restoration of 
HIF degradation, turnover, and inactivation. Transient activation of HIF thereby precludes 
sustained gene expression and the induction of genes that are expressed late after HIF activation, 
as well as expression of additional genes that are secondary to activation of HIF-dependent 
genes. Both nonclinical and clinical studies of roxadustat have successfully used the intermittent 
dosing paradigm to induce selective erythropoiesis and to optimize the Hb dose response. 
Furthermore, roxadustat was selected for development over other HIF-PH-inhibiting candidate 
molecules based on an optimal biodistribution profile that enhances its selective actions. The 
specific tissues where roxadustat enters the cytoplasm and triggers gene expression reside in the 
main target organs for erythropoiesis:  the kidney (EPO production), the bone marrow (increase 
in EPO receptors), the duodenum (transepithelial iron transport), and the liver (EPO production 
and down-regulation of hepcidin production); roxadustat distributes preferentially to these 
organs. 
The physiologic mechanisms underlying the effects of roxadustat on erythropoiesis are distinct 
from that of ESAs, and these differences result in several potential advantages over ESAs 
beyond the convenience of oral therapy. These potential advantages include: 
• Increase in the number of EPO receptors in the bone marrow 
• Improved iron metabolism and bioavailability 
• Effective erythropoiesis at nonsupraphysiologic plasma EPO levels (10- to 20-fold lower 
than with parenteral ESA therapy) 
• Absence of hypertensive effect 
• Effective erythropoiesis in the presence of inflammation 
• Mitigation of thromboembolic risk 
• Improvement in lipid profile 

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2.5 Clinical Experience with Roxadustat 
Roxadustat is currently being studied in dialysis and nondialysis CKD subjects with anemia. 
Numerous Phase 1 and 2 clinical studies have been completed, in the United States, Europe, and 
Asia. Information from these studies is provided below and in the most recent Investigator’s 
Brochure. 
As of 14 September 2014, an estimated total of 1,485 subjects have been exposed to roxadustat 
in the clinical development program, comprising 571 healthy subjects and an estimated 483 
subjects with nondialysis-dependent chronic kidney disease (NDD-CKD) and 431 subjects with 
dialysis-dependent chronic kidney disease (DD-CKD). In completed studies, subjects with CKD 
have received up to 24 weeks of roxadustat, in doses of up to 3.0 mg/kg. In completed Phase 1 
studies, healthy volunteers received single doses of roxadustat up to 4.0 mg/kg and repeat doses 
up to 3.75 mg/kg three times weekly (TIW) for 4 weeks. In a completed thorough QT study in 
healthy volunteers, single doses up to 5 mg/kg were administered, without evidence of QT 
prolongation. 
The clinical data collected thus far suggest that roxadustat is generally safe and well tolerated in 
healthy adult subjects, and in dialysis and nondialysis CKD subjects with anemia who have been 
treated in the completed and ongoing studies. 
2.5.1 Pharmacokinetics and Pharmacodynamics 
The pharmacokinetics (PK) and pharmacodynamics (PD) of roxadustat were characterized in 
studies in healthy volunteers and in dialysis and nondialysis CKD subjects. Roxadustat showed 
generally dose proportional PK (except at the lowest dose of 0.3 mg/kg); t1/2 was 12 to 14 hours 
in healthy volunteers, and 15 to 19 hours in dialysis subjects (after a single 1 and 2 mg/kg dose).  
With an intermittent dose regimen (QW, BIW or TIW), no or limited accumulation in mean 
AUC or Cmax was observed. Furthermore, no evidence was found for time-dependent 
pharmacokinetics (no auto-induction or inhibition). Roxadustat is highly protein bound and the 
PK of roxadustat is not affected by dialysis. Metabolites found in urine suggested Phase 2 
metabolism as the major metabolic pathway. In plasma, parent roxadustat is the main 
component. The inhibitory potential of roxadustat on CYP enzymes, based on in-vitro studies is 
limited, and the lowest Ki value was observed for CYP 2C8 (16 μM). In a clinical drug-drug 
interaction study with rosiglitazone, a probe drug for CYP 2C8, roxadustat did not show any 
inhibitory potential on CYP 2C8 in vivo. 
In healthy adult male volunteers (Study FGCL-SM4592-016), roxadustat administered orally as a 
single dose up to 4.0 mg/kg, and once, twice, or TIW for 4 weeks at doses up to 3.75 mg/kg, was 
pharmacodynamically active as evidenced by dose-dependent transient increases in endogenous 
EPO (starting from single doses of 0.3 mg/kg), increases in reticulocytes (starting from doses of 
2 mg/kg), and Hb responses (starting at 3 mg/kg). The mean peak level of plasma EPO following 
the Day 26 dose of 2.0 mg/kg TIW (the high therapeutic dose studied) was 326.3 ± 
197.0 mIU/mL. 
In PD studies conducted with roxadustat in CKD subjects not on dialysis (Study FGCL-4592-
017), the mean maximum EPO increase from baseline ranged from 82-443 mIU/mL and 492-554 
mIU/mL after a single 1 and 2 mg/kg dose, respectively. In dialysis subjects (Study FGCL-4592-
039), comparable dose-dependent increases in EPO levels were observed, both predialysis and 
postdialysis. These increases in endogenous EPO were transient and the effect disappeared 
within approximately 48 hrs. 

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In contrast, EPO levels associated with therapeutic ESA dosing range from 1,500 to over 10,000 
mIU/mL (Besarab, 2009). In a clinical study with dialysis subjects, the reported mean 
administered individual ESA dose was 8,000 IU, which would correspond to plasma EPO Cmax 
levels exceeding 3,000 mIU/mL (Fishbane, 2007). This is approximately 10-fold higher than the 
physiologic range.  
2.5.2 Efficacy 
Data from a 4-week treatment study in anemic CKD subjects not on dialysis (Study FGCL-
SM4592-017) showed that roxadustat promotes erythropoiesis at lower doses in CKD subjects 
than in healthy volunteers. With roxadustat 0.7 mg/kg TIW dosing, mean Hb increased by 
1.0 g/dL over a 6-week period in anemic CKD subjects who completed 4 weeks of dosing; more 
robust mean Hb increases of 2.0 to 2.3 g/dL occurred at roxadustat doses of 1.5 and 2.0 mg/kg 
TIW, respectively. Hemoglobin responder (Hb increase of ≥ 1.0 g/dL) rates were 62%, 60%, 
91%, and 100% in the roxadustat 0.7, 1.0, 1.5, and 2.0 mg/kg TIW cohorts, respectively. With 
the additional criterion that Hb achieve a level of ≥ 11 g/dL as well as increasing by ≥ 1.0 g/dL, 
the Hb responder rate with roxadustat 2.0 mg/kg was 91% with TIW dosing. The rapid rates of 
rise in Hb with roxadustat treatment were not accompanied by elevations in blood pressure, as 
has been reported with ESA treatment (Eschbach, 1989). 
Data from a 16- to 24-week treatment study in CKD subjects not on dialysis (Study FGCL-4592-
041) showed that absolute and weight-based doses of roxadustat, administered TIW and BIW, 
effectively corrected and maintained Hb levels to a target of 11 g/dL (range of 11 -13 g/dL in 96 
subjects and 10.5 -12.0 g/dL in 48 subjects). The median time to Hb response was 28 days for 
subjects who received adequate weight-based or absolute starting doses of roxadustat and longer 
for those who received a lower absolute starting dose. Dose-response trends suggested that 
starting doses of 1.0−1.6 mg/kg roxadustat administered TIW are appropriate to correct Hb 
levels during 4 weeks of treatment in nondialysis CKD subjects. Once Hb correction is achieved, 
a dose frequency reduction appears to be feasible to maintain Hb levels. 
Data from a 6- and 19-week treatment study in ESRD subjects on dialysis (Study 
FGCL-4592-040) showed the feasibility of converting subjects from a stable ESA dose to 
roxadustat. In the 6-week dose range portion of this conversion study (during which roxadustat 
doses were mostly fixed upon switching from stable doses of epoetin alfa), a dose response was 
observed. The 1.0 mg/kg roxadustat dose was comparable to the epoetin alfa control, which had 
a small decline in Hb levels from baseline and a lower percent Hb responder rate compared with 
the higher doses of roxadustat. The 1.5 and 2.0 mg/kg roxadustat dose arms resulted in a Hb 
increase of about 1 g/dL from baseline and an 89% response rate, more than double that of the 
epoetin alfa arm, despite the absence of IV iron supplementation. In the 19-week portion of the 
study, during which dose-titration was allowed, Hb maintenance was demonstrated to be durable 
in roxadustat treatment arms (combined) over a 19-week period. In contrast, the Hb levels of 
epoetin alfa controlled subjects appeared to decline gradually over time despite steady levels of 
epoetin alfa doses, possibly because IV iron was not permitted during the treatment period.  
2.5.3 Safety 
The overall frequency and type of treatment-emergent adverse events (TEAEs) and serious 
adverse events (SAEs) observed in these clinical studies reflect events that would be expected to 
occur in CKD subjects with multiple comorbidities and on a number of concomitant medications. 
Safety analyses did not reveal any association between the rates of occurrence of cardiovascular 

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events with roxadustat, or any effect on AE rates related to either increasing Hb levels or on the 
rate of change of Hb levels.  
In general, the most commonly reported adverse events (AEs; ≥ 4% and ≥ 1% above placebo 
rate) in healthy subjects were headache and dizziness. The most commonly reported AEs (≥ 5%) 
in subjects with NDD-CKD were diarrhea, nausea, urinary tract infection, nasopharyngitis, 
peripheral edema, hyperkalemia, headache, and hypertension (none were ≥ 8%). The most 
commonly reported AEs (≥ 3%) in subjects with DD-CKD were diarrhea, nausea, hypertension, 
and upper respiratory tract infection (none were ≥ 5%). Adverse event rates of hypertension (1% 
in Study FGCL-SM4592-017, and 7.6% in Study FGCL-4592-041) and thrombosis (overall 
incidence < 1%) compare favorably with the rates reported in published ESA studies in similar 
patient populations (Krapf, 2009; Fishbane, 2007). No safety risks could be associated with rate 
of rise of Hb levels or with achieving any Hb level above 11 g/dL using roxadustat. FGCL-4592-
041 study subjects achieved Hb ≥ 11 g/dL in > 50% of the exposure time during study, and there 
were no cardiovascular safety events (death, MI, stroke, unstable angina, hospitalization for 
congestive heart failure, or hospitalization for arrhythmias) reported while Hb ≥ 11 g/dL during 
treatment with roxadustat.  
No increased cancer risk has been noted with roxadustat treatment; however, the study program 
was not powered to detect absence of cancer risk. 
Liver enzymes were monitored closely throughout the roxadustat clinical development program. 
Increases in liver enzymes were seen infrequently, and were generally mild and transient in 
nature. No cases of Hy’s Law were observed throughout the program. An independent data and 
safety monitoring committee concluded that there was no concern for hepatotoxicity with 
roxadustat. 
Based on the safety data collected to date, roxadustat has an acceptable safety profile that 
supports its further development. For detailed safety information, please refer to the most current 
version of the Investigator’s Brochure (IB). 
2.6 Summary 
In summary, roxadustat is an orally active HIF-PHI with erythropoietic effects. Intermittent 
dosing of roxadustat results in transient activation of HIF, intermittent induction of endogenous 
physiologic-range EPO, and dose-dependent erythropoiesis, suggesting a coordinated mechanism 
of erythropoiesis that is different from ESA therapy, including beneficial effects on iron 
handling. The clinical data collected thus far suggest that roxadustat is generally safe and well 
tolerated in healthy adult subjects, and in dialysis and nondialysis CKD subjects with anemia.  
2.7  Roxadustat Dose Rationale 
Starting doses of roxadustat were studied in three ways in the Phase 2 clinical development 
program:  1) using an absolute weight-based dosing approach that was useful in the proof of 
concept stage; 2) using a tiered weight-based approach where a subject’s starting dose was 
selected based on categorizing the subject’s body weight as low (45 to 60 kg), medium (> 60 to 
90 kg), or high (> 90 to 140 kg); and 3) using an absolute starting dose regardless of body 
weight. The tiered weight-based approach has been chosen for the development of roxadustat in 
the Phase 3 program. 
The tiered, weight-based roxadustat starting doses selected for this study are 70 mg for subjects 
who weigh <70 kg and 100 mg for subjects who weigh ≥ 70 kg. These dose tiers are based 
primarily on the safety and efficacy data generated in the CKD non-dialysis correction of anemia 

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study (FGCL-4592-041), adjusted slightly downward at equivalent weights to achieve slower Hb 
correction and lower levels in the present study. These starting doses will be administered at a 
dosing frequency of TIW. Using this dosing scheme, subjects will receive starting roxadustat 
doses ranging between 0.6 to 1.6 mg/kg TIW across the eligible weight range for the present 
study. This is comparable to the starting doses that effectively corrected Hb levels in study 
FGCL-4592-041. Further dose adjustment to achieve correction and subsequent maintenance is 
based upon regular monitoring of Hb and application of a dose adjustment algorithm, which was 
successfully used in Phase 2, with minor modification for ease of use in Phase 3.  
The Phase 2 studies evaluated the need for dose adjustments for both Hb correction and Hb 
maintenance. Dose adjustments were allowed at regular 4-week intervals to maintain, increase, 
or decrease the dose according to prespecified rules. Prespecified dosing steps were used to 
correct and maintain Hb based on absolute Hb levels and change in Hb in the previous 4 weeks. 
Additional rules for dose adjustment were provided to minimize excessive hematopoiesis. These 
dose adjustment rules were successful in Hb correction and maintenance and will be adopted in 
this study with minor modifications. 
2.8 Risks/Benefits of Roxadustat Treatment 
The primary benefit of roxadustat is the correction of anemia, including the relief of associated 
signs and symptoms and an increased QOL. Roxadustat is expected to be at least as safe as 
ESAs, and the current data suggest that cardiovascular risk may be lower than with ESAs.  
An established dose adjustment algorithm will be used during the study to titrate roxadustat 
doses to enable subjects to achieve and maintain optimal Hb levels, while closely monitoring the 
rate of rise of Hb levels. Roxadustat doses may be held and/or the use of therapeutic phlebotomy 
is allowed in the event of excessive hematopoiesis.  
The safety of treatment with roxadustat and placebo will be carefully monitored. Adverse and 
serious adverse events, and laboratory parameters including CBC, electrolytes, liver enzymes, 
CPK, and iron indices, will be closely monitored. An independent expert panel will assess and 
adjudicate prespecified cardiovascular, cerebrovascular, and thromboembolic events. In addition, 
an independent Data and Safety Monitoring Board (DSMB) will perform regular, periodic 
assessments of safety data to detect any potential safety signals that may arise during the study 
and advise the Sponsor accordingly.  
Based on the clinical and nonclinical experimental results to date, it is anticipated that orally 
administered roxadustat will be comparable in efficacy to marketed parenteral ESA products in 
the treatment of anemia of CKD, with an acceptable safety profile. Roxadustat may offer a 
valuable alternative to the current treatment options in the management of anemia of CKD. 

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3 OBJECTIVES 
3.1 Primary Objectives 
The primary objectives of this study are to: 
• Evaluate the efficacy of roxadustat for the treatment of anemia (correction and 
maintenance of Hb) in CKD subjects not on dialysis. 
• Evaluate the safety of roxadustat administered over a minimum of 52 weeks of treatment. 
3.2 Secondary Objectives 
The secondary objectives in this study are to: 
• Evaluate the effect of roxadustat in CKD anemia on: 
o Serum lipid parameters  
o HRQoL  
o Blood pressure 
o The need for anemia rescue therapy: red blood cell (RBC) transfusion, or ESA, or 
intravenous (IV) iron 
o Time to achieve Hb response 

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4 STUDY DESIGN 
4.1 Description of the Study 
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate 
the safety and efficacy of roxadustat in the treatment of anemic subjects with Stage 3, 4 or 5 
CKD who are not on dialysis. This study is planned to recruit up to 1200 subjects from 
approximately 200 study centers worldwide. 
This study will consist of three study periods as follows: 
• Screening Period: Up to 6 weeks 
• Treatment Period: Treatment duration is variable for individual subjects.  In order to 
complete the Treatment Period simultaneously for all study subjects, the minimum 
treatment duration may be less than 52 weeks, with a maximum treatment duration of up 
to 3 years after the last subject is randomized. 
• Post-treatment Follow-Up Period*: 4 weeks 
(*or enroll into an Open Label Extension study) 
Refer to Appendix 3 for a diagrammatic representation of the study schema. 
Following the Screening Period, subjects will be randomized in a 2:1 ratio to receive roxadustat 
(approximately 800 subjects) or placebo (approximately 400 subjects). Dosing will be TIW 
throughout the study, except in subjects who have already converted to BIW or QW dosing 
regimens as a result of being enrolled under previous Study FGCL-4592-060 protocol versions. 
Starting doses of , respectively. 
Table 1. 
Treatment Arms  
Treatment 
Arms 
Correction 
Maintenance 
n 
(FG-4592) 
n 
(Placebo) 
1A 
TIW 
QW 
100a 
0 
1P 
TIW 
QW 
0 
50a 
2A 
TIW 
BIW 
100 
0 
2P 
TIW 
BIW 
0 
50 
3A 
TIW 
TIW 
100 
0 
3P 
TIW 
TIW 
0 
50 
Abbreviations: 
A = active control; BIW = twice a week; n = number of subjects; P = placebo; TIW = three 
times a week; QW = once a week. 
a 
These numbers are based on a sample size of 450 and will increase if the overall sample size increases. 
The initial study drug dose (per dose amount) is based on a tiered, weight-based dosing scheme 
shown in Table 2. 

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Table 2. 
Initial Study Drug (FG-4592 or Placebo) Dosing  
Study Drug 
(Dose Frequency) 
Low Weight 
(<70 kg) 
Medium Weight 
(70 to 100 kg) 
High Weight 
(>100 kg) 
FG-4592/Placebo 
(TIW) 
70 mg 
100 mg 
120 mg 
Abbreviations: 
TIW = three times a week; QW = once a week. 
Study drug will be dose adjusted according to anemia correction guidelines until subjects achieve 
a Hb value of ≥ 11 g/dL and ≥ 1 g/dL increase from baseline by central lab. Once these criteria 
are met, subjects will enter into the maintenance phase of anemia treatment and will be dose-
adjusted according to maintenance guidelines (Section 4.5.2, Appendix 1). 
Study drug dose will remain constant during the first 4 weeks of the Treatment Period, unless a 
dose reduction is required for excessive hematopoiesis. Dose adjustments are permitted starting 
at Week 4, and at intervals of every 4 weeks thereafter.  
4.2 Randomization and Treatment Assignment 
Up to 1200 planned subjects will be randomized to receive either roxadustat or placebo in a 
double-blind manner, resulting in approximately 800 subjects receiving roxadustat and 
approximately 400 subjects receiving placebo.  
Randomization is stratified by the following factors:  
• Screening Hb values (≤ 8 g/dL vs > 8 g/dL) 
• History of cardiovascular, cerebrovascular or thromboembolic diseases (Yes vs No) 
• eGFR (< 30 mL/min/1.73 m2 vs ≥ 30 mL/min/1.73 m2) 
• Geographic region (US vs Ex-US).  
Randomization schedules will be prospectively prepared. Automated randomization and 
treatment assignments will be provided by an Interactive Response System (IWRS). 
4.3 Replacement of Subjects  
Subjects who drop out prematurely will not be replaced in the study. 
4.4 Blinding 
This is a double-blind, placebo-controlled study. The Investigator, study site staff, subject, and 
the Sponsor and designees, are blinded to study drug assignment, but not to the dose. 
Additionally, all efforts should be made to keep subjects blinded to study Hb values.  
4.4.1 Maintenance of Blinding 
Neither the subjects nor the Investigators and their staff can distinguish the roxadustat tablets 
from the matching placebo tablets. Both will be identical in appearance, packaging, and labeling 
in order to maintain the blind. 
4.4.2 Planned and Unplanned Unblinding of Treatment Assignment 
Treatment assignments will be unblinded after the completion of the study.  

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Any intentional or unintentional breaking of the blind should be reported and documented. 
Breaking the blind (for a single subject) should be considered only when knowledge of the 
treatment assignment is deemed essential by the Investigator for the subject’s care. Unplanned 
unblinding will result in the discontinuation of subject participation from the study. When 
possible and appropriate the blind will be maintained for Sponsor personnel responsible for 
analysis and interpretation of results at the study’s conclusion. 
4.5 Study Treatment 
4.5.1 Dose and Schedule Overview 
Subjects will be randomized via IWRS to receive roxadustat or placebo. Dosing will be TIW 
throughout the study, except in subjects who have already converted to BIW or QW dosing 
regimens under previous Study FGCL-4592-060 protocol versions.  
The initial study drug dose (per dose amount) is based on the tiered, weight-based dosing scheme 
(Table 3) and the first study drug administration will be on Day 1 (Week 0).  
Table 3. 
Initial Study Drug (FG-4592 or Placebo) Dosing  
Tiered Weight Category 
<70 kg 
≥70 kg 
Initial Tiered Weight 
Dose (TIW) 
70 mg 
100 mg 
 
Abbreviations: 
TIW = three times weekly. 
Study drug dose will remain constant during the first 4 weeks of the Treatment Period, unless a 
dose reduction is required for excessive hematopoiesis. Dose adjustments are permitted starting 
at Week 4, and at intervals of every 4 weeks thereafter. Starting doses of study drug will be dose-
adjusted according to anemia correction guidelines until subjects achieve a Hb value of ≥ 11 
g/dL and ≥ 1 g/dL increase from baseline by central lab. Once these criteria are met, subjects will 
enter into the maintenance phase of anemia treatment and will be dose-adjusted according to 
maintenance guidelines (Section 4.5.2 and Appendix 1). Study drug doses will be considered as 
meeting the definition of TIW if they are administered at least 2 days apart, and no more than 4 
days apart. Subjects enrolled under previous FGCL-060-4592 protocols will continue taking 
study drug BIW or QW if they have already converted to those dosing frequencies. Study drug 
doses taken BIW must be administered at least 3 days apart, and no more than 5 days apart. 
Study drug doses taken QW must be administered at least 5 days apart, and no more than 9 days 
apart.  
During the Treatment Period, subjects will attend consecutive weekly study visits for the first 2 
weeks of study treatment (from Weeks 0 to 2) followed by every other week study visits starting 
at Week 4 until week 24. After Week 24, subjects will attend study visits every 4 weeks until the 
end of the Treatment Period. Treatment duration is variable for individual subjects.  In order to 
complete the Treatment Period simultaneously for all study subjects, the minimum treatment 
duration may be less than 52 weeks, with a maximum treatment duration of up to 3 years after 
the last subject is randomized. After the Treatment Period, study subjects may enter a separate 
Open Label Extension study or will proceed to the 4-week post-treatment Follow-up Period, and 
will attend a final study visit at 4 weeks after end of treatment.  

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4.5.2 Dose Adjustment  
Dose adjustments will occur in two separate study-dosing phases. All subjects will start with the 
Correction Phase during which an attempt to correct their Hb levels is made (Section 4.5.2.1). If 
successfully corrected, the subject will then enter into the Maintenance Phase. Each of these 
phases will follow unique dose adjustment rules per Appendix 1.The determination of Hb 
response and transition from the Correction to Maintenance Phase of the study is based on 
central laboratory Hb values. 
4.5.2.1 Correction Phase of Dosing 
The aim of the Correction Phase is to increase Hb levels from baseline to a level that avoids the 
need for blood transfusion, by using the dose adjustment algorithm in Appendix 1, and taking 
into account physiologic fluctuations and test variability. This phase is variable in length for each 
subject, depending on when the subject achieves a Hb level ≥11.0 g/dL and ≥1.0 g/dL increase 
from baseline by central lab. 
Study drug dose will remain constant during the first 4 weeks of the Treatment Period, unless a 
dose reduction is required for excessive hematopoiesis (Appendix 1).  
All dose adjustments are based on Hb values using HemoCue, a point-of-care device. Dose 
adjustment reviews will occur on Week 4, and at intervals of every 4 weeks thereafter (Weeks 8, 
12, 16, etc), except in the event of excessive hematopoiesis, in which case doses may be adjusted 
at any time. In such cases, dose adjustment reviews are to be resumed at 4-week intervals. For 
example, if the subject’s Hb increases > 2.0g/dL from Weeks 2 to 3, the subject’s dose is reduced 
by one dose step at Week 3. The next dose adjustment review occurs 4 weeks later at Week 7 
and at 4-week intervals thereafter.  
If the dose adjustment interval falls on a nonvisit study week the dose adjustment review should 
be performed at the next scheduled clinic visit. For example, if a subject’s visit is scheduled for 
Weeks 10 and 12, and the dose adjustment should occur at Week 11, then the dose adjustment 
should be evaluated at the Week 12 visit.  
4.5.2.2 Maintenance Phase of Dosing 
The aim of the Maintenance Phase is to maintain Hb levels after the initial correction by utilizing 
the dose adjustment algorithm described in Appendix 1 and taking into account physiologic 
fluctuations and test variability. 
Dose adjustment reviews will continue every 4 weeks. If the dose adjustment interval falls on a 
nonvisit study week, the dose adjustment review should be performed at the next scheduled 
clinic visit. For example, if a subject’s visit is scheduled for Weeks 10 and 12, but the dose 
adjustment review falls on Week 11, then the dose adjustment should be evaluated at the Week 
12 visit and at 4-week intervals thereafter.  
• Given the complexities of the dose adjustment algorithm, and the need to take into 
consideration various clinical parameters, it is not considered a protocol deviation when 
study subjects are dosed based on their clinical circumstance, whether or not this is 
concordant with the roxadustat dosing algorithm, unless it is related to “excessive 
hematopoiesis” (refer to Section 4.5.1) or “Overdose”  (prescribed >3.0 mg/kg per dose) 

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4.6 Concomitant Medications, Procedures and Nondrug Therapies 
4.6.1 Concomitant Medications 
Concomitant medications are any prescription or over-the-counter preparations, including herbal 
products and “natural remedies”, used by a subject while participating in this clinical study, 
including those taken within 30 days prior to screening.  
For all concomitant medication use, an indication for its use should be provided. If the stated 
indication is a nonspecific condition (eg, “rash”), documentation of the condition, as specific as 
possible, should be maintained in the subject’s clinical study records as source documentation.  
To avoid confounding effects on study endpoints, changes to antihypertensive medications 
should be minimized, and made only if deemed medically necessary by the Investigator or if 
prespecified changes in blood pressure are met. A similar consideration should be made for lipid 
lowering therapies. 
4.6.1.1 Statin interaction 
When coadministered with roxadustat in clinical pharmacology studies, hydroxymethylglutaryl 
coenzyme A reductase inhibitor (statin) exposure was increased 2- to 3-fold. Investigators should 
consider this interaction as well as additional local prescribing information when deciding on the 
appropriate statin dose for individual patients, bearing in mind the potential additional impact of 
ethnicity, other concomitant medications, and renal and hepatic function. Goals of lipid lowering 
treatment should be maintained as clinically indicated. It is recommended that the maximum 
daily dose of statins should not exceed the doses shown in the table below. 
Table 4. 
Recommended Maximum Daily Dose of Statins for Subjects in 
FGCL-4592-060 
Statin 
Recommended maximum dose (mg/day) 
Atorvastatin  
40 
Simvastatin 
20 (5 if eGFR < 30 mL/min) 
Rosuvastatin 
10 
Pravastatin 
40 
Fluvastatin 
40 (20 if eGFR < 30 mL/min) 
Pitavastatin 
2 (1 if eGFR < 30 mL/min) 
Lovastatin 
20 
Abbreviations: 
eGFR = estimated glomerular filtration rate. 
4.6.1.2 Phosphate Binders 
When coadministered with phosphate binders in a clinical pharmacology study, the 
bioavailability of roxadustat was reduced. Subjects should be advised to discuss with the 
investigator when changing the dose or dosing time of their phosphate binder, including high 
dose calcium used for this purpose. To optimize absorption of roxadustat, it is recommended that 
subjects take roxadustat at least 1 hour before or 3 hours after their phosphate binder, if possible. 

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4.6.1.3 Supplemental Iron Use 
Oral iron is recommended for dietary supplementation to support erythropoiesis and as the first-
line for prevention and treatment of iron deficiency, unless the patient is intolerant to this route 
of treatment. The recommended daily oral dose for the treatment of iron deficiency is 200 mg of 
elemental iron. Intravenous iron is restricted as rescue therapy, using the Rescue Therapy 
Guidelines below. 
4.6.2 Rescue Therapy Guidelines 
Rescue therapy guidelines are provided to optimize standardization of the use of rescue therapy 
by Investigators and to ensure safety of the individual study subjects. Use of rescue therapy and 
reason for rescue therapy should be recorded in the eCRF. 
4.6.2.1 Red Blood Cell Transfusion 
Red blood cell (RBC) transfusion is allowed if rapid correction of anemia is required to stabilize 
the patient’s condition (eg, acute hemorrhage) or the Investigator is of the opinion that the blood 
transfusion is a medical necessity. Study drug treatment may continue during or after RBC 
transfusion administration. 
4.6.2.2 Erythropoiesis-Stimulating Agent (ESA) 
Use of more than two courses of ESA for anemia rescue is a withdrawal criterion requiring early 
termination from study treatment. Nevertheless, criteria are provided in order to standardize the 
use of ESA rescue. The Investigator should consider initiating use of an approved ESA only if all 
of the following criteria are met: 
• The subject’s Hb level has not sufficiently responded to two or more dose increases or 
maximum doses (by body weight) of the study drug; and 
• The subject’s Hb is < 8.0 g/dL; and 
• Reducing the risk of alloimmunization in transplant eligible subjects and/or reduction of 
other RBC transfusion-related risks is a goal 
ESA treatment must be stopped after 4 weeks of use or when Hb ≥ 9 g/dL is reached, whichever 
occurs first. Study drug treatment may be resumed after the following intervals: 
• Two days after stopping epoetin  
• One week after stopping darbepoetin alfa  
• Two weeks after stopping methoxy polyethylene glycol-epoetin beta (Mircera) 
After two successful courses of rescue with ESA and return to study drug, subjects who again 
meet the above criteria for ESA rescue and receive a third course of ESA must be discontinued 
from the study drug at this point. Such a subject will complete procedures for early termination 
and subsequent modified follow-up according to the procedures outlined in Section 7.1.2.6, if 
consent is not withdrawn to do so. 
Note: ESA administration in during hospitalization: Such ESA use is not considered a protocol 
deviation, if study subjects have no access to study drug while hospitalized. 
4.6.2.3 Intravenous Iron  
The use of intravenous iron is discouraged in the setting of this placebo-controlled trial. In 
roxadustat phase 2 studies where IV iron was restricted, iron repletion was not required for 

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treatment of anemia. IV iron is not standard of care in CKD nondialysis patients in most regions 
of the world. Therefore, the subject may receive IV iron supplementation only if each of the 
following criteria are met:  
• The subject has not responded adequately to two or more dose increases or the maximum 
dose (by body weight) of study drug; and  
• The subject is unresponsive to or does not tolerate oral iron; and  
• Ferritin levels are < 100 ng/mL (< 220 pmol/L) or transferrin saturation is (TSAT) < 20% 
If IV iron rescue criteria are met, the dose in a single administration (day) should be no more 
than 250 mg. The selection and dosing of the IV iron formulation should be consistent with 
regional package inserts that are applicable to CKD-ND patients. Study drug treatment may 
continue during IV iron administration.  
At 4 to 8 weeks after the single dose of IV iron, a repeat dose of IV iron can be administered if 
the Hb remains < 9 g/dL AND the subject still meets iron deficiency criteria (ferritin < 100 
ng/mL(< 220 pmol/L) or TSAT < 20%). After this 8 week period, full IV iron rescue criteria 
would need to be met again in order to qualify a subject for a second course of IV iron at a later 
point in the trial. 
4.6.3 Therapeutic Phlebotomy 
If there are clinical concerns due to excessive elevation in Hb levels, the Investigator may decide 
to perform a therapeutic phlebotomy instead of, or in addition to, a dose hold. This should be 
documented and discussed with the study medical monitor. 
4.6.4 Prohibited Medications/Therapies/Substances 
Subjects are not permitted to consume more than three alcohol-containing drinks per day during 
the Treatment or Follow-up Periods. 
The following medications are prohibited from the day of randomization until completion of the 
study: 
• Androgens and iron-chelating agents (eg, deferoxamine, deferiprone, or deferasirox 
therapy) 
• Dapsone 
• Acetaminophen or paracetamol > 2.0 g/day or > 500 mg per dose repeated every 6 hours 
if use is chronic or consistent  
• Use of herbal medicine is not prohibited but strongly discouraged  
• RBC transfusion or IV iron administration that does not meet the rescue criteria 
described in Section 4.6.2.1 

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• ESA administration that does not meet the rescue criteria described in Section 4.6.2.2. 
Additionally, if a subject meets rescue criteria and receives more than two courses of 
ESA for anemia rescue, such a subject should be discontinued from the study drug. 
Note: ESA administration in during hospitalization: Such ESA use is not considered a 
protocol deviation, if study subjects have no access to study drug while hospitalized. 
4.6.5 Contraception 
Female subjects of childbearing potential must agree to practice a dual method of contraception, 
for example, a combination of the following: (1) oral contraceptive, depot progesterone, or 
intrauterine device; and (2) a barrier method (condom or diaphragm). Male subjects with female 
partners of childbearing potential who are not using birth control as described above must use a 
barrier method of contraception (eg, condom) if not surgically sterile (ie, vasectomy). 
Contraceptive methods must be practiced upon entering the study and through 12 weeks after the 
last dose of study treatment. If a subject discontinues prematurely, the contraceptive method 
must be practiced for 12 weeks following final administration of study drug. Sexual abstinence 
satisfies the contraceptive requirement.  
Pregnancy, spontaneous or therapeutic abortion, or events related to pregnancy must be reported 
(see Section 10.3.6). 
4.7 Safety Monitoring Plan 
Safety will be assessed throughout the study. A complete baseline profile of each subject will be 
established through demographics, medical history, clinical laboratory values, vital signs, 
physical assessments, and electrocardiogram (ECGs). During the course of the study, vital signs, 
complete and targeted physical assessments, laboratory tests, and ECGs will be performed at 
regular intervals. Any medically significant changes from baseline will be monitored throughout 
the study and appropriate interventions will be taken accordingly. Clinical laboratory tests may 
be assessed at additional times on unscheduled visits for safety reasons. Liver function 
abnormalities will be managed according to the liver safety and monitoring guidance  
(Appendix 4). 
Adverse events, SAEs, and ongoing concomitant medication usage will be monitored and 
recorded throughout the study. Serious adverse event reports will be evaluated individually to 
assess for the impact of the event, if any, on the overall safety of the product and on the study 
itself. Cumulative AEs will be monitored throughout the study. Serious adverse events and AEs 
will be followed until resolved, stable, or until the subject’s End of Study (EOS) Visit. See 
Section 10.2.1 for details on AE and SAE reporting. 
Prespecified and adjudicated cardiovascular, cerebrovascular, and thromboembolic safety events 
of interest (ie, death, MI, stroke, congestive heart failure requiring hospitalization, and unstable 
angina requiring hospitalization), hypertensive emergency, deep vein thrombosis [DVT], 
pulmonary embolism [PE], and vascular access thrombosis [VAT]) will be captured. A separate 
adjudication charter will describe the process in detail, and training and training materials will be 
provided to study sites. The CV adjudication committee will review blinded events in this study 
and in other studies of roxadustat across the development program for anemia of CKD. 
4.8 Data Safety and Monitoring Board 
A Data Safety Monitoring Board (DSMB) will review prespecified safety data periodically in 
collaboration with the Sponsor to ensure subject safety. The DSMB will review data in this study 

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and in other studies of roxadustat across the development program for anemia of CKD. A 
separate charter will establish the rules, meeting frequency and scope of responsibilities of the 
DSMB.  

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5 STUDY ENROLLMENT AND DISCONTINUATION 
5.1 Inclusion Criteria 
1. Age ≥ 18 years 
2. Subject has been informed of the investigational nature of this study and has given 
written informed consent in accordance with institutional, local, and national guidelines 
3. Diagnosis of CKD, with Kidney Disease Outcomes Quality Initiative (KDOQI) Stage 3, 4, or 
5, not receiving dialysis; with an eGFR < 60 mL/min/1.73 m2 estimated using the 
abbreviated 4-variable Modification of Diet in Renal Disease (MDRD) equation 
4. Mean of the three most recent Hb values during the Screening Period, obtained at least 4 
days apart, must be ≤ 10.0 g/dL, with a difference of ≤ 1.0 g/dL between the highest and 
the lowest values. The last screening Hb value must be within 10 days prior to 
randomization 
5. Ferritin ≥ 30 ng/mL(≥ 66 pmol/L) 
6. TSAT ≥ 5% 
7. Serum folate level ≥ lower limit of normal (LLN) 
8. Serum vitamin B12 level ≥ LLN 
9. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x upper limit 
of normal (ULN), and total bilirubin (Tbili) ≤ 1.5 x ULN 
10. Body weight 45 to 160 kg  
5.2 Exclusion Criteria 
1. Any ESA treatment within 12 weeks prior to randomization 
2. More than one dose of IV iron within 12 weeks prior to randomization 
3. RBC transfusion within 8 weeks prior to randomization  
4. Active, clinically significant infection that could be manifested by white blood cell 
(WBC) count > ULN, and/or fever, in conjunction with clinical signs or symptoms of 
infection 
5. History of chronic liver disease (eg, chronic infectious hepatitis, chronic auto-immune 
liver disease, cirrhosis, or fibrosis of the liver) 
6. New York Heart Association Class III or IV congestive heart failure 
7. Myocardial infarction, acute coronary syndrome, stroke, seizure, or a thromboembolic 
event (eg, deep vein thrombosis or pulmonary embolism) within 12 weeks prior to 
randomization 
8. Systolic BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg (confirmed by repeat 
measurement), within 2 weeks prior to randomization  
9. Diagnosis or suspicion (eg, complex kidney cyst of Bosniak Category 2F or higher) of 
renal cell carcinoma on renal ultrasound within 12 weeks prior to randomization  

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10. History of malignancy, exceptions made for the following malignancies: a) those 
determined to be cured or in remission for ≥ 5 years, b) curatively resected basal cell or 
squamous cell skin cancers, c) cervical cancer in situ, or resected colonic polyps 
11. Positive for any of the following: human immunodeficiency virus (HIV); hepatitis B 
surface antigen (HBsAg); or antihepatitis C virus antibody (anti-HCV Ab) 
12. Chronic inflammatory disease that could impact erythropoiesis or is determined to be the 
principal cause of anemia (eg, systemic lupus erythematosus, rheumatoid arthritis, celiac 
disease) even if it is currently in remission 
13. Known untreated proliferative diabetic retinopathy, diabetic macular edema, macular 
degeneration and retinal vein occlusion 
14. Known history of myelodysplastic syndrome or multiple myeloma  
15. Known hereditary hematologic disease such as clinically apparent thalassemia or sickle 
cell anemia, pure red cell aplasia, or other known causes for anemia other than CKD 
16. Known hemosiderosis, hemochromatosis, coagulation disorder, or hypercoagulable 
condition 
17. Any prior organ transplant (that has not been explanted), or a scheduled organ 
transplantation 
18. Anticipated elective surgery that is expected to lead to significant blood loss or 
anticipated elective coronary revascularization 
19. Known active or chronic gastrointestinal bleeding  
20. Any prior treatment with roxadustat or a hypoxia-inducible factor prolyl hydroxylase 
inhibitor (HIF-PHI) 
21. Use of iron-chelating agents within 4 weeks prior to randomization 
22. Use of an investigational drug or treatment, participation in an investigational study, or 
presence of expected carryover effect of an investigational treatment, within 4 weeks 
prior to randomization 
23. Anticipated use of dapsone or androgens in any dose amount or anticipated chronic use of 
acetaminophen or paracetamol > 2.0 g/day during the treatment or follow-up periods of 
the study 
24. History of alcohol or drug abuse within 2 years prior to randomization 
25. Females of childbearing potential, unless using contraception as detailed in the protocol, 
or sexual abstinence; male subjects with sexual partners of childbearing potential who are 
not on birth control unless the male subject agrees to use contraception, or sexual 
abstinence 
26. Pregnant or breastfeeding females 
27. Any medical condition that in the opinion of the Investigator or Sponsor may pose a 
safety risk to a subject in this study, which may confound efficacy or safety assessment, 
or may interfere with study participation 

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5.3 Subject Discontinuation 
Subjects may discontinue from the study at any time. Discontinued subjects should be 
encouraged to complete the ET and the EOS visit procedures. The reason for subject 
discontinuation will be documented. Subjects will then continue to be followed up for vital 
status, safety events requiring potential adjudication, as well as important concomitant 
medication use (eg, ESA), at periodic intervals of 3-6 months until the end of the overall study, 
unless the subject withdraws consent for this modified follow-up. 
Subjects should be discontinued from the study for any of the following reasons: 
• Subject no longer consents to participate in the study  
• Investigator’s decision that it is in the best interest of the subject to be withdrawn from 
the study 
• Significant noncompliance with study procedures, as determined by Investigator or 
Sponsor 
• Subject is lost to follow-up  
• Pregnancy 
• Death 
• Subjects who receive more than 2 courses of ESA rescue that meets the protocol-
specified rescue criteria 
Women of childbearing potential who withdraw from this study will continue contraception or 
sexual abstinence for at least 12 weeks following the last study drug administration. Male 
subjects with partners of childbearing potential must agree to use a medically acceptable method 
of contraception or practice sexual abstinence during the study and for at least 12 weeks 
following the last study drug administration.  

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6 INVESTIGATIONAL PRODUCT 
6.1 Formulation 
Roxadustat and placebo drug product are supplied by FibroGen, Inc. as red coated, oval tablets 
for oral administration, in strengths of 20 mg, 50 mg and 100 mg. The excipients include lactose 
monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, magnesium stearate, 
and colorant Red Opadry II. All ingredients used for manufacture of roxadustat and placebo 
tablets comply with US and European Union compendial or regulatory standards. Strengths are 
different in size, and debossing reflects the strength (ie, 20, 50 or 100 mg). Placebo tablets match 
the roxadustat tablets in appearance and size. Both active and placebo tablets are presented in 
white High-density polyethylene (HDPE) bottles with a black lining, for optimal light protection, 
and closed with a foil induction seal and a white, child resistant cap. Due to the light-sensitive 
nature of roxadustat and to minimize exposure of the active pharmaceutical ingredient to light, 
tablets should remain in the original packaging for as long as possible and be administered as 
intact tablets only. 
6.2 Storage 
Roxadustat and placebo tablets should be protected from light, and stored at 15º to 30ºC (59º to 
86ºF). 
All study drug should also be stored in a securely locked area to which access is limited to 
appropriately qualified and authorized study personnel.  
6.3 Study Drug Handling and Disposal 
All study drugs provided by the Sponsor or provided at the study site should be retained at the 
site until otherwise instructed in writing by the Sponsor. Upon completion of the study or 
termination of the investigational site, all used (bottles), unused, and partially used study drugs; 
and all study drugs that were not dispensed will be shipping to a site designated by the Sponsor 
or may be destroyed according to local/institutional policies by the Pharmacy/authorized staff 
after drug accountability and reconciliation has been completed by Sponsor. Please refer to the 
Study Reference Manual for additional information.  
6.4 Administration 
Study drug dispensing to subjects will generally occur every two weeks for the first 24 weeks 
and then every four weeks for the remainder of the study, with instructions for self-
administration of the tablets on each dosing day, according to the dosing schedule. The first dose 
may be administered at the study site after completion of procedures or may be taken at home. 
The tablets are to be swallowed whole with water. Dosing should occur at approximately the 
same time of day. The subject may take the study drug with or without food. 
Study drug doses will be considered as meeting the definition of TIW if they are administered at 
least 2 days apart, and no more than 4 days apart. Subjects enrolled under previous FGCL-4592-
060 protocols will continue taking study drug BIW or QW if they have already converted to 
those dosing frequencies. Study drug doses taken BIW must be administered at least 3 days 
apart, and no more than 5 days apart. Study drug doses taken QW must be administered at least 5 
days apart, and no more than 9 days apart. It may facilitate dosing if the days of the week of 
dosing remain consistent throughout the study, but this is not mandatory. 

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Compliance with study drug dosing will be closely monitored and recorded throughout the study 
to enable a determination of whether a subject meets sufficient overall compliance with study 
therapy, which will be defined in the Statistical Analysis Plan (SAP). For study drug handling 
and disposal please refer to the Study Manual. 
See Section 2.1 and Appendix 1 for dose adjustments. 

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7 STUDY PROCEDURES 
7.1 Study Procedures by Visit 
7.1.1 Screening Period (Up to 6 Weeks) 
Subjects must be consented before any screening tests or assessments are performed. For all 
screen failures, the reason(s) will be documented. 
7.1.1.1 Screening 1  
• Signed written informed consent 
• Inclusion/Exclusion criteria verification 
• Demographics and medical history  
• Complete physical examination  
• Height, weight 
• Blood pressure, heart rate  
• Laboratory tests: 
o Complete blood count (CBC) with WBC differential  
o Serum chemistry 
o Lipid panel (fasting whenever possible)  
o Serum iron, ferritin, TIBC, TSAT  
o Reticulocyte Hb Content (CHr) 
o Hemoglobin A1c (HbA1c) 
o Vitamin B12 and folate  
o Enzyme-linked immunosorbent assay (ELISA) for HIV 
o Hepatitis B surface antigen and anti-HCV Ab 
o Urine human chorionic gonadotropin (hCG) pregnancy test for women of 
childbearing potential only 
• Adverse event recording  
• Concomitant medication recording 
• Procedures and nondrug therapy recording 
7.1.1.2 Screening 2  
Hemoglobin values must be obtained at least 4 days apart. 
• Blood pressure, heart rate  
• Hemoglobin only  
• Renal ultrasound to exclude renal carcinoma- not required if results of a previous renal 
ultrasound within 3 months prior to randomization are available. If no results are 

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available, a renal ultrasound must be performed during screening, at or after the 
Screening 2 visit. 
• Adverse event recording  
• Concomitant medication recording 
• Procedures and nondrug therapy recording 
7.1.1.3 Screening 3  
Hemoglobin values must be obtained at least 4 days apart. 
• Blood pressure, heart rate  
• Hemoglobin only 
• Adverse event recording  
• Concomitant medication recording 
• Procedures and nondrug therapy recording 
7.1.1.4 Additional Screening 
If a subject’s laboratory results do not meet the eligibility criteria at Screening, in some cases the 
laboratory assessment may be repeated within the Screening Period. 
For example, an additional Hb value may be collected if necessary. The mean of the 3 most 
recent Hb values during the screening period, obtained at least 4 days apart, will be used to 
calculate the subject’s eligibility. Iron, Vitamin B12, and folate may be repeated once during the 
screening period if necessary, in particular if these have been supplemented during the screening 
period. Other labs pertaining to the eligibility criteria should not be repeated unless there is 
reason to believe the initial value(s) is/are incorrect, and not without the prior approval of the 
Sponsor’s medical monitor. If subjects fail screening, they may be rescreened as deemed 
appropriate, with approval by the Sponsor’s medical monitor. 
7.1.2 Treatment Period 
Eligible subjects will be randomized via IWRS to receive roxadustat or placebo. The Treatment 
Period begins on the first day of dosing with study treatment (Day 1/Week 0). Scheduled visit 
days will be calculated from first day of dosing (Day 1/Week 0), for example:  Week 1 (Day 8 
±2 days), Week 12 (Day 85 ±2 days), Week 48 (Day 336 ±3 days), etc. 
7.1.2.1 Day 1 (Week 0) 
All assessments are to be completed prior to study drug administration. 
• Inclusion/Exclusion criteria verification 
• Complete physical examination 
• Weight 
• Blood pressure, heart rate, respiratory rate, temperature 
• Laboratory tests  
o Urinalysis, including microalbumin/creatinine ratio 
o CBC with WBC differential 

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o Serum chemistry  
o Lipid panel (fasting, whenever possible)  
o Serum iron, ferritin, TIBC, TSAT  
o CHr  
o HbA1c 
o Reticulocyte count 
o Special laboratory analytes: Hepcidin and high sensitivity-C-reactive protein (hs-
CRP) 
o Archival serum/plasma samples(optional donation, separate consent form) 
• HemoCue assessment 
• Point of care qualitative urine pregnancy test for women of child bearing potential 
only 
• HRQoL questionnaires (SF-36, FACT-An, and European Quality Of Life Questionnaire 
in Five Dimensions, Five Levels [EQ-5D-5L]) 
• 12-lead electrocardiogram  
• Adverse event recording 
• Concomitant medication recording 
• Procedures and nondrug therapy recording 
• Dispense study drug (2 weeks supply) 
7.1.2.2 Weeks 1 and 2 (Weekly, ±2 days)  
• Laboratory tests (must be performed prior to next dosing week): 
o CBC with WBC differential  
o Week 2 only: Liver Function Test (LFTs) and CPK 
o Week 2 only: CHr 
o Reticulocyte count 
• HemoCue assessment 
• Dose adjustment review in the event of excessive hematopoiesis. Refer to Section 2.1 and 
Appendix 1.  
• BP and heart rate 
• Adverse event recording 

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• Concomitant medication recording 
• Procedures and nondrug therapy recording 
• Dispense study drug, 2 weeks supply (Week 2 only) 
7.1.2.3 Weeks 4 to 24 (Every 2 weeks, ±2 days) 
• Laboratory tests (must be performed prior to next dosing cycle): 
o Weeks 4, 8, 12, and 20: CBC with WBC differential 
o Week 6 followed by every visit where no CBC is collected: Hb only  
o Weeks 4, 8, 12, and 20: Serum chemistry 
o Weeks 6 and 16: LFTs and CPK only 
o Weeks 4, 8, 12, and 20: Lipid panel (fasting whenever possible)  
o Weeks 4, 8, 12, and 20: Serum iron, ferritin, TIBC, TSAT  
o Weeks 4, 6, 8, 12, and 20: CHr 
o Week 12 only: HbA1c 
o Weeks 8, 12, and 20: Reticulocyte count 
o Weeks 4, 12, and 20: Special laboratory analytes (hepcidin, hsCRP) 
o Weeks 4, 12, and 20: Archival serum/plasma samples (optional donation, separate 
consent form) 
• HemoCue assessment 
• Weeks 12 and 24: Targeted physical examination 
• Weeks 12 and 24: Point of care qualitative urine pregnancy test for women of child 
bearing potential only 
• Dose adjustment review beginning at Week 4 followed by every 4 weeks thereafter 
(except/or more frequently in the event of excessive hematopoiesis). Refer to Section 2.1 
and Appendix 1.  
• Week 12 only: HRQoL questionnaires (SF-36, FACT-An, and EQ-5D-5L) 
• Adverse event recording 
• Concomitant medication recording 
• Procedures and nondrug therapy recording 

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• Dispense study drug 
o Weeks 4 to 22 (2 week supply) 
o Week 24 (4 week supply) 
7.1.2.4 Week 28 to End of Treatment (Every 4 weeks, ± 3 days) 
• Laboratory tests (must be performed prior to next dosing cycle): 
o Week 28 followed by every 8 weeks: CBC with WBC differential 
o Week 28 followed by every visit where no CBC is collected: Hb only  
o Week 28 followed by every 8 weeks: Serum chemistry 
o Weeks 28, 36, 44, and 52 followed by every 12 weeks: Lipid panel (fasting 
whenever possible)  
o Week 28 followed by every 8 weeks: Serum iron, ferritin, TIBC, TSAT  
o Week 28 followed by every 8 weeks: CHr 
o Week 28 followed by every 16 weeks: HbA1c 
o Weeks 44, 68 and 84: Reticulocyte count 
o Weeks 44, 68 and 84: Special laboratory analytes (hepcidin, hsCRP) 
o Weeks 44, 68 and 84: Archival serum/plasma samples (optional donation, 
separate consent form) 
• HemoCue assessment 
• Week 36 followed by every 12 weeks: Targeted physical examination 
• Week 36 followed by every 12 weeks: Point of care qualitative urine pregnancy test 
for women of child bearing potential only 
• Weeks 28, 52, and 76: 12-lead electrocardiogram 
• Dose adjustment review every 4 weeks (except/or more frequently in the event of 
excessive hematopoiesis). Refer to Section 2.1 and Appendix 1.  
• All visit weeks: BP and B.  
• All visit weeks: BP and heart rate  
• Weeks 28, 52, and 76: HRQoL questionnaires (SF-36, FACT-An, and EQ-5D-5L) 
• Adverse event recording 
• Concomitant medication recording 

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• Procedures and nondrug therapy recording 
• Dispense study drug (4 weeks supply), except at End of Treatment 
7.1.2.5 End of Treatment (EOT) (± 3 days) 
• Laboratory tests: 
o CBC with WBC differential  
o Serum chemistry 
o Lipid panel (fasting whenever possible)  
o Serum iron, ferritin, TIBC, TSAT  
o CHr  
o HbA1c 
o Reticulocyte count 
o Special laboratory analytes (hepcidin, hs-CRP) 
o Archival serum/plasma samples (optional donation, separate consent form) 
• Complete physical examination  
• Blood pressure, heart rate, respiration rate, temperature 
• Point of care qualitative urine pregnancy test for women of childbearing potential 
only 
• HRQoL questionnaires (SF-36, FACT-An, and EQ-5D-5L) 
• 12-lead electrocardiogram  
• Adverse event recording 
• Concomitant medication recording 
• Procedures and nondrug therapy recording 
7.1.2.6 Early Termination (ET) 
If a subject discontinues from the study during the Treatment Period prior to completing 
treatment, the Investigator should perform the End of Treatment/Early Termination (EOT/ET) 
assessments as soon as possible after withdrawal from dosing (Section 5.3). Whenever possible, 
the subject should also return for a follow-up visit to complete the End of Study (EOS) 
assessments (Section 7.1.3.1). Such a subject will be considered a noncompleter of the treatment 
and/or the study, regardless of whether the patient conducts the EOT assessments at early 
termination and/or the early EOS visit(s). These subjects will continue to be followed for vital 
status, safety events requiring potential adjudication, as well as important concomitant 
medication use (eg, ESA), at periodic intervals of 3 to 6 months until the end of the overall 
study, or unless the subject withdraws consent for this modified follow-up. 

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7.1.3 Post-Treatment Follow-Up Period 
7.1.3.1 End of Study (EOS): 4 weeks after EOT (or ET) (± 2 days) 
• Laboratory tests: 
o CBC with WBC differential 
o Serum chemistry 
o Lipid panel (fasting whenever possible)  
o Serum iron, ferritin, TIBC, TSAT  
o CHr  
o HbA1c 
o Reticulocyte count 
o Special laboratory analytes (hepcidin, hs-CRP) 
o Archival serum/plasma samples (optional donation, separate consent form) 
• Targeted physical examination 
• Blood pressure, heart rate 
• Point of care qualitative urine pregnancy test for women of childbearing potential only 
• Adverse event recording 
• Concomitant medication recording 
• Procedures and nondrug therapy recording 
7.2 Missed Visits 
Every attempt should be made to complete all study visits as outlined in the Schedule of 
Assessments (Appendix 2).  
If a subject fails to return for scheduled visits, a documented effort must be made to return the 
patient to the study or to determine the reason for failed return. If the subject cannot be reached 
by telephone, a certified/registered letter should be sent to the subject (or the subject’s legally 
authorized representative, if appropriate) requesting contact with the Investigator. This 
information should be recorded in the study records. 
7.3 Unscheduled Visits 
Unscheduled visit(s) and laboratory assessments may be required at the discretion of the 
Investigator. Please refer to the CRF Completion Guidelines located in the Study Reference 
Manual for additional information. 
7.4 Laboratory Assessments 
Central laboratory results should be reviewed by the Investigator or another qualified study staff 
member as soon as they are received. Subject management is dependent upon close review of the 
laboratory data.  

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7.4.1 HemoCue 
Hemoglobin values obtained by HemoCue are used to allow “real-time” dose adjustments for all 
subjects. HemoCue results will be collected in the CRF. 
7.4.2 Central Laboratory 
All study related tests of blood specimens will be performed by a central laboratory.  
Unscheduled and repeat laboratory tests will also be performed by the central laboratory. 
However, if the turnaround time from the central laboratory is not sufficiently rapid for clinical 
management of the subject, local laboratory test results may be used to make the necessary 
clinical judgments.  
A Central Laboratory Manual with instructions on specimen collection, processing, storing, and 
shipping to the central laboratory will be provided to all participating sites.  
Laboratory parameters to be measured in this study are as described in Table 5. 

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Table 5. 
Laboratory Tests 
CBC: 
Chemistry Panel: 
 
Additional Laboratory Analytes: 
Basophils 
Albumin 
Phosphorus 
Vitamin B12 
Eosinophils 
Bicarbonate  
Potassium 
Folate 
Erythrocyte count (RBC) 
BUN 
Sodium 
HIV and viral Hepatitis Panel: 
Hb  
Calcium 
Total protein 
Anti-HCV Ab tests 
Hct 
Chloride 
Uric acid 
HBsAg 
Leukocyte count (WBC)  
CPK 
Liver Function Tests 
HIV ELISA 
Lymphocytes 
Creatinine 
ALP 
Urinalysis:  
Mean corpuscular volume  
Glucose 
ALT 
Microalbumin/creatinine ratio 
Mean corpuscular Hb 
Lipase 
AST  
Standard UA with reflex 
microscopic and culture 
Mean corpuscular Hb 
concentration 
Lactate 
dehydrogenase 
Bilirubin, total and 
direct 
Special Laboratory Analytes: 
Monocytes 
Magnesium 
GGT 
Hepcidin 
Neutrophils 
 
 
High-sensitivity CRP 
Neutrophils, immature 
(banded) 
Serum Iron 
Profile 
 
Serum Lipid Panel: 
Platelets 
Ferritin 
TIBC 
Total Cholesterol 
Reticulocyte count 
Iron 
TSAT 
HDL 
 
Reticulocyte Hb 
content 
 
LDL 
 
 
 
Triglycerides 
 
 
 
 
 
 
 
 
Abbreviations: 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; CBC = complete blood count; CPK = creatine phosphokinase; 
CRP = C-reactive protein; ELISA = enzyme-linked immunosorbent assay; GGT = gamma-glutamyl 
transferase; Hb = hemoglobin; HbA1c = glycated hemoglobin; HBsAg = hepatitis B surface antigen; 
Hct = hematocrit; HCV = hepatitis C virus; HDL = high-density lipoprotein; HIV = human 
immunodeficiency virus; LDL = low-density lipoprotein; RBC = red blood cell; TIBC = total iron binding 
capacity; TSAT = transferrin saturation; WBC = white blood cell. 
7.4.3 Archival Serum/Plasma Samples  
A set of serum/plasma samples may be drawn and stored for the future analysis of relevant select 
biomarkers. Donation of these samples is optional and will be sought through a separate 
informed consent form. No genetic testing will be performed using these samples. 
7.5 Electrocardiogram 
Local 12-lead ECGs will be performed on all subjects at baseline Day 1 (Week 0) prior to first 
treatment and treatment Weeks 28, 52, and 76, and at EOT (or ET). 

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7.6 Renal Ultrasound 
A renal ultrasound examination will be required within 3 months prior to randomization. If not 
on record within this timeframe, the subject should have a renal ultrasound performed during 
screening, at or after Screening Visit 2. Renal ultrasound must exclude the presence or suspicion 
of renal cell carcinoma for patient to be eligible. Sites are reminded to schedule the renal 
ultrasound in a timely manner. 
7.7 Health-Related Quality of Life Questionnaires 
All study subjects will be required to complete HRQoL questionnaires (SF-36, FACT-An, and 
EQ-5D-5L) at Day 1 (Week 0), treatment Weeks 8, 12, 28, 52, and 76, and at EOT (or ET). 
Health-related quality of life assessments should be administered approximately at the same time 
of day.  
7.7.1 36-Item Short Form Health Survey 
The 36-Item Short Form Health Survey (SF-36) is a QoL instrument designed to assess generic 
health concepts relevant across age, disease, and treatment groups. It is aimed at both adults and 
adolescents ages eighteen years and older. The SF-36 consists of eight domains of health status: 
physical functioning (PF) (10 items), role physical (4 items), bodily pain (2 items), general 
health (5 items), vitality (4 items), social functioning (2 items), role emotional (3 items) and 
mental health (5 items). Two component scores, the Physical Component Scores and the Mental 
Component Summary can also be calculated. For both the SF-36 domain scores and summary 
scores, higher scores indicate better health status. 
7.7.2 FACT-An 
The Functional Assessment of Cancer Therapy—General (FACT-G; Version 4) contains 27 
items that cover four dimensions of well-being: physical (7 items), functional (7 items), 
social/family (7 items), and emotional (6 items). A subscale of 13 fatigue specific items plus 7 
additional items related to anemia were developed for use in conjunction with the FACT-G 
(Cella 1997). The 13 fatigue items plus the 7 additional items related to anemia comprise the 
Anemia Subscale. Administration of the FACT-G plus the Anemia Subscale is referred to as the 
FACT-An. The FACT-An has a recall period of the ‘past seven days’. Respondents are asked to 
provide responses, (ie, ‘Not at all’, ‘A little bit’, ‘Somewhat’, ‘Quite a bit’ and ‘Very much’), to 
a list of statements which are either positively or negatively phrased. For all FACT-An scales, a 
higher score indicates better QoL.  
7.7.3 European Quality of Life Questionnaire in Five Dimensions, Five Levels (EQ-5D-
5L) 
The EQ-5D-5L consists of the EQ-5D-5L descriptive system and the EQ-5D-5L visual analog 
scale. The EQ-5D-5L descriptive system comprises five dimensions of health: mobility, self-
care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no 
problems, slight problems, moderate problems, severe problems, extreme problems. The visual 
analog scale records the respondent's self-rated health status on a graduated (0 to 100) scale, 
where the endpoints are labeled ‘Best imaginable health state’ and ‘Worst imaginable health 
state’ with higher scores for higher HRQoL. The EQ-5D-5L health states, defined by the 
EQ-5D-5L descriptive system, may be converted into a single summary index by applying a 
formula that essentially attaches values (also called weights) to each of the levels in each 
dimension. 

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7.8 Blood Pressure Measurement 
Blood pressure and heart rate should be performed with the subject comfortably at rest for a 
minimum of 5 minutes, in the seated position with the legs uncrossed, and the back and arm 
supported, such that the middle of the cuff on the upper arm is at the level of the right atrium (the 
midpoint of the sternum). If another position is required, that position should be utilized 
consistently throughout the study. The subject will be instructed to relax as much as possible and 
to refrain from talking during the measurement procedure. Preferably, measurement will be done 
with an electronic automated oscillometric device. From Day 1 through EOT/ET, blood pressure 
must be taken and recorded in triplicate, at least 5 minutes apart.  

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8 ENDPOINTS AND ASSESSMENTS 
8.1 Primary Efficacy Endpoint 
There are two separate regionally-based primary efficacy endpoints in this study depending upon 
whether the data are being filed to support submission to the US FDA or to Ex-US health 
authorities, such as the European EMA. 
The primary endpoint for the US (FDA) submission is defined as the change in Hb from 
baseline to the average level during the evaluation period (defined as Week 28 until Week 52). 
The primary endpoint for the Ex-US submission is defined as the proportion of subjects who 
achieve a Hb response at two consecutive visits during the first 24 weeks of treatment, without 
rescue therapy (ie, RBC transfusion, ESA, or IV iron) 
A Hb response is defined, using central laboratory values, as the following:  
• Hemoglobin ≥ 11 g/dL and Hb increase from baseline by ≥ 1 g/dL in subjects with 
baseline Hb > 8 g/dL, or  
• An increase in Hb by ≥ 2 g/dL in subjects with baseline Hb ≤ 8.0 g/dL  
8.2 Secondary Endpoints 
The secondary efficacy endpoints in this study are: 
• For Ex-US submission only: Hb maintenance: Mean change from baseline (CFB) in Hb 
averaged over 8 weeks of treatment at Weeks 28 to 36, without rescue therapy within 6 
weeks prior to and during this 8-week evaluation period. 
• Mean CFB in LDL cholesterol averaged over Weeks 12 to 28 
• Mean CFB in the SF-36 PF subscore averaged over Weeks 12 to 28 in the Intent to Treat 
(ITT) subjects with baseline PF subscore below 35 
• Mean CFB in SF-36 Vitality subscore averaged over Weeks 12 to 28 in ITT subjects with 
baseline vitality subscore below 50 
• Blood pressure effect 
a. Mean CFB in mean arterial pressure (MAP) averaged over Weeks 20 to 28, 
measured as the mean of the triplicate measurements 5 minutes apart 
b. Time to (and proportion of subjects with) worsened hypertension (defined as 
systolic BP > 170 mmHg or diastolic BP > 110 mmHg measured, and an increase 
from baseline of ≥ 20 mmHg [systolic BP] or ≥ 15 mmHg [diastolic BP], 
confirmed by the mean of triplicate measurements 5 minutes apart) 
• Time to (and proportion of subjects who received) rescue therapy (composite of RBC 
transfusion, ESA use, and IV iron) in the first 24 weeks of treatment 
• Time to (and proportion of subjects who received) rescue therapy (composite of RBC 
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8.3 Additional Evaluation of Efficacy 
Hemoglobin correction and maintenance: 
• For Ex-US submission only: Mean Hb level averaged over 8 weeks of treatment at 
Weeks 28 to 36, without rescue therapy within 6 weeks prior to and during this 8-week 
evaluation period 
• For Ex-US submission only: Time to first Hb response as defined by the primary 
endpoint for Ex-US submission 
• Change from baseline in Hb at each of the selected postdosing time points 
Hospitalization 
• Percentage (%) of subjects hospitalized  
• Number of days of hospitalization per patient-year exposure (PEY) 
Rescue therapy use  
• Time to (and proportion of subjects who receive) RBC transfusions 
• Number of RBC packs per patient-month exposure to study medication 
• Number of ESA-week dose per PEY: 1~3 doses of epoetin alfa or beta or biosimilar 
thereof (in Europe) administered within 1 week = 1 ESA-week; 1 darbepoetin 
subcutaneous (subcut) or IV dose = 2 ESA-week; 1 Mircera IV or subcut dose = 4 ESA-
week; 1 peginesatide dose IV or subcut = 4 ESA-week  
Changes in cholesterol levels 
• Change from baseline at each of the selected treatment time points in:  
o Total cholesterol  
o Low-density lipoprotein/high-density lipoprotein ratio 
o Non-HDL cholesterol 
• Proportion of subjects achieving LDL target of < 100 mg/dL averaged over Weeks 12 to 
28 of treatment 
Blood pressure effect 
• Proportion of subjects achieving blood pressure treatment goal in CKD subjects (systolic 
BP < 130 mmHg systolic and diastolic BP < 80 mmHg) based upon the average blood 
pressures over Weeks 12 to 28 of treatment 
Health-Related Quality of Life (HRQoL) and European Quality of Life in Five Dimensions, 
Five Levels (EQ-5D-5L) benefits of anemia therapy in subjects with CKD anemia 
• Mean CFB averaged over Weeks 12 to 28 of treatment in: 
o Vitality Subscale of SF-36 
 In all ITT subjects 
o Physical Functioning (PF) Subscale of SF-36 
 In all ITT subjects 

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o Physical Component Scores of SF-36 
 In ITT subjects with baseline physical component scores below 40  
 In all ITT subjects 
o SF-36 total score 
 In all ITT subjects 
o Anemia Subscale (“Additional Concerns”) of Functional Assessment of Cancer 
Therapy-Anemia (FACT-An) Scores  
 In ITT subjects with baseline subscale scores below 55 (generally 
associated with fatigue.)  
 In all ITT subjects 
o Total FACT-An Scores 
 In ITT subjects with baseline FACT-An scores below 135 
 In all ITT subjects 
o EQ-5D-5L Scores 
 In all ITT subjects 
Hepcidin, Iron Parameters, HbA1c, and CKD Progression  
• Change from baseline in serum hepcidin at each of the selected treatment time points 
• Change from baseline in serum ferritin at each of the selected treatment time points, 
subgrouped by baseline values of < 100 ng/mL, 100to 400 ng/mL, and > 400 ng/mL  
• Change from baseline in TSAT at each of the selected postdosing time points, 
subgrouped by baseline values of < 20%, 20% to 40%, and > 40% 
• Change from baseline in HbA1c level at each of the selected treatment time points in all 
subjects, in subjects with history of diabetes and those with no diabetes 
• Rate of progression of CKD: rate of change in eGFR over time adjusted by baseline 
eGFR 
• Proportion of subjects requiring renal replacement therapy, adjusted by baseline eGFR 
8.4 Safety Assessments and Endpoints 
Study-specific safety will be assessed by evaluating the following: 
• AEs, SAEs, and clinically significant changes in laboratory values from baseline  
• Vital signs, ECG parameters, and clinical laboratory values 
Pooled safety interpretation will also be determined based on analyses of composite endpoints 
derived from adjudicated events pooled across multiple studies in the roxadustat Phase 3 
program. The members of an independent adjudication committee blinded to treatment 
assignment will adjudicate the following events in multiple phase 3 studies: 
All cause death, MI, stroke, congestive heart failure requiring hospitalization, unstable angina 
requiring hospitalization, hypertensive emergency, deep venous thrombosis, pulmonary 
embolism, and vascular access thrombosis.  

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Various region-specific pooled analyses of composites of these adjudicated events, pooled across 
multiple studies will be conducted. The analyses of the adjudicated events will be detailed in the 
region-specific pooled SAP. 
• For US (FDA) Only: The primary safety endpoint in this study is the MACE (Major Adverse 
Cardiac Event) composite endpoint, defined as time to first occurrence of death from all 
causes, MI, or stroke, only for the purpose of being pooled across multiple similar studies in 
the Phase 3 program. None of the individual studies are powered to meet the MACE primary 
safety endpoint individually. The pooled MACE analysis is only for purposes of supporting a 
US FDA regulatory filing of roxadustat. 
• The above adjudicated safety events may also be used to support the pooled analyses of 
additional composite safety endpoints across multiple studies in the Phase 3 program, such as 
MACE+ (death, MI, stroke, congestive heart failure requiring hospitalization, and unstable 
angina requiring hospitalization), or a composite which consists of all of the adjudicated 
events. 
 

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9 STATISTICAL CONSIDERATIONS 
9.1 Sample Size Determination 
A total of up to 1200 planned subjects will be randomized in a 2:1 ratio to receive either 
roxadustat (approximately 800 subjects) or placebo (approximately 400 subjects) in a double-
blind manner.  
The study is sufficiently powered for both regionally-based primary efficacy endpoints. A 
minimum of 450 subjects are planned to be randomized to receive roxadustat or placebo (2:1 
with approximately 300 roxadustat vs 150 placebo) in a double-blind manner in order to support 
the primary endpoint(s) of the study. 
For US (FDA) Submission Primary Efficacy Endpoint 
A sample size of 450 will have > 99% power to detect a 1 g/dL difference in mean Hb values 
between the two treatment groups, assuming that the common standard deviation is 1.2 g/dL, 
using an analysis of variance (ANOVA) test with a 0.05 two-sided significance level. 
For the comparisons of individual treatment arms versus pooled placebo, a sample size of 35 
roxadustat and 150 placebo will have 90% power to detect a 0.75 g/dL difference in mean Hb 
values between the two treatment groups, assuming that the common standard deviation is 1.2 
g/dL, using an ANOVA test with a 0.05 two-sided significance level. 
For Ex-US Submission Primary Efficacy Endpoint 
Based on a two-sided test at the alpha = 0.05 level of significance, the study will have > 95% 
power to demonstrate a statistically significant difference between roxadustat and placebo, 
assuming that the proportion of subjects with a Hb response in the roxadustat group is at least 
65% and the cumulative proportion of subjects with a Hb response in the placebo group is at 
most 25%.  
During the course of this Phase 3 study, which is being conducted in parallel with other Phase 3 
studies, up to 1200 subjects may be enrolled in this study to support the overall safety evaluation 
of roxadustat across pooled multiple studies in the Phase 3 program, including adjudicated 
composite safety endpoints of interest. The study will stop enrollment at the Sponsor’s discretion 
if: 1) the minimum of 450 subjects has been achieved to support the primary endpoint in this 
individual study, and 2) sufficient safety events of interest have been accumulated across the 
nondialysis Phase 3 program to support a pooled analysis of these events across multiple studies 
in the same population.  
9.2 Analysis Populations 
The following analysis populations will be used for the statistical analysis: 
• Intent-to-Treat Population (ITT): All randomized/enrolled subjects. All efficacy data will 
be analyzed using the ITT population. 
• Safety Population: All subjects who took any dose of study medication will be included in 
the safety population. All safety data will be analyzed using the safety population. 
• Per Protocol Set (PPS): All randomized/enrolled subjects who receive at least 12 weeks of 
study treatment, have valid corresponding Hb measurements, and are without major 

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protocol violations. The PPS population will be utilized for supportive analysis of primary 
and secondary endpoints. Full criteria for PPS exclusion will be specified in the SAP. 
9.3 Interim Analysis 
The study will have no interim analysis with statistical inference. Safety data and dosing 
decisions will be monitored on an ongoing basis. Additional ongoing review of safety data will 
be conducted by an independent DSMB (see Section 4.8).  
9.4 Statistical Analysis 
Safety and efficacy data will be summarized and presented by treatment group and time point in 
summary tables. Descriptive statistics including number of subjects (N), means, standard 
deviations, medians, and minimum and maximum values will be presented for continuous 
variables. Counts and percentages will be presented for categorical variables. For efficacy 
endpoints, the standard error and 95% confidence intervals (CI) will be presented as part of the 
descriptive summaries. In addition, by-subject listing for all safety and efficacy data will be 
presented.  
9.4.1 Subject Enrollment, Accountability and Disposition 
A table will provide the number of enrolled subjects, Safety, ITT and PPS subjects, subjects who 
are completers of the treatment period, subjects who are completers of the study (treatment and 
follow-up), and subjects who terminated the Treatment Period early along with the reason for 
early termination. 
9.4.2 Demographics and Baseline Characteristics 
Demographics (age, race, sex), baseline characteristics including stratification factors, and 
subject disease characteristics will be summarized for the Safety, ITT and PPS populations.  
Descriptive statistics will be calculated for continuous variables (eg, age, weight, baseline Hb, 
body mass index, and baseline eGFR) and frequency counts and percentages will be tabulated for 
categorical variables (eg, sex, race, Hb category, region, iron status, eGFR category, and history 
of cardiovascular disease, cerebrovascular, or thromboembolic disease) by treatment and overall. 
9.4.3 Efficacy Analyses 
Hemoglobin results obtained from the central laboratory will be used for all efficacy analyses. 
Baseline Hb is defined as the mean of the last four central laboratory Hb values prior to the first 
dose of study treatment. Hemoglobin values after a rescue therapy will not be excluded for the 
US (FDA) submission primary efficacy analysis. Hemoglobin values within 6 weeks after a 
rescue therapy will be excluded for the Ex-US submission primary efficacy endpoint as well as 
other sensitivity efficacy analyses. For subjects with missing values, the MMRM model will be 
used for missing data handling unless otherwise specified. 
9.4.3.1 Primary Efficacy Analysis 
The primary efficacy endpoint will be analyzed using the ITT population as the primary analysis 
population and PPS population as a supportive analysis population.  
For US (FDA) Submission 
The primary efficacy endpoint for the US (FDA) submission is the Hb CFB to the average level 
during the evaluation period, defined as Weeks 28 to 52.  

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The planned treatment duration is at least 52 weeks. The rationale for choosing the specified 
evaluation period as the primary endpoint for US (FDA) submission is that one would expect to 
have achieved Hb correction by Week 28, and averaging it to Week 52 would be an accurate 
reflection of a longer term therapeutic effect of roxadustat. 
The hypothesis to be tested for the primary efficacy analysis is: 
H0: Hb CFB to the average of Weeks 28 to 52 in the roxadustat group = Hb CFB to the average 
of Weeks 28 to 52  in the placebo group 
Versus 
H1: Hb CFB to the average of Weeks 28 to 52 in the roxadustat group = Hb CFB to the average 
of Weeks 28 to 52 in the placebo group 
A Multiple Imputation Analysis of Covariance model (MI ANCOVA) will be used to compare the 
roxadustat and pooled placebo groups in a fixed sequence procedure: 1) pooled roxadustat 
(TIW+BIW+QW) vs. pooled placebo, 2) roxadustat TIW vs. pooled placebo, 3) roxadustat BIW 
vs. pooled placebo, 4) roxadustat QW vs. pooled placebo. The latter are being performed to test 
the BIW and QW maintenance dosing frequencies that are enrolled from earlier versions of the 
protocol. If a null hypothesis is rejected, the claim of the tested roxadustat regimen over placebo 
will be declared successful and the test will progress to the next comparison in sequence. 
H0 will be tested at the two-sided alpha = 0.05 level of significance and will be rejected if the p < 
0.05 from the test. 
Hemoglobin values under the influence of a rescue therapy will not be censored in the primary 
analysis. The model will contain terms for treatment arm, baseline measurement, visit, visit by 
treatment arm, and other randomization stratification factors. The primary efficacy analysis will 
be based on the estimated difference in the overall mean effect between the two treatment groups 
throughout the evaluation period based on the MI ANCOVA model. 
For Ex-US Submission 
The primary efficacy endpoint for the Ex-US submission of proportion of responders will be 
compared using Cochran-Mantel-Haenszel (CMH) adjusting for the stratification factors 
comparing the pooled roxadustat (TIW+BIW+QW) to pooled placebo (TIW+BIW+QW). The 
hypothesis to be tested for the primary efficacy analysis is: 
H0: Hb responder rate in the roxadustat group = Hb responder rate in Placebo group 
Versus 
H1:  Hb responder rate in the roxadustat group ≠ Hb responder rate in Placebo  
H0 will be tested at the two-sided alpha = 0.05 level of significance and will be rejected if the 
p < 0.05 from the test. 
The 95% CIs based on CMH adjusted odds ratio will be reported. In addition, the 95% CIs of the 
responder rate based on the exact method of Clopper-Pearson will be calculated and presented. 
The impact of missing data on the analysis of the primary efficacy endpoint will be examined 
using sensitivity analyses detailed in a SAP. 

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9.4.3.2 Secondary Efficacy Analyses 
The secondary efficacy endpoints will be analyzed using the ITT population as the primary 
analysis population and PPS population as a supportive analysis population.  
A Mixed Model of Repeated Measures will be used to compare the roxadustat and pooled 
placebo groups in a fixed sequence procedure. Secondary endpoints will be tested using a fixed 
sequence approach to adjust for multiple endpoints comparing between the pooled roxadustat vs. 
pooled placebo, followed by roxadustat TIW vs. pooled placebo. If a null hypothesis is rejected, 
the claim of roxadustat over placebo will be declared successful and the test will progress to the 
next comparison in sequence. 
1. Ex-US only: Mean CFB in Hb averaged over 8 weeks of treatment at Weeks 28 to 36, 
without rescue therapy within 6 weeks prior to and during this 8-week evaluation period 
for the 2 treatment groups (in a fixed sequence of pooled roxadustat vs. pooled placebo, 
followed by roxadustat TIW vs pooled placebo) will be compared using an MMRM 
model with baseline Hb and eGFR as covariates and treatment group, visit, 
treatment*visit, and the other randomization stratification factors as fixed effects. The 
test for this endpoint will compare the roxadustat group to pooled placebo. Separately, as 
an exploratory analysis to assess the effect of the QW and BIW maintenance dosing 
frequencies, pairwise comparisons of roxadustat BIW and QW (from the original and 
amendment 1 versions of the protocol) to pooled placebo (1P+2P+3P) will also be 
performed.  
2. Mean CFB in LDL cholesterol averaged over Weeks 12 to 28 for the 2 treatment groups 
(pooled roxadustat vs pooled placebo) will be compared using MMRM models with 
baseline value as covariate and stratification factors as fixed effects.  
3. Mean CFB in the SF-36 PF subscore averaged over Weeks 12 to 28 in the ITT subjects 
with baseline PF subscore below 35 for the 2 treatment groups will be compared using an 
MMRM model as outlined above . 
4. Mean CFB in the SF-36 Vitality subscore averaged over Weeks 12 to 28 in the ITT 
subjects with baseline vitality subscore below 50 for the two treatment groups will be 
compared using an MMRM model as outlined above. 
5. Mean CFB in MAP averaged over Weeks 20 to 28 for the two treatment groups will be 
compared using an MMRM model as outlined above.  
6. Time to (and proportion of subjects with) protocol defined worsened hypertension for the 
pooled roxadustat vs pooled placebo will be compared using Cox Proportional Hazards 
model adjusting for stratification factors. A hazard ratio and its associated 95% CI will be 
computed between the roxadustat group versus pooled placebo. Noninferiority will be 
declared if the upper bound of the 2-sided 95% CIs of the odds ratio does not exceed 1.3. 
Superiority will be declared if the upper bound of the 2-sided 95% CI of the odds ratio 
does not exceed one. The incidence rate per PEY by treatment group will also be 
reported. 
7. Time to (and proportion of subjects who received) rescue therapy (composite of RBC 
transfusion, ESA use, and IV iron) over the first 24 and first 52 weeks for the roxadustat 
TIW group versus pooled placebo will be compared using Cox Proportional Hazards 
model adjusting for stratification factors. A hazard ratio and its associated 95% CI will be 
computed between the roxadustat group versus pooled placebo. Superiority will be 

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declared if the upper bound of the 2-sided 95% CI of the hazard ratio does not exceed 
one. 
Comparisons of the individual treatment arms from the original and Amendment 1 versions of 
the protocol (ie, BIW, QW) in roxadustat against pooled placebo will be reported descriptively. 
Subgroup analyses will also be performed for primary and secondary endpoints by sex, age 
group, etc. 
Due to the large amount of visits to include in the model, the unstructured covariance pattern 
model will be applied first. If the algorithm for unstructured covariance pattern does not 
converge, then the heterogeneous Toeplitz structure will be used instead. If this second model 
also does not converge, then the (homogeneous) Toeplitz structure will be tried, and finally 
compound symmetry as a covariance structure to achieve convergence. 
9.4.3.3 Additional Efficacy Analyses 
The additional efficacy analyses will use the ITT population. 
Additional efficacy analyses of continuous endpoints will use an MMRM model using baseline 
value as covariate and other stratification factors as fixed effects. 
Additional analyses of proportions will use the CMH model adjusting for stratification factors. A 
CMH adjusted odds ratio and its associated 95% CI will be computed to compare between the 
roxadustat TIW group and pooled placebo. A two-sided 95% CI of the proportion based on the 
exact method of Clopper-Pearson will be computed for each treatment group.  
Additional efficacy analyses of time-to-event endpoints will use the Cox Proportional Hazards 
model adjusting for stratification factors. Median time to event and associated 95% CI will be 
estimated using Kaplan-Meier method.  
9.4.4 Safety Analyses 
Safety analyses will be performed using the Safety Population. Safety parameters include 
adverse events, laboratory parameters, vital signs, and ECG parameters. For each safety 
parameter, unless otherwise specified, the last assessment made prior to the first dose of double-
blind study medication will be used as the baseline for all analyses. The analytical methods for 
the composite safety endpoints of interest will be described in a region-specific pooled SAP to 
reflect the nature of the pooling of these endpoints across multiple studies in the Phase 3 program 
and the region-specific safety endpoints. 
9.4.4.1 Adverse Events 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA).  
An AE (classified by preferred term) occurring during the double-blind treatment period will be 
considered a treatment emergent adverse event (TEAE) if it was not present prior to the first dose 
of study medication, or it was present prior to the first dose of study medication but increased in 
severity during the double-blind treatment period. An AE that occurs more than 28 days after the 
last dose of study medication will not be counted as a TEAE. 
The number and percentage of subjects reporting TEAEs in each treatment group will be 
tabulated by system organ class (SOC) and preferred term; by SOC, preferred term, and severity; 
and by SOC, preferred term, and relationship. If more than one event occurs with the same 
preferred term for the same subject, the subject will be counted only once for that preferred term 

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using the most severe and most related occurrence for the summarization by severity and by 
relationship to the study medication.  
The overall distribution of TEAEs by severity and relationship to study medication will be 
summarized by treatment group. 
The number and percentage of subjects reporting common (≥ 5% of subjects in any treatment 
group) TEAEs, Treatment-Emergent serious AEs (TESAE), fatal SAEs (ie, events that caused 
death), and AEs leading to discontinuation of study medication will be summarized by SOC, 
preferred term and treatment group, sorted in decreasing frequency overall 
Treatment emergent adverse events will also be reported in terms of incidence rate per PEY. 
Listings will be presented of subjects with SAEs, subjects with AEs leading to discontinuation, 
and subjects who died. 
9.4.4.2 Clinical Laboratory Parameters 
Descriptive statistics for laboratory values and changes from baseline at each assessment time 
point, and for the maximum and minimum value on treatment will be presented by treatment 
group for each laboratory parameter. To assess potentially clinically meaningful laboratory 
abnormalities, the number and percentage of subjects with postbaseline laboratory values outside 
a predefined range or limit of change will be tabulated by treatment group. 
9.4.4.3 Vital Signs 
Descriptive statistics for vital signs (eg, systolic and diastolic blood pressure, and pulse rate) and 
their changes from baseline at each visit, and for the maximum and minimum value on treatment 
will be presented by treatment group. 
9.4.4.4 Electrocardiogram  
Descriptive statistics for ECG parameters (eg, Heart Rate, PR interval, QRS interval, QT 
interval, and QTc interval) at baseline and changes from baseline at each assessment time point 
and for the maximum and minimum value on treatment will be presented by treatment group. 
QTc interval will be calculated using both Bazett (QTcB = QT/(RR)1/2) and Fridericia (QTcF = 
QT/(RR)1/3) corrections; and if RR is not available, it will be replaced with 60/heart rate (HR) in 
the correction formula. To assess potentially clinically meaningful ECG abnormalities, the 
number and percentage of subjects with postbaseline ECG values outside a predefined range or 
limit of change will be tabulated by treatment group, as well as shift tables for results of ECG 
interpretation (normal, abnormal not significant, abnormal significant). 
9.5 Statistical Analysis Plan  
A detailed SAP will be finalized prior to the final database lock. Any significant changes to the 
analyses described in this protocol will be highlighted in the SAP and the Clinical Study Report. 
The analytical methods for the composite safety endpoints of interest will be described in a 
region-specific pooled SAP to reflect the nature of the pooling of these endpoints across 
comparable studies in the Phase 3 program and the region-specific safety endpoints. 
9.5.1 Protocol Deviation  
Due to the complex study design and standard of clinical practice, the following issues should 
not be captured and reported as protocol deviations.  

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• Given the complexities of the dose adjustment algorithm, and the need to take into 
consideration various clinical parameters, it is not considered a protocol deviation when 
study subjects are dosed based on their clinical circumstance, whether or not this is 
concordant with the roxadustat dosing algorithm, unless it is related to “excessive 
hematopoiesis” (refer to Section 4.5.1) or “Overdose”  (prescribed >3.0 mg/kg per dose). 
• ESA administration in during hospitalization: Such ESA use is not considered a protocol 
deviation, if study subjects have no access to study drug while hospitalized. 

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10 SAFETY 
10.1 Background 
Adverse event reports from Investigators are the critical building blocks to the developing safety 
profile of the study drug. Subjects will be asked nonleading questions in general terms to 
determine the occurrence of AEs, according to the schedule outlined in Appendix 2. 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 described 
below in accordance with the Food and Drug Administration (FDA) Final Rule Vol 75, No 188, 
September 29, 2010; Article 18 of Directive 2001/20/EC of the European Parliament and of the 
Council of 4 April 2001and the International Conference on Harmonisation (ICH) E2A 
guidance. 
10.2 Definitions  
10.2.1 Definition of an Adverse Event  
An adverse event is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug-related.  
An AE can be any unfavorable and unintended sign (eg, 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 (eg, 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 
(see Section 10.3.1). 
10.2.2 Definition of a Serious Adverse Event  
A serious adverse event is any adverse event or suspected adverse reaction that results in any of 
the following outcomes: 
• Death, 
• A life-threatening adverse event (ie, 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 

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• An important medical event (based on appropriate medical judgment, the event 
jeopardizes the subject and may require medical or surgical intervention to prevent one of 
the above-listed outcomes) 
10.2.3 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.” 
10.2.4 Definition of an Adverse Reaction 
An adverse reaction means any adverse event caused by a drug.  
10.3 Procedures for Eliciting, Recording, and Reporting Adverse Events 
10.3.1 Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after informed consent 
is obtained and ends 28 days after the last dose of study drug, except for pregnancy reporting 
(see Section 10.3.6). In addition, all AEs reported spontaneously by the subject to site personnel, 
outside the study period, may be recorded. 
AEs 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 Sponsor’s Medical Monitor to determine if further monitoring of the event is 
warranted.  
AEs collected prior to dosing of study drug will be considered “nontreatment emergent” while 
those reported after the first dose of study drug and up to 28 days after the last dose of study drug 
will be considered “treatment emergent” and be assessed for relationship to study drug. 
10.3.2 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 28 days after the last dose of study 
drug may qualify an AE; 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 adverse event: 
• Description (Investigator’s verbatim term describing the event) 
• Dates of onset and resolution 

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• Severity 
• Judgment of relationship to blinded study drug  
• Outcome 
• Action taken regarding study drug as a direct result of the adverse event 
• Other treatment required 
• Determination of “seriousness” 
10.3.3 Assessing Adverse Event Severity 
The Investigator should use the National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0. For terms not specified as part of NCI-CTCAE, the 
following guidelines should be used to determine grade: 
• Grade 1, Mild: Asymptomatic or mild symptoms that 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 (eg, 
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 related to AE 
10.3.4 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 
studies; 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 
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Related (Adverse Reaction): 
• Any event for which there is evidence to conclude that the study drug caused the event. 
Possibly Related (Suspected Adverse Reaction):  
• 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. 
• 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. 
Not Related: 
• The event represents the underlying disease (eg, disease-related symptoms, disease 
progression). 
• The event represents a comorbid condition present at the time the subject entered the 
study. 
• The event represents a known adverse reaction associated with a co-medication received 
by the study subject. 
• The event is common for the study population (eg, cardiovascular events in an elderly 
population). 
• The event has no plausible relationship to study drug. 
• The event is a study endpoint (eg, mortality, specified cardiovascular event). 
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, Sponsor is responsible for making the final causality 
assessment for individual reports, and for reporting suspected adverse reactions and adverse 
reactions to Health Authorities. 
While the Investigator must provide an assessment of the relationship of the event to study drug, 
in most cases only aggregate data review will be used to make the determination of the 
relationship of the study drug to a given AE. This information will be updated periodically and 
provided in the Investigator Brochure (IB). 
10.3.5 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 send (via fax or electronic submission) an SAE Report 
Form to Sponsor’s designated safety management vendor within 24 hours of becoming aware of 
the serious event. (See SAE report form in the study documentation). In case of emergency or 
doubt, the Investigator shall call Sponsor’s Medical Monitor for guidance. Follow-up reports 
must be submitted in a timely manner as additional information becomes available.  
Full details of the SAE should also be recorded on the medical records and in the CRF. All 
correspondence on SAEs must be marked URGENT. The following minimum information is 
required: 

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• Subject number, sex and age 
• The date of report 
• A description of the SAE (event, seriousness of the event) 
• Judgment of 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). 
10.3.5.1 Reporting Serious Adverse Events to the Institutional Review Board / Independent 
Ethics Committee 
The Investigator is responsible for notifying his/her Institutional Review Board or Ethics 
Committee (EC) 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.  
10.3.5.2 Deaths  
For any death occurring during the subject’s study participation, regardless of attribution, the 
Investigator will report the death immediately to the Sponsor’s Medical Monitor and their 
designated safety management vendor. 
The Investigator should notify Sponsor and their designated safety management vendor of any 
death or other SAE occurring after a subject has discontinued or terminated study participation 
that may reasonably be related to the study.  
The Investigator must submit the SAE Report Form and complete the appropriate CRF page for 
the event that led to the subject’s death.  
When reporting a death, the event or condition that caused or contributed to the fatal outcome 
should be recorded as the primary event term on the SAE Report Form.  
10.3.6 Pregnancies: Reporting and Follow-up of Subjects 
A pregnancy in a female subject or a male subject’s female partner must be confirmed by a 
positive serum β-HCG test. If a female subject or the female partner of a male subject becomes 
pregnant while the subject is receiving study treatment or within 12 weeks after the last dose of 
study treatment, a Pregnancy Report Form must be completed and submitted to 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 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. The outcome period 
may vary in length from birth to one year of age, depending on the initial outcome and 
circumstance of the birth. The initial outcome of the pregnancy/birth 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 

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outcome. Follow-up pregnancy outcome reports may be required for longer follow-up of the 
newborn. 
10.3.7 Definition and Reporting of Overdose 
The maximum tolerated dose of roxadustat has not been established in humans. For the purpose 
of this study, the maximum allowed roxadustat dose is 300 mg/dose or 3.0 mg/kg/dose, 
whichever is lower. Any dose exceeding this should be reported within 24 hours, except in 
patients who may be on maximum doses of 400 mg/dose or 3.5 mg/kg/dose from previous 
versions of the protocol. Those patients will undergo a dose adjustment to the new maximum 
dose level in the present protocol, at the next scheduled visit. The Sponsor’s Medical Monitor 
should also be informed of an overdose as soon as possible. In an event of a suspected roxadustat 
overdose, the subject should be monitored closely. Symptoms associated with an overdose, if 
any, will be reported as an adverse event. An overdose without associated symptoms is not an 
AE and will be recorded on the overdose CRF only.  
10.3.8 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. New or worsening 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/SAE. If the abnormal laboratory finding meets criteria for an AE/SAE, report the underlying 
diagnosis in lieu of the abnormal laboratory value.  
Clinically significant laboratory abnormalities that reflect a change from the initial screening 
value and that require active management are to be considered by the Investigator as AEs (eg, 
abnormalities that require study treatment dose modification, discontinuation, more frequent 
follow-up assessments). 

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11 DIRECT ACCESS TO SOURCE DOCUMENTS 
Following site prequalification 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 
Good Clinical Practice (GCP) and ICH E6 guideline. 
The purpose of study 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 Sponsor or designee, 
including unscheduled and missed assessments 
• The reported data are reconciled across all data sources (eg, laboratory, safety, IWRS, 
clinical databases).  
• The conduct of the study is in compliance with the currently approved 
protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s) 
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 Sponsor immediately. 

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12 QUALITY CONTROL AND QUALITY ASSURANCE 
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 site visit 
• Routine study site monitoring 
• Documented study and system training 
• CRF and query review against source documents 
12.2 Audit and Inspection 
Authorized representatives of the sponsor, a regulatory authority, an independent ethics 
committee (IEC) or an institutional review board (IRB) 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 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, GCP guidelines of the International Conference on Harmonization, and any 
applicable regulatory requirements. The investigator should contact the sponsor immediately if 
contacted by a regulatory agency about an inspection. 
 

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13 ETHICS 
13.1 Ethical Considerations 
The study will be conducted in accordance with US Food and Drug Administration (FDA) 
regulations, ICH E6 Guideline for GCP, the Declaration of Helsinki, any other applicable 
regulatory requirements, and Institutional Review Board (IRB) or independent ethics committee 
(IEC) requirements. 
13.2 Communication with the Institutional Review Board or Independent 
Ethics Committee 
This protocol, the Informed Consent Form, the Investigator’s Brochure, and any information to 
be given to the subject must be submitted to a properly constituted IRB/IEC by the Investigator 
for review and approved by the IRB/IEC before the study is initiated and before any 
investigational product is shipped to the Investigator. In addition, any subject recruitment 
materials must be approved by the IRB/IEC before the material is used for subject recruitment.  
The Investigator is responsible for obtaining reapproval by the IRB/IEC annually or more 
frequently in accordance with the regulatory requirements and policies and procedures 
established by the IRB/IEC. Copies of the Investigator’s annual report and other required report 
to the IRB/IEC and copies of the IRB/IEC continuance of approval must be furnished to 
Sponsor. A copy of the signed form FDA 1572 must also accompany the above approval letter 
provided to Sponsor. 
Investigators are also responsible for promptly informing the IRB/IEC of any protocol changes 
or amendments, changes to the Investigator’s Brochure, and other safety-related communications 
from Sponsor. Written documentation of IRB/IEC 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, written Informed Consent 
Form (ICF) from the subject or the subject’s legally authorized representative. IRB/IEC review 
and approval are required for the ICF. The final IRB/IEC approved ICF must be provided to 
Sponsor 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/IEC’s written approval before use and subjects must be 
reconsented 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 Health Insurance 
Portability and Accountability Act (HIPAA), if applicable. 
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 Health Insurance Portability 

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and Accountability Act (HIPAA) Authorization Form or separate authorization to use and 
disclose personal health information 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 DATA HANDLING AND RECORD KEEPING 
14.1 Source Documents 
Source records are original documents, data, and records that are relevant to the clinical study. 
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 study. Source records must be adequate to reconstruct all data transcribed 
onto the CRFs and resolved queries. 
14.2 Data Collection, Handling, and Verification 
All required data will be entered onto CRFs/eCRFs by authorized site personnel. or will be 
provided as a data transfer from authorized service providers (such as laboratory results from a 
central laboratory). Data will be entered or uploaded into a validated, clinical database compliant 
with 21 CFR Part 11 regulations. The database will be a secured, password-protected system 
with full audit trail.  
All subject data will be reviewed by Sponsor and/or designee. Data that appear inconsistent, 
incomplete or inaccurate will be queried for site clarification. 
Medical history, adverse events and medications will be coded using industry standard 
dictionaries (eg, MedDRA and World Health Organization Drug [WHODrug]) Dictionary. 
The Investigator is responsible for reviewing, verifying, and approving all subject data (ie, CRFs 
and queries prior to study completion) ensuring that all data is verifiable with source documents. 

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15 INVESTIGATOR REQUIREMENTS 
The Investigator must be medically qualified to directly supervise the conduct of the study at his 
or her site. The Investigator will permit study-related monitoring, audits, IRB/IEC review, and 
regulatory inspection(s), providing direct access to source data/documents. 
15.1 Study Drug Accountability 
The investigational product (roxadustat and placebo) required for completion of this study will 
be provided by Sponsor. The recipient will acknowledge receipt of the drug by returning the 
appropriate documentation form indicating shipment content and condition. Damaged supplies 
will be replaced. 
The investigational product, including partial and empty bottles, must be maintained at the study 
site until Sponsor or its designee verifies drug accountability and provides instruction for 
destruction or the return of the investigational product to Sponsor’s drug distribution depot. 
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. 
15.2 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, 
Sponsor’s monitors/representatives and collaborators, auditors, and the IRB/IEC for each study 
site. 
The Investigators should promptly notify the Sponsor and/or designee of any audits scheduled by 
any regulatory authorities and promptly forward copies of any audit reports received to the 
sponsor. 
15.3 Retention of Records 
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 Sponsor. 

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16 FINANCING AND INSURANCE 
Financing and insurance are addressed in a separate document.  
 

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

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18 REFERENCES 
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chronic kidney disease patients anyway?" Advances in Chronic Kidney Disease 16.2 (2009): 
131-42. 
Buchler, P., et al. "Hypoxia-inducible factor 1 regulates vascular endothelial growth factor 
expression in human pancreatic cancer." Pancreas 26.1 (2003): 56-64. 
Collins, A. J., et al. "Trends in anemia treatment with erythropoietin usage and patient 
outcomes." American Journal of Kidney Diseases : The Official Journal of the National Kidney 
Foundation 32.6 Suppl 4 (1998): S133-S141. 
Coresh, J., et al. "Prevalence of chronic kidney disease in the United States." JAMA : the journal 
of the American Medical Association 298.17 (2007): 2038-47. 
Eschbach, J. W., et al. "Recombinant human erythropoietin in anemic patients with end-stage 
renal disease. Results of a phase III multicenter clinical trial." Annals of Internal Medicine 
111.12 (1989): 992-1000. 
Eschbach, J. W., et al. "Correction of the anemia of end-stage renal disease with recombinant 
human erythropoietin. Results of a combined phase I and II clinical trial." N Engl J Med 316.2 
(1987): 73-78. 
Eschbach, J. W., et al. "Treatment of the anemia of progressive renal failure with recombinant 
human erythropoietin." N Engl J Med 321.3 (1989): 158-63. 
Fan, C., et al. "Gene expression and phenotypic characterization of mouse heart after chronic 
constant or intermittent hypoxia." Physiol Genomics 22.3 (2005): 292-307. 
Fishbane, S. and A. Besarab. "Mechanism of increased mortality risk with erythropoietin 
treatment to higher hemoglobin targets." Clinical Journal of the American Society of Nephrology 
2.6 (2007): 1274-82. 
Go, A. S., et al. "Chronic kidney disease and the risks of death, cardiovascular events, and 
hospitalization." N Engl J Med 351.13 (2004): 1296-305. 
Gray, M. J., et al. "HIF-1alpha, STAT3, CBP/p300 and Ref-1/APE are components of a 
transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in 
pancreatic and prostate carcinomas." Oncogene 24.19 (2005): 3110-19. 
Greijer, A., et al. "Up-regulation of gene expression by hypoxia is mediated predominantly by 
hypoxia-inducible factor 1 (HIF-1)." J Pathol 206.3 (2005): 291-304. 
Hu, C. J., et al. "Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-
2alpha in hypoxic gene regulation." Mol Cell Biol 23.24 (2003): 9361-74. 
Krapf, R. and H. N. Hulter. "Arterial hypertension induced by erythropoietin and erythropoiesis-
stimulating agents (ESA)." Clinical Journal of the American Society of Nephrology 4.2 (2009): 
470-80. 
Langsetmo, I., Stephenson.R., Jacob, C., Zhang, W., Klaus, S., Lin, A., Kochendoerfer, G., and 
Yeowell, D. Effect of FG-4592 in a Rat Model of Anemia of Chronic Disease. 
301_05_3510_047 (ACD6). 2005.  

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NKF K/DOQI. "KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for 
anemia in chronic kidney disease: update of hemoglobin target." American Journal of Kidney 
Diseases : The Official Journal of the National Kidney Foundation 50.3 (2007): 471-530. 
Peyssonnau, C., V. Nizet, and R. S. Johnson. "Role of the hypoxia inducible factors HIF in iron 
metabolism." Cell Cycle 7.1 (2008): 28-32. 
Scortegagna, M., et al. "HIF-2alpha regulates murine hematopoietic development in an 
erythropoietin-dependent manner." Blood 105.8 (2005): 3133-40. 
Semenza, G. L. "Hypoxia-inducible factor 1: master regulator of O2 homeostasis." 
Curr.Opin.Genet.Dev. 8.5 (1998): 588-94. 
Semenza, G. L. "HIF-1: mediator of physiological and pathophysiological responses to hypoxia." 
J.Appl.Physiol 88.4 (2000): 1474-80. 
Tonelli, M., et al. "Chronic kidney disease and mortality risk: a systematic review." American 
Society of Nephrology 17.7 (2006): 2034-47. 
Unger, E. F. FDA Perspectives on ESAs for Anemia of Chronic Renal Failure: Hemoglobin 
Target and Dose Optimization. 9-11-2007. FDA Department of Health and Human Services. 
Joint Meeting of the Cardiovascular and renal Drugs Advisory Committee and the Drug Safety 
and risk Management Advisory Committee. 10-16-2007.  
USRDS. "US Renal Data System, USRDS 2000 Annual Data Report: Atlas of End-Stage Renal 
Disease in the United States,National Institutes of Health, National Institute of Diabetes and 
Digestive and Kidney Diseases, Bethesda, MD, 2000." United States Renal Data System (2000). 
USRDS. "US Renal Data System, USRDS 2001 Annual Data Report: Atlas of End-Stage Renal 
Disease in the United States,National Institutes of Health, National Institute of Diabetes and 
Digestive and Kidney Diseases, Bethesda, MD, 2001." United States Renal Data System (2001). 
USRDS. "US Renal Data System, USRDS 2002 Annual Data Report: Atlas of End-Stage Renal 
Disease in the United States,National Institutes of Health, National Institute of Diabetes and 
Digestive and Kidney Diseases, Bethesda, MD, 2002." United States Renal Data System (2002). 
USRDS. "US Renal Data System, USRDS 2003 Annual Data Report: Atlas of End-Stage Renal 
Disease in the United States,National Institutes of Health, National Institute of Diabetes and 
Digestive and Kidney Diseases, Bethesda, MD, 2003." United States Renal Data System (2003). 
USRDS. "US Renal Data System, USRDS 2009 Annual Data Report: Atlas of End-Stage Renal 
Disease in the United States, National Institutes of Health, National Institute of Diabetes and 
Digestive and Kidney Diseases, Bethesda, MD, 2009." United States Renal Data System (2009): 
(http://www.usrds.org/atlas.htm). 
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Disease and End-Stage Renal Disease in the United States." United States Renal Data System 
(2011). 
Wang, G. L., et al. "Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer 
regulated by cellular O2 tension." Proc Natl Acad Sci U S A 92.12 (1995): 5510-14. 
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Winearls, C. G., et al. "Effect of human erythropoietin derived from recombinant DNA on the 
anaemia of patients maintained by chronic haemodialysis." Lancet 2.8517 (1986): 1175-78. 
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(2004): 866-76. 

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19 APPENDICES

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Appendix 1 
Dose Adjustment Algorithm 
 
CORRECTION PHASE 
Maintenance 
MAINTENANCE PHASE 
Change in Hb 
From 4 Wks 
Prior (g/dL) 
(To achieve 
initial Hb 
response) 
Hb ≥ 13.0g/dL 
Hb < 10.5 g/dL 
Hb 10.5 to 11.9 
g/dL 
Hb 12.0 to 12.9 g/dL 
Hb ≥ 13.0 g/dL 
< -1.0 
↑ 
Hold, then resume 
dosing using 
maintenance phase 
rules when: 
Hb ≤ 11.9 g/dL, at a 
dose that is reduced by 
two dose steps 
↑ 
↑ 
No change 
Hold, then 
resume dosing 
when: 
Hb ≤ 11.9 g/dL, 
at a dose that is 
reduced by two 
dose steps 
-1.0 to 1.0 
↑ 
↑ 
No change 
↓ 
> 1.0 
No change 
No change 
↓ 
↓ 
Abbreviations: 
↑ = increase; ↓ = decrease; Hb = hemoglobin; wk(s) = week(s). 
 
Dose Increases and Reductions: 
Dose increases (↑) and reductions (↓) are preset to dose steps. 
The dose steps are as follows: 
20, 40, 50, 70, 100, 150, 200, 250, and 300 mg.  
Example: A dose increase at a dose of 70 mg results in 100 mg 
as the new dose. A dose reduction at a dose of 200 mg results in 
150 mg as the new dose. 
*Note: Subjects who were on the 120 mg dose step prior to 
Amendment 2 may still use that dose unless/until a dose review 
requires a change, at which point new dose steps should be 
implemented. 
Note: Maximum dose capped at 3.0 mg/kg per dose or 300 mg, 
whichever is lower. Subjects on higher maximum doses from 
previous protocol versions must change to the new maximum 
dose at the next scheduled visit. 
In a subject whose baseline Hb level was < 8.0 g/dL, a 
dose increase can be made with either a 1 or 2 dose step 
increase, per Investigator discretion, to minimize the risk 
of requiring rescue treatment. 
Dose Adjustment for Excessive Hematopoiesis: 
At any time during the Treatment Period: 
• If Hb increases by > 2.0 g/dL in ≤ 4 weeks (eg, any 
4-week time period), the dose should be reduced by 
one dose step.
Contact the Medical Monitor if dose adjustments are required past the limits of the dose steps; ie, 20 or 300 mg.  
 
 

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Confidential and Proprietary 
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Appendix 2 
Schedule of Assessments 
 
Study Period: 
Screening 
Treatment 
Follow-up 
Visit / Week: 
Up to 
6 Weeks  
Day 1 
(Wk 0) 
Weekly 
(Wks 1 & 2) 
± 2 days 
Every 2 Weeks 
(From Wks 4 to 24)  
± 2 days 
Every 4 Weeks 
(Wks 28 to EOT)± 3 
days  
EOT 
(or ET)  
± 3 days 
EOS  
(4wks post EOT or 
ET) 
± 2 days 
 
1 
2 
3 
 
 
 
 
 
 
Written informed consent 
X 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
X 
 
 
 
 
 
Demographics and medical history 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
X 
 
Wks 12, 24  
Wks 36, Q12Wk  
X 
X  
Height, weight 
X 
 
 
X  
 
 
 
 
 
Blood pressure, heart rate, respiratory rate, 
temperature  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hemoglobin 
 
X  
X  
 
 
Wk 6  
X 
 
 
CBC with WBC differential 
X 
 
 
X 
X 
Wks 4, 8, 12, 20 
Wks 28, Q8Wk 
X 
X 
Serum chemistry 
X 
 
 
X 
 
Wks 4, 8, 12, 20  
Wks 28, Q8Wk 
X 
X 
LFTs and CPK 
 
 
 
 
Wk 2 
Wks 6, 16 
 
 
 
Lipid panel (fasting whenever possible) 
X 
 
 
X 
 
Wks 4, 8, 12, 20  
Wks 28, 36, 44, 52, 
Q12Wk 
X 
X 
Serum iron, ferritin, TIBC, TSAT 
X 
 
 
X 
 
Wks 4, 8, 12, 20  
Wks 28, Q8Wk 
X 
X 
CHr 
X 
 
 
X 
Wk 2 
Wks 4, 6, 8, 12, 20  
Wks 28, Q8Wk 
X 
X 
HbA1c 
X 
 
 
X 
 
Wk 12 
Wks 28, Q16Wk 
X 
X 
Vitamin B12, folate 
X 
 
 
 
 
 
 
 
 
HIV ELISA, HBsAg, anti-HCV Ab 
X 
 
 
 
 
 
 
 
 
Urine hCG pregnancy test  
X 
 
 
 
 
 
 
 
 
Point of care qualitative urine pregnancy test  
 
 
 
X 
 
Wk 12, 24,  
Wk 36, Q12Wk 
X 
X 
Reticulocyte count 
 
 
 
X 
X 
Wks 8, 12, 20 
Wks 44, 68, 84 
X 
X 
Urinalysis 
 
 
 
X 
 
 
 
 
 
Special laboratory analytes (hepcidin, hs-CRP) 
 
 
 
X 
 
Wks 4, 12, 20 
Wks 44, 68, 84 
X 
X 
Archival serum/plasma samples 
 
 
 
X 
 
Wks 4, 12, 20 
Wks 44, 68, 84 
X 
X 
HemoCue assessment 
 
 
 
X 
X 
X 
X 
 
 
Quality-of-life questionnaires 
 
 
 
X 
 
Wks 12  
Wks 28, 52, 76 
X 
 
12-lead ECG 
 
 
 
X 
 
 
Wks 28, 52, 76 
X 
 
Renal ultrasound 
 
X 
 
 
 
 
 
 
Dose adjustment  
 
 
 
 
X 
Wk 4, Q4Wk 
X, Q4Wk 
 
 
Adverse event recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Procedure and nondrug therapy recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dispensing  
 
 
 
X 
X 
X 
X 
 
 

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Appendix 3 
Study Schema 
Screening
Treatment
Follow-up
ICF & Eligibility 
Assessments
(n ≤1200 Subjects with 
NDD-CKD)
ICF & Eligibility 
Assessments
(n ≤1200 Subjects with 
NDD-CKD)
Up to 6 Weeks Before First Dose of 
Treatment
Variable duration of 52 weeks minimum and maximum of  52 weeks after the last subject is randomized
4 Weeks After Last 
Dose of Treatment
Randomization
(2:1, roxadustat:placebo)
Abbreviations: EOS=end of study; EOT=end of treatment; Hb=hemoglobin; ICF=informed consent form; n=number of subjects; NDD-CKD=nondialysis-dependent chronic kidney disease; TIW=three times a week.
a
EOT + 4 weeks ±3 days
EOT
EOSa
EOSa
Correction & Maintenance Phase
Roxadustat, n ≤ 800 Subjects
 or
Placebo, n ≤ 400 subjects
Starting Dose: 
Tiered/Weight based 70  or 100 mg TIW
Correction Phase: 
Subject will be dosed according to dose adjustment algorithm in Appendix 1 until they achieve a Hb level     
11.0 g/dL and a 1.0 g/dL increase from baseline (variable in length).
Maintenance Phase: The investigator will aim to maintain Hb values after initial correction by using the dose adjustment algorithm 
described in Appendix 1 and taking into account physiologic fluctuations and test variability.  
 

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Appendix 4 
Liver Safety Monitoring and Assessment Guidelines 
The guidelines described in this section are intended to enable early detection and action following 
abnormal LFT results and are consistent with FDA guidance for monitoring of Drug Induced Liver 
Injury (DILI). 
It is the responsibility of the Investigator to expeditiously review LFTs, follow these guidelines 
and contact the Medical Monitor if a study subject meets any of the LFT abnormalities 
specified below.  
In addition: 
 Repeat LFTs within 2-3 days 
if: 
 Discontinue Study Drug, if: 
• 
ALT or AST > 3x ULN, 
or  
• 
Tbili > 2x ULN 
• 
ALT or AST > 8x ULN, or 
• 
ALT or AST > 5x ULN for > 2 weeks, or 
• 
ALT or AST > 3x ULN and (Tbili > 2x ULN or INR > 1.5), or 
• 
ALT or AST > 3x ULN with appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(> 5%) 
Abbreviations; 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; Tbili = total 
bilirubin; ULN = upper limit of normal. 
Repeat LFTs 2-3 times weekly, then weekly or less until abnormalities stabilize or return to 
within normal limits. LFTs should include the usual 4: ALT, AST, Tbili and ALP 
If close monitoring for LFTs in a subject is not possible, study drug should be discontinued 
Evaluate the subject for potential causes, which may include the following: 
• Detailed history of symptoms and prior or concurrent diseases 
• Concomitant drug use, including nonprescription medications, herbal and dietary 
supplements, alcohol or recreational drug use, or special diets 
• Exposure to environmental chemical agents 
• Rule out acute viral hepatitis types A,B,C,D,E; autoimmune or alcoholic hepatitis; 
nonalcoholic steatohepatitis; hypoxic/ischemic hepatopathy; biliary tract disease 
• Obtain additional tests as appropriate: eg, INR, GGT or direct bilirubin; ultrasound or 
other imaging to assess biliary tract disease 
• Consider gastroenterology or hepatology consultations 
Once LFTs return to normal, and depending on whether there is an explanation for the LFT 
elevations, study drug dosing may resume, after discussion with the Medical Monitor 
Ref: FDA Guidance for Industry, titled: “Drug-Induced Liver Injury: Premarketing Clinical 
Evaluations”, issued July 2009 

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Confidential and Proprietary 
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Appendix 5 
Sponsor Signature(s) 
A Phase 3, Randomized, Double-Blind, Placebo Controlled Study of the Efficacy and Safety 
of Roxadustat (FG-4592) for the Treatment of Anemia in Chronic Kidney Disease Patients 
not on Dialysis 
 
Protocol Number: FGCL-4592-060, Amendment 3, 20 September 2017 
 
Signature:_____________________________ 
 
 
 
 
Date: _____________________ 
 
 
Signature:_____________________________ 
 
 
 
 
Date: _____________________