Conditions: Anemia Associated With End Stage Renal Disease (ESRD)
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 203
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the safety and effectiveness of Roxadustat dosing regimens among chronic dialysis participants converted from ESA therapy or who are ESA-naïve.

Detailed description:

Arms:
arm 1: Participants will receive roxadustat as an oral tablet, 3 times per week (TIW) for up to a maximum of 24 weeks. If a participant requires roxadustat \<60 milligrams (mg)/week to maintain Hb levels, the dose frequency will be reduced in a stepwise manner, for example, to BIW, and then QW. For participants converted from CERA, the initial roxadustat dose will be based on the average prescribed CERA dose in the last 8 weeks prior to conversion. For participants with \<6 weeks of prior CERA use, the initial roxadustat dose will be based on a 2-tiered, weight-based dosing scheme. Dose adjustment evaluations will be made every 4 weeks and doses will be titrated based on Hb level and rate of Hb change. The prescribed dose will not exceed the maximum allowable dose of 3.0 mg/kilogram (kg)/dose or 400 mg per dose, whichever is lower.

Interventions: intervention 1: Roxadustat
Intervention descriptions: intervention 1: Roxadustat will be administered per dose and schedule specified in the arm description.

Protocol document:
Prot_000.pdf: 
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Confidential 
Page 1 of 74 
TITLE PAGE 
CLINICAL STUDY PROTOCOL 
STUDY TITLE: 
Phase 3b Multicenter, Open-Label Single Arm Study of 
Roxadustat: Either as Conversion from a Continuous 
Erythropoietin Receptor Activator (CERA), or as Initial 
Anemia Treatment in Hemodialysis (HD) Patients - 
DENALI Study 
PROTOCOL 
NUMBER: 
FGCL-4592-097 
SPONSOR: 
FibroGen, Inc. 
409 Illinois Street 
San Francisco, California 94158 USA 
IND NUMBER: 
074454 
STUDY DRUG: 
Roxadustat (FG-4592) 
INDICATION: 
Anemia associated with ESRD 
FIBROGEN MEDICAL 
MONITOR: 
PROTOCOL VERSION 
& DATE: 
ORIGINAL: 
AMENDMENT 1: 
AMENDMENT 2: 
Name: 
 
Title: 
 
Telephone: 
 
Mobile: 
 
Fax: 
 
E-mail: 
28 February 2020 
27 April 2020 
20 August 2020 
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 #NCT04410198


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Roxadustat 
Protocol FGCL-4592-097 A2 
Confidential 
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INVESTIGATOR SIGNATURE PAGE 
STUDY ACKNOWLEDGEMENT 
 
Phase 3b Multicenter, Open-Label Single Arm Study of Roxadustat: Either as Conversion from 
a Continuous Erythropoietin Receptor Activator (CERA), or as Initial Anemia Treatment in 
Hemodialysis (HD) Patients – DENALI Study 
 
FGCL-4592-097 
 
Amendment 2, Date: 20 August 2020 
 
 
 
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 


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Roxadustat
Protocol FGCL-4592-097 A2
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CONFIRMATION OF PROTOCOL APPROVAL
Amendment 2, Date: 20 August 2020 
This protocol is approved by FibroGen. 
09-Sep-20 | 08:22:06 PDT
Date
FibroGen, Inc.


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Roxadustat 
Protocol FGCL-4592-097 A2 
Confidential 
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SUMMARY OF CHANGES 
Amendment 2 
 
Description of Change 
Rationale for Change 
Section(s) 
Affected 
Major Changes: 
Exclusion criterion # 13 updated From: 
Subject has a diagnosis or suspicion (e.g., 
complex kidney cyst or Bosniak Category II 
or higher) of renal cell carcinoma as shown 
on renal imaging performed within 24 weeks 
prior to enrollment 
To: 
Subject has a diagnosis or suspicion (e.g., 
complex kidney cyst or Bosniak Category II 
or higher) of renal cell carcinoma (PI’s 
discretion) 
To allow the Principal Investigator 
to make a determination based on 
clinical judgement in order to 
minimize additional clinic visit for 
renal imaging during current 
pandemic 
Synopsis 
Section 5.2 
Minor editorial changes (to correct 
typographical errors and to improve 
consistency and clarity) 
Subjects who wish to permanently 
discontinue roxadustat, after EOT should 
receive the first ESA dose at least two days 
after the last roxadustat dose instead of three 
days. 
To correct typographic error 
Synopsis 
Section 4.6 
Section 7.4 
Word “estimated” added before “Dry weight 
in HD subjects” for inclusion # 9 
For better clarification and 
consistency 
Synopsis 
Section 5.1 
Exclusion criteria #24 and #25 were not 
numbered separately due to formatting error. 
This is corrected. 
To correct formatting error 
Synopsis 
Updated the Note to remove the word “post 
dialysis” for subject’s dry weight at 
enrollment 
For better clarification and 
consistency 
Table S2 
Body weight categories for patents initiating 
roxadustat dosing have been corrected as 
follows (to align with the synopsis): from ≤ 
100 kg to < 100 kg and from > 100 kg to ≥ 
100 kg 
To correct typographic error 
Table 2 
Temperature collection requirement added 
with vital signs for applicable visits 
To correct an inadvertent error 
Section 7 
Clarified that central Hemoglobin during 
weeks 12 to 24 should be a part of CBC 
For better clarification 
Section 7.3.3 
Protocol requirement to perform renal 
ultrasound removed from screening visit 
To align with the revised 
Exclusion Criterion # 13 
Table 4 


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Roxadustat 
Protocol FGCL-4592-097 A2 
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................................... 1 
INVESTIGATOR SIGNATURE PAGE ......................................................................................... 2 
CONFIRMATION OF PROTOCOL APPROVAL ......................................................................... 3 
SUMMARY OF CHANGES ........................................................................................................... 4 
TABLE OF CONTENTS .................................................................................................................. 5 
LIST OF ABBREVIATIONS .......................................................................................................... 9 
1. 
PROTOCOL SYNOPSIS ........................................................................................... 11 
2. 
BACKGROUND ........................................................................................................ 21 
2.1. 
Introduction ................................................................................................................ 21 
2.1.1. 
Epidemiology of Chronic Kidney Disease and End-Stage Renal Disease ................. 21 
2.1.2. 
Anemia Associated with Chronic Kidney Disease ..................................................... 22 
2.2. 
Current standard of care for CKD or DD-CKD Anemia ............................................ 23 
2.3. 
Mechanism of Action of Roxadustat .......................................................................... 24 
2.4. 
Clinical Experience with Roxadustat .......................................................................... 26 
2.4.1. 
Pharmacokinetics and Pharmacodynamics ................................................................. 27 
2.5. 
Summary .................................................................................................................... 28 
2.6. 
Roxadustat Dose Rationale ......................................................................................... 28 
2.6.1. 
Maximum Dose for Roxadustat .................................................................................. 28 
2.7. 
Risks/Benefits of Roxadustat Treatment .................................................................... 29 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................ 30 
3.1. 
Objectives ................................................................................................................... 30 
3.1.1. 
Primary Objectives ..................................................................................................... 30 
3.1.2. 
Safety/Exploratory Objectives .................................................................................... 30 
3.2. 
Efficacy Endpoints ..................................................................................................... 30 
3.2.1. 
Efficacy Endpoints ..................................................................................................... 30 
3.2.2. 
Exploratory Endpoints/Analyses ................................................................................ 30 
3.3. 
Safety Endpoints ......................................................................................................... 31 
4. 
STUDY DESIGN ....................................................................................................... 32 
4.1. 
Description of the Study ............................................................................................. 32 
4.2. 
Study Rationale .......................................................................................................... 33 
4.3. 
Screening Period ......................................................................................................... 33 
4.4. 
Treatment Period ........................................................................................................ 33 


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4.5. 
Starting Dose of Study Drug....................................................................................... 33 
4.5.1. 
Route of Administration ............................................................................................. 33 
4.5.2. 
Dosing Frequency ....................................................................................................... 33 
4.5.3. 
Initial Doses ................................................................................................................ 34 
4.6. 
Post-Treatment Follow-Up Period .............................................................................. 35 
4.7. 
Concomitant Medications, Procedures and Nondrug Therapies................................. 35 
4.7.1. 
Concomitant Medications ........................................................................................... 35 
4.7.2. 
Supplemental Iron Use ............................................................................................... 36 
4.7.3. 
Rescue Therapy Guidelines ........................................................................................ 36 
4.7.4. 
Prohibited Medications/Therapies/Substances ............................................................ 37 
4.7.5. 
Contraception .............................................................................................................. 38 
4.8. 
Safety Monitoring Plan ............................................................................................... 38 
5. 
STUDY ENROLLMENT AND WITHDRAWAL ..................................................... 39 
5.1. 
Inclusion Criteria ........................................................................................................ 39 
5.2. 
Exclusion Criteria ....................................................................................................... 39 
5.3. 
Subject Discontinuation and Withdrawal ................................................................... 41 
5.4. 
Replacement of Subjects ............................................................................................ 42 
6. 
INVESTIGATIONAL PRODUCT ............................................................................. 43 
6.1. 
Formulation ................................................................................................................ 43 
6.2. 
Storage ........................................................................................................................ 43 
6.3. 
Study Drug Handling and Disposal ............................................................................ 43 
6.4. 
Route of Administration and Dose ............................................................................. 43 
6.5. 
Overdose, Emergency Procedures and Management of Overdose ............................. 43 
7. 
STUDY PROCEDURES ............................................................................................. 45 
7.1. 
Study Procedures by Visit / Schedule of Assessments ............................................... 45 
7.2. 
Screening Period ......................................................................................................... 45 
7.2.1. 
Additional Screening Assessments ............................................................................. 46 
7.3. 
Treatment Period ........................................................................................................ 46 
7.3.1. 
Day 1 .......................................................................................................................... 46 
7.3.2. 
Weeks 2 to 8 (Every 2 Weeks, ±4 days) ..................................................................... 47 
7.3.3. 
Weeks 12 to 24 (Every 4 weeks, ±4 days) .................................................................. 47 
7.4. 
Post-Treatment Follow-up visit (for subjects discontinuing roxadustat treatment 
at Week 24 or Early Termination) (±7 days) .............................................................. 48 
7.5. 
Missed Visits .............................................................................................................. 48 


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7.6. 
Unscheduled Visits ..................................................................................................... 48 
7.7. 
Laboratory Assessments ............................................................................................. 49 
7.8. 
Central Laboratory ...................................................................................................... 49 
8. 
SAFETY ..................................................................................................................... 51 
8.1. 
Background ................................................................................................................. 51 
8.2. 
Definitions .................................................................................................................. 51 
8.2.1. 
Definition of an Adverse Event .................................................................................. 51 
8.2.2. 
Definition of a Serious Adverse Event ....................................................................... 51 
8.3. 
Procedures for Eliciting, Recording, and Reporting Adverse Events ......................... 52 
8.3.1. 
Adverse Event Reporting Period ................................................................................ 52 
8.3.2. 
Adverse Event Eliciting/Reporting ............................................................................. 52 
8.3.3. 
Assessing Adverse Event Severity ............................................................................. 53 
8.3.4. 
Assessing Relationship to Study Drug ....................................................................... 53 
8.3.5. 
Reporting Serious Adverse Events on the Serious Adverse Event Report Form ....... 54 
8.3.6. 
Pregnancies: Reporting and Follow-up ...................................................................... 55 
8.3.7. 
Abnormal Laboratory Findings .................................................................................. 55 
8.3.8. 
Disease Progression .................................................................................................... 56 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 57 
9.1. 
Sample Size Determination ........................................................................................ 57 
9.2. 
Analysis Sets .............................................................................................................. 57 
9.3. 
Analysis of the Efficacy Endpoints ............................................................................ 57 
9.4. 
Safety Analysis ........................................................................................................... 58 
10. 
DIRECT ACCESS TO SOURCE DOCUMENTS ..................................................... 59 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 60 
11.1. 
Data Quality Assurance .............................................................................................. 60 
11.2. 
Audit and Inspection ................................................................................................... 60 
12. 
ETHICS ...................................................................................................................... 61 
12.1. 
Ethical Considerations ................................................................................................ 61 
12.2. 
Communication with the Institutional Review Board or Independent Ethics 
Committee .................................................................................................................. 61 
12.3. 
Informed Consent Form.............................................................................................. 61 
12.4. 
Subject Confidentiality ............................................................................................... 62 
13. 
DATA HANDLING AND RECORD KEEPING ...................................................... 63 
13.1. 
Source Documents ...................................................................................................... 63 


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13.2. 
Data Collection, Handling, and Verification .............................................................. 63 
14. 
FINANCING AND INSURANCE ............................................................................. 64 
15. 
PUBLICATION POLICY .......................................................................................... 65 
16. 
INVESTIGATOR REQUIREMENTS ....................................................................... 66 
16.1. 
Study Drug Accountability .......................................................................................... 66 
16.2. 
Disclosure of Data ...................................................................................................... 66 
16.3. 
Retention of Records .................................................................................................. 66 
17. 
REFERENCES ........................................................................................................... 67 
18. 
APPENDIX ................................................................................................................ 71 
 
LIST OF TABLES 
 
Table 1: Conversion from CERA to Roxadustat ........................................................................... 34 
Table 2: Initial Roxadustat Dosing: ............................................................................................... 34 
Table 3: Recommended Maximum Daily Dose of Statins ........................................................... 36 
Table 4: Schedule of Assessments ................................................................................................ 45 
Table 5: Central Laboratory Tests ................................................................................................ 50 
 
LIST OF FIGURES 
 
Figure 1. 
Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor (HIF-PHI) Mechanism of 
Action ......................................................................................................................... 24 
Figure 2: Study Design Overview ................................................................................................ 32 
 
 
LIST OF APPENDICES 
Appendix 1: Roxadustat Dose Adjustment Rules ......................................................................... 72 
Appendix 2: Liver Function Monitoring ...................................................................................... 73 


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Protocol FGCL-4592-097 A2 
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LIST OF ABBREVIATIONS 
 
~ 
approximately 
Ab 
antibody 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration curve 
AV 
arteriovenous 
BIW 
twice weekly 
BL 
baseline 
BP 
blood pressure 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CHr 
reticulocyte hemoglobin content 
CI 
confidence interval 
CKD 
chronic kidney disease 
Cmax 
maximum concentration 
CM 
Concomitant Medication 
CS 
clinically significant 
CYP 
cytochrome P450 
dBP 
diastolic blood pressure 
DD-CKD 
dialysis-dependent chronic kidney disease 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
eEPO 
endogenous erythropoietin 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
End of Study 
EOT 
End of Treatment 
EPO 
Erythropoietin 
ESA 
erythropoiesis-stimulating agent 
ESRD 
end-stage renal disease 
ET 
Early Termination (visit) 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
Hb 
Hemoglobin 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HD 
Hemodialysis 
HEENT 
Head Eye Ear Nose and Throat 
HIF 
hypoxia-inducible factor 
HIF-PH 
HIF prolyl hydroxylase 
HIF-PHI 
HIF prolyl hydroxylase inhibitor 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HR 
heart rate 
hs-CRP 
high-sensitivity C-reactive protein 
IB 
Investigator’s brochure 


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Roxadustat 
Protocol FGCL-4592-097 A2 
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ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
investigational new drug 
IRB 
Institutional Review Board 
ITT 
Intent to Treat Population 
IV 
Intravenous 
KDOQI 
kidney disease outcomes quality initiative 
LFT 
liver function test 
N (or n) 
sample size 
NCS 
not clinically significant 
NDD-CKD 
Non-dialysis dependent chronic kidney disease 
NYHA 
New York Heart Association 
PD 
peritoneal dialysis 
PH 
prolyl hydroxylase 
PK 
Pharmacokinetics 
QW 
once weekly 
RBC 
red blood cell 
RR 
respiratory rate 
RRT 
renal replacement therapy 
SAE 
serious adverse event 
SAF 
safety analysis set 
sBP 
systolic blood pressure 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TIBC 
total iron binding capacity 
TIW 
three times weekly 
TSAT 
transferrin saturation 
UIBC 
unsaturated iron binding capacity 
ULN 
Upper limit of normal 
USRDS 
United States Renal Data System 
VEGF 
vascular endothelial growth factor 
WBC 
white blood cell 
Wt 
Weight 


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Roxadustat 
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1. 
PROTOCOL SYNOPSIS 
 
 
Study Title: 
Phase 3b Multicenter, Open-Label Single Arm Study of Roxadustat: Either 
as Conversion from a Continuous Erythropoietin Receptor Activator 
(CERA), or as Initial Anemia Treatment in Hemodialysis (HD) Patients – 
DENALI Study 
Protocol 
Number: 
FGCL-4592-097 
Investigational 
Product: 
Roxadustat (FG-4592) 
Target 
Population: 
Subjects with end-stage renal disease (ESRD) on HD, who either are on a 
stable CERA dose, or are newly initiating anemia treatment 
IND Number: 
074454 
Study Phase: 
Phase 3b 
Study Centers 
Planned: 
Approximately 20 sites in the USA 
Number of 
Subjects 
Planned: 
Approximately 200 subjects 
Primary 
Objective: 
To confirm safe and effective Roxadustat dosing regimens among chronic 
dialysis subjects converted from ESA therapy (>=6 weeks ESA treatment) or 
who are ESA-naïve (<6 weeks ESA treatment) 
Safety / 
Exploratory 
Objectives: 
• Assessment of treatment-emergent adverse events (TEAEs) and 
serious adverse events (TESAEs) 
• Laboratory parameters, including iron indices 
• Utilization of intravenous (IV) iron 
• Dosing compliance 
• To test operational characteristics of converting a population of 
ESRD subjects from an injectable to oral anemia therapy 
Study Design 
Overview: 
Single-arm study to evaluate roxadustat in correcting or maintaining Hb in 
ESRD subjects receiving chronic dialysis: 
• Either after conversion from a stable CERA dose: 
CERA use > 6 weeks prior to conversion to roxadustat dosing 
• Or as initial anemia treatment, in subjects with < 6 weeks of CERA 
use or no prior ESA use prior to start of roxadustat dosing 
The study periods are as follows: 
o Screening Period: Up to 6 weeks 
o Treatment Period: 24 weeks 
o Post-Treatment Follow-Up Period: Subjects permanently 
discontinuing roxadustat should have one final safety 
assessment 28 days after the last roxadustat dose 
For subjects converted from a CERA, the initial roxadustat dose is based on 
the average prescribed CERA dose in the last 8 weeks prior to conversion 
(See Table S1). 


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Roxadustat treatment should start two weeks after stopping CERA 
For subjects initiating anemia treatment (< 6 weeks of prior CERA use), the 
initial roxadustat dose is based on estimated dry weight at enrollment (See 
Table S2). 
Roxadustat dose adjustments should follow the Dose Adjustment Rules, to 
maintain Hb within the target range specified in Table S3). 
During the Treatment Period, subjects will attend biweekly study visits from 
Day 1 to Week 8, followed by every 4-week study visits from Week 8 – 24. 
Local Hb values will be drawn, prior to dialysis, in order to determine the 
need for a dose adjustment, and to assess for excessive rate of hemoglobin 
rise, in real-time. 
After completing the Treatment Period (Week 24 /EOT), subjects who wish 
to permanently discontinue roxadustat, should receive the first ESA dose at 
least two days after the last roxadustat dose. Subjects permanently 
discontinuing roxadustat should also have one final safety assessment 28 
days after the last roxadustat dose. 
See Table 4 for the complete Schedule of Assessments. 
An extension of roxadustat treatment after 24 weeks may be offered to 
interested subjects within the context of this study protocol upon agreement 
of the study site, until roxadustat is commercially available, or up to 1 year 
after completing the 24 weeks, whichever comes first. 
Guidelines for patients receiving home-dialysis: 
Home-dialysis patients are allowed to participate in this study. Investigators 
may use delivery services for medication dispense and/or local laboratory 
blood draw and/or testing. 
For home-dialysis patients, investigators may adjust study visit frequency 
and method of visits such as use of telemedicine including dose-dispensation 
schedule in consideration of clinical circumstances and convenience of the 
patient. 
To simplify the study procedures for home-dialysis patients, renal ultrasound 
can be exempted, Screening Visit and Day 1 Visit may be combined into 
Day 1 Visit. Patients on home-dialysis must visit research-center during 
Screening/Day 1, and Week 24 (or if discontinued prematurely) and clinical 
laboratory testing for these visits need to be sent to the central lab. For other 
visits (per SOA), investigator/authorized study staff should contact the 
patient via telemedicine, such as phone (audio, video call etc.) to collect 
study related information e.g. documentation of study drug dose, 
hemoglobin level, adverse events including hospitalization, conmed changes, 
transfusion etc, and to provide instructions on study drug dose adjustments. 
When possible, investigator should make efforts to combine standard of care 
visits to the clinic with the study visit that falls around that time frame (out 
of window protocol deviation will be exempted) in order to perform in- 
center assessments, central laboratory draws as deemed necessary by the 
investigator based on the clinical circumstances. 
Hemoglobin levels every 2 to 4 weeks (as part of CBC listed in SOA) are 
needed for dose adjustments of roxadustat. The hemoglobin testing between 
Weeks 2 to 24 may be conducted via central lab, local lab, or validated 


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point-of-service testing device. Chemistry and iron parameter tests should be 
evaluated at least every 2-3 months, per discretion of the investigator. 
Whenever central laboratory draws were not feasible but local laboratory 
tests were performed, key test results need to be made available to the study 
file. 
Combining Screening and Day 1 visits: 
Laboratory values related to eligibility assessments (e.g. LFTs, Hepatitis B 
and C, HIV, serum pregnancy, CBC/Hb, iron parameters) performed at a 
local lab within 12 weeks prior to enrollment/Day 1 may be used instead of 
central laboratory values (done during screening) to confirm eligibility, if 
available. If local laboratory values are not available, Screening and Day 1 
visit may still be combined if PI has no safety concerns and if PI prefers to 
start oral anemia therapy right away considering the current clinical 
condition and convenience of the patient. Upon reviewing central lab values 
collected at Day 1, PI may ask the patient to stop taking roxadustat if there is 
any significant safety concerns (e.g. very high LFT values). 
Inclusion 
Criteria: 
A subject is eligible for the study if all of the following criteria are met: 
1. 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 
2. Subject is ≥ 18 years of age 
3. Receiving chronic dialysis for end stage renal disease (ESRD) 
4. Prior ESA use: 
• For a subject converting from an ESA: On CERA ≥ 6 weeks and the 
prescribed CERA dose should remain stable (as determined by PI) 
during the 4 weeks prior to initiating roxadustat treatment 
• Subject is initiating anemia treatment: Defined as: < 6 weeks of prior 
CERA use or no prior ESA use 
5. Vascular access must be a functioning native arteriovenous fistula or 
graft with adequate flow in the opinion of the investigator, or permanent 
tunneled catheter. 
6. Screening Hb (based on central lab value; measured within 10 days prior 
to initiating roxadustat treatment): 
• Subjects converting from an ESA: screening Hb is between 9.0 to 
12.0 g/dL 
• Subjects initiating anemia treatment: screening Hb is < 10.0 g/dL 
7. Ferritin ≥ 50 ng/mL, Transferrin saturation (TSAT) ≥ 10% at screening 
(subject may qualify after receiving iron supplement per local standard 
of care) 
8. Subject’s alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) are ≤ 3 x upper limit of normal (ULN), and total bilirubin (TBL) 
is ≤ 1.5 x ULN at screening and prior to initiating roxadustat treatment. 
(TBL up to 2 x ULN may be allowed if AST and ALT are within normal 
limit) 
9. Subject’s body weight (estimated dry weight in HD subjects) is 45.0 to 
160.0 kg 


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Exclusion 
Criteria: 
Subjects will be excluded if any of the following criteria are met: 
1. Subject has received a red blood cell (RBC) transfusion within 4 weeks 
prior to enrollment 
2. Subject has a known history of myelodysplastic syndrome or multiple 
myeloma 
3. Subject has a known hereditary hematologic disease such as thalassemia 
or sickle cell anemia, pure red cell aplasia or other known causes for 
anemia other than chronic kidney disease (CKD) 
4. Subject has known hemosiderosis, hemochromatosis, coagulation 
disorder, or hypercoagulable condition 
5. Subject has a known chronic inflammatory disease that is determined by 
the investigator to be the primary cause of anemia (e.g., systemic lupus 
erythematosus, rheumatoid arthritis, celiac disease) 
6. Subject is anticipated to undergo elective surgery that is expected to lead 
to significant blood loss during the study period or anticipated elective 
coronary revascularization. 
7. Subject has active or chronic gastrointestinal bleeding 
8. Subject has been treated with iron-chelating agents within 4 weeks prior 
to enrollment 
9. Subject has a history of chronic liver disease (e.g., chronic infectious 
hepatitis, chronic auto-immune liver disease, cirrhosis, or fibrosis of the 
liver) 
10. Subject with New York Heart Association (NYHA) Class III or IV 
congestive heart failure 
11. Subject has had an MI, acute coronary syndrome, stroke, seizure, or a 
thrombotic/thromboembolic event (excluding vascular dialysis access 
stenosis/thrombosis) (e.g. DVT or pulmonary embolism) within 
12 weeks prior to enrollment 
12. Subject has uncontrolled hypertension, in the opinion of the Investigator 
13. Subject has a diagnosis or suspicion (e.g., complex kidney cyst or 
Bosniak Category II or higher) of renal cell carcinoma (PI’s discretion) 
14. Subject has a history of malignancy, except for the following: cancers 
determined to be cured or in remission for ≥ 2 years, curatively resected 
basal cell or squamous cell skin cancers, cervical cancer in situ, or 
resected colonic polyps 
15. Subject is positive for any of the following: 
• Human immunodeficiency virus (HIV) 
• Hepatitis B surface antigen (HBsAg) 
• Anti-hepatitis C virus antibody (anti-HCV Ab) 
16. Subject has an active, clinically significant infection at the time of 
enrollment as determined by the investigator 
17. Subject has any of the following known untreated conditions as 
determined by the investigator: proliferative diabetic retinopathy, 
diabetic macular edema, macular degeneration or retinal vein occlusion 
(subjects who are already blind may qualify to participate) 


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18. Subjects with prior organ transplant who have one of the following 
conditions or states 
a) Experienced rejection of transplanted organ within 6 months of 
transplantation 
b) Currently on high doses of immunosuppressive therapy (per 
discretion of the investigator) 
c) Are scheduled for organ transplantation (on the waiting list for kidney 
transplant is not exclusionary) 
19. Subject has participated in an interventional clinical study or has been 
treated with an investigational drug within 4 weeks prior to screening 
20. Subject has drug-treated gastroparesis, short-bowel syndrome, or any 
other gastrointestinal condition that may lead to reduced absorption of 
study drug (determined by the investigator) 
21. Subject has an anticipated use of dapsone or androgen in any dose 
amount or anticipated chronic use of acetaminophen or paracetamol 
> 2.0 g/day during the study 
22. Subject has a history of alcohol or drug abuse within 6 months prior to 
screening as determined by the clinical judgment of the investigator 
23. Females of childbearing potential, if not practicing complete sexual 
abstinence or using contraception as detailed in the protocol; male 
subjects (if not surgically sterile; i.e., no vasectomy) with sexual 
partners of childbearing potential, if not practicing complete sexual 
abstinence or using contraception 
24. Pregnant or breastfeeding females 
25. Subject has any medical condition that in the opinion of the Investigator 
may pose a safety risk to the 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 
Roxadustat tablets may be available in 20, 50, 70, 100 and 150 mg doses for 
oral administration. All tablets must be administered whole. 
Route of Administration: Oral (all tablets must be administered whole) 
Dosing Frequency: Subjects will be dosed three times weekly (TIW), 
except if a subject requires < 60 mg/week to maintain Hb levels, in which 
case dose frequency may be reduced in a stepwise fashion, e.g., to twice 
weekly (BIW), then once weekly (QW). 
Initial Doses: 
• Conversion from CERA to Roxadustat: 
The initial roxadustat dose is determined using a conversion table based on 
the subject’s prescribed ESA dose in the last 4 weeks prior to enrollment (for 
Mircera®:in the last 8 weeks prior to enrollment) (Table S1). 
Roxadustat treatment should start two weeks after stopping CERA 
If the converted initial dose exceeds the maximum dose of 3.0 mg/kg/dose 
then the next-lower dose step should be chosen as the initial dose. 


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L
Current Hb level:
<10.5 g/dL
10.5 to 11.9 g/dL 12.0 to 12.9 g/d
≥13.0 g/dL
> 1.0 g/dL
-1.0 g/dL to
+1.0 g/dL
< -1.0 g/dL
No change*
↑
↑
↓
No change
↑
• Hold dosing
• Check Hb and
resume dosing when
Hb <12.0 g/dL, at a
dose reduced by 2
steps
↓
↓
No change
If a subject is on ESA dose hold for high haemoglobin during screening, 
enrollment should be delayed until the subject is ready to resume anaemia 
treatment. Upon enrollment, all subjects must initiate roxadustat at Day 1. 
Table S1: Conversion from ESA to Roxadustat 
Previous Dose of Mircera®
(mcg/month)
Starting Dose of Roxadustat
(mg/dose TIW)
<80
70
80 to 120
100
121 to 200
150
>200
200
•
Initiation of Roxadustat in subjects with < 6 weeks of prior 
CERA use or no prior ESA use:
Initial roxadustat dosing is based on broad body weight categories (estimated 
dry weight at enrollment): 
Table S2: Initial Roxadustat Dosing:
Body Weight Category
< 100 kg
≥100 kg
Roxadustat Dose (TIW)
70 mg
100 mg
Note: Weight in HD subjects = subject’s estimated dry weight at enrollment.
Dose Adjustments:
During the Treatment Period, roxadustat dose adjustment will be made 
starting at Week 4 and at intervals of every 4 weeks thereafter according to 
the dose adjustment algorithm below, in order to achieve an Hb level of 11 
g/dL and maintain an Hb of 11±1 g/ dL: 
Table S3: Dose Adjustments: 
↑: Increase dose by one step; ↓: reduce dose by one step.
*Continue to hold dose
Dose adjustment steps: 20, 40, 50, 70, 100, 150, 200, 250, 300 and 400 mg
If Hb increases by >2.0 g/dL within a 4-week period, reduce dose by one step. 
Roxadustat dose adjustment reviews should occur every 4 weeks, except if 
the following criteria are met:
•
Rate of Hb rise > 2 g/dL within 4 weeks: reduce dose by 1 dose step
Change in Hb over
previous 4 weeks:


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• Hb level > 13g/dL: hold dose, check Hb weekly or as deemed 
necessary by investigator until Hb drops to < 12g/dL, resume dosing 
at 2 dose steps lower 
Dose adjustments or temporary dose holds for excessive rate of Hb rise or 
Hb above 13 g/dL can occur at any time during the Treatment Period. Any 
dose adjustment will reset the dose-adjustment window to every 4 weeks 
thereafter (e.g., dose adjustment for a qualified reason at Week 6 leads to 
next dose adjustment at Week 10). 
Prescribed dose must not exceed the maximum allowable dose of 
3.0 mg/kg/dose or 400 mg per dose, whichever is lower. Estimated dry- 
weight at enrollment should be used for the entire treatment period. 
Rescue Therapy 
and Emergency 
Procedures: 
Rescue Therapy Guidelines: 
Rescue therapy guidelines are provided to optimize the standardization of 
rescue therapy, and to ensure the safety of individual study subjects. 
Red Blood Cell Transfusion (for all subjects) 
RBC transfusion should be considered if rapid correction of anemia is 
required to stabilize the subject’s condition (e.g., acute hemorrhage) or the 
Investigator is of the opinion that the blood transfusion is a medical 
necessity. If the situation permits, the Medical Monitor should be informed 
prior to any scheduled RBC transfusion. Study treatment may continue 
during or after the RBC transfusion. 
Erythropoiesis Stimulating Agent (ESA) Use 
If possible, the use of ESAs as a “Rescue” modality should be carefully 
considered, and should be restricted to no more than one cycle of use during 
the Treatment Period; the Investigator may initiate use of an approved 
erythropoietin (EPO) analogue if all of the following criteria are met: 
• A subject’s Hb level has not sufficiently responded to two or more 
dose increases or the maximum dose of study drug has been reached, 
and 
• The subject’s Hb is < 8.5 g/dL on two consecutive measurements at 
least five days apart; and 
• Clinical judgment does not suggest iron deficiency or bleeding as a 
cause of lack of response or rapid decline in Hb, and 
• Reducing the risk of alloimmunization in transplant eligible subjects 
and/or reduction of other RBC transfusion-related risks is a goal 
Such ESA Rescue should be started ≥ 2 days after the last dose of 
roxadustat. 
ESA Rescue should be stopped when Hb > 9 g/dL or after 4-weeks, 
whichever comes first. If a subject requires longer than 4-weeks therapy due 
to inadequate response, or in other extenuating circumstances, the Medical 
Monitor should be contacted. 
Study treatment should 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®) 


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If more than one cycle of ESA rescue is required, the Investigator should 
permanently discontinue study drug. 
Inadvertent ESA administration, such as ESA administration during a 
hospitalization, should not be counted as rescue unless above criteria are 
met; these subjects may be allowed to restart roxadustat dosing if considered 
safe by the Investigator or Medical Monitor. 
All ESAs used during the Treatment Period, either planned or inadvertent, 
should be recorded. 
ESAs and Roxadustat should not be administered concomitantly. 
Emergency Procedure (Therapeutic Phlebotomy) 
If there are clinical concerns for a subject’s high Hb levels, the Investigator 
may decide to perform a therapeutic phlebotomy in addition to temporarily 
withholding the study drug. This should be documented and discussed with 
the Medical Monitor. 
IV Iron Use: 
Intravenous Iron Supplementation 
Intravenous iron should be considered for subjects with ferritin <200 ng/mL 
or TSAT <20%. 
In this study, oral iron may be administered for iron supplementation without 
restriction. Dose and frequency of administration of oral iron are to be 
determined by the investigator. 
Prohibited 
Medication: 
The following medications/therapies are prohibited during the period 
identified: 
• Any investigational drug from 4 weeks prior to screening until EOS 
• Androgens from screening until EOS 
• Iron-chelating agents (e.g., deferoxamine/desferrioxamine, 
deferiprone, or deferasirox therapy) from 4 weeks prior to enrollment 
until EOS 
• Dapsone (at any dose) from screening until EOS 
Chronic doses acetaminophen/paracetamol > 2.0 g/day from 
enrollment until 1 week after EOT 
Efficacy 
Endpoints and 
Assessments: 
Efficacy Endpoints: 
• Proportion of subjects with mean Hb > 10g/dL, averaged from Week 
16 through Week 24. 
• Mean Hb change from baseline to average Hb from Week 16-Week 
24 
Exploratory Endpoints/Analyses: 
• 
Time to first RBC transfusion 
• Proportion of patients with a mean Hb levels ≥10 g/dL in the first 8 
weeks after conversion 
• Proportion of patients with mean Hb level ≥10 g/dL based on 
baseline ESA use status (≥ 6 weeks and < 6 weeks) 
• 
Evaluate the utilization of intravenous (IV) iron (IV iron use/4 weeks) 
• 
Evaluate the effect on iron indices 
• Evaluate dosing adherence 
• Conversion subjects: 


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o Comparison of starting dose of roxadustat to roxadustat 
dose at Week 16-24 
• Mean number of dose adjustments during study 
Safety 
Assessments and 
Endpoints: 
Study-specific safety will be assessed by evaluating the following: 
• Incidence of treatment emergent adverse events (TEAEs) and 
treatment emergent serious adverse events (TESAEs) 
• Clinically significant changes in laboratory values from baseline 
• Vital signs 
Statistical 
Methods: 
Stratification: Not applicable 
Sample size determination: 
Approximately 200 subjects with anemia of CKD (either with or without 
treatment with ESA at enrollment) and on hemodialysis are planned in this 
study. This number of subjects distributed across the specified number of 
sites is adequate to evaluate the primary study objective. 
Assuming the proportion of subjects that maintain Hb levels ≥10g/dL from 
Weeks 16 to 24 is at least 80%, with a sample size of 200, the study will be 
able to produce a two-sided 95% confidence interval (CI) with a width equal 
of 11.5%. 
Analysis Sets: 
The FAS set will consist of all subjects who signed informed consent, who 
were enrolled, and who provided baseline Hb data and data for at least one 
post baseline Hb time point. The FAS set will be used for all efficacy 
endpoints and analyses. 
The Safety analysis set will include all enrolled subjects receiving at least 1 
dose of study treatment. The safety analysis set will be used for all safety 
endpoints and exposure to study treatment outcomes. 
Efficacy analyses: 
The efficacy endpoint will be evaluated using the proportion (%) of subjects 
with mean value of Hb measurements of > 10g/dL from Week 16 through 
Week 24. 
For the efficacy analysis, a multiple imputation (MI) method will be used. 
This will be implemented on the raw Hb values, then the endpoint will be 
derived based on the imputed data (algorithm as used for the previous phase 
3 studies). 
For continuous endpoints, changes from baseline will be presented 
descriptively. 
Proportion of responders will be presented descriptively with count and 
percentages and 95% confidence interval of the responder rate. 
Time to response will be analyzed using the Kaplan-Meier method with KM 
curve plotted. 
Safety: 
The safety analyses will be performed using the Safety Analysis Set (SAF). 
Safety parameters include TEAEs, TESAEs, laboratory parameters and vital 
signs. 
The number and percentage of subjects reporting treatment-emergent AEs 
(TEAEs) and TESAEs will be tabulated. 


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Descriptive statistics will be presented for laboratories and vital signs. 
This study will be conducted in accordance with the guidelines of Good Clinical Practice and the 
applicable regulatory requirement(s), including the archiving of essential documents. 


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2. 
BACKGROUND 
Hypoxia-inducible factor (HIF) is a key transcription factor that coordinates the body’s physiological 
response to changes in oxygen levels in the cellular environment (Semenza, 2000). It induces the 
expression of erythropoietin (EPO) and the EPO receptor, as well as the expression of other proteins 
that promote iron absorption and recycling (Peyssonnaux et al, 2008). The activity of HIF is regulated 
by hypoxia-inducible factor prolyl hydroxylase (HIF-PH) enzymes (HIF-PHD1 to D3). These 
enzymes target HIF for degradation. 
Roxadustat (FG-4592/ ASP1517/ AZD9941) is an orally active novel small-molecule that inhibits 
these HIF-PH enzymes. By inhibiting HIF-PH, roxadustat stimulates erythropoiesis via the HIF 
pathway in a manner consistent with the body’s normal response to hypoxia. Its ability to stimulate 
erythropoiesis makes it a candidate for the treatment of anemia associated with chronic kidney 
disease (CKD) in patients with nondialysis-dependent (NDD-CKD) and dialysis-dependent 
(DD-CKD). 
 
2.1. 
Introduction 
2.1.1. 
Epidemiology of Chronic Kidney Disease and End-Stage Renal Disease 
Chronic kidney disease is a growing worldwide public health problem. It is associated with 
significant morbidity and mortality, yet is underdiagnosed and undertreated. It is characterized by 
progressive loss of kidney function, resulting in premature death or renal replacement therapy (RRT) 
(kidney transplant or dialysis). 
The average prevalence of CKD, regardless of age, ranges between 3%-17% in Europe and the all- 
cause mortality risk increases exponentially as CKD stages advance (Bruck K, et al). The prevalence 
of DD-CKD is 887 per million people in China (2011 Shanghai Dialysis Registry Report) and in the 
US, CKD affected 13% of the US adult population (~ 29 million adults) in 2007, and the prevalence 
is rapidly growing in both the US (Coresh et al., 2007) and worldwide (Xie Y, et al). In Europe, the 
average prevalence of CKD regardless of age lies between 5 and 11% (Zoccali et al., 2010). 
The number of patients suffering from end-stage renal disease (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 patients with ESRD per million population, a 23% increase compared to 10 years 
before (USRDS, 2011). In 2009 (point prevalence as of December 31st), there were approximately 
570,000 patients with ESRD in the US, of whom 370,000 were receiving hemodialysis (HD), 27,000 
were receiving peritoneal dialysis (PD), and 173,000 had a functioning kidney transplant 
(USRDS, 2011). In recent years, those older than 75 years have been observed to have the highest 
incidence of treated ESRD (1735 per million populations in 2007, US by age and race/ethnicity). The 
adjusted ESRD incidence rates were 998 per million populations for African Americans, 396 per 
million population for Asians/Pacific Islanders, and 273 per million populations for whites in 2007 
(USRDS, 2009). In Europe, over the period 1992–2005, the overall crude prevalence of RRT for 
patients with ESRD increased from 480 to 807 patients per million populations (Zoccali et al., 2010). 
The average expected life expectancy of a dialysis patient is 5.9 years, compared to 16.4 years for a 
transplant patient, and 25.2 years for someone of comparable age in the general population (USRDS, 
2009). The prevalence of ESRD is projected to grow to 774,000 by the year 2020 (USRDS, 2009). 
Data from selected countries in Europe indicate that the 5-year mortality rates in incident patients on 
RRT are 52% in all patients, and 21%, 32% and 73% for patients 0 to 14, 15 to 64 and over 65 years 
of age, respectively (Zoccali et al., 2010). 


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2.1.2. 
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 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 the 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 disease who have not yet progressed to requiring 
dialysis (Coresh et al., 2007; Go et al., 2004). Over 90% of patients undergoing dialysis are anemic. 
Half of all patients new to dialysis (50.1%) have hemoglobin (Hb) levels below 10 g/dL and 
approximately 28% have Hb levels below 9 g/dL (USRDS, 2003). Some studies from Europe provide 
data on anemia rates in patients who have been under care of nephrologists. In 1999, Jungers 
prospectively studied 403 consecutive ambulatory predialysis patients and found that 60% of patients 
with a creatinine clearance of < 20 ml/min/1.73 m2 were anemic (Hb < 11 g/dL) (Jungers et al., 
2002). Between 2003 and 2005, Thilly studied predialysis anemia care in 6271 incident dialysis 
patients. The average level of predialysis Hb was 10.3 g/dl, and 63.6% of the patients had a Hb value 
lower than 11 g/dl (Thilly et al., 2008). 
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 is associated with excess morbidity and mortality in patients with CKD and ESRD. In 
patients with CKD, the severity of anemia correlates directly with the risk of hospitalization, 
cardiovascular (CV) disease, and death (Collins et al., 1998). Anemia contributes to eccentric left 
ventricular hypertrophy and maladaptive remodeling of the left ventricle. 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) study in the 
Food and Drug Administration (FDA) briefing document for the October 2007 Cardiovascular and 
Renal Advisory Committee (Unger, 2007). Similar observations are found in the United States Renal 
Data System (USRDS) mortality data stratified by Hb. All-cause mortality stratified by Hb (between 
the years of 1993 to 1996) indicated significantly higher first-year death rates in patients with Hb 
levels < 9 g/dL, compared to 11 to 12 g/dL. This trend continued to worsen, as reflected in USRDS 
data collected between 1998 1999 where the death rate rose by ~75% compared to the 1993 to 1996 
period (USRDS, 2000; USRDS, 2002). 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). 
The relative risk ratio of CV hospitalization increases significantly to 1.26 in patients with Hb levels 
<9 g/dL compared to those with Hb at 11 to 12 g/dL (USRDS, 2001). 
Multiple studies have suggested that treatment of anemia reduces the need for blood transfusions and 
improves health-related quality of life (HRQoL) (NKF K/DOQI, 2007). 


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2.2. 
Current standard of care for CKD or DD-CKD 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 the treatment of anemia in patients with CKD (Winearls et al., 1986; Eschbach 
et al., 1987; Eschbach et al.,1989a, Eschbach et al. 1989b), despite the documented safety risks. 
These safety risks include hypertension, thrombosis, and cerebrovascular events which may be 
associated with 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 contribute positively to a patient’s 
quality of life, several studies in subjects with ESRD and NDD-CKD have shown higher mortality or 
trends in that direction in the higher-dosed ESA-treated cohorts when the protocol objective was to 
treat one of the cohorts to high, almost normal target Hb levels (Besarab et al., 1998; Drueke et al., 
2006; Singh et al., 2006). An ESA dose relationship to mortality has been reported in a review of the 
USRDS database (Zhang et al., 2004) of ESRD patients who received higher ESA doses, particularly 
in those more anemic (i.e., Hb < 11 g/dL). The FDA has recognized these excess morbidity and 
mortality risks (FDA, 2007). Updated product labeling for the approved ESAs in 2007 include a 
boxed warning of greater risk of death and CV events when ESAs are administered to target high Hb 
concentrations (≥ 13.5 g/dL) compared with lower Hb targets. The FDA also acknowledged the 
potential off-target effect of ESAs contributing to excess mortality due to CV events and thrombosis 
(Unger, 2010). The currently approved ESA labeling directs prescribers to target Hb levels of 10 to 
11 g/dL in the US and 10 to 12 g/dL outside the US. The literature on this topic, including meta- 
analyses, supports the view that the AEs associated with ESAs are typically observed when high 
doses are administered (Zhang et al., 2004; Unger, 2007; Szczech, 2008; Fishbane and Beserab, 2007; 
Besarab et al., 2009). Posthoc analyses of three major RCTs, (Kilpatrick et al., 2008; Szczech, 2008; 
Solomon et al., 2010) NHCT, CHOIR, and TREAT, indicates that outcomes correlate with 
“achieved” and not “target” Hb levels. 
Additionally, some patients are hyporesponsive to ESA therapy. A significant proportion (~ 17%) of 
DD-CKD patients require stable ESA dosing at 2 to 6 times the median seen in the entire CKD 
population (150 to 450 U/kg of IV epoetin TIW). This “hyporesponder” patient population accounts 
for approximately 50% of epoetin alfa consumption in the US (Besarab et al., 2009). This is a 
significant economic burden, and as noted above, higher doses of ESAs have been associated with 
higher rates of morbidity and mortality (Zhang et al., 2004; Unger, 2007; Szczech, 2008). Thus, this 
patient population has the greatest need for an effective and safe therapy for anemia. In turn, the 
increasing perception that high ESA dosing is associated with significant risk, especially in patients 
not achieving target, is expected to lead to lower ESA dosing and an associated higher prevalence of 
patients with low Hb levels. In December of 2007, 2.1% of patients had Hb levels < 9 g/dL, 7% had 
Hb levels < 10 g/dL, and 21.6% did not reach 11 g/dL, while 34.8% were 11 to 12 g/dL (USRDS, 
2009). Hb levels < 11 g/dL in this population are associated with increased mortality and 
hospitalization rates, and failure to achieve a Hb level > 11 g/dL is a prognostic indicator of poor 
outcomes (Ma, 1999; Regidor, 2006). In patients with persistently low Hb levels, mortality risk is 
strongly associated with the patient's ability to achieve a hematopoietic response (Bradbury, 2009). 
Additionally, ESA therapy for anemia in patients with ESRD on HD usually requires concomitant IV 
iron supplementation to avoid functional iron deficiency and epoetin dose escalation; however; IV 
iron use is not without risk. However, as reported by the USRDS (USRDS, 2013), administration of 


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IV iron is at an all-time high. Among patients on HD, the transfusion rate, at 2.7% to 2.9% at the 
beginning of 2010, reached 3.3–3.8 percent in the first six months of 2012. Among patients on PD, 
the rate has increased from 2.3–2.9 to 3.0–3.9. 
There is currently an unmet medical need for an oral treatment that can correct anemia in patients 
with NDD-CKD and DD-CKD while avoiding supraphysiologic levels of circulating plasma EPO 
levels. 
Roxadustat is an oral medication that could potentially deliver effective treatment for CKD-related 
anemia with less need for IV iron supplementation and without producing supraphysiologic levels of 
circulating EPO, which may translate into an improved safety profile. Roxadustat is being evaluated 
as a potential alternative treatment for anemia in subjects with NDD-CKD and DD-CKD. 
 
2.3. 
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 is a transcription factor that is believed to be the key element in the body’s 
oxygen sensing mechanism (Semenza, 2000). Hypoxia-inducible factor 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 hypoxia and intermittent hypoxia 
induce different sets of genes associated with HIF transcriptional activity (Fan et al., 2005). Hypoxia- 
inducible factor 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 et al.,2005; 
Hu et al., 2003). For example, HIF-1α has been shown to regulate vascular endothelial growth factor 
(VEGF) expression (Gray et al., 2005; Buchler et al., 2003), while HIF 2α is critical for the induction 
of the EPO gene and erythropoiesis (Warnecke et al., 2004; Scortegagna et al., 2005). 
Figure 1.  Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor (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, 2001 


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Hypoxia-inducible factor target genes are expressed when the active heterodimer binds to a conserved 
DNA motif found within all HIF target genes, termed the hypoxia response element, and in 
cooperation with other co-activators 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 red blood cell (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-PHs 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 et al., 1995; Semenza, 1998). 
Roxadustat is a potent and reversible hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) 
that transiently induces HIF stabilization and leads to a functional HIF transcriptional response that 
mimics the erythropoietic 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 from the macrophage iron storage system (Peyssonnaux et al., 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 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 anemia 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-PHIs 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 et al., 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-PHI 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, transferrin production, and 
down-regulation of hepcidin production); roxadustat distributes preferentially to these organs. 


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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 
• Improvement in lipid profile 
2.4. 
Clinical Experience with Roxadustat 
In the recently completed global Phase 3 program, roxadustat was studied in a broad range of adult 
CKD patients (including both non-dialysis-dependent [NDD] and dialysis-dependent [DD] CKD 
populations) with anemia. Roxadustat was compared against placebo in three pivotal NDD CKD 
studies comprising 4277 patients, and against epoetin alfa (standard of care ESA) in three pivotal DD 
studies comprising 3880 patients. 
The effectiveness of roxadustat was consistently demonstrated across this wide spectrum of adult 
CKD patients, including NDD patients with baseline eGFR <15 mL/min/1.73 m2 who were not 
previously included in prior NDD ESA studies. Roxadustat significantly increased Hb compared to 
placebo in NDD patients and was non-inferior with respect to ESA comparator in maintaining Hb 
within intended target range in DD patients. Moreover, roxadustat-treated patients had lower risk of 
red blood cell transfusions compared to placebo-treated and epoetin alfa-treated patients in the pooled 
NDD and DD CKD studies, respectively. Roxadustat also effectively treated anemia in patients 
whose baseline C-reactive protein (CRP), a marker of inflammation, was >ULN (roxadustat dosing 
was similar regardless if CRP was >ULN or <ULN), and roxadustat improved iron metabolism 
efficiency by reducing serum hepcidin and ferritin levels. 
The safety of roxadustat was evaluated against placebo in NDD CKD studies and against epoetin alfa 
in DD CKD studies. Incident dialysis (ID) patients (a sub-group of the overall DD population who 
initiated chronic dialysis with the past four months) who were treated with roxadustat had a lower 
risk of major adverse CV events (MACE defined as stroke, myocardial infarction, all-cause death) 
and MACE+ (events that comprised MACE plus hospitalized unstable angina and congestive heart 
failure), and a trend towards reduction of risk in all-cause mortality, compared with those who were 
treated with epoetin alfa. The overall safety profile of roxadustat was comparable to placebo for NDD 
CKD patients and comparable to epoetin alfa for DD and ID CKD patients with respect to most 
adverse events and serious adverse events. A number of adverse drug reactions (ADRs) were 
identified, including vascular access thrombosis, deep vein thrombosis, and seizures. Serious 
infection was considered an important potential risk, but causality was not established. No adverse 
hepatic risks from liver enzyme monitoring were identified, and there were no clinically important 
changes in ECG parameters, including no evidence of QT prolongation. 
For detailed safety information, please refer to the most current version of the IB. 


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2.4.1. 
Pharmacokinetics and Pharmacodynamics 
The pharmacokinetics (PK) and pharmacodynamics 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). The exposure 
was higher in dialysis patients compared to healthy volunteers. Roxadustat can be administered 
before or after dialysis, since the PK of roxadustat was not significantly altered when administered 
prior to the start of dialysis compared with after dialysis (Study FGCL-4592-039). 
A relative bioavailability study was conducted in 24 healthy volunteers comparing capsule 
formulation, which was used in Phase 1 and Phase 2 studies, with tablet formulation, which was 
developed for Phase 3. The study demonstrated bioequivalence to bridge the two formulations. With 
an intermittent dose regimen (once weekly [QW], twice weekly [BIW[ or three times a week [TIW]), 
no or limited accumulation in mean area under the concentration curve (AUC) or maximum 
concentration (Cmax) was observed. Furthermore, no evidence was found for time-dependent PK (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 cytochrome P450 (CYP) enzymes, based on in-vitro studies is limited, and the lowest inhibition 
constant (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 QW, BIW 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 pharmacodynamic 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. Results from PK studies in subjects 
on HD (Study FGCL-4592-039 in the US and Study CL-1517-203 in Japan) showed similarity in PK 
and pharmacodynamics of roxadustat in Caucasians and Japanese subjects with ESRD, and the timing 
of roxadustat dosing relative to dialysis (given before or after dialysis) did not impact the PK profile. 
Also, comparable dose-dependent increases in EPO levels were observed with both pre and 
postdialysis dosing. These increases in endogenous EPO (eEPO) were transient, peaked at around 10 
hours postdose with eEPO levels returning to BL in 24 to 48 hrs. The magnitude of this transient 
increase in plasma eEPO levels was modest and the peak plasma eEPO were within physiologic 
range. 
In contrast, EPO levels associated with therapeutic ESA dosing range from 1,500 to over 
10,000 mIU/mL (Besarab et al., 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 and Besarab, 2007). This is approximately 10-fold higher than 
the physiologic range. 


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2.5. 
Summary 
In summary, roxadustat is an orally active HIF-PHI with potent erythropoietic effects. Intermittent 
dosing of roxadustat results in transient activation of HIF, intermittent induction of endogenous, 
physiologic-range EPO, and dose-dependent erythropoiesis, suggests 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 who have been enrolled and treated in 
completed and ongoing clinical studies. 
 
2.6. 
Roxadustat Dose Rationale 
The starting roxadustat doses and dose titration algorithm in this study are based on Phase 3 program 
involving ESRD patients with anemia who converted to roxadustat from stable ESA and patients who 
never used ESA before. These dosing schedules effectively corrected anemia and or maintained Hb 
levels close to 11.0 g/dL. 
Analysis of the Hb time course after initiation of treatment with roxadustat in patients previously not 
on ESA treatment stratified by body weight indicated that the starting doses for patients not 
previously receiving ESA treatment should be 70 mg for patients with a body weight of <100 kg, and 
100 mg for patients with a body weight of ≥100kg. The proposed dose adjustment algorithm, applied 
every 4 weeks, effectively maintained Hb levels close to 11.0 g/dL in these patients. 
For patients previously treated with an ESA, the applied starting doses of roxadustat (based on the 
conversion table) in conjunction with the dose adjustment algorithm resulted in Hb levels that were 
maintained close to 11.0 g/dL. The full dose range of 20 to 400 mg TIW was utilized in the Phase 3 
dialysis studies. 
In this study, the initial dose of roxadustat will be determined by the subject’s average prescribed 
ESA dose in the last 4 weeks prior to enrollment if on epoetin or darbepoetin (8 weeks if on 
Mircera®). 
Using the conversion table (Table 1), in this study, subjects will receive starting roxadustat doses of 
70 mg, 100 mg, 150 mg, or 200 mg. If the converted initial dose exceeds the maximum dose of 3.0 
mg/kg/dose then the lower dose step should be chosen as the initial dose. Roxadustat doses will be 
administered at a frequency of TIW. If a subject requires < 20 mg TIW (i.e., < 60 mg per week) to 
maintain a Hb level of 11±1 g/ dL, the dosing frequency should be reduced in a step-wise fashion e.g. 
TIW to BIW, BIW to QW, QW to Q-2 Week etc. 
 
2.6.1. 
Maximum Dose for Roxadustat 
The maximum allowed roxadustat dose in this study is set at 400 mg or 3.0 mg/kg/dose (based on 
estimated dry weight at enrollment in subjects on HD), whichever is lower. The highest dose tested in 
healthy subjects is 5 mg/kg single dose and 3.75 mg/kg TIW. The doses were safe and well tolerated 
with transient dose-dependent HR increases observed. No maximum tolerated dose (MTD) was 
reached in the clinical development of roxadustat based on the observed pharmacodynamic response 
(plasma EPO levels) and the predicted relation between EPO levels and Hb response; therefore 
exploration of higher doses was not deemed necessary. Plasma EPO levels increased in a supralinear 
manner with increasing roxadustat doses. In Phase 3 dialysis studies, the full dose range of 20 to 400 
mg TIW was utilized. 


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In this study, prescribed dose must not exceed the maximum allowable dose of 3.0 mg/kg/dose or 400 
mg per dose, whichever is lower. 
 
2.7. 
Risks/Benefits of Roxadustat Treatment 
The primary benefit of roxadustat is the treatment of anemia, including the relief of associated signs 
and symptoms of anemia and reduced risk of blood transfusion. 
Similar to the Phase 3 dialysis studies, dose adjustment algorithm will be used to titrate roxadustat 
doses based on current Hb levels and the rate of change of Hb levels. Roxadustat doses may be held 
and/or the use of therapeutic phlebotomy is allowed in the event of Hb excursions above the intended 
target range. Adverse events (AEs) and serious adverse events (SAEs), and laboratory parameters 
including electrolytes, liver enzymes, and iron indices, will be closely monitored to ensure the safety 
of treatment with roxadustat. 
In all three pivotal dialysis studies, roxadustat was non-inferior and superior to epoetin alfa in the 
primary efficacy endpoint of the mean change in Hb from baseline averaged over Weeks 28-52. The 
efficacy of roxadustat, achieved with less IV iron supplementation, is accompanied by reduction in 
RBC transfusion, and demonstrated effective erythropoiesis regardless of inflammation with 
sustained response with stable mean roxadustat doses over time. In these dialysis studies, roxadustat 
treatment has shown a 14% reduction in MACE+ risk compared to epoetin alfa, and the risk of 
MACE and ACM in roxadustat treated patients are non-inferior to those treated with epoetin alfa. In 
incident dialysis patients, roxadustat treated patients had a 30% reduction in the risk of MACE and a 
34% reduction in MACE+, with a trend towards lower ACM risk, in comparison to epoetin alfa. 
The safety of treatment with roxadustat will be carefully monitored by the sponsor to 
detect any potential safety signals that may arise during the study. Based on data so far obtained, 
treatment with roxadustat is expected to be efficacious in treating anemia in patients with CKD. 
The safety profile of the compound, together with the safety monitoring implemented would 
minimize the risk to study participants. The benefit-risk in this study is therefore deemed acceptable. 


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3. 
OBJECTIVES AND ENDPOINTS 
3.1. 
Objectives 
3.1.1. 
Primary Objectives 
To confirm safe and effective Roxadustat dosing regimens among chronic dialysis subjects 
converted from ESA therapy (>=6 weeks ESA treatment) or who are ESA-naïve (<6 weeks ESA 
treatment). 
 
3.1.2. 
Safety/Exploratory Objectives 
• Assessment of treatment-emergent adverse events (TEAEs) and serious adverse events 
(TESAEs) 
• Laboratory parameters, including iron indices 
• Utilization of intravenous (IV) iron 
• To test operational characteristics of converting a population of ESRD subjects from an 
injectable to oral anemia therapy 
 
3.2. 
Efficacy Endpoints 
3.2.1. 
Efficacy Endpoints: 
• Proportion of subjects with mean Hb > 10g/dL, averaged from Week 16-through Week 24 
• Mean Hb change from baseline to average Hb from Week 16-Week 24 
3.2.2. 
Exploratory Endpoints/Analyses 
The additional exploratory endpoints in this study are: 
• Time to first RBC transfusion 
• Proportion of patient with a mean Hb levels ≥10 g/dL in the first 9 weeks after conversion 
• Proportion of patient with a mean Hb level ≥10 g/dL based on baseline ESA use status (≥ 
6 weeks and < 6 weeks) 
• Evaluate the utilization of intravenous (IV) iron (IV iron use/4 weeks) 
• Evaluate the effect on iron indices 
• Evaluate dosing adherence 
• Conversion subjects: 
− Comparison of starting dose of roxadustat to roxadustat dose at Week 16-24 
• Mean number of dose adjustments during study 


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3.3. 
Safety Endpoints 
Study-specific safety will be assessed by evaluating the following: 
• Incidence of treatment emergent adverse events (TEAEs) and treatment emergent serious 
adverse events (TESAEs) 
• Clinically significant changes in laboratory values from baseline 
• Vital signs 


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4. 
STUDY DESIGN 
4.1. 
Description of the Study 
This open-label single arm study is designed to evaluate roxadustat in maintaining Hb in ESRD 
subjects receiving chronic dialysis either after conversion from a stable ESA dose: ESA use > 6 
weeks prior to conversion to roxadustat dosing or as initial anemia treatment, in subjects with < 6 
weeks of total ESA use prior to start of roxadustat dosing. 
The study periods are: 
• Screening Period: Up to 6 weeks 
• Treatment Period: 24 weeks 
• Post-Treatment Follow-Up Period: Subjects permanently discontinuing roxadustat, should 
have one final safety assessment (TEAEs and TESAEs) 28 days after the last roxadustat 
dose. 
An extension of roxadustat treatment after 24 weeks may be offered to interested subjects within the 
context of this study protocol upon agreement of the study site, until roxadustat is commercially 
available, or up to 1 year after completing the 24 weeks, whichever comes first. 
Figure 2: Study Design Overview 
 
 
Guidelines for patients receiving home-dialysis: 
Home-dialysis patients are allowed to participate in this study. Investigators may use delivery 
services for medication dispense and/or local laboratory blood draw and/or testing 
For home-dialysis patients, investigators may adjust study visit frequency and method of visits such 
as use of telemedicine including dose-dispensation schedule in consideration of clinical 
circumstances and convenience of the patient. 
To simplify the study procedures for home-dialysis patients, renal ultrasound can be exempted, 
Screening Visit and Day 1 Visit may be combined into Day 1 Visit. Patients on home-dialysis must 
visit research-center during Screening/Day 1, and Week 24 (or if discontinued prematurely) and 
clinical laboratory testing for these visits need to be sent to the central lab. For other visits (per SOA), 
investigator/authorized study staff should contact the patient via telemedicine, such as phone (audio, 
video call etc.) to collect study related information e.g. documentation of study drug dose, 
hemoglobin level, adverse events including hospitalization, conmed changes, transfusion etc, and to 
provide instructions on study drug dose adjustments. When possible, investigator should make 


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efforts to combine standard of care visits to the clinic with the study visit that falls around that time 
frame (out of window protocol deviation will be exempted) in order to perform in-center assessments, 
central laboratory draws as deemed necessary by the investigator based on the clinical circumstances. 
Hemoglobin levels every 2 to 4 weeks (as part of CBC listed in SOA) are needed for dose 
adjustments of roxadustat. The hemoglobin testing between Weeks 2 to 24 may be conducted via 
central lab, local lab, or validated point-of-service testing device. Chemistry and iron parameter tests 
should be evaluated at least every 2-3 months, per discretion of the investigator. 
Whenever central laboratory draws were not feasible but local laboratory tests were performed, key 
test results need to be made available to the study file. 
Combining Screening and Day 1 visits: 
Laboratory values related to eligibility assessments (e.g. LFTs, Hepatitis B and C, HIV, serum 
pregnancy, CBC/Hb, iron parameters) performed at a local lab within 12 weeks prior to 
enrollment/Day 1 may be used instead of central laboratory values (done during screening) to confirm 
eligibility, if available. If local laboratory values are not available, Screening and Day 1 visit may still 
be combined if PI has no safety concerns and if PI prefers to start oral anemia therapy right away 
considering the current clinical condition and convenience of the patient. Upon reviewing central lab 
values collected at Day 1, PI may ask the patient to stop taking roxadustat if there is any significant 
safety concerns (e.g. very high LFT values). 
 
4.2. 
Study Rationale 
The roxadustat phase 3 program provided minimal data about conversion of subjects from CERA to 
roxadustat. The purpose of this trial is to enhance the understanding of safe and effective conversion 
from CERA to roxadustat in a population of patients receiving chronic dialysis. 
 
4.3. 
Screening Period 
After signing the informed consent, subjects enter the Screening Period. All screening procedures are 
to be completed within 6 weeks. Subjects will be evaluated per the protocol inclusion/exclusion 
criteria to determine eligibility for participation in this trial. 
 
4.4. 
Treatment Period 
At the Day 1, subjects will have had discontinued prior prescription of CERA therapy for 2 weeks 
and will initiate roxadustat therapy. 
 
4.5. 
Starting Dose of Study Drug 
4.5.1. 
Route of Administration 
Oral (all tablets must be administered whole) 
 
4.5.2. 
Dosing Frequency 
Subjects will be dosed three times weekly (TIW), except if a subject requires < 60 mg/week to 
maintain Hb levels, in which case dose frequency may be reduced in a stepwise fashion, e.g., to twice 
weekly (BIW), then once weekly (QW). 


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4.5.3. 
Initial Doses 
 
4.5.3.1. 
Conversion from CERA to Roxadustat: 
The initial roxadustat dose is determined using a conversion table based on the subject’s previous 
prescribed CERA dose in the last 8 weeks prior to enrollment (Table 1). 
Roxadustat treatment should start two weeks after stopping CERA. 
If the converted initial dose exceeds the maximum dose of 3.0 mg/kg/dose then the next-lower dose 
step should be chosen as the initial dose. 
Table 1: Conversion from CERA to Roxadustat 
 
 
Previous Dose of 
Mircera® 
(mcg/month) 
Starting Dose of 
Roxadustat (mg/dose 
TIW) 
<80 
70 
80 to 120 
100 
121 to 200 
150 
>200 
200 
 
 
4.5.3.2. 
Initiation of Roxadustat Dosing in subjects with < 6 weeks of prior CERA or no prior 
ESA use: 
The initial roxadustat dosing is based on broad body weight categories (estimated dry weight at 
enrollment) as described in Table 2. 
Table 2: Initial Roxadustat Dosing: 
 
 
 
Body Weight Category 
< 100 kg 
≥ 100 kg 
Roxadustat Dose (TIW) 
70 mg 
100 mg 
Note: Weight in HD subjects = subject’s estimated dry weight at enrollment. 
 
4.5.3.3. 
Dose Adjustments: 
Dose adjustment evaluations will be made every 4 weeks and doses will be titrated based on Hb level 
and rate of Hb change according to Appendix 1. Any potential dose escalation/dose reduction will be 
at pre-defined dose step increments. 
A dose reduction may be implemented at any time if the following criteria are met: 
• Rate of Hb rise > 2 g/dL within 4 weeks: reduce dose by 1 dose step 
• Hb level > 13g/dL: hold dose, until Hb drops to < 12g/dL, resume dosing at 2 dose steps 
lower 
Any dose adjustment will reset the dose-adjustment window to every 4 weeks thereafter (e.g., dose 
adjustment for a qualified reason at Week 6 leads to next dose adjustment at Week 10). 


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Prescribed dose must not exceed the maximum allowable dose of 3.0 mg/kg/dose or 400 mg per dose, 
whichever is lower. 
Dose titration decisions will be based on results from local Hb testing. 
 
4.6. 
Post-Treatment Follow-Up Period 
After completing the Treatment Period (Week 24/EOT) , subjects who wish to permanently 
discontinue roxadustat and switch to an ESA, the first ESA dose should be administered at least two 
days after the last roxadustat dose. 
Subjects permanently discontinuing roxadustat (at Week 24 or early termination), should have one 
final safety assessment 28 days after the last roxadustat dose. 
 
4.7. 
Concomitant Medications, Procedures and Nondrug Therapies 
4.7.1. 
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. 
For all concomitant medication use, an indication for its use should be provided. If the stated 
indication is a nonspecific condition (e.g., “rash”), documentation of the condition, as specific as 
possible, should be maintained in the subject’s clinical study records as source documentation. 
Use of herbal medicine during the study is not prohibited but strongly discouraged. All herbal and 
natural remedies should be reviewed by the investigator and if considered safe, may be allowed to 
continue at the same dose. 
 
4.7.1.1. 
Phosphate Binders 
When coadministered with roxadustat, 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 while taking roxadustat. To optimize the absorption 
of roxadustat, subjects should be advised that roxadustat be taken at least one hour before or one hour 
after their phosphate binder. This does not apply to Lanthanum. 
 
4.7.1.2. 
CYP2C8 and UGT1A9 Modifiers 
Titrate the dose of roxadustat based on monitoring of Hb levels when initiating or discontinuing 
concomitant treatment with inducers or inhibitors of CYP2C8, or inhibitors of UGT1A9. 
 
4.7.1.3. 
Statins 
When coadministered with roxadustat, in clinical pharmacolgical studies, hydroxymethylglutaryl 
coenzyme A reductase inhibitor (statin) exposure was increased 2- to 3-fold. Investigators should 
consider this interaction and local prescribing information when deciding on the appropriate statin 
dose for individual subjects, bearing in mind the impact of ethnicity, other concomitant medications, 
renal and hepatic function. Goals of lipid lowering treatment should be maintained as clinically 
indicated. The dose of statins should not exceed the recommended daily dose in Table 3. 


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Table 3: Recommended Maximum Daily Dose of Statins 
 
Statins 
Recommended maximum dose (mg/day) 
Atorvastatin 
40 
Simvastatin 
5 
Rosuvastatin 
5 
Pravastatin 
40 
Fluvastatin 
20 
Pitavastatin 
1 
Lovastatin 
20 
 
4.7.2. 
Supplemental Iron Use 
In the phase 3 dialysis studies, all subjects were encouraged to take oral iron supplements as their 
first-line iron supplementation. Subjects randomized to roxadustat had a reduced need of IV iron 
compared to the active ESA comparator. 
In this study, oral iron may be administered. Dose and frequency of administration are to be 
determined by the investigator. 
 
4.7.2.1. 
Oral Iron Supplementation 
In this study, oral iron may be administered for iron supplementation without restriction. Dose and 
frequency of administration of oral iron are to be determined by the investigator. 
 
4.7.2.2. 
Intravenous (IV) Iron Supplementation 
Intravenous iron should be considered for subjects with ferritin < 200ng/mL or TSAT <20%. 
In addition to scheduled assessments (Appendix 2), iron indices may be assessed anytime (via central 
lab) to evaluate iron storage status of the subjects, if considered necessary by the Investigator. 
 
4.7.3. 
Rescue Therapy Guidelines 
Rescue therapy guidelines are provided to optimize the standardization of rescue therapy by 
Investigators and to ensure the safety of individual study subjects. Use of rescue therapy and reason 
for rescue therapy should be recorded in the electronic case report form (eCRF). 
 
4.7.3.1. 
Red Blood Cell Transfusion (all subjects) 
RBC transfusion should be considered if rapid correction of anemia is required to stabilize the 
subject’s condition (e.g., acute hemorrhage) or the Investigator is of the opinion that the blood 
transfusion is a medical necessity. If the situation permits, the Medical Monitor should be informed 
prior to any scheduled RBC transfusion. Study treatment may continue during or after the RBC 
transfusion. 


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4.7.3.2. 
Erythropoiesis Stimulating Agents 
If possible, the use of ESAs as a “Rescue” modality should be carefully considered, and should be 
restricted to no more than one cycle of use during the Treatment Period; the Investigator may initiate 
use of an approved erythropoietin (EPO) analogue if all of the following criteria are met: 
• A subject’s Hb level has not sufficiently responded to two or more dose increases or the 
maximum dose of study drug has been reached, and 
• The subject’s Hb is < 8.5 g/dL on two consecutive measurements at least five days apart; 
and 
• Clinical judgment does not suggest iron deficiency or bleeding as a cause of lack of 
response or rapid decline in Hb, and 
• Reducing the risk of alloimmunization in transplant eligible subjects and/or reduction of 
other RBC transfusion-related risks is a goal 
Such ESA Rescue should be started ≥ 2 days after the last dose of roxadustat. 
ESA Rescue should be stopped when Hb > 9 g/dL or after 4-weeks, whichever comes first. If a 
subject requires longer than 4-weeks therapy due to inadequate response, or in other extenuating 
circumstances, the Medical Monitor should be contacted. 
Study treatment should 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®) 
If more than one cycle of ESA rescue is required, the Investigator should permanently discontinue 
study drug. 
Inadvertent ESA administration, such as ESA administration during a hospitalization, should not be 
counted as rescue unless above criteria are met; these subjects may be allowed to restart Roxadustat 
dosing if considered safe by the Investigator or Medical Monitor. 
All ESAs used during the Treatment Period, either planned or inadvertent, should be recorded. 
ESAs and Roxadustat should not be administered concomitantly. 
4.7.3.3. 
Emergency Procedure (Therapeutic Phlebotomy) 
If there are clinical concerns for a subject’s high Hb levels, the Investigator may decide to perform a 
therapeutic phlebotomy in addition to temporarily withholding the study drug. This should be 
documented and discussed with the Medical Monitor. 
 
4.7.4. 
Prohibited Medications/Therapies/Substances 
The following medications/therapies are prohibited during the period identified: 
• Any investigational drug from 4 weeks prior to screening until EOS 
• Androgens from screening until EOS 


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• Iron-chelating agents (e.g., deferoxamine/desferrioxamine, deferiprone, or deferasirox 
therapy) from 4 weeks prior to enrollment until EOS 
• Dapsone (at any dose) from screening until EOS 
• Chronic doses acetaminophen/paracetamol > 2.0 g/day from enrollment until 1 week after 
EOT 
 
4.7.5. 
Contraception 
Female subjects of childbearing potential, if not practicing complete sexual abstinence, must agree to 
practice a dual method of contraception, for example, a combination of the following: (1) oral 
contraceptive, depo progesterone, or intrauterine device; and (2) a barrier method (condom or 
diaphragm). Male subjects (nonsurgically sterile; i.e., no vasectomy) with female partners of 
childbearing potential who are not on birth control must agree to use a barrier method of 
contraception (e.g., condom) or the female partner must agree to use contraception as described above 
unless practicing complete sexual abstinence. 
Subjects must agree to practice above contraceptive methods, as applicable, for the entire duration of 
the study, from enrollment through the EOS visit. It is highly recommended that they continue to 
practice the contraceptive methods for 1 week following the last dose of study treatment. For subjects 
discontinuing study medication prematurely, it is recommended that they continue to practice 
contraceptive methods for 1 week following the last dose of study treatment. 
Pregnancy, spontaneous or therapeutic abortion, or events related to pregnancy are to be reported on 
the study pregnancy form provided. 
 
4.8. 
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 
examination (PE) During the course of the study, vital signs, PE, and laboratory tests will be 
performed at regular intervals as described in schedule of assessments (Appendix 2). 
Any significant findings prior to administration of study drug will be considered as baseline 
conditions and if appropriate, will be captured as baseline medical history. Any clinically significant 
(CS) 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. 
All adverse events, SAEs, and ongoing concomitant medication usage will be monitored and recorded 
throughout the treatment and post-treatment follow-up periods. Serious adverse event reports will be 
evaluated individually to assess the impact of the event, if any, on the overall safety of the product 
and on the study itself. Cumulative AEs will be monitored. Serious adverse events and AEs will be 
followed until resolved, or deemed stable. See Section 8 for details on AE and SAE reporting. 


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5. 
STUDY ENROLLMENT AND WITHDRAWAL 
5.1. 
Inclusion Criteria 
A subject is eligible for the study if all of the following criteria are met: 
1. 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 
2. Subject is ≥ 18 years of age 
3. Receiving chronic dialysis for end stage renal disease (ESRD) 
4. Prior ESA use: 
• For a subject converting from a ESA: On CERA ≥6 weeks and the prescribed CERA dose 
remain stable (as determined by PI) during the 4 weeks prior to initiating roxadustat 
treatment. 
• Subject is initiating anemia treatment: Defined as: < 6 weeks of prior CERA use or no 
prior ESA use. 
5. Vascular access must be a functioning native arteriovenous fistula or graft with adequate flow 
in the opinion of the investigator, or permanent tunneled catheter. 
6. Screening Hb (based on central lab value; measured within 10 days prior to initiating 
roxadustat treatment): 
• Subjects converting from an ESA: screening Hb is between 9.0 to 12.0 g/dL 
• Subjects initiating anemia treatment: screening Hb is < 10.0 g/dL 
7. Ferritin ≥ 50 ng/mL, Transferrin saturation (TSAT) ≥ 10% at screening (subject may qualify 
after receiving iron supplement per local standard of care) 
8. Subject’s alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are ≤ 3 x 
upper limit of normal (ULN), and total bilirubin (TBL) is ≤ 1.5 x ULN at screening and prior 
to initiating roxadustat treatment. TBL up to 2 x ULN may be allowed if AST and ALT are 
within normal limit) 
9. Subject’s body weight (estimated dry weight in HD subjects) is 45.0 to 160.0 kg 
 
5.2. 
Exclusion Criteria 
Subjects will be excluded if any of the following criteria are met: 
1. Subject has received a red blood cell (RBC) transfusion within 4 weeks prior to enrollment 
2. Subject has a known history of myelodysplastic syndrome or multiple myeloma 
3. Subject has a known hereditary hematologic disease such as thalassemia or sickle cell anemia, 
pure red cell aplasia or other known causes for anemia other than chronic kidney disease 
(CKD) 
4. Subject has known hemosiderosis, hemochromatosis, coagulation disorder, or 
hypercoagulable condition 


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5. Subject has a known chronic inflammatory disease that is determined by the investigator to be 
the primary cause of anemia (e.g., systemic lupus erythematosus, rheumatoid arthritis, celiac 
disease) 
6. Subject is anticipated to undergo elective surgery that is expected to lead to significant blood 
loss during the study period or anticipated elective coronary revascularization. 
7. Subject has active or chronic gastrointestinal bleeding 
8. Subject has been treated with iron-chelating agents within 4 weeks prior to enrollment 
9. Subject has a history of chronic liver disease (e.g., chronic infectious hepatitis, chronic auto- 
immune liver disease, cirrhosis, or fibrosis of the liver) 
10. Subject with New York Heart Association (NYHA) Class III or IV congestive heart failure 
11. Subject has had an MI, acute coronary syndrome, stroke, seizure, or a 
thrombotic/thromboembolic event (excluding vascular dialysis access stenosis/thrombosis) 
(e.g., DVT or pulmonary embolism) within 12 weeks prior to enrollment 
12. Subject has uncontrolled hypertension, in the opinion of the Investigator 
13. Subject has a diagnosis or suspicion (e.g., complex kidney cyst or Bosniak Category II or 
higher) of renal cell carcinoma (PI’s discretion) 
14. Subject has a history of malignancy, except for the following: cancers determined to be cured 
or in remission for ≥ 2 years, curatively resected basal cell or squamous cell skin cancers, 
cervical cancer in situ, or resected colonic polyps 
15. 
Subject is positive for any of the following: 
• Human immunodeficiency virus (HIV) 
• Hepatitis B surface antigen (HBsAg) 
• Anti-hepatitis C virus antibody (anti-HCV Ab) 
16. Subject has an active clinically significant infection at the time of enrollment as determined 
by the investigator 
17. Subject has any of the following known untreated conditions as determined by the 
investigator: proliferative diabetic retinopathy, diabetic macular edema, macular degeneration 
or retinal vein occlusion (subjects who are already blind may qualify to participate) 
18. Subjects with prior organ transplant who have one of the following conditions or states 
19. a) Experienced rejection of transplanted organ within 6 months of transplantation 
20. b) Currently on high doses of immunosuppressive therapy (per discretion of the investigator) 
21. c) Are scheduled for organ transplantation (on the waiting list for kidney transplant is not 
exclusionary) 
22. Subject has participated in an interventional clinical study or has been treated with an 
investigational drug within 4 weeks prior to screening 
23. Subject has drug-treated gastroparesis, short-bowel syndrome, or any other gastrointestinal 
condition that may lead to reduced absorption of study drug (determined by the investigator) 


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24. Subject has an anticipated use of dapsone or androgen in any dose amount or anticipated 
chronic use of acetaminophen or paracetamol > 2.0 g/day during the study 
25. Subject has a history of alcohol or drug abuse within 6 months prior to screening as 
determined by the clinical judgment of the investigator 
26. Females of childbearing potential, if not practicing complete sexual abstinence or using 
contraception as detailed in the protocol; male subjects (if not surgically sterile; i.e., no 
vasectomy) with sexual partners of childbearing potential, if not practicing complete sexual 
abstinence or using contraception 
27. Pregnant or breastfeeding females 
28. Subject has any medical condition that in the opinion of the Investigator may pose a safety 
risk to the subject in this study, which may confound efficacy or safety assessment, or may 
interfere with study participation 
 
5.3. 
Subject Discontinuation and Withdrawal 
The subject is free to permanently discontinue study medication at any time, without prejudice to 
further treatment. Discontinuation from study medication is not the same as complete withdrawal 
from the study (i.e., withdrawal of consent). 
Subjects may withdraw consent and discontinue from the study at any time by discontinuing study 
medication and refusing to return for any form of follow-up without any prejudice. 
A subject who decides to discontinue study medication will always be asked about the reason(s) to 
discontinue study medication and the presence of AEs (if any). These data will be ascertained and 
documented by the investigator and recorded in the eCRF as appropriate. Any subject discontinuing 
study medication will be followed up for 28 days after discontinuing study medication whenever 
feasible for purposes of adverse event reporting. 
Reasons for permanent discontinuation of study medication: 
• Subject’s decision (subject no longer wants to continue study medication (i.e., withdrawal 
of consent) 
• Investigator’s decision that it is in the best interest of the subject to be withdrawn from the 
study 
• Adverse events 
• Significant noncompliance with study procedures, as determined by Investigator or 
Sponsor 
• Lack of efficacy / Meets ESA withdrawal criteria 
• Subject is lost to follow-up 
• Subject got transferred to a different location/dialysis center 
• Subject is no longer requiring dialysis due to kidney transplant 
• Site terminated by the sponsor 
• Pregnancy 


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• Death 
Upon discontinuation from the study, both female subjects of childbearing potential and male 
subjects with partners of childbearing potential must continue to use a medically acceptable method 
of contraception for 1 week following the last study drug administration. 
5.4. 
Replacement of Subjects 
Subjects will not be replaced from this study. 


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6. 
INVESTIGATIONAL PRODUCT 
6.1. 
Formulation 
Roxadustat is supplied by FibroGen, Inc. as red coated, tablets for oral administration, in strengths of 
20 mg, 50 mg, 70 mg100 mg and 150 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 comply with US and European Union 
compendia or regulatory standards. Strengths are different in size and debossing reflects the strength 
(i.e., 20, 50, 70 100 or 150 mg). 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 tablets should be protected from light, and stored at room temperature between 15°C and 
30°C (59ºF to 86ºF). 
Study drug should be stored in a securely locked area to which access is limited to appropriately 
authorized study personnel. 
 
6.3. 
Study Drug Handling and Disposal 
Study drug and packaging provided by the Sponsor 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, unused, and partially used study drugs; and all study drugs that were not 
dispensed will be shipped 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 or Pharmacy Manual for additional information. 
 
6.4. 
Route of Administration and Dose 
Route of Administration: Oral (all tablets must be administered whole) 
Dosing Frequency: Subjects will be dosed three times weekly (TIW), except if a subject requires < 
60 mg/week to maintain Hb levels, in which case dose frequency may be reduced in a stepwise 
fashion, e.g., to twice weekly (BIW), then once weekly (QW), then every-2-weekly (Q2W), etc. 
The first dose of roxadustat should be administered on Day 1 after completion of all procedures 
including laboratory draws. Roxadustat doses should be administered at least 2 days apart, and no 
more than 4 days apart. Dosing should occur at approximately at the same time of day. Roxadustat 
can be taken with or without food. If phosphate binders are taken with food, roxadustat is advised to 
be taken at least one hour before or one hour after the phosphate binder. 
6.5. 
Overdose, Emergency Procedures and Management of Overdose 
The maximum allowed roxadustat dose is 400 mg or 3.0 mg/kg/dose, whichever is lower. Any dosing 
exceeding the maximum allowed roxadustat dose should be reported within 24 hours. The Medical 
Monitor should be contacted as soon as possible. Symptoms associated with overdosing, if any, will 
be reported as adverse events. 


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In the event of suspected roxadustat overdose, the subject should receive supportive care and 
monitoring. The Sponsor’s Medical Monitor should be contacted as applicable. 


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7. 
STUDY PROCEDURES 
7.1. 
Study Procedures by Visit / Schedule of Assessments 
During study visits, unless otherwise indicated, it is preferred that all assessments including labs and 
physical examinations should be completed prior to dialysis. For subjects on home-dialysis please 
also see guidelines in Section 4.1. 
Table 4: Schedule of Assessments 
 
Visit / Week: Screening 
Visit 
Day 1 
Wk 2 to 8 
(Every 2 weeks 
± 4 days) 
Wk 12 to24 f 
(Every 4 weeks 
± 4 days) 
Post-Treatment d 
Follow-up 
± 7 days 
Written informed consent 
X 
Eligibility criteria 
X 
X 
Demographics and medical history 
X 
Height, weight (estimated dry 
weight) 
X 
X a 
Blood pressure, heart rate, 
temperature 
X 
X 
X 
X 
X 
Physical Exam 
X 
X f 
Hemoglobin (central and local) 
X c 
X e 
X e 
X c 
CBC with WBC differential 
X 
X 
Wks 4, 8 
Wks 16, 24 
X 
Serum chemistry 
X 
X 
Wks 4, 8 
Wks 16, 24 
X 
CPK 
X 
X 
Wk 8 
Wks 16, 24 
Serum iron, ferritin, TIBC, TSAT, 
CHr, reticulocytes 
X 
X 
Wk 8 
Wks 16, 24 
HIV ELISA, HBsAg, anti-HCV Ab 
X 
Serum hCG pregnancy test 
X b 
Wk 8 
Wks 16, 24 
X 
Dose adjustment 
X 
X 
AE/CM recording 
X 
X 
X 
X 
X 
Study drug dispensing 
X 
X 
X 
Ab = antibody; CBC = complete blood count; CHr = reticulocyte hemoglobin content; ELISA = enzyme- 
linked immunosorbent assay; ET = early termination; HBsAg = hepatitis B surface antigen; hCG = 
human chorionic gonadotropin; HCV = hepatitis C virus; HIV = human immunodeficiency virus; LFTs 
= liver function tests TIBC = total iron binding capacity; TSAT = transferrin saturation; WBC =white 
blood cells; Wk(s) = week(s); 
a 
Weight only 
b 
Collect from female subjects of child bearing potential only 
c 
Central labs only 
d 
28 days post last dose of roxadustat 
e 
Collect a separate central Hb only when CBC is not collected 
f 
Week 24 = EOT 
 
7.2. 
Screening Period 
• Signed written informed consent 


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• Inclusion/Exclusion criteria verification 
• Demographics and medical history 
• Height and weight (estimated dry weight) 
• 
Vital signs (BP, HR, temperature) 
• Physical Examination: HEENT, respiratory, cardiovascular, abdomen, extremities, and 
neurological parameters 
• Laboratory tests: 
− Hemoglobin (central) 
− Complete blood count (CBC) with WBC differential 
− Serum chemistry 
− CPK 
− Serum iron, ferritin, total iron-binding capacity (TIBC), transferrin saturation (TSAT), 
Reticulocyte count and hemoglobin in reticulocytes (CHr) 
− Enzyme-linked immunosorbent assay (ELISA) for HIV 
− Hepatitis B surface antigen (HBsAg) 
− Anti-HCV Ab 
− Serum hCG pregnancy test 
• Renal ultrasound or other imaging may be performed during screening to rule out renal 
cell carcinoma or suspicion of renal cell carcinoma if deemed necessary by the PI. 
• Review and record concomitant medications 
• Review and record procedures and nondrug therapies 
• Review and record AEs, if any (capture the event under medical history, if applicable) 
7.2.1. 
Additional Screening Assessments 
If a subject’s laboratory results do not meet eligibility criteria at Screening, specific laboratory 
assessments may be repeated within the Screening Period. 
If a subject fails screening, he/she may be re-screened once deemed appropriate by the investigator. 
Where possible, an approval should be obtained from the Medical Monitor prior to re-screening. 
 
7.3. 
Treatment Period 
The Treatment Period begins on the first day of dosing with study treatment (Day 1). 
 
7.3.1. 
Day 1 
All assessments are to be completed prior to first dose of study drug 
• Inclusion/Exclusion criteria verification 
• Vital signs (BP, HR, temperature) 


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• Estimated dry weight 
• Local Hb assessment 
• Laboratory tests: 
− Complete blood count (CBC) with WBC differential 
− Serum chemistry 
− CPK 
− Serum iron, ferritin, total iron-binding capacity (TIBC), transferrin saturation (TSAT), 
Reticulocyte count and hemoglobin in reticulocytes (CHr) 
− Hemoglobin local 
− AE/CM recording 
− Study drug administration 
7.3.2. 
Weeks 2 to 8 (Every 2 Weeks, ±4 days) 
• Vital signs (BP, HR, temperature) 
• Laboratory tests: 
− Hemoglobin (central and local lab) 
 Draw a central Hb only on visits CBC is not collected 
• Week 4 and Week 8: 
− Complete blood count (CBC) with WBC differential 
− Serum chemistry 
• Week 8: 
− CPK 
− Serum iron, ferritin, total iron-binding capacity (TIBC), transferrin saturation (TSAT), 
Reticulocyte count and hemoglobin in reticulocytes (CHr) 
− Serum hCG pregnancy test 
• Dose review at every visit and dose adjustment every 4 weeks 
• TEAE/CM recording 
• Study drug dispensing 
7.3.3. 
Weeks 12 to 24 (Every 4 weeks, ±4 days) 
• Vital signs (BP, HR, temperature) 
• Physical Examination: HEENT, respiratory, cardiovascular, abdomen, extremities, and 
neurological parameters (at EOT/Week 24 only) 
• Hemoglobin (central as part of CBC and local lab) 


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• Week 16 and Week 24: 
− Complete blood count (CBC) with WBC differential 
− Serum chemistry 
− CPK 
− Serum iron, ferritin, total iron-binding capacity (TIBC), transferrin saturation (TSAT), 
Reticulocyte count and hemoglobin in reticulocytes (CHr) 
− Serum hCG pregnancy test (female of child bearing potential only) 
• Dose adjustment 
• AE/CM recording 
• Study drug dispensing 
Week 24 visit is considered as End of Treatment (EOT) visit 
Subjects permanently discontinuing roxadustat before Week 24 should have Early Termination visit 
(same as Week 24/EOT visit) as soon as possible. 
 
7.4. 
Post-Treatment Follow-up visit (for subjects discontinuing roxadustat 
treatment at Week 24 or Early Termination) (±7 days) 
• Final safety assessment 28 days after the last roxadustat dose. 
• Vital signs (BP, HR, temperature) 
• Laboratory tests: 
− Complete blood count (CBC) with WBC differential 
− Serum chemistry 
− Serum hCG pregnancy test (female of child bearing potential only) 
− AE/CM recording 
Subjects who wish to permanently discontinue roxadustat, should receive the first ESA dose at least 
two days after the last roxadustat dose. 
An extension of roxadustat treatment after 24 weeks may be offered to interested subjects within the 
context of this study protocol upon agreement of the study site, until roxadustat is commercially 
available, or up to 1 year after completing the 24 weeks, whichever comes first. 
 
 
7.5. 
Missed Visits 
Every attempt should be made to complete all study visits within the visit window as outlined in the 
Schedule of Assessments. 
 
7.6. 
Unscheduled Visits 
Unscheduled visit(s) and laboratory assessments may be required at the discretion of the investigator. 
Please refer to the eCRF completion guidelines for additional information. 


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7.7. 
Laboratory Assessments 
Details regarding sample collection, preparation and transport can be found in the central laboratory 
manual. Importantly, dose adjustments per the dosing algorithm will be made on results from local 
Hb testing. 
 
7.8. 
Central Laboratory 
The following labs will be evaluated by a central laboratory in accordance with the SOA in Appendix 
2 


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Chemistry Panel: 
Albumin 
Bicarbonate 
BUN 
Calcium 
Chloride 
Creatinine 
Creatine phosphokinase 
Glucose 
Lactic Acid Dehydrogenase 
Liver Function Tests1 
ALP 
ALT 
AST 
Bilirubin, total and direct 
GGT 
Magnesium 
Phosphorus 
Potassium 
Total protein 
Uric acid 
HIV and viral Hepatitis Panel: 
Anti-HCV Ab tests 
HBsAg 
HIV ELISA 
CBC: 
Basophils 
Eosinophils 
Erythrocyte count (RBC) 
Hct 
Hb 
Leukocyte count (WBC) 
Lymphocytes 
Mean corpuscular volume 
Mean corpuscular Hb 
Mean corpuscular Hb concentration 
Monocytes 
Neutrophils 
Neutrophils, immature (banded) 
Platelets 
Serum Iron Profile 
Ferritin 
Iron 
TIBC 
UIBC 
TSAT 
Additional Laboratory Analytes: 
Reticulocyte count 
CHr 
Serum hCG pregnancy test (for women of 
childbearing potential only) 
Table 5: Central Laboratory Tests 
 
Abbreviations: 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood 
urea nitrogen; CBC = complete blood count; CHr = reticulocyte hemoglobin content;; ELISA = enzyme-linked 
immunosorbent assay; GGT = gamma-glutamyl transferase; Hb = hemoglobin; HBsAg = hepatitis B surface 
antigen; Hct = hematocrit; HCV = hepatitis C virus; HIV = human immunodeficiency virus; RBC = red blood cell; 
TIBC = total iron binding capacity; UIBC=unsaturated iron binding capacity TSAT = transferrin saturation; 
WBC = white blood cell. 
 
1 In case a patient shows an AST or ALT ≥3xULN and total bilirubin ≥ 2xULN Please refer to 
Appendix 2 “Liver Function Monitoring”. 


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8. 
SAFETY 
8.1. 
Background 
Subjects will be asked for the occurrence of potential AEs during each study visit. In addition, all 
AEs reported spontaneously during the course of the study will be recorded. The Investigator must 
immediately (within 24 hours of becoming aware) 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 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 ICH E2A 
guidance. 
 
8.2. 
Definitions 
8.2.1. 
Definition of an Adverse Event 
An AE 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 (e. g., an abnormal and clinically significant 
laboratory finding), symptom, or disease temporally associated with the use of a drug, without any 
judgment about causality. This includes any occurrence that is new in onset or aggravated in severity 
or frequency from the BL condition, or abnormal results of diagnostic procedures, including 
laboratory test abnormalities. An AE can arise from any use of the drug (e.g.,, off-label use, use in 
combination with another drug) and from any route of administration, formulation, or dose, including 
an overdose. 
An AE includes medical conditions, signs, and symptoms not previously observed in the subject that 
emerge during the protocol-specified AE reporting period, including signs or symptoms associated 
with an underlying condition that were not present prior to the AE reporting period (Section 8.3.1) 
 
8.2.2. 
Definition of a Serious Adverse Event 
An SAE is any AE or suspected adverse reaction that results in any of the following outcomes: 
• Death 
• A life-threatening AE (i.e., if in the view of the Investigator or sponsor, the subject was at 
immediate risk of death at the time of the event). Life-threatening does not refer to an 
event which hypothetically might have caused death if it were more severe. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly or birth defect 
• A medically important event not meeting the above criteria, but which may jeopardize a 
patient or may require medical or surgical intervention to prevent one of the other criteria 
listed in this definition. Examples of such medical events include allergic bronchospasm 


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requiring intensive treatment in an emergency room or at home, and blood dyscrasias or 
convulsions that do not result in inpatient hospitalization 
 
8.3. 
Procedures for Eliciting, Recording, and Reporting Adverse Events 
8.3.1. 
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 study visit, except for pregnancy reporting (Section 8.3.6). 
AEs (non-SAE) reported during screening should be reviewed and captured under medical history, if 
applicable. 
Adverse events will be followed until resolved, stable, or until the subject’s last study visit or lost to 
follow-up. If an AE is not resolved or stabilized at the subject’s last visit, it is up to the discretion of 
the investigator and/or study Medical Monitor to determine if further monitoring of the event is 
warranted. 
Adverse events collected prior to dosing of study drug will be considered “non-treatment emergent” 
while those reported after the first dose of study drug and up to 28 days after the last dose of study 
drug will be considered “treatment emergent” and be assessed for relationship to study drug. If an 
AE starts on Day 1, the investigator must assess as to whether the AE started prior to or after the 
administration of study medication and record accordingly. 
 
8.3.2. 
Adverse Event Eliciting/Reporting 
During the AE reporting period, study site personnel will query each subject/caregiver at each visit to 
assess for any AEs occurring since the previous visit. All AEs will be collected in response to non- 
leading, general questions about the subject’s well-being and any possible changes from the baseline 
or previous visit. This does not preclude the site from collecting and recording any AEs reported by 
the subject/caregiver to site personnel at any other time. 
Whenever possible, AE diagnoses should be recorded rather than just the signs and symptoms, 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 will be recorded as AEs; recurrence 
or worsening of medical conditions will also be recorded as AEs. Abnormal, clinically significant 
laboratory results, and PE findings will be recorded as AEs if they are deemed by the Investigator to 
meet the AE criteria. 
The following attributes must be assigned to each AE: 
• Description (Investigator’s verbatim term describing the event). 
• Dates of onset and resolution 
• Severity 
• Relationship to study drug 
• Outcome 
• Action taken regarding study drug (action taken by the PI in response to an AE) 
• Other treatment required 
• Determination of “seriousness” 


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8.3.3. 
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 which the subject finds easily tolerated. 
The event is of little concern to the subject and/or of little-or-no clinical significance; 
clinical or diagnostic observations only; intervention not indicated. 
• Grade 2, Moderate: The subject has enough discomfort to cause interference with or 
change in some of their age-appropriate instrumental activities of daily living (e.g., 
preparing meals, shopping for groceries or clothes, using the telephone, managing 
money); local or noninvasive intervention indicated. 
• Grade 3, Severe: The subject is incapacitated and unable to work or participate in many 
or all usual activities. The event is of definite concern to the subject and/or poses 
substantial risk to the subject’s health or well-being; Likely to require medical 
intervention and/or close follow-up, including but not limited to hospitalization or 
prolongation of hospitalization. 
• Grade 4, Life-threatening: The subject was at immediate risk of death from the event as 
it occurred. 
• Grade 5, Death related to AE. 
8.3.4. 
Assessing Relationship to Study Drug 
Most of the information about the safety of a drug prior to marketing comes from clinical trials; 
therefore, AE reports from Investigators are critically important. Moreover, appropriately deciding 
whether the AE meets the definition of a suspected adverse reaction is usually the most difficult 
determination, but it is critical to avoid the mis-categorization of the product’s safety profile. 
Default reporting of individual events as possibly related is uninformative and does not meaningfully 
contribute to the development of the drug’s safety profile. 
The Investigator must provide an assessment of the relationship of the AE to study drug in 
accordance with the guidance below. Absence of an alternative cause would not normally be 
considered enough evidence to assess an event as possibly related or related to study drug. The 
following are examples of adverse events and their relationship to study drug: 
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, but is a typical drug toxicity and known to be 
strongly associated with drug exposure, such as 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. 


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Not Related: 
The event represents the underlying disease (e.g., disease-related symptoms, disease progression) and 
the presentation of the event is typical. 
The event represents a comorbid condition present at the time the subject entered the study that has 
not worsened. 
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 (e.g., cardiovascular events in an elderly population). 
The Investigator must provide an assessment of the relationship of the event to study drug, as this 
information is very important to monitor the real-time safety of the study drug. However, as the 
manufacturer of the study drug, FibroGen is responsible for reporting suspected adverse reactions and 
adverse reactions to Health Authorities. 
 
8.3.5. 
Reporting Serious Adverse Events on the Serious Adverse Event Report Form 
All SAEs must be reported immediately to the Sponsor and/or its designated safety management 
vendor. 
To report an SAE, the Investigator must fax or email an SAE Report Form to the Sponsor’s 
designated safety management vendor within 24 hours of becoming aware of the serious event. 
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. The following 
minimum information is required: 
• Subject number, sex and age 
• The date of report 
• A description of the SAE (event, seriousness of the event) 
• Causal relationship to the study drug 
For each SAE observed, the Investigator should obtain all of the information available about the 
event, including (but not limited to): clinical course of the event, 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). 
The medical monitor is available to discuss safety issues if needed. 
 
8.3.5.1. 
Reporting Serious Adverse Events to the Institutional Review Board / Independent 
Ethics Committee 
The Investigator is responsible for notifying his/her Institutional Review Board (IRB) or Ethics 
Committee (EC) of SAEs in accordance with local regulations. Sponsor, or its safety representative, 
will provide to the Investigator a copy of any expedited safety reports that it intends to file with a 
regulatory authority. 


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8.3.5.2. 
Deaths 
For any death occurring during the subject’s study participation, regardless of attribution, the 
Investigator will report the death within 24 hours to the Sponsor’s Medical Monitor and their 
designated safety management vendor on an SAE form. 
The Investigator should notify the 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. 
 
8.3.6. 
Pregnancies: Reporting and Follow-up 
A pregnancy in a female subject or a male subject’s female partner must be confirmed by positive 
serum β-HCG test(s). If pregnancy is suspected, study drug may need to be interrupted until 
pregnancy is ruled out. 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 the Sponsor (by way of its 
designated safety management vendor) within 24 hours of the Investigator learning of the pregnancy. 
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 of the pregnancy 
must be reported by the Investigator on a Pregnancy Outcome Report Form, which should be sent to 
the Sponsor and/or its designated safety management vendor within 24 hours of the Investigator 
learning of the outcome. 
 
8.3.7. 
Abnormal Laboratory Findings 
Laboratory values will be collected throughout the study to assess for safety. The Investigator must 
review and assess all laboratory results in a timely manner, and determine whether the abnormal 
laboratory values, if any, are clinically significant or not clinically significant, and whether there are 
associated signs and symptoms. Clinically significant laboratory abnormalities will be reported as 
AEs. 
An abnormal laboratory finding in absence of any other signs or symptoms is not necessarily an AE. 
If the abnormal laboratory finding is accompanied by signs or symptoms, report the signs and 
symptoms as the AE in lieu of the abnormal laboratory value. If a diagnosis is available, report the 
diagnosis. 
An abnormality identified during a medical test should be defined as an AE only if the abnormality 
meets one of the following criteria: 
• Induces clinical signs or symptoms 
• Requires active intervention 
• Requires interruption or discontinuation of study medication 


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• In the opinion of the Investigator, the abnormality is clinically meaningful and 
significantly different from baseline. 
 
8.3.8. 
Disease Progression 
Disease progression can be considered as a worsening of a subject’s condition attributable to the 
disease for which the investigational product is being studied. It may be an increase in the severity of 
the disease under study and/or increases in the symptoms of the disease. As anemia is the condition 
being investigated in this study, worsening anemia should not be reported as an AE unless the subject 
is hospitalized 


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9. 
STATISTICAL CONSIDERATIONS 
Descriptive summaries will be presented for study parameters including baseline characteristics, 
safety, and efficacy. 
Continuous variables will be reported in mean, standard deviation or standard error, median, 
minimum, and maximum. 
Categorical variables will be reported by the frequency and percentage of subjects within each 
outcome category. 
Analyses of the efficacy data will be based on the Full Analysis Set (FAS) Population. 
Safety data will be summarized descriptively based on the Safety Population. 
Operational characteristics of the drug will be evaluated qualitatively and descriptively 
 
9.1. 
Sample Size Determination 
Approximately 200 subjects with anemia of CKD (either with or without prior treatment with an ESA 
before enrolment) and on hemodialysis are planned in this study. This number of subjects distributed 
across the specified number of sites is adequate to evaluate the primary study objective. 
Assuming the proportion of subjects that maintain Hb levels ≥10g/dL from Weeks 16 to 24 is at least 
80%, with a sample size of 200, the study will be able to produce a two-sided 95% confidence 
interval (CI) with a width equal of 11.5%. 
 
9.2. 
Analysis Sets 
The FAS set will consist of all subjects who signed informed consent, who were enrolled, and who 
provided baseline Hb data and data for at least one post baseline Hb time point. The FAS set will be 
used for all efficacy endpoints. 
The Safety analysis set will include all enrolled subjects receiving at least 1 dose of study treatment. 
The safety analysis set will be used for all safety endpoints and exposure to study treatment 
outcomes. 
 
9.3. 
Analysis of the Efficacy Endpoints 
The efficacy endpoint will be evaluated using the proportion (%) of subjects with mean value of Hb 
measurements of Week 16-Week 24 > 10g/dL. 
The 95% CI of the response rate will be presented based on the exact method of Clopper-Pearson. 
For the efficacy analysis, a multiple imputation (MI) method will be used. This will be implemented 
on the raw Hb values, then the Hb-relates endpoint summaries will be derived based on the imputed 
data (algorithm as used for the previous phase 3 studies). For continuous endpoints, changes from 
baseline will be presented descriptively. Missing Hb values will be imputed using a multiple 
imputation procedure. 
Proportion of responders will be presented descriptively with count and percentages and 95% 
confidence interval of the responder rate. 
Time to response will be analyzed using the Kaplan-Meier method with KM curve plotted. 


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9.4. 
Safety Analysis 
The Safety analysis will be performed using the Safety Analysis Set (SAF). Safety parameters include 
AEs, SAEs, laboratory parameters and vital signs. 
The number and percentage of subjects reporting treatment-emergent AEs (TEAEs) and TESAEs will 
be tabulated. 
Descriptive statistics will be presented for laboratory and vital signs. 


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10. 
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 Sponsor or its designee. The investigator must provide direct access 
to, and allocate sufficient space and time for, the monitor to inspect subject source records, eCRFs, 
queries, collection of local laboratory normal ranges (if applicable), investigational product 
accountability records, and regulatory documents in accordance with 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 (e.g., 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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11. 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. 
Data Quality Assurance 
Quality assurance and quality control systems will be implemented and maintained with Standard 
Operating Procedures by FibroGen and its designee(s), as appropriate, to ensure that this clinical 
study is conducted and data are generated, documented (recorded) and reported in compliance with 
the protocol, ICH E6 (GCP), and other applicable regulations. 
This study will be monitored by FibroGen or designee in accordance with GCP, and may be audited 
or reviewed by an independent Quality Assurance department, IRB/IEC, and/or regulatory 
authorities. This implies that monitors and auditors/inspectors will have the right to inspect the study 
sites at any time during and/or after completion of the study and will have direct access to data/source 
documents, including the subject's file. By participating in this study, Investigators agree to this 
requirement. 
The purpose of trial monitoring is to verify the following: 
• The rights and well-being of human subjects are protected. 
• The reported data are accurate, complete, and verifiable from source documents. 
• All data are collected, tracked, and submitted by the site to FibroGen or designee, 
including unscheduled and missed assessments 
• The reported data are reconciled across all data sources (e.g., laboratory, safety, IRT, 
clinical databases). 
• The conduct of the trial is in compliance with the currently approved 
protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s). 
Measures will be undertaken to protect the confidentiality of records that could identify subjects, 
respecting the privacy and confidentiality rules in accordance with applicable regulatory 
requirements. 
 
11.2. 
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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12. 
ETHICS 
12.1. 
Ethical Considerations 
The study will be conducted in accordance with FDA regulations, ICH E6 Guideline for GCP, the 
Declaration of Helsinki, any other applicable regulatory requirements, and IRB or independent ethics 
committee (IEC) requirements. 
 
12.2. 
Communication with the Institutional Review Board or Independent 
Ethics Committee 
This protocol, the Informed Consent Form, the IB, and any information to be given to the subject 
must be submitted to a properly constituted IRB/IEC by the Investigator for review and approved by 
the IRB/IEC before the study is initiated and before any investigational product is shipped to the 
Investigator. In addition, any subject recruitment materials must be approved by the IRB/IEC before 
the material is used for subject recruitment. 
The investigator is responsible for obtaining reapproval by the IRB/IEC annually or 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 FibroGen. A copy of the signed 
form FDA 1572 must also accompany the above approval letter provided to FibroGen. 
Investigators are also responsible for promptly informing the IRB/IEC of any protocol changes or 
amendments, changes to the Investigator’s Brochure, and other safety-related communications from 
FibroGen. Written documentation of IRB approval must be received before the amendment is 
implemented. 
Investigators must also enter the names of the staff that are involved in the study on the Delegation of 
the Authority form and sign the form (including their responsibilities). This form must be updated 
when responsibilities of the staff change. 
 
12.3. 
Informed Consent Form 
No study procedure may be implemented prior to provision of a written Informed Consent Form 
(ICF) from the subject or the subject’s legally authorized representative. Institutional Review 
board/IEC review and approval are required for the ICF. The final IRB/IEC approved ICF must be 
provided to FibroGen for regulatory purposes. 
If there are any changes to the Sample ICF during the subjects’ participation in the study, the revised 
ICF must receive the IRB/IEC’s written approval before use and subjects must be re-consented to the 
revised version of the ICF. 
Guidance for Clinical Teams: For studies conducted in the United States, each subject must provide 
his or her consent for the use and disclosure of personal health information under the US Health 
Insurance Portability and Accountability Act (HIPAA) regulations by signing a HIPAA Authorization 
Form. The HIPAA Authorization Form may be part of the ICF or may be a separate document. IRB 
review may or may not be required for the HIPAA Authorization Form according to study site 
policies. 


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12.4. 
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 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 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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13. 
DATA HANDLING AND RECORD KEEPING 
13.1. 
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. 
 
13.2. 
Data Collection, Handling, and Verification 
All required data will be entered onto CRFs by authorized site personnel. Data will be entered into a 
validated, clinical database compliant with 21 Code of Federal Regulation (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, AEs, and medications will be coded using industry standard dictionaries (e.g., 
MedDRA and World Health Organization Drug [WHODrug]) Dictionary. 
The Investigator is responsible for reviewing, verifying, and approving all subject data, i.e., CRFs and 
queries prior to study completion, ensuring that all data is verifiable with source documents. 


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14. 
FINANCING AND INSURANCE 
Financing and insurance are addressed in a separate document. 


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


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16. 
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. 
 
16.1. 
Study Drug Accountability 
The investigational product (roxadustat) 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, 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 or Pharmacy Manual should be recorded using the Drug 
Inventory Log. 
 
16.2. 
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. 
 
16.3. 
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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17. 
REFERENCES 
Besarab, A., et al. "The effects of normal as compared with low hematocrit values in patients with 
cardiac disease who are receiving hemodialysis and epoetin." N Engl J Med 339.9 (1998): 584-90. 
Besarab, A., S. Frinak, and J. Yee. "What is so bad about a hemoglobin level of 12 to 13 g/dL for 
chronic kidney disease patients anyway?" Advances in Chronic Kidney Disease 16.2 (2009): 131-42. 
Bradbury BD, Danese MD, Gleeson M, Critchlow CW "Effect of Epoetin alfa dose changes on 
hemoglobin and mortality in hemodialysis patients with hemoglobin levels persistently below 
11 g/dL". Clin J Am Soc Nephrol 4 : 630– 637, 2009 
Bruck, K., et al. “CKD Prevalence Varies across the European General Population.” JASN 27.7 
(2016): 2135-47. 
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 32.6 Suppl 4 (1998): S133-S141. 
Coresh, J., et al. "Prevalence of chronic kidney disease in the United States." JAMA 298.17 (2007): 
2038-47. 
Drueke, T. B., et al. "Normalization of hemoglobin level in patients with chronic kidney disease and 
anemia." N Engl J Med 355.20 (2006): 2071-84. 
Epstein AC, Gleadle JM, McNeill LA, et al. “C. elegans EGL-9 and mammalian homologs define a 
family of dioxygenases that regulate HIF by prolyl hydroxylation.” Cell. 2001:107(1):43-54. 
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. 


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Greijer, A. E., 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. 
Jungers PY, Robino C, Choukroun G, Nguyen-Khoa T, Massy ZA, Jungers P (2002) “Incidence of 
anaemia, and use of epoetin therapy in pre-dialysis patients: a prospective study in 403 patients.” 
Nephrol Dial Transplant 17: (9):1621-1627 
Kilpatrick RD, Critchlow CW, Fishbane S, Besarab A, Stehman-Breen C, Krishnan M, Bradbury BD: 
“Greater epoetin alfa responsiveness is associated with improved survival in hemodialysis patients.” 
Clin J Am Soc Nephrol 3 : 1077– 1083, 2008 
Langsetmo, I., Nichols, B., Seeley, T., Stephenson, B., Klaus, S., Lin, A., and Liu, D. (2005) 
“FG-2216 Corrects Anemia and Improves Iron Utilization in a Rat Model of Anemia of Chronic 
Disease: Comparison to Darbepoetin.” Abstract #F-PO674, J Am Soc Nephrol 16: 481A. 
Ma, J., Ebben, J. Z, Xia, H., Collins, A. J. (1999). Hematocrit Level and Associated Mortality in 
Hemodialysis Patients. J Am Soc Nephrol 10: 610-619. 
NKF KDOQI. "KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for 
anemia in chronic kidney disease: update of hemoglobin target." American Journal of Kidney 
Diseases 50.3 (2007): 471-530. 
Peyssonnaux, C., V. Nizet, and R. S. Johnson. "Role of the hypoxia inducible factors HIF in iron 
metabolism." Cell Cycle 7.1 (2008): 28-32. 
Regidor DL, Kopple JD, Kovesdy CP, et al. (2006) Associations between changes in hemoglobin and 
administered erythropoiesis-stimulating agent and survival in hemodialysis patients. J Am Soc 
Nephrol. 17: (4):1181-1191 
Scortegagna, M., et al. "HIF-2a 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 GL (2000) HIF-1: mediator of physiological and pathophysiological responses to hypoxia. 
J Appl Physiol 88: (4):1474-1480 
Szczech LA, Barnhart HX, Inrig JK, et al. (2008) Secondary analysis of the CHOIR trial epoetin- 
alpha dose and achieved hemoglobin outcomes. Kidney Int 74: (6):791-798 
Singh, A. K., et al. "Correction of anemia with Epoetin alfa in chronic kidney disease." N Engl J Med 
355.20 (2006): 2085-98. 
Solomon SD, Uno H, Lewis EF, et al. Erythropoietic response and outcomes in kidney disease and 
type 2 diabetes. N Engl J Med. 2010;363(12):1146-1155. 
Thilly N, Stengel B, Boini S, Villar E, Couchoud C, Frimat L (2008) Evaluation and determinants of 
underprescription of erythropoiesis stimulating agents in pre-dialysis patients with anaemia. Nephron 
Clin Pract 108: (1):c67-c74 
Tonelli, M., et al. "Chronic kidney disease and mortality risk: a systematic review." J Am Soc 
Nephrol 17.7 (2006): 2034-47. 


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Unger, E. F. FDA Perspectives on ESAs for Anemia of Chronic Renal Failure: Hemoglobin Target 
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reevaluation. N Engl J Med 362: (3):189-192 
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(1997): 63-74. 


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Zhang, Y., et al. "Epoetin requirements predict mortality in hemodialysis patients." American Journal 
of Kidney Diseases 44.5 (2004): 866-76. 
Zoccali C, Kramer A, Jager KJ. Epidemiology of CKD in Europe: an uncertain scenario. Nephrol 
Dial Transplant. 2010;25(6):1731-3. 


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18. 
APPENDIX 


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Appendix 1: Roxadustat Dose Adjustment Rules
Current Hb level:
<10.5 g/dL
10.5 to 11.9 g/dL
12.0 to
12.9 g/dL
≥13.0 g/dL
Change in Hb over 
previous 4 weeks:
> 1.0 g/dL
No change
↓
↓
• Hold dosing
• Check Hb and 
resume dosing when 
Hb <12.0 g/dL, at a 
dose reduced by 2 
steps
-1.0 g/dL to
+1.0 g/dL
↑
No change
↓
< -1.0 g/dL
↑
↑
No change*
↑: Increase dose by one step; ↓: reduce dose by one step.
*Continue to hold dose
Notes:
Dose Increases and Reductions:
•
Dose increases (↑) and reductions (↓) are preset.
•
The dose steps are as follows: 20, 40, 50, 70, 100, 150, 200, 250, 300, and 400 mg.
If < 20 mg /dose is required, dosing frequency should be reduced in a step-wise fashion e.g., TIW to BIW, BIW to QW
•
The maximum dose is capped at 400 mg or 3.0 mg/kg/dose (whichever is lower). Rounding the mg/kg calculated roxadustat 
dose up to 10 mg may be allowed, if no safety concerns.
Roxadustat dose adjustment reviews should occur every 4 weeks, except if the following criteria are 
met:
•
Rate of Hb rise > 2 g/dL within 4 weeks: reduce dose by 1 dose step
•
Hb level > 13g/dL: hold dose, until Hb drops to < 12g/dL, resume dosing at 2 dose steps 
lower
Dose adjustments or temporary dose holds for excessive rate of Hb rise or Hb above 13 g/dL can 
occur at any time during the Treatment Period. 
Prescribed dose must not exceed the maximum allowable dose of 3.0 mg/kg/dose or 400 mg per dose, 
whichever is lower; rounding the mg/kg calculated roxadustat dose up to 10 mg may be allowed, if no 
safety concerns. For dose adjustment purposes, estimated dry-weight at enrollment should be used for 
the entire duration of the treatment period. 


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Appendix 2: Liver Function Monitoring 
The guidelines described in this section are intended to enable early detection and action following 
abnormal liver function test (LFT) results. Any patient enrolled in a clinical study with active drug 
therapy and reveals an increase of serum aminotransferases (AT) to > 3 × upper limit of normal 
(ULN), or bilirubin > 2 × ULN, should undergo detailed testing (including at least alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and total 
bilirubin [TBL]) for further evaluation and follow-up. Alerts will be generated by the central lab to 
inform the investigator, study monitor and study team. Testing should be repeated within 48-72 
hours of notification. Patients should be asked if they have any symptoms suggestive of hepatobiliary 
dysfunction. 
Definition of Liver Abnormalities 
Confirmed abnormalities should be characterized as follows: 
 
ALT or AST 
Total Bilirubin 
Moderate 
> 3× ULN 
Or 
> 2× ULN 
Severe 
> 3× ULN 
And 
> 2× ULN 
Abbreviations: 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal. 
Hy’s Law: Drug-induced jaundice caused by hepatocellular injury, without a significant obstructive component, has a 
high rate of bad outcomes, from 10% to 50% mortality (or transplant). The two “requirements” for Hy’s Law are: 
1) Evidence that a drug can cause hepatocellular-type injury, generally shown by an increase in transaminase elevations 
higher than 3 times the upper limit of normal (“2 × ULN elevations are too common in treated and untreated Patients to 
be discriminating”). 2) Cases of increased bilirubin (at least 2 × ULN) with concurrent transaminase elevations at least 
3 × ULN and no evidence of intra- or extrahepatic bilirubin obstruction (elevated alkaline phosphatase) or Gilbert’s 
syndrome: Temple, R (2006) Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf 15: (4):241- 
243 
 
In addition, the patient should be considered to have severe hepatic abnormalities for any of the 
following: 
• ALT or AST > 8× ULN 
• ALT or AST > 5× ULN for more than 2 weeks 
• ALT or AST > 3× ULN and international normalized ratio (INR) > 1.5 (if INR testing is 
applicable/evaluated). 
• ALT or AST > 3× ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
The investigator may determine that abnormal liver function results, other than as described above, 
may qualify as moderate or severe abnormalities and require additional monitoring and follow-up. 


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Follow-up Procedures 
Patients with confirmed abnormal liver function results should be closely monitored and followed as 
described below. If close monitoring for LFTs in a patient is not possible, study drug should be 
discontinued. 
Repeat LFTs 2-3 times weekly, then weekly or less until abnormalities stabilize or return to within 
normal limits. LFTs should include ALT, AST, TBL and ALP 
In addition, evaluate the patient 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: e.g., INR, gamma glutamyltransferase (GGT) or 
direct bilirubin; ultrasound or other imaging to assess biliary tract disease 
• Consider gastroenterology or hepatology consultations 
In general, in the absence of an explanation for increased LFTs, such as viral hepatitis, preexisting or 
acute liver disease or exposure to other agents associated with liver injury, the study drug should be 
discontinued. 
Discontinuation of treatment should be considered if: 
• ALT or AST > 8 × ULN 
• ALT or AST > 5 × ULN for more than 2 weeks 
• ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5) (If INR testing is 
applicable/evaluated) 
• ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%) 
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 
See also: FDA Guidance for Industry, titled: “Drug-Induced Liver Injury: Premarketing 
Clinical Evaluations”, issued July 2009 

SAP_001.pdf: 
Veeva Document Number: FG-CLPLN-0049 
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FG-CLPLN-0049 
Confirm Current Version After Print Date: 09 Sep 2021 12:05PM GMT-07:00 
 
 
 
 
NCT #NCT04410198 
FibroGen, Inc. 
 
 
 
 
 
 
 
 
 
A Phase 3b Multicenter, Open-Label Single Arm Study of Roxadustat: Either 
as Conversion from a Continuous Erythropoietin Receptor Activator (CERA), 
or as Initial Anemia Treatment in Hemodialysis (HD) Patients 
 
Protocol Number: FGCL-4592-097 
 
Amendment 2 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
 
 
 
 
Version: 
1.0 
Release Date: 
09Sep2021 
 
 
Confidentiality Statement 
This document is the property of FibroGen, Inc. and may notin full or partbe passed 
on, reproduced, published, distributed to any person, or submitted to any regulatory 
authority without the express written permission of FibroGen, Inc. 


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FGCL-4592-097 
Statistical Analysis Plan, v 1.0 
9/9/2021 
Approvals 
I have reviewed and accept the information in this document to be a true and accurate 
representation of the Statistical Analysis Plan for Study FGCL-4592-097. 
 
 
Initiator: 
Signature: 
Date: 
Reviewed by: 
Signature: 
Date: 
Signature: 
Date: 
 
Signature: 
Date: 
 
 
 
Signature Significance 
The following significance is lent to the signatures on the Approvals page of this 
document. 
 
Signature 
Significance 
Author 
By signing, the author is attesting that the content of the document 
is complete and accurate. 
Reviewer 
By signing, the reviewer is attesting that the document’s approach 
and contents are compliant with the study protocol, all appropriate, 
regulatory requirements, and other significant guidelines. This 
individual(s) has reviewed the document for accuracy and 
completeness. 
*See appended final page for 21CFR Part 11 compliant approval 
*See appended final page for 21CFR Part 11 compliant approval 
*See appended final page for 21CFR Part 11 compliant approval 
*See appended final page for 21CFR Part 11 compliant approval 


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FGCL-4592-097 
Statistical Analysis Plan, v 1.0 
9/9/2021 
Table of Contents 
List of Abbreviations ....................................................................................................................................... 5 
1 
Introduction ....................................................................................................................................... 6 
2 
Study Design ..................................................................................................................................... 6 
3 
Study Objectives .............................................................................................................................. 10 
3.1 
Primary Objective ............................................................................................................. 10 
3.2 
Secondary/Exploratary Objectives ..................................................................................... 10 
4 
Study Endpoints ............................................................................................................................... 10 
4.1 
Efficacy Endpoints ............................................................................................................ 10 
4.2 
Exploratory Endpoints ....................................................................................................... 10 
4.3 
Safety Assessments ........................................................................................................... 11 
5 
General Statistical Considerations ................................................................................................... 11 
5.1 
Statistical Methodology ..................................................................................................... 11 
5.2 
Sample Size Determination ............................................................................................... 12 
5.3 
Analysis Populations ......................................................................................................... 12 
5.3.1 
Safety Population (SAF) ..................................................................................... 12 
5.3.2 
Full Analysis Set (FAS) ...................................................................................... 12 
5.4 
Additional Data Handling Rules and Presentation Specifications...................................... 12 
5.5 
Protocol Deviations ........................................................................................................... 13 
6 
Subject Accountability and Disposition ........................................................................................... 14 
7 
Demographics and Other Baseline Characteristics .......................................................................... 14 
7.1 
Demographics and Baseline Characteristics ...................................................................... 14 
7.2 
Medical History ................................................................................................................. 15 
8 
Treatment and Medications ............................................................................................................. 15 
8.1 
Study Drug Exposure ........................................................................................................ 15 
8.1.1 
Dosing Changes .................................................................................................. 16 
8.1.2 
Treatment Compliance ........................................................................................ 16 
8.2 
Prior and Concomitant Medications .................................................................................. 16 
9 
Efficacy Analyses ............................................................................................................................ 17 
9.1 
Analysis of Efficacy Endpoints ......................................................................................... 17 
9.1.1 
Proportion of subjects with mean Hb ≥ 10 g/dL, averaged from Week 16 to 
Week 24 .............................................................................................................. 17 
9.1.2 
Mean Hb change from baseline to average Hb from Week 16 to Week 24 ......... 19 
9.2 
Analysis of Exploratory Endpoints .................................................................................... 19 
9.2.1 
Time to first RBC Transfusion ............................................................................ 19 
9.2.2 
Hb Level ............................................................................................................. 20 
9.2.3 
IV iron use every 4 weeks during the treatment period ....................................... 20 
9.2.4 
Iron indices ......................................................................................................... 20 
9.2.5 
Dosing adherence ................................................................................................ 21 
9.2.6 
Comparison of starting dose to Weeks 16 to 24 dose .......................................... 21 


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FGCL-4592-097 
Statistical Analysis Plan, v 1.0 
9/9/2021 
9.2.7 
Dosing adjustments ............................................................................................. 21 
9.2.8 
Blood Transfusion and ESA Usage as Rescue Therapy ...................................... 21 
9.3 
Subgroup Analysis ............................................................................................................ 21 
10 
Safety Analyses ............................................................................................................................... 21 
10.1 
Adverse Events.................................................................................................................. 21 
10.1.1 
Proportion of Subjects with TEAE ...................................................................... 22 
10.2 
Clinical Laboratory Parameters ......................................................................................... 22 
10.3 
Vital Signs ......................................................................................................................... 23 
10.4 
COVID-19 Positive Patients .............................................................................................. 23 
11 
Interim Analysis .............................................................................................................................. 23 
12 
References ....................................................................................................................................... 23 
13 
Appendix ......................................................................................................................................... 25 
13.1 
Appendix 1: Schedule of Assessments .............................................................................. 25 
13.2 
Appendix 2: Data Handling Conventions .......................................................................... 26 
13.2.1 
Visit Time Window............................................................................................. 26 
13.2.2 
Repeated or Unscheduled Assessments of Safety Parameters ............................. 27 
13.2.3 
Missing Date of Study Medication ...................................................................... 27 
13.2.4 
Missing Severity Assessment for Adverse Events .............................................. 27 
13.2.5 
Missing Relationship to Study Drug for Adverse Events .................................... 27 
13.2.6 
Missing Date Information for Adverse Events .................................................... 27 
13.2.7 
Missing Date Information for Prior or Concomitant Medications ....................... 29 
13.2.8 
Missing Date Imputation for last dose date ......................................................... 30 
13.2.9 
Character Values of Clinical Laboratory Parameters .......................................... 30 
13.3 
Appendix 3: Ranges of Potentially Clinically Significant Lab Values ............................. 31 
13.4 
Appendix 4: Temporal profile of TEAEs of special interest .............................................. 32 
13.5 
Appendix 5: Medication WHO Drug Dictionary Codes .................................................... 33 
13.6 
Appendix 6: Cardiovascular/cerebrovascular/thromboembolic medical history terms 
used in Medical History of interest CRF ........................................................................... 34 
13.7 
Appendix 7: Search Criteria For Specific Adverse Events ................................................ 35 
13.8 
Appendix 8: Medical History Preferred Term For Baseline Vascular Access Type .......... 36 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Class 
BUN 
Blood Urea Nitrogen 
CHr 
Reticulocyte Hemoglobin Content 
COVID-19 
 Coronavirus disease 2019 
CRF 
Case Report Form 
CPK 
Creatine Phosphokinase 
EOS 
End of Study 
EOT 
End of Treatment 
ESRD 
End Stage Renal Disease 
ET 
Early Termination 
FAS 
Full Analysis Set 
Hb 
Hemoglobin 
LDH 
Lactate Dehydrogenase 
MCH 
Mean Corpuscular Hb 
MCHC 
Mean Corpuscular Hb Concentration 
MCV 
 Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
PCS 
Potentially Clinically Significant 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class (used in MedDRA dictionary) 
TEAE 
Treatment Emergent Adverse Event 
TESAE 
 Treatment Emergent Serious Adverse Event 
TIBC 
Total Iron Binding Capacity 
TIW 
Three Times Weekly 
TSAT 
Transferrin Saturation 
WBC 
White Blood Cell 
WHO 
World Health Organization 


Veeva Document Number: FG-CLPLN-0049 
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9/9/2021 
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1 
INTRODUCTION 
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of the 
statistical analyses of efficacy and safety as outlined and/or specified in the final study 
protocol. Specifications of tables, figures, and data listings are contained in a separate 
document. 
 
2 
STUDY DESIGN 
This open-label single arm study is designed to evaluate roxadustat in maintaining 
hemoglobin (Hb) in ESRD subjects receiving chronic dialysis either after conversion from a 
stable ESA dose: ESA use ≥ 6 weeks prior to conversion to roxadustat dosing or as initial 
anemia treatment, in subjects with < 6 weeks of total ESA use prior to start of roxadustat 
dosing. 
 
The study periods are as follows: 
• Screening Period: Up to 6 weeks 
• Treatment Period: 24 weeks 
• Post-Treatment Follow-Up Period: Subjects permanently discontinuing roxadustat, 
should have one final safety assessment (Treatment Emergent Adverse Events 
(TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)) 28 days after 
the last roxadustat dose. 
An extension of roxadustat treatment after 24 weeks may be offered to interested subjects 
within the context of this study protocol upon agreement with the study site. Data listings for 
the extension phase will be generated upon database lock and will include serious adverse 
events (SAEs), concomitant medications related to SAEs, and hospitalization records related 
to SAEs. 
 
Study Design Overview 
 
 
 
 
 
Subjects will be dosed three times weekly (TIW), except if a subject requires < 60 mg/week 
to maintain Hb levels, in which case dose frequency may be reduced in a stepwise fashion, 
e.g., to twice weekly (BIW), then once weekly (QW). 


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Initial Dose 
 
Conversion from ESA to Roxadustat 
 
The initial roxadustat dose is determined using a conversion table based on the subject’s 
previous prescribed CERA dose in the last 8 weeks prior to enrollment (Table 1.1). 
 
Roxadustat treatment should start two weeks after stopping CERA. 
 
If the converted initial dose exceeds the maximum dose of 3.0 mg/kg/dose then the next 
lower dose step should be chosen as the initial dose. 
 
Table 1.1. Conversion from CERA to Roxadustat 
 
Previous Dose of Mircera® 
(mcg/month) 
Starting Dose of Roxadustat 
(mg/dose TIW) 
<80 
70 
80 to 120 
100 
121 to 200 
150 
>200 
200 
 
Initiation of Roxadustat Dosing in Subjects with < 6 weeks of Prior CERA or No Prior ESA 
Use 
 
The initial roxadustat dosing is based on broad body weight categories (estimated dry weight at 
enrollment) as described in Table 1.2. 
 
Table 1.2. Initial Roxadustat Dosing 
 
 
Body Weight Category 
< 100 kg 
≥ 100 kg 
Roxadustat Dose (TIW) 
70 mg 
100 mg 
Note: Weight in HD subjects = subject’s estimated dry weight at enrollment. 
 
Dose Adjustments 
 
During the treatment period, roxadustat dose adjustments will be made starting at Week 4 and 
at intervals of every 4 weeks thereafter according to the dose adjustment algorithm in Table 
1.3, in order to achieve an Hb level of 11 g/dL and maintain an Hb of 11±1 g/ dL. Any 
potential dose escalation/dose reduction will be at pre-defined dose step increments. 


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Table 1.3. Roxadustat Dose Adjustment Rules 
 
 
Current Hb level: 
<10.5 g/dL 
10.5 to 11.9 g/dL 
12.0 to 12.9 g/dL 
≥13.0 g/dL 
Change in Hb over 
previous 4 weeks: 
> 1.0 g/dL 
No change 
↓ 
↓ 
• 
Hold dosing 
• 
Check Hb and 
resume dosing 
when Hb <12.0 
g/dL, at a dose 
reduced by 2 
steps 
-1.0 g/dL to +1.0 
g/dL 
↑ 
No change 
↓ 
< -1.0 g/dL 
↑ 
↑ 
No change* 
↑: Increase dose by one step; ↓: reduce dose by one step. 
*Continue to hold dose 
 
Notes: 
Dose Increases and Reductions: 
• 
Dose increases (↑) and reductions (↓) are preset. 
• 
The dose steps are as follows: 20, 40, 50, 70, 100, 150, 200, 250, 300, and 400 mg. 
If < 20 mg /dose is required, dosing frequency should be reduced in a step-wise fashion e.g., TIW to BIW, BIW to QW. 
• 
The maximum dose is capped at 400 mg or 3.0 mg/kg/dose (whichever is lower). Rounding the mg/kg calculated 
roxadustat dose up to 10 mg may be allowed, if no safety concerns. 
Roxadustat dose adjustment reviews should occur every 4 weeks however, a dose reduction 
may be implemented at any time if the following criteria are met: 
 
• Rate of Hb rise > 2 g/dL within 4 weeks: reduce dose by 1 dose step 
• Hb level ≥ 13g/dL: hold dose, until Hb drops to < 12g/dL, resume dosing at 2 dose 
steps lower 
Any dose adjustment will reset the dose-adjustment window to every 4 weeks thereafter (e.g., 
dose adjustment for a qualified reason at Week 6 leads to next dose adjustment at Week 10). 
 
Prescribed dose must not exceed the maximum allowable dose of 3.0 mg/kg/dose or 400 mg 
per dose, whichever is lower. 
 
Dose titration decisions will be based on results from local Hb testing. 
 
Rescue Therapy Guidelines: 
Rescue therapy guidelines are provided to optimize the standardization of rescue therapy, and 
to ensure the safety of individual study subjects. 
Blood/Red Blood Cell Transfusion 
Blood/RBC transfusions should be considered if rapid correction of anemia is required to 
stabilize the subject’s condition (e.g., acute hemorrhage) or the Investigator is of the opinion 
that the blood transfusion is a medical necessity. Study treatment may continue during or 
after the RBC transfusion. 
Erythropoiesis Stimulating Agent (ESA) Use 
The use of ESAs as a “rescue” modality should be carefully considered, and should be 
restricted to no more than one cycle of use during the treatment period; the Investigator may 
initiate use of an approved erythropoietin (EPO) analogue if all of the following criteria are 
met: 


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• A subject’s Hb level has not sufficiently responded to two or more dose increases or 
the maximum dose of study drug has been reached, and 
• The subject’s Hb is < 8.5 g/dL on two consecutive measurements (central lab) drawn 
at least five days apart; and 
• Clinical judgment does not suggest iron deficiency or bleeding as a cause of lack of 
response or rapid decline in Hb, and 
• Reducing the risk of alloimmunization in transplant eligible subjects and/or reduction 
of other RBC transfusion-related risks is a goal 
ESA rescue should be started ≥ 2 days after the last dose of roxadustat. 
ESA rescue should be stopped when Hb > 9 g/dL or after 4-weeks, whichever comes first. If 
a subject requires longer than 4 weeks therapy due to inadequate response, or in other 
extenuating circumstances, the Medical Monitor should be contacted. 
Study treatment should 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®) 
 
If more than one cycle of ESA rescue is required, the Investigator should permanently 
discontinue study drug. 
Inadvertent ESA administration, such as ESA administration during a hospitalization, should 
not be counted as rescue unless the above criteria are met; these subjects may be allowed to 
restart roxadustat dosing if considered safe by the Investigator or the Medical Monitor. 
ESAs and roxadustat should not be administered concomitantly. 
 
Emergency Procedure (Therapeutic Phlebotomy) 
If there are clinical concerns for a subject’s high Hb levels, the Investigator may decide to 
perform a therapeutic phlebotomy in addition to temporarily withholding the study drug. 
 
Iron Supplementation 
Oral iron may be administered for iron supplementation without restriction. Dose and 
frequency of administration of oral iron are to be determined by the Investigator. 
 
Intravenous iron (IV) should be considered for subjects with ferritin <200 ng/mL or TSAT 
<20%. IV iron should administered in 5 doses of 50 mg/dose. The Medical Monitor should 
be contacted if more IV iron is required. 
 
Prohibited Medication: 
 
The following medications/therapies are prohibited during the period identified: 
 
• 
Any investigational drug from 4 weeks prior to screening until End of Study (EOS) 
• 
Androgens from screening until EOS 
• 
Iron-chelating agents (e.g., deferoxamine/desferrioxamine, deferiprone, or deferasirox 
therapy) from 4 weeks prior to enrollment until EOS 


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• 
Dapsone (at any dose) from screening until EOS 
• 
Chronic doses acetaminophen/paracetamol > 2.0 g/day from enrollment until 1 week 
after End of Treatment (EOT) 
 
 
3 
STUDY OBJECTIVES 
3.1 
PRIMARY OBJECTIVE 
 
To confirm safe and effective roxadustat dosing regimens among chronic dialysis subjects 
converted from ESA therapy (≥6 weeks ESA treatment) or who are ESA-naïve (<6 weeks 
ESA treatment). 
 
3.2 
SECONDARY/EXPLORATARY OBJECTIVES 
 
• Assessment of TEAEs and TESAEs 
• Laboratory parameters, including iron indices 
• Utilization of IV iron 
• To test operational characteristics of converting a population of ESRD subjects from 
an injectable to oral anemia therapy 
 
4 
STUDY ENDPOINTS 
 
4.1 
EFFICACY ENDPOINTS 
• Proportion of subjects with mean Hb level ≥ 10g/dL, averaged from Week 16 to 
Week 24 
• Mean Hb change from baseline to average Hb from Week 16 to Week 24 
Baseline Hb is defined as the mean of available central laboratory Hb values prior to first 
dose of study medication including the pre-dose Hb value collected on day 1. 
 
4.2 
EXPLORATORY ENDPOINTS 
 
• Proportion of subjects with a mean Hb level within 10-12 g/dL from Week 16 to 
Week 24 
• Proportion of subjects with Hb > 12 g/dL any time during treatment 
• Proportion of subjects with Hb > 13 g/dL any time during treatment 
• Percentage of time with Hb values within 10.0 to 12.0 g/dL from Week 16 to Week 
24 
• Time to first RBC transfusion 
• Proportion of subjects with a mean Hb level ≥10 g/dL in the first 8 weeks after 
conversion or initiation of treatment 
• Proportion of subjects with a mean Hb level ≥10 g/dL (averaged from Week 16 to 
Week 24) based on baseline ESA use status ≥ 6 weeks (conversion form ESA to 
roxadustat based on prior ESA use) and < 6 weeks (initiation of roxadustat based on 
body weight) 
• Evaluate the utilization of IV iron (IV iron use/4 weeks) 
• Evaluate the effect on iron indices 


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• Evaluate dosing adherence 
• Conversion subjects: Comparison of starting dose of roxadustat to roxadustat dose at 
Week 16 to 24 
• Mean number of dose adjustments (including dose-hold) during study 
• Proportion of subjects requiring blood/pRBC transfusion from Week 5 (Day 29) to 
Week 24/ET. 
• Proportion of subjects requiring rescue therapy (blood/pRBC transfusion or ESA 
rescue) from Week 5 (Day 29) to Week 24/ET 
In addition to the exploratory endpoints in the protocol, additional exploratory efficacy 
endpoints of interest are presented in this section. 
RBC transfusion data is collected in the Blood Transfusions form of the eCRF. 
For efficacy evaluation, Hb values will be censored for 4 weeks if blood/pRBC is 
administered during the treatment period. Hb results obtained from the central laboratory will 
be used to determine the Hb response. 
 
4.3 
SAFETY ASSESSMENTS 
 
Study-specific safety will be assessed by evaluating the following: 
• Incidence of TEAEs and TESAEs 
• Vascular Access Thrombosis (Using Hemodialysis population): 
o Time to a TEAE of vascular access thrombosis 
o Proportion of subjects with a TEAE of vascular access thrombosis 
o Proportion of subjects with a TEAE of vascular access thrombosis based on 
baseline type of vascular access 
• Clinically significant changes in laboratory values from baseline 
• Vital signs 
• Specific adverse events (see Appendix 7) 
o Time to a TEAE for a specific adverse event 
o Proportion of subjects with a TEAE for specific adverse events 
In addition to the safety assessments in the protocol, additional safety endpoints of interest 
are presented in this section. 
 
Baseline vascular access (see Appendix 8) is determined using the vascular access medical 
history record. The start date of subject’s last available vascular access medical history record 
must be prior to first dose of study medication and the end date must be on or after first dose 
of study medication. Patients on peritoneal dialysis are deemed as “Not Applicable” for 
vascular access categorization. 
 
5 
GENERAL STATISTICAL CONSIDERATIONS 
 
5.1 
STATISTICAL METHODOLOGY 
 
Safety and efficacy data will be summarized and presented by time points in summary tables. 
Continuous variables will be presented by descriptive statistics: n, mean, standard deviation, 


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median, minimum, and maximum. Categorical variables will be tabulated by frequency 
counts and percentages. 
 
Lab results obtained from the central laboratory, rather than local laboratories, will be used 
for all efficacy and safety analyses. Some lab data are collected using local labs (in lieu of the 
ICON central lab) due to central lab kit shortages caused by the COVID-19 pandemic. In 
these cases, local lab values and reference ranges collected from eCRFs will be integrated 
with central lab data when appropriate and feasible. Local lab values will be flagged in 
datasets and data listings to be differentiated from central lab values. Sensitivity analyses may 
be performed for key analyses of lab parameters without local lab values. 
 
Unless otherwise stated, all confidence intervals will be two-sided 95% confidence intervals. 
All analyses will be performed using SAS® Version 9.4 or higher. 
5.2 
SAMPLE SIZE DETERMINATION 
 
Approximately 200 subjects with anemia of CKD (either with or without prior treatment with 
an ESA before enrollment) and on hemodialysis are planned in this study. This number of 
subjects distributed across the specified number of sites is adequate to evaluate the primary 
study objective. 
 
Assuming the proportion of subjects that maintain Hb levels ≥10g/dL from Weeks 16 to 24 is 
at least 80%, with a sample size of 200, the study will be able to produce a two-sided 95% 
confidence interval (CI) with a width equal to 11.5%. 
 
5.3 
ANALYSIS POPULATIONS 
 
5.3.1 Safety Population (SAF) 
The safety analysis set will include all enrolled subjects receiving at least 1 dose of study 
treatment. The safety analysis set will be used for all safety endpoints and exposure to study 
treatment outcomes. 
 
5.3.2 Full Analysis Set (FAS) 
The FAS set will consist of all subjects who signed the informed consent, were enrolled, and 
provided baseline Hb data and data for at least one post baseline Hb time point. The FAS set 
will be used for all efficacy endpoints. 
 
5.4 
ADDITIONAL DATA HANDLING RULES AND PRESENTATION 
SPECIFICATIONS 
 
The following general guidelines will apply to all statistical analyses and data presentations: 
 
• Baseline is defined as the last available value obtained prior to the first dose of study 
drug, unless otherwise specified in this SAP. 
• Hb baseline is defined as the mean of available values obtained during screening prior 
to the first dose (including pre-dose Day 1 Hb value). 


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• Baselines for reticulocyte count, reticulocyte hemoglobin content (CHr), serum iron 
parameters (transferrin, TIBC, TSAT, ferritin, sTfR, and iron) are defined as the 
values obtained on Day 1 (excluding screening) prior to the first dose. 
• Baselines for blood pressure and heart rate are defined as the mean of values obtained 
during screening (including Day 1) prior to the first dose. 
• Unscheduled visits within an allowable window will be grouped into the closest 
scheduled visits based on the visit window specified in Appendix 1. For subjects who 
have more than one measurement at a certain scheduled visit, the last measurements 
will be used, with the exception of CPK, WBC, liver function tests (i.e., ALT, AST, 
GGT, ALP, and total bilirubin), in which the maximum measurement will be used. 
• By default, US conventional units will be used for laboratory value presentations. A 
separate set of laboratory tables with SI units may be required by regulators, such as 
the European Medicines Agency (EMA). 
• Age is calculated as of date that the informed consent form was signed. 
- 
age = INTCK(‘YEAR’, Birth date, date of Informed Consent, ‘C’) where 
INTCK is a SAS function. 
• Duration of treatment or days on treatment is calculated as: last dose date – first dose 
date +1 
• Body weight, height and temperatures will be converted using the following formulas: 
- 
kg = lb/2.2 
- 
cm = 2.54 x in 
- 
Co = (5/9) x (Fo – 32) 
• Mean Arterial Pressure (MAP) will be calculated for each subject using the following 
formula: MAP = (2/3) * diastolic blood pressure+ (1/3) * systolic blood pressure. 
• All percentages will be rounded to one decimal place and lined up by the decimal 
place. The percentage will be suppressed when the count is zero. 
• All tables and listings will have a header showing “FibroGen, Inc.”, the protocol 
number, and the page number. Footer will indicate the program file path/name, run 
date and run time. 
• For continuous variables that are recorded as “< X” or “> X”, the value of “X” will be 
used in the calculation of summary statistics. The original values will be used for the 
listings. 
• Decimal points will be presented as follows: N will be presented without decimals, 
minimum and maximum in same precision as in the database, mean and median in 
one more decimal than minimum and maximum, and SD in one more decimal than 
mean and median. 
• Tables and figures will use derived analysis visits. Listings will use nominal visits, 
and the analysis visits used will be flagged. Namely, both nominal visits and analysis 
visits will be presented in the listing. 
• Additional data handling conventions are detailed in Appendix 2. 
 
5.5 
PROTOCOL DEVIATIONS 
Major protocol deviations of interest may include, but are not limited to the criteria in Table 
2. 
 
Table 2. Criteria for Assessing Major Protocol Deviations 
Number 
Major Protocol Deviation 
1 
Violation of key* inclusion or exclusion criteria which may affect the assessment of the 
efficacy of the study drug 


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Number 
Major Protocol Deviation 
2 
Administration of ESA for more than 4 weeks before Week 16; any duration from Week 16 to 
Week 24 
3 
Study drug compliance < 75% or >125% (up to Week 24) 
4 
Administration of prohibited concomitant medication that may impact evaluation of efficacy of 
the study drug* 
5 
Significant noncompliance with study procedures that may impact evaluation of efficacy of the 
study drug will be evaluated case by base* 
*Subject to Medical Monitor’s decision 
 
 
The number and percentage of major protocol deviations will be categorized and summarized 
as deemed appropriate. 
 
6 
SUBJECT ACCOUNTABILITY AND DISPOSITION 
 
The following subject data will be summarized and presented if applicable, by number and 
percentage: 
• Subjects enrolled at each center, and for all centers combined (using the enrolled 
population) 
• Subjects in each analysis set (using the enrolled population) 
• Subjects who prematurely discontinued during the treatment period, and 
discontinuation reason for the enrolled population. 
• Subjects who complete the treatment period (will be considered as “completers”) 
• Subjects who participated in the Post-treatment Follow-Up 
• Subjects who completed the EOS Visit 
• Subjects who entered extension study 
 
Kaplan-Meier plots will be generated for premature treatment discontinuations showing one 
curve. 
 
7 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
7.1 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographic parameters and important baseline and disease characteristics will be 
summarized for the safety and FAS populations. These include but may not be limited to age, 
age group (18 to <65, 65 to <75, ≥75), sex, ethnicity, race, weight, body-mass index (BMI), 
Hb, baseline Hb categories (<10, ≥10 g/dL), iron repletion status at baseline, ferritin, ferritin 
group (<100, 100-<400, ≥400 ng/mL), TSAT and TSAT group (<20%, 20%-<40%, ≥40%), 
hepcidin, serum iron, iron deplete (ferritin <100 or TSAT <20%) vs. not, cardiovascular or 
cerebrovascular or thromboembolic medical history (yes vs. no), blood pressure (systolic 
≥140 or diastolic ≥90 vs systolic <140 and diastolic <90), incident dialysis vs stable dialysis, 
starting dose, baseline ESA type, baseline ESA dose categories (low/medium/high/very 
high), type of dialysis, vascular access at baseline. 
 
Table 3. Baseline ESA Dose Categories 
Baseline ESA 
dose categories 
Mircera 
(ug/month) 
Low 
0 - < 80 
Medium 
80 – 120 


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High 
> 120- 200 
Very High 
>200 
 
Identify dialysis based on medical history of interest CRF MHINTERM ((Dialysis 
(Peritoneal), Dialysis (Home Hemodialysis), and Dialysis (Hemodialysis). Dialysis start date 
equals to MHSTDAT if not partial. If it is partial and day is missing impute the date with 1st 
day of the month. If missing month and day, impute to January 1st. 
 
ESA naive is defined as patients who started ESA for < 6 weeks prior to Day 1. ESA 
dependent is defined as patients who started ESA for ≥6 weeks prior to Day 1. 
 
ESA baseline window is defined as 28 days prior to enrollment and the date right before first 
dose. For patients with more than one ESA type at baseline, the ESA type that was 
administered immediately before Day 1 was used. 
 
Total duration of ESA use is calculated from first chronic ESA use to date of first dose date. 
 
Stable dialysis is defined as patients who have been on dialysis for > 4 months at the time of 
enrollment into the study. Incident dialysis is defined as patients who have been on dialysis 
for ≤ 4 months at the time of enrollment into the study. 
 
Dialysis duration is calculated from first chronic dialysis date to date of enrollment. 
 
In addition, 25%-75% values of Hb and platelets will be presented. Frequency distributions 
(number and percentage of subjects) will be presented for categorical variables. 
 
The baseline characteristics, iron indices, and iron IV given between ESA naïve and those 
converted from ESA therapy will be summarized and presented in a table. 
 
Descriptive statistics of baseline values for other parameters will be presented in their change 
from baseline tables. 
 
7.2 
MEDICAL HISTORY 
Medical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA). Medical history of interest including Chronic Kidney Disease (CKD) history 
inclusive of CKD cause, cardiovascular disease, cerebrovascular disease, thrombosis history, 
hypertension history, diabetes history, and anemia history will be summarized by system 
organ class and preferred term for the safety population. 
 
8 
TREATMENT AND MEDICATIONS 
8.1 
STUDY DRUG EXPOSURE 
 
Exposure to study medication will be summarized in terms of treatment duration in weeks, 
which is calculated using the following formula: (the date of last medication taken - the date 
of first dose taken +1)/7. 
 
Total weekly study drug exposure is defined as the total actual dose (in mg and mg/kg) of 
study drug administered within the week (windowed by 7-day period from Day 1). 


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Weekly exposure and total study drug exposure will be tabulated for the safety population. 
 
Per administration amount and administration frequency will also be tabulated for the safety 
population. 
 
Patient-Exposure-Year (PEY) is defined as (Last Dose Date – First Dose Date + 1)/365.25. 
 
8.1.1 Dosing Changes 
 
 
Prescribed dose adjustments (dose increase, dose reduced, dose interrupted, and dose 
resumed) along with the adjustment reasons (protocol mandated dose amount adjustment, AE 
related, and other) recorded on the Prescribed Dose Adjustments Form in the eCRF will be 
tabulated by time point (Week 2, 4, 6, 8, 12, 16, 20, 24). Mean number of dose adjustments 
(including dose-hold) during study and number (%) of subjects with dose adjustment in each 
adjustment category will be summarized. 
 
 
8.1.2 Treatment Compliance 
 
Study medication dosing compliance for a specified period is defined as the total dose (mg 
actually taken by a patient during that period divided by the prescribed dose expected to be 
taken during the same period multiplied by 100. An overall per-dose compliance measure can 
be calculated by (total amount of actual dose administrations)/ (total amount of expected dose 
administrations) *100 during the subject’s treatment period. Descriptive statistics for study 
medication compliance will be presented for the entire treatment period of the study. 
 
Compliance will be summarized as follows: 
• Descriptive statistics will be summarized for the entire treatment period. 
• Percent compliance will be categorized according to the following categories for the 
entire treatment period for safety population: 
o less than 75% (drug noncompliance) 
o at least 75%, less than 125% (drug compliance) 
o greater or equal 125% (drug noncompliance) 
o unknown 
 
8.2 
PRIOR AND CONCOMITANT MEDICATIONS 
 
The World Health Organization Drug Dictionary (WHO Drug) will be used to classify prior 
and concomitant medications by therapeutic class and generic name based on ATC code level 
3. Prior medication is defined as any medication taken and stopped prior to the first dose of 
the study medication. Concomitant medication is defined as any medication taken between 
the day of first dose of the study medication and the day of last study medication date + 28 
days. For subjects who complete the treatment period and decide to participate in the 
extension treatment, any medication taken after the Treatment Period (Week 24/EOT) will 
not be counted as concomitant medications for the main study, but will be listed for the 
extension period. 


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Medication start and end dates and times will be compared with the start date of study drug 
and classified as per Table 4. 
 
In case of partial or missing dates, comparisons will be made based on the level of detail 
available. For example, if start date of study drug is 04Jan2013, and a medication has a start 
date of Jan2013 but missing day, the medication will be classified as concomitant. 
 
Table 4. Classification of prior and concomitant medications 
 
End 
date 
Before start of 
study drug 
administration 
On or after start of 
study drug 
administration 
Missing 
Start 
date 
Before start of 
study drug 
administration 
Prior 
Concomitant 
Concomitant 
On or after start of 
study drug 
administration 
– 
Treatment Emergent 
Concomitant 
Treatment 
Emergent 
Concomitant 
Missing 
Prior 
Concomitant 
Concomitant 
 
Both prior and concomitant medication usage will be summarized by the number and 
proportion of subjects. Subjects will only be counted one time in each unique ATC Class and 
generic name if multiple drugs are used by a subject. 
 
Detailed analyses may be performed on prior and concomitant medications of special 
interests such as oral iron, blood pressure medications, and lipids medications. 
 
9 
EFFICACY ANALYSES 
Efficacy analysis will be conducted on the FAS population. 
 
9.1 
ANALYSIS OF EFFICACY ENDPOINTS 
 
9.1.1 Proportion of subjects with mean Hb ≥ 10 g/dL, averaged from Week 16 to Week 
24 
 
The efficacy endpoint will be evaluated using the proportion (%) of subjects with mean value 
of Hb measurements from Week 16 to Week 24 ≥ 10 g/dL. 
 
Proportion of responders will be presented descriptively with counts and percentages and a 
95% confidence interval of the responder rate. The 95% CI of the response rate will be 
presented based on normal approximation. 
 
For the Hb efficacy analysis, a multiple imputation (MI) method will be used. This will be 
implemented on the raw Hb values, then the Hb-relates endpoint summaries will be derived 
based on the imputed data (algorithm as used for the previous phase 3 studies). 


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The following steps will be used to conduct the MI procedure of the Hb values: 
 
1. 
Generate 200 datasets, using seed 12345, where only intermittent missing Hb data 
will be imputed relying on non-missing data from all subjects using the Monte Carlo Markov 
Chain (MCMC) imputation model using baseline Hb and the available non missing Hb for 
each scheduled week. 
The MCMC statement in the SAS PROC MI procedure with monotone option will be used. 
As a result, each dataset will only have missing ending data, or a monotone missing data 
pattern. 
 
2. 
For each dataset from step 1, missing ending data (Hb up through end of evaluation 
period) will be imputed. As a result, 200 imputed complete datasets will be generated. 
• 
Missing data at Week 2 will be imputed using the regression imputation model with 
baseline and Hb from Week 2, using the SAS PROC MI procedure with the REGRESSION 
option in the MONOTONE statement. 
 
• 
Repeat for all other scheduled weeks sequentially (Week 4 to the end of evaluation 
period). Subjects whose missing data were imputed for previous weeks will contribute to the 
imputation for the current week. 
 
• 
The regression imputation model includes an intercept and the slopes of the Hb from 
previous weeks. 
 
Steps 3 and 4 will be used to analyze proportion of subjects with a mean Hb level ≥ 10 g/dL, 
averaged from Week 16 to Week 24 using the imputed Hb data above: 
 
3. 
Analyze each imputed complete dataset to estimate proportions of responders and their 
standard errors using the mean of all observed or imputed Hb values within the evaluation 
period (Weeks 16 to 24). 
Sample SAS code: 
 
PROC FREQ DATA=xx; 
TABLES resp_week16_24 / cl binomial (level=2); 
BY _Imputation_; 
ODS OUTPUT BINOMIALPROP=prop; 
RUN; 
 
4. 
Combine estimates from the results for each of the 200 proportion estimates using SAS 
PROC MIANALYZE. 
PROC MIANALYZE DATA=prop; 
MODELEFFECTS prop; 
STDERR prop_se; 
ODS OUTPUT PARAMETERESTIMATES=mian_prop; 
RUN; 
 
Report the results of the proportion of subjects with a mean Hb level ≥ 10g/dL, averaged 
from Week 16 to Week 24. 


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9.1.2 
Mean Hb change from baseline to average Hb from Week 16 to Week 24 
 
For continuous endpoints, changes from baseline will be presented descriptively. Missing Hb 
values will be imputed using a MI procedure. 
 
Steps 3 and 4 below will be used to calculate the mean Hb change from baseline to average 
Hb from Week 16 to Week 24 using the imputed Hb data in Steps 1-2 above in section 9.1.1. 
 
3. 
Analyze each imputed complete dataset to estimate the mean Hb change from baseline 
to average Hb and their standard errors using the mean of all observed or imputed Hb values 
within the evaluation period (Weeks 16 to 24). 
Sample SAS code: 
 
PROC MEANS DATA=xx MEAN STDERR; 
BY _imputation_; 
VAR change_Week24; 
WEIGHT covariates; 
OUTPUT OUT=avg MEAN=mean_hb STDERR=se_hb; 
RUN; 
 
4. 
Combine estimates from the results for each of the 200 proportion estimates using 
SAS PROC MIANALYZE. 
PROC MIANALYZE DATA= avg; 
MODELEFFECTS mean_hb; 
STDERR se_hb; 
ODS OUTPUT PARAMETERESTIMATES=mian_mean; 
RUN; 
 
Report the results of the mean Hb change from baseline to average Hb from Week 16 to 
Week 24. 
 
9.2 
ANALYSIS OF EXPLORATORY ENDPOINTS 
 
The analysis for the exploratory endpoints will be based on the FAS population. 
 
9.2.1 
Time to first RBC Transfusion 
For a subject receiving a RBC transfusion, the Time at Risk (time up to first RBC 
transfusion) will be calculated (in weeks) as: 
(First RBC transfusion date – First dose date of study medication + 1) / 7 
 
For a subject not receiving a transfusion, the Time at Risk (time until they get censored) is 
calculated as: 
(Date of last study visit – First dose date of study medication + 1) / 7 
 
Subjects with no events were censored at the date of minimum (last dose date, last visit date, 
death date, Week 24*7). 


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Time to first RBC transfusion will be analyzed using the Kaplan-Meier method with KM 
curve plotted to derive the following: 
• Proportion of subjects with any RBC transfusion up to Week 24 
9.2.2 
Hb Level 
• Proportion of subjects with a mean Hb level ≥ 10 g/dL in the first 8 weeks after 
conversion or initiation of treatment 
• Proportion of patient with a mean Hb level ≥ 10 g/dL (averaged from Week 16 to 
Week 24) based on baseline ESA use status ≥ 6 weeks (conversion form ESA to 
roxadustat based on prior ESA use) and < 6 weeks (initiation of roxadustat based on 
body weight) 
 
For the Hb level exploratory analysis above, a MI method will be used. The imputation data 
will be generated in a method similar to the one described in section 9.1.1. 
Similarly, the Rubin’s method will then be used to combine the estimates of the proportion of 
responders and standard errors from each of the PROC FREQ procedure. 
 
• Proportion of subjects with mean a Hb within 10-12 g/dL from Week 16 to Week 24 
• Proportion of subjects with Hb > 12 g/dL any time during treatment 
• Proportion of subjects with Hb > 13 g/dL any time during treatment 
• Percentage of time with Hb values within 10.0 to 12.0 g/dL from Week 16 to Week 
24 
 
For the Hb level exploratory analysis above, observed Hb values will be used. 
 
9.2.3 
IV iron use every 4 weeks during the treatment period 
The IV iron use every 4 weeks during the treatment period will be calculated for monthly 
intervals. The treatment period will be divided into 28 days and the monthly mean of IV iron 
for each period will be calculated using the following formula: 
 
Monthly iron use for each subject = total IV iron in mg / [(last dose date – first dose 
date of IV Iron in the period +1)/ 28] 
 
9.2.4 
Iron indices 
The mean change from baseline in the following endpoints will be summarized and data up to 
the Week 24 visit will be included in the analyses: 
 
• Value and change from baseline in CHr at each of the selected time points (e.g., 
Weeks 8, 16, 24) 
• Value and change from baseline in serum ferritin at each of the selected time points, 
total and sub-grouped by baseline values of <100 ng/mL, 100 to <400 ng/mL and 
≥400 ng/mL. 
• Value and change from baseline in TSAT at each of the selected time points, total and 
sub-grouped by baseline values of <20%, 20% to <40%, and ≥40%. 
• Value and change from baseline in serum iron at each of the time points tested 
• Proportion of patients with CHr > ULN at each time point tested: Weeks 8, 16, 24 


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9.2.5 
Dosing adherence 
See SAP section 8.1.2 Treatment Compliance 
 
9.2.6 
Comparison of starting dose to Weeks 16 to 24 dose 
For proportion of patients with dose increased, dose decreased, and dose not changed, an 
analysis will be done comparing starting dose to average prescribed dose over Weeks 16 to 
24. 
 
9.2.7 
Dosing adjustments 
See SAP section 8.1.1 Dosing Changes 
 
9.2.8 
Blood Transfusion and ESA Usage as Rescue Therapy 
Blood/pRBC transfusions will be recorded in the Blood Transfusion Form of the eCRF. ESA, 
as rescue therapy will be recorded in the Concomitant Medication eCRF. 
 
The following 2 endpoints will be analyzed: 
 
• Proportion of patients requiring a blood/pRBC transfusion from Week 5 (Day 29) to 
Week 24/ET. The 95% CI of the response rate will be presented based on normal 
approximation. 
• Proportion of patients requiring rescue therapy (blood/pRBC transfusion or ESA 
rescue) from Week 5 (Day 29) to Week 24/ET. The 95% CI of the response rate will 
be presented based on normal approximation. 
 
9.3 
SUBGROUP ANALYSIS 
Primary efficacy endpoints will be presented by forest plots based on the following 
subgroups: sex, age group, baseline Hb categories, baseline iron status, 
cardiovascular/cerebrovascular/thromboembolic medical history, starting dose, baseline ESA 
dose categories, and home dialysis vs in-center dialysis. 
 
Dose adjustments, iron indices and IV iron use will be analyzed by subgroups of home 
dialysis patients. Overall summary of TEAEs will be analyzed by subgroups of starting doses 
of roxadustat and subgroups of home dialysis patients. 
 
Other endpoints of interest may be analyzed by the subgroups listed above as needed. 
 
10 
SAFETY ANALYSES 
 
The safety analysis will be performed using the safety population. Safety parameters include 
adverse events, laboratory parameters, vital signs, and physical examinations. 
 
For each safety parameter, the last assessment made prior to the first dose of study 
medication will be used as the baseline for all analyses for that safety parameter. 
 
10.1 
ADVERSE EVENTS 
 
Adverse events will be coded using the latest MedDRA version. 


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10.1.1 
Proportion of Subjects with TEAE 
An AE (classified by preferred term) started during the treatment period will be considered a 
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 treatment period. For 
subjects who permanently discontinue roxadustat early or complete the treatment period (24 
weeks) but decide not to participate in the extension treatment, all AEs that occur up to 28 
days after the last roxadustat dose will be counted as a TEAE. For subjects who complete the 
treatment period and decide to participate in the extension treatment, an AE that occurs after 
the treatment period (Week 24/EOT) will not be counted as a TEAE. 
 
The number and percentage of subjects reporting TEAEs will be tabulated separately by 
system organ class and preferred term; by system organ class, preferred term, and severity; 
and by system organ class, preferred term, and relationship to study medication. If more than 
one event occurs with the same preferred term for the same patient, the patient will be 
counted only once for that preferred term using the most severe and most related occurrence 
for the summarization by severity and by relationship to the study medication. 
 
The distribution of TEAEs by severity and relationship to study medication will be 
summarized. 
 
The incidence of common (≥ 5% of subjects) TEAEs, common non-serious (≥ 5% of 
subjects) TEAEs (excluding TESAE), TESAEs, and AEs leading to discontinuation of study 
medication will be summarized by preferred term and sorted by decreasing frequency. In 
addition, the incidence of deaths and SAEs with a fatal outcome (i.e., events that caused 
death) will be summarized separately by preferred term. 
 
AE summaries are presented as a crude incidence rate and patient exposure year (PEY) 
adjusted incidence rate. The PEY-adjusted incidence rate, per 100 patient exposure years, is 
defined as the incidence of an event divided by 100 times the PEY which is defined as (last 
dose date – first dose date +1) divided by 365.25. 
 
Listings of subjects with SAEs, adverse events leading to discontinuation, and those who died 
will be presented. 
 
Temporal profile of TEAEs of special interest may also be plotted showing the subjects in the 
y-axis and time to these TEAEs in the x-axis (Appendix 4). 
 
10.2 
CLINICAL LABORATORY PARAMETERS 
 
Descriptive statistics for laboratory values (in US conventional and SI units) and changes 
from baseline for each assessment time point will be presented for the following laboratory 
parameters collected in the study including but not limited to the following: 
 
• Hematology: Hb, hematocrit, RBC count, MCV, MCH, MCHC, WBC count, WBC 
differential, platelet counts and reticulocyte count; 
• Chemistry: CPK, ALP, ALT, AST, total bilirubin, LDH, total protein, albumin, 
glucose, phosphate, BUN, creatinine and potassium; 
• Serum iron, ferritin, TIBC, TSAT, and CHr 


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Laboratory values are clinically significant (CS) if they meet either the low or high CS 
criteria. The number and percentage of subjects with post-baseline CS values will be 
tabulated. The percentages are to be calculated relative to the number of subjects with 
available non-CS baseline values and at least one post-baseline assessment. The numerator is 
the total number of subjects with at least one post-baseline CS value. In addition, shift tables 
will be presented by time point. The following 2 data listings will be presented by subject: 
 
• A listing of lab values for all lab tests at all collected time points. 
• A listing of subjects with post-baseline CS values will be provided including the 
baseline and post-baseline values. 
Due to central lab kit shortages caused by Covid-19, lab data may be collected using local 
labs in lieu of the central lab. The local lab data will be integrated with central lab data when 
appropriate and feasible. Sensitivity analyses may be performed for key analyses of lab 
parameters with and without local lab values. 
 
10.3 
VITAL SIGNS 
 
Blood pressure and heart rate baselines are defined as the mean of values obtained from the 
last 6 weeks of screening including Day 1 prior to the first dose. For subjects on 
hemodialysis, pre-dialysis vital signs will be used. For subjects on peritoneal dialysis, vital 
signs may be recorded at any time during the visit. 
 
Descriptive statistics for vital signs (e.g., systolic and diastolic blood pressure, MAP, heart 
rate, respiratory rate and temperature) and their changes from baseline at each visit and at the 
end of study will be presented. 
 
10.4 
COVID-19 POSITIVE PATIENTS 
 
Patients who tested positive for COVID-19 during the study will be recorded on the Adverse 
Events Form in the eCRF. The following 2 data listings will be presented in COVID-19 
positive patients: 
 
• A listing of central lab Hb values with COVID-19 AE start date/stop date, mean Hb 
before COVID-19 diagnosis, mean Hb after COVID-19 diagnosis. 
• A listing of COVID-19 related AEs leading to study drug interruption or withdrawal 
up to 28 days after last dose. 
 
11 
INTERIM ANALYSIS 
 
An interim analysis may be performed to report topline results at the Sponsor’s discretion. 
Since no statistical hypothesis testing is performed for this study, no multiplicity adjustment 
is required. 
 
12 
REFERENCES 
 
ICH Harmonized Tripartite Guideline E3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics) 


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ICH Harmonized Tripartite Guideline E9. Statistical Principles for Clinical Trials, February 
1998. (www.ich.org; Guidelines; "Efficacy" Topics) 
 
Carpenter JR, Roge JH and Kenward MG, Analysis of longitudinal trials with protocol 
deviation: a Framework for Relevant, Accessible Assumptions, and Inference via Multiple 
Imputation. Journal of Biopharmaceutical Statistics, issue 6 (November/December) in 
volume 23 (2013). 1352-137 
 
Haybittle, J. L. (1971), “Repeated Assessment of Results in Clinical Trials of Cancer 
Treatment,” British Journal of Radiology, 44, 793-797. 
 
Peto, R., Pike, M. C., Armitage, P., Breslow, N. E., Cox, D. R., Howard, S. V., Mantel, N., 
McPherson, K., Peto, J., and Smith, P. G. (1976), “Design and Analysis of Randomized 
Clinical Trials Requiring Prolonged Observation of Each Patient: I. Introduction and 
Design,” British Journal of Cancer, 34, 585-612. 
 
Little RJA, Rubin D.1987. Statistical Analysis with Missing Data. John Wiley and Sons. 
Rubin, D. B. (1987) Multiple imputation for nonresponse in surveys. New York: Wiley. 
Schafer, J. L. (1997) Analysis of incomplete multivariate data. London: Chapman and Hall. 


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13 
APPENDIX 
 
13.1 
APPENDIX 1: SCHEDULE OF ASSESSMENTS 
 
Visit / Week: 
Screening 
Visit 
Day 1 
Wk 2 to 8 
± 4 days 
Wk 12-24 g 
± 4 days 
Post- 
Treatment e 
or ET 
± 7 days 
Written informed consent 
X 
Eligibility criteria 
X 
X 
Demographics and medical history 
X 
Height, weight 
X 
X a 
Blood pressure, heart rate, 
temperature 
X 
X 
X 
X 
X 
Physical Exam 
X 
X 
Hemoglobin (central and local) 
X d 
X f 
X f 
X d 
CBC with WBC differential 
X 
X 
Wks 4. 8 
Wks 16, 24 
X 
Serum chemistry 
X 
X 
Wks 4, 8 
Wks 16, 24 
X 
CPK 
X 
X 
Wks 8 
Wk 16, 24 
Serum iron, ferritin, TIBC, TSAT , 
CHr, reticulocytes 
X 
X 
Wk 8 
Wks 16, 24 
HIV ELISA, HBsAg, anti-HCV Ab 
X 
Serum hCG pregnancy test 
X b 
Q8Wks 
X 
Dose adjustment 
X 
X 
AE/CM recording 
X 
X 
X 
X 
X 
Study drug dispensing 
X 
X 
X 
Ab = antibody; CBC = complete blood count; CHr = reticulocyte hemoglobin content; ELISA 
= enzyme-linked immunosorbent assay; ET = early termination; HBsAg = hepatitis B surface 
antigen; hCG = human chorionic gonadotropin; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; LFTs = liver function tests TIBC = total iron binding capacity; TSAT 
= transferrin saturation; WBC =white blood cells; Wk(s) = week(s); 
a 
Weight only 
b 
Collect from female subjects of child bearing potential only 
c 
Renal ultrasound examination will be performed during screening if no record of a renal 
imaging modality exists within 24 weeks prior to enrollment. 
d 
Central labs only 
e 
28 days post last dose of roxadustat 
f 
Collect a separate central Hb only when CBC is not collected 
g 
Week 24 = EOT 


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13.2 
APPENDIX 2: DATA HANDLING CONVENTIONS 
 
13.2.1 
Visit Time Window 
Table 5 below presents the visits assigned for efficacy and safety analyses corresponding to 
the range of treatment days (window) during which an actual visit may have occurred. 
 
Table 5. Analysis Visit Windows 
 
Derived Visit 
Scheduled Visit 
Daya 
Window 
Baseline, Week 0 
Day 1 
Days ≤ 1 
Week 2 
Day 7*(Week #)+1 
Days [Day 2, 21] 
Weeks 4-6 
Day 7*(Week #)+1 
Days [Scheduled Day -7, Scheduled Day + 6 ] 
Week 8 
Day 7*(Week #)+1 
Days [Scheduled Day -7, Scheduled Day + 13 ] 
Weeks 12-24 
Day 7*(Week #)+1 
Days [Scheduled Day -14, Scheduled Day +13] 
ETb 
Last assessment between Day 2 and EOT/Week 24 visit day, match to a closest 
scheduled visit in protocol. 
EOS 
Final visit in the Study; For subjects who permanently discontinue roxadustat 
early or complete the treatment period (24 weeks) but decide not to participate 
in the extension treatment: around 28 days after the last dose. For subjects who 
complete the treatment period and decide to participate in the extension 
treatment: EOT/Week 24 visit day. 
a: Relative to the first study medication date. For example, Day 1 = the first dose date of study medication. 
b: For patients that are early terminated (ET), the ET visit will be collected on the Week 24/EOT visit eCRF. 


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13.2.2 
Repeated or Unscheduled Assessments of Safety Parameters 
 
If a patient has repeated assessments prior to the start of study medication, then the results 
from the final assessment made prior to the start of study medication will be used as baseline. 
If EOS assessments are repeated or unscheduled, the last post-baseline assessment will be 
used as the EOS for generating summary statistics. However, all post-baseline assessments 
will be used for potentially clinically significant (PCS) value determinations and all 
assessments will be presented in the data listings. 
 
13.2.3 
Missing Date of Study Medication 
 
When the last date of study medication during the study treatment phase is missing, all efforts 
should be made to obtain the date from the Investigator. If it is still missing after all efforts, 
then the last dispensation visit date during the treatment period will be used in the calculation 
of treatment duration. 
 
13.2.4 
Missing Severity Assessment for Adverse Events 
 
If severity is missing for an AE started prior to the first study medication, then a severity of 
“Mild” will be assigned. If the severity is missing for an AE started on or after the first study 
medication dosing, then a severity of “Severe” will be assigned. The imputed values for 
severity assessment will be used for incidence summary, while the actual missing values will 
be presented in data listings. 
 
13.2.5 
Missing Relationship to Study Drug for Adverse Events 
 
If the relationship to the study medication is missing for an AE started after baseline, a 
causality of “Related” will be assigned. The imputed values for relationship to study 
medication will be used for incidence summary, while the actual values will be presented in 
data listings. 
 
13.2.6 
Missing Date Information for Adverse Events 
 
The following imputation rules only apply to the case where the start date is incomplete (i.e., 
partial missing) for adverse events. 
 
• Incomplete Start Date 
Missing day and month 
− If the year is same as the year of first day on study medication, then the day and month 
of the start date of study medication will be assigned to the missing fields. 
− If the year is not the same as the year of first day on study medication, then January 1 
will be assigned to the missing fields. 
Missing month only 
Treat day as missing and replace both month and day according to the above procedure. 


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Missing day only 
If the month and year are same as the year and month of first day on study medication, then 
the start date of study medication will be assigned to the missing day. 
If the month and year are not the same as the year and month of first day on study 
medication, then the first day of the month will be assigned to the missing day. 
• Incomplete Stop Date 
If the stop date is complete and the imputed start date as above is after the stop date, the start 
date will be imputed by the stop date. 
If needed, the following imputation rules apply to the case where the end date is incomplete 
(i.e., partially missing) for adverse events. Other partial end date will not be imputed. 
 
Missing day and month, or Missing month only 
December 31 will be assigned to the missing fields. 
Missing day only 
The last day of the month will be assigned to the missing day. 
 
Table 6.1 
Imputation of the Analysis Adverse Event Start Date 
 
Reported Date 
Date of First Drug Intake 
Analysis Date (Derived) 
--/MM/YYYY 
DD/MM/YYYY 
--/02/2008 
14/02/2008 
14/02/2008* 
--/02/2008 
14/02/2007 
01/02/2008 
--/02/2008 
14/02/2009 
01/02/2008 
--/--/YYYY 
DD/MM/YYYY 
--/--/2008 
14/02/2008 
14/02/2008 
--/--/2008 
14/02/2007 
01/01/2008 
--/--/2008 
14/02/2009 
01/01/2008 
DD/--/---- 
--/MM/---- 
No imputation 
/ / 
 
 
Table 6.2 
Imputation of the Analysis Adverse Event Stop Date 
 
Reported Date 
Analysis Date (Derived) * 
--/MM/YYYY 
31/MM/YYYY or 
30/MM/YYYY or 
29/MM/YYYY or 
28/MM/YYYY 
--/--/YYYY 
31/12/YYYY 
DD/--/ --- , or 
--/MM/ --- , or 
/ / 
No imputation 
*Death has to be taken into consideration when calculating this. 


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13.2.7 
Missing Date Information for Prior or Concomitant Medications 
 
For prior or concomitant medications, including rescue medications, incomplete (i.e., partial 
missing) start date and/or stop date will be imputed. When the start date and the stop date are 
both incomplete for a patient, impute the start date first. 
 
• Incomplete Start Date 
The following rules will be applied to impute the missing numerical fields. If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date. 
 
Missing day and month 
If the year of the incomplete start date is the same as the year of the first dose date of study 
medication, then the day and month of the first dose date will be assigned to the missing 
fields. 
If the year of the incomplete start date is not the same as the year of the first dose date of 
study medication, then January 1 will be assigned to the missing fields. 
Missing month only 
Treat day as missing and replace both month and day according to the above procedure. 
Missing day only 
If the month and year of the incomplete start date are the same as the month and year of the 
first dose date of study medication, then the day of the first dose date will be assigned to the 
missing day. 
If the month and year of the incomplete start date are the same as the first dose date of study 
medication, then the first day of the month will be assigned to the missing day. 
 
• Incomplete Stop Date 
The following rules will be applied to impute the missing numerical fields, if needed. If the 
last dose date of study medication is missing, impute it with the last visit date. If the imputed 
stop date is before the start date (imputed or non-imputed start date), then the imputed stop 
date will be equal to the start date. 
 
Missing day and month 
 
If the year of the incomplete stop date is the same as the year of the last dose date of study 
medication, then the day and month of the last dose date will be assigned to the missing 
fields. 
If the year of the incomplete stop date is not the same as the year of the last dose date of 
study medication, then December 31 will be assigned to the missing fields. 
Missing month only 
Treat day as missing and replace both month and day according to the above procedure. 
Missing day only 
If the month and year of the incomplete stop date are the same as the month and year of the 
last dose date of study medication, then the day of the last dose date will be assigned to the 
missing day. 
If the month and year of the incomplete stop date are not the same as the month and year of 
the last dose date of double-blind study medication, then the last day of the month will be 
assigned to the missing day. 


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13.2.8 
Missing Date Imputation for last dose date 
Imputed last dose date = earliest date of (last drug dispense date + number of days of drug 
dispensed, date of death, date of EOT/EOS visit, and other dates as appropriate). 
 
13.2.9 
Character Values of Clinical Laboratory Parameters 
If the reported value of a clinical laboratory parameter cannot be used in a statistical 
summary table due to, for example, that a character string is reported for a parameter of the 
numerical type, coded value needs to be appropriately determined and used in the statistical 
analyses. However, the actual values as reported in the database will be presented in data 
listings. 
 
Table 7. 
Example for Coding of Special Character Values for 
Clinical Laboratory Parameters 
Lab Test 
Possible Lab Results 
(in SI unit) 
Coded Value for Analysis 
Urinalysis: Ketones 
= OR > 8.0, ≥8.0, > 0 
Positive 
≤ 0, Negative 
Negative 
Urinalysis: pH 
> 8.0, ≥ 8.0 
8.0 
≥ 8.5, 
8.5 
Urinalysis: Protein 
= OR > 3.0, ≥3.0, > 0 
Positive 
≤ 0 
Negative 


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13.3 
APPENDIX 3: RANGES OF POTENTIALLY CLINICALLY SIGNIFICANT 
LAB VALUES 
 
 
 
Parameter 
SI Unit 
Lower Limit 
Higher Limit 
CHEMISTRY 
Alanine 
Aminotransferase 
(ALT) 
U/L 
≥3 * ULN 
Alkaline Phosphatase 
U/L 
≥3 * ULN 
Aspartate 
Aminotransferase (AST) 
U/L 
≥3 * ULN 
Severe liver abnormality 
ALT or AST ≥ 3 x ULN AND 
Total bilirubin > =2 x ULN 
GGT 
U/L 
≥3 * ULN 
Calcium 
mmol/L 
<0.8*LLN 
>1.2 * ULN 
Potassium 
µmol/L 
<0.75*LLN 
>1.2 * UNL 
Sodium 
mmol/L 
<0.9*LNL 
>1.1 * UNL 
Total Bilirubin 
µmol/L 
>1.5 * UNL 
Total Protein 
µmol/L 
<0.9*LNL 
>1.1 * UNL 
HEMATOLOGY 
Neutrophils 
109/L 
≤1 
Platelet Count 
109/L 
≤ 100 
≥700 
White Blood Cell Count 
109/L 
≤2.5 
≥15 
LLN: Lower limit of normal, value provided by the laboratory 
ULN: Upper limit of normal, value provided by the laboratory 


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13.4 
APPENDIX 4: 
TEMPORAL PROFILE OF TEAES OF SPECIAL 
INTEREST 
 
 
 
 
 
 
 
 
 
 


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13.5 
APPENDIX 5: 
MEDICATION WHO DRUG DICTIONARY CODES 
 
 
Name 
Code 
ESA except darbepoetin alfa 
ATC level 4 = B03XA 
Darbepoetin alfa 
ATC level 4 = B03XA 
IV Iron 
ATC level 4 = B03AC 
RBC transfusion 
ATC level 4 = B05AX 
Any investigational drug 
WHODD drug code = 99999701001 
Hypoxia-inducible factor HIF-PHI 
ATC level 4 = B03XA 
Iron-chelating agents 
ATC level 4 = B03AA, B03AD, B03AE, A12CX 
Androgens 
ATC level 3 = G03B and G03E 
Dapsone 
ATC level 4 = J04BA 
Acetaminophen/paracetamol 
ATC level 4 = N02BE, N02AA, R05X 
 
 
The following WHO-DRL codes will be classified as ESA: '00909301001', '00928301001', 
'02198701001', '07973701001', ‘01703101001’. 
 
The following WHO-DRL code where route is INTRAVENOUS will be classified as IV 
IRON: '00023501001' and ‘90135401001’. 
 
The following WHO-DRL code will be classified as RBC transfusion: '01186901001'. 


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13.6 
APPENDIX 6: 
CARDIOVASCULAR/CEREBROVASCULAR/THROMBOEMBOLIC MEDICAL 
HISTORY TERMS USED IN MEDICAL HISTORY OF INTEREST CRF 
 
 
 
Medical Condition Term 
Hypertension 
Myocardial infarction(STEMI or NSTEMI) 
Angina, Stable 
Angina, Unstable 
Coronary artery bypass 
Percutaneous coronary intervention 
Atrial fibrillation, flutter or supraventricular tachycardia 
Ventricular tachycardia or fibrillation 
Stroke: Ischemic 
Stroke: Hemorrhagic 
Stroke: Unknown 
Transient ischemic attack 
Congestive heart failure (NYHA): Class I 
Congestive heart failure (NYHA): Class II 
Congestive heart failure (NYHA): Class III 
Congestive heart failure (NYHA): Class IV 
Cardiomyopathy 
Peripheral vascular disease 
Deep vein thrombosis 
Pulmonary embolism 
Vascular access thrombosis 
Valvular heart disease 


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13.7 
APPENDIX 7: SEARCH CRITERIA FOR SPECIFIC ADVERSE EVENTS 
 
Specific Adverse Events 
Search Criteria 
Myocardial Infarction 
PTs: 
Acute myocardial infarction 
Myocardial infarction 
Stroke Selected PTs 
PTs: 
Brain Stem Haemorrhage 
Brain Stem Infarction 
Brain Stem Stroke 
Cerebellar Infarction 
Cerebral Infarction 
Cerebral Thrombosis 
Cerebrovascular Accident 
Embolic Stroke 
Haemorrhagic Cerebral Infarction 
Haemorrhagic Stroke 
Ischaemic Cerebral Infarction 
Ischaemic Stroke 
Lacunar Infarction 
Lacunar Stroke 
Thalamic Infarction 
Stroke SMQs 
Two SMQS combined : 
• 
Haemorrhagic central nervous system vascular 
conditions (SMQ) 
• 
Ischaemic central nervous system vascular conditions 
(SMQ) 
Hypertension 
Hypertension Narrow SMQ 
Seizures 
Convulsions Narrow SMQ 
Deep vein thrombosis (DVT) 
PT: 
Deep vein thrombosis 
Pulmonary embolism 
PTs: 
Pulmonary artery thrombosis 
Pulmonary embolism 
Infections SOC 
Infections SOC 
Infections SAE 
Infections SOC + SAE 
Infections Fatal 
Infections SOC + Fatal 
Sepsis 
Sepsis Narrow SMQ 
Malignancy 
Malignant tumors SMQ 


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13.8 
APPENDIX 8: MEDICAL HISTORY PREFERRED TERM FOR BASELINE 
VASCULAR ACCESS TYPE 
 
 
 
Baseline Vascular Access Type 
Preferred Term 
AVF 
Arteriovenous fistula 
AVG 
Arteriovenous graft 
Catheter 
Central venous catheterisation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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