A Phase 3, Multicenter, Randomized, Open-Label, Active-Controlled Study of the Efficacy and Safety of FG-4592 in the Treatment of Anemia in Incident-Dialysis Patients
Phase: PHASE3
Conditions: Anemia in Incident Dialysis Patients
Sponsor: Kyntra Bio

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CLINICAL STUDY PROTOCOL 
STUDY TITLE: 
A Phase 3, Multicenter, Randomized, Open-Label, Active- 
Controlled Study of the Efficacy and Safety of FG-4592 in the 
Treatment of Anemia in Incident-dialysis Patients 
PROTOCOL NUMBER: 
FGCL-4592-063 
SPONSOR: 
FibroGen, Inc. 
409 Illinois Street 
San Francisco, California 94158 USA 
IND NUMBER: 
74,454 
STUDY DRUG: 
Roxadustat (FG-4592) 
INDICATION: 
Anemia associated with end-stage renal disease 
FIBROGEN MEDICAL 
MONITOR (US): 
Name: 
 
Title: 
 
Telephone: 
Mobile: 
E-mail: 
 
FIBROGEN MEDICAL 
MONITOR (Ex-US): 
Name: 
 
Title: 
 
Telephone: 
Mobile: 
E- mail:
 
ORIGINAL PROTOCOL: 
31 May 2013 
PROTOCOL VERSION 
& DATE: 
Amendment 1: 20 Oct 2014 
Amendment 2 (United States only): 24 Nov 2015 
Amendment 3 (United States only): 12 Aug 2016 
Amendment 4: 20 Sep 2017 
CONFIDENTIALITY STATEMENT 
The information contained in this document is confidential and proprietary to 
FibroGen, Inc. No part of this document or any of the information contained 
herein may be transmitted, disclosed, shared, reproduced, published or utilized 
by any persons without prior written authorization by FibroGen, Inc. 
NCT # NCT02052310

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INVESTIGATOR SIGNATURE PAGE 
STUDY ACKNOWLEDGEMENT 
A Phase 3, Multicenter, Randomized, Open-Label Active-Controlled Study of the Efficacy and 
Safety of FG-4592 in the Treatment of Anemia in Incident-dialysis Patients 
FGCL-4592-063 
Amendment 4 
20 September 2017 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices and the current Investigator’s Brochure (IB), 
and I agree that it contains all necessary details for me and my staff to conduct this study as 
described. I will conduct this study as outlined herein and will make a reasonable effort to 
complete the study within the time designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by FibroGen, Inc. I will discuss this material with them to ensure that they 
are fully informed about the drugs and the study. 
I will conduct the trial in accordance with the guidelines of Good Clinical Practice (GCP) 
including the archiving of essential documents, the Declaration of Helsinki, any applicable local 
health authority, and Institutional Review Board (IRB) requirements. 
 
 
 
 
 
 
 
 
 
 
Investigator Name (Printed) 
Institution 
 
 
 
 
 
 
Signature 
Date 
 
 
Please retain the original for your study files. 

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SUMMARY OF MAJOR PROTOCOL AMENDMENT CHANGES 
Amendment 4 (Global) 
In addition to the major changes listed below, minor editorial changes were made throughout the 
document to correct typographical errors and to improve consistency and clarity. 
 
 
Description of Change 
Rationale for Change 
Section(s) 
Affected a 
Inclusion Criteria: 
Inclusion criteria # 3 has been modified by removing 
“native kidney” – the revised verbiage reads as follows: 
Incident dialysis subjects receiving dialysis for ESRD for 
≥ 2 weeks but ≤ 4 months at the time of randomization 
Inclusion criteria # 6, 7, 8, 9 were modified as follows 
(added text is italicized): 
6. Ferritin ≥ 100 ng/mL (≥ 220pmol/L). 
Subjects with ferritin level < 100 ng/mL 
(<220pmol/L) during screening qualify after 
receiving iron supplementation (per local standard 
of care) without the need to retest ferritin prior to 
randomization. 
7. Transferrin saturation ≥ 20%. 
Subjects with a TSAT level < 20% during screening 
qualify after receiving iron supplementation (per 
local standard of care), without the need to retest 
TSAT prior to randomization. 
8. Serum folate level, performed within 8 weeks prior 
to randomization ≥ lower limit of normal (LLN). 
Subjects with a serum folate level < LLN during 
screening qualify after receiving folate supplement 
(per local standard of care), without the need to 
retest folate prior to randomization. 
9. Serum vitamin B12 level, performed within 8 weeks 
prior to randomization ≥ LLN. 
Subjects with a Vitamin B12 level < LLN at 
screening qualify after receiving vitamin B12 
supplement (per local standard of care), without 
the need to retest vitamin B12 prior to 
randomization. 
To allow subjects who restarted dialysis 
recently due to transplanted kidney end- 
stage renal disease (see revised Exclusion 
# 17 below) 
Revised TSAT/ferritin/Vit.B12/folate 
criteria:  Subjects with 
TSAT/ferritin/folate/Vit.B12 levels below 
the screening values are eligible, upon 
receiving the respective 
supplementations, without the need for 
re-testing during screening. This will 
improve the screening success rate 
without altering the patient population 
intended for inclusion in this study, and 
will help shorten the screening period by 
minimizing the need for additional visits 
to retest these parameters. 
Synopsis; 
Section 4.1 
Exclusion Criteria: 
Exclusion criteria 2, 3, 4, 6, 9, 13, 17, 19, and 25 were 
modified to read as follows (added text is italicized, 
revised text is bolded and italicized): 
2. Intravenous iron: there is no restriction regarding 
IV iron use during screening, provided it is 
administered in accordance with local standard of 
These exclusion criteria have been 
modified to allow more incident subjects 
to be eligible, who are otherwise good 
study candidates , in order to retain a 
representative sample of real-life incident 
dialysis patients. 
Easing the restriction on the amount of IV 
iron allowed during screening will help 
Synopsis; 
Section 4.2 

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Description of Change 
Rationale for Change 
Section(s) 
Affected a 
care. 
3. Red blood cell (RBC) transfusion within 4 weeks 
prior to randomization. 
4. Active, clinically significant infection that could be 
manifested by white blood cell (WBC) count 
>ULN, and/or fever, in conjunction with clinical 
signs and symptoms of infection at the time of 
randomization. 
6. 
New York Heart Association Class III or IV 
congestive heart failure at screening. 
9. 
Renal imaging performed within 12 weeks prior to 
randomization indicative of a diagnosis or 
suspicion (eg, complex kidney cyst of Bosniak 
Category 2 or higher) of renal cell carcinoma. 
13.   Known, untreated proliferative diabetic 
retinopathy, diabetic macular edema, macular 
degeneration, or retinal vein occlusion.  (Subjects 
who are already blind for the above reasons 
qualify to participate). 
17. Organ transplant: subjects with any of the 
following: 
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) scheduled for organ transplantation. Note: being 
on a waiting list for kidney transplant is not 
exclusionary 
19. Active or chronic gastrointestinal bleeding 
25. Subject has a history of alcohol or drug abuse 
within 6 months prior to screening 
accrue subjects meeting TSAT/ferritin 
eligibility criteria (see also updates to 
eligibility criteria related to TSAT and 
ferritin levels). This will improve the 
screening success rate without altering the 
patient population intended for inclusion 
in this study, and will help shorten the 
screening period by minimizing the need 
for additional screening visits to retest 
these parameters 
RBC transfusion was updated to state 
within 4 weeks instead of 8 weeks prior 
to randomization. It is not expected to 
impact baseline Hb and there are no 
additional safety concerns. 
“at the time of randomization” has been 
added to clarify the timing of exclusion 
#4 due to this criterion. 
“at screening” has been added to clarify 
the timing of exclusion #6 due to this 
criterion. 
Changing from renal ultrasound to renal 
imaging will allow all acceptable imaging 
options eg, ultrasound, CT scans, MRI 
etc. 
Text is added to clarify that subjects who 
are already blind due to the complications 
of one or more of these conditions are OK 
to participate as there is no possibility of 
further worsening. 
Revised to allow otherwise eligible 
incident subjects with prior organ 
transplant to participate except who 
experienced transplant rejection within 6 
months of transplantation or on high 
doses of immunosuppressive therapy (due 
to potential confounding effects on safety 
and efficacy assessments) 
“Known” was removed to clarify 
exclusion criterion #19 applies to only 
active gastrointestinal bleeding. 
Potential subjects with no history of 
alcohol or drug abuse was updated from 
within 2 years to within 6 months to 
allow more subjects to qualify and does 
not pose any additional safety risk. 

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Description of Change 
Rationale for Change 
Section(s) 
Affected a 
Treatment Period (added text is italicized, revised text 
is bolded and italicized): 
Treatment duration is variable for individual subjects. In 
order to complete the Treatment Period simultaneously 
for all study subjects, the minimum treatment duration 
may be less than 52 weeks, with a maximum treatment 
duration of up to approximately 3 years after the last 
subject is randomized.   Subjects will be informed at 
least 4 weeks prior to their treatment period end. 
In order to complete the Phase 3 program 
in a timely manner and simultaneously 
for all study subjects, the minimum 
treatment duration of subjects enrolled 
after March 2017 (as part of Amendment 
4) may be less than 52 weeks. Such 
subjects will be informed at least 4 weeks 
in advance if such a decision is made. 
Synopsis, 
Section 3.1 
Procedures for Handling Incorrectly Enrolled 
Subjects 
The following section was added: 
Subjects who fail to meet all eligibility criteria should 
not be enrolled.  If it is discovered in retrospect that a 
subject did not meet all eligibility criteria, the 
Investigator should inform the Medical Monitor 
immediately, and a discussion should occur regarding 
whether or not to discontinue the study subject.  All 
decisions from such a discussion should be 
appropriately documented. 
This language was added to align the 
protocol with a new SOP for protocol 
templates 
Section 3.3 
Excessive Hematopoiesis 
The following section was added: 
For subjects randomized to roxadustat, the following 
scenarios are defined as “excessive hematopoiesis”; 
• 
Hb increases by > 2.0 g/dL at any time within a 
4 week period: reduce the dose by one dose 
step. 
• 
Hb reaches or exceeds 13 g/dL: hold dosing, 
check Hb weekly.  Resume dosing when Hb < 
12.0 g/dL (for US subjects central lab Hb value 
preferred), at a dose that is reduced by two 
dose steps. 
For subjects on prolonged dose hold with stable (not 
dropping) Hb, the Investigator may use discretion to 
schedule less frequent visits. 
Anytime Hb is assessed via HemoCue®/CritLine®/local 
lab, a central lab Hb should be obtained as well. 
Instructions have been added to the body 
of the protocol, specifying when to reduce 
or hold dosing in case of excessive Hb 
rate of rise, in order to further emphasize 
these specific dosing instructions; in 
addition, these instructions also allow for 
PI discretion to determine the frequency 
of visits, in case of prolonged dose-hold, 
with stable (not dropping) Hb 
Section 
3.5.3.4, 
Appendix 2 
Investigational Product 
To provide further guidance on roxadustat 
Synopsis; 
The following text was added (revised text is bolded and 
italicized): 
dosing, if a subject requires further dose 
reductions from 20 mg TIW, given 20 mg 
is the lowest tablet strength available. 
Sections 
3.5.2.1, 
3.5.3.2, 
If a subject requires < 20 mg TIW (ie, < 60 mg per 
3.5.3.3, 
week) to maintain Hb levels in the Maintenance Phase, 
the dosing frequency should be reduced in a step-wise 
fashion eg, TIW to BIW, BIW to QW, QW to Q-2 Week 
Roxadustat subjects: various factors, such 
as discrepancies between HemoCue® Hb 
and Central lab Hb value, Investigator 
5.3.1, 
Appendix 2 

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Description of Change 
Rationale for Change 
Section(s) 
Affected a 
etc. 
The following paragraphs were added to clarify: 
Given the complexity in  roxadustat dose adjustments, 
and the need to take into account the various clinical 
parameters in roxadustat dose titration, one would not 
consider it a protocol deviation when study subjects are 
dosed based on their clinical circumstances, whether or 
not it is concordant with the roxadustat dose adjustment 
guidelines unless it was related to “excessive 
hematopoiesis”  (eg, Hb ≥ 13 g/dL, requiring a dose 
hold) or “Overdose”  (prescribed >3.0 mg/kg per dose 
or 400 mg per dose whichever is lower) 
ESA administration in roxadustat subjects during 
hospitalization is not considered a protocol deviation if 
roxadustat is not allowed or available during that 
hospitalization. 
Given the complexity in EPO dose adjustments and the 
need to take into account the various clinical 
parameters in EPO dose titration, one would not 
consider it a protocol deviation when study subjects are 
dosed according to local standard of care whether or 
not it is concordant with  package insert/SmPC 
decision etc. can influence dose titration 
decisions at the time of the visit or after 
the visit. As a result, the dose prescribed 
may not exactly match the dose per the 
dose adjustment algorithm. 
However, as the stable dose would be 
achieved through titration, dosing 
discrepancy when subjects are dosed 
based on their clinical status is not 
considered a protocol deviation unless it 
is related to excessive hematopoiesis 
(≥13.0 g/dL, requiring a dose-hold) or 
overdose (>3.0 mg/kg/dose). 
Roxadustat subjects may receive ESA 
while hospitalized, in part due to lack of 
access to roxadustat while in hospital, 
and/or as part of hospital standard-of-care 
of anemia treatment; therefore, ESA 
administration in such circumstances is 
not considered a protocol deviation. 
EPO subjects; To allow flexibility with 
EPO dosing where investigators/sites are 
not able to follow epoetin-alfa package 
insert guidelines due to various factors 
including local standard of care, and 
clinical status of the subjects. 
Supplemental Iron Use: 
Text was modified as follows (added text is italicized, 
revised text is bolded and italicized) : 
In this study, oral iron should be allowed as first-line 
Many ESRD patients cannot tolerate oral 
iron therapy due to GI adverse effects 
including GI bleeding. The modified text 
allows for that. 
Synopsis; 
Sections 
3.6.2.1, 
3.6.2.2, 
Appendix 6 
iron supplementation without restrictions, for both study 
IV iron has been the standard of care for 
arms. 
iron supplementation in ESRD anemia 
All subjects should be encouraged to take oral iron as 
the first-line iron supplementation during the Treatment 
Period, except for subjects not tolerating oral iron. 
subjects and it is routinely administered 
in subjects who are on ESA therapy. The 
original IV iron administration guidelines 
are considered overly restrictive and not 
Intravenous iron supplementation is permitted if in the 
in line with the current standard of care. 
opinion of the Investigator the subject’s Hb has not 
Therefore, this section has been revised to 
responded adequately and the subject is considered iron 
allow IV iron per discretion of the PI. 
deficient. 
IV iron administration in study subjects during 
hospitalization is not considered a protocol deviation. 
IV iron is the standard of care for iron 
supplementation in this patient 
population. IV iron is administered 
routinely in all hospitalized patients who 
are on dialysis, including study subjects, 
as part of the hospital standard of 
practice. Therefore, IV iron administered 
in study subjects while hospitalized is not 
considered a protocol deviation. 

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Description of Change 
Rationale for Change 
Section(s) 
Affected a 
Rescue Therapy and Emergency Procedures: 
Text was modified as follows: 
From: 
Subjects who receive an ESA inadvertently (and do not 
meet the criteria above) may be allowed to continue on 
study, if considered safe by the Investigator and Medical 
Monitor. 
To: 
Inadvertent ESA administration, including ESA 
administration by hospital staff in roxadustat subjects, 
should not be counted as rescue, unless above criteria 
are met; these subjects may be allowed to continue on 
study, if considered safe by the Investigator and Medical 
Monitor. 
The following paragraph was updated to (added text is 
italicized): 
Subjects may receive one course of ESA rescue during 
the Treatment Period. Erythropoiesis-stimulating agent 
rescue should stop after 4 weeks or once Hb exceeds 9 
g/dL, whichever occurs first.  If a subject requires more 
than 4 weeks of ESA rescue therapy due to inadequate 
Hb response, the Medical Monitor should be contacted. 
ESA therapy is the only standard of care 
to treat anemia in ESRD patients. It is a 
common practice to administer ESA 
during dialysis session. Clarification has 
been added that inadvertent ESA 
administration, or ESA administration by 
hospital staff as part of the standard of 
care in roxadustat subjects, should not be 
counted as ESA rescue, unless protocol 
specified rescue criteria are met. 
Synopsis; 
Section 
3.6.3.2 
Contraception 
The following section was added: 
In female subjects of childbearing potential, a serum 
pregnancy test will be done per the Schedule of 
Assessments (Appendix 3) to rule out pregnancy.   A 
pregnancy test is not required for female subjects of no 
childbearing potential eg, postmenopausal 
(determination whether a woman is post-menopausal is 
at the discretion of the Investigator), surgically sterile, 
etc. 
This language was added to align the 
protocol with a new SOP for protocol 
templates 
Section 
3.6.6 
Additional Screening 
Section was updated as follows (added text is italicized, 
revised text is bolded and italicized): 
Screening procedures that are not done at the scheduled 
visit must be completed prior to randomization. 
If subjects fail screening, they may be re-screened once 
as deemed appropriate by the investigator. Where 
possible, an approval should be obtained from the 
Medical Monitor prior to rescreening. 
To allow further flexibility for subjects 
during the screening period. This would 
allow further subjects to participate. 
Section 
6.1.1.3 

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Description of Change 
Rationale for Change 
Section(s) 
Affected a 
Treatment Period 
The increased visit window update was 
Section 
made to avoid unnecessary protocol 
6.1.2.3, 
Section 6.1.2.3 was changed from: 
deviations given dialysis sessions are 
6.1.2.4, 
Weeks 6 to 24 (Every 2 weeks, ± 2 days ) 
scheduled in general every other day, the 
6.1.2.5, 
To: 
4-day window will allow subjects who 
Appendix 3 
Weeks 6 to 24 (Every 2 weeks, ± 4 days) 
miss one dialysis session to be within the 
visit window. 
Section 6.1.2.4 was changed from: 
Weeks 28 to End of Therapy (Every 4 weeks, ±3 days) 
To: 
Weeks 28 to End of Therapy (Every 4 weeks, ±4 days) 
Section 6.1.2.5 was changed from: 
End of Treatment (± 3 days) 
To: 
End of Treatment (± 7 days) 
Appendix 3 was updated to align with the above sections 
Subject Discontinuation 
Adverse Events was added as a possible reason for 
subject discontinuation from the study. 
The schedule of Assessments already 
includes this assessment at the 
discontinuation visit.  The text was 
updated to match the table. 
Section 
6.1.3.2 
HemoCue®/CritLine® 
Section was updated as follows: 
Anytime an Hb is obtained via such a point-of-care 
device, a central lab Hb should be obtained as well, 
either as part of the regular visit labs, or anytime when 
a point-of-care Hb is obtained at unscheduled visits, 
such as during dose-hold for excessive hematopoiesis. 
Instructions were added to obtain a 
central laboratory Hb anytime a 
HemoCue®/CritLine®   or other local Hb 
is obtained, for proper documentation in 
the central laboratory database, and  to 
improve Sponsor oversight 
Section 
6.4.1 
Protocol Deviation: 
Text has been added to pre-specify issues that are not 
considered protocol deviations. Added text reads as 
follows: 
A protocol deviation is generally an unplanned 
excursion from the protocol that is not implemented or 
intended as a systematic change. The investigator is 
responsible for ensuring the study is conducted in 
accordance with the procedures and evaluations 
described in this protocol and must protect the rights, 
safety and welfare of subjects. The investigator should 
not implement any deviation from, or changes to, the 
protocol, unless it is necessary to eliminate an 
immediate hazard to study subjects. 
Guidelines related to roxadustat, epoetin-alfa, and IV 
iron administration deviations are described in the 
respective sections. 
This section was added to align the 
protocol with a new SOP for protocol 
templates. 
Section 
8.4.6 

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Description of Change 
Rationale for Change 
Section(s) 
Affected a 
Adverse Event Eliciting/Reporting 
Added clarification regarding action taken with study 
drug (added text is bolded and italicized): 
Action taken regarding study drug (action taken by PI 
in response to an AE) 
To clarify that “Action taken regarding 
the study drug” refers to PI’s decision in 
response to an AE (eg, PI temporarily 
stopped the study drug) as opposed to 
subject’s own decision (subject did not 
take study drug as s/he was not feeling 
well or did not have with him/her) 
Section 
9.3.2 
Pregnancies: Reporting and Follow-up of Subjects 
Added clarification regarding confirmation of pregnancy 
(added text is italicized and bolded) 
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. 
Text is added to reflect the current 
clinical practice to confirm pregnancy in 
this patient population (known to have 
high false positive pregnancy results). 
Also, to minimize exposure to the fetus as 
a precaution (in case pregnancy is 
confirmed). 
Section 
9.3.6 
Disease Progression 
The following section was added: 
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. 
Gradual worsening of ESRD should be considered 
disease progression and should not be reported as an 
AE during the study. 
This language was added to align the 
protocol with a new SOP for protocol 
templates 
Section 
9.3.8 
Blood Pressure and Heart Rate Measurement 
Guidelines 
Revised BP and HR measurement guidelines (added text 
is bolded and italicized): 
Blood pressure should be measured in triplicate 
(preferred) with at least one minute interval between the 
measurements. 
Heart rate (HR) should be measured in triplicate 
(preferred) with at least one minute interval between the 
measurements. 
Measuring BP and HR three times (at 
least one minute interval) before dialysis 
is not per standard clinical practice and is 
difficult to implement as it requires 
additional time and manpower. Added 
verbiage “preferred” will provide 
flexibility to the sites. Also, will help to 
avoid protocol deviations. 
Appendix 5 
Sample Size Determination 
The following section was added: 
(ie, the proportion of subjects who achieve a Hb 
response at two consecutive visits during the first 24 
weeks of treatment). 
The analysis of EMA primary endpoint is 
to be more specifically described in the 
section. 
Section 8.1 

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Description of Change 
Rationale for Change 
Section(s) 
Affected a 
Potential EMA Interim Analysis 
Potential EMA interim analysis description part was 
removed. 
Minimum 52-week treatment was not a 
requirement anymore per FDA response. 
Hence, no such Potential EMA interim 
analysis. 
Section 8.3 
Analysis Model Description 
a) Other stratification factors changed to 
randomization stratification factors in the model 
terms. 
b) Factors were updated to fixed effects in the model 
Changes a and b are making the wording 
more precise. 
Changes c and d are corrections. 
Synopsis; 
Section 
8.4.3.1, 
8.4.3.2, 
8.4.3.3 
terms. 
c) LOCF was removed from MMRM models. 
d)   Visit and interaction of visit and treatment arm were 
removed from MI ANCOVA models and added to 
MMRM models 
The Evaluation Period of Ex-US Submission 
EMA only required following up to Week 
Synopsis, 
Ex-US submission: Mean Hb change from baseline to 
the average level during the Evaluation Period, defined 
as “Week 28 until Week 36”. It was Week 28 to Week 
36. 
Section 
7.3, 
8.4.3.2 
52. 
Evaluation period for additional efficacy 
To align with other similar protocols 
Evaluation time frame for hemoglobin maintenance has 
under this Phase 3 program 
been revised to Weeks 28 to 52 
Evaluation time frame for mean change in Hb has been 
revised to “96 to 104 weeks of treatment” 
Baseline Hb value calculation 
Added text regarding baseline Hb value calculation for 
subjects enrolled under Amendment 4. Revised text 
reads as follows (added text is italicized, revised text is 
bolded and italicized): 
Baseline Hb is defined as the mean of at least three 
central laboratory Hb values: the last two screening Hb 
values prior to randomization plus the one pre-dose Hb 
value on Day 1of the Treatment Period. 
To align with the revised Inclusion 
Criteria #5 
Section 
8.4.3 

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TABLE OF CONTENTS 
1 Introduction ........................................................................................................................... 35 
1.1 
Background Information ............................................................................................... 35 
1.1.1 Epidemiology of CKD and ESRD ............................................................................ 35 
1.1.2 Anemia Associated with Chronic Kidney Disease .................................................... 35 
1.2 
Treatment of Anemia .................................................................................................... 36 
1.3 
Mechanism of Action of Roxadustat ............................................................................. 36 
1.4 
Clinical Experience with Roxadustat ............................................................................ 39 
1.4.1 Pharmacokinetics and Pharmacodynamics................................................................ 39 
1.4.2 Efficacy ..................................................................................................................... 40 
1.4.3 Safety ........................................................................................................................ 42 
1.5 
Summary ....................................................................................................................... 43 
1.6 
Roxadustat Dose Rationale ........................................................................................... 44 
1.7 
Risks/Benefits of Roxadustat Treatment ....................................................................... 44 
2 Objectives .............................................................................................................................. 46 
2.1 
Primary Objectives ........................................................................................................ 46 
2.2 
Secondary Objectives .................................................................................................... 46 
3 Study Design ......................................................................................................................... 47 
3.1 
Description of the Study ................................................................................................ 47 
3.2 
Randomization and Treatment Assignment .................................................................. 47 
3.3 
Procedures for Handling Incorrectly Enrolled Subjects ................................................ 47 
3.4 
Replacement of Subjects ............................................................................................... 47 
3.5 
Study Treatment ............................................................................................................ 47 
3.5.1 Dose and Schedule .................................................................................................... 47 
3.5.2 Starting Dose of Study Drug ..................................................................................... 48 
3.5.3 Dose Adjustment for Roxadustat .............................................................................. 48 
3.6 
Concomitant Medications, Procedures and Nondrug Therapies ................................... 50 
3.6.1 Concomitant Medications ......................................................................................... 50 
3.6.2 Supplemental Iron Use .............................................................................................. 51 
3.6.3 Rescue Therapy Guidelines ....................................................................................... 52 
3.6.4 Therapeutic Phlebotomy ........................................................................................... 52 
3.6.5 Excluded Medications/Therapies/Substances ............................................................ 53 

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3.6.6 Contraception ............................................................................................................ 53 
3.7 
Safety Monitoring Plan ................................................................................................. 53 
3.8 
Data Safety and Monitoring Board ............................................................................... 54 
4 
Eligibility Criteria ................................................................................................................. 55 
4.1 
Inclusion Criteria ........................................................................................................... 55 
4.2 
Exclusion Criteria .......................................................................................................... 55 
5 
Investigational Product .......................................................................................................... 58 
5.1 
Formulation ................................................................................................................... 58 
5.2 
Storage .......................................................................................................................... 58 
5.3 
Administration............................................................................................................... 58 
5.3.1 Roxadustat ................................................................................................................. 58 
5.3.2 Active Control-Epoetin Alfa ..................................................................................... 58 
5.4 
Overdose, Emergency Procedures and Management of Overdose ................................ 59 
6 
Study Procedures ................................................................................................................... 60 
6.1 
Study Procedures by Visit ............................................................................................. 60 
6.1.1 Screening Period (Up to 6 Weeks) ............................................................................ 60 
6.1.2 Treatment Period ....................................................................................................... 62 
6.1.3 Post-Treatment Follow-Up Period ............................................................................ 66 
6.2 
Missed Visits ................................................................................................................. 67 
6.3 
Unscheduled Visits ........................................................................................................ 68 
6.4 
Laboratory Assessments ................................................................................................ 68 
6.4.1 HemoCue® / CritLine® .............................................................................................. 68 
6.4.2 Central Laboratory .................................................................................................... 68 
6.5 
Electrocardiogram ......................................................................................................... 70 
6.6 
Renal Ultrasound ........................................................................................................... 70 
6.7 
Health Related Quality of Life Questionnaires ............................................................. 70 
6.7.1 36-Item Short Form Health Survey ........................................................................... 70 
6.7.2 FACT-An .................................................................................................................. 70 
6.7.3 European Quality of Life Questionnaire in 5 Dimensions ........................................ 71 
7 
Endpoints and Assessments .................................................................................................. 72 
7.1 
Primary Endpoint .......................................................................................................... 72 
7.2 
Secondary Endpoints ..................................................................................................... 72 
7.3 
Additional Evaluation of Efficacy ................................................................................. 73 

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7.4 
Safety Assessments and Endpoints ............................................................................... 75 
8 
Statistical Considerations ...................................................................................................... 76 
8.1 
Sample Size Determination ........................................................................................... 76 
8.2 
Analysis Populations ..................................................................................................... 76 
8.3 
Interim Data Cut ............................................................................................................ 77 
8.4 
Statistical Analysis ........................................................................................................ 77 
8.4.1 Subject Enrollment and Disposition .......................................................................... 77 
8.4.2 Demographics and Baseline Characteristics ............................................................. 77 
8.4.3 Efficacy Analyses ..................................................................................................... 77 
8.4.4 Safety Analyses ......................................................................................................... 82 
8.4.5 Statistical Analysis Plan ............................................................................................ 83 
8.4.6 Protocol Deviation .................................................................................................... 83 
9 
Safety .................................................................................................................................... 84 
9.1 
Background ................................................................................................................... 84 
9.2 
Definitions ..................................................................................................................... 84 
9.2.1 Definition of an Adverse Event ................................................................................. 84 
9.2.2 Definition of a Serious Adverse Event ...................................................................... 84 
9.2.3 Definition of a Suspected Adverse Reaction ............................................................. 85 
9.2.4 Definition of an Adverse Reaction ............................................................................ 85 
9.2.5 Special situations ....................................................................................................... 85 
9.3 
Procedures for Eliciting, Recording, and Reporting Adverse Events ............................ 85 
9.3.1 Adverse Event Reporting Period ............................................................................... 85 
9.3.2 Adverse Event Eliciting/Reporting ........................................................................... 86 
9.3.3 Assessing Adverse Event Severity ............................................................................ 86 
9.3.4 Assessing Relationship to Study Drug ...................................................................... 87 
9.3.5 Reporting Serious Adverse Events on the Serious Adverse Event Report Form ...... 88 
9.3.6 Pregnancies: Reporting and Follow-up of Subjects .................................................. 89 
9.3.7 Abnormal Laboratory Findings ................................................................................. 89 
9.3.8 Disease Progression .................................................................................................. 89 
10 Direct Access to Source Documents ..................................................................................... 91 
11 Quality Control and Quality Assurance ................................................................................ 92 
11.1 
Data Quality Assurance ................................................................................................. 92 
11.2 
Audit and Inspection ..................................................................................................... 92 

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11.3 
Database Audit .............................................................................................................. 92 
12 Ethics..................................................................................................................................... 93 
12.1 
Ethical Considerations .................................................................................................. 93 
12.2 
Communication with the Institutional Review Board or Independent Ethics Committee 
....................................................................................................................................... 93 
12.3 
Informed Consent Form ................................................................................................ 93 
12.4 
Subject Confidentiality .................................................................................................. 94 
13 Data Handling and Record Keeping ..................................................................................... 95 
13.1 
Source Documents ........................................................................................................ 95 
13.2 
Data Collection, Handling, and Verification ................................................................ 95 
14 Financing and Insurance ....................................................................................................... 96 
15 Publication Policy ................................................................................................................. 97 
16 Investigator Requirements .................................................................................................... 98 
16.1 
Study Drug Accountability ........................................................................................... 98 
16.2 
Disclosure of Data......................................................................................................... 98 
16.3 
Retention of Records ..................................................................................................... 98 
17 Reference List ....................................................................................................................... 99 
18 Appendices .......................................................................................................................... 102 
LIST OF TABLES 
Table 1 Initial Study Drug Dosing ............................................................................................. 48 
Table 2 Recommended Maximum Daily Dose of Statins for Subjects Randomized to 
Roxadustat..................................................................................................................................... 51 
Table 3 Laboratory Tests ........................................................................................................... 69 
LIST OF FIGURES 
 
Figure 1 
HIF-PHI Mechanism of Action ........................................................................ 37 
LIST OF APPENDICES 
 
Appendix 1 
Study Schema ...................................................................................................... 103 
Appendix 2 
Roxadustat Dose Adjustment Rules .................................................................... 104 
Appendix 3 
Schedule of Assessments .................................................................................... 106 
Appendix 4 
Liver Safety Monitoring Assessment .................................................................. 108 
Appendix 5 
Blood Pressure and Heart Rate Measurement Guidelines .................................. 109 
Appendix 6 
Permitted Intravenous Iron Therapy ................................................................... 110 

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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
~ 
approximately 
Ab 
antibody 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance model 
AST 
aspartate aminotransferase 
AV 
arteriovenous 
BIW 
twice weekly 
BP 
blood pressure 
CBC 
complete blood count 
CERA 
continuous erythropoietin receptor activator 
CFR 
Code of Federal Regulations 
CHr 
reticulocyte hemoglobin content 
CI 
confidence interval 
CKD 
chronic kidney disease 
Cmax 
maximum concentration 
CMH 
Cochran-Mantel-Haenszel 
CRF 
case report form 
CYP 
cytochrome P450 
dBP 
diastolic blood pressure 
DD-CKD 
dialysis-dependent chronic kidney disease 
DNA 
deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics committee 
ECG 
electrocardiogram 
eEPO 
endogenous erythropoietin 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
end of study 
EOT 
end of treatment 
EPO 
erythropoietin 

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Abbreviation 
Definition 
EQ-5D-5L 
European Quality Of Life questionnaire in 5 Dimensions, 5 Levels 
ESA 
erythropoiesis-stimulating agent 
ESRD 
end-stage renal disease 
ET 
early termination (visit) 
FACT-An 
Functional Assessment of Cancer Therapy-Anemia 
FACT-G 
Functional Assessment of Cancer Therapy-General 
FAS 
full analysis set 
FDA 
US Food and Drug Administration 
GCP 
good clinical practice 
GGT 
gamma-glutamyl transferase 
Hb 
hemoglobin 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HD 
hemodialysis 
HHD 
Home-hemodialysis 
HDL 
high-density lipoprotein 
HIF 
hypoxia-inducible factor 
HIF-PH 
hypoxia-inducible factor prolyl hydroxylase 
HIF-PHI 
hypoxia-inducible factor prolyl hydroxylase inhibitor 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRQoL 
Health-Related Quality of Life 
hs-CRP 
high-sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IND 
investigational new drug 
INR 
international normalized ratio 

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Abbreviation 
Definition 
IRB 
Institutional Review Board 
IV 
intravenous 
IXRS 
interactive voice and web response system 
KDOQI 
Kidney Disease Outcomes Quality Initiative 
LDL 
low-density lipoprotein 
LLN 
lower limit of normal 
LFT 
liver function test 
LOCF 
last observation carried forward 
MAA 
Marketing Authorization Application 
MACE 
major adverse cardiac event 
MAP 
mean arterial pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
myocardial infarction 
MI ANCOVA 
Multiple imputation Analysis of ANCOVA model 
MMRM 
Mixed Model Repeated Measures 
N 
sample size 
n 
subsample size 
NDD-CKD 
nondialysis-dependent chronic kidney disease 
PD 
peritoneal dialysis 
PE 
physical examination 
PEY 
patient-exposure-year 
PK 
pharmacokinetics 
PPS 
Per Protocol Set 
QW 
once weekly 
RBC 
red blood cell 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
sBP 
systolic blood pressure 
SF-36 
The 36-Item Short Form Health Survey 
SmPC 
Summary of Product Characteristics 
Tbili 
total bilirubin 

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Abbreviation 
Definition 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TIBC 
total iron binding capacity 
TIW 
three times weekly 
TSAT 
transferrin saturation 
ULN 
upper limit of normal 
USRDS 
United States Renal Data System 
VEGF 
vascular endothelial growth factor 
WBC 
white blood cell 

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PROTOCOL SYNOPSIS 
 
Study Title: 
A Phase 3, Multicenter, Randomized, Open-Label, Active-Controlled 
Study of the Efficacy and Safety of FG-4592 in the Treatment of 
Anemia in Incident-dialysis Patients 
Protocol Number: 
FGCL-4592-063 
Investigational 
Product: 
Roxadustat (FG-4592) 
Target Population: 
Incident dialysis patients with anemia due to end-stage renal disease 
(ESRD) 
IND Number: 
74,454 
Study Phase: 
Phase 3 
Study Centers 
Planned: 
Up to approximately 400 study centers worldwide 
Number of Subjects 
Planned: 
A total of up to approximately 1200 subjects are planned to be 
randomized in an open-label, 1:1 ratio to receive either of the following 
two treatments: 
• Roxadustat (up to approximately 600 subjects) 
• Epoetin alfa (active control, up to approximately 600 subjects) 
Primary Objectives: 
Evaluate the efficacy and safety of roxadustat in the treatment of 
anemia in incident-dialysis subjects compared with Active Control. 
Secondary Objectives: 
• Evaluate the utilization of intravenous (IV) iron with roxadustat 
compared with Active Control 
• Evaluate effect of roxadustat on serum lipid parameters compared 
with Active Control 
• Evaluate the effect of roxadustat on blood pressure (BP) compared 
with Active Control 
• Evaluate time to achieve a hemoglobin (Hb) response compared 
with Active Control 
Study Design: 
This is a Phase 3, multicenter, randomized, open-label, active- 
controlled study to evaluate the efficacy and safety of roxadustat in the 
treatment of anemia in incident-dialysis subjects. 
The study periods are as follows: 
• Screening Period: Up to 6 weeks 

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• Treatment Period: Treatment duration is variable for individual 
subjects.  In order to complete the Treatment Period simultaneously 
for all study subjects, the minimum treatment duration may be less 
than 52 weeks with a maximum treatment duration of up to 
approximately 3 years after the last subject is randomized. Subjects 
will be informed at least 4 weeks prior to their treatment period end. 
 
 
• Post-Treatment Follow-Up Period: 4 weeks 
A total of up to approximately 1200 subjects will be randomized to 
receive either roxadustat or Active Control (epoetin alfa) in a 1:1 ratio 
(Appendix 1). 
Randomization is stratified by geographical region, screening Hb 
values, and cardiovascular/cerebrovascular/thromboembolic medical 
history. 
Scheduled Visits During Treatment 
During the Treatment Period, subjects will attend weekly study visits 
from Weeks 0 to 4, followed by every other week study visits starting 
Week 6 until Week 24. Starting with Week 28, subjects will attend 
study visits every 4 weeks until the end of the Treatment Period. 
After the Treatment Period, subjects will proceed to the 4-week Post- 
Treatment Follow-up Period. 
Starting Dose of Study Drug 
Roxadustat Arm 
For subjects receiving roxadustat, the initial dose (per dose amount) is 
based on a tiered, weight-based dosing scheme (Table S1). Roxadustat 
will be dosed orally three times weekly (TIW) throughout the 
Treatment Period, except if a subject requires < 20 mg TIW (ie, < 60 
mg per week) to maintain an Hb levels in the Maintenance Phase, the 
dosing frequency should be reduced in a step-wise fashion eg, TIW to 
BIW, BIW to QW, QW to Q-2 Week etc.. 
 
Epoetin Alfa Arm 
• Subjects on hemodialysis (HD) receiving epoetin alfa will 
initiate IV epoetin alfa treatment according to the epoetin alfa 
US Package Insert (USPI) or Summary of Product 
Characteristics (SmPC). 
• For subjects on home-hemodialysis (HHD) or peritoneal 
dialysis (PD), epoetin alfa will be administered according to the 
epoetin USPI or SmPC, or local standard-of-care. 

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Table S1. Initial Study Drug Dosing 
 
Study Drug 
(Dose 
Frequency) 
Low Wt 
(≤ 70 kg) 
High Wt 
(> 70 to160 kg) 
Roxadustat 
(TIW) 
70 mg 
100 mg 
Epoetin 
alfa HD 
(TIW) 
IV dosing according to epoetin alfa USPI or SmPC 
Epoetin 
alfa 
PD/HHD 
Epoetin alfa should be administered according to the USPI or SmPC 
or local standard of care. 
Abbreviations: 
HD = hemodialysis; HHD= home-hemodialysis; IV = intravenous;  
PD = peritoneal dialysis; SmPC = summary of product characteristics; 
TIW = three times a week; USPI = United States Package Insert; 
wt = weight. 
Note: Weight in HD subjects = subject’s dry weight. 
Dose Adjustments for Roxadustat 
Dose adjustments will occur in two separate dosing phases: the 
Correction Phase and the Maintenance Phase. Each of these phases will 
follow unique dose adjustment rules according to Appendix 2. All 
subjects in the roxadustat arm will be dosed orally TIW during the 
Treatment Period. The maximum roxadustat dose is 3.0 mg/kg per dose 
or 400 mg, whichever is lower. 
All dose adjustments as well as assessments of excessive hematopoiesis 
are based on Hb values using a point-of-care device such as HemoCue® 
or CritLine®. In the event that the central lab Hb value of the site visit is 
significantly different and the dose adjustment decision based on the 
HemoCue® or CritLine® value is being reconsidered, the Medical 
Monitor should be contacted, if possible. 
The determination of Hb response and transition from the Correction to 
the Maintenance Phase of the study is based on the central laboratory 
Hb value. 
Correction Phase of Dosing for Roxadustat 
The aim of the Correction Phase is to increase Hb levels from baseline 
to the target Hb level by using the dose adjustment algorithm in 
Appendix 2. This phase is variable in length for each subject. 
Dose adjustment reviews will occur on Week 4, and at intervals of 
every 4 weeks thereafter (Weeks 8, 12, 16, etc.) except in the event of 
excessive hematopoiesis, in which case doses may be adjusted at any 
time. In such cases, dose adjustment reviews are resumed at 4-week 

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intervals. For example, if the subject’s Hb increases >2.0 g/dL from 
Week 1 to Week 3, the subject’s dose is reduced by one dose step at 
Week 3. The next dose adjustment review should occur 4 weeks later at 
Week 7 and at 4-week intervals thereafter. 
If the dose adjustment interval falls on a non-study visit week (starting 
Week 4), the dose adjustment review should be performed at the next 
scheduled clinic visit, if a dose adjustment was not required at the 
previous visit. For example, if a subject’s visit is scheduled for Weeks 6 
and 8, and the dose adjustment would occur at Week 7, then the dose 
adjustment should be evaluated at the Week 8 visit. 
.M aintenance Phase of Dosing for Roxadustat 
The aim of the Maintenance Phase is to maintain Hb levels after the 
initial correction by using the dose adjustment algorithm in Appendix 2. 
Dosing and Dose Adjustment for Active Control Arm (Epoetin alfa) 
Subjects on epoetin alfa should maintain their Hb levels within the 
target range accepted by their health authorities, specifically: 
• Hb 10 to 11 g/dL in the United States 
• Hb 10 to 12 g/dL in countries outside the United States 
Subjects receiving HD on epoetin alfa will be dosed IV TIW, with 
starting doses and dose adjustment rules according to the epoetin alfa 
USPI or SmPC. HD subjects requiring ultra-low dose of EPO (eg, 
≤1000 IU/per week), frequency of administration may be adjusted per 
local standard of care. 
Subjects receiving PD or HHD on epoetin alfa will be dosed according 
to the epoetin alfa USPI or SmPC, or local standard of care. 
For countries using prefilled syringes, the initial epoetin alfa dose and 
dose adjustments should be approximated to the closest calculated 
weekly dose. 
Excessive Hematopoiesis 
For subjects randomized to Roxadustat, the following scenarios are 
defined as “excessive hematopoiesis” ; 
• Hb increases by > 2.0 g/dL at any time within a 4 week period: 
reduce the dose by one dose step. 
• Hb reaches or exceeds 13 g/dL: hold dosing, check Hb weekly. 
Resume dosing when Hb < 12.0 g/dL (for US subjects central 
lab Hb value preferred), at a dose that is reduced by two dose 
steps. 
For subjects on prolonged dose-hold, with stable (not dropping) Hb, 
the Investigator may use discretion to schedule less frequent visits. 

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Anytime Hb is assessed via HemoCue®/CritLine®/local lab, a 
central lab Hb should be obtained as well. 
Supplemental Iron Use 
In a Phase 2 study of roxadustat, in which study subjects were 
randomized to either receive no iron, oral iron or IV iron, there was no 
significant difference in Hb levels in subjects receiving oral iron 
compared to subjects receiving IV iron. Therefore, based on the 
mechanism of action of roxadustat and the Phase 2 study results, in 
subjects randomized to roxadustat, oral iron may be sufficient for iron 
supplementation. 
In this study, oral iron should be allowed as first-line iron 
supplementation without restrictions, for both study arms. 
In addition to the scheduled assessments (Appendix 3), iron indices 
may be assessed at any time (via central lab) to evaluate iron storage 
status of the subjects, if considered necessary by the Investigator. 
a) Oral Iron Supplementation 
All subjects should be encouraged to take oral iron as the 
preferred first-line iron supplementation during the Treatment 
Period, except subjects not tolerating oral iron. The dose and 
frequency are at the discretion of the Investigator. Oral iron 
supplementation should be started before the subject becomes 
iron depleted. 
b) Intravenous Iron Supplementation 
Intravenous iron supplementation is permitted if in the opinion 
of the Investigator the subject’s Hb has not responded 
adequately, and the subject is considered iron-deficient. 
 
 
Treatment with study medication will continue during IV iron 
administration. Discontinuation of IV iron is recommended 
once the subject is no longer deemed iron deficient (eg, ferritin 
≥ 100 ng/ml [≥ 220 pmol/L], TSAT ≥ 20%) and has evidence of 
a hematopoietic response. 
Rescue Therapy Guidelines 
Rescue therapy guidelines are provided to standardize the use of rescue 
therapy. 
 
Red Blood Cell Transfusion 
Red blood cell (RBC) transfusion should be considered if rapid 
correction of anemia is required to stabilize the subject’s condition (eg, 
acute hemorrhage) and the Investigator is of the opinion that the blood 
transfusion is a medical necessity. Study drug treatment may continue 

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during RBC transfusion administration. 
Erythropoiesis Stimulating Agents (Roxadustat Arm only) 
The use of erythropoiesis-stimulating agents (ESAs) is not permitted 
during the Treatment Period, except if all of the following criteria are 
met: 
• A subject’s Hb level has not responded adequately despite two 
or more consecutive roxadustat dose increases or the roxadustat 
dose has reached the maximum dose limit 
• Other causes for lack of response or declining Hb, such as iron 
deficiency, bleeding, acute inflammatory conditions, have been 
ruled out 
• Reducing risk of alloimmunization in transplant eligible patients 
is a goal. 
Roxadustat and ESA may not be co-administered. Treatment with an 
approved ESA may be initiated ≥ 3 days after the last roxadustat dose. 
If the situation permits, the Investigator should inform the Medical 
Monitor prior to initiation of ESA therapy. 
Subjects may receive one course of ESA rescue during the Treatment 
Period. Erythropoiesis-stimulating agent rescue should stop after 4 
weeks or once Hb exceeds 9 g/dL, whichever occurs first. If a subject 
requires more than 4 weeks of ESA rescue therapy due to inadequate 
Hb response, the Medical Monitor should be contacted. 
Treatment with roxadustat may resume after the following intervals: 
• Two days after stopping epoetin alfa 
• One week after stopping darbepoetin alfa 
• Two weeks after stopping methoxy polyethylene glycol-epoetin 
beta (Mircera®) 
If more than one course of ESA rescue is required during the Treatment 
Period, the subject must be discontinued permanently from the study, 
and is considered a Treatment Failure. 
Inadvertent ESA administration including ESA administered by 
hospital staff in Roxadustat subjects should not be counted as rescue 
unless, above criteria are met; these ssubjects may be allowed to 
continue on study, if considered safe by the Investigator and Medical 
Monitor. 
Therapeutic Phlebotomy 
If there are clinical concerns of excessive elevation of Hb levels, the 
Investigator may decide to perform a therapeutic phlebotomy in 
addition to a dose hold. This should be discussed with the Medical 

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Monitor and documented. 
Inclusion Criteria: 
1. Age ≥ 18 years. 
2. Subject has been informed of the investigational nature of this study 
and has given written informed consent in accordance with 
institutional, local, and national guidelines. 
3. Receiving HD or PD for end-stage renal disease (ESRD) for a 
minimum of 2 weeks and a maximum of 4 months, prior to 
randomization. 
4. Hemodialysis access consisting of an arteriovenous (AV) fistula, 
AV graft, or tunnelled (permanent) catheter; or PD catheter in use. 
5. Mean of the two most recent Hb values during the Screening 
Period, obtained at least 2 days apart, must be ≤ 10.0 g/dL, with a 
difference of ≤ 1.3 g/dL between the highest and the lowest values. 
The last Hb value must be drawn within 10 days prior to 
randomization. 
6. Ferritin ≥ 100 ng/mL (≥ 220 pmol/L); subjects with ferritin level < 
100 ng/mL (<220pmol/L) during screening qualify after receiving 
iron supplementation (per local standard of care), without the need 
to retest ferritin prior to randomization. 
7. Transferrin saturation ≥ 20%; subjects with TSAT level < 20% 
during screening qualify after receiving iron supplementation (per 
local standard of care), without the need to retest TSAT prior to 
randomization. 
8. Serum folate level, performed within 8 weeks prior to 
randomization ≥ lower limit of normal (LLN); subjects with serum 
folate level < LLN during screening qualify after receiving folate 
supplement (per local standard of care), without the need to retest 
folate prior to randomization. 
9.   Serum vitamin B12 level, performed within 8 weeks prior to 
randomization ≥ LLN; subjects with vitamin B12 level < LLN 
during screening qualify after receiving Vitamin B12 supplement 
(per local standard of care), without the need to retest Vitamin B12 
prior to randomization. 
10. Alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) ≤ 3 x upper limit of normal (ULN), and total bilirubin (Tbili) 
≤ 1.5 x ULN. 
11. Body weight up to 160 kg (HD subjects: dry weight). 

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Exclusion Criteria: 
1.  Total duration of prior effective ESA use must be ≤3 weeks within 
the preceding 12 weeks at the time informed consent is obtained. 
Specific dosing guidance, depending on the type of ESAs, 
injected IV or SC within 12 weeks prior to start of screening are 
as follows: 
Short-acting ESAs (EPO-alfa or equivalents) 
• 
IV: Up to 9 doses; last EPO dose must be ≥2 days prior to start 
of screening 
• 
SC:  Up to 3 doses; last EPO dose must be ≥1 week (7 days) 
prior to start of screening 
Darbepoetin 
• 
IV:  Up to 3 doses; last darbepoetin dose must be ≥1 week 
(7 days) prior to start of screening 
• 
SC:  Up to 2 doses; last darbepoetin dose must be ≥2 weeks 
(14 days) prior to start of screening 
Continuous erythropoietin receptor activator (CERA) 
• 
IV or SC:  Up to 2 doses; last CERA dose must be ≥2 weeks (14 
days) prior to start of screening 
2. Intravenous iron: there is no restriction regarding IV iron use during 
screening, provided it is administered in accordance with local 
standard of care.. 
3. Red blood cell transfusion within 4 weeks prior to randomization. 
4. Active, clinically significant infection that could be manifested by 
white blood cell (WBC) count > ULN, and/or fever, in conjunction 
with clinical signs or symptoms of infection at the time of 
randomization. 
5. History of chronic liver disease (eg, chronic infectious hepatitis, 
chronic auto-immune liver disease, cirrhosis, or fibrosis of the 
liver). 
6. New York Heart Association Class III or IV congestive heart failure 
at screening. 
7. Myocardial infarction (MI), acute coronary syndrome, stroke, 
seizure, or a thromboembolic event within a major vessel 
(excluding vascular dialysis access) (eg, deep vein thrombosis 
[DVT] or pulmonary embolism) within 12 weeks prior to 
randomization. 
8. Uncontrolled hypertension, in the opinion of the Investigator, (eg, 
that requires change in anti-hypertensive medication) within 2 
weeks prior to randomization. 

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9. Renal imaging performed within 12 weeks prior to randomization 
indicative of a diagnosis or suspicion (eg, complex kidney cyst of 
Bosniak Category 2 or higher) of renal cell carcinoma. 
10. History of malignancy, except for the following: cancers 
determined to be cured or in remission for ≥ 5 years, curatively 
resected basal cell or squamous cell skin cancers, cervical cancer in 
situ, or resected colonic polyps. 
11. Positive for any of the following: human immunodeficiency virus 
(HIV); hepatitis B surface antigen (HBsAg); or anti-hepatitis C 
virus antibody (anti-HCV Ab). 
12. Chronic inflammatory disease that could impact erythropoiesis 
(eg, systemic lupus erythematosus, rheumatoid arthritis, celiac 
disease) even if it is currently in remission. 
13. Known, untreated proliferative diabetic retinopathy, diabetic 
macular edema, macular degeneration, or retinal vein occlusion 
(subjects who are already blind for the above reasons qualify to 
participate). 
14. Known history of myelodysplastic syndrome or multiple myeloma. 
15. 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). 
16. Known hemosiderosis, hemochromatosis, coagulation disorder, or a 
hypercoagulable condition. 
17. Organ transplant: subjects with any of the following. 
a) Experienced  rejection of a transplanted organ within 6 
months of transplantation 
b) Currently on high doses of immunosuppressive therapy (per 
discretion of the investigator) 
c) Scheduled for organ transplantation. Note: being on the 
waiting list for kidney transplant is not exclusionary 
18. Anticipated elective surgery, except for vascular access surgery or 
dialysis catheter placement, that is expected to lead to significant 
blood loss, or anticipated elective coronary revascularization. 
19. Active or chronic gastrointestinal bleeding. 
20. Any prior treatment with roxadustat or a hypoxia-inducible factor 
prolyl hydroxylase inhibitor (HIF-PHI). 
21. Use of iron-chelating agents within 4 weeks prior to randomization. 
22. Known hypersensitivity reaction to any ESA. 
23. Use of an investigational drug or treatment, participation in an 

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investigational study, or presence of an expected carryover effect of 
an investigational treatment, within 4 weeks prior to randomization. 
24. Anticipated use of dapsone or androgens at any dose amount or 
chronic use of acetaminophen or paracetamol > 2.0 g/day during the 
study. 
25. History of alcohol or drug abuse within 6 months prior to 
randomization. 
26. Females of childbearing potential, unless using contraception as 
detailed in the protocol; male subjects with sexual partners of 
childbearing potential who are not on birth control unless the male 
subject agrees to use contraception. 
27. Pregnant or breastfeeding females. 
28. Any medical condition, that in the opinion of the Investigator, may 
pose a safety risk to a subject in this study, may confound efficacy 
or safety assessment, or may interfere with study participation. 
Subjects who fail to meet the above eligibility criteria should not be 
randomized or receive study medication. If Day 1 lab values (collected 
prior to administration of study medication) are found to be of 
significant safety risk, in the opinion of the Investigator or Medical 
Monitor, the subject may be discontinued from the study. 
Study Procedures: 
See Schedule of Study Assessments (Appendix 3) 
Roxadustat 
Formulation, Dose, 
and Mode of 
Administration: 
Roxadustat tablets are available in 20, 50, and 100 mg doses for oral 
administration. All tablets must be administered whole. 
Initial Doses 
Subjects will receive tiered, weight-based initial doses (Table S1) 
Dosing Frequency 
Subjects will be dosed TIW throughout the Treatment Period. Dosing 
frequency may be reduced if a subject requires < 60 mg/week to 
maintain Hb levels in the Maintenance Phase. 
Dose Adjustment Rules 
Refer to Section 3.5.3, and Appendix 2. 
Reference Therapy: 
Active Control:  Epoetin alfa for injection 
Hemodialysis subjects: Initial dose and dose adjustments rules 
according to the epoetin alfa USPI or SmPC. For countries using 
prefilled syringes, the initial epoetin alfa dose and dose adjustments 
should be approximated to the closest calculated total weekly dose. 
Peritoneal Dialysis and HHD subjects: Epoetin alfa should be 
administered according to the epoetin alfa USPI or SmPC, or local 

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standard of care. For countries using prefilled syringes, the initial 
epoetin alfa dose and dose adjustments should be approximated to the 
closest calculated total weekly dose. 
Efficacy Endpoints 
and Assessments: 
In the endpoint definitions below, rescue therapy for roxadustat-treated 
subjects is defined as either ESA rescue or RBC transfusion; rescue 
therapy for epoetin alfa-treated subjects is defined as RBC transfusion. 
All endpoints using Hb are based on central lab. 
Primary: 
• US (FDA) submission: Mean Hb change from baseline (using 
central laboratory values) to the average level during the 
Evaluation Period, defined as Week 28 until Week 52. This 
analysis will be based on the intent-to-treat (ITT) population. 
Hemoglobin values under the influence of rescue therapy will 
not be censored for the primary analysis. 
• Ex-US submission: The proportion of subjects who achieve a 
Hb response at two consecutive visits during the first 24 weeks 
of treatment, without rescue therapy within 6 weeks prior to the 
Hb response in the Per Protocol Set (PPS). 
A Hb response is defined, using central laboratory values, as: 
o 
Hb ≥ 11.0 g/dL and a Hb increase from baseline by 
≥ 1.0 g/dL in subjects whose baseline Hb > 8.0 g/dL, or 
o Increase in Hb ≥ 2.0 g/dL in subjects whose baseline Hb 
≤ 8.0 g/dL 
Secondary: 
• US (FDA) submission: The proportion of subjects who achieve 
a Hb response at two consecutive visits during the first 24 
weeks of treatment, without rescue therapy within 6 weeks prior 
to the Hb response. 
A Hb response is defined, using central laboratory values, as 
o Hb ≥ 11.0 g/dL and a Hb increase from baseline by 
≥ 1.0 g/dL in subjects whose baseline Hb > 8.0 g/dL, or 
o Increase in Hb ≥ 2.0 g/dL in subjects whose baseline Hb 
≤ 8.0 g/dL 
• Ex-US submission: Mean Hb change from baseline to the 
average level during the Evaluation Period, defined as Week 28 
until Week 36. This analysis will be based on the PPS 
population. 
US and ex-US: 

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• Average monthly IV iron use per subject during the Treatment 
Period 
• Mean change in low-density lipoprotein (LDL) cholesterol 
averaged over Weeks 12 to 24 
• Blood pressure effects: 
o Proportion of subjects with exacerbation of 
hypertension, meeting at least one of the following 
criteria: 
- Increase in blood pressure:  An increase from 
baseline in systolic blood pressure (sBP) of ≥ 20 
mm Hg and sBP > 170 mmHg, or an increase 
from baseline in dBP of ≥ 15 mm Hg and 
diastolic blood pressure (dBP) > 100 mmHg. 
Increases from baseline in BP must be confirmed 
by repeat measurement 
- Time to an increase in BP as defined above 
- Mean change in mean arterial pressure (MAP) 
averaged over Weeks 8 to 12 
• Time to achieve first Hb response as defined by the primary 
endpoint, (ex-US) (which is the secondary endpoint for the US 
[FDA] submission). 
Safety Assessments 
and Endpoints: 
Study-specific safety will be assessed by evaluating the following: 
• Treatment-emergent adverse events (TEAEs) and 
treatment-emergent serious adverse events (TESAEs), and clinically 
significant laboratory values from baseline 
• Vital signs, electrocardiogram (ECG) findings and clinical 
laboratory values 
Safety interpretation will also be made based on analyses of composite 
endpoints derived from adjudicated events pooled across multiple 
studies in the roxadustat Phase 3 program. The members of an 
independent adjudication committee blinded to treatment assignment 
will adjudicate the following events in multiple Phase 3 studies: 
• Death from any cause, MI, stroke, congestive heart failure requiring 
hospitalization, unstable angina requiring hospitalization, 
hypertensive emergency, deep venous thrombosis, pulmonary 
embolism, and vascular access thrombosis. 
• Various region-specific pooled analyses of composites of these 
adjudicated events, pooled across multiple studies will be 
conducted. The analyses of the adjudicated events will be detailed 

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in the region-specific pooled Statistical Analysis Plan (SAP). 
For US (FDA) Only: The primary safety endpoint in this study is the 
Major Adverse Cardiac Event (MACE) composite endpoint, defined as 
time to first occurrence of death from all causes, MI, or stroke, for the 
purpose of being pooled across multiple similar studies in the Phase 3 
program. None of the individual studies are powered to meet the 
MACE primary safety endpoint individually. The pooled MACE 
analysis is only for purposes of supporting a US FDA regulatory filing 
of roxadustat. 
• The above adjudicated safety events may also be used to support the 
pooled analyses of additional composite safety endpoints across 
multiple studies in the Phase 3 program, such as MACE+ (death, 
MI, stroke, congestive heart failure requiring hospitalization, and 
unstable angina requiring hospitalization), or a composite which 
consists of all of the adjudicated events. 
Statistical Methods: 
Sample Size Estimation 
The sample size calculation is based on the primary endpoint for both 
the United States and Ex-US. 
At least 600 subjects will be enrolled in this study. During the course of 
this study, which is being conducted in parallel with other Phase 3 
studies, up to 1200 subjects may be enrolled for safety evaluation of 
roxadustat in comparison to epoetin alfa including adjudicated and pre- 
specified safety events of interest (ie, all-cause death, MI, stroke, 
congestive heart failure requiring hospitalization, unstable angina 
requiring hospitalization, DVT, pulmonary embolism, vascular access 
thrombosis, and hypertensive emergency). The final number of patients 
to be enrolled will be based on the enrollment rate of other studies 
within the same indication, in order to optimize stopping these studies 
at a comparable time frame. 
With at least 600 subjects, the study will provide at least 99% power to 
demonstrate statistical non-inferiority of roxadustat versus ESA in the 
primary endpoint for US (FDA) submission (ie, specifically, Hb change 
from baseline to the average level during the evaluation period defined 
as Week 28 until Week 52). This assumes a difference (roxadustat 
minus ESA) of 0.30 g/dL, a non-inferiority margin for this difference of 
0.75 g/dL and a standard deviation of 1.25 g/dL. This endpoint will be 
analyzed using the ITT population for the US FDA submission. 
The study will provide at least 99% power to demonstrate statistical 
non-inferiority of roxadustat versus ESA in the primary endpoint 
outside of the United States (ie, the proportion of subjects who achieve 
a Hb response at two consecutive visits during the first 24 weeks of 
treatment ). This assumes an 80% responder rate for both roxadustat 
and epoetin alfa, in order to support the primary efficacy analysis (ie, a 

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non-inferiority comparison in responder rate between roxadustat and 
epoetin alfa) and assuming a non-inferiority margin of -15% for this 
difference (roxadustat minus epoetin alfa). This endpoint will be 
analyzed using the PPS population for the European Medicines Agency 
(EMA) submission. 
Statistical Analysis 
1. Efficacy analysis for superiority will be conducted on the ITT 
population for US (FDA) submission and on the full analysis set 
(FAS) population, for Ex-US submission. 
2. Efficacy analysis for non-inferiority will be conducted on the 
ITT population for US (FDA) submission and on the PPS 
population, for Ex-US submission. 
3. Hemoglobin results obtained from the central laboratory will be 
used for all efficacy analyses. Baseline Hb is defined as the 
mean of at least three central laboratory Hb values:  at least the 
last two screening Hb values prior to randomization plus the one 
predose Hb value on Day 1 of the Treatment Period. 
Primary Efficacy Analysis 
US (FDA) submission: The primary efficacy endpoint for submission 
in the United States is defined as the mean Hb change from baseline to 
the average level during the Evaluation Period, defined as Week 28 
until Week 52. The analysis will be based on the ITT population. 
Hb values under the influence of rescue therapy will not be censored for 
the primary efficacy analysis. 
The primary hypothesis to be tested for the primary efficacy analysis is: 
H0: Hb mean change from baseline to the average level from 
Week 28 to Week 52 in the roxadustat arm ≤ Hb mean change 
from baseline in the epoetin alfa arm minus 0.75 g/dL 
Versus: 
H1: Hb change from baseline to the average level of Week 28 to 
Week 52 in the roxadustat arm > Hb mean change from 
baseline in the epoetin alfa arm minus 0.75 g/dL 
A multiple imputation Analysis of Ancova Model (MI ANCOVA) will 
be used for the primary endpoint. 
The model will contain terms for treatment arm, baseline measurement, 
and randomization stratification factors (except screening Hb values (≤ 
8g/dL vs. >8g/dL). The primary efficacy analysis will be based on the 
estimated difference between the two treatments overall mean effects 
throughout the study based on the MI ANCOVA model. 
In addition, as a sensitivity analysis, the primary efficacy endpoint will 
be analyzed using the analysis of the mixed model for repeat measures 

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(MMRM). The MMRM model will contain terms for baseline Hb 
measurement as covariate, treatment arm, visit, visit by treatment arm, 
and randomization stratification factors (except screening Hb values (≤ 
8g/dL vs. >8g/dL) as fixed effects. 
Due to the large amount of visits included in the model, the 
unstructured covariance pattern model will be tested against the less 
parameterized heterogeneous Toeplitz structure using the likelihood 
ratio test for nested models. If the algorithm for unstructured covariance 
pattern does not converge or the likelihood ratio test is not statistically 
significant then heterogeneous Toeplitz structure will be used. If this 
second model does not converge either, then the (homogeneous) 
Toeplitz structure will be tried and finally compound symmetry as a 
covariance structure to achieve convergence. 
This null hypothesis will be rejected if the two-sided 95% confidence 
interval (CI) for the difference of least square means from the mixed 
model lies entirely above –0.75 g/dL. 
Ex-US Submission: The primary efficacy endpoint for Ex-US 
submission is defined as the proportion of subjects who achieve a Hb 
response at two consecutive visits during the first 24 weeks of 
treatment, without rescue therapy within 6 weeks prior to the Hb 
response. 
• A Hb response is defined, using central laboratory values, as: 
Hb ≥ 11.0 g/dL and a Hb increase from baseline by ≥ 1.0 g/dL 
in subjects whose baseline Hb > 8.0 g/dL, or 
• Increase in Hb ≥ 2.0 g/dL in subjects whose baseline Hb 
≤ 8.0 g/dL. 
Rescue therapy for roxadustat treated subjects is defined as ESA rescue 
or RBC transfusion, and rescue therapy for epoetin alfa treated subjects 
is defined as RBC transfusion. 
The hypothesis to be tested for the primary efficacy analysis is: 
H0: Hb response rate for subjects in the roxadustat arm - Hb 
response rate for subjects in the epoetin alfa arm ≤ -15%. 
Versus 
H1: Hb response rate for subjects in the roxadustat arm - Hb 
response rate for subjects in the epoetin alfa arm > -15%. 
A two-sided 95% CI for the difference of 2 responder rates (roxadustat 
minus epoetin alfa) based on the Miettinen and Nurminen approach 
adjusting for treatment and other stratification factors will be calculated 
and the null hypothesis will be rejected if the lower bound of the 95% 
CI is greater than -15%. 
Safety: 

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This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
and the applicable regulatory requirement(s), including the archiving of essential documents. 
All subjects who have received any dose of study treatment will be 
included in the safety analyses. All safety data will be tabulated using 
descriptive statistics. 
Safety parameters include adverse events (AEs), serious adverse events 
(SAEs), laboratory parameters, vital signs, ECG parameters, and 
physical examinations (PE’s). 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 of that safety parameter. 
The analytical methods for the MACE endpoint, as well as other 
composite safety endpoints of interest, will be described in a region- 
specific pooled statistical analysis plan (PSAP) to reflect the nature of 
the pooling of these endpoints across comparable studies in the Phase 3 
program and the region-specific safety endpoints. 
Safety data and dosing decisions will be monitored on an ongoing basis. 
Ongoing review of safety data will be conducted by an independent 
Data Safety Monitoring Board (DSMB). 

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1 INTRODUCTION 
Roxadustat (FG-4592) is an investigational novel small molecule drug for oral administration 
that has not been marketed in any country. The drug is in global Phase 3 clinical development. It 
is being developed for the treatment of anemia associated with chronic kidney disease (CKD), 
including end-stage renal disease (ESRD). 
1.1 Background Information 
1.1.1 Epidemiology of CKD and ESRD 
CKD is a growing worldwide public health challenge associated with significant morbidity and 
mortality, yet it is under-diagnosed and under-treated. It is characterized by progressive loss of 
kidney function, ultimately resulting in premature death or renal replacement therapy (kidney 
transplant or dialysis). In 2007, CKD affected 13% of the US adult population (approximately 29 
million US adults) and its prevalence is growing rapidly (Coresh, 2007). All-cause mortality risk 
increases exponentially as CKD stages advance (Tonelli, 2006). 
The number of patients suffering from ESRD also continues to increase worldwide. The US has 
one of the highest prevalence rates of ESRD in the world: in 2010, the US had over 1700 ESRD 
patients per million population, a 23% increase compared with 10 years prior (United States 
Renal Data System (USRDS, 2011) Vol 2, Ch 1, p188). In 2009 (point prevalence Dec 31), there 
were approximately 570,000 ESRD patients in the US, of whom 370,000 were receiving 
hemodialysis (HD), 27,000 were receiving peritoneal dialysis (PD), and 173,000 had a 
functioning kidney transplant (USRDS, 2011) [Vol 2, Ch 1, p184]. The average expected life 
expectancy of a dialysis patient is 5.9 years, compared with 16.4 years for a transplant patient, 
and 25.2 years for someone of comparable age in the general population (USRDS, 2011) [Vol 2, 
Ch 2, p 181]. The prevalence of ESRD is projected to grow to 774,000 by the year 2020 
(USRDS, 2009) [Vol 2, Ch 2]. 
1.1.2 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 erythropoietin (EPO), a hormone produced primarily 
in the kidneys, is considered an important etiologic factor. The impaired ability of the body to 
absorb and utilize iron is likely a second important etiologic factor. 
Anemia may present in early stages of CKD and its prevalence increases as CKD progresses. 
Anemia is present in 17% of patients with late Stage 3 disease; this increases to 25% in patients 
with Stage 4 disease, and to 49% in patients with Stage 5 CKD who have not yet progressed to 
dialysis (Coresh, 2007; Go, 2004). Over 90 % of patients undergoing dialysis are anemic. Half of 
new dialysis patients (50.1%) have hemoglobin (Hb) levels below 10 g/dL and approximately 
28% have Hb levels below 9 g/dL (USRDS, 2003) [Ch 3, Figure 3.11]. 
The clinical consequences of anemia in patients with CKD have been studied extensively. 
Because the main impact of anemia on organ function is reduced oxygen delivery to tissues, it 
affects almost every organ system. 
Anemia contributes to the excess morbidity and mortality in CKD and ESRD. In patients with 
CKD, the severity of anemia correlates directly with the risk of hospitalization, cardiovascular 

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disease, and death (Collins, 1998). Patients with the lowest Hb have worse outcomes, as was 
discussed in the post hoc analysis of mortality by Hb quintiles for the Normal Hematocrit and 
Correction of Hb and Outcomes in Renal Insufficiency (CHOIR) studies in the FDA briefing 
document for the October 2007 Cardiovascular and Renal Advisory Committee (Unger, 2007). 
Similar observations are found in USRDS mortality data stratified by Hb. All-cause mortality 
stratified by Hb (1993–1996) showed significantly higher first-year death rates in patients with 
Hb levels < 9, compared with 11 to 12 g/dL. This trend continued to worsen, as reflected in 
1998–1999 data, where the death rate rose by ∼75% compared with the 1993–1996 period 
(USRDS, 2000) Ch 8, Fig 8.16; (USRDS, 2001) [Ch 9, Fig 9.14]. This increase coincides with 
the introduction of the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines in 1997. 
The relative risk of all-cause mortality for patients with Hb < 9 g/dL is twice that of patients with 
Hb > 12 g/dL (USRDS, 2002) [Ch 9, Table 9b]. The relative risk of cardiovascular 
hospitalization increases significantly to 1.26 in patients with Hb levels < 9 g/dL compared with 
those with Hb at 11 to 12 g/dL (USRDS, 2001) [Ch 5, Fig 5.27]. 
Multiple studies have shown that treatment of anemia reduces the need for blood transfusions 
and improves health-related quality of life (HRQoL) (NKF K/DOQI, 2007)). 
1.2 Treatment of Anemia 
Today, therapy with erythropoiesis-stimulating agents (ESAs) is a major alternative to 
transfusion in managing anemia associated with CKD. For those not resistant to ESAs, parenteral 
administration of exogenous recombinant human EPO (epoetin alfa or beta) or pegylated 
analogues has been a widely accepted approach for treatment of anemia in patients with CKD 
(Winearls, 1986; Eschbach, 1989; Eschbach, 1987), despite the documented safety risks. These 
safety risks include hypertension, thrombosis and cerebrovascular events and may be associated 
with the supraphysiologic plasma EPO levels frequently observed with ESA therapy. Anemic 
patients with CKD or ESRD will require life-long treatment with these agents. 
Although the treatment of anemia in CKD and ESRD is thought to contribute positively to a 
patient’s quality of life, several studies in ESRD and CKD nondialysis patients have shown 
higher mortality or trends in that direction in the higher-dosed ESA-treated cohorts when the 
protocol objective was to treat to high target Hb levels (Besarab, 1998, Drueke, 2006; 
Singh, 2006). An ESA dose relationship to mortality has been reported in a review of the 
USRDS database (Zhang, 2004) of ESRD patients who received higher ESA doses. Additionally, 
ESA therapy for anemia in ESRD patients on HD usually requires concomitant intravenous (IV) 
iron supplementation. IV iron is associated with its own set of risks, including anaphylaxis. 
There is currently an unmet medical need for an oral treatment that can correct anemia in CKD 
nondialysis and dialysis patients while avoiding supraphysiologic levels of circulating plasma 
EPO levels, and also minimizes the use of IV iron. 
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. 
1.3 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 (HIF) is a transcription factor that is believed to 

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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, 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, 2005; Hu, 2003). For 
example, HIF-1α has been shown to regulate vascular endothelial growth factor (VEGF) 
expression (Gray, 2005; Buchler, 2003), while HIF-2α is critical for the induction of the EPO 
gene and erythropoiesis (Wamecke, 2004). 
 
Figure 1 
HIF-PHI Mechanism of Action 
 
 
Abbreviations: 
DcytB = Duodenal cytochrome B; DMT1 = divalent metal transporter one; EPO = erythropoietin; 
HIF = hypoxia-inducible factor; HIF-PH = hypoxia-inducible factor prolyl hydroxylase; HIF PHI = hypoxia- 
inducible factor prolyl hydroxylase inhibitor; mRNA = messenger ribonucleic acid; Tf-R = Transferrin 
receptor; Ub = ubiquitin; VHL = Von Hippel–Lindau protein. 
Source: Epstein, et al. Cell, 2001 Oct 5; 107(1) 
 
Hypoxia-inducible factor target genes are expressed when the active heterodimer binds to a 
conserved deoxyribonucleic acid (DNA) motif found within all HIF target genes, termed the 
hypoxia response element, and in cooperation with other 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 hypoxia-inducible prolyl hydroxylases 

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(HIF-PH) that utilize molecular oxygen as the substrate for hydroxylation. Thus, HIF-PH 
constitutes the body’s main oxygen sensor by regulating the prevalence and activity of nuclear 
HIF protein. Under hypoxic conditions, HIF-PHs are inactive and lead to initiation of the HIF- 
responsive transcriptional cascade (Wang, 1995; Semenza, 1998). 
Roxadustat is a potent and reversible hypoxia inducible 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. Hypoxia inducible prolyl factor induces expression of not only EPO, but also the EPO 
receptor and proteins that promote iron absorption and recycling (Peyssonnaux, 2008). Thus, 
roxadustat pharmacologically stimulates erythropoiesis via the HIF pathway and in a manner 
consistent with the body’s normal homeostatic response to anemia, but under normoxic 
conditions. In contrast to the classical paradigm, suggesting that anemia in CKD patients is 
caused by the inability of these patients to produce EPO, results of a study of roxadustat 
treatment of CKD subjects not requiring dialysis (Study No. FGCL-SM4592-017) suggest that 
the kidneys and other sites of EPO production in this patient population retain the ability to 
produce sufficient EPO for robust erythropoiesis. 
Roxadustat also has the potential to effectively treat anemias caused by inflammation-induced 
functional iron deficiency, which are typically hyporesponsive to ESAs. In these conditions, iron 
availability for erythropoiesis is reduced due to a number of inflammatory mediators, all of 
which increase Hepcidin levels, impairing iron transport to the bone marrow. 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, 2005). 
Chronic hypoxia and intermittent hypoxia induce different sets of genes associated with HIF 
transcriptional activity, presumably because intermittent stimulation allows the restoration of 
HIF degradation, turnover, and inactivation. Transient activation of HIF thereby precludes 
sustained gene expression and the induction of genes that are expressed late after HIF activation, 
as well as expression of additional genes that are secondary to activation of HIF-dependent 
genes. Both nonclinical and clinical studies of roxadustat have successfully used the intermittent 
dosing paradigm to induce selective erythropoiesis and to optimize the Hb dose response. 
Furthermore, roxadustat was selected for development over other HIF-PH-inhibiting candidate 
molecules based on an optimal biodistribution profile that enhances its selective actions. The 
specific tissues where roxadustat enters the cytoplasm and triggers gene expression reside in the 
main target organs for erythropoiesis: the kidney (EPO production), the bone marrow (increase 
in EPO receptors), the duodenum (transepithelial iron transport), and the liver (EPO production 
and down-regulation of hepcidin production); roxadustat distributes preferentially to these 
organs. 
The physiologic mechanisms underlying the effects of roxadustat on erythropoiesis are distinct 
from that of ESAs, and these differences result in several potential advantages over ESAs 
beyond the convenience of oral therapy. These potential advantages include: 
• Increase in the number of EPO receptors in the bone marrow 
• Improved iron metabolism and bioavailability 

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• Effective erythropoiesis at nonsupraphysiologic plasma EPO levels (10- to 20-fold lower 
than with parenteral ESA therapy) 
• Absence of hypertensive effect 
• Effective erythropoiesis in the presence of inflammation 
• Mitigation of thromboembolic risk 
• Improvement in lipid profile 
1.4 Clinical Experience with Roxadustat 
Roxadustat is currently being studied in dialysis and nondialysis CKD subjects with anemia. 
Seventeen clinical studies with roxadustat have been completed. Information from these studies 
is provided below and in the current Investigator’s Brochure (IB). 
As of 7 September 2013, a total of 969 subjects have been exposed to roxadustat in the clinical 
development program, comprising 377 healthy subjects, 294 subjects with nondialysis-dependent 
chronic kidney disease (NDD-CKD), and 298 dialysis-dependent subjects with chronic kidney 
disease (DD-CKD). In completed Phase 1 studies, healthy volunteers received single doses of 
roxadustat up to 4.0 mg/kg and repeat doses up to 3.75 mg/kg three times weekly (TIW) for 
4 weeks. In a completed thorough QT study in healthy volunteers, single doses up to 5 mg/kg 
were administered, without evidence of QT prolongation. 
Of the 6 Phase 2 studies completed, 3 were in subjects with ESRD on dialysis treatment. 
Roxadustat treatment in subjects on dialysis ranging from 6 weeks to 19 weeks in the Phase 2 
studies was well tolerated. Roxadustat has been found to be effective in correcting anemia in 
subjects with incident HD and PD, as well as in maintaining Hb levels in subjects on HD whose 
Hb levels were maintained with epoetin alfa, and generally in the absence of IV iron 
supplementation. Oral iron supplementation was found as effective as IV iron when correcting 
anemia with roxadustat in subjects on incident-dialysis. 
The clinical data collected thus far suggest that roxadustat is generally safe and well tolerated in 
healthy adult subjects, and in dialysis and nondialysis CKD subjects with anemia who have been 
treated in the completed and ongoing studies. 
1.4.1 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 subjects on dialysis compared with healthy subjects. 
A relative bioavailability study was conducted in 24 healthy volunteers comparing capsule 
formulation, which was used in Phase 1 and Phase 2, with tablet formulation, which was 
developed for Phase 3. The study demonstrated bioequivalence to bridge the 2 formulation. With 
an intermittent dose regimen (once weekly [QW], twice weekly [BIW], or TIW), no or limited 
accumulation in mean AUC or 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 

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component. The inhibitory potential of roxadustat on cytochrome P450 (CYP) enzymes, based 
on in-vitro studies is limited, and the lowest Ki value was observed for CYP 2C8 (16 μM). In a 
clinical drug-drug interaction study with rosiglitazone, a probe drug for CYP 2C8, roxadustat did 
not show any inhibitory potential on CYP 2C8 in vivo. 
In healthy adult male volunteers (Study FGCL-SM4592-016), roxadustat administered orally as a 
single dose up to 4.0 mg/kg, and 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 
erythropoietin (eEPO) (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 to 
443 mIU/mL and 492 to 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 United States and in Japan 
(Study CL-1517-203) 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 PK profile. Also, comparable dose- 
dependent increases in EPO levels were observed with both predialysis and postdialysis dosing. 
These increases in eEPO were transient, peaked at around 10 hours postdose with eEPO levels 
returning to baseline 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 
> 10,000 mIU/mL (Besarab, 2009). In a clinical study with subjects on dialysis, the reported 
mean administered individual ESA dose was 8,000 IU, which would correspond to plasma EPO 
Cmax levels exceeding 3,000 mIU/mL(Fishbane, 2007). This is approximately 10-fold higher than 
the physiologic range. 
1.4.2 Efficacy 
As of 7 September 2013, 700 subjects with NDD-CKD and DD-CKD have participated in the 
Phase 2 clinical development program. This program includes 6 completed studies. Three of 
these studies have been in NDD-CKD subjects (2 US, 1 in China), and three have been in 
subjects with DD-CKD (1 US; 1 US, Asia, Russia; 1 China). For details about dialysis, please 
see the IB. 
1.4.2.1 Studies in Subjects with NDD-CKD 
Data from a 4-week dose ranging study in anemic CKD subjects not on dialysis (Study 
FGCL-SM4592-017) showed that roxadustat promotes erythropoiesis at lower doses in CKD 
subjects than in healthy volunteers. With roxadustat 0.7 mg/kg TIW dosing, mean Hb increased 
by 1.0 g/dL over a 6-week period in anemic CKD subjects who completed 4 weeks of dosing; 
more robust mean Hb increases of 2.0 to 2.3 g/dL occurred at roxadustat doses of 1.5 and 2.0 
mg/kg TIW, respectively. Hemoglobin responder (Hb increase of ≥ 1.0 g/dL) rates were 62%, 
60%, 91%, and 100% in the roxadustat 0.7, 1.0, 1.5, and 2.0 mg/kg TIW cohorts, respectively. 
The Hb responses were also robust at higher roxadustat doses (1.5 to 2.0 mg/kg) in the BIW 
dosing groups. With the additional criterion that Hb achieve a level of ≥11 g/dL as well as 

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increasing by ≥ 1.0 g/dL, the Hb responder rate with roxadustat 2.0 mg/kg was 89% and 91% in 
with BIW and TIW dosing, respectively. The rapid rates of rise in Hb with roxadustat treatment 
were not accompanied by elevations in blood pressure (BP), as has been reported with ESA 
treatment (Eschbach, 1989). 
Data from 16- to 24-week treatment Phase 2b study in CKD subjects not on dialysis (Study 
FGCL-4592-041) showed that absolute and weight-based doses of roxadustat, administered TIW 
and BIW, effectively corrected Hb levels to a Hb target of 11 g/dL (range of 11 to 13 g/dL in 
96 subjects and 10.5 to 12.0 g/dL in 48 subjects). Dose-response trends suggested that starting 
doses of 1.0 to1.6 mg/kg roxadustat administered TIW are appropriate to correct Hb levels 
during 4 weeks of treatment in nondialysis CKD subjects. Roxadustat was also effective in 
maintaining Hb level following anemia correction. 
1.4.2.2 Studies in Subjects with DD-CKD 
Data from a 12-week study in incident-dialysis (48 HD and 12 PD) subjects (Study FGCL-4592- 
053), using similarly tiered, weight-based doses as Study FGCL-4592-041 demonstrated 
increases in mean Hb of approximately 2 g/dL after 6 weeks of treatment. Subjects were 
randomized to receive either no iron, oral iron or IV iron. The Hb responses were 
indistinguishable between the oral and IV iron arms; subjects in the no iron arm had a similar Hb 
response during the first 8 weeks of treatment, with plateauing during the last 4 weeks of 
treatment, suggesting that with long-term roxadustat treatment, iron supplementation may be 
necessary, however, oral iron appears to be as effective as IV iron, and is recommended as the 
first-line treatment in Phase 3. Starting roxadustat doses between 1.0 and 1.6 mg/kg appeared 
adequate to correct Hb in these subjects. In addition to Hb response, in this study, statistically 
significant (p< 0.001) improvements of 5 to 10% overall average in the 36-Item Short Form 
Health Survey (SF-36) Physical Functioning, Role physical, and Vitality scores, as well as in the 
Functional Assessment of Cancer Therapy-Anemia (FACT-An) anemia and total scores were 
noted in the roxadustat-treated subjects. Significantly, these improvements were more 
pronounced (33% on average and up to 100%) in subjects with low BL scores (< 35), and 
improvement was time-dependent. Also, in this study, roxadustat transiently lowered total 
cholesterol by about 20 mg/dL on average. Importantly, highly significant low-density 
lipoprotein (LDL) cholesterol reduction was also observed. 
Data from a 6 and 19-week treatment study in US ESRD subjects on dialysis (Study 
FGCL-4592-040) showed the feasibility of converting subjects from a stable ESA dose to 
roxadustat. In the 6-week dose range portion of this conversion study in subjects on HD, a dose 
relationship was observed for Hb response. In subjects dosed with roxadustat at 1 mg/kg, the Hb 
response was comparable to that in the epoetin alfa control group, which had a small decline 
from baseline in Hb levels and a lower percentage of Hb responders than did subjects receiving 
the higher doses of roxadustat. In the 1.5 mg/kg and 2.0 mg/kg dose arms, roxadustat produced 
an average increase in Hb of 0.9 and 0.7 g/dL from baseline Hb, respectively, and was associated 
with a 78% to 80% response rate, ie, more than twice that in the epoetin alfa arm (33%). In the 
19-week portion of the study, Hb maintenance was durable and noninferior to epoetin alfa in the 
roxadustat treatment arms (combined) over a 19-week period. The roxadustat dose requirement 
for Hb maintenance was mostly between 0.7 mg/kg to 2.0 mg/kg in normoresponder subjects, 
with occasional subjects requiring doses up to 3.0 mg/kg TIW. Roxadustat treatment also 
resulted in increased levels of serum iron at the End of Treatment (EOT) compared with baseline 
in the 6-week treatment arms, whereas serum iron levels decreased from baseline in subjects 

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treated with epoetin alfa. Reticulocyte Hb content (CHr) was better maintained in the pooled 
roxadustat treatment arm than in the pooled epoetin alfa arm, suggesting that functional iron 
deficiency does not occur when treating with roxadustat unaccompanied by IV iron. Serum 
hepcidin was reversibly suppressed during roxadustat treatment. In addition, total cholesterol 
levels decreased during the course of treatment in subjects treated with roxadustat, but were 
unchanged in epoetin alfa-treated subjects. Following discontinuation of roxadustat dosing, total 
cholesterol levels returned to BL at post-treatment follow-up. 
Data from a Phase 2 clinical trial in China (FGCL-4592-048), in DD-CKD subjects, roxadustat 
was found effective for maintaining Hb for 6 weeks. Hemoglobin correction and maintenance 
was dose-dependent. Roxadustat also transiently lowered total and LDL-cholesterol by about 20 
mg/dL on average. Serum iron levels were maintained and total iron binding capacity (TIBC) 
increased in roxadustat-treated subjects compared with subjects randomized to continue epoetin 
alfa. Other serum iron parameters were not significantly different between the treatment arms. 
1.4.2.3 Ongoing Studies 
Data from an ongoing open-label extension study (Study FGCL-4592-059, to which some 
subjects from Studies FGCL-4592-041 and FGCL-4592-040 rolled over) further shows 
durability of roxadustat effect in maintaining Hb levels in subjects with CKD over 52 to 76-week 
treatment as of 07 September 2013. 
1.4.3 Safety 
The overall frequency and type of treatment-emergent adverse events (TEAEs) and treatment- 
emergent serious adverse events (TESAEs) observed in these clinical studies reflect events that 
would be expected to occur in CKD subjects with multiple co-morbidities and on a number of 
concomitant medications. Safety analyses did not reveal any association between the rates of 
occurrence of cardiovascular events with roxadustat, or any effect on adverse event (AE) rates 
related to either increasing Hb levels or on the rate of change of Hb levels. 
As of 7 September 2013, a total of 969 subjects have been exposed to roxadustat in the clinical 
development program, comprising 377 healthy subjects, 294 NDD-CKD subjects, and 298 DD- 
CKD subjects. In the healthy subject trials, most subjects were male as enrollment in these trials 
was generally restricted to men. In the NDD-CKD and DD-CKD studies roughly half of the 
subjects were male. Most of the healthy subjects were Asian or Caucasian, reflecting the 
countries where these studies were conducted (Europe, United Kingdom, US, China, and Japan). 
Most NDD-CKD and DD-CKD subjects were either Caucasian or African-American, as most 
trials for which demographic data are pooled were conducted in the United States or Eastern 
Europe. In general, the most commonly reported AEs (≥ 4% and ≥ 1% above placebo rate) in 
healthy volunteers were headache and dizziness. The most commonly reported AEs (≥ 5%) in 
subjects with NDD-CKD were diarrhea, nausea, urinary tract infection, nasopharyngitis, 
peripheral edema, hyperkalemia, headache, and hypertension (none were ≥ 8%), The most 
commonly reported AEs (≥ 3%) in subjects with DD-CKD were diarrhea, nausea, hypertension, 
and upper respiratory tract infection (none were ≥ 5%). Adverse event rates of hypertension (1% 
in Study FGCL-SM4592-017and 7.6% in Study FGCL-4592-041) and thrombosis (overall 
incidence < 1%), compare favorably with the rates reported in published ESA studies in similar 
patient populations (Krapf, 2009). No safety risks were associated with rate of rise of Hb levels 
or with achieving an Hb level above 11 g/dL using roxadustat. Study FGCL-4592-041 subjects 
achieved Hb > 11 g/dL in > 50% of exposure time during study, and there were no 

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cardiovascular safety events (death, myocardial infarction [MI], stroke, unstable angina, 
hospitalization for congestive heart failure, or hospitalization for arrhythmias) reported while Hb 
> 11 g/dL during treatment of roxadustat. 
Supratherapeutic doses of roxadustat in healthy volunteers were associated with an increased 
frequency of mild to moderate musculoskeletal pain and headaches, tachycardia, and less 
commonly, low BP. These findings have not been observed at the usual therapeutic dose range in 
Phase 2 studies in the target populations. In CKD subjects, the observed changes in heart rate 
(HR) and BP were in general within the normal variations of daily living. 
Cumulatively, 5 TESAEs of pancreatitis have been reported during roxadustat clinical studies. 
The pancreatitis for three subjects was associated with cholelithiasis or biliary sludge, confirmed 
by radiological imaging; all three subjects underwent cholecystectomy with complete resolution 
postoperatively. One subject was found to have a pancreatic duct stricture. One of the 5 TESAEs 
of acute pancreatitis was considered by the Investigator to be possibly related to roxadustat. 
However, the causality was assessed as unrelated to study drug by the sponsor after 
investigations revealed the presence of multiple risk factors for pancreatitis, including a long 
history of cigarette smoking, diabetes, hyperparathyroidism, and use of vicodin and lisinopril. Of 
note, approximately 28 months after the last dose of roxadustat, the subject was hospitalized with 
another episode of acute pancreatitis. Additional information regarding this subject is available in 
the IB. 
Of note, cholelithiasis is reported to be more common in subjects with CKD compared with the 
general population, with a prevalence as high as 20% (Li Vecchi, 2003; Gladziwa, 1993). 
Furthermore, a higher incidence of pancreatitis in patients with type 2 diabetes mellitus, and 
hence CKD, has been well described in the literature. No increased cancer risk has been noted 
with roxadustat treatment; however, the study program was not powered to detect absence of 
cancer risk. 
Liver parameters were monitored closely throughout the roxadustat clinical development 
program. Increases in liver parameters were infrequently seen, and were generally mild and 
transient in nature. No cases of Hy’s Law were observed throughout the program. An 
independent data and safety monitoring committee concluded that there was no concern for 
hepatotoxicity with roxadustat. Based on the safety data collected to date, roxadustat is generally 
well tolerated and has an acceptable safety profile that supports its further development. 
In summary, the cumulative safety data have not identified major risks related to roxadustat. At 
therapeutic doses, roxadustat is well tolerated by healthy subjects and subjects with CKD. 
Potential additional benefits of roxadustat compared with ESAs for the treatment of NDD-CKD 
and DD-CKD anemia include efficacy without the need for IV iron supplementation, and a 
favorable change in lipid profile. 
Taking into account the general measures taken to minimize risk to subjects participating in the 
Phase 3 clinical trials, the anticipated benefits of treating the anemia associated with CKD in 
subjects on dialysis and not on dialysis, the data support conduct of Phase 3 trials. For detailed 
safety information, please refer to the most current version of the IB. 
1.5 Summary 
In summary, roxadustat is an orally active HIF-PHI with erythropoietic effects. Intermittent 
dosing of roxadustat results in transient activation of HIF, intermittent induction of endogenous 

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physiologic-range EPO, and dose-dependent erythropoiesis, suggesting a coordinated mechanism 
of erythropoiesis that is different from ESA therapy, including beneficial effects on iron 
handling. The clinical data collected thus far suggest that roxadustat is generally safe and well 
tolerated in healthy adult subjects, and in dialysis and nondialysis CKD subjects with anemia 
treated up to 60 weeks. 
1.6 Roxadustat Dose Rationale 
Starting doses of roxadustat were studied in three ways in the Phase 2 program: using a strict 
weight-based dosing approach that was useful in the proof of concept stage; using a tiered 
weight-based approach where a subject’s starting dose was selected based on categorizing the 
subject’s body weight as low (45 to < 70 kg), medium (70 to 100 kg), or heavy (> 100 kg); and 
using an absolute starting dose regardless of body weight. The tiered weight-based approach has 
been chosen for the development of roxadustat in the Phase 3 program to provide a practical 
starting dose strategy for a controlled Correction to target Hb values, based on the observed 
relationship between body weight, PK, and Hb response, and the requirements of oral dosing. 
The tiered, weight-based starting doses selected for this study consist of the following roxadustat 
doses: 70, and 100 mg, for low weight (≤ 70 kg), and high weight (> 70 to 160 kg) subjects, 
respectively. These dose tiers are based primarily on the interim safety and efficacy data 
generated in the CKD nondialysis Correction of anemia study (FGCL-4592-041) and confirmed 
by the dialysis study. These doses will be administered at a frequency of TIW. Using this dosing 
scheme, subjects will receive starting roxadustat doses between 0.9 mg/kg TIW for the heaviest 
subject, and 1.6 mg/kg TIW for the lightest subject. This is comparable to the starting doses of 
1.0 to 1.6 mg/kg, which were the doses that effectively corrected Hb levels in studies 
FGCL-4592-041 and FGCL-4592-053. Further dose adjustment to achieve Correction and 
subsequent Maintenance is based upon regular monitoring of Hb. 
Based on the Phase 2 data, it is expected that subjects who receive these starting doses to correct 
anemia will be able to maintain Hb levels with a total weekly dose reduction of the order of 22 to 
35%. This dose reduction can be achieved by adjusting the per dose amount towards the 
protocol-defined Hb target range. The Phase 2 studies evaluated the need for dose adjustments 
for both Hb Correction and Hb Maintenance. Dose adjustments were allowed at regular 4-week 
intervals to maintain, increase, or decrease the dose according to prespecified rules. Pre-specified 
dosing steps were used to correct and maintain Hb levels within treatment thresholds based on 
absolute Hb levels and change of Hb in the previous 4 weeks. Additional rules for dose 
adjustment were provided to minimize excessive hematopoiesis. These dose adjustment rules 
were successful in Hb Correction and Hb Maintenance and will be adopted in this study with 
minor modifications. 
1.7 Risks/Benefits of Roxadustat Treatment 
The primary benefit of roxadustat is the treatment of anemia, including the relief of associated 
signs and symptoms and an increased quality of life. Roxadustat is expected to be at least as safe 
as ESAs, and the current data suggest that cardiovascular risk may be lower than with ESAs. 
An established dose adjustment algorithm will be used during the study to titrate roxadustat 
doses to enable subjects to achieve and maintain optimal Hb levels, while closely monitoring the 
rate of rise of Hb levels. Roxadustat doses may be held and/or the use of therapeutic phlebotomy 
is allowed in the event of excessive hematopoiesis. Adverse and serious adverse events (SAEs), 

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and laboratory parameters including electrolytes, liver enzymes, and iron indices, will be closely 
monitored to ensure the safety of treatment with roxadustat and epoetin alfa. An independent 
expert panel will assess and adjudicate prespecified cardiovascular, cerebrovascular and 
thromboembolic events. In addition, an independent Data and Safety Monitoring Board (DSMB) 
will perform regular, periodic assessments of safety data to detect any potential safety signals 
that may arise during the study and advise the Sponsor accordingly. 
Based on the clinical and nonclinical trial results to date, it is anticipated that orally administered 
roxadustat will be comparable in efficacy to marketed parenteral ESA products in the treatment 
of anemia of CKD, with an acceptable safety profile. Roxadustat may offer a valuable alternative 
to the current treatment options in the management of anemia of CKD. 

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2 OBJECTIVES 
2.1 Primary Objectives 
Evaluate the Efficacy and Safety of Roxadustat in the Treatment of Anemia in Incident-Dialysis 
Subjects, Compared with Active Control. 
2.2 Secondary Objectives 
The secondary objectives in this study are to: 
• Evaluate the utilization of IV iron with roxadustat compared with Active Control 
• Evaluate the effect of roxadustat on serum lipid parameters compared with Active Control 
• Evaluate the effect of roxadustat on BP compared with Active Control 
• Evaluate time to achieve a Hb response compared with Active Control 

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3 STUDY DESIGN 
3.1 Description of the Study 
This is a Phase 3, multicenter, randomized, open-label, and active-controlled study to evaluate 
the efficacy and safety of roxadustat in the treatment of anemia in incident-dialysis subjects. 
The study periods are as follows: 
• Screening Period: Up to 6 weeks 
• Treatment Period: Treatment duration is variable for individual subjects. In order to 
complete the Treatment Period simultaneously for all study subjects, the minimum treatment 
duration may be less than 52 weeks, with a maximum treatment duration of up to 
approximately 3 years after the last subject is randomized. Subjects will be informed at least 
4 weeks prior to their treatment period end. 
• Post-Treatment Follow-Up Period: 4 weeks 
3.2 Randomization and Treatment Assignment 
A total of up to approximately 1200 subjects will be randomized in a 1:1 ratio to receive either 
open-label roxadustat or epoetin alfa (Appendix 1). 
Randomization is stratified by the following factors: 
• Geographical region 
• Screening Hb values (≤ 8 g/dL vs. > 8 g/dL) 
• Cardiovascular/cerebrovascular/thromboembolic medical history (Yes vs. No) 
Randomization schedules will be prospectively prepared. Automated randomization and 
treatment assignments will be provided by an Interactive Voice and Web Response System 
(IXRS). 
3.3 Procedures for Handling Incorrectly Enrolled Subjects 
Subjects who fail to meet all eligibility criteria should not be enrolled. 
If it is discovered in retrospect that a subject did not meet all eligibility criteria, the Investigator 
should inform the Medical Monitor immediately, and a discussion should occur regarding 
whether or not to discontinue the study subject. All decisions from such a discussion should be 
appropriately documented. 
3.4 Replacement of Subjects 
Subjects who drop out prematurely will not be replaced in the study. 
3.5 Study Treatment 
3.5.1 Dose and Schedule 
Eligible subjects will be randomized via IXRS to receive either roxadustat or epoetin alfa. The 
first study drug administration will be on Day 1 (Week 0). 

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3.5.2 Starting Dose of Study Drug 
3.5.2.1 Roxadustat Arm 
For subjects receiving roxadustat, the initial dose (per dose amount) is based on a tiered, weight- 
based dosing scheme (Table 1). Roxadustat will be dosed orally TIW throughout the Treatment 
Period, except if a subject requires < 20 mg TIW (ie, < 60 mg per week) to maintain Hb levels in 
the Maintenance Phase, the dosing frequency should be reduced in a step-wise fashion eg, TIW 
to BIW, BIW to QW, QW to Q-2 Week etc. 
3.5.2.2 Active Control Arm (Epoetin alfa) 
Subjects on HD will initiate intravenous (IV) treatment according to the epoetin alfa US Package 
Insert (USPI) or Summary of Product Characteristics (SmPC). 
For subjects on HHD or PD, epoetin alfa will be administered according to the epoetin USPI, or 
SmPC or local standard-of-care. 
For countries using prefilled syringes, the initial epoetin alfa dose and dose adjustments should 
be approximated to the closest weekly dose. 
 
Table 1 
Initial Study Drug Dosing 
 
Study Drug 
(Dose Frequency) 
Low Weight 
(≤ 70 kg) 
High Weight 
(> 70 to 160 kg) 
Roxadustat (TIW) 
70 mg 
100 mg 
Active Control HD (TIW) 
IV dosing according to epoetin alfa Package Insert or SmPC. 
Active Control PD/HHD 
Epoetin alfa should be administered according to the epoetin alfa Package Insert or 
SmPC or local standard of care. 
Abbreviations: 
HD = hemodialysis; HHD= home-hemodialysis; PD = peritoneal dialysis; SmPC = summary of product 
characteristics; TIW = three times a week. 
Note: Weight in HD subjects = subject’s dry weight. 
 
3.5.3 Dose Adjustment for Roxadustat 
Dose adjustments will occur in two separate study dosing phases: the Correction Phase and the 
Maintenance Phase. Each of these phases will follow unique adjustment rules according to 
Appendix 2. 
All subjects will be dosed orally TIW during the Treatment period. The maximum roxadustat 
dose is 3.0 mg/kg per dose or 400 mg (whichever is lower). 
All dose adjustments as well as assessments of excessive hematopoiesis are based on Hb values 
using a point-of-care device, such as HemoCue® or CritLine®. In the event that the central lab Hb 
value of the site visit is significantly different and the dose adjustment decision based on the 
HemoCue® / CritLine® value is being re-considered, the Medical Monitor should be contacted, if 
possible. 
The determination of Hb response and transition from the Correction to the Maintenance Phase 
of the study is based on the central laboratory Hb value. 

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3.5.3.1 Correction Phase of Dosing for Roxadustat 
• The aim of the Correction Phase is to increase Hb levels from baseline to the target Hb 
level by using the dose adjustment algorithm in Appendix 2. 
• . This phase is variable in length for each subject. 
• Dose adjustment reviews will occur on Week 4, and at intervals of every 4 weeks 
thereafter (Weeks 8, 12, 16, etc.), except in the event of excessive hematopoiesis, in 
which case doses may be adjusted at any time. In such cases, dose adjustment reviews are 
resumed at 4-week intervals. For example, if the subject’s Hb increases > 2.0 g/dL from 
Week 1 to Week 3, the subject’s dose is reduced by one dose step at Week 3. The next 
dose adjustment review should occur 4 weeks later at Week 7 and at 4-week intervals 
thereafter. 
• If the dose adjustment interval falls on a non-study visit week (starting Week 4), the dose 
adjustment review should be performed at the next scheduled study visit if a dose 
adjustment was not required at the previous visit. For example, if a subject’s visit is 
scheduled for Weeks 6 and 8, and the dose adjustment would occur at Week 7, then the 
dose adjustment should be evaluated at the Week 8 visit. 
3.5.3.2 Maintenance Phase of Dosing for Roxadustat 
• The aim of the Maintenance Phase is to maintain Hb levels after the initial correction by 
using the dose adjustment algorithm in Appendix 2. 
Note: Note: Given the complexity in roxadustat dose adjustments,  and the need to take into 
account the various clinical parameters in roxadustat dose titration, one would not consider it a 
protocol deviation when study subjects are dosed based on their clinical circumstances, whether 
or not it is concordant with  the roxadustat dose adjustment guidelines unless it was related to 
“excessive hematopoiesis”  (eg, Hb ≥ 13 g/dL, requiring a dose hold) or “Overdose” (prescribed 
>3.0 mg/kg per dose or 400 mg per dose whichever is lower). 
3.5.3.3 Active Control (Epoetin alfa) Subjects 
Epoetin alfa subjects should maintain their Hb levels within the target range accepted by health 
authorities, specifically: 
• Hb 10 to 11 g/dL in the United States (US) 
• Hb 10 to 12 g/dL in countries outside the US 
Hemodialysis subjects will be dosed IV TIW, with starting doses and dose adjustment rules 
according to the epoetin alfa USPI or SmPC. In subjects requiring ultra-low dose of EPO (eg, 
≤1000 IU/per week), frequency of administration may be adjusted per local standard of care. 
Home-hemodialysis and peritoneal dialysis subjects will be dosed according to the epoetin 
Package Insert or the SmPC or local standard of care. 
For countries using prefilled syringes, the initial epoetin alfa dose and dose adjustments should 
be approximated to the closest weekly dose. 
Note: Given the complexity in EPO dose adjustments and the need to take into account the 
various clinical parameters in EPO dose titration, one would not consider it a protocol deviation 

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when study subjects  are dosed according to local standard of care whether or not it is 
concordant with  package insert/SmPC 
ESA administration in roxadustat subjects during hospitalization is not considered a protocol 
deviation if roxadustat is not allowed or available during that hospitalization. 
3.5.3.4 Excessive Hematopoiesis 
For subjects randomized to Roxadustat, the following scenarios are defined as “excessive 
hematopoiesis” 
• Hb increases by > 2.0 g/dL at any time within a 4 week period: reduce the dose by one 
dose step. 
• Hb reaches or exceeds 13 g/dL: hold dosing, check Hb weekly. Resume dosing when 
Hb < 12.0 g/dL (for US subjects central lab Hb value preferred), at a dose that is reduced 
by two dose steps. 
For subjects on prolonged dose-hold, with stable (not dropping) Hb, the Investigator may 
use discretion to schedule less frequent visits. 
Anytime Hb is assessed via HemoCue®/CritLine®/local lab, a central lab Hb should be 
obtained as well. 
3.6 Concomitant Medications, Procedures and Nondrug Therapies 
3.6.1 Concomitant Medications 
Concomitant medications are any prescription or over-the-counter preparations, including herbal 
products and “natural remedies”, used by a subject while participating in this clinical study. 
For all concomitant medication use, an indication for its use should be provided. If the stated 
indication is a nonspecific condition (eg, “rash”) documentation of the condition, as specific as 
possible, should be maintained in the subject’s clinical study records as source documentation. 
To avoid confounding effects on study endpoints, changes to anti-hypertensive medications 
should be minimized, and made only if deemed medically necessary by the Investigator or if 
prespecified changes BP are met. 
3.6.1.1 Use of Phosphate Binders During the Study (Roxadustat Subjects) 
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 three hours after their phosphate binder if possible. 
3.6.1.2 Use of Hydroxymethylglutaryl Coenzyme A (HMG-CoA) Reductase Inhibitors 
(Statins) During the Study (Roxadustat Subjects) 
When coadministered with roxadustat, in clinical pharmacolgical studies, hydroxymethylglutaryl 
coenzyme A reductase inhibitor (statin) exposure was increased 2- to 3-fold. For patients 
randomized to roxadustat, investigators should consider this interaction and local prescribing 
information when deciding on the appropriate statin dose for individual patients, bearing in mind 
the impact of ethnicity, other concomitant medications, renal and hepatic function. Goals of lipid 

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lowering treatment should be maintained as clinically indicated. The dose of statins should not 
exceed the recommended daily dose in Table 2 for subjects randomized to roxadustat. 
 
 
Table 2 
Recommended Maximum Daily Dose of Statins for Subjects Randomized to 
Roxadustat 
Statin 
Proposed Max Dose (mg/day) 
Simvastatin 
5 
Atorvastatin 
40 
Rosuvastatin 
5 
Fluvastatin 
40 
Pitavastatin 
2 
Pravastatin 
40 
Pitavastatin 
1 
Lovastatin 
20 
Abbreviations: 
max = maximum. 
 
3.6.2 Supplemental Iron Use 
In a Phase 2 study of roxadustat, in which study subjects were randomized to either receive no 
iron, oral iron or IV iron, there was no significant difference in Hb levels in subjects receiving 
oral iron compared to subjects receiving IV iron. Therefore, based on the mechanism of action of 
roxadustat and the Phase 2 study results, in subjects randomized to roxadustat, oral iron may be 
sufficient for iron supplementation. 
In this study, oral iron should be allowed as first-line iron supplementation without restrictions, 
for both study arms. In addition to the scheduled assessments (Appendix 3), iron indices may be 
assessed at any time (via central lab) to evaluate iron storage status of the subjects, if considered 
necessary by the Investigator. 
3.6.2.1 Oral Iron Supplementation 
All subjects should be encouraged to take oral iron as the first-line iron supplementation during 
the Treatment Period, except subjects not tolerating oral iron. The dose and frequency are at the 
discretion of the Investigator. Oral iron supplementation should be started before the subject 
becomes iron depleted. 
3.6.2.2 Intravenous Iron Supplementation 
Intravenous iron supplementation is permitted if in the opinion of the Investigator the subject’s 
Hb has not responded adequately and the subject is considered iron deficient. 
Treatment with study medication will continue during IV iron administration. Discontinuation 
of IV iron is recommended once the subject is no longer deemed iron deficient (eg, ferritin 
≥ 100 ng/ml [≥ 220 pmol/L], TSAT ≥ 20%) and has evidence of a hematopoietic response. 
Note: IV iron administration in study subjects during hospitalization is not considered a protocol 
deviation. 

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3.6.3 Rescue Therapy Guidelines 
Rescue therapy guidelines are provided to standardize the use of rescue therapy. 
 
3.6.3.1 Red Blood Cell Transfusion 
Red blood cell transfusion should be considered if rapid correction of anemia is required to 
stabilize the subject’s condition (eg, acute hemorrhage) and the Investigator is of the opinion that 
the blood transfusion is a medical necessity. Study drug treatment may continue during the RBC 
transfusion administration. 
3.6.3.2 Erythropoiesis Stimulating Agents (Roxadustat Arm Only): 
The use of ESAs is not permitted during the Treatment Period, except if all of the following 
criteria are met: 
• A subject’s Hb level has not responded adequately despite two or more consecutive 
roxadustat dose increases or the roxadustat dose has reached the maximum dose limit 
• Other causes for lack of response or declining Hb, such as iron deficiency, bleeding, 
acute inflammatory conditions, have been ruled out 
• Reducing risk of alloimmunization in transplant eligible patients is a goal. 
Roxadustat and ESA may not be co-administered. Treatment with an approved ESA may be 
initiated ≥ 3 days after the last roxadustat dose. 
If the situation permits, the Investigator should inform the Medical Monitor prior to initiation of 
ESA therapy. 
Subjects may receive one course of ESA rescue during the Treatment Period. 
Erythropoiesis-stimulating agent rescue should stop after 4 weeks or once Hb exceeds 9 g/dL, 
whichever occurs first. If a subject requires more than 4 weeks of ESA rescue therapy due to 
inadequate Hb response, the Medical Monitor should be contacted. 
Treatment with roxadustat may resume after the following intervals: 
• Two days after stopping epoetin alfa 
• One week after stopping darbepoetin alfa 
• Two weeks after stopping methoxy polyethylene glycol-epoetin beta (Mircera®) 
If more than one course of ESA rescue is required during the Treatment Period, the subject must 
be discontinued permanently from the study, and is considered a Treatment Failure. 
Inadvertent ESA administration including ESA administration by hospital staff in Roxadustat 
subjects should not be counted as rescue unless above criteria are met; these subjects may be 
allowed to continue on study, if considered safe by the Investigator and Medical Monitor. 
3.6.4 Therapeutic Phlebotomy 
If there are clinical concerns of excessive elevation of Hb levels, the Investigator may decide to 
perform a therapeutic phlebotomy in addition to a dose hold. This should be discussed with the 
Medical Monitor and documented. 

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3.6.5 Excluded Medications/Therapies/Substances 
Subjects are not permitted to consume more than three alcohol-containing drinks per day during 
the Treatment or Follow-up Periods. 
The following medications are prohibited from the day of randomization until completion of the 
study: 
• Androgens and iron-chelating agents (eg, deferoxamine, deferiprone, or deferasirox 
therapy) 
• Dapsone in any dose amount 
 
• For subjects receiving roxadustat: chronic use of acetaminophen or paracetamol >2.0 
g/day during the Treatment Period and up to 1 week after EOT. 
• Use of herbal medicine is not prohibited but strongly discouraged. 
 
3.6.6 Contraception 
Female subjects of childbearing potential must agree to practice a dual method of contraception, 
for example, a combination of the following: (1) oral contraceptive, depo progesterone, or 
intrauterine device; and (2) a barrier method (condom or diaphragm). Male subjects with female 
partners of childbearing potential who are not using birth control as described above must use a 
barrier method of contraception (eg, condom) if not surgically sterile (ie, vasectomy). 
Contraceptive methods must be practiced upon entering the study and through 12 weeks after the 
last dose of study treatment. If a subject discontinues prematurely, the contraceptive method 
must be practiced for 12 weeks following final administration of study drug. 
Pregnancy, spontaneous or therapeutic abortion, or events related to pregnancy must be reported 
(Section 9.3.6). 
In female subjects of childbearing potential, serum pregnancy test will be done per Schedule of 
Assessments (Appendix 3) to rule out pregnancy. Pregnancy test is not required for female 
subjects of no childbearing potential eg, postmenopausal (determination whether a woman is 
post-menopausal is at the discretion of the Investigator), surgically sterile etc.. 
3.7 Safety Monitoring Plan 
Safety will be assessed throughout the study. A complete baseline profile of each subject will be 
established through demographics, medical history, clinical laboratory values, vital signs, 
physical examinations (PEs), and electrocardiogram (ECGs). During the course of the study, 
vital signs, complete and targeted PEs, and laboratory tests will be performed at regular intervals. 
A comprehensive PE will be conducted during the Screening visit, Day 1 and at the End of Study 
(EOS) visit. A targeted PE (general appearance, cardiovascular, respiratory and abdomen) will be 
conducted throughout the study as described in Schedule of Assessments (Appendix 3). 
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 medically 
significant changes from baseline will be monitored throughout the study and appropriate 
interventions will be taken accordingly. Clinical laboratory tests may be assessed at additional 

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times on unscheduled visits for safety reasons. Liver function abnormalities will be managed 
according to Drug-Induced Liver Injury (DILI) guidance (Appendix 4). 
Adverse events, SAEs, and ongoing concomitant medication usage will be monitored and 
recorded throughout the study. Serious adverse event reports will be evaluated individually to 
assess for the impact of the event, if any, on the overall safety of the product and on the study 
itself. Cumulative AEs will be monitored throughout the study. Serious adverse events and AEs 
will be followed until resolved, stable, or until the subject’s EOS visit. See Section 9 for details 
on AE and SAE reporting. 
An Independent Event Review Committee (IERC), blinded to treatment group, will adjudicate 
prespecified cardiovascular, cerebrovascular, and thromboembolic safety events of interest. 
These events include death from any cause, MI, stroke, congestive heart failure requiring 
hospitalization, unstable angina requiring hospitalization, deep venous thrombosis, pulmonary 
embolism, vascular access thrombosis and hypertensive emergency. A separate adjudication 
charter will describe the process in detail, and training and training materials will be provided to 
study sites. 
3.8 Data Safety and Monitoring Board 
A Data Safety Monitoring Board will review safety data periodically in collaboration with the 
Sponsor to ensure subject safety. A separate DSMB charter will establish the rules, meeting 
frequency, and scope of responsibilities of the DSMB. 

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4 ELIGIBILITY CRITERIA 
4.1 Inclusion Criteria 
1. Age ≥ 18 years. 
2. Subject has been informed of the investigational nature of this study and has given 
written informed consent in accordance with institutional, local, and national guidelines. 
3. Receiving HD or PD for ESRD for a minimum of 2 weeks and a maximum of 4 months, 
prior to randomization. 
4. Hemodialysis access consisting of an arteriovenous (AV) fistula, AV graft, or tunnelled 
(permanent) catheter; or PD catheter in use. 
5. Mean of the two most recent predialysis Hb values during the Screening Period, obtained 
at least 2 days apart, must be ≤ 10.0 g/dL, with a difference of ≤ 1.3 g/dL between the 
highest and the lowest values. The last Hb value must be drawn within 10 days prior to 
randomization. 
6. Ferritin ≥  100 ng/mL (≥ 220 pmol/L); subjects with ferritin level < 100 
ng/mL(<220pmol/L) during screening, qualify after receiving iron supplement (per local 
standard of care), without the need to retest ferritin prior to randomization. 
7. Transferrin saturation ≥ 20%; subjects with TSAT level < 20% during screening, qualify 
after receiving iron supplement (per local standard of care), without the need to retest 
TSAT prior to randomization. 
8. Serum folate level, performed within 8 weeks prior to randomization ≥ lower limit of 
normal (LLN); subjects with serum folate level < LLN during screening, qualify after 
receiving folate supplement (per local standard of care), without the need to retest folate 
prior to randomization. 
9. Serum vitamin B12 level, performed within 8 weeks prior to randomization ≥ LLN; 
subjects with vitamin B12 level < LLN during screening, qualify after receiving B12 
supplement (per local standard of care), without the need to retest B12 prior to 
randomization. 
10. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 3 x upper limit of 
normal (ULN), and total bilirubin (Tbili) ≤ 1.5 x ULN. 
11. Body weight up to 160 kg (HD subjects: dry weight). 
4.2 Exclusion Criteria 
1. Total duration of prior effective ESA use must be ≤3 weeks within the preceding 12 
weeks at the time informed consent is obtained. 
Specific dosing guidance, depending on the type of ESAs, injected IV or SC within 
12 weeks prior to start of screening are as follows: 
Short-acting ESAs (EPO-alfa or equivalents) 
• IV: Up to 9 doses; last EPO dose must be ≥2 days prior to start of screening 

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• SC: Up to 3 doses;  last EPO dose must be ≥1 week (7 days) prior to start of 
screening 
Darbepoetin 
• IV: Up to 3 doses; last darbepoetin dose must be ≥1 week (7 days) prior to start of 
screening 
• SC: Up to 2 doses; last darbepoetin dose must be ≥2 weeks (14 days) prior to start of 
screening 
Continuous erythropoietin receptor activator (CERA) IV and SC 
• IV or SC:  Up to 2 doses; last CERA dose must be ≥2 weeks (14 days) prior to start 
of screening 
2. Intravenous iron: there is no restriction regarding IV iron use during screening, provided 
it is administered in accordance with local standard of care. 
 
 
3. Red blood cell transfusion within 4 weeks prior to randomization. 
4. Active, clinically significant infection that could be manifested by white blood cell 
(WBC) count > ULN, and/or fever, in conjunction with clinical signs or symptoms of 
infection at the time of randomization. 
5. History of chronic liver disease (eg, chronic infectious hepatitis, chronic auto-immune 
liver disease, cirrhosis, or fibrosis of the liver). 
6. New York Heart Association Class III or IV congestive heart failure at screening. 
7. Myocardial infarction, acute coronary syndrome, stroke, seizure, or a thromboembolic 
event within a major vessel (excluding vascular dialysis access) (eg, deep vein 
thrombosis or pulmonary embolism) within 12 weeks prior to randomization. 
8. Uncontrolled hypertension, in the opinion of the Investigator, (eg, that requires a change 
in anti-hypertensive medication) within 2 weeks prior to randomization. 
9. Renal imaging performed within 12 weeks prior to randomization indicative of a 
diagnosis or suspicion (eg, complex kidney cyst of Bosniak Category 2 or higher) of 
renal cell carcinoma. 
10. History of malignancy, except for the following: cancers determined to be cured or in 
remission for ≥ 5 years, curatively resected basal cell or squamous cell skin cancers, 
cervical cancer in situ, or resected colonic polyps. 
11. Positive for any of the following: human immunodeficiency virus (HIV); hepatitis B 
surface antigen (HBsAg); or anti-hepatitis C virus antibody (anti-HCV Ab). 
12. Chronic inflammatory disease that could impact erythropoiesis (eg, systemic lupus 
erythematosus, rheumatoid arthritis, celiac disease) even if it is currently in remission. 
13. Known, untreated proliferative diabetic retinopathy, diabetic macular edema, macular 
degeneration, or retinal vein occlusion (subjects who are already blind for the above 
reasons qualify to participate). 

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14. Known history of myelodysplastic syndrome or multiple myeloma. 
15. Known hereditary hematologic disease such as thalassemia or sickle cell anemia, pure 
red cell aplasia, or other known causes for anemia other than CKD. 
16. Known hemosiderosis, hemochromatosis, coagulation disorder, or a hypercoagulable 
condition. 
17. Organ transplant:  subjects with any of the following: 
a. Experienced rejection of a transplanted organ within 6 months of transplantation 
b. Currently on high doses of immunosuppressive therapy (per discretion of the 
Investigator) 
c. Scheduled for organ transplantation. Note: being on a waiting list for kidney 
transplant is not exclusionary 
18. Anticipated elective surgery, except for vascular access surgery or dialysis catheter 
placement, that is expected to lead to significant blood loss, or anticipated elective 
coronary revascularization. 
19. Active or chronic gastrointestinal bleeding. 
20. Any prior treatment with roxadustat or a HIF-PHI. 
21. Use of iron-chelating agents within 4 weeks prior to randomization. 
22. Known hypersensitivity reaction to any ESA. 
23. Use of an investigational drug or treatment, participation in an investigational study, or 
presence of an expected carryover effect of an investigational treatment, within 4 weeks 
prior to randomization. 
24. Anticipated use of dapsone or androgens at any dose amount or chronic use of 
acetaminophen or paracetamol > 2.0 g/day during the study. 
25. History of alcohol or drug abuse within 6 months prior to randomization. 
26. Females of childbearing potential, unless using contraception as detailed in the protocol; 
male subjects with sexual partners of childbearing potential who are not on birth control 
unless the male subject agrees to use contraception. 
27. Pregnant or breastfeeding females. 
28. Any medical condition that, in the opinion of the Investigator, may pose a safety risk to 
a subject in this study, may confound efficacy or safety assessment, or may interfere 
with study participation. 
Subjects who fail to meet the above eligibility criteria should not be randomized or receive 
study medication. If Day 1 lab values (collected prior to administration of study medication) 
are found to be of significant safety risk, in the opinion of the Investigator or Medical 
Monitor, the subject may be discontinued from the study. 

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5 INVESTIGATIONAL PRODUCT 
5.1 Formulation 
Roxadustat is supplied by FibroGen, Inc. as red coated, oval tablets for oral administration, in 
strengths of 20 mg, 50 mg and 100 mg. The excipients include lactose monohydrate, 
microcrystalline cellulose, povidone, croscarmellose sodium, magnesium stearate, and colorant 
Red Opadry 2. All ingredients used for manufacture of roxadustat comply with US and European 
Union compendial or regulatory standards. Strengths are different in size, and debossing reflects 
the strength (ie, 20, 50 or 100 mg). 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. 
5.2 Storage 
Roxadustat tablets should be protected from light, and stored at 15º to 30ºC (59º–86ºF). 
Epoetin alfa should be stored according to the USPI or SmPC. 
All study drug (roxadustat and epoetin alfa) should be stored in a securely locked area to which 
access is limited to appropriately qualified and authorized study personnel. 
Handling and disposition of unused study drug is described in the site Drug Accountability 
Binder. 
5.3 Administration 
5.3.1 Roxadustat 
Roxadustat should be dispensed to subjects with instructions for self-administration of the tablets 
on each dosing day, according to the dosing schedule below. The tablets are to be swallowed 
whole with room-temperature drinking water. Dosing should occur at approximately the same 
time of day. 
Study drug doses taken TIW must be administered at least 2 days apart, and no more than 4 days 
apart. Dosing days should remain consistent throughout the study. If a subject requires < 20 mg 
TIW (ie, < 60 mg per week) to maintain Hb levels in the Maintenance Phase, the dosing 
frequency should be reduced in a step-wise fashion eg, TIW to BIW, BIW to QW, QW to Q-2 
Week etc. 
5.3.2 Active Control-Epoetin Alfa 
5.3.2.1 Hemodialysis Subjects 
Epoetin alfa will be administered IV TIW according to the Package Insert or SmPC by 
appropriately trained personnel. In subjects requiring ultra-low dose of EPO (eg, ≤1000 
IU/week), the frequency of administration may be adjusted by the PI per local standard of care. 
For countries provided with prefilled syringes, the initial epoetin alfa dose and dose adjustments 
should be approximated to the closest calculated total weekly dose. 
5.3.2.2 Home-hemodialysis and Peritoneal Dialysis Subjects 
Epoetin alfa will be administered according to the Package Insert, or SmPC or local standard of 
care by appropriately trained personnel including subject or caregiver. For countries provided 

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with prefilled syringes, the initial epoetin alfa dose and dose adjustments should be approximated 
to the closest calculated total weekly dose. 
5.4 Overdose, Emergency Procedures and Management of Overdose 
The maximum tolerated dose of roxadustat has not been established in humans. For the purpose 
of this study, the maximum allowed roxadustat dose is set at 3.0 mg/kg/dose or 3.5 mg/kg/dose 
from the original protocol (based on dry weight in subjects on HD and normal weight in subjects 
on HHD and PD) or 400 mg per administration, 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 AEs. An overdose without associated symptoms is not an 
AE and will be recorded on the dosing case report form (CRF) only. 
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. 
In the event of suspected epoetin alfa overdose, refer to the epoetin alfa USPI of SmPC. 

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6 STUDY PROCEDURES 
6.1 Study Procedures by Visit 
During study visits, unless otherwise indicated, it is preferred that all assessments including labs 
and PEs be completed predialysis for subjects on HD. For subjects on HHD and PD, assessments 
may be completed at any time during the visit, but preferably approximately at the same time of 
the day at each study visit. Quality of life assessments should be administered approximately at 
the same time of the day. For example, in subjects on HD, these assessments should be 
completed approximately at the same time during dialysis and in subjects on HHD/PD 
approximately at the same time of the day. Weight assessment in HD subjects should be done 
after dialysis (dry weight). Blood pressure and HR should be assessed according to the 
guidelines described in Appendix 5. 
. 
6.1.1 Screening Period (Up to 6 Weeks) 
Subjects must have a signed written informed consent before any screening tests or assessments 
are performed. For all screen failures, the reason(s) will be documented. Subjects will undergo at 
least two screening visits to determine eligibility, at least two days apart. All assessments and 
their timing are outlined in Appendix 3. 
6.1.1.1 Screening 1 
• Signed written informed consent 
 
• Inclusion/Exclusion criteria verification 
 
• Demographics and medical history 
 
• Complete physical exam 
 
• Height, weight (HD subjects: use dry weight) 
 
• Blood pressure, HR 
 
• Laboratory tests: 
o Complete blood count (CBC) with WBC differential 
o Serum chemistry 
o Lipid panel (fasting whenever possible) 
o Serum iron, ferritin, TIBC, TSAT 
o CHr 
o Hemoglobin A1c (HbA1c) 
o Vitamin B12 and folate (if no value available within 8 weeks prior to 
randomization) 

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o Enzyme-linked immunosorbent assay (ELISA) for HIV 
o Hepatitis B surface antigen and anti-HCV Ab 
o Serum human chorionic gonadotropin (hCG) test for women of childbearing 
potential only (For definition, see Section 3.6.6). 
• Adverse event recording 
 
• Concomitant medication recording 
 
• Procedures and nondrug therapy recording 
 
6.1.1.2 Screening 2 
Hemoglobin values must be obtained at least 2 days apart 
• Blood pressure, HR 
 
• Hemoglobin only 
 
• Renal ultrasound - not required if results of a previous renal ultrasound or other renal 
imaging modality within 12 weeks prior to randomization to rule out renal cell carcinoma 
are available. If no results are available, a renal ultrasound must be performed during 
screening. 
• Adverse event recording. 
 
• Concomitant medication recording 
 
• Procedures and nondrug therapies recording 
 
6.1.1.3 Additional Screening 
If a subject’s laboratory results do not meet the eligibility criteria at Screening, the laboratory 
assessment may be repeated within the Screening Period. 
For example, additional Hb values may be collected if necessary. The mean of 2 most recent Hb 
values during the screening period, obtained at least 2 days apart, will be used to calculate the 
subject’s eligibility. Liver function test (LFT) parameters may not be repeated if found 
exclusionary at screening without prior approval from the Medical Monitor, unless the 
Investigator has a valid reason to believe that the original laboratory result is due to an error (eg, 
possible sample mix-up). Such a repeat should be communicated to the Medical Monitor as soon 
as possible. 
Screening procedures that are not done at the scheduled visit must be completed prior to 
randomization. 
If subjects fail screening, they may be re-screened once as deemed appropriate by the 
investigator. Where possible, an approval should be obtained from the Medical Monitor prior to 
rescreening. 

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6.1.2 Treatment Period 
Eligible subjects will be randomized via IXRS to receive roxadustat or epoetin alfa. The 
Treatment Period begins on the first day of dosing with study treatment (Day 1/Week 0). A 
common closeout will occur when a predetermined number of adjudicated CV, cerebrovascular 
or thromboembolic events have been accrued across the entire Phase 3 program. 
6.1.2.1 Day 1 (Week 0) 
All assessments are to be completed prior to study drug administration 
• Inclusion/Exclusion criteria verification 
 
• Complete PE 
 
• Weight (HD use dry weight) 
 
• Blood pressure, HR, temperature, and respiratory rate (RR) 
 
• Laboratory tests: 
 
o Complete blood count with WBC differential 
o Serum chemistry 
o Lipid panel (fasting, whenever possible) 
o Serum iron, ferritin, TIBC, TSAT 
o CHr 
o HbA1c 
o Reticulocyte count 
o Special laboratory analytes: Hepcidin and high sensitivity-C-reactive protein (hs- 
CRP) 
o Archival serum/plasma samples (optional donation, separate consent form) 
• HemoCue®/CritLine® assessment 
• 12-Lead ECG 
 
• HRQoL questionnaires (SF-36, FACT-An, and European Quality of Life in 5 
Dimensions, 5 Levels [EQ-5D-5L]) 
• Adverse event recording 
 
• Concomitant medication recording 
 
• Procedures and nondrug therapy recording 
 
• Dispense study drug 

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6.1.2.2 Weeks 1 to 4 (Weekly, ±2 days) 
• Laboratory tests (must be performed prior to dosing): 
 
o Weeks 1, 2, 3, 4, CBC with WBC differential. 
o Week 2: LFTs only 
o Week 4: Serum chemistry 
o Week 4: Lipid panel (fasting whenever possible) 
o Week 4: Serum iron, ferritin, TIBC, TSAT. 
o Week 4: CHr 
o Weeks 1, 2: Reticulocyte count 
o Week 4: Special laboratory analytes 
o Week 4: Archival serum/plasma samples (optional donation, separate consent 
form) 
• HemoCue®/CritLine® assessment. 
• Dose adjustment review beginning Week 4 and at 4-weekly intervals thereafter (except in 
the event of excessive hematopoiesis). Refer to Section 3.5.3, and Appendix 2. 
• All visit weeks: BP and HR 
• Adverse event recording 
• Concomitant medication recording 
• Procedures and nondrug therapy recording 
• Dispense study drug every 2 weeks (Week 2 and Week 4) 
 
6.1.2.3 Weeks 6 to 24 (Every 2 weeks, ± 4 days) 
• Laboratory tests (must be performed prior to dosing): 
 
o Weeks 8, 12, 20: CBC with WBC differential 
o Week 6 followed by every visit where no CBC is collected; Hb only. 
o Weeks 8, 12, 20: Serum chemistry 
o Weeks 6, 16: LFTs and CPK 
o Weeks 8, 12, 24: Lipid panel (fasting whenever possible). 
o Weeks 8, 12, 20: Serum iron, ferritin, TIBC, TSAT. 
o Weeks 8, 12, 20: CHr 
o Week 12: HbA1c 
o Weeks 8, 20: Reticulocyte count 
o Weeks 12, 20: Special laboratory analytes 

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• Weeks 12, 20: Archival serum/plasma samples (optional donation, separate consent form) 
 
• HemoCue®/CritLine® assessment 
• Weeks 12, 24: Serum hCG pregnancy test for women of childbearing potential (for 
definition, see Section 3.6.6) 
• 
 
• Week 24 followed by every 12 weeks: Targeted physical exam (eg, respiratory and 
cardiovascular system) 
• Week 24 followed by every 24 weeks: 12-lead ECG, weight (HD subjects: dry weight) 
 
• Dose adjustment review every 4 weeks (except in the event of excessive hematopoiesis or 
dose frequency conversion). Refer to Section 3.5.2, and Appendix 2. 
• All visit weeks: BP and HR 
 
• Week 12 HRQoL questionnaires (SF-36, FACT-An, and EQ-5D-5L) 
 
• Adverse event recording 
 
• Concomitant medication recording 
 
• Procedures and nondrug therapy recording 
 
• Dispense study drug 
 
6.1.2.4 Weeks 28 to End of Therapy (Every 4 weeks, ±4 days) 
• Laboratory tests (must be performed prior to dosing): 
 
o Week 28 followed by every 8 weeks: CBC with WBC differential 
o Week 32 followed by every visit where no CBC is collected; Hb only 
o Week 28 followed by every 8 weeks: Serum chemistry 
o Weeks 32, 40, 48, 60 followed by every 24 weeks: Lipid panel (fasting whenever 
possible) 
o Week 28 followed by every 8 weeks: Serum iron, ferritin, TIBC, TSAT 
o Week 28 followed by every 8 weeks: CHr 
o Weeks 28, 44, 60, followed by every 16 weeks: HbA1c 
o Week 44 followed by every 24 weeks: Reticulocyte count 
o Week 44, followed by every 24 weeks: Special laboratory analytes 

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• Week 44 followed by every 24 weeks: Archival serum/plasma samples (optional 
donation, separate consent form) 
• All visit weeks: HemoCue®/CritLine® assessment. 
• Week 36 followed by every 12 weeks: Targeted physical exam (eg, respiratory and 
cardiovascular system) 
• Week 36, followed by every 12 weeks: Serum hCG test for women of childbearing 
potential (for definition, see Section 3.6.6) 
• All visit weeks: Dose adjustment review (except in the event of excessive hematopoiesis 
or dose frequency conversion). Refer to Section 3.5.2, and Appendix 2. 
• All visit weeks: BP and HR 
 
• Weeks 36 and 52: HRQoL questionnaires (SF-36, FACT-An, and EQ-5D-5L) 
 
• Adverse event recording 
 
• Concomitant medication recording 
 
• Procedures and nondrug therapy recording 
 
• Dispense study drug 
 
∗ If the indicated assessments fall on a study treatment visit that is within two weeks of the 
planned EOT visit, then these specified assessments can be postponed until the EOT visit. 
6.1.2.5 End of Treatment (± 7 days) 
• Laboratory tests: 
 
o Complete blood count with WBC differential 
o Serum chemistry 
o Lipid panel (fasting whenever possible) 
o Serum iron, ferritin, TIBC, TSAT 
o CHr 
o HbA1c 
o Reticulocyte count 
o Special laboratory analytes 
o Archival serum/plasma samples (optional donation, separate consent form) 
• Complete physical exam. 

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• Serum hCG test for women of childbearing potential (for definition, see Section 3.6.6) 
 
• Blood pressure, HR, temperature, respiration rate 
 
• HRQoL questionnaires (SF-36, FACT-An, and EQ-5D-5L) 
 
• 12-lead electrocardiogram 
 
• Adverse event recording 
 
• Concomitant medication recording 
 
• Procedures and nondrug therapy recording 
 
Erythropoiesis-stimulating agents may be started ≥ 3 days after the last dose of roxadustat. 
 
6.1.2.6 Early Termination (ET) 
If a subject discontinues study medication permanently during the Treatment Period, perform the 
EOT assessments at the time of withdrawal from dosing or as soon as possible (Section 6.1.2.5). 
Erythropoiesis-stimulating agents may be started ≥ 3 days after the last dose of roxadustat. 
Unless consent is withdrawn, these subjects will be followed up for CV events of interest, vital 
status, and hospitalization until study closure. 
These subjects will be followed up every 3 to 6 months (depending on the availability of the 
subjects) until study closure. These visits may occur either in person or via telephone. 
6.1.3 Post-Treatment Follow-Up Period 
6.1.3.1 End of Study: 4 weeks (± 7 days) after EOT or ET 
• Laboratory tests: 
o Complete blood count with WBC differential 
o Serum chemistry 
o Lipid panel (fasting whenever possible) 
o Serum iron, ferritin, TIBC, TSAT 
o CHr 
o HbA1c 
o Reticulocyte count 
o Special laboratory analytes 
o Archival serum/plasma samples (optional donation, separate consent form) 
• Targeted physical exam 
 
• Serum hCG test for women of childbearing potential 

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• Blood pressure, HR 
 
• Adverse event recording 
 
• Concomitant medication recording 
 
• Procedures and nondrug therapy recording 
 
6.1.3.2 
Subject Discontinuation 
Subjects may discontinue from the study at any time. Discontinued subjects should be 
encouraged to complete the ET and the EOS visit procedures. The appropriate documentation 
must be entered on the CRF. Subjects should be discontinued from the study for any of the 
following reasons: 
• Subject no longer consents to participate in the study 
 
• Investigator’s decision that it is in the best interest of the subject to be withdrawn from 
the study 
• Adverse events 
 
• Significant noncompliance with study procedures, as determined by the Investigator or 
Sponsor 
• Lack of Efficacy / Meets ESA withdrawal criteria (for subjects on roxadustat; see also 
Section 3.6.3.2) 
• Subject is lost to follow-up 
 
• Subject is no longer requiring dialysis due to kidney transplant 
• Pregnancy 
 
• Death 
 
• Site terminated by Sponsor 
 
Women of childbearing potential who withdraw from this study will continue contraception for 
12 weeks following the last study drug administration. Male subjects with partners of 
childbearing potential must agree to use a medically acceptable method of contraception during 
the study and for 12 weeks following the last study drug administration. 
6.2 Missed Visits 
Every attempt should be made to complete all study visits as outlined in the Schedule of 
Assessments (Appendix 3). All missed study visits and visits outside the visit window are 
considered protocol deviations. 

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6.3 Unscheduled Visits 
Unscheduled visit(s) and laboratory assessments may be required at the discretion of the 
Investigator. Please refer to the CRF Completion Guidelines located in the Study Reference 
Manual for additional information. 
6.4 Laboratory Assessments 
Central laboratory results should be reviewed by the Investigator or another qualified study staff 
member as soon as it is received. Subject management is dependent upon close review of the 
laboratory data. 
6.4.1 HemoCue® / CritLine® 
Hemoglobin values obtained by point-of-care devices such as HemoCue® or CritLine® are used 
to allow “real-time” dose adjustments for all subjects. HemoCue®/ CritLine® results will be 
collected in the CRF. Anytime an Hb is obtained via such a point-of-care device, a central lab Hb 
should be obtained as well, either as part of the regular visit labs, or anytime when a point-of- 
care Hb is obtained at unscheduled visits, such as during dose-hold for excessive hematopoiesis. 
6.4.2 Central Laboratory 
All study related tests of blood specimens will be performed by a central laboratory. 
Unscheduled and repeat laboratory tests will also be performed by the central laboratory. 
However, if the turnaround time from the central laboratory is not sufficiently rapid for clinical 
management of the subject, local laboratory (ie, “stat” labs, USA) test results may be used to 
make the necessary clinical judgments. In all such cases, a central lab specimen should be 
obtained at the same time. 
A Central Laboratory Manual with instructions on specimen collection, processing, storing, and 
shipping to the central laboratory will be provided to all participating sites. 
Laboratory parameters to be measured in this study are listed in Table 3. 

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Table 3 
Laboratory Tests 
 
CBC: 
Chemistry Panel: 
Basophils 
Albumin 
Eosinophils 
Bicarbonate 
Erythrocyte count (RBC) 
BUN 
Hb 
Calcium 
Hct 
Chloride 
Leukocyte count (WBC) 
Creatinine 
Lymphocytes 
Glucose 
Mean corpuscular volume 
Lipase 
Mean corpuscular Hb 
Lactate dehydrogenase 
Mean corpuscular Hb concentration 
Liver Function Tests 
Monocytes 
ALP 
Neutrophils 
ALT 
Neutrophils, immature (banded) 
AST 
Platelets 
Bilirubin, total and direct 
Reticulocyte count 
CPK 
GGT 
Serum Lipid Panel: 
Magnesium 
Total Cholesterol 
Phosphorus 
LDL 
Potassium 
HDL 
Sodium 
Triglycerides 
Total protein 
Serum Iron Profile 
Uric acid 
Ferritin 
HIV and Viral Hepatitis Panel: 
Iron 
Anti-HCV Ab tests 
Reticulocyte Hb content 
HBsAg 
TIBC 
HIV ELISA 
TSAT 
Special Laboratory Analytes: 
Additional Laboratory Analytes: 
Hepcidin 
Vitamin B12 
High-sensitivity CRP 
Folate 
HbA1c 
Serum β-HCG 

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Abbreviations: 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood 
urea nitrogen; CBC = complete blood count; CRP = C-reactive protein; ELISA = enzyme-linked immunosorbent 
assay; GGT = gamma-glutamyl transferase; Hb = hemoglobin; HbA1c = glycated hemoglobin A1c; 
HBsAg = hepatitis B surface antigen; Hct = hematocrit; HCV = hepatitis C virus; HDL = high-density 
lipoprotein; HCG-  human chorionic gonadotropin; HIV = human immunodeficiency virus; LDL = low-density 
lipoprotein; RBC = red blood cell; TIBC = total iron binding capacity; TSAT = transferrin saturation; 
WBC = white blood cell. 
 
Archival serum/plasma samples: 
A set of serum and plasma samples may be drawn and 
stored for the future analysis of relevant select biomarkers. 
Donation of these samples is optional and will be sought 
through a separate informed consent form (ICF). No 
genetic testing will be performed for the diagnosis of 
genetic disorders on these samples. 
6.5 Electrocardiogram 
Local 12-lead ECGs will be performed on all subjects at specific time points as described in the 
Schedule of Assessments. ECG will be taken after the subject has been lying quietly in the 
supine position for 5 minutes. Any abnormalities must be evaluated in clinical context (based on 
subject’s medical history and concomitant medication) and the Investigator should determine if it 
is clinically significant. Clinically significant abnormalities should be reported as an AE. ECG 
recordings will be kept as source documents. Abnormal ECG findings prior to administration of 
study drug on Day 1 will be considered baseline conditions. 
6.6 Renal Ultrasound 
A renal ultrasound examination will be performed during screening if no record of a renal 
imaging modality exists within 12 weeks prior to randomization. Findings of the renal ultrasound 
to exclude the presence or suspicion of renal cell carcinoma will be required for eligibility. Sites 
are reminded to schedule the renal ultrasound in a timely manner. 
6.7 Health Related Quality of Life Questionnaires 
All study subjects will be required to complete the following HRQoL questionnaires: SF-36, 
FACT-An, and EQ-5D-5L. 
6.7.1 36-Item Short Form Health Survey 
The 36-Item Short Form Health Survey is a HRQoL instrument designed to assess generic health 
concepts relevant across age, disease, and treatment groups. It is aimed at both adults and 
adolescents ages 18 years and older. The SF-36 consists of 8 domains of health status: physical 
functioning (PF) (10 items), role physical (4 items), bodily pain (2 items), general health 
(5 items), vitality (4 items), social functioning (2 items), role emotional (3 items) and mental 
health (5 items). Two component scores, the Physical Component Scores and the Mental 
Component Summary can also be calculated. For both the SF-36 domain scores and summary 
scores, higher scores indicate better health status. 
6.7.2 FACT-An 
The Functional Assessment of Cancer Therapy-General (FACT-G; Version 4) contains 27 items 
that cover four dimensions of well-being: physical (7 items), functional (7 items), social/family 
(7 items), and emotional (6 items). A subscale of 13 fatigue specific items plus 7 additional items 

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related to anemia were developed for use in conjunction with the FACT-G (Yellen, 1997). The 
13 fatigue items plus the 7 additional items related to anemia comprise the Anemia Subscale. 
Administration of the FACT-G plus the Anemia Subscale is referred to as the FACT-An. The 
FACT-An has a recall period of the ‘past seven days’. Respondents are asked to provide 
responses, (ie, ‘Not at all’, ‘A little bit’, ‘Somewhat’, ‘Quite a bit’ and ‘Very much’), to a list of 
statements which are either positively or negatively phrased. For all FACT-An scales, a higher 
score indicates better QoL. 
6.7.3 European Quality of Life Questionnaire in 5 Dimensions 
The EQ- 5D-5L consists of the EQ-5D descriptive system and the EQ visual analog scale. The 
EQ-5D-5L descriptive system comprises 5 dimensions of health: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, 
slight problems, moderate problems, severe problems, extreme problems. The visual analog scale 
records the respondent's self-rated health status on a graduated (0–100) scale, where the 
endpoints are labeled ‘Best imaginable health state’ and ‘Worst imaginable health state’ with 
higher scores for higher HRQoL. EQ-5D-5L health states, defined by the EQ-5D-5L descriptive 
system, may be converted into a single summary index by applying a formula that essentially 
attaches values (also called weights) to each of the levels in each dimension. 

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7 ENDPOINTS AND ASSESSMENTS 
In the endpoint definitions below, rescue therapy for roxadustat treated subjects is defined as 
ESA rescue or RBC transfusion and rescue therapy for epoetin alfa-treated subjects is defined as 
RBC transfusion. 
All endpoints related to Hb are based on central lab values 
7.1 Primary Endpoint: 
• US (FDA) submission: Mean Hb change from baseline to the average level during the 
Evaluation Period, defined as Week 28 until Week 52. This analysis will be based on the 
intent-to-treat (ITT) population. Hemoglobin values under the influence of rescue therapy 
will not be censored for the primary analysis. 
• Ex-US submission: The proportion of subjects who achieve a Hb response at two 
consecutive visits during the first 24 weeks of treatment, without rescue therapy within 6 
weeks prior to the Hb response. This analysis is based on the Per Protocol Set (PPS) 
population. 
A Hb response is defined, using central laboratory values, as 
• Hb ≥ 11.0 g/dL and a Hb increase from baseline by ≥ 1.0 g/dL in subjects whose 
baseline Hb > 8.0 g/dL, or 
• Increase in Hb ≥2.0 g/dL in subjects whose baseline Hb ≤ 8.0 g/dL 
7.2 Secondary Endpoints 
• US (FDA) submission: The proportion of subjects who achieve a Hb response at two 
consecutive visits during the first 24 weeks of treatment, without rescue therapy within 6 
weeks prior to the Hb response. 
A Hb response is defined, using central laboratory values, as 
• Hb ≥ 11.0 g/dL and a Hb increase from baseline by ≥ 1.0 g/dL in subjects whose 
baseline Hb > 8.0 g/dL, or 
• Increase in Hb ≥ 2.0 g/dL in subjects whose baseline Hb ≤ 8.0 g/dL 
• Ex-US submission: Mean Hb change from baseline to the average level during the 
Evaluation Period, defined as Week 28 until Week 36 without rescue therapy within 6 
weeks prior to and during the evaluation period. This analysis will be based on the PPS 
population. 
Both, US and ex-US Submissions: 
• Average monthly IV iron use per subject during the Treatment Period. Mean change in 
low-density lipoprotein (LDL) cholesterol averaged over Weeks 12 to 24. 

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• Blood pressure effects: 
 
o Proportion of subjects with exacerbation of hypertension, meeting at least one of the 
following criteria: 
 
 Increase in BP: An increase from baseline of ≥ 20 mm Hg systolic BP and sBP 
>170 mmHg, or an increase from baseline of ≥ 15 mm Hg diastolic BP and 
dBP>100 mmHg. Increases from baseline in blood pressure must be confirmed by 
repeat measurement. 
o Time to an increase in BP as defined above. 
o Mean change in mean arterial pressure (MAP) averaged over Weeks 8 to 12. 
• Time to achieve first Hb response as defined by the primary endpoint (ex-US) (which is 
the secondary endpoint for the US [FDA]). 
7.3 Additional Evaluation of Efficacy 
• Hemoglobin Correction and Maintenance: 
o Hemoglobin maintenance: Mean change in Hb averaged over 8 weeks of 
treatment at Weeks 28 to 52, without rescue therapy within 6 weeks prior to and 
during this 8-week evaluation period. 
o Hemoglobin long-term Maintenance: Mean change in Hb averaged over 8 weeks 
of treatment at Weeks 44 to 52 without rescue therapy within 6 weeks prior to and 
during this 8-week evaluation period 
o Mean change in Hb averaged over the 96 to 104 weeks of treatment, without 
rescue therapy within 6 weeks prior to and during this 8-week evaluation period 
o Change in Hb at each of the selected time points 
o Change in Hb averaged over 8 weeks of treatment at Weeks 28 to 36, without 
rescue therapy within 6 weeks prior to and during this 8-week evaluation period, 
in subjects who have reached a Hb ≥ 11 g/dL prior to Week 28 
o Proportion of subjects with Hb within 10 to 12 g/dL in United States and 10 to 
13 g/dL in Ex-US averaged over Weeks 28 to 36, without rescue therapy within 6 
weeks prior to and during this 8-week evaluation period 
• Hospitalizations: 
o Occurrence (number) of hospitalization(s) 
o Proportion of subjects hospitalized 
o Number of days of hospitalizations per patient-exposure year (PEY) 
• Missed dialysis sessions 

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• Rescue Therapy Use: 
o Proportion of subjects who receive RBC transfusions 
o Number of RBC packs per patient-month exposure to study medication 
o The proportion of subjects requiring ESA rescue therapy will be summarized 
• Changes in Cholesterol Levels: 
o Change at each of the selected treatment time points in: 
 Total cholesterol 
 LOL/HDL ratio 
 Non-HDL cholesterol. 
o Proportion of subjects achieving LDL target of < 100 mg/dL averaged over 
Weeks 12 to 24 of treatment. 
Additional Blood Pressure Effects: 
o Proportion of subjects achieving blood pressure treatment goal in ESRD subjects 
(pre dialysis systolic BP < 140 mmHg systolic and diastolic BP< 90 mmHg) 
averaged over Weeks 12 to 28 
• HRQoL and EQ-5D-5L Benefits of Anemia Therapy: 
Mean change averaged over Weeks 12, 36 and 52 of treatment including those listed 
below. 
o Vitality Subscale of SF-36: In FAS subjects with baseline Vitality Subscore below 
50 
o Physical Component Scores of SF-36: 
 In FAS subjects with baseline physical component scores below 40 
 In all FAS subjects 
o Anemia Subscale (“Additional Concerns”) of Functional Assessment of Cancer 
Therapy-Anemia (FACT-An) Scores: 
 In FAS subjects with baseline subscale scores below 55 (generally 
associated with fatigue) 
 In all FAS subjects 
o Total FACT-An Scores: 
 In FAS subjects with baseline FACT-An scores below 135 
 In all FAS subjects 
o 
EQ-5D-5L Scores: In all FAS subjects 

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• Hepcidin, Iron, and HbA1c: 
o Change in serum hepcidin at each of the selected time points 
o Change 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 
o Change in TSAT at each of the selected time points, total and sub-grouped by 
baseline values of < 20%, 20% to 40%, and >40% 
o Change in HbA1c level at each of the selected time points in all subjects, in 
subjects with history of diabetes 
7.4 Safety Assessments and Endpoints 
Study-specific safety will be assessed by evaluating the following: 
• TEAEs, TESAEs, and clinically significant laboratory values from baseline 
• Vital signs, ECG findings and clinical laboratory values 
Safety interpretation will also be made based on analyses of composite endpoints derived from 
adjudicated events pooled across multiple studies in the roxadustat Phase 3 program. The 
members of an independent adjudication committee blinded to treatment assignment will 
adjudicate the following events in multiple phase 3 studies: 
• Death from any cause, MI, stroke, congestive heart failure requiring hospitalization, 
unstable angina requiring hospitalization, hypertensive emergency, deep venous 
thrombosis, pulmonary embolism, and vascular access thrombosis. 
• Various region-specific pooled analyses of composites of these adjudicated events, 
pooled across multiple studies will be conducted. The analyses of the adjudicated events 
will be detailed in the region-specific pooled SAPs. 
For US (FDA) Only: The primary safety endpoint in this study is the Major Adverse Cardiac 
Event (MACE) composite endpoint, defined as time to first occurrence of death from all causes, 
MI, or stroke, for the purpose of being pooled across multiple similar studies in the Phase 3 
program. None of the individual studies are powered to meet the MACE primary safety endpoint 
individually. The pooled MACE analysis is only for purposes of supporting a US FDA 
regulatory filing of roxadustat. 
The above adjudicated safety events may also be used to support the pooled analyses of 
additional composite safety endpoints across multiple studies in the Phase 3 program, such as 
MACE+ (death, MI, stroke, congestive heart failure requiring hospitalization, and unstable 
angina requiring hospitalization), or a composite which consists of all of the adjudicated events. 

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8 STATISTICAL CONSIDERATIONS 
8.1 Sample Size Determination 
The sample size calculation is based on the primary endpoint for both the US (FDA) submission 
and Ex-US submission. 
At least 600 subjects will be enrolled in this study. During the course of this study, which is 
being conducted in parallel with other Phase 3 studies, up to 1200 subjects may be enrolled for 
safety evaluation of roxadustat in comparison to epoetin alfa including adjudicated and 
prespecified safety events of interest (ie, all-cause death, MI, stroke, congestive heart failure 
requiring hospitalization, unstable angina requiring hospitalization, DVT, pulmonary embolism, 
vascular access thrombosis, and hypertensive emergency). The final number of patients to be 
enrolled will be based on the enrollment rate of other studies within the same indication, in order 
to optimize stopping these studies at a comparable time frame. 
With at least 600 subjects, the study will provide at least 99% power to demonstrate statistical 
noninferiority of roxadustat versus ESA in the primary endpoint for US (FDA) submission 
(ie, specifically, Hb change from baseline to the average level during the evaluation period 
defined as Week 28 until Week 52). This assumes a difference (roxadustat minus ESA) of 
0.30 g/dL, a noninferiority margin for this difference of 0.75 g/dL and a standard deviation of 
1.25 g/dL. This endpoint will be analyzed using the ITT population for the US (FDA) 
submission. 
The study will provide at least 99% power to demonstrate statistical noninferiority of roxadustat 
versus ESA in the primary endpoint outside of the United States (ie, the proportion of subjects 
who achieve a Hb response at two consecutive visits during the first 24 weeks of treatment). This 
assumes a 80% responder rate for both roxadustat and epoetin alfa, in order to support the 
primary efficacy analysis (ie, a noninferiority comparison in responder rate between roxadustat 
and epoetin alfa) and assuming a noninferiority margin of -15% for this difference (roxadustat 
minus epoetin alfa). This endpoint will be analyzed using the PPS population for the European 
Medicines Agency (EMA) submission. 
Randomization will be stratified by the following three factors: 
1. 
Geographical region (US vs. Ex-US) 
2. 
Screening Hb values (≤ 8 g/dL vs. > 8 g/dL) 
3. 
Cardiovascular/cerebrovascular/thromboembolic medical history (yes vs. no). 
8.2 Analysis Populations 
The following analysis populations will be used for the statistical analysis: 
• Safety Population: The Safety Population consists of all subjects who received at least 
one dose of study treatment. All safety data will be tabulated using descriptive statistics. 
If treatment received during the study differs from the randomized treatment, the actual 
treatment arm will be used for the analysis. 

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• Intent-to-Treat population: The ITT population consists of all randomized subjects. The 
primary efficacy endpoint for the US (FDA) submission will be analyzed using this 
population. In addition, the superiority comparison of this endpoint for the US (FDA) 
submission will be performed using this population as well. 
• Full Analysis Set: The FAS consists of all subjects who receive at least one dose of study 
drug and have at least one postdose Hb assessment. If treatment received differs from the 
randomized treatment, the randomized treatment arm will be used. Efficacy analysis for 
superiority will be conducted on the FAS population for the EMA submission. 
• Per Protocol Set: The PPS consists of all randomized subjects who received at least 4 
weeks of study treatment, have at least one postdose Hb assessment and are without 
major protocol violations. Criteria for PPS exclusion will be defined in the Statistical 
Analysis Plan (SAP). Non-inferiority analyses for the EMA submission will be based on 
the PPS. 
8.3 Interim Data Cut 
There are currently no plans to conduct an interim data cut.. 
Safety data and dosing decisions will be monitored on an ongoing basis. Additional ongoing 
review of safety data will be conducted by an independent DSMB (Section 3.8). 
8.4 Statistical Analysis 
Safety and efficacy data will be summarized and presented by treatment group and time point in 
summary tables. Descriptive statistics including number of subjects (N), means, standard 
deviations, medians, and minimum and maximum values will be presented for continuous 
variables. Counts and percentages will be presented for categorical variables. For efficacy 
endpoints, the standard error and 95% CIs will be presented as part of the descriptive summaries. 
8.4.1 Subject Enrollment and Disposition 
A table will provide the number of randomized subjects (ITT), treated subjects (Safety 
population), FAS and PPS subjects and subjects who terminated the Treatment Period/study 
early along with the reason for ET. 
8.4.2 Demographics and Baseline Characteristics 
Demographics (age, race, sex), baseline characteristics including stratification factors, and 
subject disease characteristics will be summarized for the Safety, ITT, FAS and PPS populations. 
Descriptive statistics will be calculated for continuous variables (eg, age, weight, baseline Hb, 
body mass index) and frequency counts and percentages will be tabulated for categorical 
variables (eg, sex, race, Hb category, region, iron status, and history of cardiovascular disease or 
cerebrovascular disease) by treatment group and overall. 
8.4.3 Efficacy Analyses 
Efficacy analysis for superiority will be conducted on the ITT population for US (FDA) 
submission and on the FAS population for Ex-US submission. 

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Efficacy analysis for non-inferiority will be conducted on the ITT population for US (FDA) 
submission and on the PPS population for Ex-US submission. 
Hemoglobin results obtained from the central laboratory will be used for all efficacy analyses. 
Baseline Hb is defined as the mean of at least three central laboratory Hb values: the last two 
screening Hb values prior to randomization plus the one predose Hb value on Day 1 of the 
Treatment Period. 
8.4.3.1 Primary Efficacy Analysis 
US (FDA) Submission: The primary efficacy endpoint for US (FDA) submission is defined as 
the mean Hb change from baseline to the average level during the Evaluation Period, defined as 
Week 28 until Week 52. The analysis will be based on the ITT population. Hb values under the 
influence of rescue therapy will not be censored for the primary efficacy analysis. 
The primary hypothesis to be tested for the primary efficacy analysis is: 
H0: Hb mean change from baseline to the average level from Week 28 to Week 52 in the 
roxadustat arm ≤ Hb mean change from baseline in the epoetin alfa arm minus 0.75 g/dL 
Versus: 
H1: Hb change from baseline to the average level of Week 28 to Week 52 in the 
roxadustat arm > Hb mean change from baseline in the epoetin alfa arm minus 0.75 g/dL 
A Multiple Imputation Analysis of Covariance (MI ANCOVA) model will be used for the 
primary endpoint (change from baseline in Hb from Week 28 to Week 52). 
The model will contain terms for treatment arm, baseline Hb measurement,  and randomization 
stratification factors, except for Screening Hb values (< 8g/dL vs. > 8g/dL). Detailed analysis of 
the primary [efficacy] endpoint will be outlined in the SAP. The primary efficacy analysis for  
US [FDA] and sensitivity analysis for the first secondary endpoint for ex-US submissions will be 
based on the estimated difference between the two treatment arms of the overall mean effects 
throughout the evaluation period based on the MI ANCOVA model. 
In addition, as a sensitivity analysis, the primary efficacy endpoint for US [FDA] and primary 
analysis for the first secondary endpoint for ex-US submissions will be analyzed using the 
analysis of a model for repeat measures (MMRM). The MMRM model will contain terms for 
baseline Hb, as covariate, treatment arm, visit, visits by treatment arm, and randomization 
stratification factors (except for Screening Hb values (,< 8g/dL vs > 8g/dL) as fixed effects. 
Additional analysis using pattern mixture approaches would be detailed in the SAP. 
Due to the large amount of visits to include in the model, the unstructured covariance pattern 
model will be tested against the less parameterized heterogeneous Toeplitz structure using the 
likelihood ratio test for nested models. If the algorithm for unstructured covariance pattern does 
not converge or the likelihood ratio test is not statistically significant then heterogeneous 
Toeplitz structure will be used. If this second model does not converge either, then the 
(homogeneous) Toeplitz structure will be tried and finally compound symmetry as a covariance 
structure to achieve convergence. 
This null hypothesis will be rejected if the two-sided 95% CI for the difference (roxadustat 
minus epoetin alfa) of two least square means from the mixed model lies entirely above –0.75 
g/dL. 

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Hb values under the influence of a rescue therapy will not be censored in the primary analysis. 
Ex–US Submission: The primary efficacy endpoint for Ex-US submission is defined as the 
proportion of subjects who achieve a Hb response at two consecutive visits during the first 24 
weeks of treatment, without rescue therapy within 6 weeks prior to the Hb response. 
• A Hb response is defined, using central laboratory values, as: Hb ≥ 11.0 g/dL and a Hb 
increase from baseline by ≥ 1.0 g/dL in subjects whose baseline Hb > 8.0 g/dL, or 
• Increase in Hb ≥ 2.0 g/dL in subjects whose baseline Hb ≤ 8.0 g/dL 
Rescue therapy for roxadustat treated subjects is defined as ESA rescue or RBC transfusion, and 
rescue therapy for epoetin alfa treated subjects is defined as RBC transfusion. 
The hypothesis to be tested for the primary efficacy analysis is: 
H0: Hb response rate for subjects in the roxadustat arm - Hb response rate for subjects in 
the epoetin alfa arm ≤ -15% 
Versus 
H1: Hb response rate for subjects in the roxadustat arm - Hb response rate for subjects in 
the epoetin alfa arm > -15% 
A two-sided 95% CI for the difference of 2 responder rates (roxadustat minus epoetin alfa) based 
on the Miettinen & Nurminen approach adjusting for treatment and other stratification factors 
will be calculated and this null hypothesis will be rejected if the lower bound of the 95% CI is 
greater than -15%. 
The stratification factors to be used in efficacy analyses are: 
1. Geographical region 
2. Screening Hb values (≤ 8 g/dL vs. > 8 g/dL) 
3. Cardiovascular/cerebrovascular/thromboembolic medical history (Yes vs. No) 
8.4.3.2 Secondary Efficacy Analyses 
Once the null hypothesis has been rejected for the primary endpoint (for both, US [FDA] and ex- 
US submissions), the secondary endpoints below will be tested using a fixed sequence testing 
procedure, in order to maintain the overall two-sided Type I error rate at 0.05. If p-value from a 
test is < 0.05, the claim of superiority (or noninferiority) will be considered met and the test will 
progress to the next comparison in sequence as follows: 
• US (FDA) Submission: The first secondary endpoint for US (FDA) submission is defined as 
the proportion of subjects who achieve a Hb response at two consecutive visits during the 
first 24 weeks of treatment, without rescue therapy within 6 weeks prior to the Hb response. 
A Hb response is defined, using central laboratory values, as: 
• Hb ≥ 11.0 g/dL and a Hb increase from baseline by ≥ 1.0 g/dL in subjects whose 
baseline Hb > 8.0 g/dL, or 
• Increase in Hb ≥ 2.0 g/dL in subjects whose baseline Hb ≤ 8.0 g/dL 

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The hypothesis to be tested for this efficacy analysis is: 
H0: Hb response rate for subjects in the roxadustat arm - Hb response rate for subjects in 
the epoetin alfa arm ≤ 15% 
Versus 
H1: Hb response rate for subjects in the roxadustat arm - Hb response rate for subjects in 
the epoetin alfa arm > 15% 
A two-sided 95% CI for the difference of 2 responder rates (roxadustat minus epoetin alfa) 
based on the Miettinen & Nurminen approach adjusting for treatment and other stratification 
factors will be calculated and H0 will be rejected if the lower bound of the 95% CI is greater 
than -15%. 
• Ex-US Submission: The first secondary endpoint for Ex-US submission is the mean change 
in Hb levels from baseline to the average level during the Evaluation Period, defined as 
Week 28 until Week 36. This analysis will be based on the PPS population. 
The primary hypothesis to be tested for this efficacy analysis is: 
H0: Hb mean change from baseline to the average level from Week 28 to Week 36 in the 
roxadustat arm ≤ Hb mean change from baseline in the epoetin alfa arm minus 0.75 g/dL 
Versus: 
H1: Hb change from baseline to the average level of Week 28 to Week 36 in the 
roxadustat group > Hb mean change from baseline in the epoetin alfa group minus 0.75 
g/dL 
This efficacy endpoint will be analyzed using a mixed model of repeated measures (MMRM) 
with Hb baseline value as covariate and treatment group and randomization stratification 
factors as fixed effects and MI ANCOVA as sensitivity analysis for Ex-US submission. 
This null hypothesis will be rejected if the two-sided 95% CI for the difference of least 
square means from the mixed model is above –0.75 g/dL. 
Hb values under the influence of a rescue therapy within 6 weeks prior to and during this 8- 
week evaluation period will be censored in the analysis. 
• The average monthly iron use will be compared between the 2 treatment groups using an 
ANCOVA model with baseline iron replete as a covariate, and treatment group and 
randomization stratification factors as fixed effects. Superiority will be declared if the lower 
bound of the two-sided 95% CI of the difference between epoetin alfa and roxadustat exceeds 
zero. 
• Mean change from baseline in LDL cholesterol averaged over Weeks 12 to 24 will be 
analyzed using an MMRM model with baseline LDL cholesterol as a covariate and treatment 
group, visit, visits by treatment arm, and randomization stratification factors as fixed effects. 
Superiority will be declared if the lower bound of the two-sided 95% CI of the difference 
between epoetin alfa and roxadustat exceeds zero. 

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• Proportion of subjects with exacerbation of hypertension, meeting at least 1 of the following 
criteria will be analyzed using CMH model adjusting for treatment group and stratification 
factors 
o Increase in blood pressure: An increase from baseline in systolic blood pressure 
(sBP) of ≥ 20 mm Hg and sBP > 170 mmHg or an increase from baseline in diastolic 
blood pressure (dBP) of ≥ 15 mm Hg and dBP > 100 mmHg. Increases from baseline 
in blood pressure must be confirmed by repeat measurement. 
Noninferiority of roxadustat vs. epoetin alfa will be tested. Non-inferiority will be declared if the 
upper bound of the two-sided 95% CI of the hazard ratio is less than 1.3. 
• Time to an increase in blood pressure (defined as an increase from baseline of ≥ 20 mm Hg 
systolic BP and sBP >170 mmHg or an increase from baseline of ≥ 15 mm Hg diastolic BP 
and dBP > 100 mmHg). Time to an increase in blood pressure will be analyzed using the 
Cox Proportional Hazards model adjusting for treatment group and randomization 
stratification factors. Superiority of roxadustat vs. epoetin alfa will be tested. 
• Mean change in mean arterial pressure (MAP) averaged over Weeks 8 to 12 will be analyzed 
using an MMRM model with baseline MAP as a covariate and treatment group, visit, visits 
by treatment arm, and randomization stratification factors as factors. Superiority will be 
declared if the lower bound of the two-sided 95% CI of the difference between epoetin alfa 
and roxadustat exceeds zero. 
The time to achieve the first Hb response defined as the primary endpoint (for ex-US 
submission) will be analyzed using the Cox Proportional Hazards model adjusting for treatment 
group and other stratification factors. Non-inferiority of roxadustat vs. epoetin alfa will be tested. 
Non-inferiority will be declared if the upper bound of the two-sided 95% CI of the hazard ratio is 
less than 1.3. 
8.4.3.3 Additional Efficacy Analyses 
• Hemoglobin maintenance: The mean change in Hb averaged over 8 weeks of treatment at 
Weeks 28 to 52 without rescue therapy within 6 weeks prior to and during this 8-week 
evaluation period. The mean change in Hb will be analyzed using an MMRM model with 
baseline Hb as a covariate and treatment group, visit, visits by treatment arm, and 
randomization stratification factors as fixed effects. Non-inferiority between roxadustat 
compared with epoetin alfa will be declared if the lower bound of the two-sided 95% CI of 
the difference between roxadustat and epoetin alfa exceeds -0.75 g/dL. All subjects will be 
included in the analysis 
• HRQoL benefit of roxadustat will be assessed using SF-36 vitality and physical functioning 
subscales. Change from baseline at Weeks 12, 36, and 52 will be computed for each 
treatment group. A paired t-test will be used to assess within treatment effect. Between 
treatment difference will be assessed using an MMRM model with baseline subscore as a 

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covariate and treatment group visit, visits by treatment arm, and randomization stratification 
factors as factors. Noninferiority of roxadustat vs. epoetin alfa will be tested. The non- 
inferiority margin is fixed as a difference of 2 points. 
The additional efficacy analyses will use the FAS population. 
Additional efficacy analyses of continuous endpoints will use an MMRM model with baseline 
value, visit, visits by treatment arm, and randomization stratification factors as covariates. 
Additional efficacy analyses of proportions will use the CMH model adjusting for treatment 
group and randomization stratification factors. 
Additional efficacy analyses of time-to-event endpoints will use the Cox Proportional Hazards 
model adjusting for treatment and randomization stratification factors. 
8.4.4 Safety Analyses 
Safety analyses will be performed using the Safety Population. Safety parameters include AEs, 
laboratory parameters, vital signs, ECG parameters, and PEs. 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 of that safety parameter. 
The analytical methods for the MACE endpoint, as well as other composite safety endpoints of 
interest, will be described in a region-specific pooled statistical analysis plan to reflect the nature 
of the pooling of these endpoints across comparable studies in the Phase 3 program and the 
region-specific safety endpoints. 
8.4.4.1 Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
An AE (classified by preferred term) occurring during the Treatment Period will be considered a 
TEAE if it was not present prior to the first dose of study medication, or if it was present prior to 
the first dose of study medication but increased in severity during the Treatment Period. An AE 
that occurs more than 28 days after the EOT/ET visit date will not be counted as a TEAE. 
The number and percentage of subjects reporting TEAEs in each treatment group will be 
tabulated by system organ class and preferred term; by system organ class, preferred term, and 
severity; and by system organ class, preferred term, and relationship. If more than one event 
occurs with the same preferred term for the same subject, the subject will be counted only once 
for that preferred term using the most severe and most related occurrence for the summarization 
by severity and by relationship to the study medication. 
The overall distribution of TEAEs by severity and relationship to study medication will be 
summarized by treatment group. 
The proportion of subjects with TESAEs, fatal SAEs (ie, events that caused death), and AEs 
leading to discontinuation of study medication will be summarized by SOC, preferred term and 
treatment group 
Treatment emergent adverse events of interest will also be reported in terms of incidence rate per 
PEY. 

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Listings will be presented of subjects with SAEs, subjects with AEs leading to discontinuation, 
and subjects who died. 
8.4.4.2 Clinical Laboratory Parameters 
Descriptive statistics for laboratory values and changes from baseline at each assessment time 
point will be presented by treatment group for each laboratory parameter. 
8.4.4.3 Vital Signs 
Descriptive statistics for vital signs (sBP and dBP, pulse rate, respiration rate) and their changes 
from baseline at each visit and, the end of study will be presented by treatment group. 
8.4.4.4 Electrocardiogram 
Descriptive statistics for ECG parameters (eg, HR, PR interval, QRS interval, QT interval, and 
QTc interval) at baseline and changes from baseline at each assessment time point will be 
presented by treatment group. 
8.4.5 Statistical Analysis Plan 
The Statistical Analysis Plan will provide details of the data analyses. As an open-label study the 
SAP will be finalized prior to accumulation of a substantial amount of data to ensure lack of bias. 
Any significant changes to the analyses described in this protocol will be highlighted in the SAP 
and the Clinical Study Report. 
8.4.6 Protocol Deviation 
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The investigator is responsible for ensuring the 
study is conducted in accordance with the procedures and evaluations described in this protocol 
and must protect the rights, safety, and welfare of subjects. The investigator should not 
implement any deviation from, or changes of, the protocol, unless it is necessary to eliminate an 
immediate hazard to trial subjects. Guidelines related to roxadustat, epoetin-alfa, and IV iron 
administration deviations are described in the respective sections. 

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9 SAFETY 
9.1 Background 
Adverse event reports from Investigators are the critical building blocks to the development of 
the safety profile of the study drug. Subjects will be asked nonleading questions in general terms 
to determine the occurrence of AEs, according to the schedule outlined in Appendix 3. In 
addition, all AEs reported spontaneously during the course of the study will be recorded. The 
Investigator must immediately (within 24 hours of awareness) report to the sponsor all SAEs, 
regardless of whether the Investigator believes they are related to the study drug. 
The definitions of an AE, suspected adverse reaction, adverse reaction, and SAE are 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. 
9.2 Definitions 
9.2.1 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 (eg, an abnormal and clinically significant 
laboratory finding), symptom, or disease temporally associated with the use of a drug, without 
any judgment about causality. This includes any occurrence that is new in onset or aggravated in 
severity or frequency from the baseline condition, or abnormal results of diagnostic procedures, 
including laboratory test abnormalities. An AE can arise from any use of the drug (eg, off-label 
use, use in combination with another drug) and from any route of administration, formulation, or 
dose, including an overdose. 
An AE includes medical conditions, signs, and symptoms not previously observed in the subject 
that emerge during the protocol-specified AE reporting period, including signs or symptoms 
associated with an underlying condition that were not present prior to the AE reporting period 
(Section 9.3.1). 
9.2.2 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 (ie, if in the view of the Investigator or sponsor, the subject was at 
immediate risk of death at the time of the event). Life-threatening does not refer to an 
event which hypothetically might have caused death if it were more severe. 
• Inpatient hospitalization or prolongation of existing hospitalization 
 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 

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• A congenital anomaly or birth defect, or 
 
• An important medical event (based on appropriate medical judgment, the event 
jeopardizes the subject and may require medical or surgical intervention to prevent one of 
the above-listed outcomes) 
9.2.3 Definition of a Suspected Adverse Reaction 
Suspected adverse reaction means any AE for which there is a reasonable possibility that the 
drug caused the AE. The term “reasonable possibility” means there is evidence to suggest a 
causal relationship between the drug and the AE. A suspected adverse reaction implies a lesser 
degree of certainty about causality than the term “adverse reaction.” 
9.2.4 Definition of an Adverse Reaction 
An adverse reaction means any AE caused by a drug. 
9.2.5 Special situations 
Certain safety events called “Special Situations” that occur in subjects while on the medicinal 
products administered as part of the study require reporting may include, but are not limited to: 
• Overdose of the medicinal product 
• Suspected abuse/misuse of the medicinal product 
• Inadvertent or accidental exposure to the medicinal product 
• Medication error involving the medicinal product (with or without subject/patient 
exposure to the Sponsor medicinal product; eg, name confusion) 
• Drug-drug interaction 
9.3 Procedures for Eliciting, Recording, and Reporting Adverse Events 
9.3.1 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 ET/EOT Visit Date (ie, completion of 4-week ET Follow- 
up visit for the Early Terminated subjects and completion of End of Study (EOS) visit for the 
Completed subjects) except for pregnancy reporting (Section 9.3.6). In addition, all AEs reported 
spontaneously by the subject to site personnel, outside the study period, may be recorded. 
Adverse events will be followed until resolved, stable, or until the subject’s last study visit or lost 
to follow-up. If an AE is not resolved or stabilized at the subject’s last visit, it is up to the 
discretion of the Investigator and study Medical Monitor to determine if further monitoring of the 
event is warranted. 
Adverse events collected prior to dosing of study drug will be considered “nontreatment 
emergent” while those reported after the first dose of study drug and up to 28 days after the last 
dose of study drug will be considered “treatment emergent” and be assessed for relationship to 
study drug. 

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9.3.2 Adverse Event Eliciting/Reporting 
During the AE reporting period, study site personnel will query each subject at each visit to 
actively solicit any AE occurring since the previous visit. All AEs will be collected in response 
to a general question about the subject’s well-being and any possible changes from the baseline 
or previous visit, but shall not be specifically solicited. There will be no directed questioning for 
any specific AE. This does not preclude the site from collecting and recording any AEs reported 
by the subject to site personnel at any other time. 
Whenever possible, diagnoses should be recorded when signs and symptoms are due to a 
common etiology, as determined by qualified medical study staff. New indications for 
medications started after informed consent is obtained until 28 days after the last dose of study 
drug will be recorded as AEs; recurrence or worsening of medical history problems requiring 
new or changes in concomitant medication, will also be recorded as AEs. Abnormal, clinically 
significant laboratory results, PE findings, and ECGs will be recorded as AEs if they are deemed 
the Investigator to meet criteria 
The following attributes must be assigned to each AE: 
• Description (Investigator’s verbatim term describing the event). 
 
• Dates of onset and resolution 
 
• Severity 
 
• Relationship to study drug 
 
• Outcome 
 
• Action taken regarding study drug (action taken by the PI in response to an AE) 
 
• Other treatment required 
 
• Determination of “seriousness” 
 
9.3.3 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 (eg, 
preparing meals, shopping for groceries or clothes, using the telephone, managing 
money); local or noninvasive intervention indicated. 

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• 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. 
 
9.3.4 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 miscategorization 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 product safety profile. 
The Investigator must provide an assessment of the relationship of the AE to study drug in 
accordance with the guidance below. Absence of an alternative cause would not normally be 
considered enough evidence to assess an event as possibly related or related to study drug. 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. 
Not Related: 
• The event represents the underlying disease (eg, 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 (eg, cardiovascular events in an elderly 
population). 

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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 making the final causality 
assessment for individual reports, and for reporting suspected adverse reactions and adverse 
reactions to Health Authorities. 
9.3.5 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 Sponsor’s 
designated safety management vendor within 24 hours of becoming aware of the serious event. 
In case of emergency or doubt, the Investigator shall call Sponsor’s Medical Monitor for 
guidance. Follow-up reports must be submitted in a timely manner as additional information 
becomes available. 
Full details of the SAE should also be recorded on the medical records and in the CRF. The 
following minimum information is required: 
• Subject number, sex and age 
 
• The date of report 
 
• A description of the SAE (event, seriousness of the event) 
 
• Causal relationship to the study drug 
 
Follow-up information for the event should be sent promptly (within 7 days) as necessary. 
For each SAE observed, the Investigator should obtain all of the information available about the 
event, including (but not limited to): hospital discharge diagnoses, hospital discharge note, death 
certificate, appropriate laboratory findings (including autopsies and biopsy results), and clinical 
examinations (including radiological examinations and clinical consultations). 
9.3.5.1 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. 
9.3.5.2 Deaths 
For any death occurring during the subject’s study participation, regardless of attribution, the 
Investigator will report the death immediately to the Sponsor’s Medical Monitor and their 
designated safety management vendor. 
The Investigator should notify Sponsor and their designated safety management vendor of any 
death or other SAE occurring after a subject has discontinued or terminated study participation 
that may reasonably be related to the study. 

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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. 
9.3.6 Pregnancies: Reporting and Follow-up of Subjects 
A pregnancy in a female subject or a male subject’s female partner must be confirmed by 
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 Sponsor (by way 
of its designated safety management vendor) within 24 hours of the Investigator learning of the 
pregnancy. If applicable, a pregnant subject is immediately withdrawn from receiving study 
treatment. The Investigator must follow the pregnancy to completion to ascertain both its 
outcome and whether any AEs occur. 
Pregnancy itself is not an AE. However, the Investigator should report the information to the 
sponsor on the designated forms. Pregnancies are followed up to outcome. The outcome 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. 
9.3.7 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 (eg, laboratory parameter, vital sign, ECG data, 
PE) 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 
• In the opinion of the Investigator, the abnormality is clinically meaningful and 
significantly different from baseline. 
9.3.8 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 

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of the disease. Gradual worsening of ESRD should be considered disease progression and 
should not be reported as an AE during the study. 

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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, CRFs, 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 (eg, laboratory, safety, IXRS, 
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 the Sponsor immediately. 

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11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 Data Quality Assurance 
The following steps will be taken to ensure that the study is conducted by the study site in 
compliance with the study protocol, GCP, and other applicable regulatory requirements. 
• Investigator meeting and/or Investigator site initiation. 
 
• Routine study site monitoring. 
 
• Documented study and system training. 
 
• CRF and query review against source documents. 
 
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. 
11.3 Database Audit 
A database audit will be conducted to ensure data quality and integrity. 
Ethics 

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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 obtaining a signed, 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 (eg, 
MedDRA and World Health Organization Drug [WHODrug]) Dictionary. 
The Investigator is responsible for reviewing, verifying, and approving all subject data, ie, CRFs 
and queries prior to study completion, ensuring that all data is verifiable with source documents. 

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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, including partial and empty bottles, must be maintained at the study 
site until Sponsor or its designee verifies drug accountability and provides instruction for 
destruction or the return of the investigational product to Sponsor’s drug distribution depot. 
Accurate records of all study drug received, dispensed, returned, and disposed of by the study 
site according to the Study Reference Manual should be recorded using the Drug Inventory Log. 
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 REFERENCE LIST 
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. 
Buchler, P., et al. "Hypoxia-inducible factor 1 regulates vascular endothelial growth factor 
expression in human pancreatic cancer." Pancreas 26.1 (2003): 56-64. 
Collins, A. J., et al. "Trends in anemia treatment with erythropoietin usage and patient 
outcomes." American Journal of Kidney Diseases : The Official Journal of the National 
Kidney Foundation 32.6 Suppl 4 (1998): S133-S141. 
Coresh, J., et al. "Prevalence of chronic kidney disease in the United States." JAMA : the journal 
of the American Medical Association 298.17 (2007): 2038-47. 
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. 
Eschbach, J. W., et al. "Recombinant human erythropoietin in anemic patients with end-stage 
renal disease. Results of a Phase 2I 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 1 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. 
FDA. "Guidance for Industry on Complicated Urinary Tract Infections: Developing Drugs for 
Treatment." Federal Register 77.37 (2012). 
Fishbane, S. and A. Besarab. "Mechanism of increased mortality risk with erythropoietin 
treatment to higher hemoglobin targets." Clinical Journal of the American Society of 
Nephrology 2.6 (2007): 1274-82. 
Go, A. S., et al. "Chronic kidney disease and the risks of death, cardiovascular events, and 
hospitalization." N Engl J Med 351.13 (2004): 1296-305. 
Gray, M. J., et al. "HIF-1alpha, STAT3, CBP/p300 and Ref-1/APE are components of a 
transcriptional complex that regulates Src-dependent hypoxia-induced expression of 
VEGF in pancreatic and prostate carcinomas." Oncogene 24.19 (2005): 3110-19. 
Greijer, A. 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. 

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Hu, C. J., et al. "Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF- 
2alpha in hypoxic gene regulation." Mol Cell Biol 23.24 (2003): 9361-74. 
Krapf, R. and H. N. Hulter. "Arterial hypertension induced by erythropoietin and erythropoiesis- 
stimulating agents (ESA)." Clinical Journal of the American Society of Nephrology 4.2 
(2009): 470-80. 
Langsetmo, I., Stephenson.R., Jacob, C., Zhang, W., Klaus, S., Lin, A., Kochendoerfer, G., and 
Yeowell, D. Effect of roxadustat in a Rat Model of Anemia of Chronic Disease. 
301_05_3510_047 (ACD6). 2005. 
NKF K/DOQI. "KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for 
anemia in chronic kidney disease: update of hemoglobin target." American Journal of 
Kidney Diseases : The Official Journal of the National Kidney Foundation 50.3 (2007): 
471-530. 
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. 
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, G. L. "HIF-1: mediator of physiological and pathophysiological responses to hypoxia." 
J.Appl.Physiol 88.4 (2000): 1474-80. 
Singh, A. K., et al. "Correction of anemia with Epoetin alfa in chronic kidney disease." N Engl J 
Med 355.20 (2006): 2085-98. 
Tonelli, M., et al. "Chronic kidney disease and mortality risk: a systematic review." American 
Society of Nephrology 17.7 (2006): 2034-47. 
Unger, E. F. FDA Perspectives on ESAs for Anemia of Chronic Renal Failure: Hemoglobin 
Target and Dose Optimization. 9-11-2007. FDA Department of Health and Human 
Services. Joint Meeting of the Cardiovascular and renal Drugs Advisory Committee and 
the Drug Safety and risk Management Advisory Committee. 10-16-2007. 
USRDS. "U.S. Renal Data System, USRDS 2000 Annual Data Report: Atlas of End-Stage Renal 
Disease in the United States, National Institutes of Health, National Institute of Diabetes 
and Digestive and Kidney Diseases, Bethesda, MD, 2000." United States Renal Data 
System (2000). 
USRDS. "U.S. Renal Data System, USRDS 2001 Annual Data Report: Atlas of End-Stage Renal 
Disease in the United States,National Institutes of Health, National Institute of Diabetes 
and Digestive and Kidney Diseases, Bethesda, MD, 2001." United States Renal Data 
System (2001). 
USRDS. "U.S. Renal Data System, USRDS 2002 Annual Data Report: Atlas of End-Stage Renal 
Disease in the United States,National Institutes of Health, National Institute of Diabetes 
and Digestive and Kidney Diseases, Bethesda, MD, 2002." United States Renal Data 
System (2002). 

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USRDS. "U.S. Renal Data System, USRDS 2003 Annual Data Report: Atlas of End-Stage Renal 
Disease in the United States, National Institutes of Health, National Institute of Diabetes 
and Digestive and Kidney Diseases, Bethesda, MD, 2003." United States Renal Data 
System (2003). 
USRDS. "U.S. Renal Data System, USRDS 2009 Annual Data Report: Atlas of Chronic Kidney 
Disease and End-Stage Renal Disease in the United States, National Institutes of Health, 
National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2009." 
United States Renal Data System (2009). 
USRDS. "U.S. Renal Data System, USRDS 2011 Annual Data Report: Atlas of Chronic Kidney 
Disease and End-Stage Renal Disease in the United States." United States Renal Data 
System (2011). 
Wang, G. L., et al. "Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer 
regulated by cellular O2 tension." Proc Natl Acad Sci U S A 92.12 (1995): 5510-14. 
Warnecke, C., et al. "Differentiating the functional role of hypoxia-inducible factor (HIF)-1alpha 
and HIF-2alpha (EPAS-1) by the use of RNA interference: erythropoietin is a HIF-2alpha 
target gene in Hep3B and Kelly cells." The FASEB Journal 18.12 (2004): 1462-64. 
Winearls, C. G., et al. "Effect of human erythropoietin derived from recombinant DNA on the 
anaemia of patients maintained by chronic haemodialysis." Lancet 2.8517 (1986): 1175- 
78. 
Yellen, S. B., et al. "Measuring fatigue and other anemia-related symptoms with the Functional 
Assessment of Cancer Therapy (FACT) measurement system." J Pain Symptom.Manage. 
13.2 (1997): 63-74. 
Zhang, Y., et al. "Epoetin requirements predict mortality in hemodialysis patients." American 
Journal of Kidney Diseases : The Official Journal of the National Kidney Foundation 
44.5 (2004): 866-76. 

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18 APPENDICES 

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Appendix 1 
Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 2 
Roxadustat Dose Adjustment Rules 
Dose adjustments should occur in two separate study dosing phases: the Correction Phase and 
the Maintenance Phase (see below). The aim of the Correction Phase is to increase Hb levels 
from baseline to the target Hb level. This phase is variable in length for each subject. The 
determination of Hb response and transition from the Correction to the Maintenance Phase of the 
study is based on the central laboratory Hb value. 
All dose adjustments should be based on Hb values using a point-of-care device, such as 
HemoCue® or CritLine®. In the event that the central lab Hb value of the site visit is significantly 
different and the dose adjustment decision based on the HemoCue® / CritLine® value is being re- 
considered, the Medical Monitor should be contacted, if possible. 
Dose adjustment reviews will occur on Week 4, and at intervals of every 4 weeks thereafter 
(Weeks 8, 12, 16, etc.), except in the event of excessive hematopoiesis, in which case doses may 
be adjusted at any time. In such cases, dose adjustment reviews are resumed at 4-week intervals. 
For example, if the subject’s Hb increases > 2.0 g/dL from Week 1 to Week 3, the subject’s dose 
is reduced by one dose step at Week 3. The next dose adjustment review should occur 4 weeks 
later at Week 7. If the dose adjustment interval falls on a non-study visit week (starting Week 4), 
the dose adjustment review should be performed at the next scheduled study visit if a dose 
adjustment was not required at the previous visit. For example, if a subject’s visit is scheduled 
for Weeks 6 and 8, and the dose adjustment would occur at Week 7, then the dose adjustment 
should be evaluated at the Week 8 visit. 
All subjects will be dosed orally TIW during the Treatment period. If a subject requires < 20 mg 
TIW (ie, < 60 mg per week) to maintain the target Hb level, the dosing frequency should be 
reduced in a step-wise fashion eg, TIW to BIW, BIW to QW, QW to Q-2 Week etc. The Medical 
Monitor should be notified as soon as possible of such dose change. The maximum roxadustat 
dose is 3.0 mg/kg per dose or 400 mg (whichever is lower). 
The following scenarios are defined as “excessive hematopoiesis”; 
1. Hb increases by > 2.0 g/dL at any time within a 4 week period: 
reduce the dose by one dose step. 
2. Hb reaches or exceeds 13 g/dL: hold dosing, check Hb weekly. 
Resume dosing when Hb < 12.0 g/dL (for US subjects central lab 
Hb value preferred), at a dose that is reduced by two dose steps. 
For subjects on prolonged dose-hold, with stable (not dropping) Hb, PI may use discretion to 
schedule less frequent visits. Anytime Hb is assessed via HemoCue®/CritLine®/local lab, a 
central lab Hb should be obtained as well. 
Given the complexity in roxadustat dose adjustments,  and the need to take into account the 
various clinical parameters in roxadustat dose titration, one would not consider it a protocol 
deviation when study subjects are dosed based on their clinical circumstances, whether or not it 
is concordant with  the roxadustat dose adjustment guidelines unless it was related to “excessive 
hematopoiesis”  (eg,,Hb ≥ 13 g/dL, requiring a dose hold)) or “Overdose” (prescribed >3.0 
mg/kg per dose or 400 mg per dose whichever is lower) 
 
 
 
 
 
 

DocuSign Envelope ID: 1B482E3D-40AC-4777-9E3D-573C49788EDD 
Roxadustat 
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FibroGen, Inc. 
Confidential and Proprietary 
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CORRECTION PHASE 
MAINTENANCE PHASE 
Change in Hb 
from 4 weeks 
earlier (g/dL) 
Hb < 11 g/dL 
(central lab)* 
Hb ≥ 13.0 g/dL 
Hb < 10.5 
g/dL 
Hb 10.5 to 11.9 
g/dL 
Hb 12.0 to 12.9 
g/dL 
Hb ≥ 13.0 
g/dL 
< -1.0 
↑ 
Hold, then 
resume dosing 
when: 
Hb < 12 g/dL, at a 
dose that is reduced 
by two dose steps 
Subjects are to 
return weekly to 
monitor Hb until 
dosing can be 
resumed** 
↑ 
↑ 
No change 
Hold, then resume 
dosing when: 
Hb < 12 g/dL, at a dose 
that is reduced by two 
dose steps 
Subjects are to return 
weekly to monitor Hb 
until dosing can be 
resumed** 
-1.0 to 1.0 
↑ 
↑ 
No change 
↓ 
> 1.0 
No change 
No change 
↓ 
↓ 
Dose Increases and Reductions: 
Dose Adjustment for Excessive Hematopoiesis: 
Dose increases (↑) and reductions (↓) are preset to dose steps. 
The dose steps are as follows: 
20, 40, 50, 70, 100, 150, 200, 250, 300, and 400 mg. 
Example: A dose increase at a dose of 70 mg results in 100 mg as the new dose. A dose 
reduction at a dose of 150 mg results in 100 mg as the new dose. 
Note: Maximum dose capped at 3.0 mg/kg per dose or 400 mg, whichever is lower. 
*Transition from Correction to Maintenance Phase will occur once the 
central laboratory Hb value is ≥ 11 g/dL and ≥ 1 g/dL from baseline 
At any time during the Treatment Period if Hb increases by 
>2.0 g/dL within 4 weeks, the dose should be reduced by one dose 
step. 
** For subjects on prolonged dose-hold, with stable (not dropping) 
Hb, PI may use discretion to schedule less frequent visits. Anytime 
Hb is assessed via HemoCue®/CritLine®/local labs, a central lab Hb 
should be obtained as well 
Abbreviations: 
↑ = increase; ↓ = decrease; Hb = hemoglobin. 

DocuSign Envelope ID: 1B482E3D-40AC-4777-9E3D-573C49788EDD 
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FibroGen, Inc. 
Confidential and Proprietary 
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Appendix 3 
Schedule of Assessments 
 
Study Period: 
Screening 
Treatment 
Follow-up 
Visit / Week: 
Up to 
6 Weeks a 
Day 1 
(Wk 0) 
Weekly 
(Wks 1 to 4) 
± 2 days 
Every 2 Weeks 
(Wks 6 to 24) 
± 4 days 
Every 4 Weeks 
(Wks 28 to EOT) 
± 4 days b 
EOT or ET 
± 7 days 
EOS 
(4 wks post EOT or ET) 
± 7 days 
1 
2 
Written informed consent 
X 
Eligibility criteria 
X 
X 
Demographics and medical history 
X 
Physical examination 
X 
X 
Wks 12 c, 24 c 
Wks 36 c, Q12Wk c, d 
X 
X c 
Height, weight 
X 
X e 
Wk 24 and every 24 
weeks e 
Blood pressure, heart rate, respiratory 
rate, temperature f 
X 
X 
X 
X 
X 
X 
X 
X 
Hemoglobin 
X 
X g 
X g 
CBC with WBC differential 
X 
X 
X 
Wks 8. 12, 20 
Wk 28, Q8Wk 
X 
X 
Serum chemistry 
X 
X 
Wk 2 
Wks 8,12, 20 
Wk 28, Q8Wk 
X 
X 
LFTs, CPK 
Wk 2 
Wks 6, 16 
Lipid panel (whenever fasting possible) 
X 
X 
Wk 4 
Wks 8, 12, 24 
Wks 32, 40, 48, 60, 
Q24Wk 
X 
X 
Serum iron, ferritin, TIBC, TSAT 
X 
X 
Wk 4 
Wks 8, 12, 20 
Wk 28, Q8Wk 
X 
X 
CHr 
X 
X 
Wk 4 
Wks 8, 12, 20 
Wk 28, Q8Wk 
X 
X 
HbA1c 
X 
X 
Wk 12 
Wks 28, 44, 60 Q16Wk d 
X 
X 
Vitamin B12, folate 
X 
HIV ELISA, HBsAg, anti-HCV Ab 
X 
Serum hCG pregnancy test 
X h 
Wks 12, 24 
Wk 36, then Q12 weeks 
X 
X 
Reticulocyte count 
X 
Wks 1, 2 
Wks 8, 20 
Wk 44, Q24Wk 
X 
X 
Special laboratory analytes (hepcidin, 
hs-CRP) 
X 
Wk 4 
Wks 12, 20 
Wk 44, Q24Wk 
X 
X 
Optional archival serum/plasma 
samples 
X 
Wk 4 
Wks 12, 20 
Wk 44, Q24Wk d 
X 
X 
HemoCue® assessment 
X 
X 
X 
X 
Quality-of-life questionnaires 
X 
Wk 12 
Wks 36, 52 d 
X 
12-lead ECG 
X 
Wk 24 and every 24 
weeks 
X 
Renal ultrasound i 
X 
Dose adjustment j 
X 
X 
X 
Adverse event recording 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication recording 
X 
X 
X 
X 
X 
X 
X 
X 
Procedure and nondrug therapy 
recording 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dispensing k 
X 
X l 
X 
X 
Footnotes on following page 

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Confidential and Proprietary 
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Abbreviations: 
Ab = antibody; BP = blood pressure; CBC = complete blood count; CHr = reticulocyte hemoglobin content; ELISA = enzyme-linked immunosorbent assay; EOT = End 
of Treatment; EOS = End of Study; ET = early termination; Hb = hemoglobin; HbA1c = glycated hemoglobin A1c; HBsAg = hepatitis B surface antigen; hCG = human 
chorionic gonadotropin; HCV = hepatitis C virus; HD = hemodialysis; HIV = human immunodeficiency virus; HR = heart rate; HRQoL = health-related quality of life 
questionnaire; HS-CRP = high-sensitivity C reactive protein; ICF = informed consent form; LFTs = liver function tests; PE = physical examination; RBC = red blood 
cell; RR = respiratory rate; SmPC = summary of product characteristics; TIBC = total iron binding capacity; TSAT = transferrin saturation; TX = treatment; WBC = 
white blood cells; Wk(s) = week(s); X = mandatory test/assessment. 
a 
Screening Hb values must be obtained at least 2 days apart. 
b 
Treatment duration is variable for each subject. All subjects will remain in the study treatment until up to 3 years after the last subject randomized. 
c 
Targeted PE only (eg, respiratory and cardiovascular). 
d 
If the indicated assessments fall on a study treatment visit that is within two weeks of the planned EOT visit, then these specified assessments can be postponed until the EOT visit. 
e 
Weight only (HD subjects: use dry weight). 
f 
Perform HR and BP at all week visits. Additional respiratory rate and temperature are measured at Day 1/Week 0 and EOT/ET. 
g 
Dedicated Hb sample for central lab should be collected during the visits where CBC is not collected. 
h 
Collect from female subjects of child bearing potential only (for definition, see Section 3.6.6) . 
i 
A renal ultrasound examination will be performed during screening if no record of a renal imaging modality exists within 12 weeks prior to randomization. 
j 
Roxadustat subjects: Dose adjustments will be permitted from Week 4 onward, and every 4 weeks thereafter (except in extenuating circumstances) to correct and maintain subjects 
to a target Hb range. Please refer to dose adjustment rules as stated in Appendix 2. 
Epoetin alfa subjects: Dose adjustments for HD subjects receiving epoetin alfa will follow the country specific product labeling (eg, PI; SmPC) for dosing and dose adjustments. 
For HHD and PD subjects, local standard of care may be followed for dosing and dose adjustments. 
k 
All assessments should be done prior to first study drug administration. 
l 
Dispense every other week 
m 
Subjects who prematurely discontinue study treatment will complete the ET and EOS visits, and – unless consent is withdrawn – will continue to be followed for CV events of 
interest, vital status and hospitalizations until study closure. These subjects will be asked to return for study visits every 3 to 6 months, or be available via telephone. 

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

DocuSign Envelope ID: 1B482E3D-40AC-4777-9E3D-573C49788EDD 
Roxadustat 
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FibroGen, Inc. 
Confidential and Proprietary 
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Appendix 5 
Blood Pressure and Heart Rate Measurement Guidelines 
Blood Pressure 
Blood pressure (BP) measurement should be done with the subject comfortably seated in a chair, 
with the legs uncrossed, and the back and arm supported, such that the middle of the cuff on the 
upper arm is at the level of the right atrium (the midpoint of the sternum). The subject should be 
instructed to relax as much as possible and to not talk during the measurement procedure; 
ideally, 5 minutes should elapse before the first reading is taken. Preferably measurement will be 
done with an electronic automated device. The same device should preferably be used for the 
subject during the course of the study, timing as indicated in the Schedule of Assessments. Also 
the same arm should be used consistently for readings throughout the study. 
Blood pressure should be measured in triplicate (preferred) with at least one-minute interval 
between the measurements. In subjects on HD, BP should be measured prior to the start of the 
dialysis procedure that day, preferably using the nondialysis arm. In subjects on HHD/PD, BP 
should be measured approximately at the same time of the day at each visit. 
Heart Rate 
Heart rate measurement should be done at rest in a sitting position wherever possible. It can be 
performed with an electronic automated device as used for BP measurement. The same device 
should preferably be used for the subject during the course of the study, timing as indicated in 
the schedule of assessments. Heart rate (HR) should be measured in triplicate (preferred) with at 
least one-minute interval between the measurements. In subjects on HD, HR should be measured 
at predialysis and in subjects on HHD/PD and should be measured approximately at the same 
time of the day at each visit. 

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Roxadustat 
Protocol FGCL-4592-063 Amendment 4 
FibroGen, Inc. 
Confidential and Proprietary 
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Appendix 6 
Permitted Intravenous Iron Therapy 
 
Iron Preparations (generic names) 
Iron gluconate 
Iron sucrose complex 
Iron dextran complex 
Iron isomaltoside 
Iron polymaltose complex