Conditions: CKD Anemia in Stable Dialysis Patients
Keywords: Anemia Chronic Kidney Disease Dialysis hemodialysis peritoneal dialysis hemoglobin End stage renal disease Stable Dialysis erythropoietins erythropoiesis stimulating agent
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 741
Healthy volunteers: no

Brief summary:
The primary objective of this study is to evaluate the efficacy and safety of roxadustat compared with active control (epoetin alfa) for the maintenance treatment of anemia in participants with ESRD on dialysis.

Detailed description:
This study will consist of three study periods as follows:

1. Screening Period of up to 6 weeks (8 weeks if on Mircera)
2. Treatment Period: a minimum of 52 weeks, a maximum of up to 3 years from the date last participant is randomized. Minimum study duration for participants enrolled under Protocol Amendment 1 or 2 may be less than 52 weeks
3. A Follow-up period of 4 weeks.

Participants will be randomized in a 1:1 ratio to receive either roxadustat or epoetin alfa (active control) in an open-label manner.

Arms:
arm 1: Participants will receive roxadustat tablets, administered orally 3 times weekly (TIW). Initial roxadustat dose will be based on the participant's average prescribed erythropoietin stimulating agent (ESA) dose in the 4 weeks (if on epoetin or darbepoetin or 8 weeks (if on Mircera®) prior to randomization. Dose adjustments will be permitted to maintain a hemoglobin (Hb) level of approximately 11 grams (g)/deciliter (dL). The maximum roxadustat dose is 3.0 milligrams (mg)/kilogram (kg) per dose or 400 mg per administration (whichever is lower). arm 2: Participants on hemodialysis (HD) will receive epoetin alfa, administered intravenously (IV) TIW and participants on home HD or peritoneal dialysis (PD) will receive epoetin alfa, administered subcutaneously (SC). Initial epoetin alfa dose will be based on the participant's average weekly prescribed ESA dose in 4 weeks prior to randomization if on epoetin or darbepoetin, and average monthly (4-week) prescribed ESA dose in 8 weeks prior to randomization if on Mircera®. In case of a change in route of administration from SC to IV (TIW), the initial dose of IV epoetin alfa will be determined by the investigator per local standard of care (SOC). Dose adjustments will follow the recommendations as per the approved country-specific product label (United States Package Insert \[USPI\] or Summary of Product Characteristics \[SmPC\]) or local SOC.

Interventions: intervention 1: Epoetin Alfa intervention 2: Roxadustat
Intervention descriptions: intervention 1: Epoetin alfa will be administered per dose and schedule specified in the arm. intervention 2: Roxadustat will be administered per dose and schedule specified in the arm.

Protocol document:
Prot_000.pdf: 
CONFIDENTIALITY STATEMENT 
The information contained in this document is confidential and proprietary to FibroGen, Inc. No part of this 
document or any of the information contained herein may be transmitted, disclosed, shared, reproduced, published 
or utilized by any persons without prior written authorization by FibroGen, Inc. 
1 TITLE PAGE 
CLINICAL STUDY PROTOCOL 
STUDY TITLE: 
A Phase 3, Open-Label, Randomized, Active-Controlled 
Study of the Efficacy and Safety of Roxadustat (FG-4592) 
in the Maintenance Treatment of Anemia in Subjects with 
End Stage Renal Disease (ESRD) on Stable Dialysis 
PROTOCOL NUMBER: FGCL-4592-064 
SPONSOR: 
FibroGen, Inc. 
409 Illinois Street 
San Francisco, California 94158 USA 
IND NUMBER: 
074454 
STUDY DRUG: 
Roxadustat (FG-4592) 
INDICATION: 
Anemia associated with ESRD 
FIBROGEN MEDICAL 
MONITOR: 
Name: 
 
Title: 
 
Telephone: 
 
Mobile: 
 
Fax: 
 
E-mail: 
PROTOCOL VERSION 
& DATE: 
Original 
25 September 2014 
Amendment 1: 13 December 2016 
Amendment 2: 18 August 2017 
NCT # NCT02273726


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INVESTIGATOR SIGNATURE PAGE 
STUDY ACKNOWLEDGEMENT 
A Phase 3, Open-Label, Randomized, Active-Controlled Study of the Efficacy and Safety of 
Roxadustat (FG-4592) in the Maintenance Treatment of Anemia in Subjects with End 
Stage Renal Disease (ESRD) on Stable Dialysis 
FGCL-4592-064 
 
Amendment 1: 13 December 2016 
Amendment 2: 18 August 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 2  
The primary purpose of this amendment is to improve current enrollment. Incident dialysis 
subjects, target patient population for this study, are difficult to find; furthermore, they are less 
willing to participate in a clinical study due to start of routine dialysis, a life changing event. 
Among those who are interested to participate, the vast majority are not qualifying per current 
protocol eligibility criteria. Upon analyzing reasons for screen-fail and feedback from various 
investigators, it appears that some of the eligibility criteria and conduct of the study are overly 
restrictive and/or not per current standard of care. As a result, a large number of incident dialysis 
subjects who are otherwise good candidates and would benefit from this study are not being able 
to participate under existing eligibility criteria and protocol design. In order to be able to enroll 
and retain a representative sample of real-life incident dialysis subjects, we modified the 
following eligibility criteria and study conducts to reflect current standard of care in this patient 
population.  None of these proposed modifications are expected to compromise safety and 
wellbeing of the subjects who may now qualify under revised criteria.     
In addition to the major changes listed below, minor editorial changes will be 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 # 3.1 has been modified by 
removing “native kidney” – the revised verbiage 
reads as follows: 
3.1   Amendment 2 : Incident dialysis subjects 
receiving dialysis for ESRD for  ≥ 2 weeks but 
≤ 4 months at the time of randomization 
Inclusion criteria # 6.1 has been streamlined by 
reducing hemoglobin (Hb) testing frequency (from 
three to two) and interval between Hb tests (from ≥4 
days to ≥2 days) to confirm eligibility - the revised 
verbiage reads as follows (revised text is italicized 
and bolded): 
     6.1  Amendment 2: For Incident dialysis 
subjects (as defined in 3.1), mean of the 
subject’s two most recent central lab Hb values 
during the Screening Period must be ≥ 8.5 g/dL 
and ≤12.0 g/dL; with an absolute difference of 
≤ 1.3 g/dL between the highest and the lowest 
value. Samples are obtained at least 2 days 
apart and the last Hb value must be within 10 
days prior to the randomization visit 
 
Inclusion criteria # 7, 8, 9, 10 additional text has 
been added to allow for subjects that may qualify 
 
To allow subjects who restarted dialysis 
recently due to transplanted kidney end-stage 
renal disease (see revised Exclusion # 20 
below) 
 
 
 
Reducing Hb testing frequency and interval 
between tests will shorten the minimum 
screening time requirement and is expected to 
improve overall screening success.  
Also, to align with the Hb eligibility criteria in 
the FGCL-4592-063 incident-dialysis study - 
currently being conducted at the same centers 
in the US.   
 
 
 
 
 
 
 
 
 
Revised TSAT/ferritin/B12/folate criteria 
(subjects with lower values are allowed to 
SYNOPSIS; 
Section 5.1 


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Description of Change 
Rationale for Change 
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upon receiving supplementation. It now reads as 
follows (added text is italicized): 
7. Subject has a ferritin level ≥ 100 ng/mL at 
screening 
Amendment 2: Subjects with a ferritin level 
< 100 ng/mL at screening may qualify upon 
receiving iron supplement (per local standard of 
care) 
8. Subject has a transferrin saturation (TSAT) 
level ≥ 20% at screening 
Amendment 2: Subjects with a TSAT level 
< 20% at screening may qualify upon receiving  
iron supplement (per local standard of care) 
9. Subject has a serum folate level ≥ lower limit of 
normal (LLN) at screening 
Amendment 2: Subjects with a serum folate 
level < LLN at screening may qualify upon 
receiving folate supplement (per local standard 
of care) 
10. Subject has a serum vitamin B12 level ≥ LLN at 
screening 
Amendment 2: Subjects with a Vitamin B12 
level < LLN at screening may qualify upon 
receiving B12 supplement (per local standard of 
care) 
 
participate upon receiving supplement) will 
improve screening success rate. Also, this 
would help to shorten screening period by 
minimizing “unscheduled visit” to retest these 
parameters via central lab.   
 
 
 
 
Exclusion Criteria: 
Exclusion criteria 1, 11, 15, 16, 18, 19, 20 and 24 
have been modified to read as follows (revised text is 
bolded and italicized): 
1. Subject has received a red blood cell (RBC) 
transfusion within 8 weeks prior to 
randomization  
Amendment 2:  Subject has received a red 
blood cell (RBC) transfusion within 4 weeks 
prior to randomization 
 
11. Subject with New York Heart Association 
(NYHA) Class III or IV congestive heart failure  
 
15. Subject has a diagnosis or suspicion (eg, 
complex kidney cyst of Bosniak Category II or 
higher) of renal cell carcinoma as shown on 
These exclusion criteria have been modified to 
allow more incident subjects to participate who 
are otherwise good candidate for this study 
 
 
RBC transfusion within 4 weeks prior to 
randomization is not expected to impact 
baseline Hb. No additional safety concerns.   
 
 
 
 
 
Changing “has known” to “with” to align with 
other incident dialysis protocol    
 
 
Changing from renal ultrasound to renal 
imaging will allow all acceptable imaging 
options e.g. ultrasound, CT scans, MRI etc.  
 
 
SYNOPSIS; 
Section 5.2 


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Description of Change 
Rationale for Change 
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Affected a 
renal imaging performed within 12 weeks prior 
to randomization 
16. Amendment 2 Subject has a history of 
malignancy, except for the following: cancers 
determined to be cured or in remission for ≥ 2 
years, curatively resected basal cell or 
squamous cell skin cancers, cervical cancer in 
situ, or resected colonic polyps 
18. Subject has an active, clinically significant (CS) 
infection or evidence of an underlying infection, 
as manifested by white blood cell count (WBC) 
> ULN, and/or fever, in conjunction with 
clinical signs or symptoms of infection at the 
time of randomization 
19. Subject has any of the following known 
untreated conditions: proliferative diabetic 
retinopathy, diabetic macular edema, macular 
degeneration or retinal vein occlusion (subjects 
who are already blind may qualify to 
participate) 
20. Prior organ transplant: subjects who have one 
of the following  conditions or states 
a) experienced  rejection of transplanted organ 
within 6 months of transplantation 
b) currently on high doses of 
immunosuppressive therapy (per discretion of 
the PI) 
c) are scheduled for organ transplantation (on 
the waiting list for kidney transplant is not 
exclusionary) 
24. Amendment 2: Subject has a history of alcohol 
or drug abuse within 6 months prior to 
screening 
 
 
 
Changing (cancer cured) from ≥5 years to ≥2 
years will allow more incident subjects to 
qualify. No apparent safety concerns. 
 
 
 
“at the time of randomization” has been added 
to clarify the timing of exclusion due to this 
criterion. 
  
 
 
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)  
 
 
 
 
Potential subjects with no history of alcohol or 
drug abuse within 6 months are OK to 
participate – changing from 2 years to 6 
months does not pose any additional safety risk  
Investigational Product 
Dose Adjustments text regarding <20 mg dosing has 
been to modified to read as follows (revised text is 
bolded and italicized): 
If a subject requires < 20 mg TIW (i.e., < 60 mg per 
week) to maintain a Hb level of approximately 11 
g/dL, the dosing frequency should be reduced in a 
step-wise fashion e.g. TIW to BIW, BIW to QW, 
QW to Q-2 Week etc. 
 
 
 
To provide guidance on IP dosing if a subject 
requires further dose reduction from 20 mg 
TIW given 20 mg is the lowest tablet strength 
available.  
 
 
 
 
 
 
 
 
 
 
SYNOPSIS; 
Sections 2.6, 
4.5.3.1, 
6.4.1, 
Appendix 2 
 
 
 
 
 
 
 
 
 


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Description of Change 
Rationale for Change 
Section(s) 
Affected a 
Added text to clarify subject weight used for dose 
adjustments as follows (revised text is bolded and 
italicized): 
For dose adjustment purposes, post-dialysis weight 
(dry-weight) should be used. If the post-dialysis 
weight of the current visit is not available at the 
time of dose adjustment, post-dialysis weight of the 
prior dialysis session or last recorded post-dialysis 
weight may be used 
Text added to clarify the options for post 
dialysis weight that may be used during dose 
adjustment to ensure that maximum allowable 
dose (3.0 mg/kg/dose) has not been exceeded. 
SYNOPSIS; 
Sections 2.6, 
4.5.3.1, 7.1 
Rescue Therapy and Emergency Procedures: 
Inadvertent ESA use or ESA received at the hospital 
with regards to ESA rescue has been revised 
From: 
Roxadustat subject who receives an ESA 
inadvertently and does not meet the criteria above 
may be allowed to continue taking study medication, 
if considered safe by the Investigator or Medical 
Monitor. 
 
To: 
Inadvertent ESA administration or ESA 
administration by the hospital staff in Roxadustat 
subjects should not be counted as rescue unless 
above criteria are met; these subjects may be allowed 
to continue taking study medication, if considered 
safe by the Investigator or Medical Monitor. 
ESA therapy is the only standard of care to 
treat anemia in ESRD patients. It is a common 
practice to administer ESA as a routine therapy 
during dialysis session. Text has been added to 
clarify that inadvertent ESA administration or 
ESA administration by the 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 
4.6.3.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Supplemental Iron Use: 
Text has been modified to change oral iron 
supplementation from 1st line of therapy to preferred 
1st line of therapy to read as follows (revised text is 
bolded) : 
In this study, oral iron should be allowed as the 
preferred first-line of iron supplementation for both 
treatment arms without restriction. 
All subjects should be encouraged to take oral iron 
if they can tolerate as the preferred first-line iron 
supplementation during the Treatment Period. 
 
 
Supplemental iron use language has been modified to 
lessen restrictions on IV iron use. IV iron 
administration criteria/rules have been replaced by 
local standard of care.  Revised text reads as follows 
(deleted IV iron guidelines is not shown here)  
Many ESRD patients cannot tolerate oral iron 
therapy due to GI adverse effects including GI 
bleeding. Channing to “preferred 1st line” 
would allow flexibility.  
 
 
 
 
 
 
 
IV iron has been the standard of care for iron 
supplementation in ESRD anemia subjects and 
it is routinely administered in subjects who are 
on ESA therapy. Current protocol IV iron 
administration guidelines are seen as overly 
restrictive and not in line with the current 
standard of care.   Text has been revised to 
SYNOPSIS; 
Sections 
4.6.2, 
4.6.2.2, 
Appendix 6 


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Description of Change 
Rationale for Change 
Section(s) 
Affected a 
Intravenous iron supplementation is permitted if in 
the opinion of the Investigator the subject has not 
responded adequately and is considered iron 
deficient. IV iron may be administered per local 
standard of care as deemed necessary by the 
investigator. 
 
allow IV iron per discretion of the PI based on 
the local standard of care.      
Screening Period: 
Text added regarding subjects who are on ESA dose-
hold due to high hemoglobin during screening reads 
as follows: 
Subjects on dose-hold due to high haemoglobin may 
qualify for screening however, they cannot be 
randomized if in investigator’s opinion they are not 
ready to resume epoetin-alfa or roxadustat upon 
randomization. 
Text has been added to guide how subjects on 
ESA dose hold are to be handled during 
screening and randomization 
SYNOPSIS; 
Section 
4.1.1  
 
Screening 3 Visit 
Screening 3 Visit has been deleted.  Unique tests and 
procedures from Screening Visit 3 have been moved 
to Screening 2 Visit.  
Additional Screening Assessments 
Following verbiage has been deleted from this 
section 
“Iron, Vitamin B12, and folate laboratory tests may 
be repeated during the screening period upon 
completing a course of therapy, if necessary.”  
 
 
Screening 3 visit has been deleted to align with 
the revised Inclusion criteria # 3.1 
 
Per revised Inclusion Criteria #7, 8, 9, and 10 – 
Iron, Vitamin B12, and folate laboratory tests 
need not to be repeated to confirm eligibility 
Sections 
7.1.1.2, 
7.1.1.3, 
Appendix 3 
Randomization/Treatment Period: 
Added text regarding 1st dose of study medication in 
subjects who were on long-acting ESAs during 
screening  to read as follows: 
Subjects on long-acting ESAs (Aranesp or Mircera) 
may not receive the 1st dose of study medication on 
the day of randomization due to ESA dosing schedule 
(e.g. once weekly or once bi-weekly); in these 
subjects, the 1st dose of study medication (roxadustat 
or epoetin-alfa) should be administered on the day 
when the next dose of current ESA would have been 
due.  For all practical purposes, the date of 1st dose 
of study drug administration should be considered as 
Day 1. 
To clarify the process of randomization and 
Day 1 dosing in subjects who are on long-
acting ESAs during screening. Typically, 
randomization and Day 1 dosing happen on the 
same day (when ESA dose is due) however, 
due to long ESA dosing interval (e.g. once 
every two weeks), randomization and Day 1 
dosing may take place on separate days.  
Sections 
4.1.1, 7.1.2 
 


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Adverse Event Eliciting/Reporting 
Added clarification regarding action taken with study 
drug (added text is bolded and italicized): 
Action taken regarding study drug (decision taken 
by the 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 (e.g. 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 
8.3.2 
Pregnancies: Reporting and Follow-up of 
Subjects 
Added clarification regarding confirmation of 
pregnancy  
A pregnancy in a female subject must be confirmed 
by positive serum β-hCG test. If β-hCG test is found 
positive in a female subject of child bearing 
potential,  study drug should be placed on hold 
temporarily until pregnancy is ruled out via a repeat 
test ≥3 days.   
Text is added to reflect the current clinical 
practice to confirm pregnancy in this patient 
population (known to have high false positive 
pregnancy results – requires repeat testing to 
confirm). Also, to minimize exposure to the 
fetus as a precaution (in case pregnancy is 
confirmed). 
Section 
8.3.6 
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 
Protocol Deviations:  
Texts have been added to pre-specify issues that are 
not to be considered as protocol deviations. Added 
texts read as follows: 
Due to the unique nature of this study, following 
issues are not to be considered as protocol 
deviations:  
 
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 patients are 
dosed according to local standard of care whether or 
not it is concordant with  package insert/SmPC 
 
Given the complexity in Roxadustat dose adjustments 
and the need to take into account the various clinical 
parameters in Roxadustat dose titration, one would 
 
 
 
To allow flexibility with EPO dosing where 
investigators/sites are not able to follow 
epoetin-alfa package insert guidelines due to 
various factors including clinical status of the 
subjects. 
Per study design, various factors such as, 
HemoCue Hb value, Central lab Hb value, PI’s 
decision etc. can influence dose titration 
decisions at the time of the visit or after the 
visit. As a result, dose prescribed may not 
match exactly with the dose that would have 
been prescribed per dose adjustment algorithm.  
However, as the stable dose would be achieved 
through titration, dosing discrepancy when 
subjects are dosed based on their clinical status 
 
 
 
 
 
 
Section 9.7 
 
 
 
 
 
 
Section 9.7 
 
 
 
 
 
 
 


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Description of Change 
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not consider it a protocol deviation when 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” (Hb ≥13 g/dL, requires a 
dose-hold) or “Overdose”  (prescribed >3.0 mg/kg 
per dose or 400 mg per dose, whichever is lower) 
 
 
 
 
ESA administrations in Roxadustat subjects during 
hospitalization are not be reported as protocol 
deviation, if the roxadustat dosing were not allowed 
or available during that hospitalized period 
 
 
 
 
 
 
IV Iron administrations in study subjects during 
hospitalization are not be reported as protocol 
deviation 
is not considered as a protocol deviation unless 
it is related to excessive hematopoiesis (≥13.0 
g/dL, requires a dose-hold) or overdose (>3.0 
mg/kg/dose or 400 mg per dose, whichever is 
lower). 
 
Roxadustat subjects often receive ESA when 
they are hospitalized either because the 
hospital doesn’t allow subjects to take any 
experimental therapy such as Roxadustat at the 
hospital or subjects do not have access to their 
study drug while they are at the hospital. Given 
that ESA is administered to treat anemia as part 
of the hospital standard care, ESA 
administration in any of these circumstances 
should not be considered as 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. IV iron administered in 
study subjects while they are hospitalized are 
not to be reported as protocol deviation in this 
study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 9.7 
 
Baseline Hb value calculation  
Added text regarding baseline Hb value calculation 
for subjects enrolled under Amendment 2. Revised 
texts read as follows - 
Subjects enrolled under Amendment 2, baseline Hb 
value for efficacy analysis is defined as the mean of 
three central laboratory Hb values, two of the latest 
screening Hb values plus the pre-dose Hb value 
collected on Day 1. 
In subjects with missing Day 1 Hb value, the mean of 
three (two, for Amendment 2) latest screening 
laboratory Hb values will be considered as BL Hb 
value.  
To align with the revised Inclusion Criteria # 
6.1  
Section 
9.4.3 
Analyses stratification 
The analyses stratified by original protocol and 
amendment 1 were updated to original protocol 
and amendments.  
 
 
 
To align with this 2nd amendment.  
Section 
9.4.3 


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Description of Change 
Rationale for Change 
Section(s) 
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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 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 
 
Changes a and b are making the wording more 
precise.  
Change c and d are corrections.  
 
 
 
SYNOPSIS; 
Section 
9.4.3 
Potential EMA Interim Analysis 
Potential EMA interim analysis description part 
was removed. 
 
Minimum 52-week treatment was not a 
requirement anymore per FDA response. It 
would be applicable to 064.   
Section 9.5 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
2 
Background ........................................................................................................................... 40 
2.1 
Introduction ................................................................................................................... 40 
2.1.1 Epidemiology of Chronic Kidney Disease and End-Stage Renal Disease ............... 40 
2.1.2 Anemia Associated with Chronic Kidney Disease ................................................... 41 
2.2 
Current standard of care for CKD or DD-CKD Anemia .............................................. 42 
2.3 
Mechanism of Action of Roxadustat ............................................................................ 43 
2.4 
Clinical Experience with Roxadustat ............................................................................ 45 
2.4.1 Pharmacokinetics and Pharmacodynamics ............................................................... 46 
2.4.2 Efficacy ..................................................................................................................... 47 
2.4.3 Safety (for detailed current safety information please refer to the Investigator’s 
Brochure) .............................................................................................................................. 49 
2.5 
Summary ....................................................................................................................... 50 
2.6 
Roxadustat Dose Rationale ........................................................................................... 50 
2.7 
Risks/Benefits of Roxadustat Treatment ...................................................................... 52 
3 
Objectives and Endpoints ..................................................................................................... 54 
3.1 
Objectives ..................................................................................................................... 54 
3.1.1 Primary Objectives.................................................................................................... 54 
3.1.2 Secondary Objectives................................................................................................ 54 
3.2 
Efficacy Endpoints ........................................................................................................ 54 
3.2.1 Primary Efficacy Endpoint: ...................................................................................... 54 
3.2.2 Secondary Efficacy Endpoints .................................................................................. 54 
3.2.3 Additional Evaluation of Efficacy ............................................................................ 55 
3.3 
Safety Endpoints ........................................................................................................... 57 
4 
Study Design ......................................................................................................................... 59 
4.1 
Description of the Study ............................................................................................... 59 
4.1.1 Screening Period ....................................................................................................... 59 
4.1.2 Treatment Period ....................................................................................................... 60 
4.1.3 Post-Treatment Follow-Up Period ............................................................................ 61 
4.1.4 Long-term Follow-Up for Premature Treatment Discontinued Subjects ................. 61 
4.2 
Randomization, Treatment Assignment, and Rationale for Open-label Design ........... 61 
4.3 
Procedures for Handling Incorrectly Enrolled or Randomized subjects ...................... 62 


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4.4 
Replacement of Subjects ............................................................................................... 62 
4.5 
Study Treatment ............................................................................................................ 62 
4.5.1 Dose and Schedule .................................................................................................... 62 
4.5.2 Starting Dose of Study Drug ..................................................................................... 62 
4.5.3 Dose Adjustment ....................................................................................................... 64 
4.6 
Concomitant Medications, Procedures and Nondrug Therapies ................................... 65 
4.6.1 Concomitant Medications ......................................................................................... 65 
4.6.2 Supplemental Iron Use .............................................................................................. 66 
4.6.3 Rescue Therapy Guidelines ...................................................................................... 67 
4.6.4 Emergency Procedure (Therapeutic Phlebotomy) .................................................... 68 
4.6.5 Prohibited Medications/Therapies/Substances ......................................................... 68 
4.6.6 Contraception ............................................................................................................ 68 
4.7 
Safety Monitoring Plan ................................................................................................. 69 
4.8 
Data Safety and Monitoring Board ............................................................................... 69 
5 
Study Enrollment and Withdrawal........................................................................................ 70 
5.1 
Inclusion Criteria .......................................................................................................... 70 
5.2 
Exclusion Criteria ......................................................................................................... 71 
5.3 
Subject Discontinuation and Withdrawal ..................................................................... 73 
5.4 
Replacement of Subjects ............................................................................................... 74 
5.5 
Study Termination ........................................................................................................ 74 
6 
Investigational Product ......................................................................................................... 75 
6.1 
Formulation ................................................................................................................... 75 
6.2 
Storage .......................................................................................................................... 75 
6.3 
Study Drug Handling and Disposal .............................................................................. 75 
6.4 
Route of Administration and Dose ............................................................................... 75 
6.4.1 Roxadustat................................................................................................................. 75 
6.4.2 Epoetin Alfa .............................................................................................................. 76 
6.5 
Overdose, Emergency Procedures and Management of Overdose ............................... 76 
7 
Assessment of Efficacy ......................................................................................................... 77 
7.1 
Study Procedures by Visit ............................................................................................. 77 
7.1.1 Screening Period ....................................................................................................... 77 
7.1.2 Treatment Period ....................................................................................................... 79 
7.2 
Post-Treatment Follow-Up Period ................................................................................ 83 


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7.2.1 End of Study (EOS): 4 weeks after EOT or ET (±7 days) ........................................ 83 
7.2.2 Long-Term Follow-Up of Subjects who Discontinued Study Medication 
Prematurely ........................................................................................................................... 83 
7.3 
Missed Visits ................................................................................................................. 84 
7.4 
Unscheduled Visits ....................................................................................................... 84 
7.5 
Laboratory Assessments ............................................................................................... 84 
7.6 
Central Laboratory ........................................................................................................ 84 
7.6.1 Archival Serum and Plasma Samples (Optional)...................................................... 86 
7.7 
Electrocardiogram ......................................................................................................... 86 
7.8 
Renal Ultrasound .......................................................................................................... 86 
7.9 
Health Related Quality of Life Questionnaires ............................................................. 86 
7.9.1 36-Item Short Form Health Survey........................................................................... 86 
7.9.2 FACT-An .................................................................................................................. 87 
7.9.3 European Quality of Life Questionnaire in 5 Dimensions........................................ 87 
8 
Safety .................................................................................................................................... 88 
8.1 
Background ................................................................................................................... 88 
8.2 
Definitions..................................................................................................................... 88 
8.2.1 Definition of an Adverse Event ................................................................................ 88 
8.2.2 Definition of a Serious Adverse Event ..................................................................... 88 
8.2.3 Definition of a Suspected Adverse Reaction ............................................................ 89 
8.2.4 Definition of an Adverse Reaction ........................................................................... 89 
8.3 
Procedures for Eliciting, Recording, and Reporting Adverse Events ........................... 89 
8.3.1 Adverse Event Reporting Period .............................................................................. 89 
8.3.2 Adverse Event Eliciting/Reporting ........................................................................... 90 
8.3.3 Assessing Adverse Event Severity............................................................................ 90 
8.3.4 Assessing Relationship to Study Drug ...................................................................... 91 
8.3.5 Reporting Serious Adverse Events on the SAE Report Form .................................. 92 
8.3.6 Pregnancies: Reporting and Follow-up of Subjects .................................................. 93 
8.3.7 Abnormal Laboratory Findings................................................................................. 94 
8.3.8 Disease Progression .................................................................................................. 94 
9 
Statistical Considerations ...................................................................................................... 95 
9.1 
Sample Size Determination........................................................................................... 95 
9.2 
Randomization .............................................................................................................. 95 


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9.3 
Analysis Populations ..................................................................................................... 95 
9.3.1 Intent to Treat Population (ITT) ............................................................................... 95 
9.3.2 Full Analysis Set (FAS) ............................................................................................ 96 
9.3.3 Per-Protocol Set (PPS) .............................................................................................. 96 
9.3.4 Safety Analysis Set (SAF) ........................................................................................ 96 
9.4 
Statistical Analysis ........................................................................................................ 96 
9.4.1 Subject Enrollment and Disposition ......................................................................... 96 
9.4.2 Demographics and Baseline Characteristics ............................................................. 96 
9.4.3 Efficacy Analyses ..................................................................................................... 96 
9.4.4 Safety Analyses ......................................................................................................... 99 
9.5 
Interim Data Cut ......................................................................................................... 101 
9.6 
Statistical Analysis Plan .............................................................................................. 101 
9.7 
Protocol Deviations ..................................................................................................... 101 
10 Direct Access to Source Documents ................................................................................... 103 
11 Quality Control and Quality Assurance .............................................................................. 104 
11.1 
Data Quality Assurance .............................................................................................. 104 
11.2 
Audit and Inspection ................................................................................................... 104 
11.3 
Database Audit ............................................................................................................ 104 
12 Ethics................................................................................................................................... 105 
12.1 
Ethical Considerations ................................................................................................ 105 
12.2 
Communication with the Institutional Review Board or Independent Ethics Committee  
 
..................................................................................................................................... 105 
12.3 
Informed Consent Form .............................................................................................. 105 
12.4 
Subject Confidentiality ............................................................................................... 106 
13 Data Handling and Record Keeping ................................................................................... 107 
13.1 
Source Documents ...................................................................................................... 107 
13.2 
Data Collection, Handling, and Verification .............................................................. 107 
14 Financing and Insurance ..................................................................................................... 108 
15 Publication Policy ............................................................................................................... 109 
16 Investigator Requirements .................................................................................................. 110 
16.1 
Study Drug Accountability ......................................................................................... 110 
16.2 
Disclosure of Data....................................................................................................... 110 
16.3 
Retention of Records................................................................................................... 110 


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17 References ........................................................................................................................... 111 
18 Appendices .......................................................................................................................... 115 
 
LIST OF TABLES 
Table 1. 
Baseline Epoetin to Starting Roxadustat Dose Conversion ...................................... 51 
Table 2. 
Initial Dosing of Roxadustat: Conversion Table from ESAs to Roxadustat ............ 63 
Table 3. 
Initial Dosing of Epoetin Alfa: Conversion table from Non-Epoetin ESAs to Epoetin 
Alfa ........................................................................................................................... 64 
Table 4. 
Laboratory Tests ....................................................................................................... 85 
LIST OF FIGURES 
Figure 1. 
Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor (HIF-PHI) Mechanism of 
Action ........................................................................................................................ 44 
LIST OF APPENDICES 
Appendix 1 Study Schema (Original Protocol) .......................................................................... 116 
Appendix 2 Roxadustat Dose Adjustment Rules ........................................................................ 117 
Appendix 3 Schedule of Assessments ........................................................................................ 119 
Appendix 4 Liver Safety Monitoring Assessment ...................................................................... 122 
Appendix 5 Blood Pressure and Heart Rate Measurement Guidelines ...................................... 124 
Appendix 6 Recommended Intravenous Iron Therapy ............................................................... 125 
 


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LIST OF ABBREVIATIONS 
~ 
Approximately 
Ab 
Antibody 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance model 
AST 
aspartate aminotransferase 
AUC 
area under the concentration curve 
AV 
Arteriovenous 
BIW 
twice weekly 
BL 
Baseline 
BP 
blood pressure 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CHr 
reticulocyte hemoglobin content 
CI 
confidence interval 
CKD 
chronic kidney disease 
Cmax 
maximum concentration 
CMH 
Cochran-Mantel-Haenszel 
CS 
clinically significant 
CYP 
cytochrome P450 
dBP 
diastolic blood pressure 
DD-CKD 
dialysis-dependent chronic kidney disease 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
eEPO 
endogenous erythropoietin 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
End of Study 
EOT 
End of Treatment 


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EPO 
Erythropoietin 
EQ-5D 
European Quality Of Life questionnaire in 5 dimensions  
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 
HDL 
HHD 
high-density lipoprotein 
home-hemodialysis 
HIF 
hypoxia-inducible factor 
HIF-PH 
HIF prolyl hydroxylase 
HIF-PHI 
HIF prolyl hydroxylase inhibitor  
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HR 
heart rate 
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 Harmonization 
IEC 
Independent Ethics Committee 
IERC 
Independent Event Review Committee 


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IND 
investigational new drug  
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent to Treat Population 
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 
MAP 
mean arterial pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
myocardial infarction 
N (or n) 
sample size 
NCS 
not clinically significant 
NDD-CKD 
nondialysis dependent chronic kidney disease 
NYHA 
New York Heart Association 
PD 
peritoneal dialysis 
PEY 
patient-exposure-year 
PH  
prolyl hydroxylase 
PK 
Pharmacokinetics 
PPS 
per protocol set 
QW 
once weekly 
RBC 
red blood cell 
RR 
respiratory rate 
RRT 
renal replacement therapy 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
Statistical Analysis Plan 
sBP 
systolic blood pressure 
SF-36 
The 36-Item Short Form Health Survey 


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SC 
Subcutaneous 
SmPC 
Summary of Product Characteristics  
SOC 
system organ class 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TIBC 
total iron binding capacity 
TIW 
three times weekly 
TSAT 
transferrin saturation 
UIBC 
unsaturated iron binding capacity 
ULN 
Upper limit of normal 
USRDS 
United States Renal Data System 
VEGF 
vascular endothelial growth factor 
WBC 
white blood cell 
Wt 
Weight 


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PROTOCOL SYNOPSIS 
Study Title: 
A Phase 3, Open-Label, Randomized, Active-Controlled Study to 
Evaluate the Efficacy and Safety of Roxadustat (FG-4592) in the 
Maintenance Treatment of Anemia in subjects with End Stage Renal 
Disease (ESRD) on Stable Dialysis  
Protocol Number: 
FGCL-4592-064 
Investigational Product: 
Roxadustat (FG-4592) 
Target Population: 
The study population consists of subjects with ESRD who are on 
stable hemodialysis (HD) or peritoneal dialysis (PD) and treated with 
an erythropoiesis-stimulating agent (ESA) for anemia. 
Amendment 1 & 2: Incident dialysis subjects with ESRD who 
are on dialysis for at least 2 weeks but no more than 4 months (at 
the time of randomization) and treated with an erythrocyte 
stimulating agent (ESA) for anemia for at least 4 weeks (prior to 
screening).  
 
IND Number: 
074454 
Study Phase: 
Phase 3 
Study Centers Planned: 
Up to approximately 200 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) 
• 
Active Control: epoetin alfa (up to approximately 600 subjects) 
Under Amendment 1 & 2, approximately 150 incident dialysis  
subjects (as defined above) will be randomized to either 
roxadustat or epoetin alfa (active control) in a 1:1 ratio 
Primary Objectives: 
Evaluate the efficacy and safety of roxadustat compared with active 
control (epoetin alfa) for the maintenance treatment of anemia in 
subjects with ESRD on stable dialysis.  
Secondary Objectives: 
• 
Evaluate the utilization of intravenous (IV) iron with roxadustat 
compared with active control (epoetin alfa) 
• 
Evaluate the effect of roxadustat on serum lipid parameters 
compared with active control (epoetin alfa) 


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Study Design Overview: 
This open-label, randomized, active controlled study is designed to 
evaluate the efficacy and safety of roxadustat compared to epoetin 
alfa for the maintenance of hemoglobin (Hb) levels in subjects on 
HD or PD originally on ESA for treatment of anemia. 
Home-hemodialysis (HHD) subjects may be allowed to participate if 
all eligibility criteria are met. 
The study periods are as follows: 
• Screening Period: Up to 6 weeks. For subjects currently 
taking Mircera®, the Screening Period can be extended up to 
8 weeks 
• Treatment Period: Treatment duration is variable for 
individual subjects, with a minimum treatment duration of 
52 weeks and a maximum duration of up to approximately 
3 years after the last subject is randomized  
Amendment 1 & 2: In order to complete the Phase 3 
program in a timely manner, minimum treatment duration of 
subjects enrolled under Amendment 1 & 2 may be shortened. 
Subjects will be informed at least 4 weeks in advance if such 
decision is made. All active subjects will end the study at the 
same time. 
• Post-Treatment Follow-Up Period: 4 weeks 
During the course of the study, visits and assessments will be 
performed as defined in the schedule of assessments. 
Screening Period 
After signing the informed consent, subjects enter the Screening 
Period. During the Screening Period eligibility assessments will be 
performed. Subjects in screening will continue their existing ESA 
therapy (eg, epoetin alfa, beta, theta, or zeta, darbepoetin alfa, 
Mircera®) for the treatment of anemia associated with ESRD. 
Subjects on dose-hold due to high haemoglobin may qualify for 
screening however, they cannot be randomized if in investigator’s 
opinion they are not ready to resume epoetin-alfa or roxadustat upon 
randomization. Upon successful completion of screening, a total of 
up to 1200 eligible subjects will be randomized to receive either 
roxadustat or epoetin alfa (active control) in a 1:1 ratio. Both 
roxadustat and epoetin alfa will be administered in an open label 
manner. 
Randomization must be completed prior to administration of study 
medication.  


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Randomization to treatment arms will be provided by an interactive 
web and voice response system (IWRS) based on stratification 
factors.  
If Day 1 lab values (collected prior to administration of study 
medication) suggests potential of pretreatment condition 
confounding safety assessment or poses safety risks to study subject, 
in the opinion of the Investigator or Medical Monitor, the subject 
may be discontinued from the study (example: At Screening 1 visit, 
LFT values were within the protocol range but at Day1, AST or ALT 
> 3x ULN and Total bilirubin > 2x ULT, or AST or ALT > 5x 
ULN). 
Treatment Period 
Administration of the first dose of study treatment (roxadustat or 
epoetin alfa) will occur on Day 1 (Week 0) which should correspond 
to the administration of the subject’s next dose of their current ESA 
treatment. At the Day 1, subjects randomized to Roxadustat Arm will 
discontinue prior ESA therapy and initiate roxadustat therapy; 
subjects randomized to Epoetin-Alfa Arm will receive epoetin-alfa 
irrespective of their prior ESA use.   
 
The initial dose of study medication will be determined based on the 
average prescribed ESA dose in the last 4 weeks prior to 
randomization if on epoetin or darbepoetin (8 weeks if on Mircera®) 
as outlined in Table S1 or Table S2 for subjects randomized to 
receive roxadustat or epoetin alfa, respectively. The initial dose of 
roxadustat will remain constant during the first 4 weeks of the 
Treatment Period, except if a dose reduction is required for excessive 
hematopoiesis. 
Subsequent dose adjustments for roxadustat subjects will follow the 
dose adjustments guidelines as outlined in Appendix 2 in order to 
maintain a Hb level of approximately 11 g/dL during the Treatment 
Period. Dose adjustments for epoetin alfa subjects should follow the 
dosing recommendations as per the approved country-specific 
epoetin alfa Package Insert or Summary of Product Characteristics 
(SmPC). In PD and HHD subjects, if receiving epoetin alfa 
subcutaneously, the dose and frequency may be determined by the 
Investigator per local standard of care. 
Day 1 study procedures including laboratory blood draws are to be 
completed prior to administration of the first dose of study treatment. 
In HD subjects, Day 1 procedures with the exception of 
health-related quality of life (HRQoL) assessments should be 
completed prior to the subject receiving dialysis that day. Weight 


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measurement will be taken after completion of dialysis (ie, dry 
weight). 
Total treatment duration is variable for individual subjects. Subjects 
will receive study treatment (roxadustat or epoetin alfa) for a 
minimum of 52 weeks. The maximum treatment duration may be up 
to approximately 3 years from the date the last subject is 
randomized.  
In order to complete the Phase 3 program in a timely manner, 
minimum treatment duration of subjects enrolled under 
Amendment 1 & 2 may be shortened. Subjects will be informed at 
least 4 weeks in advance if such decision is made. All active subjects 
will end the study at the same time. 
During the Treatment Period, subjects will attend weekly study visits 
from Day 1 to Week 2, followed by every 2 weeks study visits from 
Weeks 4 to 24 (eg, Weeks 4, 6). Following Week 24, study visits 
will occur every 4 weeks (eg, Weeks 28, 32) until End of Treatment 
(EOT). A common closeout will occur when a predetermined 
number of adjudicated cardiovascular (CV) events have been 
accrued across multiple studies in the overall Phase 3 dialysis 
program.  
At each study visit during the Treatment Period, Hb will be 
measured (prior to dialysis in HD subjects) locally to determine the 
need for a dose adjustment or to assess for excessive hematopoiesis. 
In the event that the Hb value from the central laboratory is 
significantly different from the value that measured locally, and per 
Investigator that warrants a reversal of the dose adjustment decision 
made earlier based on locally measured Hb value, the Medical 
Monitor should be informed, if possible. 
Post-Treatment Follow-Up Period 
After completing the Treatment Period, subjects proceed to the post-
treatment Follow-up Period and will return for the End of Study 
(EOS) visit. The choice of anemia treatment during the Follow-up 
Period is up to the discretion of the Investigator. If the Investigator 
decides to resume ESA treatment in roxadustat treated subjects, the 
first dose of ESA should be administered at least three days after the 
last dose of roxadustat.  
Long-term Follow-Up for Premature Treatment Discontinued 
Subjects 
Subjects who discontinue study medication prematurely will be 
followed up for vital status, CV events, and hospitalization until 
study closure, unless consent to participate is withdrawn. Upon 
completion of EOT and EOS visits, these subjects will be followed 
up every 3-6 month interval (depending on the availability of 


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subjects) until study closure. These visits may occur either in-person 
or via telephone. 
Data Safety Monitoring Board  
A Data Safety Monitoring Board (DSMB) will review safety data at 
least every 6 months or twice per calendar year while the trial is 
ongoing to ensure subject safety during the study. Details will be 
specified in a DSMB charter.  
Independent Event Review Committee 
An Independent Event Review Committee (IERC), blinded to 
treatment group, will adjudicate prespecified CV, cerebrovascular, 
and thromboembolic safety events of interest. These events include 
all cause death, myocardial infarction (MI), stroke, congestive heart 
failure requiring hospitalization, unstable angina requiring 
hospitalization, deep venous thrombosis (DVT), pulmonary 
embolism, vascular access thrombosis, and hypertensive emergency. 
A separate event adjudication charter will describe the process in 
detail, and training materials will be provided to study sites.  
Inclusion Criteria: 
A subject is eligible for the study if all of the following criteria are 
met: 
1. Subject has been informed of the investigational nature of this 
study and has given written informed consent in accordance with 
institutional, local, and national guidelines 
2. Subject age is ≥ 18 years 
3. Subject receiving adequate dialysis using the same modality of 
dialysis for native kidney ESRD for ≥ 3 months prior to 
screening and during screening  
3.1   Amendment 2: Incident dialysis subjects receiving 
dialysis for ESRD for  ≥ 2 weeks but ≤ 4 months at the time 
of randomization 
4. For subjects receiving HD, the vascular access must be via 
native arteriovenous fistula or graft, or permanent, tunneled 
catheter. For subjects receiving PD, a PD catheter must be in use 
5. Subject is on IV or subcutaneous ESA for ≥ 8 weeks prior to 
screening. The prescribed ESA dose must remain stable (≤ 30% 
change) during the 4 weeks prior to randomization if on epoetin 
or darbepoetin and 8 weeks if on Mircera®  
5.1   Amendment 2: Incident dialysis subjects (as defined in 
3.1) must be on ESA for ≥ 4 weeks prior to screening.  
6. Mean of the subject’s three most recent central lab Hb values 
during the Screening Period must be ≥ 9.0 g/dL and ≤12.0 g/dL; 


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with an absolute difference of ≤ 1.3 g/dL between the highest and 
the lowest value. Samples are obtained at least 4 days apart and 
the last Hb value must be within 10 days prior to the 
randomization visit  
6.1   Amendment 2: For Incident dialysis subjects (as defined 
in 3.1), mean of the subject’s two most recent central lab Hb 
values during the Screening Period must be ≥ 8.5 g/dL and 
≤12.0 g/dL; with an absolute difference of ≤ 1.3 g/dL between 
the highest and the lowest value. Samples are obtained at 
least 2  days apart and the last Hb value must be within 10 
days prior to the randomization visit 
7. Subject has a ferritin level ≥ 100 ng/mL at screening 
Amendment 2: Subjects with a ferritin level < 100 ng/mL at 
screening may qualify upon receiving iron supplement (per local 
standard of care) 
8. Subject has a transferrin saturation (TSAT) level ≥ 20% at 
screening 
Amendment 2: Subjects with a TSAT level < 20% at screening 
may qualify upon receiving  iron supplement (per local standard 
of care) 
9. Subject has a serum folate level ≥ lower limit of normal (LLN) at 
screening 
Amendment 2: Subjects with a serum folate level < LLN at 
screening may qualify upon receiving folate supplement (per 
local standard of care) 
10. Subject has a serum vitamin B12 level ≥ LLN at screening 
Amendment 2: Subjects with a Vitamin B12 level < LLN at 
screening may qualify upon receiving B12 supplement (per local 
standard of care) 
11. Subject’s alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) are ≤ 3 x upper limit of normal (ULN), 
and total bilirubin (TBL) is ≤ 1.5 x ULN at screening  
12. Subject’s body weight (dry weight in HD subjects) is 45.0 to 
160.0 kg 
Only incident dialysis subjects who  meet criteria 3.1, 5.1, 
and 6.1 (instead of criteria 3. 5, and 6) are allowed to 
participate under Protocol Amendment 2 
Exclusion Criteria: 
Subjects will be excluded if any of the following criteria are met:  


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1. Subject has received a red blood cell (RBC) transfusion within 8 
weeks prior to randomization  
Amendment 2: Subject has received a red blood cell (RBC) 
transfusion within  4 weeks prior to randomization 
2. Subject has a known history of myelodysplastic syndrome or 
multiple myeloma 
3. Subject has a known hereditary hematologic disease such as 
thalassemia or sickle cell anemia, pure red cell aplasia or other 
known causes for anemia other than chronic kidney disease 
(CKD) 
4. Subject has known hemosiderosis, hemochromatosis, 
coagulation disorder, or hypercoagulable condition 
5. Subject has a known chronic inflammatory disease that could in 
the opinion of the Investigator impact erythropoiesis (eg, 
systemic lupus erythematosus, rheumatoid arthritis, celiac 
disease) even if it is currently in remission 
6. Subject is anticipated to undergo elective surgery that is 
expected to lead to significant blood loss during the study period 
or anticipated elective coronary revascularization. 
7. Subject has active or chronic gastrointestinal bleeding 
8. Subject has received any prior treatment with roxadustat or 
another hypoxia-inducible factor prolyl hydroxylase inhibitor 
(HIF-PHI)  
9. Subject has been treated with iron-chelating agents within 
4 weeks prior to randomization 
10. Subject has a history of chronic liver disease (eg, chronic 
infectious hepatitis, chronic auto-immune liver disease, cirrhosis, 
or fibrosis of the liver) 
11. Subject with New York Heart Association (NYHA) Class III or 
IV congestive heart failure  
12. Subject has had an MI, acute coronary syndrome, stroke, seizure, 
or a thrombotic/thromboembolic event within a major vessel 
(excluding vascular dialysis access) (eg, DVT or pulmonary 
embolism) within 12 weeks prior to randomization 
13. Subject has uncontrolled hypertension, in the opinion of the 
Investigator, (eg, that requires change in anti-hypertensive 
medication) within 2 weeks prior to randomization 
14. Subject has one or more contraindications for treatment with 
epoetin alfa or other ESA including known hypersensitivity  


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15. Subject has a diagnosis or suspicion (eg, complex kidney cyst of 
Bosniak Category II or higher) of renal cell carcinoma as shown 
on renal imaging performed within 12 weeks prior to 
randomization 
16. Subject has a 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 
Amendment 2 Subject has a history of malignancy, except for 
the following: cancers determined to be cured or in remission for 
≥ 2 years, curatively resected basal cell or squamous cell skin 
cancers, cervical cancer in situ, or resected colonic polyps 
17. Subject is positive for any of the following:  
• Human immunodeficiency virus (HIV) 
• Hepatitis B surface antigen (HBsAg) 
• Anti-hepatitis C virus antibody (anti-HCV Ab) 
18. Subject has an active, clinically significant (CS) infection or 
evidence of an underlying infection, as manifested by white 
blood cell count (WBC) > ULN, and/or fever, in conjunction 
with clinical signs or symptoms of infection at the time of 
randomization 
19. Subject has any of the following known untreated conditions: 
proliferative diabetic retinopathy, diabetic macular edema, 
macular degeneration or retinal vein occlusion (subjects who are 
already blind  may qualify to participate) 
20. Subject has had any prior organ transplant (that has not been 
explanted),  or subject is scheduled for organ transplantation (on 
the waiting list for kidney transplant is not exclusionary) 
Amendment 2: Prior organ transplant: subjects who have one of 
the following  conditions or states 
 
a) Experienced  rejection of transplanted organ within 6 
months of transplantation 
 
b) Currently on high doses of immunosuppressive therapy 
(per discretion of the PI) 
c) Are scheduled for organ transplantation (on the waiting 
list for kidney transplant is not exclusionary) 
21. Subject has participated in an interventional clinical study or has 
been treated with an investigational drug within 4 weeks prior to 
screening 


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22. Subject has drug-treated gastroparesis, short-bowel syndrome, or 
any other gastrointestinal condition that may lead to reduced 
absorption of study drug 
23. Subject has an anticipated use of dapsone or androgen in any 
dose amount or anticipated chronic use of acetaminophen or 
paracetamol > 2.0 g/day during the study 
24. Subject has a history of alcohol or drug abuse within 2 years 
prior to screening 
Amendment 2: Subject has a history of alcohol or drug abuse 
within 6 months prior to screening 
25. Females of childbearing potential, if not practicing complete 
sexual abstinence or using contraception as detailed in the 
protocol; male subjects (if not surgically sterile; ie, no 
vasectomy) with sexual partners of childbearing potential, if not 
practicing complete sexual abstinence or using contraception 
26. Pregnant or breastfeeding females 
27. Subject has any medical condition that in the opinion of the 
Investigator may pose a safety risk to the subject in this study, 
which may confound efficacy or safety assessment, or may 
interfere with study participation 
Study Procedures: 
See Schedule of Assessments (Appendix 3) 
Investigational Product 
Roxadustat  
• Tablets 
• Strengths of 20 mg, 50 mg and 100 mg 
 
Route of Administration: 
Oral (all tablets must be administered whole) 
Doses: 
In subjects on HD or PD or HHD randomized to roxadustat, the 
initial roxadustat dose will be determined using a conversion table 
based on the subject’s previous average weekly prescribed ESA dose 
in the last 4 weeks prior to randomization if the subject is on epoetin 
or darbepoetin, and average monthly (4 weeks) prescribed ESA dose 
in 8 weeks prior to randomization if the subject is on Mircera® 
(Table S1). If the mean qualifying screening Hb value at 
randomization is < 10 g/dL, the starting roxadustat dose will be 
increased by one dose step. For example, a subject on epoetin (ie, 
epoetin alfa, beta, theta, zeta, delta, or omega) 6,000 IU/week with 


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mean screening Hb of 9.4 g/dL at randomization will start roxadustat 
at a dose of 150 mg three times weekly (TIW). 
If the converted initial dose exceeds the maximum dose of 
3.0 mg/kg/dose then the lower dose step should be chosen as the 
initial dose. 
The dose of roxadustat will remain constant during the first 4 weeks 
of the Treatment Period unless a dose reduction is required for 
excessive hematopoiesis.  
Table S1 
Initial Dosing of Roxadustat: Conversion Table 
from ESAs to Roxadustat 
Epoetin (ie, alfa, beta, 
theta, zeta, delta, or 
omega) a 
(IU/week) 
Darbepoetin 
alfaa, b 
(μg/week) 
Mircera®c 
(μg/ monthly) 
Roxadustat 
Dosed  
(mg/dose) 
TIW 
< 5,000 
< 25 
< 80 
70 
5,000 to 8,000 
25-40 
80-120 
100 
> 8,000 to 16,000 
> 40-80 
> 120-200 
150 
> 16,000 
> 80 
> 200 
200 
Abbreviations: 
ESA = erythropoiesis-stimulating agent; Hb = hemoglobin; 
IU = international units; TIW = three times a week.  
a 
Average weekly prescribed dose in last 4 weeks prior to randomization 
b 
If darbepoetin is used biweekly, use half the dose to get per week dose  
c 
Average prescribed monthly (4-wks) dose in last 8 weeks prior to 
randomization  
d 
Starting dose will be one step higher if the mean Hb at randomization is 
< 10.0 g/dL, however, not to exceed 3.0 mg/kg/dose.  
Notes: 
The roxadustat dose steps are 20, 40, 50, 70, 100, 150, 200, 250, 300, and 
400 mg.  
Dose Adjustments: 
During the Treatment Period, roxadustat dose adjustment will be 
made according to the dose adjustment algorithm in Appendix 2, in 
order to maintain a Hb level of approximately 11 g/dL.  
Roxadustat dose adjustments are permitted from Week 4 onwards, 
and every 4 weeks thereafter (eg, Week 4, Week 8, Week 12); 
however, dose may be adjusted between two prespecified windows 
(eg, anytime between Week 4 and Week 8 visits, Week 8 and Week 
12 visits) if the following two criteria are met: 
• No dose adjustment has been made in last 4 weeks, 
• Hemoglobin (Hb) < 9.0 g/dL. 
Subjects on HD or PD or HHD randomized to roxadustat will take 
doses TIW for the entire duration of the Treatment Period. If a 
subject requires < 20 mg TIW (ie, < 60 mg per week) to maintain a 


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Hb level of approximately 11 g/dL, the dosing frequency should be 
reduced in a step-wise fashion e.g. TIW to BIW, BIW to QW, QW to 
Q-2 Week etc. 
In this study, a rate of rise of Hb > 2 g/dL within 4 weeks or a Hb 
level of ≥ 13 g/dl at any time would be considered as excessive 
haematopoiesis. For a rate of rise of Hb > 2 g/dL within 4 weeks, 
dose should be reduced by one dose step and for a Hb value 
≥ 13.0 g/dL, the dose should be on hold until Hb drops < 12.0 g/dL 
per guidelines provided in the protocol (Appendix 2). When 
roxadustat will be resumed, the dose should be reduced by one dose 
step.  
Dose adjustments or temporary dose holds for excessive 
hematopoiesis can occur at any time during the Treatment Period. 
Any dose adjustment will reset the dose-adjustment window to every 
4 weeks thereafter (eg, dose adjustment for a qualified reason at 
Week 6 leads to next dose adjustment at Week 10).  
Prescribed dose must not exceed the maximum allowable dose of 
3.0 mg/kg/dose or 400 mg per dose, whichever is lower. For dose 
adjustment purposes, post-dialysis weight (dry-weight) should be 
used. If the post-dialysis weight of the current visit is not available at 
the time of dose adjustment, post-dialysis weight of the prior dialysis 
session or last recorded post-dialysis weight may be used. 
Reference Therapy: 
Epoetin Alfa (active control) 
Route of Administration: 
Hemodialysis (HD): Intravenous 
Peritoneal dialysis (PD) or home hemo-dialysis (HHD): Intravenous 
or subcutaneous 
Subjects randomized to the epoetin alfa arm who are currently taking 
nonepoetin alfa treatment will be switched to epoetin alfa treatment 
on Day 1. All subjects on HD will receive IV epoetin alfa TIW 
starting from Day 1, irrespective of their baseline route of 
administration or frequency of ESA use. Subjects requiring ultra-low 
dose of EPO (eg, ≤1000 IU/per week), frequency of administration 
may be adjusted per local standard of care. 
Subjects on PD or HHD may continue using the same route of 
administration as baseline; however, if the Investigator decides to 
change the route of administration in a PD subject from 
subcutaneous to IV after randomization it should be done during the 
early part of the treatment phase (preferably prior to Week 16).  
All epoetin alfa administrations should be performed by the 
Investigator or an authorized member of the site staff or other trained 
personnel. In subjects on PD or HHD, epoetin alfa may be self-


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administered subcutaneously by the subject or a caregiver after 
adequate training or, if in the opinion of the Investigator, the subject 
or a caregiver is already adequately trained in self-administering 
ESA prior to the study.  
 
 
 
Doses: 
In subjects who have been randomized to the epoetin alfa treatment 
arm, the initial epoetin alfa dose that the subject will receive on 
Day 1 will be determined using a conversion table based on the 
subject’s average weekly prescribed ESA dose in 4 weeks prior to 
randomization if on epoetin or darbepoetin, and average monthly 
(4-week) prescribed ESA dose in 8 weeks prior to randomization if 
on Mircera® (Table S2).  
In case of a change in route of administration from subcutaneous to 
IV (TIW), the initial dose of IV epoetin alfa will be determined by 
the Investigator per local standard of care.  
In subjects on PD or HHD, if receiving epoetin alfa subcutaneously, 
the dose and frequency may be determined by the Investigator per 
local standard of care. 
Table S2 Initial Dosing of Epoetin Alfa: Conversion Table from 
ESAs to Epoetin Alfa  
Baseline ESA 
Conversion Ratio 
Examples of Converted 
Initial Epoetin Alfa dose 
(approximate) IU/week c 
Epoetin (ie, alfa, beta, 
theta, zeta, delta, or 
omega) (IU/week) a 
x 1 
6,000 IU/week x 1  
= 6,000 IU/week 
Darbepoetin alfa 
(μg/week) a 
x 200 
40 μg/week x 200  
= 8,000 IU/week 
Mircera® (μg/once 
monthly) (ie, 4-wks) b 
x 70 – 80 
(for lower Mircera® 
dose lower conversion 
ratio may be used) d 
100 μg/month x 70 
= 7,000 IU/week 
200 μg/month x 80  
= 16,000 IU/week 
Abbreviations: ESA = erythropoiesis-stimulating agent; IU = international units.  
a 
Mean weekly ESA in 4 weeks prior to randomization 
b 
Mean monthly (4-week) ESA in 8 weeks prior to randomization 
c 
May be rounded as deemed necessary by the Investigator 
d 
Per discretion of the Investigator 


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Subsequent epoetin alfa dosing and dose adjustment during the 
study, if indicated, should be based on the country specific package 
insert or SmPC. 
For countries using prefilled epoetin alfa syringes, the initial dose 
and subsequent dosages following dose adjustments during the 
Treatment Period should be approximated to the closest total weekly 
dose. 
Rescue Therapy and 
Emergency Procedures:  
Rescue Therapy Guidelines:  
Rescue therapy guidelines are provided to optimize the 
standardization of rescue therapy by Investigators and to ensure the 
safety of individual study subjects. Use of rescue therapy and reason 
for rescue therapy should be recorded in the electronic case report 
form (eCRF). 
Red Blood Cell Transfusion (for all subjects) 
For subjects in both treatment arms, RBC transfusion is allowed if 
rapid correction of anemia is required to stabilize the subject’s 
condition (eg, acute hemorrhage) or the Investigator is of the opinion 
that the blood transfusion is a medical necessity. If the situation 
permits, the Medical Monitor should be informed prior to any 
scheduled RBC transfusion. Study treatment may continue during or 
after the RBC transfusion.  
Erythropoiesis Stimulating Agent (ESA) Use  
For subjects randomized to roxadustat the use of ESAs is generally 
prohibited. Erythropoiesis stimulating agent rescue is restricted to no 
more than one cycle of use during the Treatment Period; the 
Investigator may initiate use of an approved erythropoietin (EPO) 
analogue if all of the following criteria are met: 
• A subject’s Hb level has not sufficiently responded to two or 
more dose increases or the maximum dose limit of the study 
drug has been reached, and 
• The subject’s Hb is < 8.5 g/dL on two consecutive 
measurements (central lab) drawn at least five days apart; and 
• Clinical judgment does not suggest iron deficiency or 
bleeding as a cause of lack of response or rapid decline in Hb, 
and 
• Reducing the risk of alloimmunization in transplant eligible 
patients and/or reduction of other RBC transfusion-related 
risks is a goal 


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The subject is not allowed to be administered both EPO analogue 
and study drug at the same time. Treatment with an EPO analogue 
should be started ≥ 3 days after the last dose of roxadustat, and 
should be stopped when Hb > 9 g/dL or after 4-weeks, whichever 
comes first. If a subject requires longer than 4-weeks therapy due to 
inadequate response, the Medical Monitor should be contacted. 
Study treatment should be resumed after the following intervals: 
• Two days after stopping epoetin  
• One week after stopping darbepoetin alfa  
• Two weeks after stopping methoxy polyethylene glycol-
epoetin beta (Mircera®) 
If more than one cycle of EPO analogue rescue is required, the 
Investigator should permanently discontinue study drug. Use of EPO 
analogues will be recorded in the eCRF. 
Inadvertent ESA administration or ESA administration by the 
hospital staff in Roxadustat subjects should not be counted as rescue 
unless above criteria are met; these subjects may be allowed to 
continue taking study medication, if considered safe by the 
Investigator or Medical Monitor. 
For subjects randomized to epoetin alfa, the Investigator may initiate 
use of a different EPO analogue if clinically indicated. Use of the 
different EPO analogue will be recorded in the eCRF and will be 
considered rescue therapy. 
Emergency Procedure (Therapeutic Phlebotomy) 
If there are clinical concerns for a subject’s high Hb levels, the 
Investigator may decide to perform a therapeutic phlebotomy in 
addition to temporarily withholding the study drug This should be 
documented and discussed with the Medical Monitor. 
Supplemental Iron Use: 
In a Phase 2 study, there was no significant difference in Hb levels in 
roxadustat -treated dialysis patients receiving oral iron 
supplementation compared to subjects receiving IV iron 
supplementation, in patients with ferritin < 100 ng/mL and in those 
with TSAT< 20%. Based on the mechanism of action of roxadustat 
and the Phase 2 study results, in subjects randomized to roxadustat, 
oral iron supplementation is considered to be sufficient.  
In this study, oral iron should be allowed as the preferred first-line of 
iron supplementation for both treatment arms without restriction. 
In addition to the scheduled assessments, 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. 


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Oral Iron Supplementation  
All subjects should be encouraged to take oral iron if they can 
tolerate as the preferred first-line iron supplementation during the 
Treatment Period. Provision of an oral iron supplement is 
encouraged; the dose and frequency are at the discretion of the 
principal Investigator. Oral Iron therapy should be started before the 
subject becomes iron depleted. 
Intravenous Iron Supplementation 
Intravenous iron supplementation is permitted if in the opinion of the 
Investigator the subject has not responded adequately and is 
considered iron deficient.  IV iron may be administered per local 
standard of care as deemed necessary by the investigator.   
Treatment with study medication (roxadustat or epoetin) will 
continue during IV iron administration. Discontinuation of IV iron 
supplementation is recommended once the subject is no longer 
considered iron deficient (eg, ferritin ≥ 100 ng/mL and TSAT 
≥ 20%) 
Subjects may receive IV iron during the post-treatment Follow-up 
Period per discretion of the Investigator. If IV iron is to be 
administered at the EOT visit, all visit procedures including lab 
draws should be completed prior to administering IV iron.  
Prohibited Medication: 
The following medications/therapies are prohibited during the period 
identified: 
• 
Any investigational drug from 4 weeks prior to screening 
until EOS 
• 
Androgens from screening until EOS 
• 
Iron-chelating agents (eg, deferoxamine/desferrioxamine, 
deferiprone, or deferasirox therapy) from 4 weeks prior to 
randomization until EOS 
• 
Dapsone (at any dose) from screening until EOS 
• 
Chronic doses acetaminophen/paracetamol > 2.0 g/day from 
randomization until 1 week after EOT 
Efficacy Endpoints and 
Assessments: 
Primary: 
• 
US (FDA) submission:  Hemoglobin (Hb) change from 
baseline to the average Hb level during the evaluation period 
defined as Week 28 until Week 52  
• 
EU regulatory submission :  Hemoglobin (Hb) change from 
baseline to the average level Hb of Weeks 28 to 36, without 
having received rescue therapy (ie, RBC transfusion or rescue 


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ESA therapy) within 6 weeks prior to and during this 8-week 
evaluation period.  
Secondary: 
• 
US (FDA) submission:  proportion of subjects with mean Hb 
level during the evaluation period defined as Week 28 until 
Week 52 ≥ 10.0 g/dL. 
• 
EU regulatory submission:  Hemoglobin (Hb) response, 
defined as mean Hb during Weeks 28 to 36 within the target 
range of 10.0 to 12.0 g/dL without having received rescue 
therapy within 6 weeks prior to and during this 8-week 
evaluation period. 
• 
Average monthly IV iron use per subject during Weeks 1 to 
36 (monthly defined as a period of 4 weeks). 
• 
Change from BL in low-density lipoprotein (LDL) 
cholesterol to the average LDL cholesterol of Weeks 12 to 28 
• 
Change from BL in SF-36 Physical Functioning (PF) 
subscore to the average PF subscore of Weeks 12 to 28 
• 
Change from BL in SF-36 Vitality (VT) subscore to the 
average VT subscore of Weeks 12 to 28  
• 
Effect on predialysis blood pressure (BP):  
o Time to an exacerbation of hypertension from BL 
during Weeks 1 to 36 
 An increase from BL of ≥ 20 mm Hg systolic 
blood pressure (sBP) and sBP > 170 mmHg  
OR 
 An increase from BL of ≥ 15 mm Hg diastolic 
blood pressure (dBP) and dBP > 100 mmHg 
o Change from BL in mean arterial pressure (MAP) to 
the MAP value averaged over Weeks 20 to 28 
Additional Efficacy Endpoints:  
Additional efficacy endpoints are described in the body of the 
protocol.  
Safety Assessments and 
Endpoints:  
Study-specific safety will be assessed by evaluating the following:  
• 
Occurrence of treatment emergent adverse events (TEAEs) 
and treatment emergent serious adverse events (TESAEs) 


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• 
Adverse events (AEs), serious adverse events (SAEs), and 
clinically significant changes in laboratory values from 
baseline  
• 
Vital signs, electrocardiogram (ECG) parameters, and clinical 
laboratory values. 
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: 
 
All cause death, MI, stroke, congestive heart failure requiring 
hospitalization, unstable angina requiring hospitalization, 
hypertensive emergency, DVT, 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 PSAPs. 
For US (FDA) Submission Only:   
The primary safety endpoint in this study is the MACE (Major 
Adverse Cardiac Event) composite endpoint, defined as time to first 
occurrence of death from all causes, MI, or stroke, 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: 
Stratification: 
Up to 1200 subjects will be randomized via IWRS to receive 
roxadustat or epoetin alfa in an open-label manner in a 1:1 ratio.  
Randomization will be stratified by the following four factors: 


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• 
Mean qualifying screening hemoglobin (≤ 10.5 vs. 
>10.5 g/dL) 
• 
History of CV, cerebrovascular, or thromboembolic diseases 
(yes vs. no) 
• 
Mean prescribed weekly epoetin alfa dose (or, equivalent 
epoetin dose for nonepoetin subjects) in the 4 weeks prior to 
randomization (≤ 150 vs. > 150 IU/kg/week)  
• 
Geographical region (US vs. Ex-US regions)  
Sample size determination: 
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 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). 
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, specifically, Hb change from BL in 
the averaged Hb over Weeks 28 to 36).  
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.  
Analysis Sets 
For US regulatory submission, efficacy and safety analyses will be 
based on all subjects stratified by the protocol amendment, on 
subjects enrolled during the original protocol but before the 
amendment, and on subjects enrolled after the amendment 
separately.  
For EU regulatory submission, efficacy and safety analyses will be 
based on subjects enrolled during the original protocol before the 


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amendments, as the subjects enrolled after the amendments may be 
considered as a sub-study for EU regulatory purpose. 
The following analysis sets are defined and will be used for the 
statistical analysis: 
Intent to Treat (ITT) Population: The ITT population consists of all 
randomized subjects.  
Full Analysis Set (FAS): The FAS consists of all randomized 
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.  
Per-Protocol Set (PPS): 
The PPS consists of all randomized 
subjects who received at least 8 weeks of 
study treatment, have at least one postdose 
Hb assessment and are without major 
protocol violations. 
Safety Analysis Set (SAF): The SAF will consist of all randomized 
subjects who received at least one dose of 
study medication. If treatment received 
for the duration of the study differs from 
the randomized treatment, the actual 
treatment arm will be used. 
Efficacy:  
Primary Hypothesis 
The primary efficacy endpoint for US (FDA) submission is defined 
as each subject’s Hb change from baseline to the average level 
during the evaluation period, defined as Weeks 28 to 52. The 
analysis will be based on the ITT Population.  
A Multiple Imputation Analysis of Covariance (MI-ANCOVA) 
model will be used. The model will contain terms for treatment arm, 
baseline Hb measurement, and randomization stratification factors 
except Screening Hb values (≤10.5 g/dL vs. > 10.5 g/dL). 
The primary efficacy analysis will be based on the estimated 
difference between the two treatments throughout the evaluation 
period based on the MI-ANCOVA model. 
The primary efficacy endpoint for EU regulatory submission is 
defined as the Hb change from BL to the average Hb of Weeks 28 to 
36, without having received rescue therapy within 6 weeks prior to 
and during this 8-week evaluation period and will be based on the 
PPS population. The primary efficacy analysis will be based on the 


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estimated difference between the two treatments overall mean effects 
throughout the evaluation period based on the MMRM model.  
Secondary efficacy analyses are described in the body of the 
protocol 
Safety  
The Safety analyses will be performed using the Safety Analysis Set 
(SAF). Safety parameters include adverse events, SAEs, laboratory 
parameters, vital signs, ECG parameters, and PE 
The number and percentage of subjects reporting TEAEs and 
TESAEs in each treatment group will be tabulated. Descriptive 
statistics will be presented for laboratory, vital signs values and ECG 
parameters by visit and for the changes from BL to each visit.  
The CV safety assessment of roxadustat will also be based on pooled 
analysis of composites of adjudicated CV events pooled across 
multiple global Phase 3 clinical studies which includes this study, 
according to the regional pooled SAPs for meeting regional 
regulatory requirements.  
For the US (FDA) submission only: The primary safety endpoint in 
this study is the MACE (Major Adverse Cardiac Event) composite 
endpoint, defined as time to first occurrence of death from all causes, 
MI, or stroke, only for the purpose of being pooled across multiple 
similar studies in the Phase 3 program. None of the individual 
studies are powered to meet the MACE primary safety endpoint 
individually. The pooled MACE analysis is only for purposes of 
supporting a US FDA regulatory filing of roxadustat. 
Safety data and dosing decisions will be monitored on an ongoing 
basis. Ongoing review of safety data will be conducted by an 
independent DSMB. 
For each safety parameter, the last assessment made prior to the first 
dose of study medication will be used as the BL for all analyses of 
that safety parameter. 
This study will be conducted in accordance with the guidelines of Good Clinical Practice and the 
applicable regulatory requirement(s), including the archiving of essential documents. 


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2 BACKGROUND 
Hypoxia-inducible factor (HIF) is a key transcription factor that coordinates the body’s 
physiological response to changes in oxygen levels in the cellular environment (Semenza, 2000). 
It induces the expression of erythropoietin (EPO) and the EPO receptor, as well as the expression 
of other proteins that promote iron absorption and recycling (Peyssonnaux et al, 2008). The 
activity of HIF is regulated by hypoxia-inducible factor prolyl hydroxylase (HIF-PH) enzymes 
(HIF-PHD1 to D3). These enzymes target HIF for degradation.  
Roxadustat (FG-4592/ ASP1517/ AZD9941) is an orally active novel small-molecule that 
inhibits these HIF-PH enzymes. By inhibiting HIF-PH, roxadustat stimulates erythropoiesis via 
the HIF pathway in a manner consistent with the body’s normal response to hypoxia. Its ability 
to stimulate erythropoiesis makes it a candidate for the treatment of anemia associated with 
chronic kidney disease (CKD) in patients with nondialysis-dependent (NDD-CKD) and dialysis-
dependent (DD-CKD). 
2.1 Introduction  
2.1.1 Epidemiology of Chronic Kidney Disease and End-Stage Renal Disease 
Chronic kidney disease is a growing worldwide public health problem. It is associated with 
significant morbidity and mortality, yet is underdiagnosed and undertreated. It is characterized 
by progressive loss of kidney function, resulting in premature death or renal replacement therapy 
(RRT) (kidney transplant or dialysis). 
The average prevalence of CKD, regardless of age, ranges between 5% to 11% in Europe and the 
all-cause mortality risk increases exponentially as CKD stages advance (Tonelli et al., 2006). 
The prevalence of DD-CKD is 887 per million people in China (2011 Shanghai Dialysis Registry 
Report) and in the US, CKD affected 13% of the US adult population (~ 29 million adults) in 
2007, and the prevalence is rapidly growing (Coresh et al., 2007). In Europe, the average 
prevalence of CKD regardless of age lies between 5 and 11% (Zoccali et al., 2010). 
The number of patients suffering from end-stage renal disease (ESRD) also continues to increase 
worldwide. The US has one of the highest prevalence rates of ESRD in the world: in 2010, the 
US had over 1700 patients with ESRD per million population, a 23% increase compared to 10 
years before (USRDS, 2011). In 2009 (point prevalence as of December 31st), there were 
approximately 570,000 patients with ESRD in the US, of whom 370,000 were receiving 
hemodialysis (HD), 27,000 were receiving peritoneal dialysis (PD), and 173,000 had a 
functioning kidney transplant (USRDS, 2011). In recent years, those older than 75 years have 
been observed to have the highest incidence of treated ESRD (1735 per million populations in 
2007, US by age and race/ethnicity). The adjusted ESRD incidence rates were 998 per million 
populations for African Americans, 396 per million population for Asians/Pacific Islanders, and 
273 per million populations for whites in 2007 (USRDS, 2009). In Europe, over the period 
1992–2005, the overall crude prevalence of RRT for patients with ESRD increased from 480 to 
807 patients per million populations (Zoccali et al., 2010). 
The average expected life expectancy of a dialysis patient is 5.9 years, compared to 16.4 years 
for a transplant patient, and 25.2 years for someone of comparable age in the general population 
(USRDS, 2009). The prevalence of ESRD is projected to grow to 774,000 by the year 2020 
(USRDS, 2009). Data from selected countries in Europe indicate that the 5-year mortality rates 


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in incident patients on RRT are 52% in all patients, and 21%, 32% and 73% for patients 0 to 14, 
15 to 64 and over 65 years of age, respectively (Zoccali et al., 2010). 
2.1.2 Anemia Associated with Chronic Kidney Disease 
Anemia is a common complication in patients with CKD, and although its pathogenesis is 
multifactorial, the decreased production of EPO, a hormone produced primarily in the kidneys, is 
considered an important etiologic factor. The impaired ability of the body to absorb and utilize 
iron is likely a second etiologic factor.  
Anemia may present in the early stages of CKD and its prevalence increases as CKD progresses. 
Anemia is present in 17% of patients with late Stage 3 disease; this increases to 25% in patients 
with Stage 4 disease, and to 49% in patients with Stage 5 disease who have not yet progressed to 
requiring dialysis (Coresh et al., 2007; Go et al., 2004). Over 90% of patients undergoing dialysis 
are anemic. Half of all patients new to dialysis (50.1%) have hemoglobin (Hb) levels below 10 
g/dL and approximately 28% have Hb levels below 9 g/dL (USRDS, 2003). Some studies from 
Europe provide data on anemia rates in patients who have been under care of nephrologists. In 
1999, Jungers prospectively studied 403 consecutive ambulatory predialysis patients and found 
that 60% of patients with a creatinine clearance of < 20 ml/min/1.73 m2 were anemic (Hb < 11 
g/dL) (Jungers et al., 2002). Between 2003 and 2005, Thilly studied predialysis anemia care in 
6271 incident dialysis patients. The average level of predialysis Hb was 10.3 g/dl, and 63.6% of 
the patients had a Hb value lower than 11 g/dl (Thilly et al., 2008). 
The clinical consequences of anemia in patients with CKD have been studied extensively. 
Because the main impact of anemia on organ function is reduced oxygen delivery to tissues, it 
affects almost every organ system.  
Anemia is associated with excess morbidity and mortality in patients with CKD and ESRD. In 
patients with CKD, the severity of anemia correlates directly with the risk of hospitalization, 
cardiovascular (CV) disease, and death (Collins et al., 1998). Anemia contributes to eccentric left 
ventricular hypertrophy and maladaptive remodeling of the left ventricle. Patients with the 
lowest Hb have worse outcomes, as was discussed in the post hoc analysis of mortality by Hb 
quintiles for the Normal Hematocrit and Correction of Hb and Outcomes in Renal Insufficiency 
(CHOIR) study in the Food and Drug Administration (FDA) briefing document for the October 
2007 Cardiovascular and Renal Advisory Committee (Unger, 2007). Similar observations are 
found in the United States Renal Data System (USRDS) mortality data stratified by Hb. All-
cause mortality stratified by Hb (between the years of 1993 to 1996) indicated significantly 
higher first-year death rates in patients with Hb levels < 9 g/dL, compared to 11 to 12 g/dL. This 
trend continued to worsen, as reflected in USRDS data collected between 1998 1999 where the 
death rate rose by ~75% compared to the 1993 to 1996 period (USRDS, 2000; USRDS, 2002). 
This increase coincides with the introduction of the Kidney Disease Outcomes Quality Initiative 
(KDOQI) guidelines in 1997. The relative risk of all-cause mortality for patients with Hb < 9 
g/dL is twice that of patients with Hb > 12 g/dL (USRDS, 2002). The relative risk ratio of CV 
hospitalization increases significantly to 1.26 in patients with Hb levels <9 g/dL compared to 
those with Hb at 11 to 12 g/dL (USRDS, 2001). 
Multiple studies have suggested that treatment of anemia reduces the need for blood transfusions 
and improves health-related quality of life (HRQoL) (NKF K/DOQI, 2007).   


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2.2 Current standard of care for CKD or DD-CKD Anemia  
Today, therapy with erythropoiesis-stimulating agents (ESAs) is a major alternative to 
transfusion in managing anemia associated with CKD. For those not resistant to ESAs, parenteral 
administration of exogenous recombinant human EPO (epoetin alfa or beta) or pegylated 
analogues has been a widely accepted approach for the treatment of anemia in patients with CKD 
(Winearls et al., 1986; Eschbach et al., 1987; Eschbach et al.,1989a, Eschbach et al. 1989b), 
despite the documented safety risks. These safety risks include hypertension, thrombosis, and 
cerebrovascular events which may be associated with supraphysiologic plasma EPO levels 
frequently observed with ESA therapy. Anemic patients with CKD or ESRD will require life-
long treatment with these agents.  
Although the treatment of anemia in CKD and ESRD is thought to contribute positively to a 
patient’s quality of life, several studies in subjects with ESRD and NDD-CKD have shown 
higher mortality or trends in that direction in the higher-dosed ESA-treated cohorts when the 
protocol objective was to treat one of the cohorts to high, almost normal target Hb levels 
(Besarab et al., 1998; Drueke et al., 2006; Singh et al., 2006). An ESA dose relationship to 
mortality has been reported in a review of the USRDS database (Zhang et al., 2004) of ESRD 
patients who received higher ESA doses, particularly in those more anemic (ie, Hb < 11 g/dL). 
The FDA has recognized these excess morbidity and mortality risks (FDA, 2007). Updated 
product labeling for the approved ESAs in 2007 include a boxed warning of greater risk of death 
and CV events when ESAs are administered to target high Hb concentrations (≥ 13.5 g/dL) 
compared with lower Hb targets. The FDA also acknowledged the potential off-target effect of 
ESAs contributing to excess mortality due to CV events and thrombosis (Unger, 2010). The 
currently approved ESA labeling directs prescribers to target Hb levels of 10 to 11 g/dL in the 
US and 10 to 12 g/dL outside the US. The literature on this topic, including meta-analyses, 
supports the view that the AEs associated with ESAs are typically observed when high doses are 
administered (Zhang et al., 2004; Unger, 2007; Szczech, 2008; Fishbane and Beserab, 2007; 
Besarab et al., 2009). Posthoc analyses of three major RCTs, (Kilpatrick et al., 2008; 
Szczech,  2008; Solomon et al., 2010) NHCT, CHOIR, and TREAT, indicates that outcomes 
correlate with “achieved” and not “target” Hb levels. 
Additionally, some patients are hyporesponsive to ESA therapy. A significant proportion (~17%) 
of DD-CKD patients require stable ESA dosing at 2 to 6 times the median seen in the entire 
CKD population (150 to 450 U/kg of IV epoetin TIW). This “hyporesponder” patient population 
accounts for approximately 50% of epoetin alfa consumption in the US (Besarab et al., 2009). 
This is a significant economic burden, and as noted above, higher doses of ESAs have been 
associated with higher rates of morbidity and mortality (Zhang et al., 2004; Unger, 2007; 
Szczech, 2008). Thus, this patient population has the greatest need for an effective and safe 
therapy for anemia. In turn, the increasing perception that high ESA dosing is associated with 
significant risk, especially in patients not achieving target, is expected to lead to lower ESA 
dosing and an associated higher prevalence of patients with low Hb levels. In December of 2007, 
2.1% of patients had Hb levels < 9 g/dL, 7% had Hb levels < 10 g/dL, and 21.6% did not reach 
11 g/dL, while 34.8% were 11 to 12 g/dL (USRDS, 2009). Hb levels < 11 g/dL in this population 
are associated with increased mortality and hospitalization rates, and failure to achieve a Hb 
level > 11 g/dL is a prognostic indicator of poor outcomes (Ma, 1999; Regidor, 2006). In patients 
with persistently low Hb levels, mortality risk is strongly associated with the patient's ability to 
achieve a hematopoietic response (Bradbury, 2009).  


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Additionally, ESA therapy for anemia in patients with ESRD on HD usually requires 
concomitant IV iron supplementation to avoid functional iron deficiency and epoetin dose 
escalation; however; IV iron use is not without risk. However, as reported by the USRDS 
(USRDS, 2013), administration of IV iron is at an all-time high. Among patients on HD, the 
transfusion rate, at 2.7% to 2.9% at the beginning of 2010, reached 3.3–3.8 percent in the first six 
months of 2012. Among patients on PD, the rate has increased from 2.3–2.9 to 3.0–3.9.  
There is currently an unmet medical need for an oral treatment that can correct anemia in patients 
with NDD-CKD and DD-CKD while avoiding supraphysiologic levels of circulating plasma 
EPO levels.  
Roxadustat is an oral medication that could potentially deliver effective treatment for CKD-
related anemia with less need for IV iron supplementation and without producing 
supraphysiologic levels of circulating EPO, which may translate into an improved safety profile. 
Roxadustat is being evaluated as a potential alternative treatment for anemia in subjects with 
NDD-CKD and DD-CKD. 
2.3 Mechanism of Action of Roxadustat 
Virtually all tissues depend on a sufficient supply of oxygen for survival. Lack of oxygen 
associated with hypoxic, ischemic, and anemic conditions triggers a series of homeostatic 
responses (Figure 1). Hypoxia-inducible factor is a transcription factor that is believed to be the 
key element in the body’s oxygen sensing mechanism (Semenza, 2000). Hypoxia-inducible 
factor regulates expression of genes that modulate both the acute and chronic response to 
hypoxia, and HIF-responsive genes regulate processes as diverse as erythropoiesis, iron 
metabolism, oxidation, cellular metabolism, glycolysis, vasculogenesis, cell cycle progression, 
and apoptosis. Chronic hypoxia and intermittent hypoxia induce different sets of genes 
associated with HIF transcriptional activity (Fan et al., 2005). Hypoxia-inducible factor is a 
heterodimeric transcription factor family comprising three oxygen-sensitive isoforms (HIF 1α, 
HIF-2α and HIF-3α), and a constitutively expressed HIF-1β subunit, with each heterodimeric 
isoform responsible for the induction of specific sets of genes (Greijer et al.,2005; 
Hu et al., 2003). For example, HIF-1α has been shown to regulate vascular endothelial growth 
factor (VEGF) expression (Gray et al., 2005; Buchler et al., 2003), while HIF 2α is critical for 
the induction of the EPO gene and erythropoiesis (Warnecke et al., 2004; 
Scortegagna et al., 2005). 


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Figure 1. 
Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor (HIF-PHI) 
Mechanism of Action 
 
Abbreviations: 
DcytB = Duodenal cytochrome B; DMT1 = divalent metal transporter one; EPO = erythropoietin; 
HIF = hypoxia-inducible factor; HIF-PH = hypoxia-inducible factor prolyl hydroxylase; HIF PHI = hypoxia-
inducible factor prolyl hydroxylase inhibitor; mRNA = messenger ribonucleic acid; Tf-R = Transferrin 
receptor; Ub = ubiquitin; VHL = Von Hippel–Lindau protein. 
Source:  Epstein, et al, 2001 
Hypoxia-inducible factor target genes are expressed when the active heterodimer binds to a 
conserved DNA motif found within all HIF target genes, termed the hypoxia response element, 
and in cooperation with other co-activators initiates de novo transcription. One of the most 
sensitive and well-studied HIF-responsive genes is the EPO gene. Increased transcription of the 
EPO gene leads to increased circulating levels of EPO, which acts at sites of erythropoiesis to 
enhance the differentiation and proliferation of red blood cell (RBC) precursors.  
Although HIF-α isoforms are constitutively produced, their accumulation under normoxic 
conditions is prevented by recruitment and binding by the von Hippel-Lindau (VHL) protein, 
which targets HIF-α isoforms for degradation through the ubiquitin-proteasome pathway. The 
molecular mechanism for oxygen-dependent degradation of HIF-α is based on the hydroxylation 
of specific proline residues, as catalyzed by a family of HIF-PHs that utilize molecular oxygen as 
the substrate for hydroxylation. Thus, HIF-PH constitutes the body’s main oxygen sensor by 
regulating the prevalence and activity of nuclear HIF protein. Under hypoxic conditions, HIF 
PHs are inactive and lead to initiation of the HIF-responsive transcriptional cascade 
(Wang et al., 1995; Semenza, 1998). 
Roxadustat is a potent and reversible hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-
PHI) that transiently induces HIF stabilization and leads to a functional HIF transcriptional 
response that mimics the erythropoietic response associated with exposure of humans to 
intermittent hypoxia. HIF induces expression of not only EPO, but also the EPO receptor and 
proteins that promote iron absorption and recycling from the macrophage iron storage system 
(Peyssonnaux et al., 2008). Thus, roxadustat pharmacologically stimulates erythropoiesis via the 
HIF pathway and in a manner consistent with the body’s normal homeostatic response to anemia, 
but under normoxic conditions. In contrast to the classical paradigm, suggesting that anemia in 
CKD patients is caused by the inability of these patients to produce EPO, results of a study of 


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roxadustat treatment of CKD subjects not requiring dialysis (Study FGCL-SM4592-017) suggest 
that the kidneys and other sites of EPO production in this patient population retain the ability to 
produce sufficient EPO for robust erythropoiesis.  
Roxadustat also has the potential to effectively treat anemia caused by inflammation-induced 
functional iron deficiency, which are typically hyporesponsive to ESAs. In these conditions, iron 
availability for erythropoiesis is reduced due to a number of inflammatory mediators. Because 
HIF-PHIs such as roxadustat alter expression not only of the EPO gene but also of genes 
regulating iron metabolism, it is postulated that roxadustat may be effective in treating these 
anemias as well (Langsetmo et al., 2005). 
Chronic hypoxia and intermittent hypoxia induce different sets of genes associated with HIF 
transcriptional activity, presumably because intermittent stimulation allows the restoration of 
HIF degradation, turnover, and inactivation. Transient activation of HIF thereby precludes 
sustained gene expression and the induction of genes that are expressed late after HIF activation, 
as well as expression of additional genes that are secondary to activation of HIF-dependent 
genes. Both nonclinical and clinical studies of roxadustat have successfully used the intermittent 
dosing paradigm to induce selective erythropoiesis and to optimize the Hb dose response. 
Furthermore, roxadustat was selected for development over other HIF-PHI candidate molecules 
based on an optimal biodistribution profile that enhances its selective actions. The specific 
tissues where roxadustat enters the cytoplasm and triggers gene expression reside in the main 
target organs for erythropoiesis:  the kidney (EPO production), the bone marrow (increase in 
EPO receptors), the duodenum (transepithelial iron transport), and the liver (EPO production, 
transferrin production, and down-regulation of hepcidin production); roxadustat distributes 
preferentially to these organs. 
The physiologic mechanisms underlying the effects of roxadustat on erythropoiesis are distinct 
from that of ESAs, and these differences result in several potential advantages over ESAs 
beyond the convenience of oral therapy. These potential advantages include: 
• 
Increase in the number of EPO receptors in the bone marrow 
• 
Improved iron metabolism and bioavailability 
• 
Effective erythropoiesis at nonsupraphysiologic plasma EPO levels (10- to 20-fold lower 
than with parenteral ESA therapy) 
• 
Absence of hypertensive effect 
• 
Effective erythropoiesis in the presence of inflammation 
• 
Mitigation of thromboembolic risk 
• 
Improvement in lipid profile 
2.4 Clinical Experience with Roxadustat 
Roxadustat is currently being studied in DD-CKD and NDD-CKD subjects with anemia. As of 
7 September 2013, a total of 1190 subjects with CKD and healthy subjects have been enrolled in 
18 completed (12 Phase 1 and 6 Phase 2) and 6 ongoing studies in the United States, Europe, and 
Asia. Information from these studies is provided below and in the most recent Investigator’s 
Brochure. In these studies, a total of 969 subjects have received roxadustat, comprising 377 
healthy subjects, 294 subjects with NDD-CKD, and 298subjects with DD-CKD. 


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Subjects with CKD have received up to 24 weeks of roxadustat in doses of up to 3.0 mg/kg. In 
completed Phase 1 studies, healthy volunteers received single doses of roxadustat up to 4.0 
mg/kg and repeat doses up to 3.75 mg/kg three times a week 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 dialysis patients 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 
incident subjects on 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 incident-dialysis patients.  
The clinical data collected thus far suggest that roxadustat is generally safe and well tolerated in 
healthy adult subjects, and in dialysis and nondialysis CKD subjects with anemia who have been 
treated in the completed and ongoing studies. 
2.4.1 Pharmacokinetics and Pharmacodynamics 
The pharmacokinetics (PK) and pharmacodynamics of roxadustat were characterized in studies 
in healthy volunteers and in dialysis and nondialysis CKD subjects. Roxadustat showed 
generally dose proportional PK (except at the lowest dose of 0.3 mg/kg); t1/2 was 12 to 14 hours 
in healthy volunteers, and 15 to 19 hours in dialysis subjects (after a single 1 and 2 mg/kg dose). 
The exposure was higher in dialysis patients compared to healthy volunteers. Roxadustat can be 
administered before or after dialysis, since the PK of roxadustat was not significantly altered 
when administered prior to the start of dialysis compared with after dialysis (Study 
FGCL-4592-039). 
A relative bioavailability study was conducted in 24 healthy volunteers comparing capsule 
formulation, which was used in Phase 1 and Phase 2 studies, with tablet formulation, which was 
developed for Phase 3. The study demonstrated bioequivalence to bridge the two formulations. 
With an intermittent dose regimen (once weekly [QW], twice weekly [BIW[ or three times a 
week [TIW]), no or limited accumulation in mean area under the concentration curve (AUC) or 
maximum concentration (Cmax) was observed. Furthermore, no evidence was found for time-
dependent PK (no auto-induction or inhibition). Roxadustat is highly protein bound and the PK 
of roxadustat is not affected by dialysis. Metabolites found in urine suggested Phase 2 
metabolism as the major metabolic pathway. In plasma, parent roxadustat is the main 
component. The inhibitory potential of roxadustat on cytochrome P450 (CYP) enzymes, based 
on in-vitro studies is limited, and the lowest inhibition constant (Ki) value was observed for CYP 
2C8 (16 μM). In a clinical drug-drug interaction study with rosiglitazone, a probe drug for CYP 
2C8, roxadustat did not show any inhibitory potential on CYP 2C8 in vivo. 
In healthy adult male volunteers (Study FGCL-SM4592-016), roxadustat administered orally as a 
single dose up to 4.0 mg/kg, and QW, BIW or TIW for 4 weeks at doses up to 3.75 mg/kg, was 
pharmacodynamically active as evidenced by dose-dependent transient increases in endogenous 
EPO (starting from single doses of 0.3 mg/kg), increases in reticulocytes (starting from doses of 
2 mg/kg), and Hb responses (starting at 3 mg/kg). The mean peak level of plasma EPO following 
the Day 26 dose of 2.0 mg/kg TIW (the high therapeutic dose studied) was 326.3 ± 197.0 
mIU/mL. 


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In pharmacodynamic studies conducted with roxadustat in CKD subjects not on dialysis (Study 
FGCL-4592-017), the mean maximum EPO increase from baseline ranged from 82-443 mIU/mL 
and 492-554 mIU/mL after a single 1 and 2 mg/kg dose, respectively. Results from PK studies in 
subjects on HD (Study FGCL-4592-039 in the US and Study CL-1517-203 in Japan) showed 
similarity in PK and pharmacodynamics of roxadustat in Caucasians and Japanese subjects with 
ESRD, and the timing of roxadustat dosing relative to dialysis (given before or after dialysis) did 
not impact the PK profile. Also, comparable dose-dependent increases in EPO levels were 
observed with both pre and postdialysis dosing. These increases in endogenous EPO (eEPO) 
were transient, peaked at around 10 hours postdose with eEPO levels returning to BL in 24 to 48 
hrs. The magnitude of this transient increase in plasma eEPO levels was modest and the peak 
plasma eEPO were within physiologic range. 
In contrast, EPO levels associated with therapeutic ESA dosing range from 1,500 to over 
10,000 mIU/mL (Besarab et al., 2009). In a clinical study with dialysis subjects, the reported 
mean administered individual ESA dose was 8,000 IU, which would correspond to plasma EPO 
Cmax levels exceeding 3,000 mIU/mL (Fishbane and Besarab, 2007). This is approximately 10-
fold higher than the physiologic range. 
2.4.2 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 Investigator’s Brochure.  
2.4.2.1 Studies in NDD-CKD subjects 
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 
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 et al., 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 11-13 g/dL in 96 
subjects and 10.5-12.0 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.  


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2.4.2.2 Studies in DD-CKD subjects: 
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 SF-36 Physical 
Functioning, Role physical, and Vitality scores, as well as in the 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 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 
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) 


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increased in roxadustat-treated subjects compared to subjects randomized to continue epoetin 
alfa. Other serum iron parameters were not significantly different between the treatment arms.  
2.4.2.3 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 CKD patients over 52 to 76 week 
treatment as of 07 September 2013. 
2.4.3 Safety (for detailed current safety information please refer to the Investigator’s 
Brochure) 
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 CV 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 U.S. 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 CKD 
patients not on dialysis were diarrhea, nausea, urinary tract infection, nasopharyngitis, peripheral 
edema, hyperkalemia, headache, and hypertension (none were ≥ 8%). The most commonly 
reported AEs (≥ 3%) in CKD patients on dialysis 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 and Hulter, 2009; Fishbane and Besarab, 2007). No safety risks were 
associated with rate of rise of Hb levels or with achieving a 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 CV 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. 


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Cumulatively, five 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 five 
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 Investigator’s Brochure.  
Of note, cholelithiasis is reported to be more common in CKD patients compared to 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 to 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. 
2.5 Summary 
In summary, roxadustat is an orally active HIF-PHI with potent erythropoietic effects. 
Intermittent dosing of roxadustat results in transient activation of HIF, intermittent induction of 
endogenous, physiologic-range EPO, and dose-dependent erythropoiesis, suggests a coordinated 
mechanism of erythropoiesis that is different from ESA therapy, including beneficial effects on 
iron handling. The clinical data collected thus far suggest that roxadustat is generally safe and 
well tolerated in healthy adult subjects, and in dialysis and nondialysis CKD subjects who have 
been enrolled and treated in completed and ongoing clinical studies. 
2.6 Roxadustat Dose Rationale 
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 


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subject’s body weight as low (45 to 60 kg), medium (> 60 to 90 kg), or heavy (> 90 to 140 kg); 
and using an absolute starting dose regardless of body weight.  
In a Phase 2 conversion-maintenance study in dialysis subjects (Study FGCL-4592-040), dose 
evaluation was performed to determine a suitable conversion method from epoetin to roxadustat. 
In this study, the dose response to maintain Hb levels was observed to be related to the ratio of 
the patient’s baseline epoetin alfa dose requirement to the roxadustat dose administered, and not 
related to the roxadustat dose administered per body weight. Two methods of modeling of dose 
relationship between roxadustat and baseline stable epoetin dose yielded dose ratios for epoetin 
(U): roxadustat (mg) dose conversion between 17 (for the lowest epoetin dose quartile) and 50 
(for the highest quartile). 
For this conversion-maintenance study of stable dialysis subjects converting from stable doses of 
epoetin at baseline to roxadustat, the starting roxadustat dose will be determined using this dose 
conversion algorithm (Table 1). 
Table 1. 
Baseline Epoetin to Starting Roxadustat Dose Conversion 
Epoetin alfaa 
(IU/week) 
Roxadustat Doseb  
(mg/dose) TIW 
Equivalent Range of Epoetin: Roxadustat 
Ratioc 
< 5,000 
70 
< 23 
5,000 to 8,000 
100 
17 to 27 
> 8,000 to 16,000 
150 
18 to 36 
> 16,000 
200 
≥ 27 
Abbreviations: 
ESA = erythropoiesis-stimulating agent; Hb = hemoglobin; IU = international units; TIW = three times a week.  
a 
Average weekly prescribed dose in last 4 weeks prior to randomization 
b 
Starting dose will be one step higher if the mean Hb at randomization is < 10 g/dL  
c 
Ratio of epoetin weekly dose in IU/week to roxadustat dose in mg/week. 
Notes: 
The roxadustat dose steps are 20, 40, 50, 70, 100, 150, 200, 250, 300, and 400 mg 
Using these dose tiers, most patients are expected to be in the medium dose tier, requiring an 
epoetin: roxadustat ratio between 18 and 36, compatible with the dose relationship data derived 
from the Phase 2 study in a similar patient population (Study FGCL-4592-040).  
In this study, the initial dose of roxadustat will be determined by the subject’s average prescribed 
ESA dose in the last 4 weeks prior to randomization if on epoetin or darbepoetin (8 weeks if on 
Mircera®). 
Using the conversion table (Table 1), in this study, subjects will receive starting roxadustat doses 
of 70 mg, 100 mg, 150 mg, or 200 mg. If the mean screening Hb value at randomization is < 10 
g/dL, the starting roxadustat dose will be increased by one dose step. If the converted initial dose 
exceeds the maximum dose of 3.0 mg/kg/dose then the lower dose step should be chosen as the 
initial dose. Roxadustat doses will be administered at a frequency of TIW. 
The completed Phase 2 studies evaluated the need for dose adjustments for both Hb correction 
and Hb maintenance. Dose adjustments were allowed at regular 4-week intervals to maintain, 
increase, or decrease the dose according to prespecified rules. Prespecified dosing steps were 
used to correct and maintain Hb levels within treatment thresholds based on absolute Hb levels 


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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. Roxadustat 
subjects will follow the dose adjustments guidelines as outlined in Appendix 2.  
Subjects randomized to roxadustat will take doses TIW for the entire duration of the Treatment 
Period. If a subject requires < 20 mg TIW (ie, < 60 mg per week) to maintain a Hb level of 
approximately 11 g/dL, the dosing frequency should be reduced in a step-wise fashion e.g. TIW 
to BIW, BIW to QW, QW to Q-2 Week etc. 
Maximum Dose for Roxadustat 
The maximum allowed roxadustat dose in this study is set at 400 mg or 3.0 mg/kg/dose (based 
on dry weight in subjects on HD and normal weight subjects on PD), whichever is lower. The 
highest dose tested in healthy subjects is 5 mg/kg single dose and 3.75 mg/kg TIW. The doses 
were safe and well tolerated with transient dose-dependent HR increases observed. No maximum 
tolerated dose (MTD) was reached in the clinical development of roxadustat based on the 
observed pharmacodynamic response (plasma EPO levels) and the predicted relation between 
EPO levels and Hb response; therefore exploration of higher doses was not deemed necessary. 
Plasma EPO levels increased in a supralinear manner with increasing roxadustat doses. It is 
expected that the majority of the subjects will show adequate Hb response at substantially lower 
doses than the maximum allowed dose. This study will provide sufficient data on the efficacy 
and safety of long term treatment of anemia with roxadustat in ESRD subjects on stable dialysis. 
Prescribed dose must not exceed the maximum allowable dose of 3.0 mg/kg/dose or 400 mg per 
dose, whichever is lower. For dose adjustment purposes, post-dialysis weight (dry-weight) 
should be used. If the post-dialysis weight of the current visit is not available at the time of dose 
adjustment, post-dialysis weight of the prior dialysis session or last recorded post-dialysis weight 
may be used. 
2.7 Risks/Benefits of Roxadustat Treatment 
The primary benefit of roxadustat is the correction of anemia, including the relief of associated 
signs and symptoms and an increased quality of life. Roxadustat is expected to be at least as safe 
as ESAs, and the current data suggest that CV risk may be lower than with ESAs.  
A prespecified dose adjustment algorithm will be used during the Treatment Period to maintain a 
Hb level of approximately 11 g/dL, while closely monitoring the rate of rise of Hb and Hb levels 
(Appendix 2). In the event of excessive rate of rise or excessive Hb levels, the dose may be 
adjusted or held at any time according to the guidelines described in Appendix 2. 
If there are clinical concerns for a subject’s high Hb levels, the investigator may decide to 
perform a therapeutic phlebotomy in addition to dose hold. Adverse and serious adverse events, 
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 CV, cerebrovascular, and thromboembolic 
events. In addition, an independent Data and Safety Monitoring Board (DSMB) will perform 
regular, periodic assessments of safety data (at least every 6 months or twice per calendar year 
while the trial is ongoing) to detect any potential safety signals that may arise during the study 
and advise the Sponsor accordingly.  


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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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3 OBJECTIVES AND ENDPOINTS 
3.1 Objectives 
3.1.1 Primary Objectives 
The primary objective of this study is to evaluate the efficacy and safety of roxadustat compared 
with active control (epoetin alfa) for the maintenance treatment of anemia in subjects with ESRD 
on stable dialysis. 
3.1.2 Secondary Objectives 
The secondary objectives in this study are to: 
• 
Evaluate the utilization of intravenous (IV) iron with roxadustat compared with active 
control (epoetin alfa) 
• 
Evaluate the effect of roxadustat on serum lipid parameters compared with active control 
(epoetin alfa) 
3.2 Efficacy Endpoints 
3.2.1 Primary Efficacy Endpoint: 
For US (FDA) submission:  Hemoglobin (Hb) change from baseline to the average level during 
the evaluation period defined as Week 28 until Week 52 
For EU regulatory submission:  
Hemoglobin (Hb) change from baseline (BL) to the average 
Hb of Weeks 28 to 36, without having received rescue therapy (ie, 
RBC transfusion or rescue ESA therapy) within 6 weeks prior to 
and during this 8-week evaluation period. 
3.2.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints in this study are: 
• US (FDA) submission:  Proportion of subjects with mean Hb level during the evaluation 
period defined as Week 28 until Week 52 ≥ 10.0 g/dL. 
• EU regulatory submission:  Hemoglobin (Hb) response, defined as mean Hb during 
Weeks 28 to 36 within the target range of 10.0 to 12.0 g/dL without having received 
rescue therapy within 6 weeks prior to and during this 8-week evaluation period. 
• Average monthly IV iron use per subject during Weeks 1 to 36 (monthly defined as a 
period of 4 weeks). 
• Change from BL in low-density lipoprotein (LDL) cholesterol to the average LDL 
cholesterol of Weeks 12 to 28 
• Change from BL in SF-36 Physical Functioning (PF) subscore to the average PF subscore 
of Weeks 12 to 28 
• Change from BL in SF-36 Vitality (VT) subscore to the average VT subscore of Weeks 
12 to 28  
• Effect on predialysis BP:  
o Time to an exacerbation of hypertension from BL during Weeks 1 to 36 


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 An increase from BL of ≥ 20 mm Hg systolic blood pressure(sBP) and 
sBP > 170 mmHg  
OR 
 An increase from BL of ≥ 15 mm Hg diastolic blood pressure (dBP) and 
dBP > 100 mmHg 
o Change from BL in mean arterial pressure (MAP) to the MAP value averaged 
over Weeks 20 to 28 
3.2.3 Additional Evaluation of Efficacy  
The additional efficacy evaluations in this study are: 
• Hb Maintenance: 
o Hemoglobin Long-Term Maintenance: Mean change from BL 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 from BL in Hb averaged over the final 8 weeks of treatment, 
without rescue therapy within 6 weeks prior to and during this 8-week evaluation 
period 
o Change from BL in Hb at each of the selected postdosing time points 
o Proportion of subjects with 10-12 g/dL averaged over Weeks 28 to 36, 44 to 52, 
and the final 8-weeks of treatment without rescue therapy within 6 weeks prior to 
and during this 8-week evaluation period 
o Hb response during Weeks 28 and 36 regardless of use of rescue therapy 
o Hb change from BL to the average Hb value of Weeks 28 to 36, 44 to 52, and the 
final 8 weeks of treatment regardless of the use of rescue therapy 
• Iron Supplement: 
o Requirement for IV iron supplementation  
o Mean monthly IV iron (mg) per subject during Weeks 37 to 52 and Week 53 to 
EOS 
o Mean monthly oral iron (mg) use per subject during Weeks 1 to 36, Weeks 37 to 
52, and Weeks 53 to EOS  
o Requirement for only oral iron supplementation 
• Hospitalizations: 
o Occurrence (number) of hospitalizations  
o Proportion of subjects hospitalized  
o Number of days of hospitalizations per patient-exposure year (PEY) 


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• Missed Dialysis: 
o Occurrence (number) of missed dialysis sessions  
o Proportion of subjects with missed dialysis sessions  
o Number of days of missed dialysis sessions per patient-exposure year (PEY) 
 
• Rescue Therapy Use:  
o Proportion of subjects who receive RBC transfusions 
o Number of RBC packs per patient-month exposure to study medication 
o Having received rescue therapy [composite of RBC transfusions and rescue ESA] 
• Changes in Cholesterol Levels: 
o Change from BL at each of the selected treatment time points in:  
 Total cholesterol  
 Low-density lipoprotein/high-density lipoprotein ratio 
 Non-HDL cholesterol 
o Proportion of subjects achieving LDL target of < 100 mg/dL averaged over 
Weeks 12 to 28 of treatment 
• Blood Pressure Effect: 
o Proportion of subjects achieving BP treatment goal in ESRD subjects (predialysis 
systolic BP < 140 mmHg and diastolic BP < 90 mmHg) averaged over Weeks 12 
to 28 
o Time to a treatment-emergent AE of hypertension  
o Time to intensification from BL of antihypertensive therapy 
o Proportion of subjects with increase in BP, defined as an increase from BL of 
≥ 20 mm Hg sBP and sBP > 170 mmHg or an increase from BL of ≥ 15 mm Hg 
dBP and dBP > 100 mmHg 
o Proportion of subjects with a treatment-emergent AE of hypertension  
o Proportion of subjects with intensification from BL of antihypertensive therapy 
• Vascular Access Thrombosis (HD subjects): 
o Time to a treatment-emergent AE of vascular access thrombosis 
o Proportion of subjects with a treatment-emergent AE of vascular access 
thrombosis 
• HRQoL and EQ-5D-5L Benefits of Anemia Therapy:  
Change from BL to the average of Weeks 12 to 28 and 28 to 52 of treatment for those 
listed below. 


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o VT Subscale of SF-36: In subjects with BL VT Subscore below 50 
o Physical Component Scores of SF-36: 
 In subjects with BL physical component scores below 40  
 In all subjects 
o Anemia Subscale (“Additional Concerns”) of Functional Assessment of Cancer 
Therapy-Anemia (FACT-An) Scores:  
 In subjects with BL subscale scores below 55 (generally associated with 
fatigue). 
 In all subjects 
o Total FACT-An Scores: 
 In subjects with BL FACT-An scores below 135 
 In all subjects 
o EQ-5D-5L Scores: In all subjects 
• Hepcidin, Iron Indices, and HbA1c:  
o Change from BL in serum hepcidin at each of the selected time points 
o Change from BL in serum ferritin at each of the selected time points, total and 
subgrouped by BL values of ≤ 400 ng/mL, and > 400 ng/mL. 
o Change from BL in TSAT at each of the selected time points, total and 
subgrouped by BL values of ≤ 40%, and > 40%. 
o Change in HbA1c level at each of the selected time points in all subjects, in 
subjects with history of diabetes  
3.3 Safety Endpoints 
Study-specific safety will be assessed by evaluating the following: 
• 
Occurrence of treatment emergent adverse events (TEAEs) and treatment emergent 
serious adverse events (TESAEs) 
• 
Adverse events (AEs), serious adverse events (SAEs), and clinically significant changes 
in laboratory values from baseline  
• 
Vital signs, electrocardiogram (ECG) parameters, and clinical laboratory values. 
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: 
All cause death, MI, stroke, congestive heart failure requiring hospitalization, unstable angina 
requiring hospitalization, hypertensive emergency, DVT, pulmonary embolism, and vascular 
access thrombosis.  


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


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4 STUDY DESIGN 
4.1 Description of the Study 
This open-label, randomized, active controlled study is designed to evaluate the efficacy and 
safety of roxadustat compared to epoetin alfa for the maintenance of hemoglobin (Hb) levels in 
subjects on HD or PD or HHD originally on ESA for treatment of anemia. 
• Screening Period: Up to 6 weeks. For subjects currently taking Mircera®, the Screening 
Period can be extended up to 8 weeks 
• Treatment Period: Treatment duration is variable for individual subjects, with a 
minimum treatment duration of 52 weeks and a maximum duration of up to 
approximately 3 years after the last subject is randomized 
Amendment 1& 2: In order to complete the Phase 3 program in a timely manner, 
minimum treatment duration of subjects enrolled under Amendment 1 & 2 may be 
shortened. Subjects will be informed at least 4 weeks in advance if such decision is made. 
All active subjects will end the study at the same time 
• Post-Treatment Follow-Up Period: 4 weeks 
During the course of the study, visits and assessments will be performed as defined in the 
schedule of assessments. 
4.1.1 Screening Period 
After signing the informed consent, subjects enter the Screening Period. During the Screening 
Period eligibility assessments will be performed. Subjects in screening will continue their 
existing ESA therapy (eg, epoetin alfa, beta, theta, or zeta, darbepoetin alfa, Mircera®) for the 
treatment of anemia associated with ESRD. 
Subjects on dose-hold due to high haemoglobin may qualify for screening however, they cannot 
be randomized if in investigator’s opinion not ready to resume epoetin-alfa or roxadustat upon 
randomization. 
Upon successful completion of screening, a total of up to 1200 eligible subjects will be 
randomized to receive either roxadustat or epoetin alfa (active control) in a 1:1 ratio. Both 
roxadustat and epoetin alfa will be administered in an open label manner. Randomization must 
be completed prior to administration of study medication. Randomization to treatment arms will 
be provided by an interactive web and voice response system (IWRS) based on stratification 
factors.  
Subjects on long-acting ESAs (Aranesp or Mircera) may not receive the 1st dose of study 
medication on the day of randomization due to ESA dosing schedule (e.g. once weekly or once 
bi-weekly); in these subjects, the 1st dose of study medication (roxadustat or epoetin-alfa) should 
be administered on the day when the next dose of current ESA would have been due.  For all 
practical purposes, the date of 1st dose of study drug administration should be considered as Day 
1.  
If Day 1 lab values (collected prior to administration of study medication) suggests the potential 
of a pretreatment condition confounding safety assessment or poses safety risks to study subject, 
in the opinion of the Investigator or Medical Monitor, the subject may be discontinued from the 


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study (example: At Screening 1 visit, LFT values were within the protocol range but at Day1, 
AST or ALT > 3x ULN and Total bilirubin > 2x ULT, or AST or ALT > 5x ULN). 
4.1.2 Treatment Period 
Administration of the first dose of study treatment (roxadustat or epoetin alfa) will occur on Day 
1 (Week 0) which should correspond to the administration of the subject’s next dose of their 
current ESA treatment.  
At the Day 1, subjects randomized to Roxadustat Arm will discontinue prior ESA therapy and 
initiate roxadustat therapy; subjects randomized to Epoetin-Alfa Arm will receive epoetin-alfa 
irrespective of their prior ESA use.  
The initial dose of study medication will be determined based on the average prescribed ESA 
dose in the last 4 weeks prior to randomization if on epoetin or darbepoetin (8 weeks if on 
Mircera®) as outlined in Table 1or Table 2 for subjects randomized to receive roxadustat or 
epoetin alfa, respectively. The initial dose of roxadustat will remain constant during the first 4 
weeks of the Treatment Period, except if a dose reduction is required for excessive 
hematopoiesis. 
Subsequent dose adjustments for roxadustat subjects will follow the dose adjustments guidelines 
as outlined in Appendix 2 in order to maintain a Hb level of approximately 11 g/dL during the 
Treatment Period. Dose adjustments for epoetin alfa subjects should follow the dosing 
recommendations as per the approved country-specific epoetin alfa Package Insert or Summary 
of Product Characteristics (SmPC). In PD and HHD subjects, if receiving epoetin alfa 
subcutaneously, the dose and frequency may be determined by the Investigator per local standard 
of care. 
Day 1 study procedures including laboratory blood draws are to be completed prior to 
administration of the first dose of study treatment. In HD subjects, Day 1 procedures with the 
exception of health-related quality of life (HRQoL) assessments should be completed prior to the 
subject receiving dialysis that day. Weight measurement will be taken after completion of 
dialysis (ie, dry weight). 
Total treatment duration is variable for individual subjects. Subjects will receive study treatment 
(roxadustat or epoetin alfa) for a minimum of 52 weeks. The maximum treatment duration may 
be up to approximately 3 years from the date the last subject is randomized.  
In order to complete the Phase 3 program in a timely manner, minimum treatment duration of 
subjects enrolled under Amendment 1 & 2 may be shortened. Subjects will be informed at least 4 
weeks in advance if such decision is made. All active subjects will end the study at the same 
time. 
During the Treatment Period, subjects will attend weekly study visits from Day 1 to Week 2, 
followed by every 2 weeks study visits from Weeks 4 to 24 (eg, Weeks 4, 6). Following Week 
24, study visits will occur every 4 weeks (eg, Weeks 28, 32) until EOT. A common closeout will 
occur when a predetermined number of cardiovascular (CV) events have been accrued across 
multiple studies in the overall Phase 3 dialysis program.  
At each study visit during the Treatment Period, Hb will be measured (prior to dialysis in HD 
subjects) locally to determine the need for a dose adjustment or to assess for excessive 
hematopoiesis. In the event that the Hb value from the central laboratory is significantly different 


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from that measured locally, and per Investigator that warrants a reversal of the dose adjustment 
decision made earlier based on locally measured Hb value, the Medical Monitor should be 
informed, if possible. 
4.1.3 Post-Treatment Follow-Up Period 
After completing the Treatment Period, subjects proceed to the post-treatment Follow-up Period 
and will return for the End of Study (EOS) visit. The choice of anemia treatment during the 
Follow-up Period is up to the discretion of the Investigator. If the Investigator decides to resume 
ESA treatment in roxadustat treated subjects, the first dose of ESA should be administered at 
least three days after the last dose of roxadustat. 
4.1.4 Long-term Follow-Up for Premature Treatment Discontinued Subjects  
Subjects who discontinue study medication prematurely will be followed up for vital status, CV 
events, and hospitalization until study closure, unless consent to participate is withdrawn. Upon 
completion of EOT and EOS visits, these subjects will be followed up every 3 to 6 month 
interval (depending on the availability of subjects) until study closure. These visits may occur 
either in-person or via telephone.  
4.2 Randomization, Treatment Assignment, and Rationale for Open-label 
Design 
A randomized design has been chosen in order to ensure a balanced and unbiased allocation of 
study subjects to the treatment arms and to minimize bias in therapeutic management and in 
outcomes assessment.  
An open-label design was chosen since double-blinding would require a double-blind, double-
dummy design to match the different ESAs made by different manufacturers having different 
dosing specifications which is considered too challenging without much added benefits to the 
study. It would expose subjects to multiple additional injections or infusions without additional 
benefit. Furthermore, the difference in iron supplementation requirements between roxadustat 
and the ESA will further complicate any efforts to blind, or alternatively end up in inadvertent 
unblinding. The high probability of these confounding factors rendering the conduct of a double-
blind double-dummy study and data becoming invalid is outweighing the advantage of a lower 
risk for bias. Therefore, in light of the objectivity of primary endpoint measures not influenced 
by blinding and the lack of operational feasibility without addition of values to subjects, the open 
label study design is to be considered the most reasonable option. 
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) 
• Active Control: epoetin alfa (up to approximately 600 subjects) 
Randomization is stratified by the following four factors:  
• Mean qualifying screening Hb (≤ 10.5 vs. > 10.5 g/dL) 
• History of CV, cerebrovascular, or thromboembolic diseases (Yes vs. No) 
• Mean prescribed weekly baseline epoetin alfa dose (or, equivalent epoetin dose for 
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• Geographical region (US vs. Ex-US region) 
Randomization of qualified subjects will take place prior to administration of study drug.  
4.3 Procedures for Handling Incorrectly Enrolled or Randomized subjects  
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be enrolled 
or receive study medication. There can be no exceptions to this rule. Where a subject does not 
meet all the eligibility criteria but is randomized in error or incorrectly received study 
medication, the Investigator should inform the Medical Monitor immediately, and a discussion 
should occur regarding whether to continue or discontinue the patient from treatment. All 
decisions from such meeting should be appropriately documented.  
4.4 Replacement of Subjects  
Subjects who drop out prematurely will not be replaced in the study. 
4.5 Study Treatment 
4.5.1 Dose and Schedule 
Eligible subjects will be randomized via IWRS to receive either roxadustat or epoetin alfa. The 
first dose of study drug should be administered on Day 1 (Week 0), which should correspond to a 
day when their next dose of ESA would have been administered. All subjects will attend weekly 
study visits from Day 1 to Week 2, followed by every two weeks study visits from Weeks 4 to 
24. Following Week 24, study visits will occur every four weeks until the EOT. Subjects will 
receive study medication in an open label manner.  
4.5.2 Starting Dose of Study Drug 
4.5.2.1 Roxadustat Arm 
In subjects on HD or PD or HHD randomized to roxadustat, the initial roxadustat dose will be 
determined using a conversion table based on the subject’s previous average weekly prescribed 
ESA dose in the last 4 weeks prior to randomization if the subject is on epoetin or darbepoetin, 
and average monthly (4 weeks) prescribed ESA dose in 8 weeks prior to randomization if the 
subject is on Mircera® (Table 2). If the mean qualifying screening Hb value at randomization is 
< 10 g/dL, the starting roxadustat dose will be increased by one dose step. For example, a subject 
on epoetin (ie, epoetin alfa, beta, theta, zeta, delta, or omega) 6,000 IU/week with mean 
screening Hb of 9.4 g/dL at randomization will start roxadustat at a dose of 150 mg three times 
weekly (TIW).  
If the converted initial dose exceeds the maximum dose of 3.0 mg/kg/dose then the lower dose 
step should be chosen as the initial dose.  


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The dose of roxadustat will remain constant during the first 4 weeks of the Treatment Period 
unless a dose reduction is required for excessive hematopoiesis.  
Table 2. 
Initial Dosing of Roxadustat: Conversion Table from ESAs to Roxadustat 
Epoetin (ie, alfa, beta, 
theta, zeta, delta, or 
omega) a 
(IU/wk) 
Darbepoetin 
alfa a, b 
(μg/wk) 
Mircera® c 
(μg/monthly) 
Roxadustat Dose d  
(mg/dose) TIW 
< 5,000 
< 25 
< 80 
70 
5,000 to 8,000 
25-40 
80-120 
100 
> 8,000 to 16,000 
> 40-80 
> 120-200 
150 
> 16,000 
> 80 
> 200 
200 
Abbreviations: 
ESA = erythropoiesis-stimulating agent; Hb = hemoglobin; IU = international units; TIW = three times a week; 
wk(s) = week(s).  
a 
Average weekly prescribed dose in last 4 weeks prior to randomization 
b 
If darbepoetin is used biweekly, use half the dose to get per week dose  
c 
Average prescribed monthly (4 wks) dose in last 8 weeks prior to randomization  
d 
Starting dose will be one step higher if the mean Hb at randomization is < 10.0 g/dL, however, not to exceed 3.0 
mg/kg/dose.  
Notes: 
The roxadustat dose steps are 20, 40, 50, 70, 100, 150, 200, 250, 300, and 400 mg. 
4.5.2.2 Epoetin Alfa Arm (Active Control) 
Subjects randomized to the epoetin alfa arm who are currently taking nonepoetin alfa treatment 
will be switched to epoetin alfa treatment on Day 1. All subjects on HD will receive IV epoetin 
alfa TIW starting from Day 1, irrespective of their baseline route of administration or frequency 
of ESA use. Subjects requiring ultra-low dose of EPO (eg, ≤1000 IU/per week), frequency of 
administration may be adjusted per local standard of care. 
Subjects on PD or HHD may continue using the same route of administration as baseline; 
however, if the Investigator decides to change the route of administration in a PD or HHD 
subject from subcutaneous to IV after randomization it should be done during the early part of 
the treatment phase (preferably prior to Week 16).  
All epoetin alfa administrations should be performed by the Investigator or an authorized 
member of the site staff or other trained personnel. In subjects on PD or HHD, epoetin alfa may 
be self-administered subcutaneously by the subject or a caregiver after adequate training or, if in 
the opinion of the Investigator, the subject or a caregiver is already adequately trained in self-
administering ESA prior to the study.  
Doses: 
In subjects who have been randomized to the epoetin alfa treatment arm, the initial epoetin alfa 
dose that the subject will receive on Day 1 will be determined using a conversion table based on 
the subject’s average weekly prescribed ESA dose in 4 weeks prior to randomization if on 
epoetin or darbepoetin, and average monthly (4-week) prescribed ESA dose in 8 weeks prior to 
randomization if on Mircera® (Table 3). 


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In case of a change in route of administration from subcutaneous to IV (TIW), the initial dose of 
IV epoetin alfa will be determined by the Investigator per local standard of care.  
In subjects on PD or HHD, if receiving epoetin alfa subcutaneously, the dose and frequency may 
be determined by the Investigator per local standard of care. 
Subsequent epoetin alfa dosing and dose adjustment during the study, if indicated, should be 
based on the country specific package insert or SmPC. 
For countries using prefilled epoetin alfa syringes, the initial dose and subsequent dosages 
following dose adjustments during the Treatment Period should be approximated to the closest 
total weekly dose. 
Table 3. 
Initial Dosing of Epoetin Alfa: Conversion table from Non-Epoetin ESAs to 
Epoetin Alfa 
Baseline ESA 
Conversion Ratio 
Examples of Converted 
Initial Epoetin Alfa dose (approximate) IU/week c 
Epoetin (ie, alfa, beta, 
theta, zeta, delta, or 
omega) (IU/week) a 
x 1 
6,000 IU/week x 1  
= 6,000 IU/week 
Darbepoetin alfa 
(μg/week) a 
x 200 
40 μg/week x 200  
= 8,000 IU/week 
Mircera® (μg/once 
monthly (ie, 4-wks) b 
x 70 – 80 
(for lower Mircera® dose 
lower conversion ratio may 
be used) d 
100 μg/month x 70 
= 7,000 IU/week 
200 μg/month x 80  
= 16,000 IU/week 
Abbreviations: 
ESA = erythropoiesis-stimulating agent; IU = international units.  
a 
Mean weekly ESA in 4 weeks prior to randomization 
b 
Mean monthly (4-week) ESA in 8 weeks prior to randomization 
c 
May be rounded as deemed necessary by the investigator 
d 
Per discretion of the investigator 
4.5.3 Dose Adjustment 
4.5.3.1 Roxadustat Arm 
During the Treatment Period, roxadustat dose adjustment will be made according to the dose 
adjustment algorithm in Appendix 2, in order to maintain a Hb level of approximately 11 g/dL. 
Roxadustat dose adjustments are permitted from Week 4 onwards, and every 4 weeks thereafter 
(eg, Week 4, Week 8, Week 12); however, dose may be adjusted between two prespecified 
windows (eg, anytime between Week 4 and Week 8 visits, Week 8 and Week 12 visits) if the 
following two criteria are met: 
• No dose adjustment has been made in last 4 weeks, 
• Hemoglobin (Hb) < 9.0 g/dL. 


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Subjects on HD or PD or HHD randomized to roxadustat will take doses TIW for the entire 
duration of the Treatment Period. If a subject requires < 20 mg TIW (ie, < 60 mg per week) to 
maintain a Hb level of approximately 11 g/dL, the dosing frequency should be reduced in a step-
wise fashion e.g. TIW to BIW, BIW to QW, QW to Q-2 Week etc. 
In this study, a rate of rise of Hb > 2 g/dL within 4 weeks or a Hb level of ≥ 13 g/dl at any time 
would be considered as excessive haematopoiesis. For a rate of rise of Hb > 2 g/dL within 4 
weeks, dose should be reduced by one dose step and for a Hb value ≥ 13.0 g/dL, the dose should 
be on hold until Hb drops < 12.0 g/dL per guidelines provided in the protocol (Appendix 2). 
When roxadustat will be resumed, the dose will be reduced by one dose step.  
Dose adjustments or temporary dose holds for excessive hematopoiesis can occur at any time 
during the Treatment Period. Any dose adjustment will reset the dose-adjustment window to 
every 4 weeks thereafter (eg, dose adjustment for a qualified reason at Week 6 leads to next dose 
adjustment at Week 10). If a dose adjustment review is scheduled on Week 22, then the next 
dose adjustment review will be scheduled on Week 28, since there is no scheduled visit on Week 
26. 
Prescribed dose must not exceed the maximum allowable dose of 3.0 mg/kg/dose or 400 mg per 
dose, whichever is lower. For dose adjustment purposes, post-dialysis weight (dry-weight) 
should be used. If the post-dialysis weight of the current visit is not available at the time of dose 
adjustment, post-dialysis weight of the prior dialysis session or last recorded post-dialysis weight 
may be used. 
4.5.3.2 Active Control (Epoetin alfa) Arm  
Epoetin dose adjustments during the Treatment Period should be based on country-specific 
epoetin alfa Package Insert or SmPC.  
In subjects on PD or HHD, if receiving epoetin alfa subcutaneously, the dose and frequency may 
be determined by the Investigator per local standard of care. 
4.6 Concomitant Medications, Procedures and Nondrug Therapies 
4.6.1 Concomitant Medications 
Concomitant medications are any prescription or over-the-counter preparations, including herbal 
products and “natural remedies”, used by a subject while participating in this clinical study.  
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.  
Use of herbal medicine during the study is not prohibited but strongly discouraged. All herbal 
and natural remedies should be reviewed by the investigator and if considered safe, may be 
allowed to continue at the same dose. 
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.  
4.6.1.1  Phosphate Binders 
When coadministered with roxadustat, in a clinical pharmacology study, the bioavailability of 
roxadustat was reduced. Subjects should be advised to discuss with the Investigator when 


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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. 
4.6.1.2  Statins 
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 
lowering treatment should be maintained as clinically indicated. The dose of statins should not 
exceed the recommended daily dose in the table below for subjects randomized to roxadustat. 
Recommended Maximum Daily Dose of Statins for Subjects Randomized to Roxadustat  
Statins 
Recommended maximum dose (mg/day) 
Atorvastatin  
40 
Simvastatin 
5 
Rosuvastatin 
5 
Pravastatin 
40 
Fluvastatin 
20 
Pitavastatin 
1 
Lovastatin 
20 
4.6.2 Supplemental Iron Use 
In a Phase 2 study, there was no significant difference in Hb levels in roxadustat-treated subjects 
on dialysis receiving oral iron supplementation compared to subjects receiving IV iron 
supplementation, in subjects with ferritin < 100 ng/mL and in those with TSAT< 20%. Based on 
the mechanism of action of roxadustat and the Phase 2 study results, in subjects randomized to 
roxadustat, oral iron supplementation is considered to be sufficient.  
In this study, oral iron should be allowed as the preferred first-line of iron supplementation for 
both treatment arms without restriction.  
In addition to scheduled assessments (Appendix 3), iron indices may be assessed anytime (via 
central lab) to evaluate iron storage status of the subjects, if considered necessary by the 
Investigator. 
4.6.2.1 Oral Iron Supplementation 
All subjects should be encouraged to take oral iron if they can tolerate as the preferred first-line 
iron supplementation during the Treatment Period. Provision of an oral iron supplement is 
encouraged; the dose and frequency are at the discretion of the principal Investigator. Oral Iron 
therapy should be started before the subject becomes iron depleted. 


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4.6.2.2 Intravenous (IV) Iron Supplementation 
Intravenous iron supplementation is permitted if in the opinion of the Investigator the subject has 
not responded adequately and is considered iron deficient. IV iron may be administered per local 
standard of care as deemed necessary by the investigator. 
Treatment with study medication (roxadustat or epoetin) will continue during IV iron 
administration. Discontinuation of IV iron supplementation is recommended once the subject is 
no longer considered iron deficient (eg, ferritin ≥ 100 ng/mL and TSAT ≥ 20%) 
Subjects may receive IV iron during the post-treatment Follow-up Period per discretion of the 
Investigator. If IV iron is to be administered at the EOT visit, all visit procedures including lab 
draws should be completed prior to administering IV iron. 
4.6.3 Rescue Therapy Guidelines 
Rescue therapy guidelines are provided to optimize the standardization of rescue therapy by 
Investigators and to ensure the safety of individual study subjects. Use of rescue therapy and 
reason for rescue therapy should be recorded in the electronic case report form (eCRF). 
4.6.3.1 Red Blood Cell Transfusion (all subjects) 
For subjects in both treatment arms, RBC transfusion is allowed if rapid correction of anemia is 
required to stabilize the subject’s condition (eg, acute hemorrhage) or the Investigator is of the 
opinion that the blood transfusion is a medical necessity. If the situation permits, the Medical 
Monitor should be informed prior to any scheduled RBC transfusion. Study treatment may 
continue during or after the RBC transfusion.  
4.6.3.2 Erythropoiesis Stimulating Agents  
For subjects randomized to roxadustat the use of ESAs is generally prohibited. Erythropoiesis 
stimulating agent rescue is restricted to no more than one cycle of use during the Treatment 
Period; the Investigator may initiate use of an approved EPO analogue if all of the following 
criteria are met: 
• A subject’s Hb level has not sufficiently responded to two or more dose increases or the 
maximum dose limit of the study drug has been reached; and 
• The subject’s Hb is < 8.5 g/dL on two consecutive measurements (central lab) drawn at 
least five days apart; and 
• Clinical judgment does not suggest iron deficiency or bleeding as a cause of lack of 
response or rapid decline in Hb; and 
• Reducing the risk of alloimmunization in transplant eligible patients and/or reduction of 
other RBC transfusion-related risks is a goal 
The subject is not allowed to be administered both the EPO analogue and roxadustat at the same 
time. Treatment with an EPO analogue should be started ≥ 3 days after the last dose of 
roxadustat, and should be stopped when Hb > 9 g/dL or after 4-weeks, whichever comes first. If 
a subject requires longer than 4-weeks therapy due to inadequate response the Medical Monitor 
should be contacted. Study treatment should be resumed after the following intervals: 


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• Two days after stopping epoetin  
• One week after stopping darbepoetin alfa  
• Two weeks after stopping methoxy polyethylene glycol-epoetin beta (Mircera®) 
If more than one cycle of EPO analogue rescue is required, the Investigator should permanently 
discontinue roxadustat. Use of EPO analogues will be recorded in the eCRF. 
Inadvertent ESA administration or ESA administration by the hospital staff in Roxadustat 
subjects should not be counted as rescue unless above criteria are met; these subjects  may be 
allowed to continue taking study medication, if considered safe by the Investigator or Medical 
Monitor. 
For subjects randomized to epoetin alfa, the Investigator may initiate use of a different EPO 
analogue if clinically indicated. Use of the different EPO analogue will be recorded in the eCRF 
and will be considered rescue therapy. 
4.6.4 Emergency Procedure (Therapeutic Phlebotomy) 
If there are clinical concerns for a subject’s high Hb levels, the Investigator may decide to 
perform a therapeutic phlebotomy in addition to temporarily withholding the study drug. This 
should be documented and discussed with the Medical Monitor. 
4.6.5 Prohibited Medications/Therapies/Substances 
The following medications/therapies are prohibited during the period identified: 
• 
Any investigational drug from 4 weeks prior to screening until EOS 
• 
Androgens from screening until EOS 
• 
Iron-chelating agents (eg, deferoxamine/desferrioxamine, deferiprone, or deferasirox 
therapy) from 4 weeks prior to randomization until EOS 
• 
Dapsone (at any dose) from screening until EOS 
• 
Chronic doses acetaminophen/paracetamol > 2.0 g/day from randomization until 1 week 
after EOT 
4.6.6 Contraception 
Female subjects of childbearing potential, if not practicing complete sexual abstinence, must 
agree to practice a dual method of contraception, for example, a combination of the following:  
(1) oral contraceptive, depo progesterone, or intrauterine device; and (2) a barrier method 
(condom or diaphragm). Male subjects (nonsurgically sterile; ie, no vasectomy) with female 
partners of childbearing potential who are not on birth control must agree to use a barrier method 
of contraception (eg, condom) or the female partner must agree to use contraception as described 
above unless practicing complete sexual abstinence.  
Subjects must agree to practice above contraceptive methods, as applicable, for the entire 
duration of the study, from randomization through the EOS visit. It is highly recommended that 
they continue to practice the contraceptive methods for 12 weeks following the last dose of study 
treatment. For subjects discontinuing study medication prematurely, it is recommended that they 
continue to practice contraceptive methods for 12 weeks following the last dose of study 
treatment. 


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Pregnancy, spontaneous or therapeutic abortion, or events related to pregnancy must be reported 
(Section 8.3.6) 
4.7 Safety Monitoring Plan 
Safety will be assessed throughout the study. A complete baseline profile of each subject will be 
established through demographics, medical history, clinical laboratory values, vital signs, 
physical examination (PE), and electrocardiogram (ECG). During the course of the study, vital 
signs, PE, and laboratory tests will be performed at regular intervals as described in schedule of 
assessments (Appendix 3).  
Blood pressure and HR should be assessed according to the guidelines described in Appendix 5.  
A comprehensive PE will be conducted during the Screening visit, Day 1 and at the EOT/ET 
visit. Targeted PEs (eg, general appearance, CV, respiratory and abdomen,) will be conducted 
throughout the study as described in the Schedule of Assessments.  
Any significant findings prior to administration of study drug will be considered as baseline 
conditions and if appropriate, will be captured as baseline medical history. Any clinically 
significant (CS) changes from baseline will be monitored throughout the study and appropriate 
interventions will be taken accordingly. Clinical laboratory tests may be assessed at additional 
times on unscheduled visits for safety reasons. Liver function abnormalities will be monitored 
according to drug-induced liver injury (DILI) guidance (Appendix 4). 
All 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, deemed stable, or until the subject’s EOS visit. See Section 8 for 
details on AE and SAE reporting. 
An Independent Event Review Committee (IERC), blinded to treatment group, will adjudicate 
prespecified CV, cerebrovascular, and thromboembolic safety events of interest. These events 
include all-cause death, MI, stroke, hospitalization for congestive heart failure, hospitalization 
for unstable angina, deep venous thrombosis, pulmonary embolism, and hypertensive 
emergency. A separate adjudication charter will describe the process in detail, and training and 
training materials will be provided to study sites.  
4.8 Data Safety and Monitoring Board 
A Data Safety Monitoring Board (DSMB) will review safety data at least every six months or 
twice per calendar year while the trial is ongoing 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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5 STUDY ENROLLMENT AND WITHDRAWAL 
5.1 Inclusion Criteria 
A subject is eligible for the study if all of the following criteria are met: 
1. Subject has been informed of the investigational nature of this study and has given 
written informed consent in accordance with institutional, local, and national guidelines 
2. Subject age is ≥ 18 years 
3. Subject receiving adequate dialysis using the same modality of dialysis for native kidney 
ESRD for ≥ 3 months prior to screening and during screening  
3.1 Amendment 2: Incident dialysis subjects receiving dialysis for ESRD for ≥ 2 
weeks but ≤ 4 months at the time of randomization  
4. For subjects receiving HD, the vascular access must be via native arteriovenous fistula or 
graft, or permanent, tunneled catheter. For subjects receiving PD, a PD catheter must be 
in use 
5. Subject is on IV or subcutaneous ESA for ≥ 8 weeks prior to screening. The prescribed 
ESA dose must remain stable (≤ 30% change) during the 4 weeks prior to randomization 
if on epoetin or darbepoetin and 8 weeks if on Mircera® 
5.1   Amendment 2: Incident dialysis subjects (as defined in 3.1) must be on ESA for 
≥ 4 weeks prior to screening  
6. Mean of the subject’s three most recent central lab Hb values during the Screening Period 
must be ≥ 9.0 g/dL and ≤12.0 g/dL; with an absolute difference of ≤ 1.3 g/dL between the 
highest and the lowest value. Samples are obtained at least 4 days apart and the last Hb 
value must be within 10 days prior to the randomization visit 
6.1   Amendment 2: For Incident dialysis subjects (as defined in 3.1), mean of the 
subject’s two most recent central lab Hb values during the Screening Period must 
be ≥ 8.5 g/dL and ≤12.0 g/dL; with an absolute difference of ≤ 1.3 g/dL between the 
highest and the lowest value. Samples are obtained at least 2 days apart and the last 
Hb value must be within 10 days prior to the randomization visit 
7. Subject has a ferritin level ≥ 100 ng/mL at screening 
Amendment 2: Subjects with a ferritin level < 100 ng/mL at screening may qualify upon 
receiving iron supplement (per local standard of care) 
8. Subject has a transferrin saturation (TSAT) level ≥ 20% at screening 
Amendment 2: Subjects with a TSAT level < 20% at screening may qualify upon 
receiving iron supplement (per local standard of care) 
9. Subject has a serum folate level ≥ lower limit of normal (LLN) at screening 
Amendment 2: Subjects with a serum folate level < LLN at screening may qualify upon 
receiving folate supplement (per local standard of care) 


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10. Subject has a serum vitamin B12 level ≥ LLN at screening 
Amendment 2: Subjects with a Vitamin B12 level < LLN at screening may qualify upon 
receiving B12 supplement (per local standard of care) 
11. Subject’s alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are ≤ 3 x 
upper limit of normal (ULN), and total bilirubin (TBL) is ≤ 1.5 x ULN at screening  
12. Subject’s body weight (dry weight in HD subjects) is 45.0 to 160.0 kg 
 
Only incident dialysis subjects who meet criteria 3.1, 5.1, and 6.1 (instead of criteria 
3, 5, and 6) are allowed to participate under Protocol Amendment 2 
5.2 Exclusion Criteria 
Subjects will be excluded if any of the following criteria are met: 
1. Subject has received a red blood cell (RBC) transfusion within 8 weeks prior to 
randomization  
Amendment 2:  Subject has received a red blood cell (RBC) transfusion within 4 weeks 
prior to randomization 
2. Subject has a known history of myelodysplastic syndrome or multiple myeloma 
3. Subject has a known hereditary hematologic disease such as thalassemia or sickle cell 
anemia, pure red cell aplasia or other known causes for anemia other than chronic kidney 
disease (CKD) 
4. Subject has known hemosiderosis, hemochromatosis, coagulation disorder, or 
hypercoagulable condition 
5. Subject has a known chronic inflammatory disease that could in the opinion of the 
Investigator impact erythropoiesis (eg, systemic lupus erythematosus, rheumatoid 
arthritis, celiac disease) even if it is currently in remission 
6. Subject is anticipated to undergo elective surgery that is expected to lead to significant 
blood loss during the study period or anticipated elective coronary revascularization. 
7. Subject has active or chronic gastrointestinal bleeding 
8. Subject has received any prior treatment with roxadustat or another HIF-PHI 
9. Subject has been treated with iron-chelating agents within 4 weeks prior to randomization 
10. Subject has a history of chronic liver disease (eg, chronic infectious hepatitis, chronic 
auto-immune liver disease, cirrhosis, or fibrosis of the liver) 
11. Subject with New York Heart Association (NYHA) Class III or IV congestive heart 
failure  
12. Subject has had a MI, acute coronary syndrome, stroke, seizure, or a 
thrombotic/thromboembolic event within a major vessel (excluding vascular dialysis 
access) (eg, DVT or pulmonary embolism) within 12 weeks prior to randomization 


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13. Subject has uncontrolled hypertension, in the opinion of the Investigator, (eg, that 
requires change in anti-hypertensive medication) within 2 weeks prior to randomization 
14. Subject has one or more contraindications for treatment with epoetin alfa or other ESA 
including known hypersensitivity  
15. Subject has a diagnosis or suspicion (eg, complex kidney cyst of Bosniak Category II or 
higher) of renal cell carcinoma as shown on renal imaging performed within 12 weeks 
prior to randomization 
16. Subject has a 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 
Amendment 2:  Subject has a history of malignancy, except for the following: cancers 
determined to be cured or in remission for ≥ 2 years, curatively resected basal cell or 
squamous cell skin cancers, cervical cancer in situ, or resected colonic polyps 
17. Subject is positive for any of the following:  
• Human immunodeficiency virus (HIV) 
• Hepatitis B surface antigen (HBsAg) 
• Anti-hepatitis C virus antibody (anti-HCV Ab) 
18. Subject has an active, clinically significant (CS) infection or evidence of an underlying 
infection, as manifested by white blood cell count (WBC) > ULN, and/or fever, in 
conjunction with clinical signs or symptoms of infection at the time of randomization 
19. Subject has any of the following known untreated conditions: proliferative diabetic 
retinopathy, diabetic macular edema, macular degeneration or retinal vein occlusion 
(subjects who are already blind  may qualify to participate) 
20. Subject has had any prior organ transplant (that has not been explanted), or subject is 
scheduled for organ transplantation (on the waiting list for kidney transplant is not 
exclusionary) 
Amendment 2: Prior organ transplant: subjects who have one of the following conditions 
or states 
 
a)  Experienced rejection of transplanted organ within 6 months of transplantation 
 
b)  Currently on high doses of immunosuppressive therapy (per discretion of the PI) 
c)  Are scheduled for organ transplantation (on the waiting list for kidney transplant is not 
exclusionary) 
21. Subject has participated in an interventional clinical study or has been treated with an 
investigational drug within 4 weeks prior to screening 
22. Subject has drug-treated gastroparesis, short-bowel syndrome, or any other 
gastrointestinal condition that may lead to reduced absorption of study drug 
23. Subject has an anticipated use of dapsone or androgen in any dose amount or anticipated 
chronic use of acetaminophen or paracetamol > 2.0 g/day during the study 


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24. Subject has a history of alcohol or drug abuse within 2 years prior to screening 
Amendment 2: Subject has a history of alcohol or drug abuse within 6 months prior to 
screening 
25. Females of childbearing potential, if not practicing complete sexual abstinence or using 
contraception as detailed in the protocol; male subjects (if not surgically sterile; ie, no 
vasectomy) with sexual partners of childbearing potential, if not practicing complete 
sexual abstinence or using contraception 
26. Pregnant or breastfeeding females 
27. Subject has any medical condition that in the opinion of the Investigator may pose a 
safety risk to the subject in this study, which may confound efficacy or safety assessment, 
or may interfere with study participation 
Subjects who fail to meet the above eligibility criteria should not, under any circumstances, be 
randomized or receive study medication. No exceptions to this rule will be allowed. No prospective 
waiver with regards to eligibility criteria (inclusion/exclusion) will be issued. 
5.3 Subject Discontinuation and Withdrawal 
The subject is free to permanently discontinue study medication at any time, without prejudice to 
further treatment. Discontinuation from study medication is not the same as complete withdrawal 
from the study (ie, withdrawal of consent).  
Subjects may withdraw consent and discontinue from the study at any time by discontinuing 
study medication and refusing to return for any form of follow-up without any prejudice.  
A subject who decides to discontinue study medication will always be asked about the reason(s) 
to discontinue study medication and the presence of AEs (if any). These data will be ascertained 
and documented by the investigator and recorded in the eCRF as appropriate. The subject should 
return all study medications.  
Reasons for permanent discontinuation of study medication: 
• Subject’s decision (subject no longer wants to continue study medication (ie, withdrawal 
of consent) 
• Investigator’s decision that it is in the best interest of the subject to be withdrawn from 
the study 
• Adverse events 
• Significant noncompliance with study procedures, as determined by Investigator or 
Sponsor 
• Lack of efficacy / Meets ESA withdrawal criteria  
• Subject is lost to follow-up  
• Subject is no longer requiring dialysis due to kidney transplant 
• Site terminated by the sponsor 


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• Pregnancy 
• Death 
Upon discontinuation from the study, both female subjects of childbearing potential and male 
subjects with partners of childbearing potential must continue to use a medically acceptable 
method of contraception for 12 weeks following the last study drug administration.  
5.4 Replacement of Subjects 
Subjects may not be replaced from this study.  
5.5 Study Termination 
This trial can be terminated by the sponsor at any time for any reason.  


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6 INVESTIGATIONAL PRODUCT  
6.1 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 II. All ingredients used for manufacture of roxadustat comply with US and 
European Union compendia or regulatory standards. Strengths are different in size and debossing 
reflects the strength (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.  
6.2 Storage 
Roxadustat tablets should be protected from light, and stored at room temperature between 15°C 
and 30°C (59ºF to 86ºF).  
Epoetin alfa should be stored according to the package insert. 
All study drugs (roxadustat and epoetin alfa) should be stored in a securely locked area to which 
access is limited to appropriately authorized study personnel.  
6.3 Study Drug Handling and Disposal 
All study drugs provided by the Sponsor or provided at the study site should be retained at the 
site until otherwise instructed in writing by the Sponsor. Upon completion of the study or 
termination of the investigational site, all used (vials/syringes or bottles), unused, and partially 
used study drugs; and all study drugs that were not dispensed will be shipped to a site designated 
by the Sponsor or may be destroyed according to local/institutional policies by the 
Pharmacy/authorized staff after drug accountability and reconciliation has been completed by 
Sponsor. Please refer to the Study Reference Manual or Pharmacy Manual for additional 
information. 
6.4 Route of Administration and Dose 
6.4.1 Roxadustat  
Subjects on HD or PD or HHD randomized to roxadustat will take doses TIW for the entire 
duration of the Treatment Period. If a subject requires < 20 mg TIW (ie, < 60 mg per week) to 
maintain a Hb level of approximately 11 g/dL, the dosing frequency should be reduced in a step-
wise fashion e.g. TIW to BIW, BIW to QW, QW to Q-2 Week etc.  
Roxadustat will be dispensed to subjects with instructions for self-administration of the tablets 
orally on each dosing day, according to the dosing schedule. The tablets are to be swallowed 
whole.  
First dose of roxadustat should be administered on Day 1 after completion of all procedures 
including laboratory draws. Roxadustat doses should be administered at least 2 days apart, and 
no more than 4 days apart. Dosing should occur at approximately at the same time of day. 
Roxadustat can be taken with or without food.  


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6.4.2 Epoetin Alfa  
During the Treatment Period, starting from Day 1, all subjects on HD randomized to epoetin alfa 
arm will receive epoetin alfa intravenously TIW irrespective of their baseline route of 
administration or frequency of ESA use. Epoetin alfa dose adjustments should be based on the 
country specific package insert or SmPC. 
Subjects requiring ultra-low dose of EPO (eg, ≤1000 IU/per week), frequency of administration 
may be adjusted per local standard of care. For peritoneal dialysis subjects and home hemo-
dialysis subjects, the route of administration (IV or SC) may remain the same as baseline. 
However, if the investigator decides to change the route of administration in PD subjects from 
SC to IV after randomization it should be done during the early part of the treatment phase 
(preferably prior to Week 16). 
In case of a change in route of administration from subcutaneous to intravenous (TIW), the initial 
dose of IV epoetin alfa will be determined by the investigator per local standard of care.  
All epoetin alfa administrations should be performed by the investigator or an authorized 
member of the site staff or other trained personnel. In PD and HHD subjects, epoetin alfa may 
also be self-administered subcutaneously by the subject or a caregiver after adequate training or, 
if in the opinion of the investigator, the subject or a caregiver is already adequately self-
administering ESA prior to the study. 
6.5 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 400 mg or 3.0 mg/kg/dose, 
whichever is lower. Any dosing exceeding the maximum allowed roxadustat dose should be 
reported within 24 hours. The Medical Monitor should be contacted as soon as possible. 
Symptoms associated with overdosing, if any, will be reported as adverse events. An overdose 
without associated symptoms is not an AE and will be recorded on the overdose eCRF 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 Package Insert or SmPCs. 


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7 ASSESSMENT OF EFFICACY 
7.1 Study Procedures by Visit 
During study visits, unless otherwise indicated, it is preferred that all assessments including labs 
and physical examinations should be completed predialysis for subjects on HD. For subjects on 
PD or HHD, 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 PD or HHD approximately at the same time of the day. Weight measurement in HD 
subjects should be done after dialysis (dry weight). For dose adjustment if the post-dialysis 
weight of the current visit is not available, post-dialysis weight of the prior dialysis session or 
last recorded post-dialysis weight may be used.  Blood pressure and HR should be assessed 
according to the guidelines described in Appendix 5. 
7.1.1 Screening Period  
Subjects must be consented before any screening tests or assessments are performed. All 
screening procedures should be completed within 6 weeks. For subjects currently taking 
Mircera®, the screening period can be extended up to 8 weeks. During the screening period 
eligibility assessments will be performed. 
Subjects in screening will continue their existing ESA therapy for the treatment of anemia 
associated with ESRD. 
7.1.1.1 Screening 1  
• 
Signed written informed consent 
• 
Inclusion/Exclusion criteria verification 
• 
Demographics and medical history  
• 
Height and weight (use dry weight in HD subjects) 
• 
Vital signs (BP, HR, respiratory rate [RR], and temperature [Temp])  
• 
Laboratory tests: 
o Complete blood count (CBC) with WBC differential 
o Serum chemistry 
o Serum lipid panel  
o Serum iron, ferritin, total iron-binding capacity (TIBC), unsaturated iron-binding 
capacity (UIBC), transferrin saturation (TSAT)  
o Reticulocyte count and hemoglobin in reticulocytes (CHr)  
o Hemoglobin A1c (HbA1c) 
o Vitamin B12 and folate 
o Enzyme-linked immunosorbent assay (ELISA) for HIV 
o Hepatitis B surface antigen (HBsAg) 


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o Anti-HCV Ab 
• 
Review and record concomitant medications 
• 
Review and record procedures and nondrug therapies 
• 
Review and record AEs, if any (capture the event under medical history, if applicable) 
7.1.1.2 Screening 2 (≥ 2 days apart from Screening 1) 
Hemoglobin values must be obtained at least 2 days apart. 
• Vital signs (BP, HR, RR, and Temp)  
• Laboratory test:  
o Hemoglobin (Hb) only 
o Serum human chorionic gonadotropin (hCG) pregnancy test for female subjects of 
childbearing potential only [not required for females of no childbearing potential 
e.g. postmenopausal (per discretion of the PI), surgically sterile etc.] 
• Complete physical examination 
• Renal ultrasound - not required if results of a previous renal ultrasound or other imaging 
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 the screening period 
prior to randomization. Renal ultrasound can be done at any time between Screening 2 
and randomization, as convenient. The report must be reviewed prior to randomization.  
• Review and record concomitant medications 
• Review and record procedures and nondrug therapies  
• Review and record AEs, if any (capture the event under medical history, if applicable) 
7.1.1.3 Additional Screening Assessments 
If a subject’s laboratory results do not meet the eligibility criteria, the laboratory assessment may 
be repeated within the Screening Period. The visits must be at least 2 days apart.  
For example, an additional Hb value may be collected if necessary. The mean of the 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 a prior approval from the Medical Monitor unless the 
investigator has a valid reason to believe that the original lab result is due to an error (eg, 
possible sample mix-up). Such repeat should be communicated to the Medical Monitor as soon 
as possible.  
A subject who fails screening may be rescreened if deemed appropriate by the investigator. 
Where possible, an approval should be obtained from the Medical Monitor prior to rescreening.  
For all screen failures, the reason(s) will be documented.  
7.1.1.4 Randomization 
Eligible subjects will be randomized via IWRS based on stratification factors to receive 
roxadustat or epoetin alfa. Randomization must take place prior to administration of study drug. 


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7.1.2 Treatment Period 
The Treatment Period begins on the first day of dosing with study treatment (Day 1/Week 0) 
which should correspond to the administration of the subject’s next dose of their current ESA 
treatment. At the Day 1, subjects randomized to Roxadustat Arm will discontinue prior ESA 
therapy and initiate roxadustat therapy; subjects randomized to Epoetin-Alfa Arm will receive 
epoetin-alfa irrespective of their prior ESA use. All study procedures must be completed prior to 
administration of the 1st dose of study treatment.  
Subjects on long-acting ESAs (Aranesp or Mircera) may not receive the 1st dose of study 
medication on the day of randomization due to ESA dosing schedule (e.g. once weekly or once 
bi-weekly); in these subjects, the 1st dose of study medication (roxadustat or epoetin-alfa) should 
be administered on the day when the next dose of current ESA would have been due.  For all 
practical purposes, the date of 1st dose of study drug administration should be considered as Day 
1.  
During the Treatment Period, subjects will attend weekly study visits from Day 1 to Week 2, 
followed by every two weeks study visits from Weeks 4 to 24. Following Week 24, study visits 
will occur every four weeks until the EOT. A common closeout will occur when a predetermined 
number of CV events have been accrued. 
7.1.2.1 Day 1 (Week 0) 
The following assessments must be completed prior to study drug administration. 
• Inclusion/Exclusion criteria verification 
• Complete physical examination 
• Weight (dry weight in HD subjects) 
• Vital signs (BP, HR, RR, and Temp) 
• 12 Lead ECG 
• Laboratory tests:  
o CBC with WBC differential 
o Serum chemistry  
o Serum lipid panel  
o Serum iron, ferritin, TIBC, UIBC, TSAT  
o Reticulocyte count, CHr 
o HbA1c 
o Special laboratory analytes:  High-sensitivity C-reactive protein (hs-CRP) and 
hepcidin and  
o Archival serum and plasma samples 
• Local Hb 
• Health Related Quality of Life (HRQoL) Assessments (SF-36, Functional Assessment of 
Cancer Therapy-Anemia [FACT-An], and EQ-5D-5L). 


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• Review and record concomitant medications 
• Review and record procedures and nondrug therapies 
Review and record baseline conditions, AEs, if any (capture the event under medical history, if 
applicable).  
Dispense study drug. 
7.1.2.2 Weeks 1 to 2 (Weekly, ±2 days)  
• Laboratory tests (must be performed prior to dosing): 
o Week 1, 2, : CBC with WBC differential  
o Week 2: Liver function test (LFTs) only 
o Weeks 1, 2: Reticulocyte count and CHr 
o Week 2: Dispense study drug 
All visit weeks:  
• Local Hb 
• Vital Signs (BP, HR, RR, Temp)  
• Review dose adjustment for excessive hematopoiesis.  
• Review and record concomitant medications 
• Review and record procedures and nondrug therapies  
• Review and record AEs, if any 
• Drug accountability 
7.1.2.3 Weeks 4 to 24 (Every 2 weeks, ±4 days) 
• Laboratory tests (must be performed prior to dosing): 
o Week 4, 8, 12, 20: CBC with WBC differential 
o Week 6 followed by every visit where no CBC is collected: Hb only  
o Week 4, 8, 12, 20: Serum chemistry  
o Weeks 6, 16, 24: LFTs only 
o Weeks 4, 8, 12, and 20: Lipid panel  
o Weeks 4, 8, 12, 20: Serum iron, ferritin, TIBC, UIBC, TSAT  
o Weeks 4, 6, 8, 12, 16, 20: Reticulocyte count and CHr 
o Weeks 12, 24: HbA1c 
o Weeks 4, 12, 20: Special laboratory analytes (hs-CRP, hepcidin) 
o Weeks 4, 12, 20: Archival serum and plasma samples 
o Weeks 12, 24: Serum hCG pregnancy test for women of childbearing potential 
only  


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• Weeks 12, 24: Targeted physical examination 
• Dose adjustment review: At Week 4, followed by every 4 weeks. 
• Weeks 24: 12-lead ECG  
• Week 12: HRQoL questionnaires (SF-36, FACT-An, and EQ-5D-5L)* 
All visit weeks:  
• Local Hb 
• Vital signs (BP, HR, RR, and Temp) 
• Review dose adjustment for excessive hematopoiesis.  
• Review and record concomitant medications 
• Review and record procedures and nondrug therapies  
• Review and record AEs, if any 
• Drug accountability and dispense study drug 
7.1.2.4 Weeks 28 to End of Treatment (EOT; Every 4 weeks, ±4 days)  
• Laboratory tests (must be performed prior to dosing): 
o Weeks 28, 36, 44, followed by every 8 weeks: CBC with WBC differential 
o Week 32 followed by every visit where no CBC is collected: Hb only  
o Weeks 28, 36, 44, followed by every 8 weeks: Serum chemistry 
o Week 32: LFTs only 
o Weeks 28, 36, 48, followed by every 12 weeks: Lipid panel  
o Weeks 28, 36, 44, followed by every 8 weeks: Serum iron, ferritin, TIBC, UIBC, 
TSAT  
o Weeks, 28, 36, 52, followed by every 16 weeks: Reticulocyte count, CHr 
o Weeks 36, 52, followed by every 52 weeks: HbA1c* 
o Weeks 36, 52: Special laboratory analytes (hs-CRP, hepcidin) 
o Weeks 36, 48, followed by every 12 weeks: Serum hCG pregnancy test for 
women of childbearing potential only  
o Weeks 36, 52, followed by every 24 weeks: Archival serum and plasma samples* 
• Weeks 36, 52, followed by every 24 weeks: Targeted physical examination* 
• Weeks 36, 52, followed by every 24 weeks: Weight (dry weight in HD subjects) 
• Weeks 36, 52, followed by every 24 weeks 12-lead ECG  
• Weeks 28, 52 HRQoL questionnaires (SF-36, FACT-An, and EQ-5D-5L)* 
• Dose adjustment review: At Week 28, followed by every 4 weeks  


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All visit weeks:  
• Local Hb 
• Vital signs (BP, HR, RR, and Temp) 
• Review dose adjustment for excessive hematopoiesis  
• Review and record concomitant medications 
• Review and record procedures and nondrug therapies  
• Review and record AEs, if any 
• Drug accountability and dispense study drug 
* If the indicated assessments fall on a study treatment visit that is within 2 weeks of the 
planned EOT visit then these specified assessments can be postponed until the EOT visit. 
At each study visit during the Treatment Period, a Hb value will be measured (prior to dialysis in 
HD subjects) locally to determine the need for a dose adjustment or to assess for excessive 
hematopoiesis. In the event that the Hb value from the central laboratory is significantly different 
from that measured locally, and per Investigator that warrants a reversal of the dose adjustment 
decision made earlier based on locally measured Hb value, the Medical Monitor should be 
informed, if possible. 
7.1.2.5 End of Treatment (EOT) / Early Termination (ET) (±7 days)  
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. 
• Laboratory tests: 
o CBC with WBC differential  
o Serum chemistry 
o Lipid panel  
o Serum iron, ferritin, TIBC, UIBC, TSAT  
o Reticulocyte count and CHr  
o HbA1c 
o Special laboratory analytes (hs-CRP, hepcidin) 
o Archival serum and plasma samples 
o Serum hCG pregnancy test for women of childbearing potential only  
• Complete physical examination 
• Local Hb 
• Vital signs (BP, HR, RR, and Temp) 
• Weight (dry weight in HD subjects) 
• HRQoL questionnaires (SF-36, FACT-An, and EQ-5D-5L) 


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• 12-lead ECG 
• Review and record concomitant medications 
• Review and record procedures and nondrug therapies  
• Review and record AEs, if any 
• Final drug accountability 
7.2 Post-Treatment Follow-Up Period 
7.2.1 End of Study (EOS): 4 weeks after EOT or ET (±7 days) 
• Laboratory tests: 
o CBC with WBC differential 
o Serum chemistry 
o Lipid panel  
o Serum iron, ferritin, TIBC, UIBC, TSAT 
o Reticulocyte count and CHr 
o HbA1c 
o Special laboratory analytes (hs-CRP, hepcidin) 
o Archival serum and plasma samples 
• Targeted physical examination 
• Weight (dry weight in HD subjects) 
• Vital signs (BP, HR, RR, and Temp) 
• Review and record concomitant medications 
• Review and record procedures and nondrug therapies  
• Review and record AEs, if any. Reconcile all ongoing adverse events at this visit.  
7.2.2 Long-Term Follow-Up of Subjects who Discontinued Study Medication Prematurely  
Each subject enrolled in this study is free to permanently discontinue study medication at any 
time, without prejudice to further treatment. Subject discontinuation and withdrawal are 
discussed in detail in Section 5.3 
Subjects who discontinue study medication prematurely will be followed up for vital status, CV 
events, and hospitalization until study closure, unless consent to participate is withdrawn. Upon 
completion of EOT and EOS visits, these subjects will be followed up every 3-6 month interval 
(depending on the availability of subjects) until study closure. These visits may occur either in-
person or via telephone.  
The choice of anemia treatment after ET is up to the discretion of the investigator. If the 
investigator decides to resume ESA treatment in roxadustat treated subjects, the first dose of 
ESA should be administered at least three days after the last dose of roxadustat. 


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7.3 Missed Visits 
Every attempt should be made to complete all study visits within the visit window as outlined in 
the Schedule of Assessments.  
7.4 Unscheduled Visits 
Unscheduled visit(s) and laboratory assessments may be required at the discretion of the 
investigator. Please refer to the eCRF completion guidelines for additional information. 
7.5 Laboratory Assessments 
Central laboratory results should be reviewed by the Investigator or another designated qualified 
study staff member as soon as it is received. Any abnormalities must be evaluated in clinical 
context and the investigator should determine if it is clinically significant. Subject management 
is dependent upon close review of the laboratory data. 
7.6 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 Lab) test results may be used to make the 
necessary clinical judgments. Stat lab is to be used only for urgent lab test that is needed for 
immediate decision making related to the protocol, management of adverse events as determined 
by the Investigator. In all cases, a central laboratory specimen would also be drawn 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 tests for this study are listed in Table 4. 


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Table 4. 
Laboratory Tests 
CBC: 
Chemistry Panel: 
Basophils 
Albumin 
Eosinophils 
Bicarbonate  
Erythrocyte count (RBC) 
BUN 
Hct 
Calcium 
Hb  
Chloride 
Leukocyte count (WBC)  
Creatinine 
Creatine phosphokinase 
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 
 
GGT 
Serum Lipid Panel: 
Magnesium 
Total Cholesterol 
Phosphorus 
LDL 
Potassium 
HDL 
Total protein 
Triglycerides 
Uric acid 
Serum Iron Profile 
HIV and viral Hepatitis Panel: 
Ferritin 
Anti-HCV Ab tests 
Iron 
HBsAg 
TIBC 
HIV ELISA 
UIBC 
Additional Laboratory Analytes: 
TSAT  
Vitamin B12 
Special Laboratory Analytes: 
Folate 
Hepcidin 
HbA1c 
High-sensitivity CRP 
Reticulocyte count 
 
CHr 
Serum hCG pregnancy test (for women of 
childbearing potential only) 


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Abbreviations: 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood 
urea nitrogen; CBC = complete blood count; CHr = reticulocyte hemoglobin content; CRP = C-reactive protein; 
ELISA = enzyme-linked immunosorbent assay; GGT = gamma-glutamyl transferase; Hb = hemoglobin; 
HbA1c = glycated hemoglobin; HBsAg = hepatitis B surface antigen; Hct = hematocrit; HCV = hepatitis C virus; 
HDL = high-density lipoprotein; HIV = human immunodeficiency virus; LDL = low-density lipoprotein; 
RBC = red blood cell; TIBC = total iron binding capacity; UIBC=unsaturated iron binding capacity 
TSAT = transferrin saturation; WBC = white blood cell. 
7.6.1 Archival Serum and Plasma Samples (Optional) 
At prespecified visits, a set of serum and plasma samples will be drawn and stored for the 
potential future analysis of relevant biomarkers linked with the efficacy or safety of the study 
drugs or with the progression of CKD. No genetic (DNA) testing will be performed using these 
samples for diagnosis of genetic disorders. Subjects may opt out of providing serum and plasma 
samples when providing consent for study participation or at any time during the course of the 
study. All details on the processing of the samples, storage and shipment conditions will be 
provided in the laboratory manual. 
7.7 Electrocardiogram 
Local 12-lead (ECGs) will be performed on all subjects at specific time points as described in the 
Schedule of Assessments. The ECG should be taken after 5 minutes in the supine position. 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.  
7.8 Renal Ultrasound 
A renal ultrasound examination will be performed during screening if no record of a renal 
ultrasound or other imaging exists within 12 weeks prior to randomization. Renal ultrasound 
findings must be available prior to randomization to exclude subjects with a presence or 
suspicion of renal cell carcinoma. The date of assessment and findings must be documented as 
baseline findings.  
7.9 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 at baseline and during the study at prespecified visits. HRQoL 
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 (preferably at the beginning of the dialysis session) and in subjects on PD approximately 
at the same time of the day at scheduled visits. 
7.9.1 36-Item Short Form Health Survey 
The 36-Item Short Form Health Survey (SF-36) is a quality of life (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 (VT) (4 items), social functioning (2 items), role emotional (3 
items) and mental health (5 items). Two component scores, the Physical Component Scores and 


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the Mental Component Summary can also be calculated. For both the SF-36 domain scores and 
summary scores, higher scores indicate better health status. 
7.9.2 FACT-An 
The Functional Assessment of Cancer Therapy-General (FACT-G; Version 4) contains 27 items 
that cover four dimensions of well-being: physical (7 items), functional (7 items), social/family 
(7 items), and emotional (6 items). A subscale of 13 fatigue specific items plus 7 additional items 
related to anemia were developed for use in conjunction with the FACT-G (Yellen et al, 1997). 
The 13 fatigue items plus the 7 additional items related to anemia comprise the Anemia 
Subscale. Administration of 3the 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 HRQoL.  
7.9.3 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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8 SAFETY 
8.1 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 
International Conference on Harmonization (ICH) E2A guidance. 
8.2 Definitions  
8.2.1 Definition of an Adverse Event  
An AEs 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 BL 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 8.3.1). 
8.2.2 Definition of a Serious Adverse Event  
A serious adverse event is any AE or suspected adverse reaction that results in any of the 
following outcomes: 
• Death, 
• A life-threatening AEs (ie, if in the view of the investigator or sponsor, the subject was at 
immediate risk of death at the time of the event). Life-threatening does not refer to an 
event which hypothetically might have caused death if it were more severe, 
• Inpatient hospitalization or prolongation of existing hospitalization, 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, 
• A congenital anomaly or birth defect, or 
• Other medically important events 


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Based upon appropriate medical judgment, important medical events that may not result 
in death, be life-threatening, or require hospitalization may be considered serious when, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. These 
events must be reported to the sponsor similar to serious adverse events. 
Safety events of interest (“Special Situations”) on the medicinal products administered to the 
subject as part of the study (eg, study drug, comparator, background therapy) that may require 
expedited reporting and/or safety evaluation include, but are not limited to: 
• Overdose of the medicinal product (exceeding the maximum allowable per dose i.e 400 
mg or 3.0 mg/kg, whichever is lower) 
• 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  
8.2.3 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.” 
8.2.4 Definition of an Adverse Reaction 
An adverse reaction means any AEs caused by a drug.  
8.3 Procedures for Eliciting, Recording, and Reporting Adverse Events 
8.3.1 Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after informed consent 
is obtained and ends at End of Study / 4-Week post ET/EOT Visit, except for pregnancy 
reporting (Section 8.3.6).  
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 
ET/EOT Visit will be considered “treatment emergent” and be assessed for relationship to study 
drug. If an AE starts on Day 1, the investigator must assess as to whether the AE started prior to 
or after the administration of study medication and record accordingly. 


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8.3.2 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 BL 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. Conditions including signs and symptom 
present at baseline, unless significantly worsened, shouldn’t be reported as adverse events during 
the study. 
Whenever is 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 may qualify to be recorded as AEs; 
recurrence or worsening of medical history problems requiring new or changes in concomitant 
medication, may also qualify to be recorded as AEs.  
An abnormality identified during a medical test (eg, laboratory parameter, vital sign, ECG data, 
physical exam) 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. 
The following attributes must be assigned to each AEs: 
• Description (Investigator’s verbatim term describing the event) 
• Dates of onset and resolution 
• Severity 
• Relationship to study drug  
• Outcome 
• Action taken regarding study drug (decision taken by the PI in response to an AE) 
• Other action (treatment, nondrug therapy) required 
• Determination of “seriousness”  
8.3.3 Assessing Adverse Event Severity 
The Investigator should grade the AEs using the National Cancer Institute (NCI) Common 
Terminology Criteria for AE (CTCAE) guidelines. For terms not specified as part of NCI 
CTCAE, the following guidelines should be used to determine grade: 


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All AEs will be assessed for severity using the following criteria:  
• Grade 1, Mild: Asymptomatic or mild symptoms which the subject finds easily 
tolerated. The event is of little concern to the subject and/or of little-or-no clinical 
significance; clinical or diagnostic observations only; intervention not indicated. 
• Grade 2, Moderate: The subject has enough discomfort to cause interference with or 
change in some of their age-appropriate instrumental activities of daily living (eg, 
preparing meals, shopping for groceries or clothes, using the telephone, managing 
money); local or noninvasive intervention indicated. 
• Grade 3, Severe: The subject is incapacitated and unable to work or participate in many 
or all usual activities. The event is of definite concern to the subject and/or poses 
substantial risk to the subject’s health or well-being; Likely to require medical 
intervention and/or close follow-up, including but not limited to hospitalization or 
prolongation of hospitalization. 
• Grade 4, Life-threatening:  The subject was at immediate risk of death from the event 
as it occurred. 
• Grade 5, Death: The subject died due to the event.  
8.3.4 Assessing Relationship to Study Drug 
Most of the information about the safety of a drug prior to marketing comes from clinical trials; 
therefore, AE reports from investigators are critically important. Moreover, appropriately 
deciding whether the AE meets the definition of a suspected adverse reaction is usually the most 
difficult determination, but it is critical to avoid the miscategorization of the product’s safety 
profile.  
Due to the historical tendency for assessment of relationship to default as possibly related, the 
FDA has issued new guidance that clarifies the intent of the phrase “reasonable possibility” in 
the definition of “associated with the use of the drug.” Default reporting of individual events as 
possibly related is uninformative and does not meaningfully contribute to the development of the 
product safety profile.  
The investigator must provide an assessment of the relationship of the AE to study drug in 
accordance with the guidance below. Absence of an alternative cause would not normally be 
considered enough evidence to assess an event as possibly related or related to study drug.  
• Related (Adverse Reaction): 
o Any event for which there is evidence to conclude that the study drug caused the 
event 
• Possibly Related (Suspected Adverse Reaction): 
o A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure, such as angioedema, anaphylaxis, 
rhabdomyolysis, Stevens-Johnson syndrome, etc. 
o One or more occurrences of an event that is not commonly associated with drug 
exposure but is otherwise uncommon in the population exposed to the drug, such 
as tendon rupture 


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• Not Related: 
o The event represents the underlying disease (eg, disease-related symptoms, 
disease progression) 
o The event represents a comorbid condition present at the time the subject entered 
the study 
o The event represents a known adverse reaction associated with a co-medication 
received by the study subject 
o The event is common for the study population (eg, CV events in an elderly 
population) 
o The event has no plausible relationship to study drug 
o The event is a study endpoint (eg, mortality, major morbidity) 
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 appropriate Health Authorities. 
While the investigator must provide an assessment of the relationship of the event to study drug, 
in most cases only aggregate data review will be used to make the determination of the 
relationship of the study drug to a given AE. 
8.3.5 Reporting Serious Adverse Events on the SAE Report Form 
All SAEs must be reported immediately to the Sponsor and/or its designated safety management 
vendor. 
To report an SAE, the investigator must fax an SAE Report Form to 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 onto the eCRF. 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 seven 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). 


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8.3.5.1 Reporting Serious Adverse Events to the Institutional Review Board / Independent 
Ethics Committee 
The investigator is responsible for notifying his/her Institutional Review Board (IRB) or Ethics 
Committee (EC) of SAEs in accordance with local regulations. Sponsor, or its safety 
representative, will provide to the investigator a copy of any expedited safety reports that it 
intends to file with a regulatory authority.  
8.3.5.2 Deaths  
For any death occurring during the subject’s study participation, regardless of attribution, the 
investigator will report the death immediately to the Sponsor’s Medical Monitor and their 
designated safety management vendor. 
The investigator should notify Sponsor and their designated safety management vendor of any 
death or other SAE occurring after a subject has discontinued or terminated study participation 
that may reasonably be related to the study.  
The investigator must submit the SAE Report Form and complete the appropriate eCRF for the 
event that led to the subject’s death.  
When reporting a death, the event or condition that caused or contributed to the fatal outcome 
should be recorded as the primary event term on the SAE Report Form. 
8.3.6 Pregnancies: Reporting and Follow-up of Subjects 
A pregnancy in a female subject must be confirmed by positive serum β-hCG test. If β-hCG test 
is found positive in a female subject of childbearing potential, study drug should be placed on 
hold temporarily until pregnancy is ruled out via a repeat test ≥3 days.  If a female subject 
becomes pregnant while the subject is receiving study treatment or within 12 weeks after the last 
dose of study treatment, a Pregnancy Report Form must be completed and submitted to Sponsor 
(by way of its designated safety management vendor) within 24 hours of the investigator learning 
of the pregnancy. The investigator should report the information to the sponsor on the designated 
forms. 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 occurred.  
Pregnancy itself is not an AE unless there is a suspicion that the investigational product under 
study may have interfered with the effectiveness of a contraceptive medication. Pregnancies are 
followed up to outcome even if the subject was discontinued from the study. The outcome of the 
pregnancy must be reported by the investigator, which should be sent to the Sponsor and/or its 
designated safety management vendor within 24 hours of the investigator learning of the 
outcome. Congenital abnormalities/birth defects and spontaneous miscarriages should be 
reported and handled as SAEs. Elective abortions without complications should not be handled 
as AEs. 
Pregnancy of the subject’s partners is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth or 
congenital abnormality) should if possible be followed up and documented as described. To 
capture information about a pregnancy from the partner of a male subject, the male subject’s 
partner consent must be obtained to collect information related to the pregnancy and outcome 


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(should be handled on a case by case basis with IRB/IEC approval); the male patient should not 
be asked to provide this information. 
8.3.7 Abnormal Laboratory Findings 
Laboratory values will be collected throughout the study to assess for safety. The investigator 
must review and assess all laboratory results in a timely manner, and determine whether the 
abnormal laboratory values, if any, are clinically significant (CS) or not clinically significant 
(NCS), and whether there are associated signs and symptoms.  
An abnormal laboratory finding 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 
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. 
A decrease in Hb value without any significant clinical symptoms should not be reported as an 
adverse event. In this case, worsening of anemia as evidenced by drop in Hb value may be 
considered as lack of efficacy as opposed to AE as the subject fails to response adequately to 
study drug.  
8.3.8 Disease Progression 
Disease progression can be considered as a worsening of a subject’s condition attributable to the 
disease for which the investigational product is being studied. It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. Gradual 
worsening of ESRD should be considered disease progression and should not be reported as an 
AE during the study. 


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9 STATISTICAL CONSIDERATIONS 
9.1 Sample Size Determination 
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 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). 
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, specifically, Hb change 
from BL in the averaged Hb over Weeks 28 to 36).  
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.  
9.2 Randomization 
Randomization will be stratified by the following three factors: 
• Mean qualifying screening hemoglobin (≤ 10.5 vs. > 10.5 g/dL) 
• History of CV, cerebrovascular, or thromboembolic diseases (yes vs. no) 
• Mean prescribed weekly epoetin alfa dose (or, equivalent epoetin dose for nonepoetin 
subjects) in the 4 weeks prior to randomization (≤ 150 vs. > 150 IU/kg/week)  
• Geographical region (US vs. Ex-US regions)  
9.3 Analysis Populations 
For US regulatory submission, efficacy and safety analyses will be based on all subjects 
stratified by the protocol amendments, on subjects enrolled during the original protocol but 
before the amendment 1, and on subjects enrolled after the amendments separately.  
For EU regulatory submission, efficacy and safety analyses will be based on subjects enrolled 
during the original protocol before the amendments, as the subjects enrolled after the 
amendments may be considered as a sub-study for EU regulatory purpose. 
The following analysis sets are defined and will be used for the statistical analysis.  
9.3.1 Intent to Treat Population (ITT)  
The ITT population consists of all randomized subjects.  


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9.3.2 Full Analysis Set (FAS) 
The FAS consists of all randomized 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.  
9.3.3 Per-Protocol Set (PPS) 
The PPS consists of all randomized subjects who received at least 8 weeks of study treatment, 
have at least one postdose Hb assessment and are without major protocol violations. 
9.3.4 Safety Analysis Set (SAF) 
The SAF will consist of all randomized subjects who received at least one dose of study 
medication. If treatment received for the duration of the study differs from the randomized 
treatment, the actual treatment arm will be used. 
9.4 Statistical Analysis 
Safety and efficacy data will be summarized and presented by treatment group in summary 
tables. Descriptive statistics including number of subjects (N), means, standard deviations, 
medians, and minimum and maximum values will be presented for continuous variables. Counts 
and percentages will be presented for categorical variables. For efficacy endpoints, the standard 
error and 95% confidence intervals (CI) will be presented as part of the descriptive summaries. 
9.4.1 Subject Enrollment and Disposition 
 The number of randomized subjects (ITT), treated subjects, FAS and PPS subjects and subjects 
who discontinued along with the reason for early termination will be summarized by treatment 
group and overall. 
9.4.2 Demographics and Baseline Characteristics 
Demographics (age, race, sex), BL characteristics including stratification factors, and subject 
disease characteristics will be summarized.  
Descriptive statistics will be calculated for continuous variables (eg, age, weight, BL Hb, body 
mass index) and frequency counts and percentages will be tabulated for categorical variables (eg, 
sex, race, Hb category,  iron status, and history of CV disease or cerebrovascular disease) by 
treatment group and overall. 
9.4.3 Efficacy Analyses 
Efficacy analysis for superiority will be conducted on the ITT population for US (FDA) 
submission and on FAS population for EU regulatory submission. 
Efficacy analysis for non-inferiority will be conducted on the ITT population for US (FDA) 
submission and on the PPS for EU regulatory submission. 
Hb results obtained from the central laboratory will be used for all efficacy analyses. Baseline 
Hb value for efficacy analysis is defined as the mean of four central laboratory Hb values, three 
of the latest screening Hb values plus the pre-dose Hb value collected on Day 1 for subjects who 
enrolled under original protocol and Amendment 1. Subjects enrolled under Amendment 2, 
baseline Hb value for efficacy analysis is defined as the mean of three central laboratory Hb 
values, two of the latest screening Hb values plus the pre-dose Hb value collected on Day 1. 


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In subjects with missing Day 1 Hb value, the mean of three (two, for Amendment 2) latest 
screening laboratory Hb values will be considered as BL Hb value.  
9.4.3.1 Primary Efficacy Analysis 
The primary efficacy endpoint for the US (FDA) submission is defined as the 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 all ITT population, Sensitivity analyses will be performed on 
ITT Population enrolled under the original protocol, and the ITT population enrolled under 
amended protocols, separately.    
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 group ≤ Hb mean change from baseline in the epoetin alfa group minus 0.75 
g/dL 
Versus: 
H1: Hb change from baseline to the average level of Week 28 to Week 52 in the 
roxadustat group > Hb mean change from baseline in the epoetin alfa group minus 0.75 
g/dL 
A Multiple Imputation Analysis of Covariance (MI-ANCOVA) model will be used. The 
model will contain terms for baseline Hb measurement as covariate, treatment arm, and 
randomization stratification factors except Screening Hb values (≤ 10.5 g/dL vs. > 10.5 g/dL) 
as fixed effects. Detailed analysis of the primary endpoint will be outlined in the SAP. 
In addition, as a sensitivity analysis, the primary efficacy endpoint will be analyzed using the 
analysis of MMRM model. 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 (≤ 10.5 g/dL vs. > 10.5 g/dL) as fixed effect. The primary efficacy 
analysis (for both, US [FDA] and EU regulatory submissions) will be based on the estimated 
difference between the two treatments overall mean effects throughout the evaluation period 
based on the primary analysis models.  
Due to the large amount of visits to include in the MMRM 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. 
Pattern Mixture models will be used as additional sensitivity analyses. The details will be 
described in the SAP. 
Hb values under the influence of a rescue therapy will not be censored in the primary analysis.  
The null hypothesis will be rejected if the two-sided 95% CI for the difference between the two 
least squares means of the roxadustat group and the epoetin alfa group throughout the evaluation 
lies entirely above –0.75 g/dL 


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The primary efficacy endpoint for EU regulatory submission is defined as the Hb change from 
BL to the average Hb of Weeks 28 to 36, without having received rescue therapy within 6 weeks 
prior to and during this 8-week evaluation period and will be based on the PPS population 
enrolled under original protocol only. This primary efficacy analysis will be based on the 
estimated difference between the two treatments overall mean effects throughout the evaluation 
period based on the same MMRM model as the sensitivity analysis of primary efficacy endpoint 
for US regulatory submission.  
For subjects who discontinued the study prior to Week 28, the last Hb value will be used in the 
assessment of the primary endpoint. 
The primary hypothesis to be tested for the primary efficacy analysis is: 
H0: Hb mean change from BL to the average of Weeks 28 to 36 in the roxadustat group 
≤ Hb mean change from BL in the epoetin alfa group minus 0.75 g/dL 
Versus: 
H1: Hb change from BL to the average of Weeks 28 to 36 in the roxadustat group > Hb 
mean change from BL in the epoetin alfa group minus 0.75 g/dL 
For subjects who require rescue therapy, the Hb value after to the initiation of the rescue therapy 
will be set to missing up to 6 weeks from the last date of the rescue therapy. This null hypothesis 
will be rejected if the two-sided 95% CI for the difference between the two treatment groups 
using MMRM model lies entirely above –0.75 g/dL. 
The analysis will be repeated using the FAS as a sensitivity analysis.  
9.4.3.2 Secondary Efficacy Analyses 
Once the primary hypothesis is rejected for the primary endpoint, the secondary variables will be 
tested using a fixed sequence testing procedure as follows: 
• For US (FDA) submission: Proportion of subjects with mean Hb level during the 
evaluation period defined as Week 28 until Week 52 ≥ 10.0 g/dL. 
• EU regulatory submission: Hemoglobin (Hb) response, defined as mean Hb during 
Weeks 28 to 36 within the range of 10.0 to 12.0 g/dL without having received rescue 
therapy within 6 weeks prior to and during this 8-week evaluation period. 
The hypothesis to be tested for the first secondary efficacy analysis is: 
H0: Hb response rate for subjects in the roxadustat group - Hb responder rate for subjects 
in the epoetin alfa group ≤ -15% 
Versus 
H1: Hb response rate for subjects in the roxadustat group - Hb responder rate for subjects 
in the epoetin alfa group > -15%.  
A 2-sided 95% CI for the difference of two responder rates (roxadustat-ESA) based on 
the Miettinen and Nurminen approach adjusting for treatment group and other 
stratification factors will be calculated and H0 will be rejected if the lower bound of the 
95% CI is greater than -15%. 


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• The average monthly iron use during Weeks 1 to 36 will be compared between the 2 
treatment groups using an ANCOVA model with BL iron replete as a covariate, and 
treatment arm and randomization stratification factors as fixed effects. Superiority will be 
declared if the lower bound of the 2-sided 95% CI of the difference between epoetin alfa 
and roxadustat exceeds 0. 
• The change in low-density lipoprotein (LDL) cholesterol averaged over Weeks 12 to 28 
from BL will be analyzed using an MMRM model with BL LDL cholesterol as a 
covariate and treatment arm, visit, interaction of treatment arm and visit, and 
randomization stratification factors as fixed effects. Superiority will be declared if the 
lower bound of the 2-sided 95% CI of the difference between epoetin alfa and roxadustat 
exceeds 0.  
• Time to exacerbation of BP will be analyzed using the Cox Proportional Hazards model 
adjusting for treatment arm and randomization stratification factors. Superiority of 
roxadustat vs. epoetin alfa will be declared if the upper bound of the 2-sided 95% CI of 
the hazard ratio is < 1. 
• The change in MAP averaged over Weeks 20 to 28 from BL will be analyzed and 
compared between the 2 groups using an MMRM model with BL MAP as a covariate 
and treatment arm, visit, interaction of treatment arm and visit, and randomization 
stratification factors as fixed effects. Superiority will be declared if the lower bound of 
the 2-sided 95% CI of the difference between roxadustat and epoetin alfa is below 0. 
• The change from BL in SF-36 Physical Functioning (PF) subscore to the average PF 
subscore of Weeks 12 to 28 will be analyzed using an MMRM model using BL PF 
subscore as a covariate and treatment arm, visit, interaction of treatment arm and visit, 
and randomization stratification factors as fixed effects. Non-inferiority of roxadustat vs. 
epoetin alfa will be tested. The noninferiority margin is fixed as a difference of 2 points. 
• Change from BL in SF-36 VT subscore to the average VT subscore of Weeks 12 to 28 
will be analyzed using an MMRM model using BL VT subscore as a covariate and 
treatment arm, visit interaction of treatment arm and visit, and randomization 
stratification factors as fixed effects. Non-inferiority of roxadustat vs. epoetin alfa will be 
tested. The noninferiority margin is fixed as a difference of 2 points.  
Statistical methods for additional efficacy endpoints are described in the Statistical Analysis Plan 
(SAP). 
9.4.4 Safety Analyses 
The Safety analyses will be performed using the safety analysis set (SAF).  
Safety parameters include adverse events, SAEs, laboratory parameters, vital signs, ECG 
parameters, and PE.  
The number and percentage of subjects reporting TEAEs and TESAEs in each treatment group 
will be tabulated. Descriptive statistics will be presented for laboratory, vital signs values and 
ECG parameters by visit and for the changes from BL to each visit.  


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The CV safety assessment of roxadustat will also be based on pooled analysis of composites of 
adjudicated CV events pooled across multiple global Phase 3 clinical studies which includes this 
study, according to the regional pooled SAPs for meeting regional regulatory requirements. 
For US (FDA) submission only: The primary safety endpoint in this study is the MACE (Major 
Adverse Cardiac Event) composite endpoint, defined as time to first occurrence of death from all 
causes, MI, or stroke, only for the purpose of being  pooled across multiple similar studies in the 
Phase 3 program. None of the individual studies are powered to meet the MACE primary safety 
endpoint individually. The pooled MACE analysis is only for purposes of supporting a US FDA 
regulatory filing of roxadustat.  
Safety data and dosing decisions will be monitored on an ongoing basis. Ongoing review of 
safety data will be conducted by an independent DSMB. 
For each safety parameter, the last assessment made prior to the first dose of study medication 
will be used as the BL for all analyses of that safety parameter. 
9.4.4.1 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 
treatment emergent AEs (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 ET/EOT 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 and preferred term. 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 TESAE, fatal SAEs (ie, events that caused death), and AEs 
leading to permanent discontinuation of study medication will be summarized by System Organ 
Class (SOC), preferred term and treatment group 
Treatment emergent adverse events of interest will also be reported in terms of incidence rate per 
Patient Exposure Year (PEY). 
Listings will be presented of subjects with SAEs, subjects with AEs leading to discontinuation, 
and subjects who died. 
9.4.4.2 Clinical Laboratory Parameters 
Descriptive statistics for laboratory values and changes from BL at each assessment time point 
will be presented by treatment group for each laboratory parameter. To assess potentially 
clinically meaningful laboratory abnormalities, the number and percentage of subjects with post-
BL lab values outside a predefined range or limit of change will be tabulated by treatment group. 


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9.4.4.3 Vital Signs 
Descriptive statistics for vital signs (systolic and diastolic BP, pulse rate, respiration rate) and 
their changes from BL at each visit and, the EOS will be presented by treatment group. 
9.4.4.4 Electrocardiogram  
Descriptive statistics for ECG parameters (eg, HR, PR interval, QRS interval, QT interval, QTc 
interval) at BL and changes from BL at each assessment time point will be presented by 
treatment group. To assess potentially clinically meaningful ECG abnormalities, the number and 
percentage of subjects with post-BL ECG values outside a predefined range or limit of change 
will be tabulated by treatment group, as well as shift tables for results of ECG interpretation 
(normal, abnormal not significant, abnormal significant). 
9.5 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 (see Section 4.8).  
9.6 Statistical Analysis Plan  
The Statistical Analysis Plan (SAP) 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 detailed in the Clinical Study Report.  
9.7 Protocol Deviations 
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.  
Due to the unique nature of this study, following issues are not to be considered as protocol 
deviations:  
• 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 patients are dosed according to local standard of care whether or not it is 
concordant with  package insert/SmPC 
• 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 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” (Hb ≥13 g/dL, requires a dose-hold) or 
“Overdose”  (prescribed >3.0 mg/kg per dose or 400 mg per dose, whichever is lower) 


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• ESA administrations in Roxadustat subjects during hospitalization are not to be reported 
as protocol deviation, if the roxadustat dosing were not allowed or available during that 
hospitalized period 
• IV iron administrations in study subjects during hospitalization are not be reported as 
protocol deviation 
For the purposes of this protocol, protocol deviations requiring notification to the Sponsor will 
be defined and detailed in the study monitoring plan. 


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10 DIRECT ACCESS TO SOURCE DOCUMENTS 
Following site prequalification and/or initiation of the study site, periodic monitoring visits and 
site closeout visits will be made by Sponsor or its designee. The investigator must provide direct 
access to, and allocate sufficient space and time for, the monitor to inspect subject source 
records, eCRFs, queries, collection of local laboratory normal ranges (if applicable), 
investigational product accountability records, and regulatory documents in accordance with 
GCP and ICH E6 guideline. 
The purpose of study monitoring is to verify the following: 
• The rights and well-being of human subjects are protected 
• The reported data are accurate, complete, and verifiable from source documents 
• All data are collected, tracked, and submitted by the site to Sponsor or designee, 
including unscheduled and missed assessments 
• The reported data are reconciled across all data sources (eg, laboratory, safety, IWRS, 
clinical databases) 
• The conduct of the study is in compliance with the currently approved 
protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s) 
The investigator must also permit the FDA or other applicable regulatory authorities to inspect 
facilities and records pertaining to this study if so requested. If the investigator is notified of an 
inspection pertaining to this study by the FDA or other applicable regulatory authorities, the 
investigator must notify Sponsor immediately. 


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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 
• Electronic case report form (eCRF) 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. 


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12 ETHICS 
12.1 Ethical Considerations 
The study will be conducted in accordance with FDA regulations, the International Conference 
on Harmonisation (ICH) E6 Guideline for GCP, the Declaration of Helsinki, any other applicable 
regulatory requirements, and Institutional Review Board (IRB) or independent ethics committee 
(IEC) requirements. 
12.2 Communication with the Institutional Review Board or Independent 
Ethics Committee 
This protocol, the Informed Consent Form, the Investigator’s Brochure, and any information to 
be given to the subject must be submitted to a properly constituted IRB/IEC by the investigator 
for review and approved by the IRB/IEC before the study is initiated and before any 
investigational product is shipped to the investigator. In addition, any subject recruitment 
materials must be approved by the IRB/IEC before the material is used for subject recruitment.  
The investigator is responsible for obtaining reapproval by the IRB/IEC annually or more 
frequently in accordance with the regulatory requirements and policies and procedures 
established by the IRB/IEC. Copies of the investigator’s annual report and other required report 
to the IRB/IEC and copies of the IRB/IEC continuance of approval must be furnished to 
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. IRB 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 
reconsented 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 
U.S. 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. 
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 documents 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 documents must be adequate to reconstruct all data entered 
into the electronic database and used to resolve queries. 
13.2 Data Collection, Handling, and Verification 
All required data will be entered into an electronic database 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, adverse events and medications will be coded using industry standard 
dictionaries (eg, MedDRA and World Health Organization Drug [WHODrug] Dictionary). 
The investigator is responsible for reviewing, verifying, and approving all subject data (ie, 
eCRFs 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 or Pharmacy Manual should be recorded using the 
Drug Inventory Log. 
16.2 Disclosure of Data 
Data records generated by this study must be available for inspection upon request by 
representatives of the FDA or other regulatory agencies, national and local health authorities, 
Sponsor’s monitors/representatives and collaborators, auditors, and the IRB/IEC for each study 
site. 
The Investigators should promptly notify the Sponsor and/or designee of any audits scheduled by 
any regulatory authorities and promptly forward copies of any audit reports received to the 
sponsor. 
16.3 Retention of Records 
The investigator shall retain records required to be maintained under 21 CFR 312.62(c) for a 
period of 2 years following the date a marketing application is approved for the drug for the 
indication for which it is being investigated. If no application is to be filed or if the application is 
not approved for such indication, the investigator shall retain these records until 2 years after the 
investigation is discontinued and the FDA is notified. 
If the investigator moves or retires, he or she should identify in writing, the designee who will be 
responsible for record keeping. Archived data may be retained on electronic records or similar 
medium provided that a back-up exists and a hard copy is obtainable if required. No records will 
be destroyed without the prior written consent of Sponsor. 


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17 REFERENCES 
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Scortegagna, M., et al. "HIF-2a regulates murine hematopoietic development in an 
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18 APPENDICES 
 


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Appendix 1 Study Schema (Original Protocol) 
Screening
Treatment
Follow-up
ICF & Baseline 
Assessments
(N ≤1200 Subjects on HD 
or PD)
Roxadustat
 (Investigational Drug)
TIW dosing, n ≤600 Subjects
Starting Dose: conversion table based on previous average ESA
Dose Adjustment: per Appendix 2
Epoetin alfa
(Active Control)
 n ≤600 subjects
Starting Dose: conversion table based on previous average ESA
Dose Adjustment: per country specific Package Insert or SmPC or local standard of care.
Up to 6 Weeksc Before First Dose 
of Treatment
Variable, targeting total: 52 weeks minimum, up to 3 years after last subject is randomized maximum
4 Weeks After Last Dose of 
Treatment
Randomization
Abbreviations:
EOS=end of study; EOT=end of treatment; ESA=erythropoesis-stimulating agent; HD=hemodialysis; n=number of subjects; PD=peritoneal dialysis; SmPC=summary of product 
characteristics; TIW=three times a week.
a
EOT/ET +  4 weeks ±7 days
c
For subjects currently taking Mircera®, the screening period can be extended up to 8 weeks
EOT
EOSb


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Appendix 2 Roxadustat Dose Adjustment Rules 
At each study visit during the Treatment Period, Hb will be measured (prior to dialysis in HD 
subjects) locally to determine the need for a dose adjustment or to assess for excessive 
hematopoiesis. This local Hb measurement may be made with the use of a point-of-care device 
(eg, HemoCue®, CritLine®) or by local laboratory (ie, Stat Lab*) testing if the point-of-care 
device is not available or the result is considered unreliable. In the event that the Hb value of the 
visit as determined by the study central laboratory is significantly different from that measured 
locally, and per Investigator that warrants a reversal of the dose adjustment decision made earlier 
based on locally measured Hb value, the Medical Monitor should be informed, if possible.  
In this study, a rate of rise of Hb > 2 g/dL in 4 weeks or a Hb level of ≥ 13 g/dl at any time 
would be considered as excessive haematopoiesis and would require either dose reduction or 
temporary dose hold. 
The dose of roxadustat will remain constant during the first 4 weeks of the Treatment Period 
unless a dose reduction is required for excessive hematopoiesis.  
Roxadustat dose adjustments are permitted from Week 4 onwards, and every 4 weeks thereafter 
(eg, Week 4, Week 8, Week 12); however, the dose may be adjusted between two prespecified 
windows (eg, anytime between Week 4 and Week 8 visits, Week 8 and Week 12 visits) if all of 
the following criteria are met: 
• No dose adjustment has been made in last 4 weeks 
• Hb < 9.0 g/dL.  
Any dose adjustment will reset the dose-adjustment window to every 4 weeks thereafter (eg, 
dose adjustment for a qualified reason at Week 6 leads to next dose adjustment at Week 10). 
Dose adjustment must not be done sooner than 4 weeks unless discussed with and preapproved 
by the medical monitor. Dose adjustments for roxadustat are described in the table below.  
Subjects randomized to roxadustat will take doses TIW for the entire duration of the Treatment 
Period. If a subject requires < 20 mg TIW (ie, < 60 mg per week) to maintain a Hb level of 
approximately 11 g/dL, the dosing frequency should be reduced in a step-wise fashion e.g. TIW 
to BIW, BIW to QW, QW to Q-2 Week etc. The Medical Monitor should be notified as soon as 
possible of such dose change. 


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Roxadustat Dose Adjustment Rules  
Change in Hb over 
past 4 weeks (g/dL) 
Hb (g/dL) at Dose Adjustment Review Visit 
< 10.5 
10.5 to < 12.0 
 12.0 to < 13.0 
≥ 13.0 
< -1.0 
↑ 
↑ 
No change 
Hold dosing, check Hb 
weekly or per PI’s 
discretion via central 
lab, then resume 
dosing when 
Hb < 12.0 g/dL, at a 
dose that is reduced by 
one dose step 
-1.0 to 1.0 
↑ 
No change 
↓ 
> 1.0 
No change 
↓ 
↓ 
Abbreviations: 
↑ = increase; ↓ = decrease; Hb = hemoglobin. 
Notes: 
Dose Increases and Reductions: 
• 
Dose increases (↑) and reductions (↓) are preset. 
• 
The dose steps are as follows: 20, 40, 50, 70, 100, 150, 200, 250, 300, and 400 mg.  
For example, a subject previously receiving 70 mg of roxadustat requiring a dose increase would have his dose changed 
to100 mg of roxadustat. A subject previously receiving 150 mg of roxadustat requiring a dose reduction would have his 
dose changed to 100 mg of roxadustat.  
 If < 20 mg /dose is required, dosing frequency should be reduced in a step-wise fashion e.g. TIW to BIW, BIW to QW, 
QW to Q-2 Week etc. 
• 
The maximum dose is capped at 400 mg or 3.0 mg/kg/dose (whichever is lower). 
Dose Adjustment for Excessive Hematopoiesis: 
• 
If Hb increases by > 2.0 g/dL at any time within 4 weeks, the dose should be reduced by one dose step. 
• 
Only one dose reduction for excessive hematopoiesis is recommended within a period of 4 weeks.  
• 
Temporary dose holds for excessive hematopoiesis should be confirmed based on central lab Hb assessments. If the Hb is 
≥ 13 g/dL, withhold dosing, check Hb weekly or per PI’s discretion via central lab, then resume dosing when 
Hb < 12.0 g/dL, at a dose that is reduced by one dose step. The subsequent Hb follow-up assessments should also be done 
by a central lab. 
* A “Stat lab" is to be used only for urgent lab test that is needed for immediate decision making related to protocol, 
management of adverse events as determined by the Investigator.  
 


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Appendix 3 Schedule of Assessments 
Study Period: 
Screening (up 
to 6 to 8 Wksa) 
Treatment Period (≥ 52 Wks) 
Follow-up 
Period (4 Wks) 
Unscheduled Visit 
Visits: 
S1 
S2 
Day 1 b 
± 2 days  
± 4 days  
± 4 days 
± 7 days 
 ±7 days 
Weekly 
(Wks 1-2) 
Every 2 Wks 
(Wks 4-24) 
Every 4 Wks 
(from Wk 28) 
EOT/ET 
EOS 
(EOT/ET 
+4 wks) c 
1 
2 
Written ICF 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Height (screening only), 
weight (dry weight [post 
dialysis] in HD subjects)  
X 
 
X 
 
 
 
Wks 36, 52 + every 24 wks 
X 
X 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
 
X 
X 
 
 
Wks 12 d, 24 d 
Wks 36 d, 52 d + every 24 wks d 
X 
X d 
O 
Vital Signs: BP e, HR e, 
RR f, Temp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Local Hb Assessments  
 
 
X 
X 
X 
X 
X 
X 
 
X 
CBC with WBC diff  
X 
 
X 
X 
X 
Wks 4, 8, 12, 20 
Wks 28, 36, 44 + every 8 wks 
X 
X 
O 
Hemoglobin g 
 
X 
 
 
 
X g 
X g 
 
 
X 
Reticulocyte count and 
CHr 
X 
 
X 
X 
X 
Wks 4, 6, 8, 12, 16, 20 
Wks 28, 36, 52 + every 16 wks 
X 
X 
O 
12-lead ECG  
 
 
X 
 
 
Wk 24 
Wks 36, 52 + every 24 wks 
X 
 
O 
Renal ultrasound h 
X 
 
 
 
 
 
 
 
 
Serum chemistry 
X 
 
X 
 
 
Wks 4, 8, 12, 20 
Wks 28, 36, 44 + every 8 wks 
X 
X 
O 
LFTs 
 
 
 
 
X 
Wks 6, 16, 24 
Wk 32 
 
 
O 
Serum Lipid panel 
X 
 
X 
 
 
Wks 4, 8, 12, 20  
Wks 28, 36, 48 + every 12 wks 
X 
X 
O 
Serum iron, ferritin, TIBC, 
UIBC, TSAT 
X 
 
X 
 
 
Wks 4, 8, 12, 20 
Wks 28, 36, 44 + every 8 wks 
X 
X 
O 
HbA1c 
X 
 
X 
 
 
Wks 12, 24 
Wks 36, 52 + every 52 wks 
X 
X 
O 
Vitamin B12, folate 
X 
 
 
 
 
 
 
 
 
 


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Study Period: 
Screening (up 
to 6 to 8 Wksa) 
Treatment Period (≥ 52 Wks) 
Follow-up 
Period (4 Wks) 
Unscheduled Visit 
Visits: 
S1 
S2 
Day 1 b 
± 2 days  
± 4 days  
± 4 days 
± 7 days 
 ±7 days 
Weekly 
(Wks 1-2) 
Every 2 Wks 
(Wks 4-24) 
Every 4 Wks 
(from Wk 28) 
EOT/ET 
EOS 
(EOT/ET 
+4 wks) c 
1 
2 
HIV ELISA, HBsAg, 
anti-HCV Ab 
X 
 
 
 
 
 
 
 
 
 
Serum (hCG) pregnancy 
test (every 12 weeks) i 
X 
 
 
 
Wks 12, 24 
Wks 36, 48 + every 12 wks 
X 
 
O 
hs-CRP, hepcidin 
 
 
X 
 
 
Wks 4, 12, 20 
Wks 36, 52 
X 
X 
 
Archival serum & plasma 
samples for biomarkers 
 
 
X 
 
 
Wks 4, 12, 20 
Wks 36, 52 + every 24 wks 
X 
X 
 
HRQoL Questionnaires j 
 
 
X 
 
 
Wks 12 
Wks 28, 52 
X 
 
 
Study drug: dispensing 
and/or accountability k 
 
 
X 
X 
X 
X 
X 
X 
 
 
Dose adjustment review l 
 
 
 
X 
X 
X 
X 
 
 
 
AE m and concomitant 
medication recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Procedure and nondrug 
therapy recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: 
Ab = antibody; AE = adverse event; BP = blood pressure; CBC = complete blood count; cHR = reticulocyte hemoglobin content; CV = cardiovascular; 
ECG = electrocardiogram; ELISA = enzyme-linked immunosorbent assay; EOT = End of Treatment; ET=Early Termination; EOS = End of Study; 
HbA1c = glycated hemoglobin; 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; O = optional test/assessment; PE = physical examination; RBC = red blood cell; RR = respiratory 
rate; TIBC = total iron binding capacity; UIBC = unsaturated iron binding capacity; TSAT = transferrin saturation; WBC = white blood cells; Wk(s) = week(s); 
X = mandatory test/assessment. 
Notes: In subjects on HD, all lab sampling is to be performed prior to the dialysis session.  
Subjects who discontinue study medication prematurely will be followed up until the end of the study, unless consent to participate is withdrawn. Upon completion of EOT and 
EOS visits, these subjects will be followed up every 3-6 month interval for vital status, CV events, and hospitalization (depending on the availability of subjects) until study 
closure. These visits may occur either in-person or via telephone. 
a 
All screening procedures should be completed within 6 weeks. For subjects currently taking Mircera®, the screening period can be extended up to 8 weeks. 
b 
Day 1 is a due treatment date per the existing ESA treatment schedule. All study assessments are to be performed prior to first study drug administration. In subjects on HD 
study assessments with the exception of HRQoL and body-weight measurement should also be performed prior to or at initiation of dialysis; HRQoL assessments should be 
done approximately during dialysis (preferably at the beginning) and weight measurement after dialysis.  


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c 
Subjects discontinuing study medication prematurely will complete EOT and EOS. Unless consent is withdrawn, CV events, vital status and hospitalizations will be collected 
every 3 to 6 months (phone or in-person clinic visit) for these subjects until study closure 
d 
Targeted PE (general appearance, CV, respiratory and abdomen) 
e 
BP and HR should be measured in triplicate (preferred) using automated calibrated instruments at pre dialysis in subjects on HD and preferably approximately at the same 
time in subjects on PD or HHD Measurement to occur prior to study drug administration (if applicable); BP and HR should be assessed per guidelines provided in Appendix 
5 
f 
Respiratory rate should be measured at predialysis in subjects on HD and preferably approximately at the same time in subjects on PD. Measurement should occur prior to 
study drug administration (if applicable) 
g 
Separate Hb samples should be collected at all the visits where a CBC is not collected (ie, Hb at Weeks 6, 10, 14, 16, 18, 22, 24, 32, 40, 48, etc) 
h 
Not required if result of a renal ultrasound or other imaging report within 12 weeks prior to randomization is available 
i 
Collect from female subjects of childbearing potential only can be collected at Screen 1, Screen 2 or as an unscheduled visit.  Must be reviewed prior to randomization. 
j 
Including SF-36, FACT-An, EQ-5D 5L, HRQoL assessments should be administered approximately at the same time of the day. Example: in HD subjects, questionnaires to 
be completed by subject approximately at the same time during dialysis and in PD subjects approximately at the same time of the day  
k 
Initial dosing of roxadustat and epoetin alfa per Table 1 and Table 2, respectively. Dose adjustment per Appendix 2 (roxadustat subjects) or epoetin package insert or SmPC 
(epoetin subjects); dose review for excessive hematopoiesis at every visit. All subjects on HD will receive epoetin alfa TIW intravenously (IV). For peritoneal dialysis and 
home hemodialysis subjects, the route of administration (IV or SC) of epoetin alfa may remain the same as baseline (per discretion of the Investigator) 
l 
Subjects randomized to roxadustat: dose adjustment begins at Week 4 refer to Appendix 2 
m 
AEs and SAEs reporting period begins after informed consent is obtained and ends at End of Study / 4-week post ET/EOT Visit or EOS/Disposition date for subjects who 
did not complete the ET/EOT visit 
. 


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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. Any subject enrolled in a clinical study with 
active drug therapy and reveals an increase of serum aminotransferases (AT) to > 3 × upper limit 
of normal (ULN), or bilirubin > 2 × ULN, should undergo detailed testing (including at least 
alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], 
and total bilirubin [TBL]) for further evaluation and follow-up. Alerts will be generated by the 
central lab to inform the investigator, study monitor and study team. Testing should be repeated 
within 48-72 hours of notification. Subjects should be asked if they have any symptoms 
suggestive of hepatobiliary dysfunction. 
Definition of Liver Abnormalities 
Confirmed abnormalities should be characterized as follows: 
 
ALT or AST 
 
Total Bilirubin 
Moderate 
> 3× ULN 
or 
> 2× ULN 
Severea 
> 3× ULN 
and 
> 2× ULN 
Abbreviations: 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal. 
a 
Hy’s Law: Drug-induced jaundice caused by hepatocellular injury, without a significant obstructive component, has a high 
rate of bad outcomes, from 10% to 50% mortality (or transplant).” The two “requirements” for Hy’s Law are: 1) Evidence 
that a drug can cause hepatocellular-type injury, generally shown by an increase in transaminase elevations higher 3 times 
the upper limit of normal (“2 x ULN elevations are too common in treated and untreated subjects to be discriminating”). 2) 
Cases of increased bilirubin (at least 2 x ULN) with concurrent transaminase elevations at least 3x ULN and no evidence 
of intra- or extrahepatic bilirubin obstruction (elevated alkaline phosphatase) or Gilbert’s syndrome. [Temple R. Hy's law: 
predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf 2006 Apr;15(4):241-3.] 
In addition, the subject should be considered to have severe hepatic abnormalities for any of the 
following: 
• ALT or AST > 8× ULN 
• ALT or AST > 5× ULN for more than 2 weeks  
• ALT or AST > 3× ULN and international normalized ratio (INR) > 1.5 (if INR testing is 
applicable/evaluated). 
• ALT or AST > 3× ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%).  
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring and 
follow-up. 
Follow-up Procedures 
Subjects with confirmed abnormal liver function results should be closely monitored and 
followed as described below. If close monitoring for LFTs in a subject is not possible, study drug 
should be discontinued. 


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Repeat LFTs 2-3 times weekly, then weekly or less until abnormalities stabilize or return to 
within normal limits. LFTs should include ALT, AST, TBL and ALP 
In addition, evaluate the 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 
In general, in the absence of an explanation for increased LFTs, such as viral hepatitis, 
preexisting or acute liver disease or exposure to other agents associated with liver injury, the 
study drug should be discontinued. 
Discontinuation of treatment should be considered if: 
• ALT or AST > 8 × ULN 
• ALT or AST > 5 × ULN for more than 2 weeks  
• ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5) (If INR testing is 
applicable/evaluated) 
• ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%) 
Once LFTs return to normal, and depending on whether there is an explanation for the LFT 
elevations, study drug dosing may resume, after discussion with the Medical Monitor 
Ref: FDA Guidance for Industry, titled: “Drug-Induced Liver Injury: Premarketing Clinical 
Evaluations”, issued July 2009  


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Page 124 
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 a prior to the start of the 
dialysis procedure that day (predialysis), preferably using the nondialysis arm. In subjects on 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 PD and should be measured approximately at the same time of 
the day at each visit.  
 


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Page 125 
Appendix 6 Recommended Intravenous Iron Therapy 
Recommended List of IV Iron Preparations: 
• If none of the following IV iron preparation is available or can be used for any reasons, 
the Medical Monitor should be contacted prior to administration, if possible.  
Iron Preparations (generic names) 
Iron gluconate 
Iron sucrose complex 
Iron dextran complex 
Iron isomaltoside 
Iron polymaltose complex 
 

SAP_001.pdf: 
FibroGen, Inc. 
Protocol Number:  FGCL-4592-064 
A Phase 3, Open-Label, Randomized, Active-Controlled Study of the Efficacy and 
Safety of Roxadustat in the Maintenance Treatment of Anemia in Subjects with End 
Stage Renal Disease (ESRD) on Stable Dialysis    
Amendment 2 
STATISTICAL ANALYSIS PLAN 
Version:   
Final 1.0 
Release Date: 
14Oct2018 
Confidentiality Statement 
This document is the property of FibroGen, Inc. and may notin full or partbe passed 
on, reproduced, published, distributed to any person, or submitted to any regulatory 
authority without the express written permission of FibroGen, Inc. 
NCT # NCT02273726


FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
FibroGen, Inc. 
Confidential and Proprietary 
Page 2 of 84 
 
Approvals 
I have reviewed and accept the information in this document to be a true and accurate 
representation of the Statistical Analysis Plan for Study FGCL-4592-064. 
 
Initiator: 
 
 
 
Signature:  
Date:  
 
 
 
 
 
Reviewed by: 
 
 
 
Signature:  
Date:  
 
 
 
 
 
 
Signature: 
 
Date: 
 
 
 
 
 
 
 
 
Signature: 
 
Date: 
 
 
 
 
Signature: 
 
Date: 
 
 
 
 
 
 
 
 
 
 
        Signature:  
Date:  
 
 
 
 
 
 


FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
FibroGen, Inc. 
Confidential and Proprietary 
Page 3 of 84 
 
 
Signature Significance 
The following significance is lent to the signatures on the Approvals page of this 
document. 
 
Signature 
Significance 
Initiator  
By signing, the author is attesting that the content of the document 
is complete and accurate. 
Reviewer 
By signing, the reviewer is attesting that the document’s approach 
and contents are compliant with the study protocol, all appropriate, 
regulatory requirements, and other significant guidelines. This 
individual(s) has reviewed the document for accuracy and 
completeness. 
 
 


FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
FibroGen, Inc. 
Confidential and Proprietary 
Page 4 of 84 
 
Table of Contents 
1 
Introduction ................................................................................................................. 9 
2 
Study Objectives ....................................................................................................... 10 
2.1 
Primary Objectives............................................................................................ 10 
2.2 
Secondary Objectives........................................................................................ 10 
3 
Study Design ............................................................................................................. 11 
3.1 
Dose Adjustments ............................................................................................. 13 
3.2 
Rescue Therapy & Emergency Procedures ....................................................... 14 
4 
Study Endpoints ........................................................................................................ 16 
4.1 
Primary Efficacy Endpoints .............................................................................. 16 
4.2 
Secondary Efficacy Endpoints .......................................................................... 16 
4.3 
Additional Evaluation of Efficacy .................................................................... 16 
4.4 
Safety Assessments ........................................................................................... 19 
5 
General Statistical Considerations ............................................................................ 20 
5.1 
Sample Size Determination............................................................................... 20 
5.2 
Analysis Populations ......................................................................................... 20 
5.2.1 Intent-to-Treat (ITT) Population ................................................................... 20 
5.2.2 Full Analysis Set (FAS) ................................................................................ 20 
5.2.3 Per Protocol Set (PPS) .................................................................................. 20 
5.2.4 Safety Population (SAF) ............................................................................... 21 
5.2.5 Major Protocol Deviations ............................................................................ 21 
5.3 
Methodology and Conventions ......................................................................... 21 
5.4 
Additional Data Handling Rules and Presentation Specifications .................... 21 
6 
Subject Accountability and Disposition.................................................................... 24 
7 
Demographics and Other Baseline Characteristics ................................................... 25 
8 
Medical History ........................................................................................................ 26 
9 
Study Medication ...................................................................................................... 27 
9.1 
Extent of Exposure ............................................................................................ 27 


FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
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Confidential and Proprietary 
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9.1.1 Dosing Changes ............................................................................................ 27 
9.1.2 Duration of Exposure .................................................................................... 27 
9.2 
Treatment Compliance ...................................................................................... 28 
10 Prior and Concomitant MedicationS ......................................................................... 29 
11 Efficacy Analyses ..................................................................................................... 30 
11.1 
Analyses of Primary Endpoint .......................................................................... 30 
11.1.1 
Primary Endpoint and Hypothesis ............................................................ 30 
11.1.2 
Sensitivity Analyses of Primary Endpoint ................................................ 33 
11.1.3 
Subgroup Analyses ................................................................................... 37 
11.2 
Analysis of Secondary Endpoints ..................................................................... 37 
11.2.1 
Secondary Endpoints and Hypothesis Testing .......................................... 37 
11.2.2 
Primary Analysis of Secondary Endpoints ............................................... 39 
11.2.3 
Secondary Analyses .................................................................................. 41 
11.3 
Additional Efficacy Analyses ........................................................................... 41 
11.3.1 
Hemoglobin Maintenance ......................................................................... 41 
11.3.2 
Hospitalizations......................................................................................... 42 
11.3.3 
Missed Dialyses ........................................................................................ 43 
11.3.4 
Changes in Cholesterol Levels .................................................................. 45 
11.3.5 
Blood Pressure Effect ............................................................................... 45 
11.3.6 
Vascular Access Thrombosis (HD subjects): ........................................... 46 
11.3.7 
Health Related Quality of Life (HRQoL) and EQ-5D-5L Benefits of 
Anemia Therapy........................................................................................................ 46 
11.3.8 
Hepcidin, Iron, and HbA1c ....................................................................... 50 
12 Safety Analyses ......................................................................................................... 51 
12.1 
Adverse Events ................................................................................................. 51 
12.2 
Clinical Laboratory Parameters ........................................................................ 52 
12.3 
Vital Signs ......................................................................................................... 52 
12.4 
Electrocardiogram (ECG) ................................................................................. 53 


FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
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Confidential and Proprietary 
Page 6 of 84 
 
12.5 
Other Safety Analyses....................................................................................... 54 
13 Additional and Subgroup Analyses .......................................................................... 55 
14 Interim Analyses ....................................................................................................... 56 
15 References ................................................................................................................. 57 
16 Appendices ................................................................................................................ 58 
16.1 
Appendix 1 Schedule of Assessments .............................................................. 59 
16.2 
Appendix 2 Roxadustat Dose Adjustment Rules .............................................. 61 
16.3 
Appendix 3 SF-36 (Version 2) .......................................................................... 63 
16.4 
Appendix 4 FACT-An (Version 4) ................................................................... 69 
16.5 
Appendix 5 Data Handling Conventions .......................................................... 72 
16.5.1 
Visit Time Windows ................................................................................. 72 
16.5.2 
Missing Date Imputation for Adverse Events ........................................... 75 
16.5.3 
Missing Date Imputation for Prior or Concomitant Medications ............. 76 
16.5.4 
Missing Date Imputation for last dose date .............................................. 77 
16.5.5 
Character Values of Clinical Laboratory Parameters ............................... 77 
16.6 
Appendix 6 Ranges of Potentially Clinically Significant Lab Values .............. 79 
16.7 
Appendix 7 Justification of the Non-Inferiority Margin ................................... 80 
16.8 
Appendix 8 Temporal Profile of TEAE’s of Special Interest ........................... 84 


FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
FibroGen, Inc. 
Confidential and Proprietary 
Page 7 of 84 
 
List of Abbreviations 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
ATC 
Anatomical Therapeutic Class 
CMH 
Cochran-Mantel-Haenszel  
CRF 
Case Report Form 
CRP 
C-Reactive Protein 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EPO 
Epoetin 
ESA 
Erythropoiesis-stimulating agent 
ESRD 
End Stage Renal Disease 
FAS 
Full Analysis Set 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
HD 
Hemodialysis 
hs-CRP 
High Sensitivity C-Reactive Protein 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
IU 
International Unit 
IV 
Intravenous 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
NI 
Non-Inferiority 
NID 
Newly Initiated Dialysis 
OL 
Open-Label 
PCS 
Potentially Clinically Significant 
PD 
Peritoneal Dialysis 
PPS 
Per-Protocol Set 
RBC 
Red Blood Cell 
QOL 
Quality of Life 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous  


FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
FibroGen, Inc. 
Confidential and Proprietary 
Page 8 of 84 
 
SOC 
System Organ Class (used in MedDRA dictionary) 
TEAE 
Treatment Emergent Adverse Event 
TLF 
Tables, Listings, and Figures 
TIW 
Three times weekly 
US 
United States 
WHOART 
World Health Organization Adverse Event Terminology 
WHODD 
World Health Organization Drug Dictionary 
WHO 
World Health Organization 


FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
FibroGen, Inc. 
Confidential and Proprietary 
Page 9 of 84 
 
1 
INTRODUCTION 
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of the 
statistical analyses of efficacy and safety as outlined and/or specified in the amendment 2 of 
study protocol dated 18 August 2017. Specifications of tables, figures, and data listings are 
contained in a separate document. 
 
A separate pooled-statistical analysis plan (SAP) for pre-specified analyses based on 
adjudicated safety data will complement this study specific SAP. 


FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
FibroGen, Inc. 
Confidential and Proprietary 
Page 10 of 84 
 
2 
STUDY OBJECTIVES 
 
2.1 
Primary Objectives 
Evaluate the efficacy and safety of roxadustat compared with active control (epoetin alfa) for 
the maintenance treatment of anemia in ESRD subjects on stable dialysis. 
 
2.2 
Secondary Objectives 
• Evaluate the utilization of intravenous (IV) iron with roxadustat compared with active 
control (epoetin alfa) 
• Evaluate the effect of roxadustat on serum lipid parameters compared with active 
control (epoetin alfa) 


FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
FibroGen, Inc. 
Confidential and Proprietary 
Page 11 of 84 
 
3 
STUDY DESIGN 
This Phase 3, multi-center, open-label, randomized, active-controlled study is designed to 
evaluate the efficacy and safety of roxadustat compared to epoetin alfa for the maintenance of 
hemoglobin levels in subjects on stable hemodialysis (HD) or peritoneal-dialysis (PD) and 
newly initiated dialysis (NID) originally on erythropoiesis-stimulating agent (ESA) for 
treatment of anemia. 
 
A total of up to 1200 subjects are planned to be randomized to receive roxadustat or epoetin 
alfa (active control) in a 1:1 ratio, respectively. 
For subjects randomized to roxadustat, the initial roxadustat dose will be determined using a 
conversion table based on the subject’s previous average weekly prescribed ESA dose in the 
last 4 weeks prior to randomization if the subject is on epoetin or darbepoetin, and average 
monthly (4 weeks) prescribed ESA dose in 8 weeks prior to randomization if the subject is on 
Mircera® (Table 1).  
 
If the mean qualifying screening hemoglobin value at randomization is less than the lower 
limit of the target hemoglobin range (i.e. <10 g/dL), the starting roxadustat dose will be 
increased by one dose step. If the converted initial dose exceeds the maximum dose of 3.0 
mg/kg then the lower dose step should be chosen as the initial dose. Roxadustat will be dosed 
three times weekly (TIW) for the entire duration of the Treatment Period. Dosing frequency 
may only be adjusted to BIW or QW if a subject requires < 20 mg TIW (i.e., < 60 mg per 
week) to maintain an Hb level of approximately 11 g/dL. 


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Table 1. 
Initial Dosing of Roxadustat: Conversion Table from ESAs to Roxadustat   
 
Epoetin (i.e., alfa, beta, theta, 
zeta, delta, or omega) a 
(IU/week) 
Darbepoetin 
alfaa, b 
(μg/week) 
Mircera®c 
(μg/ 
monthly) 
Roxadustat Dosed  
(mg/dose) TIW 
< 5,000 
< 25 
< 80 
70 
5,000 to 8,000 
25-40 
80-120 
100 
> 8,000 to 16,000 
> 40-80 
> 120-200 
150 
> 16,000 
> 80 
> 200 
200 
a 
Average weekly prescribed dose in last 4 weeks prior to randomization 
b 
If darbepoetin is used biweekly, use half the dose to get per week dose  
c 
Average prescribed monthly (4-wks) dose in last 8 weeks prior to randomization  
d 
Starting dose will be one step higher if the mean hemoglobin at randomization is < 10.0 g/dL, however, not to 
exceed 3.0 mg/kg/dose.  
Notes: 
The roxadustat dose steps are 20, 40, 50, 70, 100, 150, 200, 250, 300, and 400 mg.  
 
For subjects randomized to epoetin alfa, the initial epoetin alfa dose will be determined using 
a conversion table based on the subject’s weekly average prescribed ESA dose in the last 4 
weeks prior to randomization if on epoetin or darbepoetin, and average monthly (4-week) 
prescribed ESA dose in 8 weeks prior to randomization if on Mircera® (Table 2). 
 
All hemodialysis subjects randomized to Epoetin Alfa arm will receive epoetin alfa 
intravenously TIW during the Treatment Period. For PD and HD subjects, the route of 
administration should remain same as baseline. However, if the investigator decides to 
change the route of administration from subcutaneous (SC) to IV after randomization that 
should be done during the early part of the treatment phase (preferably prior to Week 16).  
 
In case of a change in route of administration from SC to IV, the initial dose of IV epoetin 
alfa will be determined by the investigator per local standard of care.   


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Table 2. 
Initial Dosing of Epoetin Alfa: Conversion Table from Non-Epoetin ESAs 
to Epoetin Alfa 
 
 
The study periods are as follows: 
• Screening Period: Up to 6 weeks. For subjects currently taking Mircera®, the 
screening period may be extended up to 8 weeks. 
• Treatment Period: Treatment duration is variable for individual subjects with a 
maximum treatment duration could be up to approximately 3 years from the date the 
last subject is randomized. 
• Post-Treatment Follow-Up Period: 4 weeks 
 
During the Treatment Period, subjects will attend weekly study visits from Day 1 to Week 2, 
followed by every two weeks study visits from Weeks 4 to 24. Following Week 24, study 
visits will occur every four weeks until the End of Treatment (EOT). After EOT, subjects 
proceed to the post-treatment Follow-up Period and will return for the End of Study (EOS) 
visit. The schedule of assessments for the study is provided in Appendix 1. 
 
All subjects discontinuing study medication prematurely will be followed up for vital status, 
cardiovascular events, and hospitalization until study closure, unless consent to participate is 
withdrawn. Upon completion of ET and 4-week Follow-up (EOS) visits, these subjects will 
be followed up every 3-6 month interval (depending on the availability of subjects) until 
study closure. These visits may occur either in-person or via telephone. 
 
3.1 
Dose Adjustments 
During the Treatment Period, roxadustat dose adjustment will be made according to the dose 
adjustment algorithm in Appendix 2, in order to maintain a hemoglobin level of 
approximately 11 g/dL, while closely monitoring the rate of rise of hemoglobin and 
hemoglobin levels.  
  
The dose of roxadustat will remain constant during the first 4 weeks of the Treatment Period 
unless a dose reduction is required for predefined out of range hemoglobin elevations. 
Roxadustat dose adjustments are permitted from week 4 onwards, and every 4 weeks 
Baseline ESA 
Conversion Ratio 
Examples of Converted 
Initial Epoetin Alfa dose (approximate) 
IU/weekc 
Epoetin (i.e., alfa, beta, theta, 
zeta, delta, or omega) 
(IU/week) a 
x 1 
6,000 IU/week x 1  
= 6,000 IU/week 
Darbepoetin alfa (μg/week) a 
x 200 
40 μg/week x 200  
= 8,000 IU/week 
Mircera® (μg/once monthly) 
(i.e., 4-wks) b 
x 70 – 80 
(for lower Mircera® dose 
lower conversion ratio may 
be used)d 
100 μg/month x 70 
= 7,000 IU/week 
200 μg/month x 80  
= 16,000 IU/week 
a 
Mean weekly ESA in 4 weeks prior to randomization 
b 
Mean monthly (4-week) ESA in 8 weeks prior to randomization 
c 
May be rounded as deemed necessary by the Investigator 
d 
Per discretion of the Investigator 


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thereafter i.e. Week 4, Week 8, Week 12, etc.; however, the dose may be adjusted between 
the two pre-specified windows if the following two criteria are met: 
• No dose adjustment has been made in last 4 weeks 
• Hemoglobin < 9.0 g/dL  
In this study, a rate of rise of hemoglobin > 2 g/dL within 4 weeks or a hemoglobin level of ≥ 
13 g/dl at any time would be considered as predefined out of range hemoglobin elevations. 
For a rate of rise of hemoglobin > 2 g/dL within 4 weeks, dose should be reduced by one 
dose step and for a hemoglobin value ≥ 13.0 g/dL, the dose should be on hold until 
hemoglobin drops < 12.0 g/dL per guidelines provided in the protocol (Appendix 2). When 
roxadustat will be resumed, the dose will be reduced by one dose step.  
 
Dose adjustments or temporary dose holds for predefined out of range hemoglobin elevations 
can occur at any time during the Treatment Period. Any dose adjustment will reset the dose-
adjustment window to every 4 weeks thereafter (e.g., dose adjustment for a qualified reason 
at Week 6 leads to next dose adjustment at Week 10). If a dose adjustment review is 
scheduled on Week 22, then the next dose adjustment review will be scheduled on Week 28, 
since there is no scheduled visit on Week 26. 
  
3.2 
Rescue Therapy & Emergency Procedures 
 
Red Blood Cell Transfusion (for all subjects): 
 
For subjects in both treatment groups, red blood cell (RBC) transfusion is allowed if rapid 
correction of anemia is required to stabilize the subject’s condition (e.g. acute hemorrhage) or 
the investigator is of the opinion that the blood transfusion is a medical necessity. Study 
treatment may continue during or after RBC transfusion administration. 
 
ESA use: 
For subjects randomized to roxadustat the use of ESAs is generally prohibited. ESA rescue is 
restricted to no more than one 4-week cycle of use during the Treatment Period; the 
Investigator may initiate use of an approved epoetin (EPO) analogue if all of the following 
criteria are met: 
• A subject’s hemoglobin level has not sufficiently responded to two or more dose 
increases or the maximum dose limit of the study drug has been reached; and 
• The subject’s hemoglobin is < 8.5 g/dL on two consecutive measurements (central 
lab) drawn at least five days apart; and 
• Clinical judgment does not suggest iron deficiency or bleeding as a cause of lack of 
response or rapid decline in hemoglobin; and 
• Reducing the risk of alloimmunization in transplant eligible patients and/or reduction 
of other RBC transfusion-related risks is a goal 
The subject is not allowed to be administered both the EPO analogue and roxadustat at the 
same time. Treatment with an EPO analogue should be started ≥ 3 days after the last dose of 
roxadustat, and should be stopped when hemoglobin > 9 g/dL or after a 4-week cycle has 
been completed, whichever comes first. If a subject requires longer than 4-week therapy due 
to inadequate response, the Medical Monitor should be contacted. Study treatment should be 
resumed after the following intervals: 
• Two days after stopping epoetin  
• One week after stopping darbepoetin alfa  
• Two weeks after stopping methoxy polyethylene glycol-epoetin beta (Mircera®) 


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If more than one cycle of EPO analogue rescue is required, the Investigator should 
permanently discontinue roxadustat. Use of EPO analogues will be recorded in the eCRF. 
Roxadustat subject who receives an ESA inadvertently and does not meet the criteria above 
may be allowed to continue taking study medication, if considered safe by the Investigator or 
Medical Monitor. 
 
For subjects randomized to epoetin alfa, the Investigator may initiate use of a different EPO 
analogue if clinically indicated. Use of the different EPO analogue will be recorded in the 
eCRF and will be considered rescue therapy. 
 
Emergency Procedures 
Therapeutic Phlebotomy: 
 
If there are clinical concerns for a subject’s high hemoglobin levels, the investigator may 
decide to perform a therapeutic phlebotomy in addition to a temporary study treatment dose 
hold – this should be documented and discussed with the study Medical Monitor. 
 
Supplemental Iron 
 
Oral Iron Supplementation: 
  
In this study, all subjects will be encouraged to take oral iron as the first-line iron 
supplementation. The dose and frequency are at the discretion of the principal Investigator. 
Oral iron therapy should be started before the subject becomes iron depleted. 
 
Intravenous Iron Supplementation:  
 
Intravenous iron supplementation is permitted if in the opinion of the Investigator the subject 
has not responded adequately while taking oral iron or cannot tolerate oral iron, AND is  
considered iron deficient as determined by either ferritin < 100 ng/ml or TSAT < 20%. 
 
A dose of up to 250 mg IV iron per dose administration cycle may be administered per 
regional package insert. A list of recommended IV irons is listed in the protocol (Appendix 
6). Three to four weeks following the last dose of IV iron infusion, central lab ferritin and 
TSAT levels and hemoglobin level will be assessed; a dose of IV iron may be repeated only 
if hemoglobin response is still lacking, and either ferritin < 100 ng/ml or TSAT < 20%. If 
there is no hematopoietic effect with the first administration of IV iron but with 
accompanying increases in TSAT and ferritin, then the Investigator should exercise judgment 
whether additional IV iron should be given. Treatment with study medication will continue 
during IV iron administration. Discontinuation of IV iron supplementation is recommended 
once subject is no longer iron deficient (e.g. ferritin >= 100 ng/mL and TSAT >= 20%). 
 
In Protocol Amendment 2, above IV Iron administration guidelines have been revised – 
intravenous iron supplementation is permitted if in the opinion of the Investigator the subject 
has not responded adequately and is considered iron deficient.  IV iron may be administered 
per local standard of care as deemed necessary by the investigator. 


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4 
STUDY ENDPOINTS 
 
4.1 
Primary Efficacy Endpoints 
For US (FDA) submission:  Hemoglobin change from baseline to the average level during 
the evaluation period defined as Week 28 until Week 52. 
For Ex-US submission:  
Hemoglobin change from baseline to the average hemoglobin 
of Weeks 28 to 36, without having received rescue therapy (i.e., 
RBC transfusion or rescue ESA therapy) within 6 weeks prior 
to and during this 8-week evaluation period. 
Rescue therapy for all subjects is defined as ESA use (for rescue or inadvertent use) or 
RBC/blood transfusion. 
 
Hemoglobin results obtained from the central laboratory will be used to determine 
Hemoglobin response.   
 
Baseline hemoglobin is defined as the mean of the at least last three available central 
laboratory hemoglobin values obtained prior to the first dose, three of the latest screening 
hemoglobin values plus the predose hemoglobin value collected on Day 1. In subjects with 
missing Day 1 hemoglobin value, the mean of three latest screening laboratory hemoglobin 
values will be considered as baseline hemoglobin value. 
 
4.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints in this study are as below for both US and Ex-US 
submission unless otherwise specified: 
• US (FDA) submission:  Proportion of subjects with mean hemoglobin level during the 
evaluation period defined as Week 28 until Week 52 ≥ 10.0 g/dL. 
• Ex-US submission:  Proportion of subjects with hemoglobin response, defined as 
mean hemoglobin during Weeks 28 to 36 within the target range of 10.0 to 12.0 g/dL 
without having received rescue therapy within 6 weeks prior to and during this 8-
week evaluation period. 
• Change from baseline in Low Density Lipoprotein (LDL) cholesterol to the average 
LDL cholesterol of weeks 12 to 28.  
• Hemoglobin change from baseline to the average level during the Weeks 18 to 24 for 
subjects with baseline hs-CRP > ULN. 
• Average monthly IV iron use per subject during the Treatment Period during Weeks 
28 to 52 (monthly defined as a period of 4 weeks). 
• Time to first RBC Transfusion during the treatment 
• Change from BL in mean arterial pressure (MAP) to the MAP value averaged over 
weeks 20 to 28 
• Time to first exacerbation of hypertension: An increase from BL of ≥ 20 mm systolic 
blood pressure (SBP) and SBP ≥ 170 mmHg or an increase from baseline of ≥15 
mmHg diastolic blood pressure (DBP) and DBP ≥ 100 mmHg during Weeks 28 to 52.  
 
4.3 
Additional Evaluation of Efficacy 
The additional efficacy evaluations in this study are: 
 
• Hemoglobin Maintenance: 
o Hemoglobin long-term Maintenance: Mean change from baseline in 
hemoglobin averaged over 8 weeks of treatment at Weeks 44-52 without 


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rescue therapy within 6 weeks prior to and during this 8-week evaluation 
period. 
o Mean change from baseline in hemoglobin averaged over the Week 96 to 104 
of treatment, without rescue therapy within 6 weeks prior to and during this 
8-week evaluation period. 
o Change from baseline in hemoglobin at each of the selected post-dosing time 
points. 
o Proportion of subjects with Hb >=10 g/dL averaged over Weeks 28 to 36, 44 
to 52, and 96 to 104 of treatment without rescue therapy within 6 weeks prior 
to and during the evaluation periods. 
 
o Proportion of subjects with Hb >=10 g/dL averaged over Weeks 28 to 36, 44 
to 52, and 96 to 104 of treatment regardless of rescue therapy 
o Proportion of subjects with Hb within10-12 g/dL averaged over Weeks 28 to 
36, 44 to 52, and 96 to 104 of treatment without rescue therapy within 6 
weeks prior to and during these 8-week evaluation periods. 
o Proportion of subjects with Hb within 10-12 g/dL averaged over Weeks 28 to 
36, 44 to 52, and 96 to 104 of treatment regardless of rescue therapy use. 
 
o Hemoglobin change from baseline to the average hemoglobin value of weeks 
28 to 36, 44 to 52, and 96 to 104 of treatment regardless of the use of rescue 
therapy. 
• Iron Supplement: 
o Time to and Proportion of subjects who has requirement for IV iron 
supplementation.  
o Mean monthly IV iron (mg) per subject during weeks 28-52, 53-104, and 105 
-EOT. 
o Mean monthly oral iron (mg) use per subject during 28-52, 53-104, and 105 -
EOT. 
o Proportion of subjects who has Requirement for only oral iron 
supplementation (Week 1 to 52). 
• Hospitalizations  
o Time to first hospitalization (% of subjects) up to Week 52, 7 days after Last 
Dose.  Time to first hospitalization or skilled nursing facility (% of subjects) 
up to Week 52, 7 days after Last Dose.  
o Number of days of hospitalizations due to AE per subject-exposure year 
(PEY) 
o Number of days in hospital or skilled nursing facility due to AE per patient-
year exposure (PEY) 
o Number of days in medical-facility (hospital, skilled nursing facility, 
emergency room, or overnight observation) due to AE per patient-year 
exposure (PEY) 
o Hospitalization-free survival days on treatment up to Week 52, 7 days after 
Last Dose. The days will be compared between the 2 treatment groups using 
ANCOVA model with baseline Hb and the baseline stratification factors. 
o Number of days on treatment out of hospital and skilled nursing facility up to 
Week 52, 7 days after Last Dose. Similar analysis as above will be performed. 
 
 


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• Missed Dialysis:  
o Occurrence (number) of missed dialysis sessions per subject.  
o Proportion of subjects with missed dialysis sessions.  
o Number of days of missed dialysis sessions per patient-exposure year (PEY). 
• Rescue Therapy Use:  
o Proportion of subjects who receive RBC/blood transfusions. 
o Number of RBC/blood packs per subject-month exposure to study medication. 
o Proportion of subjects who received rescue therapy [composite of RBC 
transfusions and/or rescue ESA]. 
o Time to initial rescue therapy. 
• Changes in Cholesterol Levels: 
o Change from baseline at each of the selected treatment time points (Weeks 12-
28, every 8 weeks onward until Week 52) in:  
 total cholesterol,  
 low-density lipoprotein/high-density lipoprotein ratio, 
 Non-HDL cholesterol. 
o Proportion of subjects achieving LDL target of <100 mg/dL averaged over 
Weeks 12-28 of treatment for subjects whose baseline LDL ≥ 100. 
• Blood Pressure Effect: 
o Proportion of subjects achieving blood pressure treatment goal in ESRD 
subjects (predialysis systolic BP <140 mmHg and diastolic BP<90 mmHg) 
averaged over Weeks 12-28. 
o Time to first  exacerbation of hypertension from baseline during weeks 1 to 36 
defined as: 
 An increase from baseline of  ≥ 20 mmHg systolic BP (SBP) and SBP 
>170 mmHg  
Or, 
 An increase from baseline of  ≥ 15 mmHg diastolic BP (DBP) and 
DBP >100 mmHg  
o Time to a treatment-emergent AE of hypertension.  
o Time to exacerbation from baseline of antihypertensive therapy. 
o Proportion of subjects with exacerbation of hypertension, defined as an 
increase from baseline of ≥ 20 mmHg systolic BP and sBP >170 mmHg or an 
increase from baseline of ≥ 15 mmHg diastolic BP and dBP>100 mmHg.   
o Proportion of subjects with a treatment-emergent AE of hypertension.  
o Proportion of subjects with exacerbation from baseline of antihypertensive 
therapy. 
• Vascular Access Thrombosis (HD subjects): 
o Time to a treatment-emergent AE of vascular access thrombosis 
o Proportion subjects with a treatment-emergent AE of vascular access 
thrombosis 
• Health Related Quality of Life (HRQoL) and EQ-5D-5L Benefits of Anemia 
Therapy:  
Change from baseline averaged over Weeks 12 to 28, and 28 to 52 of treatment for 
parameters listed below. 
o Vitality Sub-score of SF-36 (Appendix 3):  
 In FAS subjects with baseline Vitality Sub-score below 50.  
 In all FAS subjects. 


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o Physical Functioning Sub-score of SF-36:  
 In FAS subjects with baseline Physical Functioning Sub-score below 
40.  
 In all FAS subjects. 
o Anemia Subscale (“Additional Concerns”) of Functional Assessment of 
Cancer Therapy-Anemia (FACT-An) Scores (Appendix 4):  
 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 and other QoL Measures/Other Component scores of SF-
36:     In all FAS subjects. 
• Hepcidin, Iron Indices, and HbA1c:  
o Change from baseline in serum hepcidin at each of the selected time points  
o Change from baseline in serum ferritin at each of the selected time points, total 
and sub-grouped by baseline values of <400 ng/mL, and >400 ng/mL. 
o Change from baseline in TSAT at each of the selected time points, total and 
sub-grouped by baseline values of <40%, and >40%. 
o Change in HbA1c level at each of the selected time points, in all subjects, in 
subjects without history of diabetes and in subjects with history of diabetes.  
 
4.4 
Safety Assessments 
Study-specific Safety will be assessed by evaluating the following: 
• treatment emergent adverse events (TEAEs), treatment emergent serious adverse events 
(TESAEs)  
• Vital signs, electrocardiogram (ECG) findings, and clinical laboratory values  
Safety interpretation will also be made based on analyses of adjudicated safety data pooled 
across multiple studies in the roxadustat Phase 3 program as described in PSAP. 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, heart failure requiring hospitalization, unstable 
angina requiring hospitalization, hypertensive emergency, deep venous thrombosis, 
pulmonary embolism, and vascular access thrombosis.  
 


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5 
GENERAL STATISTICAL CONSIDERATIONS 
 
5.1 
Sample Size Determination 
At least 600 subjects and up to 1200 subjects will be randomized via IXRS to receive 
roxadustat or epoetin alfa in a 1:1 ratio. Study drug will be administered in an open-label 
manner. Randomization will be stratified by the following four factors: 
• Mean qualifying screening hemoglobin (≤10.5 vs. >10.5 g/dL) 
• History of cardiovascular, cerebrovascular or thromboembolic diseases (Yes vs. No) 
• Mean prescribed baseline epoetin alfa dose (or, equivalent epoetin dose for non-
epoetin subjects) in 4 weeks prior to randomization (≤150 vs. >150 IU/kg/week)   
 
Up to 600 subjects will be enrolled in this study in each treatment group. 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 pre-specified and adjudicated safety events of interest (i.e., 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 
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 
(i.e., specifically, hemoglobin change from baseline to the average level during the evaluation 
period defined as Week 28 until Week 52). 
 
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 (i.e., specifically, 
hemoglobin change from baseline in the averaged hemoglobin over Weeks 28 to 36).  
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. Appendix 7 has 
description on the justification that the non-inferiority margin of 0.75 was used.  
 
5.2 
Analysis Populations 
 
5.2.1 Intent-to-Treat (ITT) Population 
The ITT population consists of all randomized subjects. If treatment received differs from the 
randomized treatment, the randomized treatment group will be used. 
 
5.2.2 Full Analysis Set (FAS) 
The FAS population will consist of all randomized/enrolled subjects who received at least 
one dose of study drug and have at least one post-dose hemoglobin assessment. If treatment 
received differs from the randomized treatment, the randomized treatment group will be used. 
 
5.2.3 Per Protocol Set (PPS)   
The PPS population will consist of all subjects in the FAS population who received at least 8 
weeks of treatment, have at least one valid post-dose hemoglobin assessment and are without 
Major protocol violations. If treatment received differs from the randomized treatment, the 
randomized treatment group will be used. 


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5.2.4 Safety Population (SAF) 
The Safety Population will consist of all randomized/enrolled subjects who received at least 
one dose of study medication. If treatment received differs from the randomized treatment, 
the actual treatment group will be used.  
 
5.2.5 Major Protocol Deviations   
A subject who meets any of the major protocol deviation criteria in Table 3 will be excluded 
from the PPS. These will be identified while data are collected and a blinded review will 
occur before database lock.  
 
Table 3. 
Criteria for Assessing Major protocol Deviations  
Number 
Major Protocol Deviation 
1 
Violation of key* inclusion or exclusion criteria which may affect the assessment of the efficacy 
of the study drug.  
2 
Administration of wrong randomization study drug for more than 4 weeks of wrong treatment 
before week 24; any duration from week 24 to week 52. 
3 
Study drug compliance < 75% (up to Week 52). 
4 
Administration of prohibited concomitant medication that may impact evaluation of study drug*. 
5 
Significant noncompliance with study procedures, that may impact evaluation of efficacy of the 
study, will be evaluated case by base*. 
*Subject to Medical Monitor’s decision  
The number and percentage of Major protocol deviations will be categorized and summarized 
by treatment group as deemed appropriate.    
 
5.3 
Methodology and Conventions 
Continuous variables will be presented by descriptive statistics: n, mean, standard deviation, 
median, minimum, and maximum. Categorical variables will be tabulated by frequency count 
and percentage. For efficacy endpoints, the standard error and 95% confidence intervals (CI) 
will be presented as part of the descriptive summaries. 
Safety and efficacy data will be summarized and presented by treatment group and time point 
in summary tables.   
 
Lab results obtained from the central laboratory will be used for all efficacy and safety 
analyses. Local laboratory values, if collected in the CRF’s, will be listed only in data listing.  
Unless otherwise stated, all statistical tests will be two-sided hypothesis tests performed at the 
5% level of significance for main effects and all confidence intervals will be two-sided 95% 
confidence intervals. 
 
The secondary endpoints will be tested sequentially using the fixed sequence approach for 
multiplicity adjustments at an alpha level of 0.05. There will be no adjustments for multiple 
comparisons for other tests. 
 
All analyses will be performed using SAS® Version 9.1.3 or higher.  
 
5.4 
Additional Data Handling Rules and Presentation Specifications 
The following general guidelines will apply to all statistical analyses and data presentations: 
• Baseline is defined as the last available value obtained prior to the first dose of study 
drug, unless otherwise specified in this SAP. 
• Hemoglobin baseline is defined as the mean of the at least last three available central 
laboratory hemoglobin values obtained prior to the first dose of study medication (three 


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of the latest screening hemoglobin values plus the predose hemoglobin value collected on 
Day 1). In subjects with missing Day 1 hemoglobin value, the mean of three latest 
screening laboratory hemoglobin values will be considered as baseline hemoglobin value. 
• Baselines for reticulocyte count, reticulocyte hemoglobin content (CHr), hepcidin, hs-
CRP, serum  iron parameters (transferrin, TIBC, ferritin, sTfR, and iron), blood pressures 
and heart rate are defined as the mean of central lab values obtained within 6 weeks prior 
to the first dose of study medication. 
• Randomization stratification factors derived from actual data (not the ones from the 
randomization system) will be used in all applicable analysis models 
• The stratification factors to be included in the analyses, where appropriate, include the 
randomization stratification factors and incident dialysis within ≤ 4 months vs. > 4 
months of starting dialysis when randomized.  
• When the actual treatment received by a subject is different from the randomized 
treatment assigned, the subject will be analyzed per the randomized treatment for the 
efficacy parameters; while they will be analyzed per actual treatment that was taken for 
the safety parameters for US submission.   
• Unscheduled visits within an allowable window will be grouped into the closest 
scheduled visits based on the visit window specified in Appendix 5. For subjects who 
have more than one measurement at a certain scheduled visit, the last measurements will 
be used, with the exception of CPK, WBC, liver function tests (i.e., ALT, AST, GGT, 
ALP, and total bilirubin), in which the maximum measurement will be used. 
• By default, US conventional units will be used for laboratory value presentations. A set of 
lab summary tables in SI units will alsao be provided based on TLF index. 
• Age is calculated as of date that the informed consent form was signed. 
 age = INTCK( ‘YEAR’, Birth date, date of Informed Consent, ‘C’) where INTCK is a SAS 
function. 
• Duration of treatment or days in treatment is calculated as: last dose date of study 
medication – first dose date of study medication + 1 
• Body weight, height and temperatures will converted using the following formula: 
- kg = lb/2.2 
- cm = 2.54 x in 
- Co = (5/9) x (Fo – 32) 
• The mean, standard deviation and median will be presented with adding one more 
decimal to raw data with rounding off. The minimum and maximum will be presented 
with the same number of decimals as in the raw data. 
• All percentages will be rounded to one decimal place and lined up by the decimal place. 
The percentage will be suppressed when the count is zero. 
• Any p-values will be rounded to four decimal places and will be presented as ‘<.0001’ if 
they are less than 0.0001 after rounding. 
• All tables and listings will have a header showing “FibroGen, Inc.”, the protocol number, 
and Page x of y. Footer will indicate the program file path/name, run date and run time.  
• For continuous variables that are recorded as “< X” or “> X”, the value of “X” will be 
used in the calculation of summary statistics. The original values will be used for the 
listings. 
• Decimal points will be presented as follows: N will be presented without decimal, 
minimum and maximum in same precision as in the database, mean and median in one 


FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
FibroGen, Inc. 
Confidential and Proprietary 
Page 23 of 84 
 
more decimal than minimum and maximum, and SD and SE in one more decimal than 
mean and median. 
• Tables and figures will use derived analysis visit.  Listings will use nominal visits, show 
the flag to indicate analysis visit to be used. Namely, both Nominal visit and analysis visit 
will be presented in the listing. 
• Additional data handling conventions are detailed in Appendix 5. 
• Analysis visits assigned for hemoglobin samples collection corresponding to the range of 
treatment days (window) during which an actual visit may have occurred are presented in 
Appendix 5. All scheduled and unscheduled hemoglobin samples that belong to each 
window will be taken into account.  
 


FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
FibroGen, Inc. 
Confidential and Proprietary 
Page 24 of 84 
 
6 
SUBJECT ACCOUNTABILITY AND DISPOSITION 
The following subject data will be summarized and presented by treatment group (roxadustat 
and active control) unless specified otherwise: 
• 
Number and percentage of subjects screened (overall only) and randomized (using the 
screened subjects population) 
• 
Number and percentage of subjects screened (overall only) and randomized (using the 
screened subject population) in the original protocol and amendments. 
• 
Number and percentage of subjects randomized at each center, and for all centers 
combined, by treatment group (using the ITT population) 
• 
Number and percentage of subjects in each analysis set, by treatment group (using the 
ITT population) 
• 
Number and percentage of subjects excluded from the Per Protocol analysis set by reason 
for exclusion, treatment group (using the ITT population) 
• 
Kaplan-Meier plots will be generated for premature treatment discontinuation by 
randomization arm showing 2 curves (one curve per treatment group).  
• 
All subjects who prematurely discontinued during the Treatment Period will be listed by 
discontinuation reason for the ITT population. 


FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
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Confidential and Proprietary 
Page 25 of 84 
 
7 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Demographic parameters and important baseline disease characteristics will be summarized 
by treatment group for the ITT, Safety, FAS and PPS populations. These include but may not 
be limited to age, age group (18 to 64, 65 to 74, ≥75), sex, ethnicity, race, region, weight, 
body mass, by stable dialysis and newly initiated dialysis, index (BMI), hemoglobin (the 
mean of the two most recent central lab results), platelets, mean hemoglobin category (≤10.5 
g/dL or > 10.5 g/dL), mean weekly baseline ESA ( EPO or EPO equivalent) dose per 
kilogram category (≤150 IU/kg/week or >150 IU/kg/week) in the 4 weeks prior to 
randomization, mean ESA (EPO or EPO equivalent) in 4 weeks (if on epoetin or darbepoetin) 
or in 8 weeks (if on Mircera) prior to randomization category (<5,000 IU/week, 5,000 to 
8,000 IU/week, >8,000 to 16,000 IU/week, >16,000 IU/week), ferritin, ferritin group (<100, 
100-<400,  ≥400 ng/mL), TSAT and TSAT group (<20, 20-<40,  ≥40%), iron deplete (ferritin 
<100 or TSAT <20%) vs. not, baseline C-reactive protein (CRP) group (CRP ≤ULN vs. 
CRP > ULN), and history of cardiovascular disease or cerebrovascular disease or 
thromboembolic disease (Yes or No), primary reason for CKD/ESRD (DM and HPT vs. all 
others). 
 
Descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) will be 
presented for continuous variables. In addition, 25%-75% values of hemoglobin and platelets 
will be presented. Frequency distributions (number and percentage of subjects) will be 
presented for categorical variables. 
 
Descriptive statistics of baseline values for other parameters will be presented in their change 
from baseline tables. 
 


FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
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Confidential and Proprietary 
Page 26 of 84 
 
8 
MEDICAL HISTORY 
 
Medical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA). Medical History of interest including chronic kidney disease (CKD) History 
inclusive of CKD cause, cardiovascular disease including dyslipidemia, cerebrovascular 
disease, thromboembolic history, hypertension history, diabetes history, and anemia history 
will be summarized by system organ class, preferred term and treatment group for the Safety 
Population.   


FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
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Confidential and Proprietary 
Page 27 of 84 
 
9 
STUDY MEDICATION 
 
9.1 
Extent of Exposure 
Exposure to study medication will be summarized by treatment group in terms of treatment 
duration in weeks, which is calculated using the following formula: (the last dose date of 
study medication taken - the first dose date of study medication taken +1)/7. 
 
Total weekly study drug exposure is defined as the total prescribed dose (in mg and mg/kg 
for roxadustat and IU and IU/kg for ESAEPO) of study drug administered within the week 
(windowed by 7-day period from Day 1).  
 
Duration of exposure, weekly exposure and total study drug exposure will be tabulated by 
treatment group for the safety population. 
 
Per dose amount and dosing frequency will also be tabulated by treatment group for the 
safety population and PPS population.  
 
Patient-Exposure-Year (PEY) is defined as Last Dose Date – First Dose Date + 1.  
 
9.1.1 Dosing Changes  
Dosing changes for both treatment groups are collected in the Study Drug Administration/ 
Dose Adjustment Form in the eCRF. Two types of dosing changes will be calculated.  
 
A dose-per-intake change is the change in the number of milligrams on the intake day (for 
example from 200 mg TIW to 250 mg TIW). A weekly-dose change is the change in the 
prescribed weekly dose, calculated as the dose-per-intake times the weekly frequency. 
 
For example a change from 200 TIW to 250 TIW is a change of 600 mg to 750 mg per week 
which is considered as a change in dose-per-intake and a change in weekly-dose as well.  
 
For each subject the total number of dose-per-intake changes and the weekly-dose changes 
will be calculated for safety and PPS population. 
 
9.1.2 Duration of Exposure  
Exposure time will be categorized according to the following categories by treatment arm 
(roxadustat and ESA) for safety and PPS population: 
• Less than 2 weeks 
• At least 2 weeks, less than 4 weeks 
• At least 4 weeks, less than 26 weeks 
• At least 26 weeks, less than 52 weeks 
• At least 52 weeks, less than 78 weeks 
• At least 78 weeks, less than 104 weeks 
• At least 104 weeks, less than 130 weeks 
• At least 130 weeks, less 156 weeks 
• More than 156 weeks 
• Unknown 
 


FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
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Confidential and Proprietary 
Page 28 of 84 
 
9.2 
Treatment Compliance 
Study medication dosing compliance for a specified period is defined as the total dose (mg or 
IU) actually taken by a subject during that period divided by the prescribed dose expected to 
be taken during the same period multiplied by 100.   
An overall per-dose compliance measure can be calculated by (# of actual dose 
administrations)/ (Total # of expected dose administrations) *100 during the subject’s 
Treatment Period. Descriptive statistics for study medication compliance will be presented by 
treatment group for the entire Treatment Period of the study for safety population. 
Compliance will be summarized as follows: 
• 
Descriptive statistics will be summarized by the 2 treatment groups. 
• 
Percent compliance will be categorized according to the following categories by 
treatment groups: 
o less than 50% (significant drug noncompliance) 
o at least 50%, less than 75% (moderate drug noncompliance) 
o greater or equal 75% (drug compliance) 
o unknown 


FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
FibroGen, Inc. 
Confidential and Proprietary 
Page 29 of 84 
 
10 PRIOR AND CONCOMITANT MEDICATIONS 
The World Health Organization Drug Dictionary (WHODD) will be used to classify prior 
and concomitant medications by therapeutic class and generic name based on ATC code level 
3. Prior medication is defined as any medication taken and stopped prior to the first dose of 
the study medication within 30 days before signing the informed consent. Concomitant 
medication is defined as any medication taken between the day of first dose of the study 
medication and the day of ET/EOT Visit date + 28 days, inclusive.  
 
Medication start and end dates will be compared with the start date of study drug and 
classified as per Table 4.  
 
In case of partial or missing dates, comparisons will be made based on the level of detail 
available. For example, if start date of study drug is 04Jan2013, and a medication has a start 
date of 04Jan2013, the medication will be classified as concomitant. A start date of Jan2013 
(i.e., missing day) would also see the medication classified as concomitant. 
 
Table 4. 
Classification of Prior and Concomitant Medications 
 
End 
date 
 
Before start of study 
drug administration 
On or after start of 
study drug 
administration 
 
Missing 
Start 
date 
 
Before start of study 
drug administration 
 
Prior 
 
 
Concomitant 
 
 
Concomitant 
On or after start of 
study drug 
administration 
 
– 
 
Treatment Emergent 
Concomitant 
 
Treatment Emergent 
Concomitant 
 
Missing 
 
Prior 
 
 
Concomitant 
 
Concomitant 
 
Both prior and concomitant medication usage will be summarized by the number and 
proportion of subjects in each treatment group. Subjects will only be counted one time in 
each unique ATC Class and generic name if multiple drugs are used by a subject.  
 
Detailed analyses may be performed on prior and concomitant medications of special 
interests such as oral iron, blood pressure medications and lipids medications. 
 


FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
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Confidential and Proprietary 
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11 EFFICACY ANALYSES  
Efficacy will be conducted on the ITT and FAS for US (FDA) submission. Efficacy analysis 
of non-inferiority on the PPS population and superiority on FAS population will be used for 
EU regulatory submission. 
 
The Efficacy Emergent Period is defined as the evaluation period from the Analysis date of 
first dose intake up to 7 days after the Last Dose of study drug or EOT Visit, whichever 
occurs first. This period will be used as reference period for the time to event analyses related 
to efficacy endpoints, unless specified otherwise.  
 
11.1 Analyses of Primary Endpoint 
 
11.1.1 Primary Endpoint and Hypothesis 
 
11.1.1.1 U.S. Submission 
The primary efficacy endpoint for the US (FDA) submission is defined as the hemoglobin 
change from baseline to the average level during the evaluation period defined as Week 28 
until Week 52.  
 
The primary hypothesis to be tested for the primary efficacy analysis for US (FDA) 
submission is: 
H0: Hemoglobin mean change from baseline to the average level from Week 28 to 
Week 52 in the roxadustat group ≤ hemoglobin mean change from baseline in the 
epoetin alfa group minus 0.75 g/dL 
Versus: 
H1: Hemoglobin change from baseline to the average level of Week 28 to Week 52 in 
the roxadustat group > hemoglobin mean change from baseline in the epoetin alfa 
group minus 0.75 g/dL 
A Multiple Imputation (MI) analysis of covariance (ANCOVA) model will be used. The 
model will contain terms for treatment group, baseline Hb measurement, and stratification 
factors except mean qualifying screening hemoglobin (≤ 10.5 vs. >10.5 g/dL). The primary 
efficacy analysis will be based on the estimated difference between the two treatments overall 
mean effects throughout the evaluation period based on the pooled ANCOVA model.   
 
This null hypothesis will be rejected if the two-sided 95% CI for the difference between the 
two treatment groups using MI ANCOVA model lies entirely above -0.75 g/dL. 
Hemoglobin values under the influence of a rescue therapy will not be censored in this 
analysis.  
 
The below stratification factors will be used in efficacy analyses.  
• 
Mean qualifying screening hemoglobin (≤ 10.5 vs. >10.5 g/dL) for other than Hb 
related endpoints 
• 
History of CV, cerebrovascular, or thromboembolic diseases (yes vs. no) 
• 
Mean prescribed weekly epoetin alfa dose (or, equivalent epoetin dose for nonepoetin 
subjects) in the 4 weeks prior to randomization (≤ 150 vs. > 150 IU/kg/week)  
• 
Incident dialysis within ≤ 4 months vs. > 4 months of starting dialysis when 
randomized.  


FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
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The following steps will be used to conduct the primary analysis of the primary endpoints for 
both regions: 
 
1. Generate 200 datasets, using seed 162345 for U.S. and 347631 for Ex-U.S., where 
only intermittent  missing hemoglobin data will be imputed for each treatment relying 
on non-missing data from all subjects within each treatment group using the Monte 
Carlo Markov Chain, MCMC) imputation model and the available non missing 
hemoglobin for each scheduled Week by treatment group.  
 
The MCMC statement in the SAS PROC MI procedure with monotone option will be 
used. As a result, each dataset will only have missing ending data, namely, a 
monotone missing data pattern.  
2. For each dataset from step 1, missing ending data (hemoglobin up through end of 
evaluation period) will be imputed. As a result, 200 imputed complete datasets will be 
generated. 
• Missing data at Week 1 will be imputed using the regression imputation model 
with baseline stratification factor, baseline and hemoglobin from Week 1, 
using the SAS PROC MI procedure with the REGRESSION option in the 
MONOTONE statement.  
• The SAS PROC MI procedure will use data separately from each treatment 
subjects to impute the missing data for a specific Week (i.e. only those that 
need the imputation for the Week). Since subjects from the different treatment 
groups for that Week are excluded from the step, they will not contribute to 
the imputation for the Week. 
• Repeat for all other scheduled Weeks sequentially (Week 2 to the end of 
evaluation period). Subjects whose missing data were imputed for previous 
Weeks will contribute to the imputation for the current Week.  
• The regression imputation model includes an intercept and the slopes of the 
hemoglobin from previous Weeks. 
 
3. Analyze each imputed complete dataset using the ANCOVA model using the mean of 
observed or otherwise imputed Hb values within the evaluation period (week 28 -52). 
The model will contain terms for baseline Hb measurement as a covariate and 
treatment group and stratification factors except mean qualifying screening 
hemoglobin (≤ 10.5 vs. >10.5 g/dL) as fixed effects. 
Sample SAS code: 
 
PROC MIXED data=xx; 
  class treatment categorical covariates; 
  model change_Week36 = treatment covariates / solution; 
  lsmeans treatment / diff cl; 
  ods output Diffs=lsdiffs LSMeans=lsm solutionF=Parms;  
  by _Imputation_; 
run; 


FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
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4. Combine estimates from the results for each of the 200 ANCOVA model using SAS 
PROC MIANALYZE.  
Sample SAS code: 
 
PROC MIANALYZE parms(classvar=full)=lsdiffs; 
  class treatment categorical covariates; 
  modeleffects treatment; 
  ods output ParameterEstimates=MIAN_lsdiffs; 
run; 
 
Report the results of the least-squares mean estimates of the change from baseline in 
hemoglobin during the evaluation period, the estimates of treatment effect (e.g. least-squares 
mean CFB in hemoglobin for the treatment group minus the least-squares mean CFB in 
hemoglobin for the active comparator group) and the corresponding p-values during the 
evaluation period. 
 
11.1.1.2 EU Regulatory Submission 
 
The primary efficacy endpoint for Ex-U.S. submission is defined as the hemoglobin change 
from baseline to the average hemoglobin of Weeks 28 to 36, without having received rescue 
therapy within 6 weeks prior to and during this 8-week evaluation period and will be based 
on the PPS population based on patients enrolled during the original protocol before the 
amendment 1. This primary efficacy analysis will be based on the estimated difference 
between the two treatments overall mean effects throughout the evaluation period based on 
the MMRM model described below.  
 
The primary hypothesis to be tested for the primary efficacy analysis for Ex-US submission 
is: 
H0: Hemoglobin mean change from baseline to the average of week 28 to week 36 in 
the Roxadustat group 
≤ Hemoglobin mean change from baseline in the Epoetin alfa group minus 0.75 
g/dL 
Versus 
H1: Hemoglobin change from baseline to the average of week 28 to week 36 in the 
roxadustat group 
> Hemoglobin mean change from baseline in the Epoetin alfa group minus 0.75 
g/dL 
 
Rescue therapy for all subjects is defined as ESA rescue or RBC transfusion. For subjects 
who require rescue therapy, the hemoglobin value after the initiation of the rescue therapy 
will be set to missing up to 6 weeks (or 8 weeks if during the evaluation period) from the last 
date of the rescue therapy.  
 
The primary endpoint for EU Regulatory. will be analyzed using MMRM using baseline 
value as covariate and treatment group, visit (up to Week 52), interaction of treatment group 


FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
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Confidential and Proprietary 
Page 33 of 84 
 
and visit, and stratification factors except mean qualifying screening hemoglobin (≤ 10.5 vs. 
>10.5 g/dL) as fixed effects. 
 
Due to the large amount of visits (up to Week 52) to be included in the model, the 
unstructured covariance pattern model will be applied first. If the algorithm for unstructured 
covariance pattern does not converge then the heterogeneous Toeplitz structure will be used. 
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. 
 
The estimates for difference of change in Hb averaged over Weeks 28 to 36 between the two 
treatment groups will be generated from an estimate statement from Visit Week 28 to 36. 
 
This null hypothesis will be rejected if the two-sided 95% confidence interval for the 
difference of least square means between the two treatment groups using the MMRM model 
lies entirely above –0.75 g/dL. 
 
11.1.2 Sensitivity Analyses of Primary Endpoint 
The potential impact of missing data on the estimates of the primary efficacy endpoint will be 
examined using the following sensitivity analyses. The results of the analyses will be 
summarized in Table 5. These sensitivity analyses are further detailed in each Section. 


FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
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Table 5: Primary Endpoint Analysis Results  
* Maximum of Degree of Freedom from each individual ANCOVA. The actual Degrees of Freedom in PMM will be calculated using  
 where B is 
between-imputation variance and 
with U the standard error associated with estimates, Rubin (1987). 
 
**Rescue therapy for all subjects is defined as ESA rescue or RBC transfusion. For subjects who require rescue therapy, the hemoglobin value after the initiation of the 
rescue therapy will be set to missing up to 6 weeks (or 8 weeks if during the evaluation period) from the last date of the rescue therapy.  
Analysis 
 (ITT for U.S. and PPS Ex-U.S.) 
Treatment Difference 
and 95% CI (roxadustat  
vs Epo) 
Std. 
Err. 
Degree of 
Freedom* 
t-statistics 
p-value 
ANCOVA with Multiple Imputations  
.xxx (.xxx, .xxx) 
.xxx 
xxx 
.xxx 
.xxxx 
ANCOVA-MI with Hb censored** for rescue therapy (US endpoint only) 
.xxx (.xxx, .xxx) 
.xxx 
xxx 
.xxx 
.xxxx 
MMRM 
.xxx (.xxx, .xxx) 
.xxx 
xxx 
.xxx 
.xxxx 
PMM-Last Mean Carried Forward 
.xxx (.xxx, .xxx) 
.xxx 
xxx 
.xxx 
.xxxx 
ANCOVA-MI for subjects enrolled in original protocol 
.xxx (.xxx, .xxx) 
.xxx 
xxx 
.xxx 
.xxxx 


 
 
 
 
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11.1.2.1 MMRM 
The same analysis as Ex-U.S. primary endpoint will be repeated for the primary U.S. endpoint as 
one of the sensitivity analysis. 
 
11.1.2.2 Pattern Mixture Model 
PMMs provide a general and flexible framework for sensitivity analyses that allows formulating 
assumptions regarding missing data in a transparent and clinically interpretable manner. This is 
expected to address the possibility of the data being missing not at random (MNAR). All factors 
mentioned in the primary analysis will be included in the PMM. 
 
The following aspects of data missingness, may affect the estimates. 
 
• Timing and extent of missingness  
• Assumed underlying mechanism for data missingness 
 
11.1.2.2.1  Timing and Extent of Missing Data 
 
To assess the potential effect of data missingness on the estimate of treatment effect, subjects will 
be classified as full data or missing data cases. Patterns of missingness will be based on non-
missing hemoglobin before the end of the evaluation period. 
  
•  Full data cases are defined as subjects with non-missing hemoglobin for all scheduled weeks 
of the Treatment period.  
 
•  Missing data cases are defined as subjects with a missing hemoglobin on at least one 
scheduled Week of the treatment period. The missing data cases are further grouped into 
intermittent missing and monotone missing cases. 
 
o Intermittent missing hemoglobin cases are defined as subjects with a missing 
hemoglobin for at least one scheduled week of but not on consecutive scheduled 
weeks up to end of the evaluation period.  
 
o Monotone missing hemoglobin cases are defined as subjects who have consecutive 
scheduled Weeks with missing hemoglobin up to the end of evaluation period. A 
subject who is a Monotone missing case could have intermittent missing 
hemoglobin prior to the ending Week.  
 
Subjects will be grouped as follows: 
 
• Full data cases  
• Intermittent missing data cases  
• Monotone missing data cases  
 
Should the incidence of Monotone missing data cases and intermittent missing data cases 
be relatively small, 5%, then those cases will be combined so that the groups are full data 


 
 
 
 
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cases and missing data cases. The summary of missing pattern in first 52 scheduled visits 
will be presented in a table. 
 
11.1.2.2.2 Assumptions on Missing Data Mechanism  
 
In addition to the extent of data missingness, the mechanism under which missing data occur may 
affect the estimate of the parameter of interest.  
 
The potential impact of missing efficacy endpoints on the estimates of treatment effects will be 
assessed using alternative statistical models with different underlying assumptions on the missing 
data mechanism (missing not at random (MNAR)) (Little and Rubin, 1987). 
 
11.1.2.2.3  PMM –Last Mean Carried Forward 
A pattern-mixture model using a last mean carried forward multiple imputation method 
(Carpenter et al, 2013) will be used as another sensitivity analysis to explore the robustness of the 
ANCOVA results for the primary efficacy variables. Using this method, missing data after ending 
Week will be imputed based on the last non-missing mean from its own treatment group. 
 
The steps to implement this sensitivity analysis are as follows. Parameters below refer to the 
parameters of the multivariate normal distribution for baseline and post baseline Hb measurement.  
 
1. Create posterior distribution of parameters: Separately for each treatment arm, take all 
patients observed data and assuming MAR to fit a multivariate normal distribution with 
unstructured mean (i.e. a separate mean for each of the baseline plus post-baseline 
scheduled weeks and unstructured variance covariance matrix using a Bayesian approach 
with an improper prior for the mean and an uninformative Jeffreys' prior for the variance-
covariance matrix (Schafer, 1997, p. 155).  
 
2. Draw parameters: Separately for each treatment arm, draw variance-covariance matrix 
from the posterior distribution for the parameters using seed 453628 for U.S. and 386045 
for Ex-U.S. The mean Vector would be set to the marginal mean for their randomized 
treatment arm at their last non-missing measurement. 
 
3. Build joint distribution of missing data and observed data: For each subject with missing 
data, using the draws for the parameter to build the joint distribution of their observed and 
missing data. 
 
4. Construct conditional distribution of missing data give observed data: For each patient 
with missing data, use their joint distribution in previous step to construct their 
conditional distribution of missing given observed outcome data. Sample their missing 
data from this conditional distribution, to create a `completed' data set, using seed 732545 
for U.S. and 538529 for Ex U.S. 
 


 
 
 
 
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Repeat the above steps for 200 times and resulting in 200 imputed data sets. Then fit ANCOVA 
model for each imputation data set, and combine the resulting parameter estimates and standard 
errors using Rubin’s rules (Rubin, 1987) for final inference. This sensitivity analysis will be 
performed for both U.S. and Ex-U.S. primary endpoints. 
 
 
11.1.3 Subgroup Analyses  
The analysis of the primary endpoints of US and Ex-US may be performed by gender, age group, 
baseline hemoglobin categories, mean prescribed weekly epoetin alfa dose categories, baseline 
CRP categories, cardiovascular/cerebrovascular/thromboembolic medical history, baseline iron 
replete status, and stable vs incident dialysis: dialysis duration >4 months vs ≤ 4 months where 
appropriate.  
 
In addition, hemoglobin change from baseline to the average level during Weeks 18-24 may be 
analyzed by subgroups of baseline hs-CRP (<=ULN, vs. > ULN), baseline ESA dose categories, 
and dialysis status. 
 
11.2 Analysis of Secondary Endpoints 
 
11.2.1 Secondary Endpoints and Hypothesis Testing 
 
Once the null hypothesis of the primary endpoint has been rejected, the secondary endpoints 
below will be tested using a fixed sequence testing procedure, in order to maintain the overall 
two-sided type I error of 0.05. If the claim of superiority or non-inferiority is successful and the 
test will progress to the next comparison in sequence as follows. 


 
 
 
 
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Table 6   Key Secondary Endpoints Fixed Sequence Testing Procedure 
 
Test 
Variable 
Comparison 
1 
Proportion of subjects with mean hemoglobin level during the 
evaluation period defined as Week 28 until Week 52 ≥ 10.0 g/dL 
(U.S.) or  
Proportion of Hb responders in the average of weeks 28 to 36 within 
the target range of 10.0 to 12.0 g/dL without having received rescue 
therapy.  (Ex-U.S.).  
Non-inferiority of 
roxadustat versus 
EPO with margin of -
0.15 
2 
LDL cholesterol change from BL to the average of weeks 12 to 28.  
Superiority of 
roxadustat versus 
EPO 
3 
Hemoglobin change from baseline to the average level during Weeks 18 to 
24 for subjects with baseline hsCRP > ULN 
Non-inferiority of 
roxadustat versus 
EPO  
4 
Average monthly IV iron (mg) use per subject during weeks 28 to 52.  
Superiority of 
roxadustat versus 
EPO 
5 
Time to first RBC Transfusion during the treatment.  
Non-inferiority of 
roxadustat versus 
Epo with margin of 
1.8  
6 
MAP change from BL to the average MAP of weeks 20 to 28.  
Superiority  of 
roxadustat versus 
EPO 
7 
Time to first exacerbation of hypertension: An increase from baseline of ≥ 
20 mmHg systolic blood pressure (SBP) and SBP ≥ 170 mmHg or an 
increase from baseline of ≥15 mmHg diastolic blood pressure (DBP) and 
DBP ≥ 100 mmHg during Weeks 28 to 52. 
Superiority and Non-
inferiority of 
roxadustat versus 
EPO with margin of 
1.8 


 
 
 
 
FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
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11.2.2 Primary Analysis of Secondary Endpoints 
Unless otherwise specified, the primary analysis for the secondary endpoints will be analyzed 
using MMRM described in 11.1.2.1 based on the FAS for U.S., and PPS for non-inferiority 
tests and FAS for superiority tests for Ex-U.S. if applicable.  
 
11.2.2.1 Proportion of Hemoglobin Responders  
• US: Proportion of subjects with mean hemoglobin level during the evaluation period 
defined as Week 28 until Week 52 ≥ 10.0 g/dL, and patients with mean hemoglobin 
level between Hb 10-12 g/dL. 
• Ex-US: Proportion of subjects with mean Hb between range of 10.0 to 12.0 g/dL 
without having received rescue therapy within 6 weeks prior to and during this 8-week 
evaluation period. 
 
The hypothesis to be tested for the efficacy analysis is: 
H0: Hemoglobin response rate for subjects in the roxadustat group - hemoglobin 
responder rate for subjects in the Epoetin group ≤ -15% 
Versus 
H1: Hemoglobin response rate for subjects in the roxadustat group - hemoglobin 
responder rate for subjects in the Epoetin group > -15%.   
 
A 2-sided 95% confidence interval for the difference of 2 responder rates (roxadustat – ESA) 
based on the Miettinen & Nurminen approach adjusting for treatment group and stratification 
factors will be calculated and non-inferiority will be declared if the lower bound of the 95% 
CI is greater than -15%. 
 
Subjects who dropped out from the study before week 28 will be treated as non-responder. 
 
 
11.2.2.2 Change from Baseline in LDL Cholesterol Averaged over Weeks 12 to 28     
The change from baseline in LDL cholesterol will be analyzed and compared between the 2 
treatment groups using MMRM model with baseline LDL cholesterol as a covariate and 
treatment group, visit, the interaction of treatment and visit, and the above mentioned  
stratification factors as fixed effects. The same strategy as that used in MMRM for Hb will be 
used to choose variance covariance structure. Data up to visit of Week 52 will be included in 
the model. The estimates for difference of LDL Cholesterol averaged over Weeks 12 to 28 
between the two treatments groups will be generated from an estimate statement from Visit 
Week 12 to 28. Superiority will be declared if the upper bound of the 2-sided 95% confidence 
interval of the difference between roxadustat and active control does not exceed 0.  
 
Baseline, LDL, is defined as the last available value obtained prior to the first dose of study 
drug. 
 
11.2.2.3 Hemoglobin change from baseline to the average level during the Week 18 to 
24 for Subjects with CRP > ULN 
Change from baseline in Hemoglobin from baseline to the average level during the Week 18 
to 24 will be analyzed using the ANCOVA MI as the primary endpoints. Both Non-
inferiority of roxadustat vs. Epoetin and superiority will be tested. The non-inferiority margin 
is fixed as a difference of -0.75. 
 


 
 
 
 
FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
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Confidential and Proprietary 
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11.2.2.4  Average Monthly of IV Iron Use during Weeks 28 to 52. 
The average monthly IV iron use during Weeks 28 to 52 Treatment Period will be calculated 
for monthly intervals. The Treatment Period will be  divided in periods of 28 days and for 
each of these periods the monthly mean of IV iron will be calculated using the following 
formula:  
 
Monthly iron use for each subject = Total IV iron in mg / [(last visit date – first dose date of 
study medication +1)/ 28] 
 
The average monthly iron use will be compared between the 2 treatment groups using An 
ANCOVA model with baseline iron repletion status, treatment group, andstratification factors 
as fixed effects. Superiority will be declared if the lower bound of the 2-sided 95% 
confidence interval of the difference between active control and roxadustat exceeds 0.  
 
11.2.2.5 Time to first RBC Transfusion  
Time to the first RBC transfusion during treatment will be analyzed and compared between 
the 2 treatment groups using the Cox Proportional Hazards model adjusting for baseline Hb, 
treatment group and stratification factors.  
 
Non-inferiority of roxadustat vs. Epoetin will be declared if the upper bound of the 2-sided 
95% confidence interval of the hazard ratio is less than 1.8 and superiority.  
 
11.2.2.6 Mean change in pre-dialysis mean arterial pressure (MAP) averaged over 
Weeks 20-28 
Mean Arterial Pressure (MAP) will be calculated for each subject using the following 
formula:   
MAP = (2/3) * DBP + (1/3) SBP.  
Mean change from baseline in MAP will be analyzed and compared between the 2 treatment 
groups using an MMRM model with baseline MAP as a covariate, treatment group, visit, the 
interaction of treatment and visit, and stratification factors as fixed effects. The same strategy 
as that used in MMRM for Hb will be used to choose variance covariance Structure. Data up 
to visit of Week 52 will be included in the analyses. The estimates for difference of mean 
change from baseline in MAP for Week 20 to 28 between two treatment groups will be 
generated from an estimate statement. Superiority will be declared if the upper bound of the 
2-sided 95% confidence interval of the difference between roxadustat and Epoetin 
(roxadustat – Epoetin) is below 0. 
 
11.2.2.7 Blood pressure increase 
• Time to first exacerbation of hypertension During Weeks 28 to 52 
 
Time to first exacerbation during weeks 28 to 52 will be analyzed and compared between the 
2 treatment groups using the Cox Proportional Hazards model adjusting for treatment group 
and stratification factors.  
 
Superiority of roxadustat vs. Epoetin will be declared if the upper bound of the 2-sided 95% 
confidence interval of the hazard ratio is less than 1.  
 


 
 
 
 
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Confidential and Proprietary 
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Subjects will be censored at the time of the last available blood pressure if an exacerbation in 
blood pressure does not occur.  
 
Sensitivity analysis will be performed on proportion of subjects with increase in blood 
pressure at any time during the study, 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.  Increases from baseline in blood pressure are considered as confirmed 
by taking the mean of triplicates.  The proportion of subjects with increase in blood pressure 
will be compared between the 2 treatment groups using logistic regression model adjusting 
for baseline predialysis systolic and diastolic BP as covariates and treatment group and 
stratification factors as fixed effects. 
 
11.2.3 Secondary Analyses 
 
The proportion of subjects who achieve a hemoglobin response may also be analyzed using 
logistic regression test and including baseline hemoglobin and stratification factors except mean 
qualifying screening hemoglobin (≤ 10.5 vs. >10.5 g/dL). The odds ratio (ROXADUSTAT vs. 
EPO) and its 95% confidence interval will be provided. . The non-inferiority margin is fixed as 
a difference of -0.15. 
 
 
11.3 Additional Efficacy Analyses 
 
11.3.1 Hemoglobin Maintenance 
 
11.3.1.1 Hemoglobin long-term Maintenance 
Hemoglobin long-term maintenance will be assessed by: 
• Mean change in hemoglobin averaged over 8 weeks of treatment at Weeks 44-52 
without rescue therapy within 6 weeks prior to and during this 8-week evaluation 
period.  
• Mean change in hemoglobin averaged over the Week 96- 104 of treatment without 
rescue therapy within 6 weeks prior to and during this 8-week evaluation period.   
• Change in hemoglobin at each of the selected post-dosing time points 
• Proportion of subjects with hemoglobin >= 10 g/dL averaged over 36 to 44, 44 to 52, 
and the Week 96- 104 without rescue therapy within 6 weeks prior to and during this 
8-week evaluation period.   
• Proportion of subjects with hemoglobin within 10-12 g/dL averaged over 36 to 44, 44 
to 52, and the Week 96- 104 without rescue therapy within 6 weeks prior to and 
during this 8-week evaluation period.   
• Hb response during Weeks 28 and 36 regardless of use of rescue therapy 
• Hb change from BL to the average Hb value of Weeks 28 to 36, 44 to 52, and  96 to 
104 of treatment regardless of the use of rescue therapy 
 
The change in hemoglobin, will be analyzed using MMRM model with baseline hemoglobin 
as a covariate, treatment group, visit, the interaction of treatment and visit, and stratification 
factors except mean qualifying screening hemoglobin (≤ 10.5 vs. >10.5 g/dL) as factors.. The 
same strategy as that used in MMRM in Section 11.1.2.1 will be used to choose variance 
covariance. Data up to visit of Week 52 will be included in the analyses. The estimates for 


 
 
 
 
FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
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the difference of change from baseline in Hemoglobin for Week 28 to 36 and 44 to 52 
between the two treatment groups will be generated from an estimate statement. The mean 
change in Hb averaged over 8 weeks of treatment at Weeks 96-104 will be analyzed using the 
MI analyses as the one for the primary efficacy endpoint of US-submission.  
 
The proportion of subjects with hemoglobin within 10-11 g/dL in US and 10-12 g/dL in Ex-
US will be analyzed using logistic regression model including baseline hemoglobin as a 
covariate and treatment group and stratification factors except mean qualifying screening 
hemoglobin (≤ 10.5 vs. >10.5 g/dL) as fixed effects.  
 
Hemoglobin change from baseline to the average hemoglobin value of the Week 96 to 104 
weeks of treatment will be analyzed using an MI ANCOVA model with baseline hemoglobin 
as a covariate, and treatment group and stratification factors except mean qualifying 
screening hemoglobin (≤ 10.5 vs. >10.5 g/dL) as fixed effects, using the Hb mean from the 
non-missing weeks. 
In this study, there are patients in whom roxadustat dose frequency needed to be reduced to 
BIW or QW as part of their dose reduction below the lowest possible TIW dose of 20 mg 
TIW during treatment, to evaluate Hb maintenance, the following summary will be provided 
for these subgroups of subjects treated on BIW or QW (including any frequency <QW) for 
longer than 8 weeks (i.e., >=56 days): 
• Average Hb values over time for every 4-8 weeks after the initiation of BIW or QW 
• Average weekly dose over time for every 4-8 weeks after the initiation of BIW or QW 
 
 
11.3.2 Hospitalizations  
Hospitalizations are collected in the Hospitalization Records Form of the eCRF. For each 
subject, an entry will be recorded for each hospitalization. The days of hospitalization will be 
calculated as the sum of all hospitalizations durations in days (Date of discharge – Date of 
Admission + 1). In case of missing dates, the hospitalization duration will be assumed to be 5 
days. 
Only hospitalizations with admission dates that occur during the Treatment Period and up to 
7 days after the last study medication date will be taken into account.  
 
The following hospitalization-related data will be analyzed and compared between the 2 
treatment groups: 
• Time to first hospitalization (% of subjects) up to Week 52, 7 days after last dose.   
• Time to first hospitalization or skilled nursing facility (% of subjects) up to Week 52, 
7 days after last dose.  
• Number of days of hospitalizations 
• Number of days of medical-facility 
• Number of days of hospitalizations per patient-exposure year (PEY).  
• Number of days in hospital or skilled nursing facility per patient-year exposure 
(PEY).  
• Number of days of medical-facility (hospital, skilled nursing facility, emergency 
room, or overnight observation) per subject-exposure year (PEY).  
• Number of days on treatment out of hospital and skilled nursing facility up to Week 
52, 7 days after Last Dose.  


 
 
 
 
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Confidential and Proprietary 
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Note: Sensitivity analysis may be performed by excluding elective procedures using only 
hospitalization due to AE 
The time to hospitalization event will be compared between the two treatment groups using 
cox model including baseline stratification factors. The proportion of subjects hospitalized 
will be compared between the 2 treatment groups using logistic regression model and 
stratified by the baseline stratification factors.  The mean number of days of hospitalization 
will be analyzed and compared between the 2 treatment groups using the Mantel-Haenszel 
mean score test adjusting for stratification factors. 
 
11.3.3 Missed Dialyses 
Only missed dialyses (defined as a dialysis session that was planned but not received at the 
patient’s usual outpatient dialysis center) with starting dates that occur during the Treatment 
Period and up to 7 days after the last study medication date will be taken into account. The 
days of missed dialysis will be calculated as the sum of all missed dialyses in days (# of 
missed dialysis/weekly prescribed dialysis frequency* 7), where weekly prescribed dialysis is 
TIW in this study. 
 
The following missed dialysis-related data will be analyzed and compared between the 2 
treatment groups: 
• Occurrence (number) of missed dialyses. The number of missed dialysis for each 
subject will be collected. The mean number of missed dialysis will be analyzed and 
compared between the 2 treatment groups using the Mantel-Haenszel mean score test 
adjusting for stratification factors.  
• Proportion of subjects who has missed dialyses. The proportion of subjects with 
missed dialysis will be compared between the 2 treatment groups using CMH model 
adjusting for stratification factors.  
• Number of days of missed dialyses per subject-exposure year (PEY). The number of 
days of Missed Dialysis for each subject will be calculated. The mean number of days 
of Missed Dialysis will be analyzed and compared between the 2 treatment groups 
using the Mantel-Haenszel mean score test adjusting for stratification factors. 
 
 
11.3.3.1 Red Blood Cell Transfusion 
For a subject receiving RBC or whole blood transfusion, the Time at Risk (time up to first 
use) will be calculated (in years) as: 
 (First use of transfusion date – First dose date of study medication + 1) / 365.25 
For a subject not receiving transfusion, the Time at Risk (time until they get censored) is 
calculated as:  
(Date of last study medication – First dose date of study medication + 1) / 365.25 
The red blood cell transfusion form of the eCRF in the cumulative visit will be used to derive 
the number of RBC packs. The number of RBC units is collected in this form. For 
transfusions where the number of units is not given but the volume transfused is given, the 
number of units will be estimated by dividing the volume transfused by 250 mL (for 
transfusion of packed cells) or by dividing the volume transfused by 500 mL (for transfusion 
of whole blood).   
The total number of RBC units/packs during the Treatment Period is calculated for each 
subject by the sum of the transfused units between the Analysis Date of First Dose and up to 
the Analysis Date of Last Dose. The following 2 endpoints will be analyzed: 


 
 
 
 
FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
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Confidential and Proprietary 
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• Proportion of subjects who receive RBC transfusions. The proportion of subjects who 
received RBC transfusion will be compared between the 2 treatments using logistic 
regression model adjusting for baseline hemoglobin as covariate and treatment group 
and stratification factors as fixed effects.   
• Number of RBC packs per subject-month exposure to study medication. The mean 
number of RBC packs will be compared between the 2 treatment groups using 
ANCOVA model adjusting for baseline hemoglobin as covariate, treatment group, 
and stratification factors as fixed effects. 
 
11.3.3.2 ESA Usage in roxadustat patients  
For roxadustat subjects, ESA use will be recorded in the CRFs. The total number of ESA-
week dose per subject will be calculated and listed. 
When ESA dose were needed in the EPO arm, such dose will be captured as dose change of 
study drug. If another ESA were used in addition, it too will be summarized separately from 
roxadustat patients.  
For each entry that meets the criteria below the ESA-week will be calculated as follows: 
o If drug is epoetin alfa, epoetin beta, or an epoetin biosimilar (ATC code: B03XA01), 
then  ESA-Weeks = (stop date – start date + 1) / 7; 
o If drug is darbepoetin SQ or IV dose (ATC code: B03XA02), then  ESA-Weeks =  2 x 
(stop date – start date + 1) / 7;  
o If drug is Mircera IV or SQ dose (ATC code: B03XA03), then ESA-Weeks = 4 x 
(stop date – start date + 1) / 7.  
The total number of ESA-week during the Treatment Period is calculated for each subject by 
the sum of the ESA-week between the analysis date of first dose and the analysis date of last 
dose for roxadustat only. 
 
 
11.3.3.3 Use of Iron 
 
IV Iron  
Only IV iron therapy that started during the study treatment and up to the ET/EOT Visit will 
be taken into account for the total amount. 
 
The average monthly IV iron use during weeks 53 to EOS will be calculated for monthly 
intervals. The Treatment Period will be divided in periods of 28 days and for each of these 
periods the monthly mean of IV iron will be used using the following formula:  
Monthly iron use for each subject = Total IV iron in mg / [(last visit date – first dose date of 
study medication in the period+1)/ 28] 
 
The following 2 endpoints will be analyzed: 
• Proportion of subjects who receive IV iron. The proportion of subjects who received 
IV iron will be compared between the 2 treatments using logistic regression model 
adjusting for baseline iron repletion status and treatment group and stratification 
factors as fixed effects.  (This will be performed for week 1 to week 36 as well).  
• The average monthly iron use will be compared between the 2 treatment groups using 
ANCOVA model with baseline iron repletion status, and treatment group, and 
stratification factors as fixed effects.  
 
Oral iron 
 


 
 
 
 
FGCL-4592-064                                                                                                 Statistical Analysis Plan v1.0  
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The average monthly oral iron use during Weeks 28 to 52, and weeks 53 to ET/EOT will be 
calculated similarly to IV iron for monthly intervals.  
The following 2 endpoints will be analyzed: 
• Proportion of subjects who receive Oral iron. The proportion of subjects who received 
oral iron will be compared between the 2 treatment groups using logistic regression 
model adjusting for baseline iron repletion status, treatment group and stratification 
factors as fixed effects.   
• The average monthly oral iron use will be compared between the 2 treatment groups 
using ANCOVA model with baseline iron repletion status, treatment group, and 
stratification factors as fixed effects.  
 
In addition the proportion of subjects who received both IV and/or oral iron will be compared 
between the 2 treatments using logistic regression model adjusting for baseline iron repletion 
status and treatment group and stratification factors as fixed effects.   
 
11.3.4 Changes in Cholesterol Levels 
• Change at each of the selected scheduled testing timepoints  (Weeks 12-28, every 8 
weeks onward until Week 52) from baseline in:  
o Total cholesterol,  
o Low-density lipoprotein/high-density lipoprotein ratio, 
o Non-HDL cholesterol. 
The mean change in these 3 parameters at each post-dosing time point from baseline 
will be analyzed and compared between the 2 treatment groups using MMRM model 
adjusting baseline value as covariate, treatment group, visit, the interaction of 
treatment and visit, and stratification factors as fixed effects. The same strategy as that 
used in MMRM for Hb will be used to choose variance covariance structure. 
• Proportion of subjects achieving LDL target of <100 mg/dL averaged over Weeks 12-
28 of treatment for Subjects with Baseline LDL >= 100 mg/dL. The proportion of 
subjects achieving LDL target will be compared between the 2 treatment groups using 
logistic regression model adjusting for baseline LDL as covariate and treatment group 
and stratification factors as fixed effects. 
 
11.3.5 Blood Pressure Effect 
• 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 12-28. The proportion of subjects achieving blood pressure goal will be 
compared between the 2 treatment groups using logistic regression model adjusting 
for baseline pre dialysis systolic and diastolic BP as covariates and treatment group 
and stratification factors as fixed effects.  
• Time to a treatment-emergent AE (TEAE) of hypertension. Time to a TEAE of 
hypertension will be analyzed using the Cox Proportional Hazards model adjusting 
for treatment group and stratification factors as fixed effects. 
• Time to exacerbation from baseline of antihypertensive therapy. Time to 
intensification from baseline of antihypertensive therapy will be analyzed using the 
Cox Proportional Hazards model adjusting for treatment group and stratification 
factors. 
Subject with exacerbation of hypertension is defined as meeting at least 1 of the following 
criteria: 


 
 
 
 
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• An increase from baseline of ≥ 20 mmHg predialysis systolic BP (sBP) and 
predialysis SBP >170 mmHg, or  
• An Increase from baseline of ≥ 15 mmHg predialysis diastolic BP (dBP) and 
predialysis DBP >100 mmHg 
• Proportion of subjects with a treatment-emergent AE of hypertension. The proportion 
of subjects with a TEAE of hypertension will be compared between the 2 treatment 
groups using logistic regression model adjusting for baseline predialysis systolic and 
diastolic BP as covariates and treatment group and stratification factors as fixed 
effects. 
• Proportion of subjects with exacerbation from baseline of antihypertensive therapy. 
The proportion of subjects with exacerbation from baseline of antihypertensive 
therapy will be compared between the 2 treatment groups using logistic regression 
model adjusting for baseline predialysis systolic and diastolic BP as covariates and 
treatment group and stratification factors as fixed effects. 
 
11.3.6 Vascular Access Thrombosis (HD subjects): 
• Time to a TEAE of vascular access thrombosis will be analyzed using the Cox 
Proportional Hazards model adjusting for treatment group and stratification factors. 
• Proportion of subjects with a TEAE of vascular access thrombosis will be analyzed 
using CMH model adjusting for treatment group and stratification factors. 
 
11.3.7 Health Related Quality of Life (HRQoL) and 
EQ-5D-5L Benefits of Anemia Therapy 
The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) is a multi-purpose, 
short-form health survey with 36 questions (Appendix 3). It yields an 8-scale profile of 
functional health and well-being scores as well as psychometrically-based physical and 
mental health summary measures. It is a generic measure, as opposed to one that targets a 
specific age, disease, or treatment group. Accordingly, the SF-36 has proven useful in 
surveys of general and specific populations, comparing the relative burden of diseases, and in 
differentiating the health benefits produced by a wide range of different treatments. 
The SF-36 contains 36 items that measure eight dimensions: (1) physical functioning (PF); 
(2) role limitations due to physical health problems (RP); (3) bodily pain (BP); (4) social 
functioning (SF); (5) general health perceptions (GH); (6) role limitations due to emotional 
problems (RE); (7) vitality, energy or fatigue (VT); and (8) mental health (MH). 
Item scores for each dimension are coded, summed, and transformed to a scale from 0 to 100, 
with higher scores indicating better self-perceived health (Table 7. The transformed items are 
then averaged to give the subscales. The subscales are averaged to give the composite scores. 
The composite scores are averaged to give the overall score. The reliability and validity of the 
SF-36 is well documented in a variety of different subject groups, including subjects with 
vascular diseases.  
 
Table 7. 
Transformation of SF-36 items to a Scale from 0 to 100 
Question 
Self-perceived health 


 
 
 
 
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0 (Poor) 
100 (Better) 
1, 2, 6, 8, 9a, 9d, 9e, 9h, 11b, 11d 
5 
1 
3a to 3j 
1 
3 
4a to 4d, 5a to 5c, 9b, 9c, 9f, 9g, 9i, 10, 11a, 11c 
1 
5 
7 
6 
1 
Programming note: Once transformed – the items should each span the range 0 to 100. 
 
For each of the 8 dimensions, if less than 50% of the items which constitute that dimension 
are missing, the dimension score will be calculated by the mean of the available non-missing 
items. The physical health composite summary and mental health composite summary will 
only be calculated if a score has been calculated for all 4 dimensions that constitute the 
composite summary.  
 


 
 
 
 
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Figure 3.  SF-36 Model 
 
 


 
 
 
 
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 The mean change from baseline at weeks 12, 28, and 52 weeks will be computed for each 
treatment group for the following endpoints. A paired t-test will be used to assess within 
treatment effect. Between treatment difference will be assessed using MMRM using baseline 
subscore as a covariate and treatment group, visit, the interaction of treatment and visit, and 
stratification factors as fixed effects. The same strategy as that used in MMRM for Hb will be 
used to choose variance covariance structure. Non-inferiority of roxadustat vs. Epoetin will 
be tested. The non-inferiority margin is fixed as a difference of 2 points. 
Mean change in these endpoints at above-mentioned time points will be analyzed and 
compared between the 2 treatment groups using MMRM using the baseline value as a 
covariate, treatment group, visit, the interaction of treatment and visit, adjusting for the 
stratification factors. The same strategy as that used in MMRM for Hb will be used to choose 
variance covariance structure. Other than below endpoints for exploratory analyses, other 
QoL variables may be performed. 
 
HRQoL benefit will be assessed using SF-36 vitality and physical functioning subscales 
 
• 
Change from Baseline in SF-36 Vitality (VT) Sub-Score 
The change from baseline in SF-36 VT sub-score to the average VT sub-score will be 
analyzed using MMRM with baseline VT subscore as a covariate and treatment group, visit, 
the interaction of treatment and visit, and stratification factors as fixed effects. The same 
strategy as that used in MMRM for Hb will be used to choose variance covariance structure. 
Data up to visit of Week 52 will be included in the analyses. The estimates for the difference 
of change from baseline in SF-36 VT for Week 12 to 28 between two treatment groups will 
be generated from an estimate statement. Non-inferiority of roxadustat vs. Epoetin will be 
tested.  
 
• 
Change from Baseline in SF-36 Physical Functioning (PF) Sub-Score 
Change from baseline in SF-36 PF sub-score to the average PF sub-score of weeks 12 to 28 
will be analyzed using MMRM model with baseline PF subscore as a covariate, treatment 
group, visit, the interaction of treatment and visit, and stratification factors as fixed effects. 
The same strategy as that used in MMRM for Hb will be used to choose variance covariance 
structure. Data up to visit of Week 52 will be included in the analyses. The estimates for the 
difference of change from baseline in SF-36 PF for Week 12 to 28 between the two treatment 
groups will be generated from an estimate statement.  
 
• Vitality Sub-score of SF-36: In subjects with baseline vitality sub-score below 50. 
• Physical Functioning Sub-scores of SF-36: 
o In FAS subjects with baseline physical Functioning scores below 40.  
o In all FAS subjects. 
• Anemia Subscale (“Additional Concerns”) of Functional Assessment of Cancer 
Therapy-Anemia (FACT-An) Scores:  
o In FAS subjects with baseline subscale scores below 55 (generally 
associated with fatigue).  
o In all FAS subjects. 
• Total FACT-An Scores: 
o In FAS subjects with baseline FACT-An scores below 135 
o In all FAS subjects. 
• EQ-5D-5L Scores: In all FAS subjects. 
 


 
 
 
 
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11.3.8 Hepcidin, Iron, and HbA1c 
The mean change from baseline in the following endpoints will be analyzed using MMRM 
model with baseline value as a covariate, treatment group, visit, the interaction of treatment 
and visit, and stratification factors as factors. The same strategy as that used in MMRM for 
Hb will be used to choose variance covariance structure 
 
• Change in serum hepcidin at each of the selected time points during which tested, 
weeks 4, 12, 20, 36, and 52. 
• Change in serum ferritin at each of the selected time points it was tested, week 4, 8, 
12, 20, 28, 36, 44 and 52, total and sub-grouped by baseline values of <100 ng/mL, 
100 to 400 ng/mL, and >=400 ng/mL. 
• Change in TSAT at each of the selected time points, week 4, 8, 12, 20, 28, 36, 44 and 
52, total and sub-grouped by baseline values of < 20%, 20 to 40, and >=40%. 
• Change in HbA1c level at each of the selected time points, week 12, 24, 36and 52, in 
subjects without history of diabetes, in subjects with history of diabetes.  
 


 
 
 
 
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12 SAFETY ANALYSES 
The safety analysis will be performed using the Safety Population.  
For US regulatory submission, safety analyses will be based on all patients overall and 
stratified by stable dialysis and newly initiated dialysis,  
 
Safety parameters include adverse events, laboratory parameters, vital signs, ECG 
parameters, and physical examinations.  
 
The cardiovascular safety assessment of roxadustat will also be based on pooled analysis of 
composites of adjudicated cardiovascular events pooled across multiple global Phase 3 
clinical studies which includes this study, according to the pooled SAPs for meeting regional 
regulatory requirements. 
 
For each safety parameter, the last assessment made prior to the first dose of study 
medication will be used as the BL for all analyses of that safety parameter. 
 
12.1 Adverse Events 
Adverse events will be coded using the latest MedDRA version. An AE (classified by 
preferred term) started during the Treatment Period will be considered a treatment-emergent 
adverse event (TEAE) if it was not present prior to the first dose of study medication, or it 
was present prior to the first dose of study medication but increased in severity during the 
Treatment Period up to 7days after last dose of study drug or until the administration of 
another anemia drug (other than the randomized treatment). An AE that occurs more than 7 
days after study medication or after the administration of another anemia drug (other than the 
randomized treatment) 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 to study medication. 
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 distribution of TEAEs by severity and relationship to study medication will be 
summarized by treatment group. 
 
The incidence of common (≥ 5% of subjects in any treatment group) TEAEs, treatment-
emergent serious AEs (TESAE), and AEs leading to discontinuation of study medication will 
be summarized by SOC, preferred term and treatment group, sorted in decreasing frequency 
for the test treatment. In addition, the incidence of death and fatal SAEs (i.e., events that 
caused death) will be summarized separately by treatment group, SOC and preferred term.  
Treatment emergent adverse events of interest will also be reported in terms of incidence rate 
per Patient Exposure Year (PEY). 
 
Discontinuation of study medication due to worsening anemia based on hemoglobin value 
(lack of efficacy) will not be counted under AEs leading to discontinuation.   
Listings will be presented of subjects with serious adverse events (SAEs), subjects with 
adverse events leading to discontinuation, and subjects who died. 
 


 
 
 
 
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Temporal profile of TEAEs of special interest may also be plotted by treatment group 
showing the subjects in the y-axis and time to these TEAEs in the x-axis (Appendix 8). 
12.2 Clinical Laboratory Parameters 
Descriptive statistics for laboratory values (in US conventional and SI units) and changes 
from baseline at each assessment time point will be presented by treatment group for the 
following laboratory parameters collected in the study including but are not limited to the 
following: 
• Hematology: Hemoglobin, hematocrit, RBC count, MCV, WBC count, WBC 
differential, and platelet counts, reticulocyte count; 
• Chemistry: Alkaline phosphatase, ALT, AST, GGT, total bilirubin, LDH, lipase, total 
protein, albumin, fasting glucose, phosphate, uric acid, BUN, creatinine, sodium, and 
potassium;  
• Serum iron, ferritin, TIBC, TSAT, reticulocyte hemoglobin content  
• HbA1c 
• Hepcidin, high-sensitivity C-reactive protein (hs-CRP) 
Laboratory tests values are clinically significant (CS) if they meet either the low or high CS 
criteria (Appendix 6). The number and percentage of subjects with post-baseline CS values 
will be tabulated by treatment group. The percentages are to be calculated relative to the 
number of subjects with available non-CS baseline values and at least one post-baseline 
assessment. The numerator is the total number of subjects with at least one post-baseline CS 
value. In addition, shift tables will be presented by treatment group and time point. The 
following 3 data listings will be presented by subject: 
• A listing of lab values for all lab tests at all collected time points. 
• A listing of subjects with post-baseline CS values will be provided including the 
baseline and post-baseline values. 
• A listing of all AEs for subjects with CS laboratory values will also be provided. 
 
12.3 Vital Signs 
Blood pressures and heart rate baselines for predialysis are defined as the mean of values 
obtained from the last 6 weeks of screening including Day 1 prior to the first dose. 
Descriptive statistics for vital signs (e.g., systolic and diastolic blood pressure, MAP, pulse 
rate, and respiratory rate) and their changes from baseline at each visit and at the end of study 
will be presented by treatment group. 
Vital sign values are potentially clinically significant (PCS) if they meet both the observed 
value criteria and the change from baseline criteria listed in Table 8. The number and 
percentage of subjects with post-baseline PCS values will be tabulated by treatment group. 
The percentages are to be calculated relative to the number of subjects with baseline and at 
least one post-baseline assessment. The numerator is the total number of subjects with at least 
one post-baseline PCS vital sign value. Shift tables may be presented. A supportive listing of 
subjects with post-baseline PCS values will be provided including the subject ID, study 
center, baseline, and post-baseline values. A listing of all AEs for subjects with PCS vital 
signs will also be provided. 
 
Table 8. 
Criteria for Potentially Clinically Significant Vital Signs 
Vital Sign 
Parameter 
Flag 
Criteria* 
Observed Value 
Change from Baseline 
Systolic Blood 
Pressure (mmHg) 
High 
≥ 170 
Increase of  ≥ 20 
Low 
≤   90 
Decrease of ≥ 20 


 
 
 
 
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Diastolic Blood 
Pressure (mmHg) 
High 
≥ 100 
Increase of ≥ 15 
Low 
≤   50 
 
Decrease of ≥ 15 
Pulse Rate 
(bpm) 
High 
≥ 120 
Increase of ≥ 20 
Low 
≤   50 
Decrease of ≥ 20 
Weight 
(kg) 
High 
- 
Increase of ≥ 10% 
Low 
- 
Decrease of ≥ 10% 
*A post-baseline predialysis value is considered as a PCS value if it meets both criteria for 
observed value and change from predialysis baseline, respectively. 
Additional analyses include but are not limited to  
• Subgroup analyses of subjects without any change in BP meds during Treatment 
Period 
• Proportion of subjects meeting National Kidney Foundation BP target: within sBP 
120-140 mmHg/dBP 70-90 mmHg at baseline, during treatment, and 4 weeks post 
treatment 
 
12.4 Electrocardiogram (ECG) 
Descriptive statistics for ECG parameters (e.g., Heart Rate, 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. QTc interval will be calculated using both Bazett 
(QTcB = QT/ (RR)1/2) and Fridericia (QTcF = QT/(RR)1/3) corrections; and if RR is not 
available, it will be replaced with 60/HR in the correction formula.  
 
A plot for each parameter of mean (+/- 95% CI) versus visit will be produced by treatment 
group (roxadustat vs. Epoetin).   
 
ECG parameters values are potentially clinically significant (PCS) if they meet or exceed the 
upper limit values listed in Table 9. The number and percentage of subjects with post-
baseline PCS values will be tabulated by treatment group. The percentages are to be 
calculated relative to the number of subjects with available non-PCS baseline and at least one 
post-baseline assessment. The numerator is the total number of subjects with at least one 
post-baseline PCS ECG value. Shift tables may be presented. A listing for all subjects with 
post-baseline PCS value will be provided including the subject ID, study center, baseline, and 
post-baseline PCS values.  
 
In addition, a listing of all TEAEs for subjects with PCS ECG values and a listing of subjects 
with post-baseline significant ECG abnormalities as reported by the investigators will also be 
provided. 


 
 
 
 
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FibroGen, Inc. 
Confidential and Proprietary 
Page 54 of 84 
 
 
Table 9. 
Criteria for Potentially Clinically Significant ECG 
ECG Parameter 
Unit 
Higher Limit 
QRS interval 
Msec 
≥ 150 
PR interval 
Msec 
≥ 250 
QTc interval 
Msec 
> 500;  
Change from baseline > 60 
12.5 Other Safety Analyses 
A separate meta-analysis SAP for pre-specified, adjudicated (blinded) composite safety 
endpoints to assess cardiovascular, cerebrovascular and thrombo-embolic events will be 
developed to complement this study specific SAP. 


 
 
 
 
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Confidential and Proprietary 
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13 ADDITIONAL AND SUBGROUP ANALYSES 
Selected efficacy and safety analyses may be performed separately by sex, age group, 
baseline iron replete status and baseline stratification factors. 


 
 
 
 
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FibroGen, Inc. 
Confidential and Proprietary 
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14 INTERIM ANALYSES 
 
Safety data and dosing decisions will be monitored on an ongoing basis. Additional ongoing 
review of safety data will be conducted by an independent data and safety monitoring board 
(DSMB). 
 


 
 
 
 
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FibroGen, Inc. 
Confidential and Proprietary 
Page 57 of 84 
 
 
15 REFERENCES 
ICH Harmonized Tripartite Guideline E3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics) 
 
ICH Harmonized Tripartite Guideline E9. Statistical Principles for Clinical Trials, February 
1998. (www.ich.org; Guidelines; "Efficacy" Topics) 
Carpenter JR, Roge JH and Kenward MG, Analysis of longitudinal trials with protocol 
deviation:|a Framework for Relevant, Accessible Assumptions, and Inference via Multiple 
Imputation. Journal of Biopharmaceutical Statistics, issue 6 (November/December) in volume 
23 (2013). 1352-137 
Cella, D. The functional assessment of Cancer Therapy-Anemia (FACT-An) Scale: A new 
tool for the assessment of outcome in cancer anemia and fatigue. Hematology Seminars 
1997; 34: 13-19  
 
Ge M, Durham LK, Meyer RD, Xie W and Thomas N. Covariate-Adjusted Difference in 
Proportions from Clinical Trials Using Logistic Regression and Weighted Risk 
Differences. Drug Information Journal 2011 45: 481 
 
Haybittle, J. L. (1971), “Repeated Assessment of Results in Clinical Trials of Cancer 
Treatment,” British Journal of Radiology, 44, 793-797.  
 
Peto, R., Pike, M. C., Armitage, P., Breslow, N. E., Cox, D. R., Howard, S. V., Mantel, N., 
McPherson, K., Peto, J., and Smith, P. G. (1976), “Design and Analysis of Randomized 
Clinical Trials Requiring Prolonged Observation of Each Patient: I. Introduction and 
Design,” British Journal of Cancer, 34, 585-612.  
 
FDA Guidance for Industry Non-Inferiority Clinical Trials, 2010 
(http://www.fda.gov/downloads/Drugs/Guidances/UCM202140.pdf).  
 
Little RJA, Rubin D.1987. Statistical Analysis with Missing Data. John Wiley and Sons. 
 
Ratitch B, Kelly M 2011. Implementation of Pattern-Mixture Models Using Standard 
SAS/STAT Procedures, PharmaSUG2011 – Paper SP4. 
Rubin, D. B. (1987) Multiple imputation for nonresponse in surveys. New York: Wiley. 
Schafer, J. L. (1997) Analysis of incomplete multivariate data. London: Chapman and Hall. 
 


 
 
 
 
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16 APPENDICES 


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16.1 Appendix 1 
Schedule of Assessments  
Study Period: 
Screening (up 
to 6 to 8 Wks a) 
Treatment Period (≥ 52 Wks) 
Follow-up 
Period (4 Wks) 
Unscheduled Visit 
Visits: 
S1 
S2 
S3 
Day 1 b 
± 2 days  
± 4 days  
± 4 days 
± 7 days 
 ±7 days 
Weekly 
(Wks 1-2) 
Every 2 Wks 
(Wks 4-24) 
Every 4 Wks 
(from Wk 28) 
EOT/ET 
EOS 
(EOT/ET 
+4 wks) c 
1 
2 
Written ICF 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Height (screening only), 
weight (dry weight [post 
dialysis] in HD subjects)  
X 
 
 
X 
 
 
 
Wks 36, 52 + every 24 wks 
X 
X 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
X 
 
X 
 
 
Wks 12 d, 24 d 
Wks 36 d, 52 d + every 24 wks d 
X 
X d 
O 
Vital Signs: BP e, HR e, 
RR f, Temp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Local hemoglobin 
Assessments  
 
 
 
 
X 
X 
X 
X 
X 
 
X 
CBC with WBC diff  
X 
 
 
X 
X 
X 
Wks 4, 8, 12, 20 
Wks 28, 36, 44 + every 8 wks 
X 
X 
O 
Hemoglobin g 
 
X 
X 
 
 
 
X g 
X g 
 
 
X 
Reticulocyte count and 
CHr 
X 
 
 
X 
X 
X 
Wks 4, 6, 8, 12, 16, 20 
Wks 28, 36, 52 + every 16 wks 
X 
X 
O 
12-lead ECG  
 
 
 
X 
 
 
Wk 24 
Wks 36, 52 + every 24 wks 
X 
 
O 
Renal ultrasound h 
 
X 
 
 
 
 
 
 
 
 
Serum chemistry 
X 
 
 
X 
 
 
Wks 4, 8, 12, 20 
Wks 28, 36, 44 + every 8 wks 
X 
X 
O 
LFTs 
 
 
 
 
 
X 
Wks 6, 16, 24 
Wk 32 
 
 
O 
Serum Lipid panel 
X 
 
 
X 
 
 
Wks 4, 8, 12, 20  
Wks 28, 36, 48 + every 12 wks 
X 
X 
O 
Serum iron, ferritin, TIBC, 
UIBC, TSAT 
X 
 
 
X 
 
 
Wks 4, 8, 12, 20 
Wks 28, 36, 44 + every 8 wks 
X 
X 
O 
HbA1c 
X 
 
 
X 
 
 
Wks 12, 24 
Wks 36, 52 + every 52 wks 
X 
X 
O 
Vitamin B12, folate 
X 
 
 
 
 
 
 
 
 
 
 
HIV ELISA, HBsAg, 
anti-Hcardiovascular Ab 
X 
 
 
 
 
 
 
 
 
 
 
Serum (hCG) pregnancy 
test (every 12 weeks) i 
 
 
X 
 
 
 
Wks 12, 24 
Wks 36, 48 + every 12 wks 
X 
 
O 
hs-CRP, hepcidin 
 
 
 
X 
 
 
Wks 4, 12, 20 
Wks 36, 52 
X 
X 
 
Archival serum & plasma 
samples for biomarkers 
 
 
 
X 
 
 
Wks 4, 12, 20 
Wks 36, 52 + every 24 wks 
X 
X 
 
HRQoL Questionnaires j 
 
 
 
X 
 
 
Wks 12 
Wks 28, 52 
X 
 
 
Study drug: dispensing 
and/or accountability k 
 
 
 
X 
X 
X 
X 
X 
X 
 
 


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Study Period: 
Screening (up 
to 6 to 8 Wks a) 
Treatment Period (≥ 52 Wks) 
Follow-up 
Period (4 Wks) 
Unscheduled Visit 
Visits: 
S1 
S2 
S3 
Day 1 b 
± 2 days  
± 4 days  
± 4 days 
± 7 days 
 ±7 days 
Weekly 
(Wks 1-2) 
Every 2 Wks 
(Wks 4-24) 
Every 4 Wks 
(from Wk 28) 
EOT/ET 
EOS 
(EOT/ET 
+4 wks) c 
1 
2 
Dose adjustment review l 
 
 
 
 
X 
X 
X 
X 
 
 
 
AE and concomitant 
medication recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Procedure and nondrug 
therapy recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: 
Ab = antibody; AE = adverse event; BP = blood pressure; CBC = complete blood count; cHR = reticulocyte hemoglobin content; cardiovascular = cardiovascular; 
ECG = electrocardiogram; ELISA = enzyme-linked immunosorbent assay; EOT = End of Treatment; ET=Early Termination; EOS = End of Study; HbA1c = glycated 
hemoglobin; HBsAg = hepatitis B surface antigen; hCG = human chorionic gonadotropin; Hcardiovascular = 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; O = optional test/assessment; PE = physical examination; RBC = red blood cell; RR = respiratory rate; TIBC = total iron binding 
capacity; UIBC = unsaturated iron binding capacity; TSAT = transferrin saturation; WBC = white blood cells; Wk(s) = week(s); X = mandatory test/assessment. 
Notes: In subjects on HD, all lab sampling is to be performed prior to the dialysis session.  
Subjects who discontinue study medication prematurely will be followed up until the end of the study, unless consent to participate is withdrawn. Upon completion of EOT and EOS 
visits, these subjects will be followed up every 3-6 month interval for vital status, cardiovascular events, and hospitalization (depending on the availability of subjects) until study closure. 
These visits may occur either in-person or via telephone. 
a 
All screening procedures should be completed within 6 weeks. For subjects currently taking Mircera®, the screening period can be extended up to 8 weeks. 
b 
Day 1 is a due treatment date per the existing ESA treatment schedule. All study assessments are to be performed prior to first study drug administration. In subjects on HD study 
assessments with the exception of HRQoL and body-weight measurement should also be performed prior to or at initiation of dialysis; HRQoL assessments should be done 
approximately during dialysis (preferably at the beginning) and weight measurement after dialysis.  
c 
Subjects discontinuing study medication prematurely will complete EOT and EOS. Unless consent is withdrawn, cardiovascular events, vital status and hospitalizations will be 
collected every 3 to 6 months (phone or in-person clinic visit) for these subjects until study closure 
d 
Targeted PE (general appearance, CV, respiratory and abdomen) 
e 
BP and HR should be measured using automated calibrated instruments at pre dialysis in subjects on HD and preferably approximately at the same time in subjects on PD. 
Measurement to occur prior to study drug administration (if applicable); BP and HR should be assessed per guidelines provided in Appendix 5 
f 
Respiratory rate should be measured at predialysis in subjects on HD and preferably approximately at the same time in subjects on PD. Measurement should occur prior to study 
drug administration (if applicable) 
g 
Separate hemoglobin samples should be collected at all the visits where a CBC is not collected (i.e., hemoglobin at Weeks 6, 10, 14, 16, 18, 22, 24, 32, 40, 48, etc) 
h 
Not required if result of a renal ultrasound report within 12 weeks prior to randomization is available 
i 
Collect from female subjects of childbearing potential only 
j 
Including SF-36, FACT-An, EQ-5D 5L, HRQoL assessments should be administered approximately at the same time of the day. Example: in HD subjects, questionnaires to be 
completed by subject approximately at the same time during dialysis and in PD subjects approximately at the same time of the day  
k 
Initial dosing of roxadustat and epoetin alfa per Tables 1 and 2, respectively. Dose adjustment per Appendix 2 (roxadustat subjects) or epoetin package insert or SmPC (epoetin 
subjects); dose review for predefined out of range hemoglobin elevations at every visit. All subjects on HD will receive epoetin alfa TIW intravenously (IV). For peritoneal dialysis 
subjects, the route of administration (IV or SC) of epoetin alfa may remain the same as baseline (per discretion of the Investigator) 
l 
Subjects randomized to roxadustat: dose adjustment begins at Week 4 refer to Appendix 2 
Notes: In subjects on HD, all lab sampling is to be performed prior to the dialysis session. 
 
. 


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16.2 Appendix 2 
Roxadustat Dose Adjustment Rules  
Following Day 1, at each study visit during the Treatment Period, hemoglobin will be 
measured (prior to dialysis in HD subjects) locally to determine the need for a dose 
adjustment or to assess for predefined out of range hemoglobin elevations. This local 
hemoglobin measurement may be made with the use of a point-of-care device (e.g., 
HemoCue®, CritLine®) or by local laboratory (i.e., Stat Lab*) testing if the point-of-care 
device is not available or the result is considered unreliable. In the event that the hemoglobin 
value of the visit as determined by the study central laboratory is significantly different from 
that measured locally, and per Investigator that warrants a reversal of the dose adjustment 
decision made earlier based on locally measured hemoglobin value, the Medical Monitor 
should be informed, if possible.  
In this study, a rate of rise of hemoglobin > 2 g/dL in 4 weeks or a hemoglobin level of ≥ 13 
g/dl at any time would be considered as excessive haematopoiesis and would require either 
dose reduction or temporary dose hold. 
The dose of roxadustat will remain constant during the first 4 weeks of the Treatment Period 
unless a dose reduction is required for predefined out of range hemoglobin elevations.  
Roxadustat dose adjustments are permitted from Week 4 onwards, and every 4 weeks 
thereafter (e.g., Week 4, Week 8, Week 12); however, the dose may be adjusted between two 
prespecified windows (e.g., anytime between Week 4 and Week 8 visits, Week 8 and Week 
12 visits) if all of the following criteria are met: 
• No dose adjustment has been made in last 4 weeks 
• Hemoglobin < 9.0 g/dL.  
Any dose adjustment will reset the dose-adjustment window to every 4 weeks thereafter (e.g., 
dose adjustment for a qualified reason at Week 6 leads to next dose adjustment at Week 10). 
Dose adjustment must not be done sooner than 4 weeks unless discussed with and 
preapproved by the medical monitor. Dose adjustments for roxadustat are described in the 
Table 10 below.  
Subjects randomized to roxadustat will take doses TIW for the entire duration of the 
Treatment Period. Dosing frequency may only be adjusted to BIW or QW if a subject 
requires < 20 mg TIW (i.e., < 60 mg per week) to maintain a hemoglobin level of 
approximately 11 g/dL. The Medical Monitor should be notified as soon as possible of such 
dose change. 


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Table 10. Roxadustat Dose Adjustment Rules  
Change in 
hemoglobin 
over past 4 
weeks (g/dL) 
Hemoglobin (g/dL) at Dose Adjustment Review Visit 
< 10.5 
10.5 to 
< 12.0 
 12.0 to < 13.0 
≥ 13.0 
< -1.0 
↑ 
↑ 
No change 
Hold dosing, check 
hemoglobin at least weekly, 
then resume dosing when 
hemoglobin < 12.0 g/dL, at a 
dose that is reduced by one 
dose step 
-1.0 to 1.0 
↑ 
No change 
↓ 
> 1.0 
No change 
↓ 
↓ 
Abbreviations: 
↑ = increase; ↓ = decrease. 
Notes: 
Dose Increases and Reductions: 
• 
Dose increases (↑) and reductions (↓) are preset. 
• 
The dose steps are as follows: 20, 40, 50, 70, 100, 150, 200, 250, 300, and 400 mg.  
For example, a subject previously receiving 70 mg of roxadustat requiring a dose increase would have his 
dose changed to100 mg of roxadustat. A subject previously receiving 150 mg of roxadustat requiring a dose 
reduction would have his dose changed to 100 mg of roxadustat.  
Medical Monitor should be informed when < 20 mg /dose is required. 
• 
The maximum dose is capped at 400 mg or 3.0 mg/kg/dose (whichever is lower). 
Dose Adjustment for predefined out of range hemoglobin elevations: 
• 
If hemoglobin increases by > 2.0 g/dL at any time within 4 weeks, the dose should be reduced by one dose 
step. 
• 
Only one dose reduction for predefined out of range hemoglobin elevations is recommended within a period 
of 4 weeks.  
• 
Temporary dose holds for predefined out of range hemoglobin elevations should be confirmed based on 
central lab hemoglobin assessments. Upon confirmation, if the hemoglobin is ≥ 13 g/dL, withhold dosing, 
check hemoglobin at least weekly, then resume dosing when hemoglobin < 12.0 g/dL, at a dose that is 
reduced by one dose step. The subsequent hemoglobin follow-up assessments should also be done by a 
central lab. 
* A “Stat lab" is to be used only for urgent lab test that is needed for immediate decision making related to 
protocol, management of adverse events as determined by the Investigator.  
 


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16.3 Appendix 3 
SF-36 (Version 2) 
 
 
 


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SF-36 (Version 2) 
 


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SF-36 (Version 2) 
 
 
 


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SF-36 (Version 2) 
 


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SF-36 (Version 2) 
 


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SF-36 (Version 2) 
 
 
 
 
 
 
 
 
 


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16.4 Appendix 4 
FACT-An (Version 4) 
 


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FACT-An (Version 4) 
 
 


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FACT-An (Version 4) 
 


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16.5 Appendix 5 
Data Handling Conventions 
16.5.1 Visit Time Windows 
 
The table below presents the visits assigned for efficacy and safety analyses 
corresponding to the range of treatment days (window) during which an actual visit may 
have occurred.  
Table 11. Visit Time Windows 
 
Derived Visit 
Scheduled Visit 
Daya 
Window 
Baseline, Week 0 
Day 1 
Days ≤ 1 
Week 1 
Day 7*(Week #)+1 
Days [Day 2, 10] 
Week  2 
Day 7*(Week #)+1 
Days [Scheduled Day -3 Scheduled Day 
+ 6 ] 
Weeks 4  prior to 24 
Day 7*(Week #)+1 
Days [Scheduled Day -7, Scheduled Day 
+ 6 ] 
Week 24 
Day 7*(Week #)+1 
Days [Scheduled Day -7 Scheduled Day 
+ 13 ] 
>=Week 28 
Day 7*(Week #)+1 
Days [Scheduled Day -14, Scheduled 
Day +13 ] 
ET 
Earlier Termination, match to a closest scheduled visit in protocol if 
patient had not been off drug for more than 7 days. 
EoT 
Last assessment between Day 2 and EOT visit day, match to a closest 
scheduled visit in protocol if patient had not been off drug for more than 
7 days. 
EoS (FU-4Wk) 
Final visit for the Study 15 – 31 days after the last dose (excluding long 
term follow-up for early termination). 
a: Relative to the first study medication date. For example, Day 1 = the first dose date of study medication. 
 
 


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Table 12: Analysis Visit Windows for QoL 
 
CRF Visit 
Target 𝐃𝐃𝐃𝐃𝐃𝐃𝐚𝐚 
Analysis Visit Windows 
Actual Assessment Day 
Analysis Visit 
Day 1 
Day 1 
Day 1 
Baseline 
Week 12 
Day 7 * (Week 
#) + 1 
Target day -14, Target Day + 
27 
Week 12 
Week 28 
Day 7 * (Week 
#) + 1 
Target Day – 28, Target Day 
+83 
Week 28 
Week 52 
Day 7 * (Week 
#) + 1 
Target Day – 84, Target Day 
+ 83 
Week 52 
EOT Visit 
Last assessment between Day 2 
and EOT visit day, remapped to 
the closest next scheduled 
visit for HRQoL collection. 
Week 12, 28, 52 and > 1 
year 
a:  Relative to Day 1 (first dose date of study medication)  
 
 


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Table 13. Analysis Visit Windows for Lipid Panel 
Derived Visit 
Scheduled Visit 
Day a 
Window 
Baseline, Week 0 
Day 1 
Day 1 
Week 4 
Day 7*(Week #)+1 
[Day 2, Day +42] 
Week 8 
Day 7*(Week #)+1 
[Scheduled Day-14, Scheduled Day +13] 
Weeks 12 
Day 7*(Week #)+1 
[Scheduled Day -14, Scheduled Day +27] 
Week 20, 28 
Day 7*(Week #)+1 
[Scheduled Day -28, Scheduled Day +27] 
Weeks 36 
Day 7*(Week #)+1 
[Scheduled Day -28, Scheduled Day +41] 
Week  48 to xx 
Day 7*(Week #)+1 
[Scheduled Day -42, Scheduled Day +41] 
Week xx 
. 
Last assessment between Day 2 and EOT visit 
day, match to a closest scheduled visit in protocol if 
patient had not been off drug for more than 7 days 
FU-4Wk 
 
Final visit in the Study 15 – 31 days after Last Dose. 
a:  Relative to Day 1 (first dose date of study medication)  
 
Visit Day is calculated by (visit date – first dose date of study medication + 1). If a 
subject has ≥ 2 actual visits within the same window, the last visit with non-missing value 
will be used for analysis. 
 
Repeated or Unscheduled Assessments of Safety Parameters 
If a subject has repeated assessments prior to the start of study medication, then the 
results from the final assessment made prior to the start of study medication will be used 
as baseline. If end of study assessments are repeated or unscheduled, the last post-
baseline assessment will be used as the end of study assessment for generating summary 
statistics. However, all post-baseline assessments will be used for PCS value 
determination and all assessments will be presented in the data listings. 
 
Missing Date of Study Medication 
When the last date of study medication during the study treatment phase is missing, all 
efforts should be made to obtain the date from the investigator. If it is still missing after 
all efforts, then the last visit date during the Treatment Period will be used in the 
calculation of treatment duration. 
 
Missing Severity Assessment for Adverse Events 


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If severity is missing for an AE started prior to the first study medication, then a severity 
of “Mild” will be assigned. If the severity is missing for an AE started on or after the first 
study medication dosing, then a severity of “Severe” will be assigned. The imputed 
values for severity assessment will be used for incidence summary, while the actual 
missing values will be presented in data listings.  
 
Missing Relationship to Study Drug for Adverse Events 
If the relationship to the study medication is missing for an AE started after baseline, a 
causality of “Related” will be assigned. The imputed values for relationship to study 
medication will be used for incidence summary, while the actual values will be presented 
in data listings.  
 
16.5.2 Missing Date Imputation for Adverse Events 
• Incomplete Start Date 
The following imputation rules only apply to the case where the start date is incomplete 
(i.e., partial missing) for adverse events. 
Missing day and month 
− If the year is same as the year of first day on study medication, then the day and 
month of the start date of study medication will be assigned to the missing fields. 
− If the year is not the same as the year of first day on study medication, then January 
1 will be assigned to the missing fields. 
Missing month only 
Treat day as missing and replace both month and day according to the above procedure. 
Missing day only  
If the month and year are same as the year and month of first day on study medication, 
then the start date of study medication will be assigned to the missing day. 
If the month and year are not the same as the year and month of first day on study 
medication, then the first day of the month will be assigned to the missing day. 
If the stop date is complete and the imputed start date as above is after the stop date, the 
start date will be imputed by the stop date.  
• Incomplete Stop Date   
If needed, the following imputation rules apply to the case where the end date is 
incomplete (i.e., partially missing) for adverse events. Other partial end date will not be 
imputed. 
Missing day and month, or Missing month only 
December 31 will be assigned to the missing fields. 


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Missing day only  
The last day of the month will be assigned to the missing day. 
 
16.5.3 Missing Date Imputation for Prior or Concomitant Medications 
For prior or concomitant medications, including rescue medications, incomplete (i.e., 
partial missing) start date and/or stop date will be imputed. When the start date and the 
stop date are both incomplete for a subject, impute the start date first. 
 
• Incomplete Start Date 
The following rules will be applied to impute the missing numerical fields.  If the stop 
date is complete and the imputed start date is after the stop date, then the start date will be 
imputed using the stop date. 
Missing day and month 
If the year of the incomplete start date is the same as the year of the first dose date of 
study medication, then the day and month of the first dose date will be assigned to 
the missing fields.  
If the year of the incomplete start date is prior to the year of the first dose date of study 
medication, then December 31 will be assigned to the missing fields.  
If the year of the incomplete start date is after the year of the first dose date of study 
medication, then January 1 will be assigned to the missing fields. 
Missing month only 
Treat day as missing and replace both month and day according to the above procedure. 
Missing day only  
If the month and year of the incomplete start date are the same as the month and year of 
the first dose date of study medication, then the day of the first dose date will be 
assigned to the missing day.  
If either the year is before the year of the first dose date of study medication or if both 
years are the same but the month is before the month of the first dose date of study 
medication, then the last day of the month will be assigned to the missing day. 
If either the year is after the year of the first dose date of study medication or if both 
years are the same but the month is after the month of the first dose date of study 
medication, then the first day of the month will be assigned to the missing day. 


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Incomplete Stop Date   
The following rules will be applied to impute the missing numerical fields.  If the last 
dose date of study medication is missing, replace it with the last visit date. If the imputed 
stop date is before the start date (imputed or non-imputed start date), then the imputed 
stop date will be equal to the start date. 
Missing day and month 
If the year of the incomplete stop date is the same as the year of the last dose date of 
study medication, then the day and month of the last dose date will be assigned to 
the missing fields.  
If the year of the incomplete stop date is prior to the year of the last dose date of study 
medication, then December 31 will be assigned to the missing fields.  
If the year of the incomplete stop date is after the year of the last dose date of study 
medication, then January 1 will be assigned to the missing fields. 
Missing month only 
Treat day as missing and replace both month and day according to the above procedure. 
Missing day only  
If the month and year of the incomplete stop date are the same as the month and year of 
the last dose date of study medication, then the day of the last dose date will be 
assigned to the missing day.  
If either the year is before the year of the last dose date of study medication or if both 
years are the same but the month is before the month of the last dose date of study 
medication, then the last day of the month will be assigned to the missing day. 
If either the year is after the year of the last dose date of study medication or if both 
years are the same but the month is after the month of the last dose date of study 
medication, then the first day of the month will be assigned to the missing day. 
16.5.4 Missing Date Imputation for last dose date 
Imputed last dose date = earliest date of (last drug dispense date + number of days of 
drug dispensed, date of death, date of EOT/EOS visit, and other dates as appropriate).  
16.5.5 Character Values of Clinical Laboratory Parameters 
 
If the reported value of a clinical laboratory parameter cannot be used in a statistical 
summary table due to, for example, that a character string is reported for a parameter of 
the numerical type, coded value needs to be appropriately determined and used in the 
statistical analyses. However, the actual values as reported in the database will be 
presented in data listings. 
 
 


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Example for Coding of Special Character Values for Clinical Laboratory 
Parameters 
Lab Test 
Possible Lab  Results 
(in SI unit) 
Coded Value for Analysis 
Chemistry: ALT 
< 5 
5 
Chemistry: AST 
< 5 
5 
Chemistry: Bilirubin, 
Total 
< 2 
2 
Urinalysis: Glucose 
= OR > 55,  >= 55,  > 0 
Positive 
<= 0, Negative 
Negative 
Urinalysis: Ketones 
= OR > 8.0,  >=8.0,  > 0 
Positive 
<= 0, Negative 
Negative 
Urinalysis: pH 
> 8.0,  >= 8.0 
8.0 
>= 8.5, 
8.5 
Urinalysis: Protein 
= OR > 3.0, >=3.0,  > 0 
Positive 
<= 0 
Negative 


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16.6 Appendix 6 
Ranges of Potentially Clinically Significant Lab Values 
Parameter 
SI Unit 
Lower Limit 
Higher Limit 
CHEMISTRY 
Alanine 
Aminotransferase  
(ALT) 
U/L 
 
≥3 * ULN 
Alkaline Phosphatase 
U/L 
 
≥3 * ULN 
Aspartate 
Aminotransferase (AST) 
U/L 
 
≥3 * ULN 
GGT 
U/L 
 
≥3 * ULN 
Calcium 
mmol/L 
<0.8*LLN 
>1.2 * ULN 
Creatinine 
µmol/L 
 
> 1.5x Day 1 
Potassium 
µmol/L 
<0.75*LLN 
>1.2 * UNL 
Sodium 
mmol/L 
<0.9*LNL 
>1.1 * UNL 
Total Bilirubin 
µmol/L 
 
>1.5 * UNL 
Total Protein 
µmol/L 
<0.9*LNL 
>1.1 * UNL 
Urea (BUN) 
mmol/L 
 
>1.5X Day 1 
HEMATOLOGY 
Neutrophils 
109/L 
≤1 
 
Platelet Count 
109/L 
≤ 100 
≥700 
White Blood Cell Count 
109/L 
≤2.5 
≥15 
LLN: Lower limit of normal, value provided by the laboratory 
ULN: Upper limit of normal, value provided by the laboratory 
 
 
 


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16.7 Appendix 7 
Justification of the Non-Inferiority Margin 
 
Non-Inferiority (NI) Clinical Trials states that “the NI trial concept depends on how 
much is known about the size of the treatment effect the active comparator will have in 
the NI study compared to no treatment” and this effect “must be assumed, based on an 
analysis of past studies of the control”. 
 
Pursuant to this, we sought out studies that compared ESA therapies currently approved 
for use in the United States to placebo (or no therapy) in the treatment of anemia.   
Criteria to be considered relevant to estimate the potential treatment effect included: 
1- Randomized trial design 
2- Prospective follow up 
3- Treatment groups which included epoetin-alfa (or other recombinant 
erythropoeitin derivatives) and either placebo or no treatment 
4- Inclusion of treatment naïve adult patients with ESRD related anemia. 
5- Post randomization monitoring of hemoglobin following randomization 
Studies were identified through a search of the bibliographies of peer-reviewed meta-
analyses examining the effect of ESAs on outcomes. 
1. Palmer et al.  Meta-analysis: Erythropoiesis-Stimulating Agents in Patients with 
Chronic Kidney Disease.  Ann Intern Med. 2010;153:23-33. 
2. Phrommintikul A et al. "Mortality and target haemoglobin concentrations in 
anaemic patients with chronic kidney disease treated with erythropoietin: a meta-
analysis." The lancet 369.9559 (2007): 381-388. 
3. Koulouridis, Ioannis, et al. "Dose of erythropoiesis-stimulating agents and 
adverse outcomes in CKD: a metaregression analysis." American Journal of 
Kidney Diseases 61.1 (2013): 44-56. 
 
Identification of all appropriate trials was confirmed through a literature search 
(www.pubmed.gov) using combinations of the terms “ESA”, “epoetin”, “CKD”, 
“ESRD”, “placebo”, and “anemia”. 
 
The approach taken for this NI margin is the fixed margin method described in the U.S. 
Food and Drug Administration’s 2010 guidance “Non-Inferiority Clinical Trials.”  In this 
guidance, the fixed margin approach is summarized as follows:  
“Briefly, in the fixed margin method, the margin M1 is based upon estimates of the effect 
of the active comparator in previously conducted studies, making any needed adjustments 
for changes in trial circumstances.  The NI margin is then pre-specified and it is usually 
chosen as a margin smaller than M1 (i.e., M2), because it is usually felt that for an 
important endpoint a reasonable fraction of the effect of the control should be preserved.   


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The NI study is successful if the results of the NI study rule out inferiority of the test drug 
to the control by the NI margin or more.  It is referred to as a fixed margin analysis 
because the past studies comparing the drug with placebo are used to derive a single fixed 
value for M1, even though this value is based on results of placebo-controlled trials (one 
or multiple trials versus placebo) that have a point estimate and confidence interval for 
the comparison with placebo.  The value typically chosen is the lower bound of the 95% 
CI (although this is potentially flexible) of a placebo-controlled trial or meta-analysis of 
trials. This value becomes the margin M1, after any adjustments needed for concerns 
about constancy.  
The fixed margin M1, or M2 if that is chosen as the NI margin, is then used as the value to 
be excluded for C-T in the NI study by ensuring that the upper bound of the 95% CI for 
C-T is <M1 (or M2).  This 95% lower bound is, in one sense, a conservative estimate of 
the effect size shown in the historical experience. It is recognized, however, that although 
we use it as a “fixed” value, it is in fact a random variable, which cannot invariably be 
assumed to represent the active control effect in the NI study.”  This approach is shown 
schematically in Figure 1.   
Figure 1    Active Control – Test Drug differences (Point estimate, 95% CI) 
 
1. C-T point estimate = 0 and upper bound of 95% CI < M2, indicating test drug is 
effective (NI demonstrated).   
2. Point estimate of C-T favors C and upper bound of 95% CI < M1 but > M2, indicating 
effect > 0 but unacceptable loss of the control effect.  
3. Point estimate of C-T is zero and upper bound of 95% CI < M1 but it is slightly greater 
than M2.  Judgment could lead to conclusion of effectiveness.   
4. C-T point estimate favors C and upper bound of 95% CI > M1, indicating there is no 
evidence of effectiveness for test drug.”  
 


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Table 14 below displays the mean change in hemoglobin for recombinant human (EPO) 
based on 3 publications, [Canadian et al, 1990], [Bennett et al, 1991] and [Nissenson et 
al, 1995 ]. The 3 studies are all randomized, double-blinded, randomized, placebo 
controlled study to evaluate the effect EOP (epoetin alfa or beta) in anemia patient with 
ESRD with PD or HD.  
 
Using the data in Table 14 below, the weighted mean of the point estimate of treatment 
effect in mean change from baseline for EPO (mean change in hemoglobin or 
hemoglobin equivalence in EPO group  –  mean change in placebo group) was calculated, 
along with its 95% confidence interval.   
 
Table 14.     Historical studies with mean change and SD in hematocrit or hemoglobin available 
in ESRD: EPO versus Placebo 
Nissenson et al, 1995 
(Erythropoietin  in 
Peritoneal Dialysis) 
Endpoint 
EPO 
Mean (SD) 
Placebo 
 Mean (SD) 
EPO-Placebo 
Mean (Std Err) 
 
 
sample size = 78 
Sample size = 74 
 
 
Baseline in hematocrit 
23.8 (3.8) % 
23.8 (3.3) % 
 
 
12 week Follow up in 
haematocrit 
33.7 (4.8) % 
      24.1 (3.8) % 
 
 
HMG equivalent Mean 
Change* 
3.3(0.33) g/dL 
0.1( 0.17) g/dL 
3.2 (0.042) g/dL 
Bennett et al, 1991 
(Epoetin Beta - 
Hemodialysis) 
 
sample size = 90 
sample size = 41 
 
 
Baseline 
7.1 (0.1*sqrt(90)) 
g/dL 
6.8 (0.2*sqrt(41)) 
g/dL 
 
 
12 week Follow up 
11.1 (0.2*sqrt(90)) 
g/dL 
7.6 (0.3*sqrt(41)) 
g/dL 
 
 
HMG Mean Change* 
4.0 (0.95) g/dL 
0.8(0.64) g/dL 
3.2 (0.141) g/dL 
Canadian et al, 1990 
(Erythropoietin - 
hemodialysis patients) 
 
sample size = 40 
sample size = 40 
 
 
Baseline 
7.1 (0.9) g/dL 
6.9 (1.0) g/dL 
 
 
6 month follow up 
10.2 (1.0) g/dL  
7.4(1.2) g/dL 
 
 
HMG Mean Change* 
3.1(0.1) g/dL 
0.5 (0.2) g/dL 
2.6 (0.035) g/dL 
*Hematocrit in % was converted to hemoglobin in g/dL by dividing by 3. Due to the information are limited from the reference, the 
mean change in hemoglobin and the corresponding standard deviation were derived where the baseline and follow up hemoglobin 
were assumed to be independent which is very conservative.  
 
The weighted mean point estimate for mean change from baseline in hemoglobin for 
EPO (mean change from baseline in hemoglobin for EPO group – mean change from 
baseline in hemoglobin for placebo group) was estimated to be 2.859 g/dL by treating the 
studies as fixed effect, with a 95% confidence interval of (2.806, 2.911) and 2.993 g/dL 
by treating the studies as random effect, with a 95% confidence interval of (2.520, 3.466) 
from meta-data analysis.  The lower bound of this 95% confidence interval by treating 
the study as random effect, 2.520 is taken to be the NI margin M1. To ensure that not 
more than 50% of the effect of EPO was lost, giving an NI margin (M2) of 1.26. 


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However, a very conservative M2 margin was chosen, 0.75, which is 29.76% of M1, thus 
ensuring preservation of 70.24% of M1 in this study. See Figure 2 for the visual effect of 
NI margin based on EPO group versus placebo group in mean change from baseline in 
hemoglobin.    
Figure 2    Active Control – Placebo differences (Point estimate, 95% CI) in History 
Studies 
 


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16.8 Appendix 8 
Temporal Profile of TEAE’s of Special Interest