Clinical trial NCT03263091
Conditions: Primary MDS (Very Low, Low or Intermediate IPSS-R With <5% Blasts) Anemia
Keywords: Myelodysplastic Syndromes Anemia Hemoglobin (Hb) Low Risk Myelodysplastic Syndrome Low Risk MDS
Sponsor: FibroGen
Start date: 2018-01-29; Completion date: 2023-06-20
Enrollment: 184 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether FG-4592 is safe and effective in the treatment of anemia in participants with lower risk MDS and low red blood cell transfusion burden.

Detailed description:
This study includes an Open-Label Lead in, a Double-Blind component, and an Open-Label High Erythropoietin component. There is a screening period of up to 42 days followed by a treatment period of 52 weeks and a 4-week end of treatment assessment.

Arms: arm 1: Open-label, lead-in: Participants will receive sequential escalating roxadustat doses (1.5 milligrams/kilograms \[mg/kg\], 2.0 mg/kg and 2.5 mg/kg), three times a week (TIW) based upon their actual weight at the randomization visit to identify the starting dose for double-blind period.

Double-blind: Participants will receive roxadustat 2.5 mg/kg TIW based upon their body weight for a duration of 52 weeks.

Open-label: Participants with high serum erythropoietin levels (\>400 milli-international units \[mIU\]/milliliter \[mL\] mIU/mL) will receive roxadustat 2.5 mg/kg TIW based upon their body weight for a duration of 52 weeks. arm 2: Double-blind: Participants will receive placebo matching to roxadustat for a duration of 52 weeks.
Interventions: intervention 1: Roxadustat intervention 2: Placebo
Intervention descriptions: intervention 1: Oral tablets intervention 2: Oral tablets

Protocol documents:
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 Randomized Double-Blind Placebo-Controlled 
Study Investigating the Efficacy and Safety of Roxadustat (FG-
4592) for Treatment of Anemia in Patients with Lower Risk 
Myelodysplastic Syndrome (MDS) with Low Red Blood Cell 
(RBC) Transfusion Burden (LTB)  
PROTOCOL NUMBER: 
FGCL-4592-082 
SPONSOR: 
FibroGen, Inc. 
409 Illinois Street 
San Francisco, California 94158, USA 
IND NUMBER: 
129546 
STUDY DRUG: 
Roxadustat (FG-4592) 
INDICATION: 
Anemia due to MDS in International Prognostic Scoring 
System – Revised Very Low, Low, or Intermediate Risk with 
<5% Blasts, and has low red blood cell transfusion burden 
(requires 1 to 4 packed red blood cell units per 8-week period) 
FIBROGEN MEDICAL 
MONITOR: 
Name: 
 
Title: 
  
Telephone: 
Fax: 
E-mail:
PROTOCOL VERSION 
AND  DATE: 
ORIGINAL:  03 FEBRUARY 2017 
AMENDMENT 01:  27 MARCH 2017 
AMENDMENT 02:  16 MAY 2018 
NCT03263091


Roxadustat 
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Confidential and Proprietary 
Page 2 
INVESTIGATOR SIGNATURE PAGE 
STUDY ACKNOWLEDGEMENT 
A Phase 3 Randomized Double-Blind Placebo-Controlled Study Investigating the Efficacy and 
Safety of Roxadustat (FG-4592) for Treatment of Anemia in Patients with Lower Risk 
Myelodysplastic Syndrome (MDS) with Low Red Blood Cell (RBC) Transfusion Burden (LTB) 
FGCL-4592-082 
IND 129546 
INVESTIGATOR STATEMENT 
I have read the protocol dated 16 May 2018, 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 Name and Address 
 
 
 
 
Signature 
 
Date 
FG-4592 Investigator Brochure Version 9.0 
Please retain the original for your study files. 


Roxadustat 
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SUMMARY PROTOCOL AMENDMENT CHANGES 
Amendment 02 
 
Section(s) Affected 
Description of Change 
Rationale for Change 
Entire Document 
AMENDMENT 02: 16 MAY 2018 
Updated document header 
and all references from 
Amendment 1: 27 March 
2017 to Amendment 2: 16 
May 2018 
Entire Document 
Corrected minor typographical and grammatical 
errors 
Administrative changes and 
errors from previous version 
of the protocol 
Entire Document 
Replaced step with level 
Provided for additional 
clarity and details 
Title Page – FibroGen 
Medical Monitor 
Replaced 
 with 
 
telephone, mobile and email address 
Updated FibroGen Medical 
Monitor  
Table of Contents 
 
 
 
 
Added Sections 3.6, 3.6.1, 3.6.2 
 
 
 
 
Added the following sections 
for additional clarity and 
details. 
3.6 Blinding 
3.6.1 Maintenance of 
Blinding 
3.6.2 Planned and Unplanned 
Unblinding of Treatment 
Assignment 
List of Abbreviations 
 
Updated list of abbreviations  
Added and deleted 
abbreviations not included in 
previous version of the 
protocol or no longer relevant  
Protocol Synopsis – 
Number of Patients:; 
Section 2.5; 
Appendix C 
Inserted – approximately  
Provided for additional 
clarity 
Protocol Synopsis – 
Study Design Overview 
(cont.):; 
Section 3.3.1 
Inserted – Approximate and Patient Weight in 
Starting Dose Table 
Provided for additional 
clarity and details 


Roxadustat 
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Section(s) Affected 
Description of Change 
Rationale for Change 
Protocol Synopsis – 
Study Design Overview 
(cont.):; 
Protocol Synopsis – 
Inclusion Criteria:; 
Section 3.1.1; 
Section 4.1; 
Section 6.1; 
Appendix A: Footnote 5 
Replaced of ≥ 16 weeks duration, within 16 weeks 
and (documented within 16 weeks prior to 
randomization) with There is no minimum time 
from diagnosis to registration/randomization 
except to allow for proper IPSS-R classification 
to be made, and to show transfusion 
dependence for patients in both portions of the 
study 
Change in enrollment criteria 
for greater flexibility in 
patient enrollment  
Protocol Synopsis – 
Study Design Overview: 
Screening Period:; 
Protocol Synopsis – 
Inclusion Criteria; 
Section 3.1; 
Section 3.1.1; 
Section 3.3.1; 
Section 3.4.5; 
Section 3.4.6; 
Section 4.1 
Inserted – registration/randomization 
Provided for additional 
clarity and details 
Protocol Synopsis – 
Study Design Overview 
(cont.):; 
Protocol Synopsis – 
Inclusion Criteria; 
Section 3.1.1; 
Section 4.1; 
Section 6.1; 
Appendix A Footnote 11 
Inserted – Open-Label patients only, the 
requirement to demonstrate transfusion 
dependence can also be met by a principle 
investigator starting this particular patient on 
pRBC transfusion during the screening period 
Change in enrollment criteria 
for greater flexibility in 
patient enrollment 
Protocol Synopsis – 
Study Design Overview 
(cont.):; 
Section 3.1; 
Appendix A: Footnote 
15 
Inserted – The roxadustat dose per body weight 
are estimates only and the exact dose will be 
assigned per body weight ranges as shown in 
the body of the protocol 
Replaced Patient Reported Outcomes (PRO) 
assessments with Health-related quality of life 
(HRQoL) questionnaries 
Provided for additional 
clarity 


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Section(s) Affected 
Description of Change 
Rationale for Change 
Study Design Overview 
(cont.): Treatment:; 
Protocol Synopsis – 
Inclusion Criteria:; 
Protocol Synopsis – Best 
Supportive Care:; 
Section 3.4.3; 
Section 4.1; 
Section 6.1; 
Appendix A: Footnote 
11 
Inserted – The Principle Investigator (PI) and 
site staff will utilize their own institutional 
criteria for the determination of when to 
transfuse a patient.  
Provided for additional 
clarity 
Study Design Overview 
(cont.): Treatment:; 
Inserted – Documentation of standard site 
transfusion criteria will be documented in 
overall study files 
Inserted – transfusion 
Provided for additional 
clarity and details 
Study Design Overview 
(cont.):; 
Pharmacokinetics/Pharm
acodynamics (PK/PD):; 
Appendix A: Footnote 3; 
Appendix J 
Replaced self and home or at with the clinic 
 
Updated to increase 
flexibility in patients’ PK 
blood draw schedule for 
Week 5 and Week 21 based 
on Investigational Product 
availability during the PK 
time points 
Protocol Synopsis – 
Inclusion Criteria:; 
Section 4.1; 
Table 2: Additional 
Study Procedures/ 
Assessments and Blood 
Sampling by Visit for 
the 52-Week Treatment 
Period and Post-EOT 
(Appendices A, B, K); 
Appendix A: Table; 
Appendix B 
Replaced Bone marrow aspirate/biopsy with Bone 
marrow aspirate and biopsy 
Provided for additional 
clarity and details 


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Section(s) Affected 
Description of Change 
Rationale for Change 
Protocol Synopsis – 
Inclusion Criteria:; 
Section 4.1 
 
 
 
 
 
 
 
 
 
 
 
Replaced 1. No prior use of recombinant 
erythropoietins or analogues (erythropoiesis-
stimulating agents, ESAs), or received a life-time 
ESA exposure of less than 28 days, AND received 
no ESA within the 12 weeks prior to day 1 
randomization with  
1. There is no restriction on prior use of 
recombinant erythropoietins or analogues 
(erythropoiesis-stimulating agents (ESAs)), except 
that the patient must not have received any 
ESA within the 8 weeks prior to Day 1 
registration/randomization. 
 
Replaced 4. Pre-transfusion Hb ≤10.0 g/dL during 
Screening with  
4. Hb ≤10.0 g/dL during Screening. Hb values are 
obtained at Screening Visit 1 and 2; only 1 
value needs to meet the Hb < 10.0 g/dL criteria.  
These values must be the Central Laboratory 
values.  A third value may be obtained if 
necessary. 
Change in enrollment criteria 
for greater flexibility in 
patient enrollment 
 
 
 
 
 
 
 
Provided for additional 
clarity and details 
 
 
Protocol Synopsis – 
Inclusion Criteria:; 
Section 4.1 
Appendix A: Footnote 7 
Replaced 7. ECOG performance status of 0 or 1 at 
last screen visit (Appendix F) with  
ECOG performance status of 0, 1 or 2 at last 
screen visit (Appendix F) 
Change in enrollment criteria 
for greater flexibility in 
patient enrollment 
Protocol Synopsis –
Exclusion Criteria; 
Section 4.2; 
Appendix A: Footnote 8 
Alanine aminotransferase (ALT) AND aspartate 
aminotransferase (AST) >3 × upper limit of 
normal (ULN), and total bilirubin (Tbili) > 1.5 × 
ULN (Appendix H) 
Alanine aminotransferase (ALT) >3 x upper limit 
of normal (ULN), OR  aspartate aminotransferase 
(AST) >3 ×  ULN, OR total bilirubin (TBili) > 1.5 
× ULN (see Appendix H) 
Text updated to be in line 
with Appendix H 


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Section(s) Affected 
Description of Change 
Rationale for Change 
Protocol Synopsis – 
Exclusion Criteria:; 
Section 4.2 
Inserted in Exclusion 10 – for more than 7 days  
 
Inserted in Exclusion 11 – as determined by the 
investigator 
 
Replaced in Exclusion 12 Active infection(s) 
requiring antibiotic therapy with 
Active infections(s) requiring systemic 
antibiotic therapy 
 
Inserted in Exclusion 15 – e.g., warfarin or 
enoxaparin, a factor Xa inhibitor such as 
rivaroxaban or apixaban, or a direct thrombin 
inhibitor such as dabigatran. Chronic use of 
low-dose aspirin is allowed. 
 
Replaced in Exclusion 23 patients with a history of 
cured malignancy with no evidence of malignancy 
for at least 5 years are eligible with patients with 
a history of cured malignancy with no evidence 
of recurrence for at least 3 years are eligible 
 
Inserted – 25. Pregnant or breastfeeding females 
Provided for additional 
clarity and details   
 
 
 
 
 
 
 
 
 
 
 
 
Change in enrollment criteria 
for greater flexibility in 
patient enrollment 
 
 
Updated Exclusion Criteria  
Protocol Synopsis – 
Exclusion Criteria:; 
Section 4.2 
Appendix L 
Replace Creatinine Clearance with Creatinine 
Clearance/eGFR 
Provided for additional 
clarity and details 
Protocol Synopsis – 
Efficacy Endpoints and 
Assessments (double-
blind):; 
Section 2.8.2; 
Section 8.3.3.2.4 
Replaced Proportion of Patients who achieve TI 
for ≥20 weeks (140 consecutive days) with (120 
consecutive days) 
Calculation error from 
previous version of the 
protocol 
Protocol Synopsis – 
Statistical Methods 
(cont.): Data Safety 
Monitoring Board 
(DSMB); 
Section 3.6 
Inserted – prior to the start of the DB portion of 
the study 
Inserted – likely  
 
Provided for additional 
clarity 
 
Figure 3 
Study Schemas updated 
Updated in line with updated 
protocol enrollment criteria  


Roxadustat 
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Section(s) Affected 
Description of Change 
Rationale for Change 
Section 3.3.1 
Inserted – at a ratio of 3:2 to roxadustat or 
placebo 
Provided for additional 
clarity and details 
Section 3.3.2 
Inserted – There are two periods for the study 
drug dosing – the correction phase and the 
maintenance phase. 
Inserted – Correction phase: 
Inserted – Maintenance Phase: 
Inserted – Given the complexities of the dose 
adjustment algorithm, and the need to take into 
consideration various clinical parameters, it is 
not considered a protocol deviation when study 
subjects are dosed based on their clinical 
circumstance, whether or not this is concordant 
with the roxadustat dosing algorithm, unless it 
is related to “excessive hematopoiesis” or 
“Overdose” (prescribed 400 mg or > 3.5 
mg/kg/dose). 
Provided for additional 
clarity and details 
 
 
 
 
Provided for additional 
clarity and details 
 
Section 3.3.2; 
Section 8.3.3.2 
Section moved from Section 3.3.2 Dose 
Adjustments to Section 8.3.3.2 Analysis of the 
Secondary Efficacy Endpoints 
Paragraph originally in 
wrong section of the previous 
version of the protocol 
Section 3.4.1 
Replaced To avoid confounding effects on study 
endpoints, changes to anti hypertensive 
medications should be minimized, and only if 
deemed necessary by the Investigator with 
To avoid confounding effects on study endpoints, 
changes in administration of chronic 
concomitant medications should be minimized 
and done only if deemed necessary by the 
Principal Investigator 
Provided for additional 
clarity and details 
 
Section 3.4.5 
Inserted – except for ESAs which are prohibited 
for 8 weeks prior to Week 1 Day 1 of 
registration/randomization visit and at any time 
during the study (see first bullet below 
regarding ESAs)  
Change in enrollment criteria 
for greater flexibility in 
patient enrollment 
 
Section 4.3; 
Appendix O 
Replaced should be considered with will occur 
Text updated to be in line 
with Appendix H 
Section 4.3 
Inserted – Treatment with ESAs 
Provided for additional 
clarity and details 


Roxadustat 
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Section(s) Affected 
Description of Change 
Rationale for Change 
Section 4.6; 
Section 4.6.1; 
Section 4.6.2 
Added the following sections for additional clarity 
and details. 
3.6 Blinding 
3.6.1 Maintenance of Blinding 
3.6.2 Planned and Unplanned Unblinding of 
Treatment Assignment 
Provided for additional 
clarity for blinding in the 
double-blind portion of the 
study 
Section 5.1 
Inserted – Placebo tablets are identical to the 
roxadustat tablets except for the absence of 
active roxadustat 
Provided for additional 
clarity and details 
 
Section 6.1 
Replaced SAEs will be recorded with AEs and 
SAEs will be recorded in the medical record 
Inserted – SAEs will be reported to FibroGen 
Provided for additional 
clarity and details 
 
Section 6.3.1.1; 
Section 6.8 
 
 
 
Replaced Local hemoglobin level (hemocue 
device, Day 1 and all visits beyond) and Central 
Hb level with 
Local hemoglobin level (hemocue device is 
encouraged but not required) 
Updated to increase 
flexibility for sites’ method 
of local Hb blood draws with 
the intention that patients will 
receive same day Hb results 
for dose adjustment purposes 
Section 6.3.1.2 
Inserted – , EOT and Post-EOT 
Inserted – All blood samples must be drawn 
prior to dose unless otherwise noted (e.g. 
certain PK draws). 
Provided for additional 
clarity and details 


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Section(s) Affected 
Description of Change 
Rationale for Change 
Table 2: Additional 
Study Procedures/ 
Assessments and Blood 
Sampling by Visit for 
the 52-Week Treatment 
Period and Post-EOT 
(Appendices A, B, K) 
Inserted in Week 9 – Assess erythroid response 
Added 4 Weeks Post-EOT  
• Procedures and Assessments  
o Physical Exam 
o ECOG score 
o Vital signs (BP, HR, RR, and Temp) 
o Health-related quality of life (HRQoL) 
assessments  
o ECG 
• Blood Samples 
o CBC (central) and Local Hb 
o Serum chemistries 
o LFTs 
o Iron biomarkers 
o Hepcidin  
o Endogenous serum EPO level 
o PT, PTT 
o Serum lipid panel 
o B12 and folate 
o C-reactive protein 
o Reticulocytes & CHr 
o Serum pregnancy (for females of 
childbearing capability) 
Added If Early Termination, every 8 weeks 
assessment from 4 Weeks Post-EOT visit. Last 
visit at Week 52 from first dose. 
• Procedures and Assessments  
o Vital signs (BP, HR, RR, and Temp) 
• Blood Samples 
o CBC (central) and Local Hb 
o Serum chemistries 
o LFTs 
o Iron biomarkers 
o Hepcidin  
o Endogenous serum EPO level 
Provided for additional 
clarity and details 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 2: Additional 
Study Procedures/ 
Assessments and Blood 
Sampling by Visit for 
the 52-Week Treatment 
Period and Post-EOT 
(Appendices A, B, K); 
Appendix A: Table  
Added Point-of-care Urine Pregnancy (for 
females of child-bearing capabilities)   
• Week 13 
• Week 25 
• Week 39  
To be able to detect any 
pregnancy in women of 
childbearing potential  


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Section(s) Affected 
Description of Change 
Rationale for Change 
Section 7.3.8 
Replaced Gradual worsening of MDS should be 
considered disease progression and should not be 
reported as an AE during the study with 
Gradual worsening of MDS should be considered 
disease progression and should be reported as an 
AE during the study. Worsening of anemia, per 
se, should not be reported as disease 
progression because changes in Hb levels will 
be adequately monitored and assessed in the 
efficacy analyses.  
Provided for additional 
clarity 
Appendix A;  
Appendix B  
Updated numbering of Appendix A Footnote  
To ensure alignment between 
footnotes, tables and 
appendices  
Appendix A: Footnote 2  
Deleted – 2. If participant is known positive for 
any (hepatitis B, hepatitis C, HIV), no need to 
repeat test 
Inserted – Serum erythropoietin  level must be 
≤400 mIU/mL at screening; during the last 
month of treatment a serum EPO level will be 
drawn just prior to the next study drug dosing; 
patients should be told to not take their study 
drug until after the study visit on that day. 
Deleted – Serum B12 and folate must be >lower 
limit of normal at screen 
Omitted for clarity from 
previous version of the 
protocol  
 
 
 
 
 
 
 
 
 
Included in error from 
previous version of the 
protocol 
Appendix A: Footnote 5 
Replaced within 16 weeks prior to 
Enrolment/randomization with for the IPSS-R 
criteria 
Change in enrollment criteria 
for greater flexibility in 
patient enrollment 
Appendix A: Footnote 6 
Inserted – Weight at registration/randomization 
will be used for determination of starting dose. 
Provided for additional 
clarity and details 
Appendix A: Footnote 
10 
Replace 11. Pregnancy Test: must be negative for 
women of child bearing potential as screening with 
10. Pregnancy Test: must be negative for 
women of child bearing capacity at screening. 
Additional pregnancy testing for women of 
child bearing capacity will also be done at 
Weeks 13, 25, 39, EOT and Post-EOT visits. 
To align with Exclusion 25 


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Section(s) Affected 
Description of Change 
Rationale for Change 
Appendix A: Footnote 
12 
Deleted – at screening, platelets cannot be 
<100,000/mm3 and ANC <1500/mm3; a local 
(Hemocue) will be drawn at each visit  
Inserted – Regarding Central Lab Hb values: 
Two Hb values are obtained at Screening Visit 
1 and 2, only 1 of 2 value needs to meet the Hb 
≤ 10.0 g/dL criteria. 
Included in error in previous 
version of the protocol 
 
 
Provided for additional 
clarity and details 
 
Appendix A: Footnote 
13 
Deleted – Serum ferritin >50 ng/mL at screen 
Included in error in previous 
version of the protocol 
Appendix A: Footnote 
14 
Inserted – which should be given at the site 
Provided for additional 
clarity and details 
Section 3.4.1.1; 
Appendix A: Footnote 
16 
Deleted – Patients should be advised that study 
medication be taken at least one hour before or 
three hours after their phosphate binder if 
possible 
Removal of phosphate dosing 
restriction  
Appendix A: Footnote 
18 
Inserted – A re-assessment will be done for these 
patients at Week 12 and if TI is observed the 
dose will not be increased. 
Added for consistency 
through the protocol 
Appendix C: Dose 
Reduction 
Replaced After patient has achieved TI for at least 
8-weeks, or has undergone treatment with the 
maximum allowable dose, i.e., 400 mg TIW or 3.5 
mg/kg for at least 8-weeks, and there were no 
change in erythroid response compared to the 
previous 8-weeks at a lower dose level, patient 
may undergo dose reduction by 1-dose step with  
In the instance where the patient achieved TI in 
the initial 8-weeks of the study, or has undergone 
treatment with the maximum allowable dose, i.e., 
400 mg TIW or 3.5 mg/kg for at least 8-weeks, 
patient may undergo dose reduction by 1-dose 
level. 
Provided for additional 
clarity and details 
 
Appendix D 
Inserted – 8 weeks 
Inserted – RBC 
Replaced <  1.0 (or had transfusion within 4 
weeks) with <  1.0 * (or had RBC transfusion 
within 4 weeks) 
Inserted – *A change in Hb from 4 weeks earlier 
of < -1.0 g/dL means a Hb value that is lower by 
more than 1.0 g/dL compared to 4 weeks 
earlier, e.g., a Hb of 9.4 g/dL compared to 10.6 
g/dL 4 weeks earlier 
Provided for additional 
clarity and details 


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Page 13 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
Investigator Signature Page ............................................................................................................ 2 
Table of Contents .......................................................................................................................... 13 
List of Tables ................................................................................................................................ 17 
List of Figures ............................................................................................................................... 17 
List of Appendices ........................................................................................................................ 17 
List of Abbreviations .................................................................................................................... 18 
Protocol Synopsis.......................................................................................................................... 22 
2 
Background ........................................................................................................................... 32 
2.1 
Introduction ................................................................................................................... 32 
2.1.1 Epidemiology of Myelodysplastic Syndrome ........................................................... 32 
2.1.2 Anemia Associated with MDS .................................................................................. 32 
2.2 
Current Treatment for MDS .......................................................................................... 33 
2.3 
Mechanism of Action of Roxadustat ............................................................................ 34 
2.4 
Clinical Experience with Roxadustat ............................................................................ 36 
2.4.1 Pharmacokinetics and Pharmacodynamics ............................................................... 37 
2.4.2 Experience with HIF-PHI in MDS, Rationale for Roxadustat in MDS Anemia, & 
Study Overview .................................................................................................................... 38 
2.5 
Roxadustat Dose Rationale ........................................................................................... 39 
2.6 
Risks/Benefits of Roxadustat Treatment ...................................................................... 39 
2.7 
Objectives ..................................................................................................................... 40 
2.7.1 Primary Objective ..................................................................................................... 40 
2.7.2 Secondary Objectives ................................................................................................ 40 
2.7.3 Open-Label Component Objective ........................................................................... 40 
2.8 
Efficacy Endpoints ........................................................................................................ 40 
2.8.1 Primary Efficacy Endpoint: ...................................................................................... 40 
2.8.2 Secondary Efficacy Endpoints .................................................................................. 40 
2.8.3 Exploratory Endpoints .............................................................................................. 40 
2.9 
Safety Assessments ....................................................................................................... 41 
3 
Study Design ......................................................................................................................... 42 
3.1 
Description of the Study ............................................................................................... 42 
3.1.1 Screening Period ....................................................................................................... 43 


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3.1.2 Treatment Period ....................................................................................................... 44 
3.1.3 Follow-Up Period...................................................................................................... 44 
3.2 
Replacement of Patients ................................................................................................ 44 
3.3 
Study Treatment ............................................................................................................ 44 
3.3.1 Dose and Schedule .................................................................................................... 44 
3.3.2 Dose Adjustment ....................................................................................................... 45 
3.4 
Concomitant Medications, Procedures and Nondrug Therapies................................... 46 
3.4.1 Concomitant Medications ......................................................................................... 46 
3.4.2 Supplemental Iron Use .............................................................................................. 46 
3.4.3 Best Supportive Care ................................................................................................ 47 
3.4.4 Emergency Procedure (Therapeutic Phlebotomy) .................................................... 47 
3.4.5 Prohibited Medications/Therapies/Substances ......................................................... 47 
3.4.6 Contraception ............................................................................................................ 47 
3.5 
Safety Monitoring Plan ................................................................................................. 48 
3.6 
Data Safety Monitoring Board ...................................................................................... 48 
4 
Study Enrollment and Withdrawal ........................................................................................ 49 
4.1 
Inclusion Criteria .......................................................................................................... 49 
4.2 
Exclusion Criteria ......................................................................................................... 49 
4.3 
Treatment Discontinuation ............................................................................................ 51 
4.4 
Replacement of Patients ................................................................................................ 52 
4.5 
Study Termination ........................................................................................................ 52 
4.6 
Blinding......................................................................................................................... 52 
4.6.1 Maintenance of Blinding ........................................................................................... 52 
4.6.2 Planned and Unplanned Unblinding of Treatment Assignment ............................... 52 
5 
Investigational Product ......................................................................................................... 53 
5.1 
Formulation ................................................................................................................... 53 
5.2 
Storage .......................................................................................................................... 53 
5.3 
Study Drug Handling and Disposal .............................................................................. 53 
5.4 
Route of Administration and Dose ............................................................................... 53 
5.4.1 Roxadustat/Placebo ................................................................................................... 53 
5.5 
Overdose, Emergency Procedures and Management of Overdose ............................... 53 
6 
STUDY PROCEDURES ...................................................................................................... 55 
6.1 
Screening Period ........................................................................................................... 55 


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6.1.1 Screening 1................................................................................................................ 55 
6.1.2 Screening 2................................................................................................................ 56 
6.1.3 Additional Screening Assessments ........................................................................... 57 
6.2 
Registration (OL) and Randomization (DB)................................................................. 57 
6.3 
Treatment Period ........................................................................................................... 57 
6.3.1 Study Procedures and Assessments by Visit ............................................................ 57 
6.4 
Follow-up Period after EOT or Early Termination of study medication ...................... 61 
6.5 
Missed Visits ................................................................................................................. 61 
6.6 
Unscheduled Visits ....................................................................................................... 61 
6.7 
Laboratory Assessments ............................................................................................... 61 
6.8 
Local Hb Level ............................................................................................................. 62 
6.9 
Central Laboratory ........................................................................................................ 62 
6.10 
Electrocardiogram ......................................................................................................... 62 
6.11 
Health Related Quality of Life Questionnaires ............................................................. 62 
7 
Safety .................................................................................................................................... 64 
7.1 
Background ................................................................................................................... 64 
7.2 
Definitions..................................................................................................................... 64 
7.2.1 Definition of an Adverse Event ................................................................................ 64 
7.2.2 Definition of a Serious Adverse Event ..................................................................... 64 
7.3 
Procedures for Eliciting, Recording, and Reporting Adverse Events ........................... 65 
7.3.1 Adverse Event Reporting Period .............................................................................. 65 
7.3.2 Adverse Event Eliciting/Reporting ........................................................................... 65 
7.3.3 Assessing Adverse Event Severity ............................................................................ 66 
7.3.4 Assessing Relationship to Study Drug ...................................................................... 67 
7.3.5 Reporting Serious Adverse Events on the SAE Report Form .................................. 68 
7.3.6 Pregnancies: Reporting and Follow-up of Patients ................................................... 69 
7.3.7 Abnormal Laboratory Findings ................................................................................. 69 
7.3.8 Disease Progression .................................................................................................. 70 
8 
Statistical Considerations ...................................................................................................... 71 
8.1 
Sample Size Determination ........................................................................................... 71 
8.2 
Randomization and Treatment Assignment .................................................................. 71 
8.2.1 Full Analysis Set Population (FAS) .......................................................................... 71 
8.2.2 Safety Populations .................................................................................................... 71 


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8.3 
Statistical Analyses ....................................................................................................... 71 
8.3.1 Multiple Testing and Control of Family-Wise Type I Error ..................................... 71 
8.3.2 General Considerations ............................................................................................. 72 
8.3.3 Analysis of Efficacy Data ......................................................................................... 72 
8.3.4 Patient Enrollment and Disposition .......................................................................... 74 
8.3.5 Demographics and Baseline Characteristics ............................................................. 74 
8.3.6 Summary of Safety Data ........................................................................................... 74 
8.3.7 Interim Analysis ........................................................................................................ 75 
8.4 
Statistical Analyses Plan ............................................................................................... 75 
9 
Direct Access to Source Documents ..................................................................................... 76 
10 Quality Control and Quality Assurance ................................................................................ 77 
10.1 
Data Quality Assurance ................................................................................................ 77 
10.2 
Audit and Inspection ..................................................................................................... 77 
11 Ethics..................................................................................................................................... 78 
11.1 
Ethical Considerations .................................................................................................. 78 
11.2 
Communication with the Institutional Review Board or Independent Ethics Committee  
 
....................................................................................................................................... 78 
11.3 
Informed Consent Form ................................................................................................ 78 
11.4 
Patient Confidentiality .................................................................................................. 79 
12 Data Handling and Record Keeping ..................................................................................... 80 
12.1 
Source Documents ........................................................................................................ 80 
12.2 
Data Collection, Handling, and Verification ................................................................ 80 
13 Financing and Insurance ....................................................................................................... 81 
14 Publication Policy ................................................................................................................. 82 
15 Investigator Requirements .................................................................................................... 83 
15.1 
Study Drug Accountability ........................................................................................... 83 
15.2 
Disclosure of Data ......................................................................................................... 83 
15.3 
Retention of Records ..................................................................................................... 83 
16 References ............................................................................................................................. 84 
17 Appendices ............................................................................................................................ 87 
    


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LIST OF TABLES 
Table 1 Recommended Maximum Daily Dose of Statins .......................................................... 46 
Table 2 Additional Study Procedures/Assessments and Blood Sampling by Visit for the  52-
Week Treatment Period, EOT and Post-EOT (Appendices A, B, K) ........................................... 58 
    
LIST OF FIGURES 
Figure 1 
Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor (HIF-PHI) Mechanism of 
Action 
................................................................................................................................... 35 
Figure 2  
Circulating EPO Exposure with Roxadustat-Treated CKD & ESRD Patients versus 
Reported ESA Dosing Patterns in ESRD 2005 and 2009 ............................................................. 38 
Figure 3 
Study Schemas .......................................................................................................... 42 
LIST OF APPENDICES 
Appendix A – Schedule of Assessments: Screen to Week 52, Including EOT Assessments for 
Patients Completing 52 weeks Treatment..................................................................................... 87 
Appendix B – Patients who Discontinue Study Medication Prior to Week 52 ............................ 89 
Appendix C – Dose Adjustment Rules During the Titration to Achieve TI – Correction Phase 
(Prior to Maintenance Phase) ........................................................................................................ 90 
Appendix D – Dose Adjustment Rules for Patients who have TI for ≥56 Days (8 weeks) – 
Maintenance Phase ........................................................................................................................ 92 
Appendix E – Quality of Life Assessments .................................................................................. 93 
Appendix F – ECOG Assessment Scale ....................................................................................... 95 
Appendix G – International Prognostic Scoring System – Revised (IPSS-R).............................. 96 
Appendix H – Liver Function Monitoring .................................................................................... 97 
Appendix I – Erythropoiesis-Stimulating Agents (ESAs) ............................................................ 99 
Appendix J – Schedule of PK Assessments ................................................................................ 100 
Appendix K – Laboratory Tests .................................................................................................. 101 
Appendix L – Calculation of Creatinine Clearance/eGFR per Cockroft-Gault .......................... 102 
Appendix M – New York Heart Association Classification (NYHA) of Congestive Heart Failure
..................................................................................................................................................... 103 
Appendix N – Blood Pressure and Heart Rate Monitoring ........................................................ 104 
Appendix O – Individual Patient Study Stopping Criteria ......................................................... 105 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
~ 
approximately 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance model 
AST 
aspartate aminotransferase 
BP 
blood pressure 
BSC 
best supportive care 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CHr 
reticulocyte hemoglobin content 
CRP 
C-reactive protein 
CI 
confidence interval 
CKD 
chronic kidney disease 
CMH 
Cochran-Mantel-Haenszel 
CS 
clinically significant 
CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
DB 
double-blind 
DD 
dialysis-dependent 
DD-CKD 
dialysis-dependent chronic kidney disease 
DILI 
drug-induced liver injury 
DSMB 
Data and Safety Monitoring Board 
DVT 
deep vein thrombosis 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
ELISA 
enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
EOS 
end of study 
EOT 
end of treatment 
EPO 
erythropoietin 
EQ-5D 
European Quality of Life (EuroQol) five-dimension health questionnaire  
ER 
emergency room 


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Abbreviation 
Definition 
ESA 
erythropoiesis-stimulating agent 
ESMO 
European Society for Medical Oncology 
ESRD 
end-stage renal disease 
ET 
early termination  
FACT-An 
Functional Assessment of Cancer Therapy – Anemia 
FACT-F 
FACT-Fatigue, a subset of FACT-An 
FDA 
US Food and Drug Administration 
FAS 
full analysis set 
G-CSF 
granulocyte colony stimulating factor 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
Hb 
hemoglobin 
HBsAg 
hepatitis B surface antigen 
HCT 
hematocrit 
HCV 
hepatitis C virus 
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 
HLA 
human leukocyte antigen 
HMA 
hypomethylating agent 
HR 
heart rate 
HRQoL 
health-related quality of life 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IPSS-R 
International Prognostic Scoring System – Revised 
IRB 
Institutional Review Board 
ITT 
Intent to Treat Population 
IV 
intravenous 
LDH 
lactate dehydrogenase 
LDL 
low density lipoprotein 
LLN 
lower limit of normal 
LFT 
liver function test 
LTB 
low transfusion burden 
MDS 
myelodysplastic syndrome 


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Abbreviation 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model repeat measures 
N (or n) 
sample size 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCS 
not clinically significant 
NDD-CKD 
non dialysis-dependent chronic kidney disease 
NIH 
National Institute of Health 
NYHA 
New York Heart Association 
OL 
open-label 
PD 
pharmacodynamics 
PE 
physical exam 
PI 
Principal Investigator 
PK 
pharmacokinetics 
PPS 
per protocol set 
pRBC 
packs of red blood cells 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PT, PTT 
prothrombin time, partial thromboplastin time 
RBC 
red blood cell 
QALY 
quality adjusted life year 
rhEPO 
recombinant human erythropoietin 
RR 
respiratory rate 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
Statistical Analysis Plan 
SCT 
stem cell transplant  
SEER 
surveillance, Epidemiology, and End Results Program of the US National Cancer Institute 
TBili 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TG 
triglycerides 
TI 
transfusion-independent 
TIA 
transient ischemic attack 
TIBC 
total iron binding capacity 
TIW 
three times weekly 
TQT 
thorough clinical study of QT/QTc interval prolongation 
TSAT 
transferrin saturation 
UIBC 
unsaturated iron binding capacity 
ULN 
upper limit of normal 
US 
United States 


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Abbreviation 
Definition 
VEGF 
vascular endothelial growth factor 
VHL 
von Hippel-Lindau protein 
WBC 
white blood cell 
WHODrug 
World Health Organization Drug Dictionary 
 
 


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PROTOCOL SYNOPSIS 
Study Title: 
A Phase 3 Randomized Double-Blind Placebo-Controlled Study 
Investigating the Efficacy and Safety of Roxadustat (FG-4592) for 
Treatment of Anemia in Patients with Lower Risk Myelodysplastic 
Syndrome (MDS) with Low Red Blood Cell (RBC) Transfusion 
Burden (LTB) 
Protocol Number: 
FGCL-4592-082 
Investigational Product: 
Roxadustat (FG-4592) 
Target Population: 
Adult patients with International Prognostic Scoring System – 
Revised (IPSS-R) very low risk, low risk, or intermediate risk MDS 
with <5% bone marrow blasts (lower-risk MDS), and has low RBC 
transfusion burden (requires 1 to 4 packs of RBC [pRBC] per 8-week 
period) 
IND Number: 
129546 
Study Phase: 
Phase 3 
Study Centers Planned: 
Approximately 80  
Number of Patients 
Planned: 
Up to 24 patients will be enrolled in sequential dose level cohorts      
(approximately 1.5, 2.0, or 2.5 mg/kg of Roxadustat – by body 
weight at registration visit) prior to start of the double-blind portion 
of the study.  
Randomized double-blind placebo-controlled along with best 
supportive care (BSC) – 160 patients; 3:2 randomization (96:64; 
roxadustat:placebo) 
Primary Objectives: 
Evaluate the efficacy of roxadustat in the treatment of anemia in 
patients with lower risk MDS who have a low burden of RBC 
transfusion. 
Secondary Objectives: 
• 
Evaluate the safety of roxadustat 
• 
Evaluate the impact of roxadustat on RBC transfusion 
requirements 
• 
Evaluate pharmacokinetics (PK) and pharmacodynamics (PD) of 
roxadustat in MDS patients 
• 
Evaluate effect of roxadustat on quality of life parameters 
Study Design Overview: 
 
 
 
The study consists of two components.  An open-label (OL) lead-in 
component to identify the optimal starting dose for the double-blind 
(DB) phase followed by a DB component comparing treatment with 
roxadustat with placebo along with best supportive care (BSC). The 
study duration for patients in both the OL and DB components is 52 


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Study Design Overview 
(cont.): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
weeks.  A primary efficacy assessment will be made in the DB 
component when all randomised patients have completed 28 weeks 
DB treatment or have discontinued.   
Unless indicated, the same procedures will apply in both components 
of the study. 
In the OL lead-in component, up to 24 patients will be enrolled in 
sequential dose level cohorts (n=8) prior to the start of the DB 
portion of the study.  All patients will receive roxadustat in an OL 
manner.  The first 8 patients will receive a starting dose of 1.5 
mg/kg.  The next 8 patients will receive a starting dose of 2.0 mg/kg.  
The last 8 patients will receive a starting dose of 2.5 mg/kg.  The 
roxadustat dose per body weight are estimates only and the exact 
dose will be assigned per body weight ranges as shown in the body 
of the protocol.  
Upon enrolling the OL component of the study, approximately 
160 patients will be randomized in the DB placebo controlled portion 
of the study. 
Screening Period: 
All screening procedures are to be completed within 28 days prior to 
Day 1 of Treatment, except for documentation of the following 
which can be obtained from patients’ medical records: 
1. Lower risk MDS (IPSS-R very low risk, lower risk, or 
intermediate risk). There is no minimum time from diagnosis 
to registration/randomization except to allow for proper 
IPSS-R classification to be made, and to show transfusion 
dependence for patients in both portions of the study.   
2. Results from bone marrow examination and cytogenetic 
analysis performed within 16 weeks prior to Day 1 of 
treatment can be used.  The required bone marrow slides and 
report must be available for a centralized review at any time 
throughout the study. 
3. Patients are deemed to have low RBC transfusion burden 
(LTB) if they received 1 to 4 documented pRBC transfusions 
within 8 weeks prior to registration/randomization.  Patients 
with 1 pRBC/8-weeks must have a documented history of 
requiring 1 pRBC/8-weeks in 2 consecutive periods of 
8 weeks in the 16 weeks preceding registration/ 
randomization.  Pre-transfusion and post-transfusion 
hemoglobin (Hb) levels within 8 weeks prior to Day 1 of 
treatment will also be recorded.  The percentage of patients 
having 1pRBC transfusion at baseline will be capped at 30% 
for the DB portion of the study.  
Open-Label patients only, the requirement to demonstrate 


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Study Design Overview 
(cont.): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
transfusion dependence can also be met by a principal 
investigator (PI) starting this particular patient on pRBC 
transfusion during the screening period. 
Patients must meet all inclusion and none of the exclusion criteria to 
be eligible for the OL or the DB components of the study.  
Treatment: 
Up to 24 patients will be enrolled in sequential dose level cohorts 
prior to start of the DB portion of the study.  All patients will receive 
roxadustat in an OL manner.  The first 8 patients will receive a 
starting dose of 1.5 mg/kg (Dose Level 1).  The next 8 patients will 
receive a starting dose of 2.0 mg/kg (Dose Level 2).  The last 8 
patients will receive a starting dose of 2.5 mg/kg (Dose Level 3). 
 
The starting dose table for the OL component of the study is shown 
below. 
Dose 
Level 
Group 
 
Approximate 
Roxadustat 
dose level 
( mg/kg) 
Patient Weight 
 
 
 
 
45 to <70 kg 
70 - 100 kg 
> 100 kg 
1 
1.5 
70 mg TIW 
120 mg TIW 
150 mg TIW
2 
2.0 
100 mg TIW 
150 mg TIW 
200 mg TIW
3 
2.5 
150 mg TIW 
200 mg TIW 
250 mg TIW
The OL is intended to optimize the starting dose for the subsequent 
DB portion of the study in which, 160 eligible lower risk MDS 
patients with LTB will be randomized 3:2 to roxadustat or matching 
placebo. It is anticipated that the starting dose level will be Dose 
Level 2 (2.0 mg/kg) and the protocol is written to reflect this but if 
the OL data identifies Dose Level 1 or 3 as a more optimal starting 
dose, this will be implemented. 
Patients in the DB component of the study will be randomized with 
the following stratifications: 
• Serum erythropoietin (EPO) level: either ≤200 mIU/mL OR 
>200 mIU/mL and ≤400 mIU/mL 
• IPSS-R low risk /very low risk vs. intermediate risk group 
classification 
• RBC transfusion burden: 1 pRBC/8-weeks over 16 consecutive 
weeks vs 2-4 pRBC/8-weeks 
The PI and site staff will utilize their own institutional criteria for the 
determination of when to transfuse a patient.  Documentation of 


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Study Design Overview 
(cont.): 
 
 
standard site transfusion criteria will be documented in overall study 
files. 
For all patients (OL and DB components), dose 
adjustments/escalations will occur every 8 weeks at pre-defined dose 
level increments, with the exception that the starting dose will be 
maintained if an erythroid response (defined as a 50% reduction in 
pRBC transfusion from baseline) is seen after the initial 8 weeks of 
dosing.  A re-assessment will be done for these patients at week 12 
and if transfusion independence (TI) is observed the dose will not be 
increased.  If TI is NOT observed at this point, the dose will be 
increased by one dose level.  See Appendix C for details on dosing 
and dose escalation. 
Once TI for at least 8 continuous weeks has been achieved,  
Maintenance Phase will begin and the study drug dose should follow 
guidance described in Appendix D. 
During the course of the study, visits and assessments will be 
performed as defined in the schedule of assessments  
(see Appendix A and Appendix B). 
The overall study duration is 52 weeks with primary efficacy 
assessment after the first 28 weeks in the DB component, and 
continued treatment up to 52 weeks. 
The OL portion patients who receive roxadustat may remain in the 
study up to 52 weeks of treatment based on investigator discretion, 
adequate safety, and impression of benefit.  These patients will 
undergo all procedures as the randomized patients in the DB study 
with the exception of not completing the Health-related quality of 
life (HRQoL) questionnaires. 
When all the randomized (DB) patients complete 28 weeks of 
treatment or are discontinued from study medication before this time, 
the analysis of the primary and secondary efficacy endpoints will 
occur. Only Sponsor personnel who are not directly involved with 
the study sites/patients will have access to the unblinded data.  The 
blind will be maintained for study patients, PI, site staff and site 
monitoring personnel for the remainder of the study (to Week 52 
plus a 4 week follow-up period). 
Follow-Up: 
All patients who complete 52 weeks (of treatment with study 
medication) will undergo a 4 week follow-up period after the last 
dose of study medication. 
Patients who discontinue study medication early (for any reason) will 
remain in the study through the entire 52 week study period.  Patients 
will have a 4 week follow-up visit after stopping study medication 
and then be followed up at a reduced visit schedule of every 8 weeks 


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after the follow-up visit until the end of the study.  
Pharmacokinetics/Pharmacodynamics (PK/PD): 
Blood samples will be collected at the study site for determination of 
roxadustat plasma concentrations and erythropoietin levels at 1-3 and 
3-5 hours after dosing at clinic on Day 1 (Week 1) as well as 4-6 
hours at Week 5 and 8-10 hours at Week 21 after administration at 
the clinic.  
Two samples will be obtained 0-2 hours before dosing and 2-3 hours 
after dosing at Week 25.  Hepcidin levels will also be measured at 
selected timepoints. 
 
Inclusion Criteria: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. 
Diagnosis of primary MDS  (confirmed by bone marrow 
aspirate and biopsy prior to Treatment Day 1), classified by the 
IPSS-R as very low, low, or intermediate risk with <5% bone 
marrow blasts. There is no minimum time from diagnosis to 
registration/randomization except to allow for proper IPSS-R 
classification to be made, and to show transfusion dependence 
for patients in both portions of the study.   
 
2. 
RBC transfusion requirement of either  
a. 2 to 4 pRBC over the 8-weeks prior to 
registration/randomization, or  
b. 1 pRBC during the 8-weeks prior to 
registration/randomization.  Patients with 1 pRBC must have 
a documented history of requiring 1pRBC/8-weeks in 
2 consecutive periods of 8 weeks in the 16 weeks preceding 
registration/randomization  
c. The PI and site staff will utilize their own institutional 
criteria for the determination of when to transfuse a patient. 
d. Open-Label patients only, the requirement to demonstrate 
transfusion dependence can also be met by a  PI starting this 
particular patient on pRBC transfusion during the screening 
period.    
 
3. 
There is no restriction on prior use of recombinant 
erythropoietins or analogues (erythropoiesis-stimulating agents 
(ESAs)), except that the patient must not have received any 
ESA within the 8 weeks prior to Day 1 
registration/randomization.  ESAs include but are not limited to 
any recombinant human erythropoietin and other drugs listed in 
Appendix I.    
4. 
Hb ≤10.0 g/dL during Screening. Hb values are obtained at 


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Screening Visit 1 and 2; only 1 value needs to meet the Hb < 
10.0 g/dL criteria.  These values must be the Central Laboratory 
values.  A third value may be obtained if necessary. 
5. 
Age ≥18 years  
6. 
Body weight ≥45 kg 
7. 
ECOG performance status of 0, 1 or 2 at last screen visit 
(Appendix F) 
8. 
Must be capable of giving written informed consent 
Exclusion Criteria:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. 
Diagnosis of secondary MDS associated with prior 
chemotherapy, extensive radiation therapy (>25% of bone 
marrow reserve), and or/other significant chemical or radiation 
exposure 
2. 
Previous diagnosis of IPSS-R high risk or very high risk MDS 
(Appendix G) 
3. 
Planned myeloablative or craniospinal radiation during the study 
4. 
Prior bone marrow or stem cell transplantation (SCT) 
5. 
Significant myelofibrosis (>2+ fibrosis) 
6. 
MDS associated with 5q(del) cytogenetic abnormality 
7. 
Screen serum erythropoietin level >400 mIU/mL 
8. 
Alanine aminotransferase (ALT) >3 x upper limit of normal 
(ULN), OR  aspartate aminotransferase (AST) >3 × ULN, OR 
total bilirubin (TBili) > 1.5 × ULN (see Appendix H) 
9. 
Azacitidine, decitabine, thalidomide, lenalidomide, granulocyte 
colony-stimulating factor (G-CSF), or luspatercept, or any 
investigational drugs within 8-weeks prior to Day 1 Treatment 
or plans to use any of these medications during the course of 
clinical trial participation 
10. Anticipated use of dapsone at any dose amount or chronic use of 
acetaminophen or paracetamol > 2.0 g/day during the study for 
more than 7 days 
11. Clinically significant anemia, as determined by the investigator, 
due to non-MDS etiologies such as iron deficiency, vitamin B12 
or folate deficiency, autoimmune or hereditary hemolysis or 
anemia or hemorrhage or hereditary anemia such as sickle cell 
anemia or thalassemia 
12. Active infection(s) requiring systemic antibiotic therapy 
13. Cockroft-Gault calculated estimated glomerular filtration rate 
(eGFR) <30 mL/min 
14. Thromboembolic event (such as deep vein thrombosis (DVT)), 
pulmonary embolism, myocardial infarction, stroke, or transient 


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Exclusion Criteria 
(cont.): 
 
 
ischemic attack (TIA), within previous 6 months 
15. Current condition requiring anticoagulant, e.g., warfarin or 
enoxaparin, a factor Xa inhibitor such as rivaroxaban or 
apixaban, or a direct thrombin inhibitor such as dabigatran. 
Chronic use of low-dose aspirin is allowed. 
16. Significant heart disease, including New York Heart 
Association (NYHA) Class III or IV congestive heart failure, 
uncontrolled hypertension or hypotension, or significant 
valvular or endocardial disease that would put the patient at risk 
for thromboembolism 
17. Clinically significant or uncontrolled ongoing 
inflammatory/autoimmune disease (e.g., rheumatoid arthritis, 
Crohn’s disease, celiac disease, etc.) 
18. History of significant liver disease or active liver disease 
19. Major surgery planned during the treatment period 
20. Known, active or chronic gastrointestinal bleeding 
21. Known human immunodeficiency virus (HIV), hepatitis B or 
hepatitis C infection 
22. Clinically significant or uncontrolled medical condition that 
would affect the patient's ability to participate in the study or 
confound the study's efficacy or safety results 
23. History of leukemia or other active malignancy except localized 
and non-metastatic squamous or basal cell carcinoma of the 
skin, or cervical intraepithelial neoplasm;  patients with a 
history of cured malignancy with no evidence of recurrence for 
at least 3 years are eligible 
24. Previous recipient of roxadustat or another hypoxia-inducible 
factor prolyl hydroxylase inhibitor (HIF-PHI)  
25. Pregnant or breastfeeding females 
Study Procedures: 
See Schedule of Assessments (Appendix A and Appendix B) 
Investigational Product: 
 
 
 
Roxadustat  
Tablets with strengths of 20 mg, 50 mg ,100 mg and 150 mg 
Route of Administration: 
Oral (all tablets must be administered whole) 
Comparator: 
Placebo will be similar in appearance to the investigational product 
and matching the dose strengths of the investigational product.  
Best Supportive Care:  
Best supportive care (BSC) including RBC transfusion is permitted 
to ensure patient’s safety.  The PI and site staff will utilize their own 


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institutional criteria for the determination of when to transfuse a 
patient.  Use of any ESA (epoetin alfa, epoetin beta, darbepoetin or 
others) during the study is not permitted (see Appendix I) and 
patients who receive an ESA will be discontinued from further 
treatment with study medication.   Patients who discontinue study 
medication early (for any reason) will remain in the study through 
for the 52 week study period.  Patients will have a 4 week follow-up 
visit after stopping study medication and then will be followed up at 
a reduced visit schedule of every 8 weeks until the end of the study.  
Efficacy Endpoints and 
Assessments  
(DB):  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary Efficacy Endpoint: 
The primary efficacy endpoint is the proportion of patients who 
achieved transfusion-independence (TI) ≥56 consecutive days in the 
first 28 weeks of treatment 
Secondary Efficacy Endpoints (all secondary and exploratory 
endpoints will be analyzed at both for the first 28 weeks of 
treatment and for the end of the 52-week study treatment 
period): 
• Proportion of patients who achieved ≥50% reduction in 
number of RBC transfusion over any 8 weeks compared to 
their baseline 
• Cumulative number of patient-exposure-week of TI  
• Cumulative number of pRBC packs transfused  
• Proportion of patients who achieved TI for ≥20 Weeks (140 
Days) 
• Mean change from baseline in Physical Function as measured 
by Patient Reported Outcomes Measurement Information 
System (PROMIS) 
• Mean change from baseline in PROMIS Fatigue score. 
• Mean change from baseline in Euroqol Quality of Life Five 
Dimensional Five Level Health Questionnaire (EQ-5D-5L) 
assessment 
 
Exploratory endpoints: 
• Duration of  transfusion independence  
• Proportion of patients who achieve a mean Hb increase of 
≥1.0 g/dL and ≥1.5 g/dL (averaged over 8 weeks in those that 
achieved TI) compared to pre-transfusion Hb at baseline 
• Potential impact of baseline endogenous erythropoietin levels 
on roxadustat treatment response and dose requirement 


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• Effect on hepcidin and iron metabolism 
• Effect on cholesterol and lipid parameters 
 
Additional Exploratory Efficacy Endpoints:  
Additional exploratory efficacy endpoints are described in the 
statistical analysis plan and will use the Full Analysis Set (FAS) 
population. 
Safety Assessments:  
• Adverse events (AE) and serious adverse events (SAEs) 
reporting 
• N (%) patients with progression to acute myeloid leukemia 
(AML) 
• Clinical laboratory measures, including hemoglobin and liver 
function tests (LFTs) (AST, ALT, total bilirubin (TBili) and 
alkaline phosphatase(ALP)) 
• Heart rate, blood pressure and electrocardiogram (ECG)  
PK/PD Biomarkers  
& Other Labs: 
• Measurements of  PK, serum erythropoietin levels 
• Measurements of iron indices including serum iron, ferritin, 
transferrin or total iron binding capacity (TIBC), saturation 
and hepcidin 
• Measurements of lipids/cholesterol levels 
Statistical Methods: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Data from patients in the OL component will be analyzed separately 
from the DB randomized component of the study. 
DB Component: 
Descriptive statistics including number of patients (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 will be presented as 
part of the descriptive summaries.   
The following analysis sets are defined and will be used for the 
statistical analysis: 
• 
Full Analysis Set (FAS) 
• 
Safety Analysis Set (SAF) 
The FAS Population consists of all patients randomized to the 
study. This is the population used for the  efficacy analyses. 
The Safety Population consists of all patients who have received at 
least one dose of study drug. 
Analyses of the safety data will be based on the Safety Populations. 
Baseline Hb value for efficacy analysis is defined as the mean of 
Screening central laboratory Hb value and Day 1 Hb value.  


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Statistical Methods 
(cont.): 
 
 
Data Analyses  
160 patients will to be randomized in a 3:2 ratio to roxadustat or 
matching placebo.  This sample size will provide at least 90% power 
to demonstrate a statistically significant difference between 
roxadustat and placebo at the significance level of 0.05 using a two-
sided Fisher’s test, and assuming the response rates of the primary 
endpoint are 35% and 5% in roxadustat and placebo, respectively. 
The primary endpoint of the study will be compared between the two 
treatment groups using the Cochran-Mantel-Haenszel (CMH) chi-
square test, controlling for stratification factors.  
If one or more of the levels of the stratification variables are 
underrepresented during enrollment resulting one or more of the 
(2×2×2) 8 strata having with too few patients to meet the required 
per-strata sample size for the planned statistical methodology then 
the stratification variable with the highest imbalance will not be 
included in the analysis. This practice will be followed for the 
primary, secondary and exploratory variables. 
Categorical endpoints will be analyzed using the CMH test.   
Cox regression model will be used to analyze time-to-event 
endpoints. Analyses will be adjusted by stratification factors and 
baseline value if applicable. 
A sequential gate keeping procedure will be used to control the 
family-wise type I error rate in multiple testing of the primary and 
secondary efficacy endpoints. 
Summary of safety data will be based on the Safety Population. 
Safety parameters include adverse events, laboratory parameters, 
progression to AML, vital signs, ECG parameters, prior and 
concomitant medication use. 
Data Safety Monitoring Board (DSMB): 
A Data Safety Monitoring Board (DSMB) will be established prior 
to the start of the DB portion of the study and will oversee the study 
on a regular and pre-defined basis.  The role and function of the 
DSMB will be defined in the DSMB charter.  Of particular note, the 
likely initial starting dose for the study is 2.0 mg/kg. This may be 
adjusted in agreement with the DSMB if supported by data review. 
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 
The myelodysplastic syndromes (MDS) are clonal disorders of bone marrow characterized by 
ineffective hematopoiesis leading to peripheral blood cytopenias (anemia, neutropenia and 
thrombocytopenia), and an increased predisposition to developing acute myeloid leukemia 
(AML), especially in a high risk MDS category.  The reported 3-year survival rate is 42% and 
the 5-year survival rate is 29% in MDS patients. Patients with higher risks for development of 
AML tend to have lower survival. The main features of MDS are peripheral blood cytopenias 
related to clonal stem cell disorder characterized by progressive ineffective hematopoiesis 
(Tefferi, 2009). Clonal evolution of abnormal hematopoietic stem cell is a multistep process 
involving genetic changes which can be identified by standard cytogenetic techniques and 
advanced molecular testing. 
2.1 Introduction  
2.1.1 Epidemiology of Myelodysplastic Syndrome 
MDS affects at least 60,000 Americans.  An incidence of 4.5 per 100,000 people was reported in 
2006 by Surveillance, Epidemiology and End Results (SEER) and North American Association 
of Central Cancer Registries, Inc. (NAACCR) (Ma, 2007, Rollison, 2008). MDS is a disease of 
older adults, with a median age at diagnosis of approximately 71 years with a male 
predominance. With the exception of treatment-induced MDS (MDS that develops following 
chemotherapy or radiation treatment for another cancer), age of onset prior to 50 is uncommon in 
this disease. According to SEER data, only 4% of patients were reported to registries by 
physicians’ offices (Rollison, 2008). Thus, MDS disease burden in the United States may be 
heavily underestimated. 
2.1.2 Anemia Associated with MDS 
Anemia is the most common clinical presentation in lower risk MDS, which results in prolonged 
transfusion requirements and risks related to red blood cell (RBC) transfusion itself, iron 
overload, and significant impairment of the quality of life in affected patients.  The 
pathophysiology of anemia in MDS is complex, and involves ineffective erythropoiesis, 
dysregulated cytokine signaling, dysplastic features of hematopoietic progenitors and increased 
apoptosis of erythroid precursors, among other factors.  The erythroid dysfunction in MDS often 
presents with fatigue and low hemoglobin level. Anemia in MDS become more symptomatic 
when Hb level becomes lower (i.e., below 9.0 g/dL) as erythroid dysfunction continues to 
decline, RBC transfusion may become necessary supportive treatment.  Dependency on RBC 
transfusion has been associated with shorter life expectancy in patients with MDS.  Anemia 
impacts across patients in all MDS categories of the International Prognostic Scoring System 
(IPSS-R) (Appendix G). 
The disease burden of anemia in MDS is high.  Severe anemia interferes with patients’ quality of 
life and his/her ability to work as well as negatively impacting the function of other organ 
systems due to insufficient oxygen delivery to tissues.  When RBC transfusion become necessary 
to sustain bodily functions, not only are the frequent trips to the hospital burdensome to the 
patient, the risk of transfusion-related infections can further threaten MDS patients some of 
whom may also have a primary neutropenia due to bone marrow dysfunction or secondary 
neutropenia associated with medications for the treatment of MDS; infection is the number one 


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cause of death in MDS patients.  Additional risks with transfusion include transfusion reactions 
(risk accumulates with exposure to more antigens through transfusions) and the iron overload 
from cumulative transfusions may lead to additional organ complications, particularly in heart, 
liver and endocrine organs. 
2.2 Current Treatment for MDS 
The treatment options for lower risk MDS are limited. United States (US) Food and Drug 
Administration (FDA) approved treatments for MDS include the aza-nucleosides 5-azacitidine 
and decitabine, and are typically used for treating intermediate or higher IPSS risk patients.  
These hypomethylating agents (HMAs) can achieve a remission in a minority of the treated 
patients for a short duration of time before progression to AML, and are associated with 
significant levels of neutropenia and thrombocytopenia.  Lenalidomide (Revlimid) is approved in 
the US and in the European Union for MDS patients with 5q(del) resulting in a 61% to 67% 
responder rate.  Yet, 5q(del) represents only 7% to 15% of all MDS patients, and lenalidomide is 
not approved for MDS patients in many other parts of the world.  Other than the high cost of 
treatment, lenalidomide is also associated with significant side effects such as neutropenia (55 to 
75%) and thrombocytopenia (41% to 44%) (List, 2006).  Stem cell transplantation (SCT) is the 
only treatment that has the potential to cure MDS, but it is only appropriate for young MDS 
patients who have high risk disease and have a HLA matched sibling/donor.  No treatment has 
been shown to either delay disease progression or to prolong survival in lower risk MDS.  Thus, 
the goal of therapy in these patients is to improve quality of life and reduce the transfusion 
burden. 
There is no FDA or European Medicines Agency (EMA)-approved effective and safe 
pharmacologic treatment to treat anemia in lower risk MDS patients who are not suitable for 
lenalidomide or HMAs.  To address anemia in lower risk MDS patients, erythropoiesis-
stimulating agents (ESAs) are at times used off-label despite these agents are not approved for 
MDS patients by health authorities such as FDA or EMA.  The guidelines of the National 
Comprehensive Cancer Network (NCCN) (version 1, 2016) recommends for symptomatic 
anemia, with serum EPO ≤500 mU/ml and ring sideroblasts <15% that either recombinant 
human erythropoietin (rh EPO) 40,000-60,000 units be given every 1-3 weeks subcutaneously or 
darbepoetin alfa 150-300 mg/weeks subcutaneously with the addition of granulocyte colony-
stimulating factor (G-CSF) in patients with ring sideroblasts ≥15%.  If a patient responds, the 
treatment should be continued and reduced to dose tolerance; however, there is no guidance on 
titration steps (up or down) nor on duration of treatment.  This has resulted in a high degree of 
variability in clinical practice.  The Clinical Practice Guidelines of the European Society for 
Medical Oncology (ESMO) indeed use weekly doses 30,000-80,000 units of EPO.  Therefore, in 
the absence of a clear standard regimen of the available ESAs, this clinical trial will use placebo 
as the comparator not therefore require all patients to be exposed to subcutaneous 
treatment/placebo.  Patients are allowed RBC transfusions during the study so that symptomatic 
anemia will be safely managed. 
In order to achieve an erythroid response in MDS, the ESA dose used is three to five times 
higher than is required in anemia associated with chronic kidney disease (CKD).  One of the 
potential reasons for this high ESA dose requirement has been suggested is that the inflammation 
seen in MDS may contribute to ESA-resistance.  This inflammation is associated with hepcidin 


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elevation, functional iron deficiency on a progressively dysfunctional bone marrow.  Patients 
who show an initial response to ESAs generally develop resistance to ESA in the course of their 
treatment, and will ultimately become dependent on blood transfusions as they stop responding 
to ESA.  In addition to the extensively reported ESA dose-associated cardiovascular and 
thromboembolic risks in CKD patients, tumor progression risk is also reported in cancer patients 
with ESA use.  The risk and benefit of ESA treatment for MDS patients is not well characterized 
due to a lack of adequate and well controlled studies with ESA in the MDS population.   
The MDS classification system IPSS-R (Appendix G), takes into account the various prognostic 
variables of MDS including cytogenetics, bone marrow blasts, hemoglobin, platelets, and 
absolute neutrophil count.  The risk categories in IPSS-R consists of Very Low Risk, Low Risk, 
Intermediate Risk, High Risk, and Very High Risk.  “Lower risk” consisting of the majority of 
MDS patients, generally refers to very low (19% of MDS in US), low (38%), and a subset of 
intermediate (20%) depending on other risk factors in IPSS-R, and this category corresponds to 
the IPSS (International Prognostic Scoring System) categories of “low risk”, and “intermediate-1 
risk”. “Higher risk” in IPSS-R includes some of intermediate (subset of 20%), high risk (13%), 
and very high risk (10%), and corresponds to the intermediate -2 and high risk in the IPSS. 
MDS has a high disease burden without effective medical treatment.  RBC transfusion is an 
unattractive last resort being used to support MDS patients with severe anemia.  There is an 
urgent need to develop a novel, safe, and convenient therapy for addressing anemia in lower risk 
MDS. 
Roxadustat (FG-4592) is a new chemical entity belonging to a new pharmacological class of 
small molecule enzyme inhibitors (hypoxia inducible factor prolyl hydroxylase inhibitor, HIF-
PHI).   It is a potent and reversible inhibitor of the prolyl hydroxylase enzymes that regulate the 
stability of the hypoxia-inducible factor (HIF) for regulation of erythropoiesis.  We currently 
propose to evaluate roxadustat for the treatment of anemia in very risk, low risk and intermediate 
risk with <5% bone marrow blasts in patients with low RBC transfusion burden (LTB). 
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, 2005).  Hypoxia-inducible factor is a heterodimeric transcription 
factor family comprising three oxygen-sensitive isoforms (HIF-1α, HIF-2α and HIF-3α), and a 
constitutively expressed HIF-1β subunit, with each heterodimeric isoform responsible for the 
induction of specific sets of genes (Greijer, 2005, Hu, 2003).  For example, HIF-1α has been 
shown to regulate vascular endothelial growth factor (VEGF) expression (Buchler, 2003,  
Gray, 2005), while HIF-2α is critical for the induction of the erythropoietin (EPO) gene and 
erythropoiesis (Scortegagna, 2005, Warnecke, 2004).   


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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, 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 hypoxia-inducible factor prolyl 
hydroxylases (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 (Semenza, 1998, Wang, 1995). 
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, 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 patients 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 (Besarab, 2015).  
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, 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 
As of 07 September 2016, a total of 9,876 subjects, healthy and with CKD, have been enrolled in 
31 completed studies (twenty-four Phase 1 and seven Phase 2) and in 12 ongoing studies (two 
Phase 2, 8 global Phase 3 studies, and two Phase 3 studies in China). In these studies, an 
estimated total of 5,912 subjects have received roxadustat, comprising 753 healthy subjects and 
an estimated 2,483 subjects with NDD CKD and 2,676 subjects DD CKD.  Long term studies 
suggest durability of erythropoietic effect.  There have been no safety concerns to date, inclusive 


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of negative thorough clinical study of QT/QTc interval prolongation which tested roxadustat 
dose up to 5 mg/kg in healthy volunteers. 
Six completed FibroGen-sponsored phase 2 studies had 670 study patients with 545 patients 
exposed to roxadustat.  Anemia correction and Hb maintenance with dose response were 
demonstrated across multiple studies with roxadustat in CKD patients on dialysis and those not 
on dialysis.  The anemia correction response rates in anemic CKD patients not on dialysis 
(Studies FGCL-4592-041 and FGCL-4592-047) and those starting dialysis therapy (FGCL-4592-
053) were >90%, enough though about half of the patients were not iron-replete at baseline, and 
that the severity of anemia were variable with baseline Hb that ranged between 6 to 10 g/dL 
(more details are provided in the Investigator Brochure).  Roxadustat has also been shown to 
maintain Hb levels when ESA has been withdrawn in dialysis-dependent (DD) end stage renal 
disease (ESRD) patients who previously depended on ESA for Hb maintenance (Studies FGCL-
4592-040 and FGCL-4592-048).   
In CKD patients, the roxadustat dose requirement is not altered when baseline C-reactive protein 
level (CRP) is elevated, a measure of inflammation, which is suggestive of roxadustat’s ability to 
overcome the dampening effect of inflammation on erythropoiesis.  This is a challenge for ESA 
use for anemia in various patient population with chronic diseases.  Roxadustat also overcomes 
the iron dysregulation in CKD patients to enable iron utilization for erythropoiesis, by reducing 
the hepcidin level, and also lowering serum ferritin levels. 
In addition to the subjects in the completed phase 1 and 2 studies, ongoing phase 3 studies have 
exposed >8,000 patients to roxadustat, some for over 2 years, and no safety signal with 
roxadustat has been identified. 
2.4.1 Pharmacokinetics and Pharmacodynamics 
Supraphysiologic recombinant human erythropoietin (rhEPO) levels may be a contributing factor 
in the increased cardiovascular and thrombotic risk observed in ESA treated CKD patients and 
the very high doses of ESA required (up to five times the dose required in anemia associated 
with CKD) potentially contribute to ESA’s cancer progression risks in oncology patients.  
Roxadustat, a HIF-PHI mechanism impacting multiple parts of the erythropoietic pathway has 
been shown to expose CKD patients to much lower plasma EPO level than ESA when achieving 
comparable erythropoietic effects, and the transient peak levels of EPO level with roxadustat 
doses used in CKD patients are within the range of physiologic adaptation.  The Figure 2  depicts 
impact of environment on plasma EPO levels: with a range from 10 to 15 mIU/mL in healthy 
subjects at sea level, while EPO levels triggered by physiologic adaptation to phlebotomy are in 
the range of 15 to 250 mIU/mL (Goldberg, 1993, Maeda, 1992), and adaptation to moderate high 
altitude (4500 m) showed mean levels up to 70 mIU/mL  
(Milledge, 1985), to doses used in CKD patients on dialysis (far right).  The off-label ESA use 
for treatment of anemia in MDS patients are typically at doses comparable to the EPO hypo-
responsive ESRD-dialysis patients (such as those at or above the highest dose quartile in 
Figure 2) that leads to two orders of magnitude above the normal physiologic range of EPO. 
Exposure to high ESA levels are thought to be associated with higher risks to off-target effects of 
ESA.  Roxadustat has a potential to address anemia need with more physiologic EPO exposure. 
 
 


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Figure 2  Circulating EPO Exposure with Roxadustat-Treated CKD & ESRD Patients 
versus Reported ESA Dosing Patterns in ESRD 2005 and 2009 
 
1Cmax data for roxadustat estimated for a subset of 243 patients who achieved Hb response and were dosed at 
expected therapeutic doses; 2Milledge & Cotes (1985); 3Goldberg et al. (1993), Maeda et al. (1992);  
4 Kato et al. (1994); 5Based on Flaharty et al. (1990) 
Furthermore, the roxadustat intermittent dosing regimen (three times weekly, TIW) enables the 
HIF system to reset before next round of stabilization which enhances the durability of its 
therapeutic effect by avoiding tachyphylaxis while minimizing the risk of off-target effects on 
the HIF biology. 
2.4.2 Experience with HIF-PHI in MDS, Rationale for Roxadustat in MDS Anemia, & 
Study Overview 
FibroGen has conducted a study in ESA-refractory lower-risk MDS patients using FG-2216 
which is a HIF-PHI with a similar mechanism of action to roxadustat, but its potency is only 
about a fifteenth that of roxadustat.  In study FG-2216-014, 44 evaluable US ESA refractory 
lower-risk MDS patients (most of whom were transfusion-dependent) were dosed with FG-2216 
with doses between 1250 mg to 2500 mg TIW for 16 weeks; some erythroid responses were 
observed.  These doses of FG-2216 were comparable to roxadustat 70 mg to 150 mg, which is 
significantly below the maximum permitted roxadustat dose of 400 mg or 3.5 mg/kg (whichever 
is the lower).  
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, increased sensitivity to erythropoietin in the erythroid progenitor cells in 
the bone marrow, and dose-dependent erythropoiesis, suggests a coordinated mechanism of 
erythropoiesis that is different from ESA therapy, including beneficial effects on iron handling 
while overcoming barriers to erythropoiesis such as inflammation and iron availability as present 


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in many chronic disease conditions including MDS.  The clinical data collected from >4000 
subjects thus far suggest that roxadustat is generally safe and well tolerated in healthy adult 
subjects, and in dialysis-dependent and non dialysis-dependent CKD patients who have been 
enrolled and treated in completed and ongoing clinical studies.   
Extensive clinical experience with roxadustat enables the design of this protocol in Lower-Risk 
MDS anemia. The study will comprise a 3:2 randomized (roxadustat:placebo) placebo controlled 
study with 160 lower risk patients (inclusive of anemic patients, with Hb ≤10 g/dL, in those who 
require RBC transfusion), with treatment duration of 52 weeks.  The primary efficacy will be 
evaluated by the Sponsor after 28 weeks of DB treatment (Appendix A).  The sites and 
investigators will remain blinded during the treatment period. The study will have 90% power to 
detect treatment difference of 35% vs 5% in roxadustat and placebo respectively for the primary 
endpoint of transfusion independence. 
2.5 Roxadustat Dose Rationale  
For the treatment of anemia in MDS patients, roxadustat will be administered orally three times 
per week (TIW) and titrated to achieve the target response. It is expected that patients will 
require a higher dose due to bone marrow dysfunction and this is supported by experience with 
the earlier agent FG-2216 as discussed in Section 2.4.2.  The OL component will evaluate three 
cohorts (approximately 1.5 mg/kg, 2.0 mg/kg and 2.5 mg/kg) to optimize the starting dose for the 
DB component. After each 8 weeks on a dose level, the patient’s response will be assessed and 
the study treatment will be titrated (pre-defined levels, Appendix C) to achieve transfusion 
independence. The study treatment can be down titrated at any time. Once the patient has 
achieved TI, the dose will be maintained as per Appendix D. The regimen is consistent with that 
of the roxadustat CKD clinical development program and utilizes tiered body weight. The 
maximum permitted dose will be the same as that allowed in the CKD program of 400 mg or 3.5 
mg/kg TIW (whichever is lower). 
2.6 Risks/Benefits of Roxadustat Treatment 
MDS has a high disease burden without effective medical treatment. RBC transfusion is an 
unattractive last resort being used to support MDS patients with severe anemia.  There is an 
urgent need to develop an effective, safe, and convenient therapy for addressing anemia in lower 
risk MDS. 
The primary benefit of roxadustat is the correction of anemia thus the reduction of RBC 
transfusions. This will result in the relief of the associated anemia signs and symptoms, the 
avoidance of the risks associated with RBC transfusions, and an improved quality of life for 
these elderly patients. Roxadustat is expected to overcome the inhibitory effect of inflammation 
of chronic disease on erythropoiesis, to improve erythropoietic progenitor cells’ response to 
erythropoietin, to facilitate the mobilization of iron and ultimately lead to improved 
erythropoiesis. 
A dose adjustment algorithm will be used during the Treatment Period to minimize transfusion 
burden with the primary goal of reaching transfusion independence, (Appendix C and  
Appendix D).  The risk of excessive erythropoiesis (an increase in Hb of 2.0 g/dL at any time 
during the treatment period) will be mitigated by use of the dose adjustment algorithm. The 


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erythropoietic effects of roxadustat are reversible when treatment stops.  Based on the clinical 
and nonclinical trial results to date, it is anticipated that orally administered roxadustat will be 
effective in the treatment of anemia in patients with MDS who have no approved treatment with 
an acceptable safety profile.  
2.7 Objectives 
2.7.1 Primary Objective 
The primary objective of this study is to evaluate the efficacy of roxadustat in the treatment of 
anemia in patients with lower risk MDS who have a low burden of RBC transfusion. 
2.7.2 Secondary Objectives 
The secondary objectives in this study are to: 
• 
Evaluate the safety of roxadustat 
• 
Evaluate the impact of roxadustat on RBC transfusion requirements 
• 
Evaluate pharmacokinetics (PK) and pharmacodynamics (PD) of roxadustat in MDS 
patients 
• 
Evaluate effect of roxadustat on quality of life parameters 
2.7.3 Open-Label Component Objective 
• 
Optimize the starting dose for the DB component  
2.8 Efficacy Endpoints 
2.8.1 Primary Efficacy Endpoint: 
The primary efficacy endpoint is the proportion of patients who achieved TI ≥56 consecutive 
days in the first 28 weeks of treatment. 
2.8.2 Secondary Efficacy Endpoints  
• Proportion of patients who achieved ≥50% reduction in number of RBC transfusion over 
any 8 weeks compared to their baseline 
• Cumulative number of patient-exposure-week of TI  
• Cumulative number of pRBC packs transfused  
• Proportion of patients who achieved TI for > 20 weeks (140 days) 
• Mean change from baseline in Physical Function as measured by Patient Reported 
Outcomes Measurement Information System (PROMIS) 
• Mean change from baseline in PROMIS Fatigue score. 
• Mean change from baseline in EuroQol Quality of Life Five Dimensional Five Level 
Health Questionnaire (EQ-5D-5L) assessment 
2.8.3 Exploratory Endpoints 
• Duration of transfusion independence 
• Proportion of patients who achieve a mean Hb increase of ≥1.0 g/dL and  ≥1.5 g/dL 
(averaged over 8 weeks in those achieved TI) compared to pre-transfusion Hb at baseline 


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• Impact of baseline endogenous erythropoietin levels on roxadustat treatment response 
and dose requirement  
• Effect on hepcidin and iron indices metabolism 
• Effect on cholesterol and lipid parameters  
. 
2.9 Safety Assessments 
Study-specific safety will be assessed by evaluating the following over 52 weeks: 
• AE and SAE reporting 
• N (%) of patients with progression to AML 
• Clinical laboratory measures, including Hb and LFTs (AST, ALT, TBili and ALP) 
• Heart rate, blood pressure, and ECG changes (including changes from Baseline) 
• Evaluation of PK/PD data 


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3 STUDY DESIGN 
3.1 Description of the Study 
The study design is illustrated in Figure 3 below: 
Figure 3 Study Schemas 
 
 
Up to 24 patients will be enrolled in sequential dose level cohorts prior to start of the DB 
component of the study.  All patients will receive roxadustat in an OL manner.  The first 8 
patients will receive a starting dose of 1.5 mg/kg (Dose Level 1).  The next 8 patients will 
receive a starting dose of 2.0 mg/kg (Dose Level 2).  The last 8 patients will receive a starting 
dose of 2.5 mg/kg (Dose Level 3).  Each patient’s starting dose will be determined by their actual 
weight at the registration/randomization visit.  The roxadustat dose per body weight are estimates 
only and the exact dose will be assigned per body weight ranges as shown in the body of the 
protocol. 
The OL component is intended to optimize the starting dose for the subsequent double- blind 
component of the study in which 160 eligible lower risk MDS patients with LTB will be 
randomized 3:2 to roxadustat or matching placebo.  It is anticipated that the starting dose level 


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will be level 2 (2.0 mg/kg) and the protocol is written to reflect this but if the OL data suggests a 
lower (1.5 mg/kg) or a higher (2.5 mg/kg) dose to be a more optimal starting dose, then this will 
be implemented accordingly.   
Patients in the DB component of the study will be randomized with the following stratifications: 
• Serum EPO level: either ≤200 mIU/mL OR >200 mIU/mL and ≤400 mIU/mL 
• IPSS-R low risk / very low risk vs. intermediate risk group classification 
• RBC transfusion burden: 1 pRBC/8-weeks over 16 consecutive weeks vs 2-4 pRBC/8-
weeks 
For the OL and the DB components, dose adjustments/escalations will occur every 8 weeks at 
pre-defined dose level increments, with the exception that the starting dose will be maintained if 
an erythroid response (defined as a 50% reduction in pRBC from baseline) is seen after the initial 
8 weeks of dosing.  A re-assessment will be done for these patients at week 12 and if transfusion 
independence (TI) is observed the dose will not be increased.  If TI is NOT observed at this 
point, the dose will be increased by one dose level.  See Appendix C for details on dosing and 
dose adjustment.  
Once transfusion independence for at least 8 continuous weeks has been achieved and the 
“maintenance treatment period” starts, the study drug dose should follow guidance described in 
Appendix D. 
When all the randomized patients complete 28 weeks of treatment or are discontinued from study 
medication before this time, the analysis of the primary and secondary efficacy endpoints will be 
performed.  Only Sponsor personnel who are not directly involved with the study sites/patients 
will have access to the unblinded data.  The blind will be maintained for study patients, PI, site 
staff and site monitoring personnel for the remainder of the study (to Week 52 plus a 4 week 
follow-up period). 
The initial OL component with up to 24 patients who receive roxadustat may remain in the study 
up to 52 weeks of treatment based on investigator discretion, adequate safety, and impression of 
benefit.  These patients will undergo all procedures as will the randomized patients with the 
exception of not completing the Health-related quality of life (HRQoL) questionnaires. 
During the course of the study, visits and assessments will be performed as defined in the 
schedule of assessments (see Appendix A and Appendix B).   
3.1.1 Screening Period 
All screening procedures are to be completed within 28 days prior to Day 1 of Treatment, except 
for documentation of the following which can be obtained from patient medical records: 
1. Lower risk MDS (IPSS-R very low risk, lower risk, or intermediate risk) must be 
documented prior to Day 1 of Treatment. There is no minimum time from diagnosis to 
registration/randomization except to allow for proper IPSS-R classification to be made, 
and to show transfusion dependence for patients in both portions of the study.   
2. Results from bone marrow examination and cytogenetic analysis performed within 16 
weeks prior to Day 1 of treatment can be used.  The required bone marrow slides and 
report must be available for a centralized review at any time throughout the study. 


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3. Patients are deemed to have low RBC transfusion burden (LTB) if they received 1 to 
4 pRBC documented transfusion within 8 weeks prior to registration/randomization.  
Patients with 1 pRBC/8-weeks must have a documented history of requiring 1pRBC/ 8-
weeks in 2 consecutive periods of 8 weeks in the 16 weeks preceding 
registration/randomization.  Pre-transfusion and post-transfusion Hb levels within 8 
weeks prior to Day 1 of treatment will also be recorded.  The percentage of patients 
requiring 1 pRBC transfusion at baseline will be capped at 30% for the DB portion of the 
study.  For OL patients only, the requirement to demonstrate transfusion dependence can 
also be met by a PI starting this particular patient on pRBC transfusion during the 
screening period 
All patients must meet all inclusion and have none of the exclusion criteria to be eligible to 
receive study medication.  
3.1.2 Treatment Period 
The treatment duration is 52 weeks. 
3.1.3 Follow-Up Period 
All patients who complete 52 weeks (of treatment with study medication) will undergo a 4 week 
follow-up period after the last dose of study medication. 
Patients who discontinue study medication early (for any reason) will remain in the study 
through the entire 52 week study period.  Patients will have a 4 week follow-up visit after 
stopping study medication and then be followed up at a reduced visit schedule of every 8 weeks 
after the final follow-up visit until the end of the study. 
3.2 Replacement of Patients  
Patients who drop out prematurely will not be replaced in the study. 
3.3 Study Treatment 
3.3.1 Dose and Schedule 
Up to 24 patients will be enrolled in sequential dose level cohorts PRIOR to start of the DB 
component of the study.  All patients will receive roxadustat in an OL manner.  The first 8 
patients will receive a starting dose of 1.5 mg/kg (Dose Level 1).  The next 8 patients will 
receive a starting dose of 2.0 mg/kg (Dose Level 2).  The last 8 patients will receive a starting 
dose of 2.5 mg/kg (Dose Level 3).  All doses will be determined by actual patient weight on 
registration/randomization day. 


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The starting dosing table for the OL portion of the study is shown below. 
Dose 
Level 
Group 
Approximate 
Roxadustat 
Dose (mg/kg) 
Patient Weight 
 
 
45 to <70 kg 
70 - 100 kg 
> 100 kg 
1 
1.5 
70 mg TIW 
120 mg TIW 
150 mg TIW 
2 
2.0 
100 mg TIW 
150 mg TIW 
200 mg TIW 
3 
      2.5 
             150 mg TIW 
    200 mg TIW 
              250 mg TIW 
The OL is intended to optimize the starting dose for the subsequent DB component of the study 
in which 160 eligible lower risk MDS patients with LTB will be randomized 3:2 to roxadustat or 
matching placebo.  It is anticipated that the starting dose level will be level 2 (2.0 mg/kg) and the 
protocol is written to reflect this but if the OL data identifies level 1 or 3 as a more optimal 
starting dose, then this will be implemented. 
Patients in the DB component of the study will be randomized at an overall ratio of 3:2 to 
roxadustat or placebo with the following stratifications: 
• Serum EPO level: either ≤200 mIU/mL OR >200 mIU/mL and ≤400 mIU/mL 
• IPSS-R low risk / very low risk vs. intermediate risk group classification 
• RBC transfusion burden: 1pRBC/8-weeks over 16 consecutive wks vs 2-4 pRBC/8wks  
3.3.2 Dose Adjustment  
There are two periods for the study drug dosing – the correction phase and the maintenance 
phase.   
Correction phase: Dose adjustments/escalations will occur every 8 weeks at pre-defined dose 
level increments, with the exception that starting dose will be maintained if erythroid response 
(defined as a 50% reduction in pRBC from baseline) is seen after the initial 8 weeks of dosing.  
A re-assessment will be done for these patients at week 12 and if transfusion independence (TI) 
is observed the dose will not be increased.  If TI is NOT observed at this point, the dose will be 
increased by one dose level (see Appendix C). 
Maintenance Phase:  Once transfusion independence for at least 8 continuous weeks (>56 
consecutive days)  has been achieved and the “maintenance treatment period” starts, the study 
drug dose may be escalated or reduced in pre-defined levels as described in Appendix D. 
During the course of the study, visits and assessments will be performed as defined in the 
schedule of assessments (see Appendix A). 
Dose reductions can occur at any time per defined criteria (see Appendix C and Appendix D). 
Dosing with study medication may be held (not given) for one single instance not to exceed 2 
weeks. Please contact the medical monitor with any questions. 
Given the complexities of the dose adjustment algorithm, and the need to take into consideration 
various clinical parameters, it is not considered a protocol deviation when study subjects are 
dosed based on their clinical circumstance, whether or not this is concordant with the roxadustat 


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dosing algorithm, unless it is related to “excessive hematopoiesis” or “Overdose” (prescribed 
400 mg or > 3.5 mg/kg/dose). 
3.4 Concomitant Medications, Procedures and Nondrug Therapies 
3.4.1 Concomitant Medications 
Concomitant medications are any prescription or over-the-counter preparations, including herbal 
products and “natural remedies,” used by a patient while participating in this clinical study.  
For all concomitant medication use, an indication for its use should be provided. If the stated 
indication is a nonspecific condition (e.g., “rash”), documentation of the condition, as specific as 
possible, should be maintained in the patient’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 in administration of chronic 
concomitant medications should be minimized and done only if deemed necessary by the PI. 
3.4.1.1  Phosphate Binders 
When coadministered with roxadustat, in a clinical pharmacology study, the bioavailability of 
roxadustat was reduced.  Patients should be advised to discuss with the Investigator when 
changing the dose or dosing time of their phosphate binder while taking study medication.  
3.4.1.2  Statins 
When coadministered with roxadustat, in clinical pharmacolgical studies, hydroxymethylglutaryl 
coenzyme A reductase inhibitor (statin) exposure was increased 2- to 3-fold.  Investigators 
should consider this interaction and local prescribing information when deciding on the 
appropriate statin dose for individual 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 Table 1.  
Table 1 Recommended Maximum Daily Dose of Statins  
Statins 
Recommended maximum dose (mg/day) 
Atorvastatin  
40 
Simvastatin 
  5 
Rosuvastatin 
  5 
Pravastatin 
40 
Fluvastatin 
20 
Pitavastatin 
  1 
Lovastatin 
20 
3.4.2 Supplemental Iron Use 
Oral iron supplementation is allowed.  IV iron use is prohibited, but may be considered if patient 
was iron-deficient and unresponsive to oral iron supplementation and lacking erythroid response 
to study medication.  This would require discussion with the Medical Monitor. 


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3.4.3 Best Supportive Care 
Best supportive care including RBC transfusion is permitted to ensure patient’s safety.  The PI 
and site staff will utilize their own institutional criteria for the determination of when to transfuse 
a patient.  Use of any ESA (epoetin alfa, epoetin beta, darbepoetin or others) is not permitted (see 
Appendix I) and patients who receive an ESA will be discontinued from further treatment with 
study medication. 
3.4.4 Emergency Procedure (Therapeutic Phlebotomy) 
If there are clinical concerns for a patient’s Hb levels being too high, 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. 
3.4.5 Prohibited Medications/Therapies/Substances 
The following medications/therapies are prohibited from 8 weeks prior to screening through to 
the End of Treatment visit except for ESAs which are prohibited for 8 weeks prior to Week 1 
Day 1 registration/randomization visit and at any time during the study (see first bullet below 
regarding ESAs) 
• 
Any use of ESAs (erythropoietin stimulating agents) 8 weeks prior to Week 1 Day 1 
registration/randomization, such as epoetin alfa, epoetin beta, darbepoetin, etc. (see 
Appendix I). Patients who receive an ESA during the study will be discontinued from 
further treatment with study medication.  Patients who discontinue study medication early 
(for any reason) will remain in the study through the 52 week study period.  Patients will 
have a 4 week follow-up visit after stopping study medication and then be followed up at 
a reduced visit schedule of every 8 weeks until the end of the study.  
• 
Androgens 
• 
IV iron (but oral iron is allowed) 
• 
Agents intended to treat MDS, e.g., azacitidine, decitabine, thalidomide,  or lenalidomide 
• 
Granulocyte colony stimulating factors (G-CSF).  Exception is that G-CSF can be used 
per package insert/local prescribing directions to treat infections and/or pancytopenia, but 
NOT as prophylaxis. 
• 
Dapsone 
• 
Acetaminophen >2 g/day for more than 7 days 
• 
Investigational agents such as luspatercept, etc. 
3.4.6 Contraception 
Female patients of childbearing potential, if not practicing complete sexual abstinence, must 
agree to an acceptable method of contraception.  Male patients (nonsurgically sterile; i.e., no 
vasectomy) with female partners of childbearing potential who are not on birth control must 
agree to use a barrier method of contraception (e.g., condom) or the female partner must agree to 
use contraception as described above unless practicing complete sexual abstinence. 
Patients must agree to practice above contraceptive methods, as applicable, for the entire 
duration of the study, from registration/randomization through the EOT visit.  It is highly 
recommended that they continue to practice the contraceptive methods for 12 weeks following 


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the last dose of study treatment.  For patients discontinuing study medication prematurely, it is 
recommended that they continue to practice contraceptive methods for 12 weeks following the 
last dose of study treatment. 
Pregnancy, spontaneous or therapeutic abortion, or events related to pregnancy must be reported 
(Section 7.3.6). 
3.5 Safety Monitoring Plan 
Safety will be assessed throughout the study. A complete baseline profile of each patient 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 and laboratory tests will be performed at regular intervals as described in schedule of 
assessments (Appendix A and Appendix B). 
Blood pressure (BP) and heart rate (HR) should be assessed according to the guidelines 
described in Appendix N.  
A physical exam (PE) will be conducted during Screening, Day 1, Week 28, EOT and at the 4 
Week post-EOT visit.   
Any significant findings prior to administration of study drug will be considered as baseline 
conditions and 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 H). 
All adverse events (AEs), serious AEs (SAEs), and ongoing concomitant medication usage will 
be monitored and recorded throughout the study.  SAE reports will be evaluated individually to 
assess the impact of the event, if any, on the overall safety of the product and on the study itself. 
Cumulative AEs will be monitored throughout the study.  SAEs and AEs will be followed until 
resolved, deemed stable, or until the patient’s 4-week post EOT visit.  See Section 7 for details 
on AE and SAE reporting. 
3.6 Data Safety Monitoring Board 
A Data Safety Monitoring Board (DSMB) will be established prior to the start of the DB portion 
of the study and will oversee the study on a regular and pre-defined basis.  The role and function 
of the DSMB will be defined in the DSMB charter.  Of particular note, the likely initial starting 
roxadustat dose for the DB portion of the study is 2.0 mg/kg. This may be adjusted in agreement 
with the DSMB if supported by data review. 
 


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4 STUDY ENROLLMENT AND WITHDRAWAL 
4.1 Inclusion Criteria 
A patient is eligible for the study if all of the following criteria are met: 
1. Diagnosis of primary MDS (confirmed by bone marrow aspirate and biopsy prior to 
treatment Day 1), classified by the IPSS-R as very low, low, or intermediate risk with 
<5% bone marrow blasts. There is no minimum time from diagnosis to 
registration/randomization except to allow for proper IPSS-R classification to be made, 
and to show transfusion dependence for patients in both portions of the study.   
2. RBC transfusion requirement of either: 
a. 2 to 4 pRBC over the 8-weeks prior to registration/randomization,  
OR  
b. 1 pRBC during the 8-weeks prior to registration/randomization:  Patients with 1 
pRBC must have a documented history of requiring 1 pRBC/8-weeks in 
2 consecutive periods of 8 weeks in the 16 weeks preceding 
registration/randomization 
c. The PI and site staff will utilize their own institutional criteria for the 
determination of when to transfuse a patient. 
d. Open-Label patients only, the requirement to demonstrate transfusion 
dependence can also be met by a PI starting this particular patient on pRBC 
transfusion during the screening period.   
3. There is no restriction on prior use of recombinant erythropoietins or analogues 
(erythropoiesis-stimulating agents (ESAs)), except that the patient must not have received 
any ESA within the 8 weeks prior to Day 1 registration/randomization.  ESAs include but 
are not limited to any recombinant human erythropoietin and other drugs listed in 
Appendix I. 
4. Hb ≤10.0 g/dL during Screening period. Hb values are obtained at Screening Visit 1 and 
2; only 1 value needs to meet the Hb ≤ 10.0 g/dL criteria.  These values must be the 
Central Laboratory values.  A third value may be obtained if necessary. 
5. Age ≥18 years  
6. Body weight ≥45 kg 
7. ECOG performance status of 0, 1 or 2 at last screen visit (see Appendix F) 
8. Must be capable of giving written informed consent 
4.2 Exclusion Criteria 
Patients will be excluded if any of the following criteria are met: 
1. 
Diagnosis of secondary MDS associated with prior chemotherapy, extensive radiation 
therapy (>25% of bone marrow reserve), and or/other significant chemical or radiation 
exposure 
2. 
Previous diagnosis of IPSS-R high risk or very high risk MDS (see Appendix G) 


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3. 
Planned myeloablative or craniospinal radiation during the study 
4. 
Prior bone marrow or stem-cell transplantation (SCT) 
5. 
Significant myelofibrosis (>2+ fibrosis) 
6. 
MDS associated with 5q(del) cytogenetic abnormality 
7. 
Screen serum erythropoietin level > 400 mIU/mL 
8. 
Alanine aminotransferase (ALT) > 3 x ULN,  OR aspartate aminotransferase (AST) > 3 × 
ULN OR TBili > 1.5 × ULN (see Appendix H) 
9. 
Azacitidine, decitabine, thalidomide, lenalidomide, G-CSF, or luspatercept, or any 
investigational drugs within 8-weeks prior to Day 1 treatment or plans to use any of these 
medications during the course of clinical trial participation 
10. Anticipated use of dapsone at any dose amount or chronic use of acetaminophen or 
paracetamol >2.0 g/day during the study for more than 7 days 
11. Clinically significant anemia, as determined by the investigator, due to non-MDS etiologies 
such as iron deficiency, vitamin B12 or folate deficiency, autoimmune or hereditary 
hemolysis or anemia or hemorrhage or hereditary anemia such as sickle cell anemia or 
thalassemia 
12. Active infection(s) requiring systemic antibiotic therapy 
13. Cockroft-Gault calculated estimated glomerular filtration rate (eGFR) <30 mL/min 
14. Thromboembolic event such as DVT, pulmonary embolism, myocardial infarction, stroke, 
or TIA, within previous 6 months 
15. Current condition requiring anticoagulant, e.g., warfarin or enoxaparin, a factor Xa inhibitor 
such as rivaroxaban or apixaban, or a direct thrombin inhibitor such as dabigatran. Chronic 
use of low-dose aspirin is allowed. 
16. Significant heart disease, including NYHA Class III or IV congestive heart failure, 
uncontrolled hypertension or hypotension, or significant valvular or endocardial disease that 
would put the patient at risk for thromboembolism 
17. Clinically significant or uncontrolled ongoing inflammatory/autoimmune disease (e.g., 
rheumatoid arthritis, Crohn’s disease, celiac disease, etc.) 
18. History of significant liver disease or active liver disease 
19. Major surgery planned during the treatment period 
20. Known, active or chronic gastrointestinal bleeding 
21. Known human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection 
22. Clinically significant or uncontrolled medical condition that would affect the patient's ability 
to participate in the study or confound the study's efficacy or safety results 
23. History of leukemia or other active malignancy except localized and non-metastatic 
squamous or basal cell carcinoma of the skin, or cervical intraepithelial neoplasm; patients 
with a history of cured malignancy with no evidence of recurrence for at least 3 years are 
eligible 
 


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24. Previous recipient of roxadustat or another hypoxia-inducible factor prolyl hydroxylase 
inhibitor (HIF-PHI)  
25. Pregnant or breastfeeding females 
4.3 Treatment Discontinuation 
Patients who discontinue study medication early (for any reason) will remain in the study 
through the 52 week study period.  Patients will have a 4 week follow-up visit after stopping 
study medication and then be followed up at a reduced visit schedule of every 8 weeks until the 
end of the study. 
Patients will be discontinued from treatment for the following reasons  
(below and Appendix H and Appendix O): 
a. Disease progression: Diagnosis of AML during the study 
b. Liver Function: Discontinuation of treatment will occur 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 international normalized ration (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%) 
A patient who decides to discontinue treatment with study medication will always be asked about 
the reason(s) for discontinuation and the presence of AEs (if any).  These data will be ascertained 
and documented by the investigator and recorded in the electronic case report forms (eCRF) as 
appropriate.  The patient should return all study medications.  
Reasons for permanent discontinuation of treatment with study medication: 
• Patient’s decision (subject no longer wants to continue study medication (i.e., withdrawal 
of consent) 
• Investigator’s decision that it is in the best interest of the patient to be withdrawn from 
the study 
• AEs (including SAEs) 
• Significant noncompliance with study procedures, as determined by Investigator or 
Sponsor 
• Lack of efficacy  
• Treatment with ESAs 
• Patient is lost to follow-up  
• Site terminated by the Sponsor 
• Pregnancy 
• Death 


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4.4 Replacement of Patients 
Patients will not be replaced for this study.  
4.5 Study Termination 
This trial can be terminated by the Sponsor at any time for any reason.  
4.6 Blinding 
For the DB component of the study, the Investigator, study site staff, subject and the Sponsor and 
designees, are blinded to study drug assignment, but not to the dose.  Additionally, all efforts 
should be made to keep subjects blinded to study Hb values. 
4.6.1 Maintenance of Blinding 
Neither the subjects nor the Investigators and their staff can distinguish the roxadustat tablets 
from the matching placebo tablets.  Both will be identical in appearance, packaging, and labeling 
in order to maintain the blind. 
4.6.2 Planned and Unplanned Unblinding of Treatment Assignment 
Treatment assignments will be unblinded after the completion of the study. 
Any intentional or unintentional breaking of the blind should be reported and documented.  
Breaking the blind (for a single subject) should be considered only when knowledge of the 
treatment assignment is deemed essential by the Investigator for the subject’s care.  Unplanned 
unblinding will result in the discontinuation of the subject’s participation from the study.  When 
possible and appropriate the blind will be maintained for Sponsor personnel responsible for 
analysis and interpretation of results at the study’s conclusion. 


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5 INVESTIGATIONAL PRODUCT  
5.1 Formulation 
Roxadustat is supplied by FibroGen as red-coated, oval tablets for oral administration, in 
strengths of 20 mg, 50 mg, 100 mg, and 150 mg.  The excipients include lactose monohydrate, 
microcrystalline cellulose, povidone, croscarmellose sodium, magnesium stearate, and colorant 
Red Opadry II.  All ingredients used for manufacture of roxadustat comply with US and 
European Union compendia or regulatory standards.  Strengths are different in size and 
debossing reflects the strength (i.e., 20, 50, 100 and 150 mg).  Placebo tablets are similar to the 
roxadustat tablets except for the absence of active roxadustat. 
5.2 Storage 
Roxadustat tablets should be stored at room temperature between 15°C and 30°C (59ºF to 86ºF).  
Placebo should be stored under the same conditions. 
All study drugs should be stored in a securely locked area to which access is limited to 
appropriately authorized study personnel.  
5.3 Study Drug Handling and Disposal 
All study drugs provided by the Sponsor or provided at the study site should be retained at the 
site until otherwise instructed in writing by the Sponsor.  Upon completion of the study or 
termination of the investigational site, all used bottles, unused, and partially used study drugs; 
and all study drugs that were not dispensed will be 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 and with Sponsor 
approval.  Please refer to the Study Reference Manual or Pharmacy Manual for additional 
information. 
5.4 Route of Administration and Dose 
5.4.1 Roxadustat/Placebo  
All patients will take doses TIW for the entire duration of the study.  Roxadustat/placebo will be 
dispensed to patients 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.  Tablets should 
not be cut. 
First dose of roxadustat /placebo should be administered on Day 1 after completion of all 
procedures including laboratory draws.  Study drug 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/placebo can be taken with water and with or without food. 
5.5 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 3.5 mg/kg/dose, 
whichever is lower.  Any dosing of study medication in this study exceeding the maximum 
allowed roxadustat dose should be reported within 24 hours.  The Medical Monitor should be 
contacted as soon as possible.  Symptoms associated with overdosing, if any, will be reported as 
adverse events. 


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


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6 STUDY PROCEDURES 
During study visits, all assessments including laboratory assessments and physical examinations 
must be completed prior to registration/randomization and first dose.  Quality of life (QoL 
assessments (Appendix E) should be administered approximately at the same time of the day 
throughout the entire study.  Laboratory tests are tabulated in Appendix K.  Blood pressure and 
heart rate (HR) should be assessed according to the guidelines described in Appendix N. 
6.1 Screening Period  
After signing the Informed Consent, patients will enter the Screening Period.  AEs and SAEs 
will be recorded in the medical record as of the signing of consent date.  SAEs will be reported to 
FibroGen. All screening procedures are to be completed within 28 days prior to Day 1 except for 
documentation of the following which can be obtained from patients’ medical records: 
1. Lower risk MDS (IPSS-R very low risk, lower risk, or intermediate risk) prior to Day 1 
of treatment. There is no minimum time from diagnosis to registration/randomization 
except to allow for proper IPSS-R classification to be made, and to show transfusion 
dependence for patients in both portions of the study.    
2. Results from bone marrow examination and cytogenetic analysis performed within 16 
weeks prior to registration/randomization can be used.  The required bone marrow slides 
and report must be readily available for a centralized review at any time throughout the 
study. 
3. Patients are deemed to have low RBC transfusion burden (LTB) if they received 1 to 4 
documented pRBC transfusions within 8 weeks prior to randomization.  Patients with 
1 pRBC/8-weeks must have a documented history of requiring 1 pRBC/8-weeks in 2 
consecutive periods of 8 weeks in the 16 weeks preceding registration/ randomization.  
Pre-transfusion and post-transfusion Hb levels within 8 weeks prior to Day 1 of treatment 
will also be recorded.  The percentage of patients having 1pRBC transfusion at baseline 
will be capped at 30% for the DB portion of the study. For Open-Label patients only, the 
requirement to demonstrate transfusion dependence can also be met by a PI starting this 
particular patient on pRBC transfusion during the screening period.  
4. RBC transfusions over the 16 weeks prior to Day 1 will be recorded for all patients.  Pre-
transfusion and post-transfusion Hb levels within 8 weeks prior to randomization will 
also be recorded. The PI and site staff will utilize their own institutional criteria for the 
determination of when to transfuse a patient. 
6.1.1 Screening 1  
• 
Signed written informed consent 
• 
Inclusion/Exclusion criteria verification (eligibility review) 
• 
Demographics and medical history (including bone marrow biopsy) 
• 
ECG 
• 
ECOG Score 
• 
Physical Exam 


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• 
Weight 
• 
Vital signs (BP, HR, respiratory rate [RR], and temperature [Temp])  
• 
Laboratory tests (Appendix K): 
o Complete blood count (CBC) with Hb level and white blood cell (WBC) 
differential 
o Serum chemistries (sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
glucose, calcium, magnesium, phosphorus, lactate dehydrogenase (LDH), 
albumin) 
o Liver function tests (LFTs) – AST, ALT, total bilirubin, alkaline phosphatase 
o Iron Biomarkers: 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 Vitamin B12 and folate 
o Enzyme-linked immunosorbent assay (ELISA) for HIV 
o Hepatitis B surface antigen (HBsAg) 
o Anti-hepatitis C virus (HCV) antibody  
o Prothrombin time (PT) and partial thromboplastin time (PTT) 
o Hepcidin level 
o Serum pregnancy (for females of childbearing capability) 
o Serum endogenous erythropoietin level 
• 
Review and record concomitant medications 
• 
Review and record transfusions (for 16 weeks prior to anticipated first dose date) 
• 
Review and record procedures and nondrug therapies 
• 
Review and record AEs, if any (capture the event under medical history, if applicable) 
6.1.2 Screening 2  
Hemoglobin values must be obtained at least 4 days apart and the screening 2 visit must be ≥4 
days apart from the screening 1 visit. 
• ECOG 
• CBC with Hb level and WBC differential  
• Liver function tests (LFTs) 
• Review and record concomitant medications 
• Review and record transfusions since Screen 1 visit 
• Review and record procedures and nondrug therapies  
• Review and record AEs, if any (capture the event under medical history, if applicable) 


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6.1.3 Additional Screening Assessments 
A patient who fails screening may be rescreened, only upon approval from the Medical Monitor.   
For all screen failures, the reason(s) will be documented.  
6.2 Registration (OL) and Randomization (DB) 
For the OL component, eligible patients will be sequentially assigned to the cohorts, starting with 
1.5mg/kg for the first 8 patients, then 2.0mg/kg for the next 8 patients and at 2.5mg/kg for the 
last 8 patients. 
For the DB component eligible patients will be randomized based on stratification factors to 
receive roxadustat or placebo.  Randomization must take place prior to administration of study 
drug. 
6.3 Treatment Period  
Patients will attend weekly study visits for the first four weeks, from Day 1, Week 1 to Week 4, 
then from Weeks 5 to Week 28 study visits will be performed every two weeks.  At Week 27 an 
additional CBC and Hb will be collected. 
When all the randomized patients complete 28 weeks of treatment or have study medication 
discontinued before this time, the analysis of the primary efficacy and secondary endpoints will 
be performed.  Only sponsor personnel who are not directly involved with the study sites/patients 
will have access to the unblinded data.  The blind will be maintained for study patients, PI, site 
staff and site monitoring personnel for the remainder of the study (to Week 52 plus a 4 week 
follow-up period). From Week 31 to Week 52, study visits will be performed every 4 weeks.  
Patients who discontinue treatment early (for any reason) will remain in the study through the 52 
week study period, but at reduced visit schedule of every 8 weeks with the exception of a follow-
up visit 4 weeks after the last dose of study medication.   
6.3.1 Study Procedures and Assessments by Visit  
6.3.1.1 Study Procedures and Assessments to be Done at All Study Visits 
The following will be done at ALL study visits within the Treatment and Follow-Up Periods: 
• Recording of transfusions 
• Central CBC with Hb level and WBC differential 
• Local hemoglobin level (hemocue device is encouraged but not required)  
• Review and record AEs 
• Review and record concomitant medications, procedures and non-drug therapies 
• Review hemoglobin level for any dose adjustments that are deemed necessary   
(Appendix C and Appendix D) 
• Ensure patient dosing compliance 
Local laboratory testing of Hb for dose adjustment decisions will be done at the Local level – use 
of the Hemocue device is encouraged but not required.   Central laboratory values of Hb will be 
used for all data analysis purposes 


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6.3.1.2 Additional Study Procedures/Assessments and Blood Sampling by Visit 
Table 2 below lists additional study procedures/assessments and blood sampling by visit for the 
52-week Treatment Period, EOT and Post-EOT.  
All blood samples must be drawn prior to dose unless otherwise noted (e.g. certain PK draws). 
Table 2 Additional Study Procedures/Assessments and Blood Sampling by Visit for the  
52-Week Treatment Period, EOT and Post-EOT (Appendices A, B, K)  
Study Visit 
Procedures and Assessments 
Blood Samples 
Day 1  
(Week 1) 
• Inclusion/Exclusion criteria 
verification/review (including 
documentation of MDS) 
• ECOG score 
• Weight  
• Vital signs (BP, HR, RR, and Temp) 
immediately prior to the time of the PK 
sampling 
• Health-related quality of life (HRQoL) 
assessments  
• Review and record baseline conditions, 
AEs, if any (capture the event under 
medical history, if applicable)  
• Register/Randomize patient (dose 
confirmation) 
• Dispense study drug 
• Dose patient (first dose should be given 
at the site) 
• Serum chemistries 
• Serum lipid panel 
• LFTs 
• Iron biomarkers 
• PT and PTT 
• Hepcidin  
• C-reactive protein 
• Serum pregnancy (for females of 
childbearing capability) 
• Endogenous serum EPO level 
• PK samples 1-3 and 3-5 hours after 
dosing 
• CBC (central) and Local Hb 
Week 2 
 
• CBC (central) and Local Hb 
Week 3 
• Dispense study drug 
• LFTs 
• CBC (central) and Local Hb 
Week 4 
 
• CBC (central) and Local Hb 
Week 5 
• Vital signs (BP, HR, RR, and Temp) at 
the time of PK sampling 
• ECOG score 
• Dispense study drug 
• Serum chemistries 
• Serum lipid panel 
• LFTs 
• Iron biomarkers 
• Hepcidin  
• Endogenous serum EPO level 
• Reticulocytes & CHr 
• PK sample 4-6 hours after dosing 
• CBC (central) and Local Hb 
Week 7 
• Dispense study drug 
• CBC (central) and Local Hb 
Week 9 
• Dose adjustment review 
• Vital signs (BP, HR, RR, and Temp) 
• Dispense study drug 
• Health-related quality of life HRQoL 
• CBC (central) and Local Hb 
• Serum chemistries 
• LFTs 
• Iron biomarkers 


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Table 2 Additional Study Procedures/Assessments and Blood Sampling by Visit for the  
52-Week Treatment Period, EOT and Post-EOT (Appendices A, B, K)  
Study Visit 
Procedures and Assessments 
Blood Samples 
assessments 
• Assess erythroid response 
• Reticulocytes & CHr 
Week 11 
• Dispense study drug 
• CBC (central) and Local Hb 
Week 13 
• Dose adjustment review 
• Vital signs (BP, HR, RR, and Temp) 
• Point-of-care urine pregnancy test 
• ECOG score 
• Dispense study drug 
• CBC (central) and Local Hb 
• Serum chemistries 
• LFTs 
• Iron biomarkers 
• Hepcidin 
• Reticulocytes & CHr 
Week 15 
• Dispense study drug 
• CBC (central) and Local Hb 
Week 17 
• Dose adjustment review 
• Vital signs (BP, HR, RR, and Temp) 
• Dispense study drug 
• Health-related quality of life HRQoL 
assessments 
• ECOG score 
• CBC (central) and Local Hb 
• Serum chemistries 
• LFTs 
• Iron biomarkers 
• Reticulocytes & CHr 
Week 19 
 
• Dispense study drug 
• CBC (central) and Local Hb 
 
Week 21 
 
 
 
 
 
 
• Dose adjustment review 
• Vital signs (BP, HR, RR, and Temp) at 
time of PK sampling 
• Dispense study drug 
• CBC (central) and Local Hb 
• Serum chemistries 
• Serum lipid panel 
• LFTs 
• Iron biomarkers 
• Hepcidin  
• Endogenous serum EPO level 
• Reticulocytes & CHr 
• PK sample 8-10 hours after dosing 
Week 23 
• Dispense study drug 
 
• CBC (central) and Local Hb 
Week 25  
 
• Dose adjustment review 
• Vital signs (BP, HR, RR, and Temp) at 
the time of the PK sampling 
• Point-of-care urine pregnancy test 
• Dispense study drug 
• ECOG 
• CBC (central) and Local Hb 
• Serum chemistries 
• LFTs 
• Iron biomarkers 
• Hepcidin  
• Endogenous serum EPO level 
• Reticulocytes & CHr 
• PK samples 0-2 hours before dosing 
and 2-3 hours after dosing 
Week 27  
• Dispense study drug 
• CBC (central) and Local Hb 
 


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Table 2 Additional Study Procedures/Assessments and Blood Sampling by Visit for the  
52-Week Treatment Period, EOT and Post-EOT (Appendices A, B, K)  
Study Visit 
Procedures and Assessments 
Blood Samples 
Week 28 
• Physical Exam  
• ECG 
• Weight  
• Vital signs (BP, HR, RR, and Temp) 
• Health-related quality of life (HRQoL) 
assessments  
• ECOG 
• CBC (central) and Local Hb 
• Serum chemistries 
• Serum lipid panel 
• LFTs 
• Iron biomarkers 
• B12 and folate 
• PT and PTT 
• Hepcidin  
• C-reactive protein 
• Endogenous serum EPO level 
• Reticulocytes & CHr 
Week 31 
• Dose Adjustment review 
• Dispense study drug 
• CBC (central) and Local Hb 
Week 35 
• Dose adjustment review  
• Dispense study drug 
• CBC (central) and Local Hb 
 
Week 39 
• Vital signs (BP, HR, RR, and Temp) 
• Point-of-care urine pregnancy test 
 
• Dispense study drug 
• Serum chemistries 
• Serum lipid panel 
• LFTs 
• Hepcidin  
• Iron biomarkers 
• Reticulocytes & CHr 
• CBC (central) and Local Hb 
• Endogenous serum EPO level 
Week 43 
• Dose adjustment review  
• Dispense study drug 
• CBC (central) and Local Hb 
Week 47 
• Dispense study drug 
• CBC (central) and Local Hb 
Week 
52/EOT 
• Bone marrow aspirate and biopsy 
• Physical Exam  
• Vital signs (BP, HR, RR, and Temp) 
• ECG 
• ECOG score 
• Health-related quality of life HRQoL 
assessments 
• CBC (central) and Local Hb 
• Serum chemistries 
• LFTs 
• Iron biomarkers 
• Hepcidin  
• Endogenous serum EPO level 
• PT, PTT 
• Serum lipid panel 
• B12 and folate 
• C-reactive protein 
• Reticulocytes & CHr 
• Serum pregnancy (for females of 
childbearing capability) 
4 Weeks 
Post-EOT  
• Physical Exam 
• ECOG score 
• Vital signs (BP, HR, RR, and Temp) 
• Health-related quality of life (HRQoL) 
• CBC (central) and Local Hb 
• Serum chemistries 
• LFTs 
• Iron biomarkers 


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Table 2 Additional Study Procedures/Assessments and Blood Sampling by Visit for the  
52-Week Treatment Period, EOT and Post-EOT (Appendices A, B, K)  
Study Visit 
Procedures and Assessments 
Blood Samples 
assessments  
• ECG 
• Hepcidin  
• Endogenous serum EPO level 
• PT, PTT 
• Serum lipid panel 
• B12 and folate 
• C-reactive protein 
• Reticulocytes & CHr 
• Serum pregnancy (for females of 
childbearing capability) 
If Early 
Termination, 
every 8 
weeks 
assessment 
from 4 
Weeks Post-
EOT visit.  
 
Last visit at 
Week 52 
from first 
dose. 
• Vital signs (BP, HR, RR, and Temp) 
 
• CBC (central) and Local Hb 
• Serum chemistries 
• LFTs 
• Iron biomarkers 
• Hepcidin 
• Endogenous serum EPO level 
6.4 Follow-up Period after EOT or Early Termination of study medication  
Patients who discontinue study medication early (before week 52) will have an EOT visit and 
then a 4 week follow-up visit.  They will then be followed up at a reduced visit schedule of every 
8 weeks until the end of the study (see Table 2).  
6.5 Missed Visits 
Every attempt should be made to complete all study visits within the visit window as outlined in 
the Schedule of Assessments (Weeks 1-5 (± 1 day), Weeks 7-52 ± 2 days).  Appendix A 
6.6 Unscheduled Visits 
Unscheduled visit(s) and laboratory assessments may be required at the discretion of the 
investigator.  Please refer to the eCRF completion guidelines for additional information on 
entering unscheduled visit and lab assessments. 
6.7 Laboratory Assessments 
Central laboratory results should be reviewed by the Investigator as it is received.  Any 
abnormalities must be evaluated in clinical context and the investigator should determine if it is 
clinically significant.  Patient management is dependent upon close review of the laboratory data. 


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6.8 Local Hb Level  
Hb levels will also be done at specified visits.  Use of a HemoCue device is encouraged but not 
required.   These values will be recorded in the CRF and used for dose adjustment assessments 
only. 
6.9 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 patient, local laboratory (i.e., 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 are 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 Appendix K. 
6.10 Electrocardiogram 
Local 12-lead ECGs will be performed on all patients at screening, Week 28, end of treatment 
and the 4 week follow-up visit 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 patient’s medical history and concomitant medication) and the investigator 
should determine if it is clinically significant. Clinically significant abnormalities should be 
reported as an AE.  ECG recordings will be kept as source documents.  Abnormal ECG findings 
prior to administration of study drug on Day 1 will be considered baseline conditions.  
6.11 Health Related Quality of Life Questionnaires  
The main goal of therapy in lower risk MDS patients is to provide symptom control related to 
anemia and also improve HRQoL. 
Moreover, in Phase 2 studies in patients with NDD-CKD (Study FGCL-4592-041) and DD-CKD 
(Study FGCL-4592-053) in which Hb correction was an objective, patients were administered 
patient-reported outcome (PRO) questionnaires to assess the effect of roxadustat on HRQoL.  In 
general, significant improvements from baseline were observed in the anemia and physical well-
being subscales of the Functional Assessment of Cancer Therapy-Anemia (FACT-An) 
questionnaire (FACIT, 2014), and in the vitality, mental, and physical component subscales of 
the Short Form-36 (SF-36) questionnaire (Ware, 1993).  The improvements were more 
pronounced in patients with the lowest scores at baseline.  The impact of roxadustat on the 
remaining PRO subscores and questionnaires was less clear in these studies, over this duration. 
Based on this experience, this protocol prospectively includes HRQoL instruments to evaluate 
the impact of roxadustat on MDS patients’ HRQoL.  Our goal is to demonstrate improvements in 
HRQoL utilizing specific items and domains from instruments most appropriate for the targeted 
population.  All these instruments will be performed with the patients as the rater, including: 


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1. Patient-Reported Outcomes Measurement Information System  
(PROMIS®; Cella, 2007; Cella, 2010) 
2. European Quality of Life Five Dimension, Five Level Health Questionnaire (EQ-5D-
5L, Rabin, 2001) 
The rationale for each of the PRO items and domains selected includes consideration of the 
applicable concepts to be evaluated and context of use for this study. 
Specific symptoms that are most important to the MDS population are fatigue/tiredness. 
Currently, there are no existing perfect measures to capture these symptoms. 
PROMIS provides clinicians and researchers access to reliable, valid, and flexible measures of 
health status that assess physical, mental, and social well–being from the patient perspective.  
PROMIS measures are standardized, allowing for assessment of many patient-reported outcome 
domains, including pain, fatigue, emotional distress, physical functioning and social role 
participation, based on common metrics that allow for comparisons across domains, across 
chronic diseases, and with the general population.  Further, PROMIS tools allow for computer 
adaptive testing, efficiently achieving precise measurement of health status domains with few 
items.  There are PROMIS measures for both adults and children.  PROMIS was established in 
2004 with funding from the National Institutes of Health (NIH) as one of the initiatives of the 
NIH Roadmap for Medical Research. 
EQ-5D-5L is a standardized instrument for measuring generic health status.  The health status 
measured with EQ-5D-5L is used for estimating preference weight for that health status, then by 
combining the weight with time, quality-adjusted life year (QALY) can be computed.  QALYs 
gained is used as an outcome in cost-utility analysis which is a type of economic evaluation that 
compares the benefit and cost of health care programs or interventions.  Many countries 
generated a value set (preference weights) of their own population and have used it for 
estimating QALY to make decisions in resource allocation.  There are currently 171 language 
versions of EQ-5D-5L questionnaire available.  EQ-5D-5L is one of the most commonly used 
generic health status measurement, and its good validity and reliability have been reported in 
various health conditions.  
Importantly, PROMIS is a validated instrument for the MDS population (Abel, 2014), and so is 
EQ-5D-5L (Efficace, 2015).  Please also refer to Appendix E. 


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7 SAFETY 
7.1 Background 
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, 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 2001 and the International Conference on 
Harmonisation (ICH) E2A guidance. 
7.2 Definitions  
7.2.1 Definition of an Adverse Event  
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug-related.  
An AE can be any unfavorable and unintended sign, symptom, or disease temporally associated 
with the use of a drug, without any judgment about causality.  This includes any occurrence that 
is new in onset or aggravated in severity or frequency from the baseline condition.  An AE can 
arise from any use of the drug (e.g., off-label use, use in combination with another drug) and 
from any route of administration, formulation, or dose, including an overdose. 
An AE includes medical conditions, signs, and symptoms not previously observed in the patient 
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 7.3.1). 
7.2.2 Definition of a Serious Adverse Event  
A serious adverse event is any AE that results in any of the following outcomes: 
• Death, 
• A life-threatening AEs (i.e., if in the view of the investigator or Sponsor, the patient 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: 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 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 


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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 patient as part of the study (e.g., study drug, comparator, background therapy) that 
may require expedited reporting and/or safety evaluation include, but are not limited to: 
o Overdose of the medicinal product (exceeding the maximum allowable per dose, 
i.e., 400 mg or 3.5 mg/kg, whichever is lower) 
o Suspected abuse/misuse of the medicinal product 
o Inadvertent or accidental exposure to the medicinal product 
o Medication error involving the medicinal product (with or without patient/patient 
exposure to the Sponsor medicinal product, e.g., name confusion).  However, 
non-clinically significant errors of this type would not require expedited 
reporting.  The medical monitor should be contacted if any clarification is 
required. 
o Drug-drug interactions 
7.3 Procedures for Eliciting, Recording, and Reporting Adverse Events 
7.3.1 Adverse Event Reporting Period  
The study period during which all AEs and SAEs must be reported begins after informed consent 
is obtained and ends 28 days after the last study visit, except for pregnancy reporting 
(Section 7.3.6).  
Adverse events will be followed until resolved, stable, or until the patient’s last study visit or lost 
to follow-up.  If an AE is not resolved or stabilized at the patient’s last visit, it is up to the 
discretion of the investigator and study Medical Monitor to determine if further monitoring of the 
event is warranted. 
Adverse events collected prior to dosing of study drug will be considered “nontreatment 
emergent” while those reported after the first dose of study drug and up to 28 days after the last 
dose of study drug will be considered “treatment emergent” and be assessed for relationship to 
study drug.  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. 
7.3.2 Adverse Event Eliciting/Reporting 
During the AE reporting period, study site personnel will collect AEs in response to general 
questions about the patient’s well-being and any possible changes from the baseline or previous 
visit, but shall not be specifically solicited.  There will be no directed questioning for any 
specific AE.  This does not preclude the site from collecting and recording any AEs reported by 
the patient to site personnel at any other time.  Conditions including signs and symptom present 
at baseline, unless significantly worsened, should not be reported as adverse events during the 
study. 
Whenever possible, diagnoses should be recorded when signs and symptoms are due to a 
common etiology, as determined by qualified medical study staff.  New indications for 
medications started after informed consent is obtained until 28 days after the last dose of study 


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drug 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 (e.g., 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  
• Other action (treatment, nondrug therapy) required 
• Determination of “seriousness”  
7.3.3 Assessing Adverse Event Severity 
Adverse Events will be graded 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: 
All AEs will be assessed for severity using the following criteria:  
• Grade 1, Mild: Asymptomatic or mild symptoms which the patient finds easily tolerated.  
The event is of little concern to the patient and/or of little-or-no clinical significance; 
clinical or diagnostic observations only; intervention not indicated. 
• Grade 2, Moderate: The patient has enough discomfort to cause interference with or 
change in some of their age-appropriate instrumental activities of daily living (e.g., 
preparing meals, shopping for groceries or clothes, using the telephone, managing 
money); local or noninvasive intervention indicated. 
• Grade 3, Severe: The patient is incapacitated and unable to work or participate in many 
or all usual activities.  The event is of definite concern to the patient and/or poses 
substantial risk to the patient’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. 


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• Grade 4, Life-threatening: The patient was at immediate risk of death from the event as 
it occurred. 
• Grade 5, Death: The patient died due to the event.  
7.3.4 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 exposure to a new drug, 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 
• Not Related: 
o The event represents the underlying disease (e.g., disease-related symptoms, 
disease progression) 
o The event represents a comorbid condition present at the time the patient entered 
the study 
o The event represents a known adverse reaction associated with a co-medication 
received by the study patient 
o The event is common for the study population (e.g., cardiovascular (CV) events in 
an elderly population) 
o The event has no plausible relationship to study drug 
o The event is a study endpoint (e.g., mortality, major morbidity) 


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The investigator must provide an assessment of the relationship of the event to study drug, as this 
information is very important to monitor the real-time safety of the study drug.  However, as the 
manufacturer of the study drug, FibroGen is responsible for making the final causality 
assessment for individual reports, and for reporting suspected adverse reactions and adverse 
reactions to 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. 
7.3.5 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 or email a 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: 
• Patient 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). 
7.3.5.1 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 
Independent Ethics Committee (IEC) of SAEs in accordance with local regulations.  Sponsor, or 
its safety representative, will provide to the investigator a copy of any expedited safety reports 
that it intends to file with a regulatory authority.  
7.3.5.2 Deaths  
For any death occurring during the patient’s study participation, regardless of attribution, the 
investigator will report the death immediately to the Sponsor or its designee as a SAE. 
The investigator should notify Sponsor or its designee of any death or other SAE occurring after 
a patient has discontinued or terminated study participation that may reasonably be related to the 
study.  


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The investigator must submit the SAE Report Form and complete the appropriate eCRF for the 
event that led to the patient’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. 
7.3.6 Pregnancies: Reporting and Follow-up of Patients 
A pregnancy in a female patient must be confirmed by a positive serum β-chorionic 
gonadotrophin test.  If a female patient becomes pregnant while the patient 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 or its designee 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 patient 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 patient 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 patient’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 patient, the male patient’s 
partner consent must be obtained to collect information related to the pregnancy and outcome 
(should be handled on a case by case basis with IRB/IEC approval); the male patient should not 
be asked to provide this information. 
7.3.7 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 


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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 patient fails to respond adequately to 
study drug.  
7.3.8 Disease Progression 
Disease progression can be considered as a worsening of a patient’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 MDS should be considered disease progression and should  be reported as an AE 
during the study. Worsening of anemia, per se, should not be reported as disease progression 
because changes in Hb levels will be adequately monitored and assessed in the efficacy analyses. 


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8 STATISTICAL CONSIDERATIONS 
Data from patients in the OL component of the study will be analyzed separately from the DB 
placebo randomized portion of the study. 
Double-blind component 
Descriptive statistics including number of patients (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 will be presented as part of the descriptive summaries.   
The Statistical Analysis Plan will provide in detail the analyses and summaries to be performed. 
The rest of this section (8.1-8.4) pertains to the DB component. 
8.1 Sample Size Determination  
160 patients are planned to be randomized in a 3:2 ratio to roxadustat or matching placebo.  This 
sample size will provide at least 90% power to demonstrate a statistically significant difference 
between roxadustat and placebo at the significance level of 0.05 using a two-sided Fisher’s test, 
and assuming the response rates of the primary endpoint are 35% and 5% in roxadustat and 
placebo, respectively. 
8.2 Randomization and Treatment Assignment  
Patients will be randomized, stratifying by the following 
• Serum EPO level: either ≤200 mIU/mL OR >200 mIU/mL and ≤400 mIU/mL  
• IPSS-R low risk / very low risk vs. intermediate risk group classification 
• RBC transfusion burden: 1 pRBC/8-weeks documented over 16 consecutive weeks vs 2- 
4 pRBC documented over 8 weeks. NOTE: 1-pRBC randomization will be limited to no 
more than 30% of the total randomized patient population 
8.2.1 Full Analysis Set Population (FAS) 
The FAS Population consists of all patients randomized to this study. 
Analyses of efficacy data will be based on the FAS Population. 
8.2.2 Safety Populations  
The Safety Populations consist of all patients who have received at least one dose of study drug. 
Analyses of the safety data will be based on the Safety Populations. 
8.3 Statistical Analyses 
8.3.1 Multiple Testing and Control of Family-Wise Type I Error 
The statistical test results of the primary and secondary endpoints at the week 28 time point will 
be used to determine and describe the treatment efficacy of roxadustat.  To control the family-
wise type I error at the level of 0.05, a sequential gatekeeping procedure will be used to test the 
primary and secondary efficacy endpoints.  Specifically, if the test of the primary endpoint is 
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The order of testing of secondary endpoints will follow the order presented in Section 8.3.3.2.  
Other secondary endpoints will be tested conditioning on the previous endpoint achieving 
statistical significance, in the order listed in the Statistical Analysis Plan (SAP).  Statistical 
testing will stop at the first endpoint that fails to achieve significance level.  All statistical tests 
will be two-sided at the significance level of 0.05.   
8.3.2 General Considerations 
Descriptive summaries will be presented for study parameters including baseline characteristics, 
safety, and efficacy.  Continuous variables will be reported in mean, standard deviation or 
standard error, median, minimum, and maximum.   
Categorical variables will be reported by the frequency and percentage of patients within each 
outcome category. 
Analyses of the efficacy data will be based on the FAS Population. 
Baseline Hb value for efficacy analysis is defined as the mean of Screening central laboratory Hb 
value and Day 1 Hb value. 
Safety data will be summarized descriptively based on the Safety Population. 
8.3.3 Analysis of Efficacy Data 
8.3.3.1 Analysis of the Primary Efficacy Endpoint 
Treatment response rate defined as the proportion of patients who achieved transfusion-
independence (TI) ≥56 consecutive days in the first 28-weeks of treatment will be summarized 
using the FAS Population and will be compared between the two treatment groups using the 
Cochran-Mantel-Haenszel (CMH) chi-square test, controlling for stratification factors.  
If one or more of the levels of the stratification variables are underrepresented during enrollment 
resulting one or more of the (2×2×2) 8 strata having too few patients to meet the required per-
strata sample size for the planned statistical methodology, then the stratification variable with the 
highest imbalance will not be included in the analysis.  This practice will be followed for the 
primary, secondary and exploratory variables. 
Two-sided 95% confidence interval (CI) of the odds ratio will also be presented.   
The 95% CI of the response rate will be presented by treatment group based on the exact method 
of Clopper-Pearson.   
8.3.3.2 Analysis of the Secondary Efficacy Endpoints 
When all the randomized patients complete 28 weeks of treatment or have discontinued study 
medication before this time, the analysis of the primary efficacy endpoint and secondary 
endpoints will be performed.  Only Sponsor personnel who are not directly involved with the 
study sites/patients will have access to the unblinded data.  The blind will be maintained for 
study patients, PI, site staff and site monitoring personnel for the remainder of the study (to 
Week 52 plus a 4 week follow-up period).   
All secondary and exploratory endpoints will be analyzed at both for the first 28 weeks of 
treatment and for the end of the 52-week study treatment period. 


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8.3.3.2.1 Proportion of Patients who Achieved ≥50% Reduction in Number of pRBC 
Transfusions over 8 Weeks Compared to Their Baseline for Any 8 Week Period 
During the Study (Factor of Erythroid Response) 
The proportion of patients who achieved ≥50% reduction in number of pRBC transfusion over 
8-weeks compared to their baseline for any 8 week period during the study will be summarized 
using the FAS Population and will be compared between the two treatment groups using the 
Cochran-Mantel-Haenszel (CMH) chi-square test, controlling for stratification factors.   
Two-sided 95% confidence interval (CI) of the odds ratio will also be presented.   
The 95% CI of the response rate will be presented by treatment group based on the exact method 
of Clopper-Pearson.   
8.3.3.2.2 Cumulative Number of Patient-Exposure-weeks of TI over the first 28 Weeks of 
the Treatment Period 
The Cumulative number of patient-exposure –week of TI over the first 28-weeks of the treatment 
period will be summarized and analyzed using the FAS Population.  A non-parametric 
ANCOVA controlling for stratification factors will be used to compare between treatment 
groups.   
8.3.3.2.3 Cumulative Number of pRBC Transfused over the first 28-weeks of the 
Treatment Period 
The Cumulative number of pRBC transfused over the first 28-weeks of the treatment period will 
be summarized and analyzed using the FAS Population.  A non-parametric ANCOVA 
controlling for stratification factors will be used to compare between treatment groups. 
8.3.3.2.4 Proportion of Patients who Achieved TI for ≥20 consecutive Weeks (140 
consecutive Days) 
The proportion of patients who achieved TI for ≥20 Weeks (140 Days) will be summarized using 
the FAS Population and will be compared between the two treatment groups using the Cochran-
Mantel-Haenszel (CMH) chi-square test, controlling for stratification factors. 
Two-sided 95% confidence interval (CI) of the odds ratio will also be presented.   
The 95% CI of the response rate will be presented by treatment group based on the exact method 
of Clopper-Pearson.   
8.3.3.2.5 Mean Change from Baseline in EQ-5D-5L assessment  
The mean change from Baseline in EQ-5D-5L assessment will be summarized and analyzed 
using the FAS Population.  A mixed model repeated measures (MMRM) analysis of covariance 
model (ANCOVA) model, controlling for stratification factors and baseline value of the 
corresponding parameter, will be used to assess treatment difference. 
8.3.3.2.6 Mean Change from Baseline in Functional Subscale of PROMIS   
The mean change from Baseline in Functional Subscale of PROMIS will be summarized and 
analyzed using the FAS Population.  A MMRM-ANCOVA model, controlling for stratification 
factors and baseline value of the corresponding parameter, will be used to assess treatment 
difference. 


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8.3.3.2.7 Mean Change from Baseline in Vitality Subscale of PROMIS 
The mean change from Baseline in Vitality Subscale of PROMIS will be summarized and 
analyzed using the FAS Population.  A MMRM-ANCOVA model, controlling for stratification 
factors and baseline value of the corresponding parameter, will be used to assess treatment 
difference 
8.3.3.3 Analysis of Exploratory Efficacy Endpoints 
The additional efficacy analyses will use the FAS Population. 
Additional efficacy analyses of continuous endpoints will use an MMRM/ANCOVA model 
using baseline value and other stratification factors as covariates.   
Additional analyses of proportions will use the CMH model adjusting for stratification factors.  
Odds ratio and its associated 95% CI will be computed to compare between the roxadustat group 
and placebo.  A two-sided 95% CI of the proportion based on the exact method of Clopper-
Pearson will be computed for each treatment group. 
Additional efficacy analyses of time-to-event endpoints will use the Cox Proportional Hazards 
model adjusting for stratification factors.  Median time to event and associated 95% CI will be 
estimated using Kaplan-Meier method. 
8.3.4 Patient Enrollment and Disposition 
Patient enrollment and disposition will be presented for all enrolled.  The total number and 
percent of patients who completed or discontinued, and reasons for early discontinuation, will be 
summarized by dose cohort or treatment group using the FAS Population.   
8.3.5 Demographics and Baseline Characteristics 
Demographic data and other patient characteristics as well as baseline disease characteristics will 
be summarized descriptively using the FAS and the Safety Populations. 
8.3.6 Summary of Safety Data 
Summary of safety data will be based on the Safety Population.  Safety parameters include 
adverse events, N (%) patients progressing to AML, laboratory parameters, vital signs, ECG 
parameters, prior and concomitant medication use.  For each safety parameter, the last 
assessment made prior to the first dose of study treatment will be used as the baseline, unless 
otherwise specified.  In general, safety data will be summarized descriptively; no inferential 
statistical procedures will be applied. 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA).  
A treatment emergent adverse event (TEAE) is defined as any new or worsening of an existing 
condition occurred after the first dose of the study medication and within 28 days after the last 
dose of study medication.  TEAEs will be tabulated to examine their frequency, severity, organ 
systems affected and relationship to study treatment.  Deaths, SAEs, AEs leading to study or 
treatment discontinuation, and AEs of special interest will be listed or tabulated separately.   
Laboratory tests, vital sign measurements, ECG parameters, as well as the changes from baseline 
will be summarized descriptively by assessment time point.  Clinically significant changes from 
baseline in these safety parameters will be identified.  Shift tables will summarize changes for 
selected laboratory measures. 


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Medications used prior to and during the study will be coded using The World Health 
Organization Drug Dictionary (WHODrug).  Prior and concomitant medications will be 
tabulated by therapeutic class and generic name. 
8.3.7 Interim Analysis 
No interim efficacy analysis is planned for the study prior to all patients completing 28 weeks of 
study treatment.    
8.4 Statistical Analyses Plan 
A detailed Statistical Analysis Plan (SAP) will be finalized prior to database lock of the primary 
efficacy analysis of the study after all patients have completed 28 weeks of treatment or 
terminated before this timepoint.  Any significant changes to the analyses described in this 
protocol will be highlighted in the SAP and the Clinical Study Report. 


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9 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 patient source 
records, eCRFs, queries, collection of local laboratory normal ranges (if applicable), 
investigational product accountability records, and regulatory documents in accordance with 
Good Clinical Practices (GCP) and ICH E6 guideline. 
The purpose of study monitoring is to verify the following: 
• The rights and well-being of human patients are protected 
• The reported data are accurate, complete, and verifiable from source documents 
• All data are collected, tracked, and submitted by the site to Sponsor or designee, 
including unscheduled and missed assessments 
• The reported data are reconciled across all data sources (e.g., laboratory, safety, 
interactive web response system, 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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10 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 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 
10.2 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 Investigative 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, patient 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 
Harmonisation, and any applicable regulatory requirements.  The investigator should contact the 
Sponsor immediately if contacted by a regulatory agency about an inspection. 


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11 ETHICS 
11.1 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. 
11.2 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 patient 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 patient recruitment 
materials must be approved by the IRB/IEC before the material is used for patient 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. 
11.3 Informed Consent Form 
No study procedure may be implemented prior to obtaining a signed, written Informed Consent 
Form (ICF) from the patient or the patient’s legally authorized representative.  IRB review and 
approval are required for the ICFs.  The final IRB/IEC approved ICFs must be provided to 
FibroGen for regulatory purposes. 
If there are any changes to the Sample ICF(s) during the patients’ participation in the study, the 
revised ICF(s) must receive the IRB/IEC’s written approval before use and patients must be 
reconsented to the revised version of the ICF.   
Guidance for Clinical Teams: For studies conducted in the United States, each patient 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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11.4 Patient 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 Code of Federal Regulations (CFR) Parts 160 
and 164, and HIPAA. 
Patient 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 patient, or 
unless permitted or required by law.  The patient may request in writing that medical information 
be given to his/her personal physician. 


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12 DATA HANDLING AND RECORD KEEPING 
12.1 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 patient 
enrolled in this clinical study.  Source documents must be adequate to reconstruct all data entered 
into the electronic database and used to resolve queries. 
12.2 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 CFR Part 11 regulations.  
The database will be a secured, password-protected system with full audit trail. 
All patient 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 (e.g., MedDRA and WHODrug). 
The investigator is responsible for reviewing, verifying, and approving all patient data (i.e., 
eCRFs and queries prior to study completion) and ensuring that all data is verifiable with source 
documents. 


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


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


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15 INVESTIGATOR REQUIREMENTS 
The investigator must be medically qualified to directly supervise the conduct of the study at his 
or her site.  The investigator will permit study-related monitoring, audits, IRB/IEC review, and 
regulatory inspection(s), providing direct access to source data/documents. 
15.1 Study Drug Accountability 
The investigational product (roxadustat/placebo) required for completion of this study will be 
provided by Sponsor.  The recipient will acknowledge receipt of the drug by returning the 
appropriate documentation form indicating shipment content and condition.  Damaged supplies 
will be replaced. 
The investigational product, including partial and empty bottles, must be maintained at the study 
site until Sponsor or its designee verifies drug accountability and provides instruction for 
destruction or the return of the investigational product to Sponsor’s drug distribution depot. 
Accurate records of all study drug received, dispensed, returned, and disposed of by the study 
site according to the Study Reference Manual or Pharmacy Manual should be recorded using the 
Drug Inventory Log. 
15.2 Disclosure of Data 
Data records generated by this study must be available for inspection upon request by 
representatives of the FDA or other regulatory agencies, national and local health authorities, 
Sponsor’s monitors/representatives and collaborators, auditors, and the IRB/IEC for each study 
site. 
The Investigators should promptly notify the Sponsor and/or designee of any audits scheduled by 
any regulatory authorities and promptly forward copies of any audit reports received to the 
Sponsor. 
15.3 Retention of Records 
The investigator shall retain records required to be maintained under 21 CFR 312.62(c) for a 
period of 2 years (or longer if required by local regulations) following the date a marketing 
application is approved for the drug for the indication for which it is being investigated.  If no 
application is to be filed or if the application is not approved for such indication, the investigator 
shall retain these records until 2 years after the investigation is discontinued and the FDA is 
notified. 
If the investigator moves or retires, he or she should identify in writing, the designee who will be 
responsible for record keeping.  Archived data may be retained on electronic records or similar 
medium provided that a back-up exists and a hard copy is obtainable if required.  No records will 
be destroyed without the prior written consent of Sponsor. 


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16 REFERENCES 
Abel et al. (2014) Patient-reported outcomes for the myelodysplastic syndromes: a new MDS-
specific measure of quality of life. Blood 123:451-452 
Besarab A, Provenzano R, Hertel J, et al. (2015) Randomized placebo-controlled dose-ranging 
and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent 
chronic kidney disease (NDD-CKD) patients. Nephrol Dial Transplant 30: (10):1665-1673 
Buchler P, Reber HA, Buchler M, et al. (2003) Hypoxia-inducible factor 1 regulates vascular 
endothelial growth factor expression in human pancreatic cancer. Pancreas 26: (1):56-64 
Cella D, Yount S, Rothrock N, et al. (2007) The Patient-Reported Outcomes Measurement 
Information System (PROMIS): Progress of an NIH Roadmap Cooperative Group During its 
First Two Years. Medical Care. 45:(5):S3-S11 
Cella D, Riley W, Stone A, et al. on behalf of the PROMIS Cooperative Group (2010) Initial 
adult health item banks and first wave testing of the patient-reported outcomes measurement 
information system (PROMIS™) Network: 2005–2008. J Clin Epidemiol 63 (11):1179-1194 
Efficace F, Gaidano G, Breccia M, et al (2015) Prevalence, severity and correlates of fatigue in 
newly diagnosed patients with myelodysplastic syndromes. Br J Haematol. 168: (3):361-370 
Epstein AC, Gleadle JM, McNeill LA, et al. (2001) C. elegans EGL-9 and mammalian homologs 
define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107: (1):43-54 
Fan C, Iacobas DA, Zhou D, et al. (2005) Gene expression and phenotypic characterization of 
mouse heart after chronic constant or intermittent hypoxia. Physiol Genomics 22: (3):292-307 
FACIT.org (2014) The FACT-Anemia questionnaire. 
http://www.facit.org/LiteratureRetrieve.aspx?ID=42367 
Flaharty KK, Caro J, Erslev A, et al. (1990) Pharmacokinetics and erythropoietic response to 
human recombinant erythropoietin in healthy men. Clin Pharmacol Ther 47: (5):557-564 
Goldberg MA, Schneider TJ, Khan S, Petersen JR (1993) Clinical validation of an RIA for 
natural and recombinant erythropoietin in serum and plasma. Clin Biochem 26: (3):183-189 
Gray MJ, Zhang J, Ellis LM, et al. (2005) HIF-1α, STAT3, CBP/p300 and Ref-1/APE are 
components of a transcriptional complex that regulates Src-dependent hypoxia-induced 
expression of VEGF in pancreatic and prostate carcinomas. Oncogene 24: (19):3110-3119 
Greijer AE, van der Groep P, Kemming D, et al. (2005) Up-regulation of gene expression by 
hypoxia is mediated predominantly by hypoxia-inducible factor 1 (HIF-1). J Pathol 206: (3):291-
304 
Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC (2003) Differential roles of hypoxia-
inducible factor 1α (HIF-1α) and HIF-2α in hypoxic gene regulation. Mol Cell Biol 23: 
(24):9361-9374 


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Kato, A., Hishida A, Kumagai H, Furuya R, et al. (1994) Erythropoietin production in patients 
with chronic renal failure. Ren Fail 16: (5): 645-651 
Langsetmo, I., Nichols, B., Seeley, T., Stephenson, B., Klaus, S., Lin, A., and Liu, D. (2005) FG-
2216 Corrects Anemia and Improves Iron Utilization in a Rat Model of Anemia of Chronic 
Disease: Comparison to Darbepoetin. Abstract #F-PO674, J Am Soc Nephrol 16: 481A 
List AF, Baker AF, Green S, Bellamy W (2006) Lenalidomide: targeted anemia therapy for 
myelodysplastic syndromes. Cancer Control 13 Suppl: 4-11 
Ma X, Does M, Raza A, Mayne ST (2007) Myelodysplastic syndromes: incidence and survival 
in the United States. Cancer 109: (8):1536-1542 
Maeda H, Hitomi Y, Hirata R, et al. (1992) The effect of phlebotomy on serum erythropoietin 
levels in normal healthy subjects. Int J Hematol 55: (2):111-115 
Milledge JS, Cotes PM (1985) Serum erythropoietin in humans at high altitude and its relation to 
plasma renin. J Appl Physiol 59: (2):360-364 
Peyssonnaux C, Nizet V, Johnson RS (2008) Role of the hypoxia inducible factors HIF in iron 
metabolism. Cell Cycle 7: (1):28-32 
Rabin and de Charro (2001) EQ-5D: a measure of health status from the EuroQol Group. Ann 
Med 33:337-343 
Rollison DE, Howlader N, Smith MT, et al. (2008) Epidemiology of myelodysplastic syndromes 
and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the 
NAACCR and SEER programs. Blood 112: (1):45-52 
Scortegagna M, Ding K, Zhang Q, et al. (2005) HIF-2α regulates murine hematopoietic 
development in an erythropoietin-dependent manner. Blood 105: (8):3133-3140 
Semenza GL (1998) Hypoxia-inducible factor 1: master regulator of O2 homeostasis. Curr Opin 
Genet Dev 8: (5):588-594 
Semenza GL (2000) HIF-1: mediator of physiological and pathophysiological responses to 
hypoxia. J Appl Physiol 88: (4):1474-1480 
Tefferi A and Vardiman JW (2009). Myelodysplastic syndromes. N Engl J Med 361:1872-1885 
Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-
loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A 92: 
(12):5510-5514 
Ware JE, Snow KK, Kosinski M, Gandek B (1993) SF-36® Health Survey Manual and 
Interpretation Guide. New England Medical Center, The Health Institute, Boston, MA. 
http://www.sf-36.org/tools/SF36.shtml  


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Warnecke C, Zaborowska Z, Kurreck J, et al. (2004) Differentiating the functional role of 
hypoxia-inducible factor (HIF)-1α and HIF-2α (EPAS-1) by the use of RNA interference: 
erythropoietin is a HIF-2α target gene in Hep3B and Kelly cells. The FASEB Journal 18: 
(12):1462-1464 
Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E (1997) Measuring fatigue and other 
anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) 
measurement system. J Pain Symptom Manage 13: (2):63-74 


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17 APPENDICES 
Appendix A – Schedule of Assessments: Screen to Week 52, Including EOT Assessments for Patients Completing 52 weeks Treatment 
Procedures 
Screening 
Treatment Weeks 
Post-EOT19 
28 days 
±1 day 
±2 days 
WK4 
S1 
S2 Week 1 
Day 1 
2 3 4 
5 
7 
9 11 13 15 17 19 21 23 25 27 28 
31 35 39 43 47 
52 
EOT17 
Informed consent signature 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Eligibility Review1 
X 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Med History/ Demographics 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Physical Exam  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
X 
X 
Weight6 
X 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
HbsAg, anti-HCV AB, HIV 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Endogenous serum EPO Level2 
X 
  
X 
  
  
  
X 
  
  
  
  
  
  
  
X 
  
X 
  
X 
  
  
X 
  
  
X 
X 
B12, Folate 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
X 
X 
PK3 
  
  
X 
  
  
  
X 
  
  
  
  
  
  
  
X 
  
X 
  
  
  
  
  
  
  
  
ECG4 
 X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
X 
X 
Bone marrow aspirate and biopsy5  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
Vital signs6 
X 
  
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
X 
  
  
X 
X 
ECOG Score7 
X 
X 
X 
  
  
  
X 
  
  
  
X 
  
X 
  
  
 X 
X 
  
  
  
  
  
X 
X 
Serum Lipid Panel 
  
  
X 
  
  
  
X 
  
  
  
  
  
  
  
X 
  
  
  
X 
  
  
X 
  
  
X 
X 
LFTs 8 
X 
X 
X 
  X   
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
X 
  
  
X 
X 
Serum chemistry9 
X 
  
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
X 
  
  
X 
X 
PT, PTT 
X 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
X 
X 
Hepcidin 
X 
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
X 
  
X 
  
  
X 
  
  
X 
X 
Pregnancy test10 
X 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
Point-of-care Urine Pregnancy Test10 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
C-reactive protein 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
X 
X 
Recording of transfusions11 
 
CBC12 
X 
X 
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Local Hemoglobin 
  
  
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Reticulocyte count; CHr 
X 
  
  
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
X 
  
  
X 
X 
Iron Biomarkers13 
X 
  
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
X 
  
  
X 
X 
Registration/Randomization14 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
HRQoL Questionnaires15 
  
  
X 
  
  
  
  
  
X 
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
X 
Study drug dosing16 
  
  
 
                                             DOSE THREE TIMES PERWEEK  
  
Study drug dispensation17 
  
  
X 
  X   
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
X  
X 
X 
X 
X 
  
  
Dose adjustment review18 
  
  
  
  
  
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
X 
X 
  
X 
  
  
  
AEs/Con Meds/Procedures 
 


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1. 
Eligibility review: pre-transfusion Hb measurements will be obtained via review of source document, must be obtained within 72-hours prior to transfusion; baseline 
Hb level will be obtained 3 to 10 days  prior to registration/randomization; GFR will be done prior to registration/randomization (see Appendix L) 
2. 
Serum erythropoietin  level must be ≤400 mIU/mL at screening; during the last month of treatment a serum EPO level will be drawn just prior to the next study drug 
dosing; patients should be told to not take their study drug until after the study visit on that day.   
3. 
PK: see Appendix J.  Levels at 1-3 and 3-5 hours after dosing at clinic on Day 1 (Week 1) as well as 4-6 hours at Week 5 and 8-10 hours at Week 21 after 
administration at the clinic.  Two samples will be obtained 0-2 hours before dosing and 2-3 hours after dosing at Week 25; vital signs will also be taken prior to the 
time of the PK draw 
4. 
ECG: no clinically significant findings per PI review at screen period  
5. 
Patients will need to have the results from the bone marrow exam and cytogenetic analysis performed for the IPSS-R criteria.  Report and slides must be available 
for centralized review.  Bone marrow exam will be done within 4 weeks of end of treatment on all patients  
6. 
Vital signs include BP, HR, RR, temperature. These will also be done prior to each PK sample taken.  If possible, use the same device for BP measurement over the 
course of the study.  Weight at registration/randomization will be used for determination of starting dose. 
7. 
ECOG score: must be 0,1, or 2 at last screen visit 
8. 
LFTs = AST, ALT, TBili, alkaline phosphatase. ALT >3 x ULN, OR AST >3 ×  (ULN), OR TBili > 1.5 × ULN will exclude a subject from entering the study (see 
Appendix H and Appendix O for liver monitoring information) 
9. 
Serum chemistry = sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, magnesium, phosphorus, LDH, albumin (Central Lab) – see 
Appendix K 
10. Pregnancy Test: must be negative for women of child bearing capacity at screening. Additional pregnancy testing for women of child bearing capacity will also be 
done at Weeks 13, 25, 39, EOT and Post-EOT visits. 
11. Recording of Transfusions: all RBC transfusions from 8 to16 weeks prior to first dose throughout end of treatment.  For study entry, patients are considered to have 
LTB if they received 1 to 4 pRBC within 8 weeks prior to registration/randomization.  Patients with 1 pRBC/8weeks must have a documented history of requiring 1 
pRBC/8weeks in at least 2 consecutive 8 weeks periods in the 16 weeks preceding registration/randomization.   Pre and post transfusion Hb will be collected at 8 
weeks post-registration/randomization. The PI and site staff will utilize their own institutional criteria for the determination of when to transfuse a patient. Open-
Label patients only, the requirement to demonstrate transfusion dependence can also be met by a PI starting this particular patient on pRBC transfusion during the 
screening period. 
12. CBC = Hb, HCT, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), RBC, WBC, 
platelets, differential; Regarding Central Lab Hb values: Two Hb values are obtained at Screening Visit 1 and 2, only 1 of 2 value needs to meet the Hb ≤ 10.0 g/dL 
criteria.  
13. Iron biomarkers = serum iron, ferritin, TIBC, TSAT, and UIBC.   
14. Registration into the OL component or Randomization into the DB component to occur on Day 1, Week 1 prior to first dose which should be given at the site 
15. HRQoL questionnaires include PROMIS and EQ-5D-5L. ONLY for patients randomized to DB study 
16. Study drug dosing: begins on the first day of dosing (Day 1/Week 1).  All study procedures must be completed prior to administration of the 1st dose of study 
treatment.  Dosing should occur at approximately the same time of day.  Roxadustat/placebo (study medication) can be taken with water with or without food. The 
dose of statins should not exceed the protocol-recommended daily dose in the protocol. 
17. Last dose of study drug must be prior to EOT assessments 
18. Dose adjustment review every 8 weeks for upward adjustments.  Week 9 evaluation requires determination of Erythroid Response. A re-assessment will be done for 
these patients at Week 12 and if TI is observed the dose will not be increased. 
19. Must be at least 28 days post-dose/EOT 


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Appendix B – Patients who Discontinue Study Medication Prior to Week 52 
Procedures 
EOT17 
Post - 
EOT19 
Every 8 weeks assessment from Post-EOT WK 4 
visit.  Last visit at Week 52 from first dose. 
WK 4 
WK 
12 
 
Informed consent signature 
  
  
  
  
  
Eligibility Review1 
  
  
  
Med History/ Demographics 
  
  
  
Physical Exam  
X 
X  
  
Weight6 
  
  
  
HbsAg, anti-HCV AB, HIV 
  
  
  
Endogenous serum EPO Level2 
X 
X 
X 
B12, Folate 
X 
X 
  
PK3 
  
  
  
ECG4 
X 
X 
  
Bone marrow aspirate and biopsy5 
X 
  
  
Vital signs6 
X 
X 
X 
ECOG Score7 
X 
X 
  
Serum Lipid Panel 
X 
X 
  
LFTs8 
X 
X 
X 
Serum chemistry9 
X 
X 
X 
PT, PTT 
 X 
 X 
  
Hepcidin 
X 
X 
X 
Pregnancy test10 
X 
X 
  
C-reactive protein 
X 
X 
  
Recording of transfusions11 
CBC12 
X 
X 
X 
  
Local Hemoglobin 
X 
X 
X 
Reticulocyte count; CHr 
X 
X 
  
Iron Biomarkers13 
X 
X 
X 
Registration/Randomization to the study 
  
  
  
HRQoL Questionnaires15 
X 
X 
  
Study drug dosing 
  
  
  
Study drug dispensation 
  
  
  
Dose adjustment review 
  
  
  
AEs/Con Meds/Procedures 
For footnotes please refer to Appendix A 


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Appendix C – Dose Adjustment Rules During the Titration to Achieve TI – Correction 
Phase (Prior to Maintenance Phase) 
Dose adjustment will follow as described in the table below.  The down titration of the dose is 
allowed at any time. The maximum dose of study medication is capped at 3.5 mg/kg per dose or 
400 mg, whichever is lower. 
In the OL component, cohort 1 (n=8) starts at 1.5 mg/kg, (Dose Level 1) followed by cohort 2 
(n=8) at 2.0 mg/kg (Dose Level 2) and finally cohort 3 (n=8) at 2.5 mg/kg (Dose Level 3). The 
optimal starting dose will be selected for the DB component following evaluation of the OL data. 
It is anticipated that for the DB component, the starting dose level will be level 2 (2.0 mg/kg) and 
the protocol is written to reflect this but if the OL data identifies level 1 or 3 as a more optimal 
starting dose, this will be implemented. 
 
Body 
Weight 
 
Dose Levels  
approx. 
1.0 mg/kg  
approx.  
1.5 mg/kg 
 
approx. 
2.0 mg/kg 
 
approx. 
2.5 mg/kg 
 
approx. 
3.0 mg/kg 
 
approx. 
3.5 mg/kg 
 
 
 
 
 
 
 
 
 
 
 
 
 
45 - <70 
kg 
 
50 mg 
TIW 
 70 mg TIW  
100 mg 
TIW 
 
150 mg 
TIW 
 
200 mg  
TIW* 
 
250 mg  
TIW* 
 
 
 
 
 
 
 
 
 
 
 
 
 
70-100 
kg 
 
100 mg 
TIW 
 
120 mg 
TIW 
 
150 mg 
TIW 
 
200 mg 
TIW 
 
250 mg  
TIW 
 
300 mg  
TIW* 
 
 
 
 
 
 
 
 
 
 
 
 
 
>100 kg 
 
120 mg 
TIW 
 
150 mg 
TIW 
 
200 mg 
TIW 
 
250 mg 
TIW 
 
300 mg  
TIW 
 
350 mg  
TIW ** 
* Patients body weight MAY require a lower dose than listed in the table above, due to the potential for 
the maximum dose being exceeded.  The next dose given should be at one dose level immediately below 
what is in the above table.  In some cases, a dose escalation will NOT be allowed. 
** Patients with body weight ≥ 120 kg will receive fixed dose of 400 mg TIW at Dose Level 3. 
If there is ANY question as to the appropriate dose to administer contact the CRA or medical 
monitor for guidance. 
Dose Escalation 
Following commencement of study treatment, patients are evaluated for response after 8 weeks 
and, if the patient has required one or more RBC transfusion in that period then the dose is 
increased by one dose level. After each dose adjustment, the patient remains on the dose level for 
a minimum of 8 weeks before further adjustment is permitted. 
With the exception that the starting dose will be maintained if an erythroid response (defined as a 
50% reduction in pRBC from baseline) is seen after the initial 8 weeks of dosing.  A re-
assessment will be done for these patients at week 12 and if transfusion independence (TI) is 
observed the dose will not be increased.  If TI is NOT observed at this point, the dose will be 
increased by one dose level. 


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Dose Reduction 
The down titration of the study treatment is allowed at any time but must be performed if any of 
the following criteria are met. Hb levels should be retested for confirmation every 2 weeks after 
a dose reduction, however it is per investigator’s discretion: 
a) Transfusion independent for ≥56 days consecutively and Hb ≥12 g/dL; or 
b) Transfusion independent for ≥56 days consecutively and the rate of rise of Hb ≥2.5 g/dL 
over 4 weeks. 
c) In the instance where the patient achieved TI in the initial 8-weeks of the study, or has 
undergone treatment with the maximum allowable dose, i.e., 400 mg TIW or 3.5 mg/kg 
for at least 8-weeks, patient may undergo dose reduction by 1-dose level.  If there were 
no difference in erythroid response (same transfusion burden and Hb was unchanged) at 
this dose level for 8-weeks compared to another lower dose level, investigator may 
contact Sponsor’s Medical Monitor to discuss another potential dose reduction.   
This is an effort to treat patients with the lowest effective dose needed to maintain erythroid 
response; thus, study drug dose can be increased again if erythroid response appeared to be 
decreased with dose decrease. 
Reduction should be to one dose level lower than the dose at which the subject is receiving. 
 
 


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Confidential and Proprietary 
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Appendix D – Dose Adjustment Rules for Patients who have TI for ≥56 Days (8 weeks) – 
Maintenance Phase 
A modified dose adjustment algorithm will apply to patients who have attained TI ≥56 days.  
The down titration of the dose is allowed at any time. 
* A change in Hb from 4 weeks earlier of < -1.0 g/dL means a Hb value that is lower by more than 1.0 g/dL compared to 4 
weeks earlier, e.g., a Hb of 9.4 g/dL compared to 10.6 g/dL 4 weeks earlier 
 
 
 
 
Hemoglobin (Hb) Values 
Change in Hb 
from 4 weeks 
earlier (g/dL) 
Hb <10.5 g/dL 
 
Hb 10.5 to 12.9 g/dL 
 
Hb >13.0 g/dL 
 
Hb ≥13.5 g/dL 
 
< -1.0 *  
(or had RBC 
transfusion within 4 
weeks) 
↑ 
↑ 
No change 
Hold, then resume dosing 
when: 
Hb <12 g/dL, at a dose that 
is reduced by one-dose level 
 
Patients are to return 
weekly to monitor Hb until 
dosing can be resumed 
-1.0 to 1.0 
↑ 
No change 
↓ 
> 1.0 
No change** 
↓ 
↓ 
**Dose Adjustment for Excessive Hematopoiesis During Maintenance Phase: 
At any time during the Treatment Period of the maintenance phase if Hb increases by 
>2.0 g/dL within 4 weeks, the dose should be reduced by one dose level.   


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Appendix E – Quality of Life Assessments 
The following health-related quality of life (HRQoL) assessment tools will be utilized for this 
study: 
1. Patient-Reported Outcomes Measurement Information System (PROMIS®,  
Cella et al.  2007; Cella et al., 2010) 
2. European Quality of Life Five Dimensional Health Questionnaire (EQ-5D-5L), 
(Rabin and de Charro, 2001) 
The rationale for each of the PRO items and domains selected includes consideration of the 
applicable concepts to be evaluated and context of use for this study. 
Specific symptoms that are most important to the MDS population are fatigue/tiredness.  
Currently, there are no existing perfect measures to capture these symptoms. 
PROMIS provides clinicians and researchers access to reliable, valid, and flexible measures of 
health status that assess physical, mental, and social well–being from the patient perspective.  
PROMIS measures are standardized, allowing for assessment of many patient-reported outcome 
domains, including pain, fatigue, emotional distress, physical functioning and social role 
participation, based on common metrics that allow for comparisons across domains, across 
chronic diseases, and with the general population.  Further, PROMIS tools allow for computer 
adaptive testing, efficiently achieving precise measurement of health status domains with few 
items.  There are PROMIS measures for both adults and children.  PROMIS was established in 
2004 with funding from the National Institutes of Health (NIH) as one of the initiatives of the 
NIH Roadmap for Medical Research. 
EQ-5D is a standardized instrument for measuring generic health status.  The health status 
measured with EQ-5D is used for estimating preference weight for that health status, then by 
combining the weight with time, quality-adjusted life year (QALY) can be computed.   QALYs 
gained is used as an outcome in cost-utility analysis which is a type of economic evaluation that 
compares the benefit and cost of health care programs or interventions.   Many countries 
generated a value set (preference weights) of their own population and have used it for 
estimating QALY to make decisions in resource allocation.   There are currently 171 language 
versions of EQ-5D questionnaire available.   EQ-5D is one of the most commonly used generic 
health status measurement, and its good validity and reliability have been reported in various 
health conditions.   
Importantly, PROMIS is a validated instrument for the MDS population (Abel et al., 2014), and 
so is EQ-5 (Efficace, 2015). 
References: 
Abel et al.  (2014) Patient-reported outcomes for the myelodysplastic syndromes: a new MDS-
specific measure of quality of life. Blood 123:451-452 
Cella D, Yount S, Rothrock N, et al. (2007) The Patient-Reported Outcomes Measurement 
Information System (PROMIS): Progress of an NIH Roadmap Cooperative Group During its 
First Two Years. Medical Care. 45:(5):S3-S11 
Cella D, Riley W, Stone A, et al. on behalf of the PROMIS Cooperative Group (2010) Initial 
adult health item banks and first wave testing of the patient-reported outcomes measurement 
information system (PROMIS™) Network: 2005–2008. J Clin Epidemiol 63 (11):1179-1194 


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Efficace et al (2015) Prevalence, severity and correlates of fatigue in newly diagnosed patients 
with myelodysplastic syndromes. Br J Haematol 168:361-370 
Rabin and de Charro (2001) EQ-5D: a measure of health status from the EuroQol Group. Ann 
Med 33:337-343 
 
 


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Appendix F – ECOG Assessment Scale 
Grade ECOG 
0 
Fully Active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up 
and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair 
5 
Dead 
 
 


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Appendix G – International Prognostic Scoring System – Revised (IPSS-R) 
International Prognostic Scoring System 
Prognostic 
variable 
0 
0.5 
1 
1.5 
2 
3 
4 
Cytogenetics 
Very Good 
  
Good  
  
Intermediate
Poor 
Very Poor
BM* Blast % 
≤2 
>2-<5% 
5-10% 
>10% 
Hemoglobin 
≥10 
8-<10 
<8 
Platelets 
≥100 
50-<100 
<50 
ANC** 
≥0.8 
<0.8 
 
 
* bone marrow 
** absolute neutrophil (white blood cell) count 
 
 
IPSS-R Risk Groups 
Risk Group 
Risk Score 
Very Low 
≤1.5 
Low 
> 1.5-3 
Intermediate 
> 3-4.5 
High 
> 4.5-6 
Very High 
> 6 
 
 


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


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Follow-up Procedures 
Patients with confirmed abnormal liver function results should be closely monitored and 
followed as described below.  If close monitoring for LFTs in a patient is not possible, study 
drug should be discontinued. 
Repeat LFTs 2-3 times weekly, then weekly or less until abnormalities stabilize or return to 
within normal limits.  LFTs should include ALT, AST, TBL and ALP 
In addition, evaluate the patient for potential causes, which may include the following: 
• Detailed history of symptoms and prior or concurrent diseases 
• Concomitant drug use, including nonprescription medications, herbal and dietary 
supplements, alcohol or recreational drug use, or special diets 
• Exposure to environmental chemical agents 
• Rule out acute viral hepatitis Types A,B,C,D,E; autoimmune or alcoholic hepatitis; 
nonalcoholic steatohepatitis; hypoxic/ischemic hepatopathy; biliary tract disease 
• Obtain additional tests as appropriate: e.g., INR, gamma glutamyltransferase (GGT) or 
direct bilirubin; ultrasound or other imaging to assess biliary tract disease 
• Consider gastroenterology or hepatology consultations 
In general, in the absence of an explanation for increased LFTs, such as viral hepatitis, 
preexisting or acute liver disease or exposure to other agents associated with liver injury, the 
study drug should be discontinued. 
Discontinuation of treatment should be considered if: 
• ALT or AST > 8 × ULN 
• ALT or AST > 5 × ULN for more than 2 weeks  
• ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5) (If INR testing is 
applicable/evaluated) 
• ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%) 
Once LFTs return to normal, and depending on whether there is an explanation for the LFT 
elevations, study drug dosing may resume, after discussion with the Medical Monitor 
See also: FDA Guidance for Industry, titled: “Drug-Induced Liver Injury: Premarketing Clinical 
Evaluations”, issued July 2009 
 


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Appendix I – Erythropoiesis-Stimulating Agents (ESAs)  
Prohibited ESAs include (but are not limited to) the following: 
• darbepoetin 
• Mircera (methoxy polyethylene glycol epoetin beta) 
• epoetin alfa 
• epoetin beta 
• epoetin delta 
• epoetin theta 
• epoetin omega 
• hematide 
 
 


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Appendix J – Schedule of PK Assessments 
Timing and Number of PK Samples; note that Vital Signs will be taken prior to each blood draw 
  
0-2 hrs pre-dose^ 
1-3 hrs 
2-3 hrs 
3-5 hrs 
4-6 hrs 
8-10 hrs 
Day 1 (Week 1) 
  
1 
  
1 
  
  
Week 5 
  
  
  
  
1 
  
Week 21 
 
 
 
 
 
1 
Week 25 
 1 
  
 1 
  
  
^Time points are post-dose unless specified otherwise 
 
 
 


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Appendix K – Laboratory Tests 
CBC: 
Serum Chemistry: 
Basophils 
Albumin 
Eosinophils 
Bicarbonate  
Erythrocyte count (RBC) 
BUN 
HCT 
Calcium 
Hb  
Chloride 
Leukocyte count (WBC) 
Creatinine 
Lymphocytes 
Glucose 
Mean corpuscular volume  
Lactate dehydrogenase 
Mean corpuscular Hb 
Magnesium 
Mean corpuscular Hb concentration 
Phosphorus 
Monocytes 
Potassium 
Neutrophils 
Na 
Neutrophils, immature (banded) 
 
Platelets 
 
Iron Biomarkers: 
LFTs: 
Ferritin 
ALP 
Iron 
ALT 
TIBC 
AST  
UIBC 
TBili 
TSAT  
 
Additional Hematology Analytes: 
HIV and Viral Hepatitis Panel: 
Reticulocyte count 
Anti-HCV Ab tests 
CHr 
HBsAg 
 
HIV  
Special Laboratory Tests: 
Hepcidin 
CRP 
Serum erythropoietin level 
PT 
Serum Lipid Panel (non-fasting)  
including total cholesterol, LDL and TG 
Point-of-care Urine Pregnancy Test 
PTT 
Vitamin B12 and folate 
Serum Pregnancy 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; 
CHr = reticulocyte hemoglobin content; Hb = hemoglobin; HBsAg = hepatitis B surface 
antigen; HCT = hematocrit; HCV = hepatitis C virus; HIV = human immunodeficiency 
virus; LDH = lactate dehydrogenase; LDL = low density lipoprotein; PT = prothrombin 
time; PTT = partial thromboplastin time; RBC = red blood cell; TBili = total bilirubin; 
TG = triglycerides; TIBC = total iron binding capacity; UIBC=unsaturated iron binding 
capacity TSAT = transferrin saturation; WBC = white blood cell. 


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Appendix L – Calculation of Creatinine Clearance/eGFR per Cockroft-Gault 
 
The Cockcroft-Gault (CG) formula (Cockroft and Gault, 1976; Gault, 1992) estimates GFR in 
ml/min and employs serum creatinine measurements and a patient's weight to predict the 
creatinine clearance as follows: 
 
When serum creatinine is measured in µmol/L, the following formula applies: 
 
Where Constant is 1.23 for men and 1.04 for women. 
 
A web-based Cockroft-Gault calculator can be accessed at http://nephron.com/cgi-bin/CGSI.cgi. 
 
 
References: 
Cockcroft DW, and Gault MH (1976). Prediction of creatinine clearance from serum creatinine. 
Nephron 16: (1): 31–41 
Gault MH, Longerich LL, Harnett JD, and Wesolowski C (1992). Predicting glomerular function 
from adjusted serum creatinine. Nephron 62: (3): 249–256 
 
 


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Appendix M – New York Heart Association Classification (NYHA) of Congestive Heart 
Failure 
The list below describes the most commonly used classification system, the NYHA Functional 
Classification.  It places patients in one of four categories based on how much they are limited 
during physical activity. 
Class 
Patient Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical activity, e.g., 
no shortness of breath when walking, climbing stairs etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation during 
ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary activity, 
e.g., walking short distances (20–100 m).  Comfortable only at rest. 
IV 
Severe limitations.  Experiences symptoms even while at rest.  Mostly bedbound 
patients. 
Reference: 
The Criteria Committee of the New York Heart Association (1994). Nomenclature and Criteria 
for Diagnosis of Diseases of the Heart and Great Vessels (9th ed.). Boston: Little, Brown & Co.  
pp. 253–256. 


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Appendix N – Blood Pressure and Heart Rate Monitoring 
Blood Pressure 
Blood pressure (BP) measurement should be done with the patient 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 patient should be 
instructed to relax as much as possible and to not talk during the measurement procedure.  
Preferably measurement will be done with an electronic automated device.  The same device 
should preferably be used for the patient 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. 
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 patient during the course of the study, timing as indicated in the 
schedule of assessments.   
 
 


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Appendix O – Individual Patient Study Stopping Criteria 
 
Patients will be discontinued from treatment for the following reasons: 
 
a. Disease progression:  Diagnosis of AML during the study 
b. Liver Function:  Discontinuation of treatment will occur 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%) 

SAP_001.pdf: 
FibroGen Inc. 
409 Illinois Street 
San Francisco, CA 94158 USA 
_____________________________________________________________________ 
Protocol Number  FGCL-4592-082, Amendment 03 
Title 
A Phase 3 Randomized Double-Blind Placebo-Controlled Study 
Investigating the Efficacy and Safety of Roxadustat (FG-4592) for 
Treatment of Anemia in Patients with Lower Risk 
Myelodysplastic Syndrome (MDS) with Low Red Blood Cell 
(RBC) Transfusion Burden (LTB)  
Document 
Statistical Analysis Plan 
Version 
1.0 
Release Date 
April 10, 2023 
NCT03263091


Protocol: FGCL-4592-082  
Statistical Analysis Plan 
Version 1.0, 2023-04-10  
 
 
FibroGen, Inc                             CONFIDENTIAL                              Page 2 of 76 
 
I have reviewed and accepted the information in this document to be a true and accurate representation of 
the Statistical Analysis Plan for Study FG-4592-082. 
Initiator: 
 
 
 
Signature:  
Date:  
 
 
 
 
 
 
 
 
Reviewed by: 
 
 
 
 
 
Signature: 
 
Date: 
 
 
 
  
 
Signature: 
 
Date: 
 
 
 
  
 
Signature: 
 
Date: 
 
 
 
 
  
 
  
 
Signature: 
 
Date: 
 
 
 
      
  
 
  
 
Signature: 
 
Date: 
 
 
 
  
 
Signature: 
 
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Approvals 
 


Protocol: FGCL-4592-082  
Statistical Analysis Plan 
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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. 
 


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Statistical Analysis Plan 
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 Table of Contents 
1. INTRODUCTION ................................................................................................................................ 9 
2. STUDY OBJECTIVES ....................................................................................................................... 10 
2.1. 
OPEN-LABEL COMPONENT OBJECTIVE ........................................................................................... 10 
2.2. 
OPEN-LABEL (OL) HIGH-ERYTHROPOIETIN COMPONENT OBJECTIVE ............................................. 10 
2.3. 
DOUBLE-BLIND COMPONENT ......................................................................................................... 10 
2.3.1. 
Primary Objective ................................................................................................................... 10 
2.3.2. 
Secondary Objectives .............................................................................................................. 10 
3. INVESTIGATIONAL PLAN ............................................................................................................. 11 
3.1. 
OVERALL STUDY DESIGN ............................................................................................................... 11 
3.2. 
SAMPLE SIZE DETERMINATION ....................................................................................................... 13 
3.3. 
RANDOMIZATION AND TREATMENT ASSIGNMENT ........................................................................... 13 
3.4. 
BLINDING ....................................................................................................................................... 14 
4. STUDY ENDPOINTS ......................................................................................................................... 15 
4.1. 
EFFICACY ENDPOINT FOR OPEN-LABEL COMPONENT AND OL HIGH-ERYTHROPOIETIN COMPONENT
 
15 
4.2. 
EFFICACY ENDPOINT FOR RANDOMIZED, DOUBLE-BLIND COMPONENT ......................................... 15 
4.2.1. 
Definition of Estimand for Primary Efficacy Endpoint .......................................................... 15 
4.2.2. 
Definition of Estimand for Secondary Efficacy Endpoints ..................................................... 15 
4.2.3. 
Exploratory Endpoints ............................................................................................................ 18 
4.3. 
SAFETY ASSESSMENTS .................................................................................................................... 18 
5. GENERAL STATISTICAL CONSIDERATIONS .......................................................................... 19 
5.1. 
GENERAL PRESENTATION OF SUMMARIES AND ANALYSES .............................................................. 19 
5.2. 
ANALYSIS POPULATION FOR OPEN-LABEL COMPONENT AND OL HIGH-ERYTHROPOIETIN 
COMPONENT.............................................................................................................................................. 19 
5.2.1. 
Full Analysis Set (FAS) ........................................................................................................... 19 
5.2.2. 
Safety Analysis Set (SAF) ........................................................................................................ 20 
5.3. 
ANALYSIS POPULATION FOR DOUBLE-BLIND COMPONENT ............................................................. 20 
5.3.1. 
Full Analysis Set (FAS) ........................................................................................................... 20 
5.3.2. 
Safety Analysis Set (SAF) ........................................................................................................ 20 
5.3.3. 
Per-Protocol Set (PPS) ........................................................................................................... 20 
5.4. 
METHODS OF DATA TRANSFORMATION AND HANDLING OF MISSING DATA .................................... 20 
5.5. 
BASELINE MEASURES AND CHANGE FROM BASELINE ..................................................................... 20 
5.6. 
RANDOMIZATION ERRORS ............................................................................................................... 21 
5.7. 
OTHER KEY DEFINITIONS AND COMPUTATIONS .............................................................................. 21 
6. PATIENT ENROLLMENT AND DISPOSITION ........................................................................... 22 
6.1. 
ELIGIBILITY CRITERIA .................................................................................................................... 22 
6.2. 
SUBJECT ACCOUNTABILITY AND DISPOSITION ................................................................................ 22 
7. PROTOCOL DEVIATIONS .............................................................................................................. 23 
8. DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ....................................... 24 
9. MEDICAL HISTORY ........................................................................................................................ 26 
10. 
EXTENT OF EXPOSURE TO STUDY MEDICATION ............................................................. 27 


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10.1. 
EXTENT OF EXPOSURE................................................................................................................. 27 
10.2. 
TREATMENT COMPLIANCE ........................................................................................................... 27 
10.3. 
DOSE MODIFICATION................................................................................................................... 28 
11. 
PRIOR AND CONCOMITANT MEDICATIONS ....................................................................... 29 
12. 
EFFICACY ANALYSES................................................................................................................. 30 
12.1. 
MULTIPLE COMPARISONS/MULTIPLICITY .................................................................................... 30 
12.2. 
ANALYSIS OF OPEN-LABEL AND OL HIGH-ERYTHROPOIETIN DATA ............................................ 30 
12.3. 
ANALYSIS OF DOUBLE-BLIND EFFICACY ENDPOINTS .................................................................. 30 
12.3.1. 
Analysis of Primary Efficacy Endpoint ............................................................................... 30 
12.3.2. 
Sequential Gatekeeping Procedure ..................................................................................... 33 
12.3.3. 
Analysis of Secondary Efficacy Endpoints .......................................................................... 34 
12.3.4. 
Analysis of Exploratory Efficacy Endpoints ....................................................................... 40 
12.4. 
EXAMINATION OF SUBGROUPS .................................................................................................... 46 
12.5. 
SUBGROUP ANALYSES BY REGION ............................................................................................... 46 
13. 
PHARMACOKINETICS / PHARMACODYNAMICS ANALYSES ........................................ 47 
14. 
SAFETY ANALYSES ..................................................................................................................... 48 
14.1. 
ADVERSE EVENTS ....................................................................................................................... 48 
14.1.1. 
AE Subgroup Analysis ......................................................................................................... 49 
14.1.2. 
Exposure Adjusted Incidence Rate ...................................................................................... 50 
14.2. 
DISEASE PROGRESSION OF AML ................................................................................................. 50 
14.3. 
CLINICAL LABORATORY DATA ..................................................................................................... 50 
14.3.1. 
Liver Function Tests ............................................................................................................ 51 
14.4. 
EXCESSIVE HEMATOPOIESIS ........................................................................................................ 52 
14.5. 
VITAL SIGNS ................................................................................................................................ 52 
14.6. 
ELECTROCARDIOGRAM (ECG) .................................................................................................... 53 
14.7. 
ECOG PERFORMANCE STATUS .................................................................................................... 53 
14.8. 
PREGNANCY TEST ....................................................................................................................... 53 
15. 
DATA SAFETY MONITORING BOARD .................................................................................... 54 
16. 
INTERIM ANALYSIS .................................................................................................................... 55 
17. 
CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ............................................ 56 
18. 
REFERENCE .................................................................................................................................. 57 
19. 
APPENDIX ...................................................................................................................................... 58 
19.1. 
DOSE ADJUSTMENT RULES FOR PATIENTS WHO HAVE TI FOR ≥ 56 DAYS .................................... 58 
19.2. 
PHARMACOKINETICS / PHARMACODYNAMICS ANALYSES ........................................................... 58 
19.3. 
DATA HANDLING CONVENTIONS ................................................................................................. 59 
19.3.1. 
Analysis Windows ................................................................................................................ 59 
19.3.2. 
Missing Date of Study Medication ...................................................................................... 62 
19.3.3. 
Missing Severity Assessment for Adverse Events ................................................................ 62 
19.3.4. 
Missing Relationship to Study Drug for Adverse Events .................................................... 62 
19.3.5. 
Missing Date Information for Adverse Events .................................................................... 62 
19.3.6. 
Missing Date Information for Prior or Concomitant Medications ..................................... 63 
19.3.7. 
Missing Start Date for Study Disease (Myelodysplastic Syndrome) ................................... 64 
19.4. 
EQ-5D 5L V2 .............................................................................................................................. 65 
19.5. 
PROMIS PHYSICAL FUNCTION 10B SHORT FORM ...................................................................... 67 


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19.6. 
FATIGUE – SHORT FORM 13A ....................................................................................................... 69 
19.7. 
AN ADJUSTED DIFFERENCE IN PROPORTIONS USING LOGISTIC REGRESSION ............................... 70 
19.8. 
PRO APPENDIX FOR PROMIS .................................................................................................... 73 
19.8.1. 
Distribution-based Minimal Clinically Important Difference (MCID) ............................... 73 
19.8.2. 
Sensitivity Analysis of PROMIS .......................................................................................... 73 
19.9. 
SCOPE OF WEEK 28 PRIMARY ANALYSIS ..................................................................................... 74 


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List of Abbreviations 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical/Therapeutic/Chemical 
ALT 
Alanine Aminotransferase  
AML 
Acute Myeloid Leukemia  
AST 
Aspartate Aminotransferase  
BSC 
Best Supportive Care 
CMH 
Cochran-Mantel-Haenszel 
COVID-19 
Coronavirus disease 2019 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
CTCAE 
DB 
Common Terminology Criteria for Adverse Events 
Double Blind 
DSMB 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram  
ECOG 
Eastern Cooperative Oncology Group 
EPO 
Gene Encoding Erythropoietin 
EQ-5d-5L 
European Quality Of Life-5 Dimensions-5 Levels 
EOT 
End of Treatment 
ET 
Early Termination 
FAS 
Full Analysis Set 
GFR 
Glomerular Filtration Rate  
PF 
Physical Function 
Hb 
Hemoglobin 
HRQoL 
Health-related Quality of Life 
ICH 
International Conference on Harmonization 
INR 
International Normalized Ratio  
IPSS-R 
International Prognostic Scoring System – Revised  
IRT 
Item Response Theory 
IWG 
International Working Group 
IWRS 
Interactive Web Response System  
LSM 
Least-Squares Mean 
LTB 
Low Red Blood Cell Transfusion Burden 
MDS 
Myelodysplastic Syndromes 
MedDRA 
Medical Dictionary For Regulatory Activities 
MCID 
Minimal Clinically Important Difference 
MMRM 
Mixed Model Repeated Measures 
NCI 
National Cancer Institute 
OL 
Open Label 
PEW 
PD 
Patient-Exposure-Week 
Pharmacodynamics 
PI 
Principal Investigator  
PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
pRBC 
packed Red Blood Cell 
PROMIS 
Patient Reported Outcomes Measurement Information System 


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PT 
Preferred Term 
QoL 
Quality of Life 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TI 
Transfusion Independence 
TIBC 
Total Iron Binding Capacity 
TSAT 
Transferrin Saturation  
ULN 
Upper Limit of Normal  
UIBC 
Unsaturated Iron Binding Capacity  
WHO 
World Health Organization 
WHODD 
WHO Drug Dictionary 
 
 


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1. 
INTRODUCTION 
This document describes prospectively the statistical analyses and presentation of data for the clinical trial 
conducted under Protocol FGCL-4592-082, A Phase 3 Randomized Double-Blind Placebo-Controlled 
Study Investigating the Efficacy and Safety of Roxadustat (FG-4592) for Treatment of Anemia in Patients 
with Lower Risk Myelodysplastic Syndrome (MDS) with Low Red Blood Cell (RBC) Transfusion 
Burden (LTB), Amendment 03, dated 30 January 2020. It contains definitions of analysis populations, 
derived variables, and statistical methods for the analysis of efficacy and safety. 
The purpose of the SAP is to ensure the credibility of the study findings by pre-specifying the statistical 
approaches to any data analysis prior to database lock. This SAP will be finalized prior to database lock 
of the primary efficacy analysis of the study after all patients have completed 28 weeks of double-blind 
treatment or terminated before this time point.  
This study consists of three components – an open-label lead-in dose-finding component followed by a 
randomized, double-blind component and an open-label high Erythropoietin (EPO) component. Data 
from patients in the open-label component and an open-label high EPO will be analyzed separately from 
the double-blind randomized component of the study. This SAP is based on protocol version 3.0 dated 30 
January 2020. 


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2.
STUDY OBJECTIVES
2.1. 
Open-Label Component Objective
Optimize the starting dose for the double-blind component 
2.2. 
Open-label (OL) High-Erythropoietin Component Objective 
This is an “exploratory cohort” for patients with higher EPO levels (serum Erythropoietin levels >400 
mIU/mL) to further understand treatment response to Roxadustat in patients with higher than 400 
mIU/mL endogenous EPO levels. 
2.3. 
Double-Blind Component 
2.3.1. 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of roxadustat in the treatment of anemia in 
patients with lower risk MDS who have a low burden of RBC transfusion.  
2.3.2. 
Secondary Objectives 
The secondary objectives in this study are to: 
• 
Evaluate the safety of roxadustat 
• 
Evaluate the impact of roxadustat on RBC transfusion requirements  
• 
Evaluate pharmacokinetics (PK) and pharmacodynamics (PD) of roxadustat in MDS patients 
• 
Evaluate effect of roxadustat on quality of life (QoL) parameters  


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3.
INVESTIGATIONAL PLAN
3.1. 
Overall Study Design
This is a Phase 3 Randomized, Double-Blind, Placebo-Controlled Study Investigating the Efficacy and 
Safety of Roxadustat (FG-4592) for Treatment of Anemia in Patients with Lower Risk Myelodysplastic 
Syndrome (MDS) with Low Red Blood Cell (RBC) Transfusion Burden (LTB). Patients are planned to be 
accrued from approximately 100 global centers.  
The study consists of three components: (1) an open-label lead-in component to optimize the starting 
dose; (2) a double-blind, randomized 2-arm component to evaluate the efficacy and safety of roxadustat 
(FG-4592) versus matching Placebo along with best supportive care (BSC); 3) an open-label (OL) high-
erythropoietin component to evaluate safety and efficacy of roxadustat (transfusion independence) in 
patients with high endogenous erythropoietin in order to facilitate decision making whether similar 
patients with elevated endogenous serum erythropoietin levels should be allowed to participate in the DB 
component. The first two components will be carried out sequentially. The third component will be 
carried out concurrent to double blind enrollment, refer to Figure 1 for the study design schema from the 
protocol. 
Figure 1: Study Schema
Open-label (OL) component (Open-Label, Dose-Finding, Lead-In Component): Dose evaluation based 
on efficacy. Up to 24 patients will be enrolled in sequential dose level cohorts prior to start of the double-
blind component of the study. All patients will receive roxadustat in an open-label manner. The first 8 


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may receive a starting dose of 1.5 mg/kg. The next 8 may receive a starting dose of 2.0 mg/kg. The last 8 
may receive a starting dose of 2.5 mg/kg. 
The initial open-label patients may remain in the study for up to 52 weeks of treatment based on 
investigator discretion, adequate safety, and clinical benefit.  
The initial open-label patients will undergo all procedures as the randomized patients in the double-blind 
study with the exception of not completing the Patient Reported Outcomes (PRO) assessments.  
Double-blind (DB) component: 160 eligible patients will be randomized in the double-blind component 
of the study. When all the randomized patients complete 28 weeks of treatment or are discontinued from 
study medication before this time, the analysis of the primary efficacy endpoints will be performed for a 
topline read-out. When all the randomized patients complete 52 weeks of treatment or are discontinued 
from study medication before this time, the full analysis of primary and secondary efficacy endpoints will 
be performed.  
In this DB component, 160 eligible patients will be randomized in a 3:2 assignment ratio to roxadustat or 
matching placebo with the following stratification factors:  
• 
Endogenous serum EPO level: ≤ 200 mIU/mL vs. > 200 mIU/mL and ≤ 400 mIU/mL  
• 
IPSS-R: low risk / very low risk vs. intermediate risk classification  
• 
RBC transfusion burden: 1 pRBC/8-weeks over 16 consecutive weeks vs. 2-4 pRBC/8-weeks   
NOTE: 1-pRBC randomization will be limited to no more than 30% of the total randomized patient 
population 
OL high-erythropoietin component：Based on the Amendment 03 of the protocol dated 30 January 
2020, concurrent to DB enrollment, up to 20 patients with high serum erythropoietin levels will be 
enrolled in an OL exploratory cohort. Unless otherwise mentioned, patients enrolled in this high 
erythropoietin cohort will follow all DB study procedures including the same starting dose (2.5 mg/kg 
TIW), same visit schedule, etc., except that the patients will all be administered roxadustat in an OL 
manner. Safety and efficacy assessments (transfusion independence) will be made on an ongoing basis to 
facilitate decision making on whether patients with elevated serum erythropoietin levels should be 
allowed to participate in the DB component of the study. 
The study will consist of the following visits: 
Baseline Assessments: To be obtained ≤ 42 days prior to starting study drug for open-label component 
and double-blind component respectively.  
Randomization (double-blind component only): Randomization into the double-blind component to 
occur on Day 1 (Week 1) prior to first dose.  
Treatment: The maximum treatment duration for patients in both the open-label and double-blind 
components is 52 weeks.  
Week 28 visit: Week 28 visit should be conducted at the end of 28 weeks of treatment (2 weeks after 
Week 27 Visit). Primary analysis of efficacy will be conducted when all the randomized (DB) patients 
complete 28 weeks of treatment or are discontinued from study medication before this time. End-of-
Treatment (EOT/ET) Visit: Patients who complete 52-week treatment period or discontinue study 
medication early (Early Termination before week 52) will have an EOT/ET visit.  
Post-Treatment Follow-Up Period: Week 56 (Post-EOT Week 4)  


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Post-Treatment Follow-Up Period for ET Patients: Patients who discontinue early will have visits 
every 8 weeks until Week 52. 
End of Study (EOS) Visit: All patients who complete 52 weeks (of treatment with study medication) 
will undergo a 4 week follow-up period after the last dose of study medication and will return for the End 
of Study (EOS) visit. Patients who discontinue study medication early (for any reason) will remain in the 
study through the entire 52 week study period. Patients will have a 4 week follow-up visit after stopping 
study medication/ET visit and then be followed up at a reduced visit schedule of every 8 weeks until the 
end of the study. 
3.2. 
Sample Size Determination 
For the open-label component, the sample size is not determined based on statistical consideration. Up to 
24 patients will be enrolled in sequential dose level cohorts. All patients will receive roxadustat in an 
open-label manner.  
For the OL high-erythropoietin component, the sample size is not determined based on statistical 
consideration. Up to 20 patients will be enrolled in an OL exploratory cohort. All patients will receive 
roxadustat in an open-label manner. 
For the double-blind component, 160 patients are planned to be randomized in a 3:2 ratio to roxadustat or 
matching placebo. This sample size will provide at least 90% power to demonstrate a statistically 
significant difference between roxadustat and placebo at the significance level of 0.05 using a two-sided 
Fisher’s test, and assuming the response rates of the primary endpoint are 35% and 5% in roxadustat and 
placebo, respectively. 
In total, approximately up to 204 patients will participate in this study. 
Due to the slow enrollment in the double-blind component, an unplanned blinded sample size estimation 
was performed. Based on this, 120 patients randomized in a 3:2 ratio to roxadustat or matching placebo 
will provide at least 90% power to demonstrate a statistically significant difference between roxadustat 
and placebo at the significance level of 0.05 using a two-sided Fisher’s exact test, and assuming the 
response rates of the primary endpoint are 56% and 13% in roxadustat and placebo, respectively. The 
response rate on roxadustat was based on the response rates from open-label and double-blind 
components in a blinded fashion. The response rate on placebo was based on the MEDALIST study. 
3.3. 
Randomization and Treatment Assignment 
For the open-label component, eligible patients will be sequentially assigned to the cohorts, starting with 
1.5mg/kg for the first 8 patients, then 2.0mg/kg for the next 8 patients and at 2.5 mg/kg for the last 8 
patients. No randomization is needed. 
For the OL high-erythropoietin component, eligible patients will be assigned to an OL exploratory cohort, 
starting with 2.5 mg/kg TIW. No randomization is needed. 
For the double-blind component, patient randomization will be performed by an Interactive Web 
Response System (IWRS) to ensure a 3:2 assignment ratio between two treatment arms within each 
stratum. The randomization will be stratified by the following 3 factors:  
• 
Endogenous serum EPO level: ≤ 200 mIU/mL vs. > 200 mIU/mL and ≤ 400 mIU/mL  
• 
IPSS-R risk category: low risk / very low risk vs. intermediate risk classification  
• 
RBC transfusion burden: 1 pRBC/8-weeks over 16 consecutive weeks vs. 2- 4 pRBC/8-weeks  


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NOTE: 1-pRBC randomization will be limited to no more than 30% of the total randomized patient 
population. 
3.4. 
Blinding 
For open-label component and OL high-erythropoietin component, blinding is not applicable. 
For double-blind component, any data displays reviewed before database lock will be blinded. Only 
Sponsor personnel who are not directly involved with the study sites/patients will have access to the 
unblinded data. The blind will be maintained for study patients, principal Investigator (PI), site staff, site 
monitoring personnel, sponsor personnel and Contract Research Organization (CRO) personnel who are 
directly involved in the study conduct with study sites / patients for the remainder of the study (to Week 
52 plus a 4-week follow-up period).  
A statistician who is not otherwise affiliated with the study will prepare the randomization schedule and 
the schedule will not be available to study staff until study unblinding. The patients, clinical site staff, 
FibroGen Medical Monitor and Clinical Operations staff are blinded to whether a patient is randomized to 
roxadustat or placebo.  
Independent Data and Safety Monitoring Board (DSMB) members who review the safety data 
periodically might be unblinded. 
Primary analysis of efficacy for the double-blind component will be conducted when all randomized (DB) 
patients complete 28 weeks of treatment or are discontinued from study medication before this time. Only 
the sponsor unblinding team who are not directly involved with the double-blind component will have 
access to the interim unblinded data, and will no longer participate in blinded trial management or 
analysis until after the final database lock of double-blind component. Sponsor personnel, sites, and 
patients who are directly involved in the study conduct will remain blinded to study treatment in the 
double-blind component until the final study database lock and unblinding. A detailed Data Access Plan 
for the primary analysis summarizes blinding and unblinding plan for interim analysis. 
Treatment assignments will be unblinded after the completion of the study. 


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4. 
STUDY ENDPOINTS 
4.1. 
Efficacy Endpoint for Open-Label Component and OL High-Erythropoietin 
Component 
For the Open-Label and OL high-erythropoietin component, the primary efficacy endpoint is the 
proportion of patients who were TI for≥8 consecutive weeks during the first 28 treatment weeks. 
Secondary endpoints include TI ≥ 56 consecutive days anytime in the first 52 weeks of treatment, 
proportion of patients who achieved ≥ 50% reduction in number of RBC transfusion over any 8 weeks 
compared to baseline, proportion of patients who achieved TI for > 20 weeks. 
4.2. 
Efficacy Endpoint for Randomized, Double-Blind Component 
Following the framework in ICH E9 guideline Addendum R1 (Final version Adopted on 20 November 
2019) (E9 (R1)), this section details estimand and selected strategies in handling intercurrent events for 
each primary and secondary endpoint. How to analyze primary and second endpoints are specified in 
Section 12.3. 
4.2.1. 
Definition of Estimand for Primary Efficacy Endpoint  
Population of interest: Male and female patients aged ≥ 18 years and with diagnosis of primary MDS 
(confirmed histopathologically by bone marrow aspirate and biopsy prior to treatment Day 1), classified 
by the IPSS-R as very low, low, or intermediate risk with <5% bone marrow blasts and with RBC 
transfusion requirement of either a. 2 to 4 pRBC during the 8-weeks prior to registration/randomization or 
b. 1 pRBC during the 8-weeks prior to registration/randomization. There is no restriction on prior use of 
recombinant erythropoietins or analogues (erythropoiesis-stimulating agents (ESAs)), except that the 
patient must not have received any ESA within the 8 weeks prior to Day 1 registration/randomization. 
ESA-naïve patients were allowed to be randomized into the study. Other key eligibility criteria include 
Hb ≤10.0 g/dL during Screening, , EPO levels ≤400 mIU/mL, No del(5q) cytogenic abnormality, Body 
weight ≥45 kg and ECOG performance status of 0, 1 or 2 during screening. 
Endpoint of interest: RBC TI (transfusion independence) response defined as if patients achieved TI ≥ 
56 consecutive days in the first 28 weeks of treatment. 
Population-level summary for the endpoint: odds ratio of patients who achieved transfusion TI ≥ 56 
consecutive days in the first 28 weeks of treatment between treatment and placebo arm. 
Handling of intercurrent events: 
Treatment discontinuation (such as: due to Death, Disease progression, lack of efficacy, impaired Liver 
function, Patient decision, Investigator decision, AE/SAE, etc.) uses ‘on treatment strategy’ in which to 
assess the response to treatments of interest while the patient is exposed to treatment All administered 
RBC transfusion records from the first dose to the end of treatment will be used to define transfusion 
independence. 
4.2.2. 
Definition of Estimand for Secondary Efficacy Endpoints  
Population of interest: The same population as defined in Primary Efficacy Endpoint. 


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Table 1: 
Other Estimand Attributes for Secondary Efficacy Endpoints 
Table Endpoint of interest 
Population-level 
summary for the 
endpoint 
Handling of intercurrent events 
Treatment 
discontinuation* 
Death 
RBC TI (transfusion 
independence) response 
defined as if patients 
achieved TI ≥ 56 consecutive 
days in the first 52 weeks of 
treatment. 
Odds ratio of patients 
who achieved 
transfusion TI ≥ 56 
consecutive days in the 
first 52 weeks of 
treatment between 
treatment and placebo 
arm. 
While on treatment 
strategy: response to 
treatment prior to the 
occurrence of treatment 
discontinuation  
While on treatment 
strategy: response to 
treatment prior to 
death. 
RBC TI (transfusion 
independence) response 
defined as if patients 
achieved TI ≥ 56 consecutive 
days anytime during the 
study  
Odds ratio of patients 
who achieved 
transfusion TI ≥ 56 
consecutive days 
anytime during the 
study between treatment 
and placebo arm 
Treatment-policy 
strategy: regardless of 
these intercurrent events 
occurred;   
Treatment-policy 
strategy: regardless 
of these intercurrent 
events occurred. 
Reduction in number of 
pRBC transfusions over 8 
weeks compared to their 
baseline for any 8-week 
period during the study 
Odds ratio of patients 
who achieved ≥50% 
reduction in number of 
pRBC transfusions over 
8 weeks compared to 
their baseline for any 8-
week period during the 
study between treatment 
and placebo arm 
Treatment-policy 
strategy: regardless of 
these intercurrent events 
occurred;  
Treatment-policy 
strategy: regardless 
of these intercurrent 
events occurred. 
Patient-exposure-weeks 
(PEW) of TI over the first 28 
weeks of the treatment period 
Difference in PEW of 
TI over the first 28 
weeks of the treatment 
period between 
treatment and placebo 
arm 
While on treatment 
strategy: treatment effect 
prior to the occurrence 
of treatment 
discontinuation  
While on treatment 
strategy: Treatment 
effect while on 
treatment  
Number of pRBC packs 
transfused compared to 
baseline over the first 28 
weeks of the treatment period  
Difference in mean of 
pRBC transfused 
change from baseline 
over the first 28 weeks 
of the treatment period 
between treatment and 
placebo arm 
While on treatment 
strategy: treatment effect 
prior to the occurrence 
of treatment 
discontinuation  
While on treatment 
strategy: Treatment 
effect while on-
treatment  


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RBC TI (transfusion 
independence) response 
defined as if patients 
achieved TI ≥ 140 
consecutive days anytime 
during the study 
Odds ratio of patients 
who achieved 
transfusion TI ≥ 140 
consecutive days 
anytime during the 
study between treatment 
and placebo arm 
Treatment-policy 
strategy: regardless of 
these intercurrent events 
occurred;  
Treatment-policy 
strategy: regardless 
of these intercurrent 
events occurred. 
Change from baseline in the 
PROMIS-SF v2.0 Physical 
Function 10b score at week 9 
Difference in mean 
change from baseline in 
the PROMIS-SF v2.0 
Physical Function 10b 
score at week 9 between 
treatment and placebo 
arm 
Due to reasons other 
than AE/SAE: 
Treatment-policy 
strategy: regardless of 
these intercurrent events 
occurred;  
Due to AE/SAE: 
Hypothetical strategy: A 
scenario is envisaged 
after the intercurrent 
event occurred; 
Treatment-policy 
strategy: regardless 
of these intercurrent 
events occurred. 
Change from baseline in the 
PROMIS-SF v1.0 Fatigue 
13a score at week 9 
Difference in mean 
change from baseline in 
the PROMIS-SF v1.0 
Fatigue 13a scores at 
week 9 between 
treatment and placebo 
arm 
Due to reasons other 
than AE/SAE: 
Treatment-policy 
strategy: regardless of 
these intercurrent events 
occurred;  
Due to AE/SAE: 
Hypothetical strategy:  
A scenario is envisaged 
after the intercurrent 
event occurred; 
Treatment-policy 
strategy: regardless 
of these intercurrent 
events occurred. 
Change from baseline in EQ-
5D-5L VAS score at week 9 
Difference in mean 
change from baseline in 
EQ-5D-5L VAS score 
at week 9 between 
treatment and placebo 
arm 
Due to reasons other 
than AE/SAE: 
Treatment-policy 
strategy: regardless of 
these intercurrent events 
occurred;  
Due to AE/SAE: 
Hypothetical strategy: A 
scenario is envisaged 
after the intercurrent 
event occurred; 
Treatment-policy 
strategy: regardless 
of these intercurrent 
events occurred. 
*Such as due to Disease progression, Liver function, Patient decision, Investigator decision, AE/SAE, etc. 


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4.2.3. 
Exploratory Endpoints  
The exploratory efficacy endpoints include: 
• 
Maximum Duration of TI 
• 
Proportion of patients who achieve a mean Hb increase of ≥ 1.0 g/dL and ≥ 1.5 g/dL (averaged 
over any 8 weeks in those achieved TI) compared to pre-transfusion Hb at baseline  
• 
Impact of baseline endogenous erythropoietin levels on roxadustat treatment response and dose 
requirement 
• 
Effect on hepcidin and iron indices metabolism (e.g., serum iron, ferritin, TIBC, TSAT, and 
UIBC)  
• 
Effect on cholesterol and lipid parameters 
4.3. 
Safety Assessments 
For both open-label and double-blind components, safety will be assessed by evaluating the following 
over 52 weeks:  
• 
AE and SAE reporting  
• 
N (%) of patients with progression to acute myeloid leukemia (AML)  
• 
Clinical laboratory measures including Hb and liver chemistries (AST, ALT, Total bilirubin, and 
alkaline phosphatase)  
• 
Vital signs (heart rate, blood pressure, respiratory rate, and temperature) and ECG 
• 
Evaluation of PK/PD data at the end of study 
An independent Data and Safety Monitoring Board (DSMB) assesses the safety profile during study 
conduct. 


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5.
GENERAL STATISTICAL CONSIDERATIONS
5.1. 
General Presentation of Summaries and Analyses
Continuous variables will be presented by descriptive statistics: n, mean, standard deviation (standard 
error, as needed), median, minimum, and maximum. Categorical variables will be presented by counts of 
patients and percentage. Unless otherwise specified, the denominator for all percentages will be the 
number of patients in the population of interest. For plasma concentrations and PK variables, coefficient 
of variation (CV%) and geometric mean will be additionally provided.  
Any p-values will be rounded to four decimal places and will be presented as ‘<.0001’ if they are less 
than 0.0001 after rounding. 
For 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.  
In this study, eGFR will be calculated by the central lab using the Cockcroft-Gault (CG) formula as 
described in protocol Appendix L. 
Decimal points will be presented as follows: N will be presented without decimal, CV with one decimal, 
minimum/maximum in same precision as in the database, mean/median in one more decimal than 
minimum/maximum, and SD in one more decimal than mean/median. 
Analyses will be conducted using SAS® Version 9.3 or higher. All tables and listings will have a header 
showing “FibroGen, Inc.” and the protocol number. A footer will show the program file name and path, 
run date, run time, and output file name and path. 
The secondary endpoints will be tested sequentially, the family-wise type I error rate will be controlled 
using the method described in Section 12.1. 
All individual data will be presented in individual patient data listings. 
Data from the open-label and double-blind component of the study will be analyzed separately. Patients 
enrolled in open-label component may remain in the study up to 52 weeks and will undergo all 
procedures as will the randomized patients (except Health-Related Quality of Life (HRQoL) assessments 
including PROMIS and EQ-5D-5L), but the data will be included in the analysis of open-label component 
only. 
For the double-blind component, data will be analyzed for the first 28 weeks of treatment and for the end 
of the 52-week study treatment period respectively.  
Patients from the OL high-erythropoietin component will undergo the same procedures as will patients 
from the OL component with the exception of completing the HRQoL questionnaires. Data from the OL 
high-erythropoietin component will be analyzed along with the OL component. HRQoL data from the OL 
high-erythropoietin component will be listed. The final analysis will be done for the end of the 52-week 
study treatment period. 
5.2. 
Analysis Population for Open-Label Component and OL High-
Erythropoietin Component 
5.2.1. 
Full Analysis Set (FAS) 
The full analysis set consists of all patients enrolled into this study who receive at least one dose of study 
medication, and at least one corresponding on-treatment Hb assessment. 


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5.2.2. 
Safety Analysis Set (SAF) 
The safety analysis set consists of all patients who have received at least one dose of study drug. Analyses 
of the safety data will be based on the safety analysis set. 
5.3. 
Analysis Population for Double-Blind Component 
5.3.1. 
Full Analysis Set (FAS) 
The full analysis set consists of all patients randomized to this study who receive at least one dose of 
study medication, and at least one corresponding on-treatment Hb assessment. Patients will be included in 
the treatment group to which they are randomized for the FAS analysis. 
5.3.2. 
Safety Analysis Set (SAF) 
The safety analysis set consists of all patients who are randomized to this study and have received at least 
one dose of study drug. Analyses of the safety data will be based on the SAF. Patients will be included in 
the treatment group based on treatment they actually received. 
5.3.3. 
Per-Protocol Set (PPS)  
The Per-Protocol Set (PPS) consists of patients who have received at least 8 weeks of treatment with 
corresponding on-treatment Hb assessments and are without major protocol deviations that affect the 
assessment of study endpoints. The PPS population will be used for supportive and/or sensitivity analyses 
of the efficacy endpoints.  
5.4. 
Methods of Data Transformation and Handling of Missing Data  
All data collected and recorded in the study database will be eligible for inclusion in the analysis. No 
substitutions for missing data will be made unless otherwise specified in this SAP, except for dates that 
occur prior to a patient being enrolled in the study (e.g., medications received before screening). For these 
date imputations, refer to Appendix 19.3. 
Some lab data are collected using local labs (in lieu of the ICON central lab) due to central lab kit 
shortages caused by the COVID-19 pandemic. In these cases, local lab values and reference ranges 
collected from CRFs will be presented in the listings along with central lab data when appropriate and 
feasible. Local lab values will be flagged in datasets and data listings to be differentiated from central lab 
values. For summary analyses of Hemoglobin efficacy and laboratory safety in tables and figures, if 
central lab is not available at a scheduled visit and local lab is available, the local lab will be used for 
substitution. 
5.5. 
Baseline Measures and Change from Baseline 
For patients who achieved ≥ 50% reduction in number of pRBC transfusions over any 8 weeks (day 1 to 
week 52) compared to their baseline, the baseline will be calculated based on the transfusions within 8 or 
16 weeks prior to the first dose.  
For subjects with transfusion records within 16 weeks prior to first dose: Baseline number of transfusions 
(pRBC/8-weeks) = total number of packs of red blood cells within 16 weeks prior to first dose/2. 
For subjects with transfusion records within only 8 weeks prior to first dose: Baseline number of 
transfusions (pRBC/8-weeks) = total number of packs of red blood cells within 8 weeks prior to first 
dose. 


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For other measurements, baseline value will be defined as the last measure taken before any study drug 
administration unless otherwise specified.  
Change from baseline is defined as the difference between the baseline value obtained and the respective 
post-baseline time point for the continuous variables. Negative values represent decreases from baseline; 
positive values reflect increases from baseline. 
Percent change from Baseline is defined as the change from Baseline divided by the Baseline value，
multiplied by 100: 
100 x (Post-Baseline value minus Baseline value) / (Baseline value) 
5.6. 
Randomization Errors 
Patients who were randomized from an incorrect stratum will be identified by comparing the strata 
recorded on the RTSM system (Randomization and Trial Supply Management)/randomization CRF page 
with the strata derived from screening data. A listing of patients who were randomized from an incorrect 
stratum will be presented. The randomized stratum (from RTSM system/randomization CRF) rather than 
actual stratum (derived from screening data) will be used for all the efficacy analyses. A sensitivity 
analysis will be performed using the actual stratum on the primary endpoint if the discrepancy rate is 
greater than 5% in the final result. 
5.7. 
Other Key Definitions and Computations 
Study Day 
Study day will be calculated in reference to the date of the first dose (Study Day 1, which refers to the 
enrollment/randomization in the protocol). For assessments conducted on or after the first dose date, 
study day is calculated as (assessment date – first dose date + 1). For assessments conducted before the 
first dose date, study day is calculated as (assessment date – first dose date). There will be no Study 
Day 0.  
In the listings, study days will be presented along with assessment date where applicable. 
Date of First Dose and Date of Last Dose of Study Drug 
The date of the first dose of study drug is defined as the date a patient receives the first dose of study drug 
(roxadustat or placebo). The date of the last dose of study drug is defined as the date a patient receives the 
last dose of study drug (roxadustat or placebo). 
Treatment Day 
Treatment day will be calculated in reference to the date of the first dose of study drug. Treatment Day 1 
corresponds to the date a patient receives the first dose of study drug. For assessments conducted on or 
after the date of the first dose of study drug, treatment day will be calculated as (assessment date – date of 
first dose of study drug + 1). There will be no Treatment Day 0.  
Treatment Period 
The treatment period is defined as the period of time from the date and time of the first dose of study drug 
through the date of last dose.  


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6. 
PATIENT ENROLLMENT AND DISPOSITION 
6.1. 
Eligibility Criteria 
Eligibility criteria will be summarized for all screened subjects in open-label component and double-blind 
component. The data will be summarized with respect to: 
• 
number of subjects screened 
• 
number (%) of subjects screen-failed 
• 
number (%) of subjects for each failed inclusion/exclusion criterion 
Subject level inclusion criteria not met/exclusion criteria met listings will be provided. 
6.2. 
Subject Accountability and Disposition 
For open-label component, patient disposition will be summarized by dose level cohort and overall. For 
OL high-erythropoietin component, the summaries will be presented along with the cohorts from open-
label component. For double-blind component, patient disposition will be summarized by treatment group 
and overall. 
The data will be summarized with respect to: 
• 
number of patients screened, 
• 
number (%) of patients screen-failed (and by major reason), 
• 
number of patients enrolled (defined as patients who signed informed consent form and received 
treatment assignment), 
• 
number (%) of patients randomized, not treated (double-blind component), 
• 
number (%) of patients randomized, treated (double-blind component), 
• 
number (%) of patient completed study treatment (Note: for 28-week analysis, the summary will 
use the data in the first 28 weeks of treatment period),  
• 
number (%) of patients prematurely discontinued from study treatment by specific reason as 
recorded on the CRF,  
• 
number (%) of patients prematurely discontinued from the study by specific reason as recorded on 
the CRF. 
Percent of screen-failed will be based on the number of patients screened. All other percentages for 
patients will be based on the number of patients enrolled.  
In addition, the number and percentage of patients included in the FAS, PPS and SAF will be 
summarized. Percentage will be based on the number of patients enrolled.  
Number and percentage of subjects with early discontinuation of study medication by demographics and 
baseline characteristics will be summarized in the SAF.  
Consort diagrams describing the disposition of patients in the SAF will be provided. 
All patients who prematurely discontinued from treatment or study will be listed by discontinuation 
reason. 


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7. 
PROTOCOL DEVIATIONS 
Important protocol deviations of interest may include, but are not limited to, the following:  
• Patients who did not meet inclusion/exclusion criteria  
• Patients who received disallowed concomitant medications or non-drug therapy during study 
treatment period 
• Patients who took IV iron while on study 
The number and percentage of important protocol deviations will be categorized and tabulated as 
appropriate. A subset of pre-specified major protocol deviations will exclude some patients in the PPS 
analyses. These will be identified prior to database lock and study unblinding. Considerations will be 
given according to the following table. The number and percentage of major protocol deviations will be 
categorized and tabulated as appropriate. 
Table 2: 
Criteria for Assessing Major Protocol Deviations Table   
Number 
Major Protocol Deviation 
1 
Violation of inclusion or exclusion criteria which may affect the assessment of the 
efficacy of the study drug  
2 
Administration of prohibited concomitant medication or non-drug therapy 
3 
Significant noncompliance with study procedures, e.g., a patient skipping consecutive 
scheduled assessments, will be evaluated case by base 
4 
Developed criteria for discontinuation of study drug but did not discontinue study drug  
treatment 
5 
Received the wrong treatment or incorrect dose resulting in any adverse event 
6 
Were incorrectly stratified by the study investigators 


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8. 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
For categorical data, frequencies and percentages will be provided and, for continuous data, descriptive 
statistics, including sample size (n), mean, median, standard deviation, and range of values (i.e., minimum 
and maximum values) will be provided. All information to be summarized will also be presented in 
listings. 
Comparability of baseline characteristics among treatment groups will be tested using analysis of variance 
(ANOVA) model for continuous variables and Chi-Square test (or Fisher’s exact test if cell count < 5) for 
categorical variables for reference only. The p-values are exploratory and no formal statistical inference 
will be made.  
For open-label component, the summaries will be presented by dose level cohort and overall using safety 
population. For OL high-erythropoietin component, the summaries will be presented along with the 
cohorts from open-label component using safety population. For double-blind component, the summaries 
will be presented by treatment group and overall using FAS, Safety and PPS. The following baseline 
characteristics will be summarized and listed: 
• 
age 
• 
age group (< 65 / >= 65 years) 
• 
sex 
• 
ethnicity 
• 
race 
• 
weight 
• 
baseline Serum EPO level 
• 
baseline Serum EPO level category [<200 (IU/L), 200-400 (IU/L), >400 (IU/L)] 
• 
serum EPO level category based on actual strata [<200 (IU/L), 200-400 (IU/L)] 
• 
pRBC-transfusion burden at baseline 
• 
baseline pRBC-transfusion burden group (1 pRBC/8-weeks vs. 2-4 pRBC/8-weeks over 16 
consecutive weeks) 
• 
pRBC-transfusion burden based on actual strata (1 pRBC/8-weeks vs. 2-4 pRBC/8-weeks over 16 
consecutive weeks) 
• 
baseline ECOG performance status 
• 
MDS duration (based on medical history)  
• 
WHO Classification of MDS 
• 
pre-transfusion hemoglobin (Hb) at baseline  
• 
baseline platelet counts 
• 
cytogenetic actual category 
• 
Anticoagulants use at baseline (Yes/No) - if applicable. 
• 
bone marrow blast 
• 
IPSS-R risk category (low risk / very low risk vs. intermediate risk classification) 


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• eGFR  
• baseline C-reactive protein (CRP)  
• CRP group (CRP ≤ULN vs. CRP > ULN) 
• Ferritin and Ferritin group (< 100 ng/mL, >= 100 ng/mL and < 400 ng/mL, >= 400 ng/mL)  
• TSAT and TSAT group (< 20%, >= 20% and < 40%, >= 40%),   
• iron repletion status ([TSAT <20% or ferritin < 100 ng/mL] vs. others)  
MDS duration will be calculated from the earliest date documented on the medial history CRF to Day 1. 


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9. 
MEDICAL HISTORY 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA, version 
19.1). A summary table will be presented by system organ class (SOC) and preferred term (PT).  
For open-label component, the summaries will be presented by dose level cohort using safety population. 
For OL high-erythropoietin component, the summaries will be presented along with the cohorts from 
open-label component using safety population. For double-blind component, the summaries will be 
presented by treatment group using FAS. 


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10. 
EXTENT OF EXPOSURE TO STUDY MEDICATION 
Extent of exposure, treatment compliance and dose modification will be summarized for the safety 
population. 
For open-label component, the summaries will be presented by dose level cohort. For double-blind 
component, the summaries will be presented by treatment group. For extent of exposure and treatment 
compliance, the summaries will be presented up to Week 28 and Week 52/EOT separately. For OL high-
erythropoietin component, the summaries will be presented along with the cohorts from open-label 
component. 
10.1. 
Extent of Exposure 
Exposure to study medication will be summarized in terms of treatment duration, which is calculated as 
the number of weeks from the date of first study medication taken to the date of last dose taken, 
inclusively.  
Duration (in weeks) = (date of last dose - date of first dose + 1) / 7 
Total actual dose (in mg or mg/kg) for dose interval k is calculated as 
dose strength in interval k * (last day of dose interval k - first day of dose interval k + 3 days) * 
(frequency for dose interval k/7)  
The first and last day of dose interval will be obtained from IP dosing form. The first day of dose interval 
k is the first date of a new doing level. For example, the dose of 50 mg TIW starts on 01/07/2017, ends on 
02/10/2017, the total dose is 50*(33+3)*(3/7) = 771.4 mg. The average weekly dose is calculated as the 
sum of all actual doses over the treatment period (in mg) divided by actual exposure duration (in weeks) 
during the period. The average weekly dose per weight is calculated as the sum of all actual doses over 
the treatment period per weight (in mg/kg) divided by actual exposure duration (in weeks) during the 
period.   
Duration of exposure and average weekly exposure over time will be tabulated for the safety population. 
Exposure duration by category (<2 weeks, 2 weeks - <8 weeks, 8 weeks - <=28 weeks) will be 
summarized for Week 28 analysis. Subject exposure over time (probability of subjects still on treatment) 
up to Week 28 and up to Week 52 will be plotted by treatment groups. 
10.2. 
Treatment Compliance 
Study medication compliance will be calculated as the total amount of doses actually administered during 
that period divided by the total amount of doses prescribed expected to be taken during the same period 
(e.g. Day1 to Last dose) multiplied 100.  
Total prescribed dose (in mg or mg/kg) for dose interval k is calculated as 
dose strength in interval k * (last day of dose interval k - first day of dose interval k + 3 days) * 
(frequency for dose interval k/7) 
The first and last day of dose interval will be obtained from Study Drug Dispensation form. The first day 
of dose interval is the first day of a new prescribed dosing level. The last day of dose interval is the day 
before the initial day of the next new prescribed dosing level, if it is the last dosing level, the last day of 
this dosing level will be the last treatment day. 
If there is a dose interruption period and the reason is “PI decision”, the amount of doses in the 
interruption period should be excluded from both the numerator and the denominator in the compliance 
calculation. 


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Descriptive statistics for study medication compliance will be presented by treatment group. A frequency 
summary of treatment compliance category (<75%, >=75% to < 85%, >=85% to <= 100% and >100%) 
will also be provided. 
Date of first/last dose, duration of treatment, dates of discontinuation of treatment and study, and reason 
for study drug discontinuation will be listed for patients who discontinued the study drug prematurely. 
10.3. 
Dose Modification 
Dose Escalation 
Following commencement of study treatment, patients are evaluated for response after 8 weeks 
(beginning at Week 9) and, if the patient has required one or more RBC transfusion in that period then the 
dose is increased by one dose level based on the body weight category. After each dose adjustment, the 
patient remains on the dose level for a minimum of 8 weeks before further adjustment is permitted based 
on the next scheduled visit. 
Dose Reduction 
The down titration of the study treatment is allowed at any time but must be performed if any of the 
following criteria are met. Hb levels should be retested for confirmation every 2 weeks after a dose 
reduction; however, it is per investigator’s discretion:  
a. Transfusion independent for ≥ 56 days consecutively and Hb ≥ 12 g/dL; or  
b. Transfusion independent for ≥ 56 days consecutively and the rate of rise of Hb ≥ 2.5 g/dL over 
4 weeks.  
c.  In the instance where the patient achieved TI in the initial 8-weeks of the study, or has 
undergone treatment with the maximum allowable dose, i.e., 400 mg TIW or 3.5mg/kg for at 
least 8-weeks, patient may undergo dose reduction by 1-dose level. If there were no difference 
in erythroid response (same transfusion burden and Hb was unchanged) at this dose level for 
8-weeks compared to another lower dose level, investigator may contact Sponsor’s Medical 
Monitor to discuss another potential dose reduction.  
Dose adjustment rules for patients who have TI for ≥ 56 Days (Maintenance Phase) can be referenced to 
Section 19.1. 
The number of dose escalations will be summarized descriptively.  
The number and percentage of patients who exceed maximum dose will be summarized. The maximum 
dose of study medication is capped at 3.5 mg/kg per dose or 400 mg, whichever is lower. 
The number and percentage of patients with a prescribed dose increase and decrease will be summarized. 
The number and percentage of patients with an actual dose hold, increase and decrease will be 
summarized. 
The summaries above will be presented by every cumulative 4-weeks, e.g., up to 4 weeks, up to 8 
weeks, …, up to 52 weeks and up to 52 weeks and beyond. 
Dose modifications by primary investigator or by patient collected on the eCRF will be listed. Hb level 
meeting the dose adjustment rules will be combined in the listing. 


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11.
PRIOR AND CONCOMITANT MEDICATIONS
For open-label component, the summaries will be presented by dose level cohort. 
For OL high-erythropoietin component, the summaries will be presented along with the cohorts from 
open-label component. 
For double-blind component, the summarizes will be presented by treatment group. 
The World Health Organization Drug Dictionary (WHODD) Version 2015 will be used to classify prior 
and concomitant medications by therapeutic class and preferred term based on ATC code level 3. Prior 
medication is defined as any medication taken and stopped prior to the first dose of the study medication. 
Concomitant medication is defined as any medication taken between the day of first dose of the study 
medication and the day of last study medication date + 28 days, inclusive.  
Medication start and end dates will be compared with the start date of study drug and classified as per 
Table 3. In case of partial or missing dates, comparisons will be made based on the level of details 
available. For example, if start date of study drug administration 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 3: 
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 
N/A 
Concomitant 
Concomitant 
Missing 
Prior 
Concomitant 
Concomitant 
Both prior and concomitant medication usage will be summarized by the number and proportion of 
patients receiving each drug within each therapeutic class using the safety population. Multiple drug 
usage in the same therapeutic class and preferred term by a patient will be counted only once. 
A summary for prior ESA use and ESA Refractory, will be presented for double-blind component. 
Detailed analyses may be performed on prior and concomitant medications of special interests such as 
oral iron, statin, phosphate binders and anticoagulants based on TLF shells. 
Procedures and non-drug therapies will be summarized by the number and percentage. Detailed analyses 
may be performed on procedures and non-drug therapies of special interest such as bone marrow 
transplant. 


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12.
EFFICACY ANALYSES
12.1. 
Multiple Comparisons/Multiplicity 
For open-label component and OL high-erythropoietin component, there will be no statistical inference 
intended; hence, no multiplicity adjustment is needed. 
For double-blind component, the statistical test results of the primary and secondary endpoints in the first 
28-week treatment period (or at Week 28) and in the 52-weeks of treatment period (or at Week 52) will 
be used to determine treatment efficacy of roxadustat. To control the family-wise type I error at the alpha 
level of 0.05, a sequential gatekeeping procedure will be used to test the primary and secondary efficacy 
endpoints. Specifically, if the test of the primary endpoint is significant at the level of 0.05, the first 
secondary endpoint will be tested at the level of 0.05. Other secondary endpoints will be tested 
conditioning on the previous endpoint achieving the statistical significance, in the order listed in Section 
12.3.3. Statistical testing will stop at the first endpoint that fails to achieve the significance level. All 
statistical tests will be two-sided at the significance level of 0.05. 
12.2. 
Analysis of Open-Label and OL High-Erythropoietin Data 
For the Open-Label and OL high-erythropoietin component, the primary efficacy endpoint is the 
proportion of patients who were TI for≥8 consecutive weeks during the first 28 treatment weeks. 
Secondary endpoints include TI ≥ 56 consecutive days anytime in the first 52 weeks of treatment, 
proportion of patients who achieved ≥ 50% reduction in number of RBC transfusion over any 8 weeks 
compared to baseline, proportion of patients who achieved TI for > 20 weeks. These estimands are 
defined in Sections 12.3.1 and 12.3.3.2. 
Because of the small sample sizes for the OL component and OL high erythropoietin component, 
descriptive analyses with frequency tables will be provided.   
A frequency table of patients with at least a 50% reduction in the number of pRBC transfusions over any 
8-week (56 consecutive days) period during the study as compared with the baseline will be provided by 
dose level cohort. Similar strategies as described in Section 12.3.3.2 will be implemented for potential 
intercurrent events. 
A frequency table of patients who achieved TI ≥ 56 consecutive days (e.g., 8 weeks) since first dose in 
the first 28-weeks of treatment will be provided by dose level cohort. TI is defined as the absence of any 
intravenous RBC transfusion (packed cell or whole blood) during any consecutive 56 days during the 
treatment period (e.g., Days 1 to 56, Days 2 to 57, Days 3 to 58). Similar strategies as described in 
Section 12.3.1.1 will be implemented for potential intercurrent events. 
A by-patient listing of transfusion records will also be provided. 
12.3. 
Analysis of Double-Blind Efficacy Endpoints 
12.3.1. 
Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint for this study is proportion of patients who achieved TI ≥ 56 consecutive 
days (e.g., 8 weeks) since first dose in the first 28-week of treatment. TI is defined as the absence of any 
intravenous RBC transfusion (packed cell or whole blood) during any consecutive 56 days during the 
treatment period (e.g., Days 1 to 56, Days 2 to 57, Days 3 to 58). All RBC transfusions from 8 to16 
weeks prior to first dose until end of study will be recorded on CRF. TI will be estimated in the duration 
beginning with the first dose date (Day 1) and ending with the date of end of treatment or last visit date at 


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week 28, whichever comes earlier. RBC transfusions after end of treatment will be recorded on the CRF 
until the last visit at week 52 from first dose but will not be used to define TI. 
The endpoint will be also analyzed for the end of the  
52-week study treatment period as a secondary endpoint. 
12.3.1.1. Primary Analysis 
The RBC TI response rate and its two-sided 95% confidence interval based on the exact method of 
Clopper-Pearson will be presented in a frequency table by treatment group using the FAS.  
The primary objective of the study will be evaluated to demonstrate a statistically significant difference 
between roxadustat and placebo group with respect to the RBC transfusion independence rate based on 
the Cochran-Mantel-Haenszel (CMH) chi-square test adjusting for the stratification factors (EPO level, 
IPSS-R risk category and RBC transfusion burden). A CMH-adjusted odds ratio (roxadustat versus 
placebo) and its associated 95% CI will be computed to compare between the roxadustat group and 
placebo group.  
This analysis will take into account the potential intercurrent events as follows:  
1. Treatment discontinuation (such as: due to Disease progression, Liver function, Patient decision, 
Investigator decision, AE/SAE, etc.): using while on treatment strategy: Patients who have discontinued 
treatment early for any reasons prior to week 8 will be classified as non-responders. For patients who 
have discontinued treatment early for any reasons after week 8, TI will be estimated in the duration 
beginning with the first dose date (Day 1) and ending with the date of end of treatment or last visit date at 
week 28, whichever comes earlier. 
2. Death: using While on treatment strategy: Treatment effect while on treatment is of interest. Patients 
who died prior to week 8 will be classified as non-responders. For patients who died after week 8, the 
RBC TI response will be based on RBC transfusion records up to the date of end of treatment or last visit 
date at week 28 or death, whichever comes earlier.  
The number of periods of 8 weeks (56 consecutive days) that meet the criterion of TI per TI responder 
will be summarized descriptively.  
Hypothesis testing: 
The odds ratio (OR) in treatment response (roxadustat vs. placebo) is given by: 
OR = (n1*(N2-n2))/n2*(N1-n1)) 
Where: 
N1 = the number of patients in roxadustat group 
N2 = the number of patients in placebo group 
n1 = the number of patients who achieved TI ≥ 56 consecutive days (e.g., 8 weeks) since first dose in 
the first 28-weeks of treatment in roxadustat group 
n2 = the number of patients who achieved TI ≥ 56 consecutive days (e.g., 8 weeks) since first dose in 
the first 28-weeks of treatment in placebo group 
 
The null and alternative hypotheses that will be tested at 2-sided significant level 5% are:  
H0: OR = 1 versus Ha: OR ≠ 1 


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The p-value from the stratified CMH chi-square test will be the confirmatory p-value for the test of the 
null hypothesis that the proportion of patients achieving RBC transfusion independence is equal between 
the two treatment groups. 
SAS code for Cochran-Mantel-Haenszel (CMH) test 
The two-sided CMH test will be performed using SAS procedure PROC FREQ with the CMH option in 
the TABLES statement. Baseline EPO level, IPSS-R risk category and RBC transfusion burden will be 
the stratification variables. The variables <treatment> and <response> determine the rows and columns of 
the tables. 
   Sample code: 
    PROC FREQ DATA = <input_dataset sorted> NOPRINT; 
       TABLES <strata_var>* <treatment_var> * <response_var> / CMH EXACT RISKDIFF; 
    RUN;   
Handling of missing values in primary analysis 
Patients who have discontinued treatment early for any reasons prior to week 8 will be classified as non-
responders. If significant differential treatment discontinuation prior to week 8 is observed between the 
two treatment groups, additional sensitivity analyses may be explored. 
Sensitivity Analysis 
Sensitivity Analysis 1:  PPS Analysis  
The primary analysis will be repeated using PPS as a sensitivity analysis.  
Sensitivity Analysis 2:  Logistic Regression Analysis  
The primary analysis for primary endpoint will also be repeated using a multivariate logistic regression. 
The following variables/factors will be used in the model:  
• treatment group (roxadustat vs. placebo);  
• age group (< 65 vs. >=65 years);  
• centrally confirmed IPSS-R category (Intermediate vs. Low-risk/very low risk); 
• transfusion burden (1 pRBC/8-weeks over 16 consecutive weeks vs. 2-4 pRBC/8-weeks);  
• baseline hemoglobin 
• baseline EPO level (≤200 mIU/mL vs. >200 mIU/mL and ≤400 mIU/mL); 
In addition, MDS duration, baseline platelet counts, and bone marrow blasts will be also investigated as 
continuous variables. 
A Wald test based on the estimated regression parameter for treatment group assignment will provide the 
basis for the hypothesis testing. The odds ratio (roxadustat versus placebo) and its 95% confidence 
interval will be provided. An example of the SAS code is displayed below: 
PROC LOGISTIC; 
      CLASS <treatment_var> <factors>; 
      MODEL <response_var> = <treatment_var> <factors>; 
RUN; 


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An adjusted difference in proportions and its 95% Confidence Interval from the same logistic regression 
model will be presented using the method proposed by Ge et al. (2011). See Appendix 19.7 for SAS 
sample code. 
A swimming plot will be provided to display the RBC transfusions and TI periods during treatment 
period. The RBC TI response rates over longer periods (at least 8 consecutive weeks, at least 12 
consecutive weeks, at least 16 consecutive weeks, and at least 20 consecutive weeks) during treatment 
will be plotted by treatment groups, in bar charts, with p-values calculated by the Cochran-Mantel-
Haenszel (CMH) chi-square test adjusting for the stratification factors (EPO level, IPSS-R risk category 
and RBC transfusion burden). 
The analyses in this section will use the FAS population. 
12.3.2. 
Sequential Gatekeeping Procedure 
Once the primary hypothesis has been rejected for the primary endpoint, the primary endpoint at week 52 
and the secondary endpoints in the order specified in the Table 4 will be tested using a sequential 
gatekeeping procedure, in order to maintain the overall two-sided type I error of 0.05. If p-value from a 
test is < 0.05, the claim of superiority will be considered successful, and the test will progress to the next 
comparison in sequence as follows. 
Table 4: 
Sequential Gatekeeping Procedure 
Test 
Variable 
Comparison 
1 
Proportion of patients who achieved TI ≥56 
consecutive days (e.g., 8 weeks) since first dose in 
the first 28-weeks of treatment 
Superiority of roxadustat versus 
placebo 
2 
Proportion of patients who achieved TI ≥56 
consecutive days (e.g., 8 weeks) since first dose in 
the 52-weeks of treatment 
Superiority of roxadustat versus 
placebo 
3 
Proportion of patients who achieved TI ≥56 
consecutive days (e.g., 8 weeks) anytime during 
the study 
Superiority of roxadustat versus 
placebo 
4 
Proportion of patients who achieved ≥50% 
reduction in number of pRBC transfusions over 8 
weeks compared to their Baseline for any 8-week 
period during the study 
Superiority of roxadustat versus 
placebo 
5 
Cumulative number of patient-exposure-weeks 
(PEW) of TI over the first 28 weeks of the 
treatment period 
Superiority of roxadustat versus 
placebo 
6 
Number of pRBC transfused change from baseline 
over the first 28 weeks of the treatment period 
Superiority of roxadustat versus 
placebo 
7 
Proportion of patients who achieved TI for ≥20 
consecutive weeks (140 consecutive Days) 
Superiority of roxadustat versus 
placebo 


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8 
Mean change from baseline in the PROMIS-SF 
v2.0 Physical Function 10b score at week 9 
Superiority of roxadustat versus 
placebo 
9 
Mean change from baseline in the PROMIS-SF 
v1.0 Fatigue 13a score at week 9 
Superiority of roxadustat versus 
placebo 
10 
Mean change from baseline in EQ-5D-5L VAS 
score at week 9 
Superiority of roxadustat versus 
placebo 
12.3.3. 
Analysis of Secondary Efficacy Endpoints 
All secondary endpoints measured for treatment periods will be analyzed both for the first 28 weeks of 
treatment and for 52-week study treatment period. Others will be analyzed for the time during the study.  
The secondary efficacy endpoints will be analyzed based on the FAS population unless it is specified 
otherwise. Analyses using the PPS will be used as sensitivity analyses. 
12.3.3.1. Proportion of Patients who achieved TI ≥56 consecutive days anytime during the study 
The proportion of patients who achieved TI for ≥ 56 consecutive days will be summarized using the FAS 
and PPS and will be compared between the two treatment groups. TI is defined as the absence of any 
intravenous RBC transfusion (packed cell or whole blood) during any consecutive 56 days anytime 
during the study. TI will be estimated in the duration beginning with the first dose date (Day 1) and 
ending with the end of study or treatment discontinuation due to AE/SAE or death, whichever comes 
earlier. RBC transfusions after end of treatment will be recorded on CRF until the last visit at week 52 
from first dose and will be used to define TI. 
The p-value obtained will be reported for the test of the null hypothesis that there is no difference 
between the two treatment groups.  
Similar methods will be used as for the primary endpoint. 
This analysis will take into account the potential intercurrent events as follows:  
1. Treatment discontinuation due to any reasons: using Treatment-policy strategy: regardless of these 
intercurrent events occurred; the TI will be estimated using RBC transfusion records in the whole study 
duration. 
2. Death: using Treatment-policy strategy: regardless of these intercurrent events occurred; Patients who 
died prior to week 8 will be classified as non-responders. TI will be estimated using RBC transfusion 
records for the study duration up to death.  
12.3.3.2. 
Proportion of Patients Who Achieved ≥ 50% Reduction in Number of pRBC 
Transfusions over 8 Weeks Compared to Their Baseline for Any 8 Week Period during 
the Study (Factor of Erythroid Response) 
See Section 5.5 for the definition of number of pRBC (packs of red blood cells) transfusions at baseline. 
Percent change from baseline for any of the post-baseline 8-week period will be rounded to one decimal 
place (i.e., xx.x %) and then compared to 50% to determine whether the required percentage of reduction 
is achieved for that period. A frequency table of patients with at least a 50% reduction in the number of 
pRBC transfusions over any 8-week period in the duration beginning with the first dose date (Day 1) and 
ending with the end of study or treatment discontinuation due to AE/SAE or death, whichever comes earlier as 
compared with the baseline will be provided. The response rate and its two-sided 95% confidence 
intervals based on the exact method of Clopper-Pearson will be presented in the table by treatment group.  


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Treatment comparison will be based on the Cochran-Mantel-Haenszel (CMH) chi-square test, controlling 
for stratification factors (Serum EPO level, IPSS-R risk category and pRBC transfusion burden).  
Two-sided 95% confidence interval (CI) of the odds ratio will also be presented. 
The p value from the stratified CMH chi-square test will be provided for the test of the null hypothesis 
that the proportion of patients with at least a 50% reduction is equal between the two treatment groups. 
The number of periods of 8 weeks (e.g., consecutive 56 days) per responder will be summarized 
descriptively. 
This analysis will take into account the potential intercurrent events as follows:  
1. Treatment discontinuation due to reasons: using Treatment-policy strategy: regardless of these 
intercurrent events occurred; the RBC transfusion reduction will be estimated using RBC transfusion 
records in the whole study duration. 
2. Death: using Treatment-policy strategy: regardless of these intercurrent events occurred;. Patients 
who died prior to week 8 will be classified as non-responders. RBC transfusion will be estimated for any 
8-week period in the study duration up to death. 
PPS analysis will be used as sensitivity analysis. 
12.3.3.3. Cumulative Number of Patient-Exposure-Weeks (PEW) of TI over the first 28 Weeks of 
the Treatment Period  
The cumulative number of patient-exposure-weeks per patient of TI over the first 28-weeks of the 
treatment period will be summarized and analyzed using the FAS and PPS population.  
The exposure time will be measured using patient-exposure-week (PEW). PEW of TI periods over the 
first 28-weeks will be added up to a cumulative number of weeks. For a patient with at least one TI 
response period over the first 28-weeks, the last TI response period will end with the date of a subsequent 
RBC transfusion, visit date at week 28, date of the end of study or treatment discontinuation due to AE/SAE 
or death, whichever comes earlier. For a patient with no TI response period over the first 28 weeks, the 
cumulative number of PEW will be set to zero.  
The cumulative number of PEW over the first 28 weeks of treatment period will be summarized using 
descriptive statistics by treatment group. Treatment comparison will be based on a non-parametric 
ANCOVA (stratified rank ANCOVA) described in Stokes, Davis, and Koch 2000. The analysis will use 
baseline hemoglobin as covariate, treatment arm as fixed effects, controlling for stratification factors 
(baseline endogenous EPO level, IPSS-R risk category and RBC transfusion burden).  See Section 5.5 
for the definition of number of pRBC (packs of red blood cells) transfusions at baseline.  
Since it is expected that the sample sizes are not large for all strata, the following steps and SAS codes are 
to be used: 
Step 1: Compute the ranks of the response variable and covariate across the two treatment groups.  
    Sample SAS code:  
        PROC RANK TIES = mean OUT = ranks; 
              BY <strata_var>; 
              VAR <baseline_var> <response_var>; 
        RUN; 


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Step 2: With the ranks of response variable, an ANCOVA model will be fitted including the baseline 
ranks and stratification factor as covariates.  
    Sample SAS code: 
     PROC MIXED DATA = ranks;  
           CLASS <strata_var>; 
           MODEL <R_response_var> = <R_Baseline_var> <strata_var>/OUTP = res;  
        RUN; 
Step 3: CMH mean score statistics will be used to compare the two treatment groups using the values of 
the residuals obtained from step 2 as scores. The p-value obtained will be reported. 
Sample SAS code:  
    PROC FREQ DATA = res;  
          TABLES <strata_var>* <treatment_var>*resid/CMH2;  
    RUN; 
The p-value from the stratified CMH chi-square will be provided for the test of the null hypothesis that 
there is no difference in two treatment groups. 
Week 28 and week 52 are the analysis endpoint for 28-week and 52-week analysis respectively. 
This analysis will take into account the potential intercurrent events as follows:  
1. Treatment discontinuation (such as: due to Disease progression, Liver function, Patient decision, 
Investigator decision, AE/SAE, etc.): using While on treatment strategy: PEW of TI will be estimated in 
the duration beginning with the first dose date (Day 1) and ending with the date of end of treatment or last 
visit date at week 28/52, whichever comes earlier. 
2. Death: using While on treatment strategy: Treatment effect while on-treatments of interest. PEW of 
TI will be based on RBC transfusion records up to the date of end of treatment or last visit date at week 
28/52 or death, whichever comes earlier.  
In addition, the cumulative number of Patient-Exposure-Weeks of TI at week 28 and week 52 will be also 
summarized using the box-whisker plot by treatment groups. 
12.3.3.4. Number of pRBC Transfused compared to Baseline over the first 28 Weeks of the 
Treatment Period  
Descriptive statistics of the number (pRBC/8 weeks) of pRBC transfused and number (pRBC/8 weeks) of 
pRBC transfused change from baseline will be presented by treatment group using FAS and PPS. See 
Section 5.5 for the definition of number of pRBC transfusions at baseline. 
Treatment comparison will be performed for the number (pRBC/8 weeks) of pRBC transfused change 
from baseline based on a non-parametric ANCOVA (stratified rank ANCOVA) using baseline 
hemoglobin and baseline pRBC transfusions (pRBC/8 weeks) as covariate, treatment arm as fixed effects, 
controlling for stratification factors baseline endogenous EPO level and IPSS-R risk category. The p-
value obtained will be reported for the test of the null hypothesis that there is no difference in two 
treatment groups. 
Week 28 and week 52 are the analysis endpoint for 28-week and 52-week analysis respectively. 


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Similar methods will be used as in Section 12.3.3.3. Similar Strategies will be implemented for potential 
intercurrent events. 
12.3.3.5. Proportion of Patients Who Achieved TI for ≥20 consecutive Weeks (140 consecutive 
Days) anytime during the study 
The proportion of patients who achieved TI for ≥ 20 Weeks (140 Days) will be summarized using the 
FAS and PPS and will be compared between the two treatment groups. TI is defined as the absence of any 
intravenous RBC transfusion (packed cell or whole blood) during any consecutive 140 days anytime 
during the study. TI will be estimated in the duration beginning with the first dose date (Day 1) and ending 
with the end of study or treatment discontinuation due to AE/SAE or death, whichever comes earlier. RBC 
transfusions after end of treatment will be recorded on CRF until the last visit at week 52 from first dose 
and will be used to define TI. 
The p-value obtained will be reported for the test of the null hypothesis that there is no difference 
between the two treatment groups. 
Similar methods will be used as in Section 12.3.3.1. Similar strategies will be implemented for potential 
intercurrent events. 
12.3.3.6. Mean Change from Baseline in Physical Functioning Subscale of PROMIS 
The PROMIS PF item measures self-reported, current capability to carry out activities that require 
physical actions, ranging from self-care (activities of daily living) to more complex activities that require 
a combination of skills, often within a social context. The questionnaire will be administrated at the Week 
1 Day 1, Week 9, Week 17, Week 28 and Week 52 (or EOT). The PF 10-item short form which contains 
10 questions will be used in this study, and each item is scored on a 5-point rating scale, with higher 
scores indicating better functioning. To find the total raw score, sum the values of the response to each 
question, with the lowest possible raw score is 10; the highest possible raw score is 50.  
PROMIS items are not scored as sums, but rather on a standardized T-score metric (Appendix 19.5) using 
IRT. The standardized norm-based T-scores will be used in the summary. The mean change from 
Baseline in the PROMIS-SF v2.0 Physical Function 10b score will be summarized and analyzed. A 
mixed model for repeated measures (MMRM) with treatment, visit, treatment*visit, and stratification 
factors as fixed effects, the baseline score value and baseline*visit interaction as covariate will be used to 
assess treatment difference. The LSM and the corresponding 95% confidence intervals for the differences 
between roxadustat and the placebo group (roxadustat – placebo) will be presented along with the p-
values for the treatment differences resulting from the model. The LSM for the difference will be 
considered clinically meaningful if it exceeds the distribution-based minimal clinically important 
difference (MCID) and will be marked in the results, see Section 19.8.1 for details of MCID. An 
unstructured variance-covariance structure will be used to model the within-patient errors. This variance-
covariance matrix will be estimated across treatment groups. If the model fails to converge, then the 
covariance structure that converges and with the highest REML log likelihood will be used.  
Missing values will be handled by the MMRM model, utilizing data from all visits and all patients. 
A sensitivity analysis will be conducted using Analysis of Covariance (ANCOVA) model with Last 
Observation Carries Forward (LOCF) imputation, see Section 19.8.3 for details. 
Week 9 and week 52 are the analysis endpoint for 28-week and 52-week analysis respectively, the p-
value obtained will be reported. 
This analysis will take into account the potential intercurrent events as follows: 


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1.
Treatment discontinuation due to reasons other than AE/SAE: using Treatment-policy strategy:
regardless of these intercurrent events occurred; 
2.
Treatment discontinuation due to AE/SAE: using Hypothetical strategy: A scenario is envisaged in
which the patient suffers from the worst quality of life after discontinuation treatment due to AE/SAE. If 
a patient discontinued treatment due to AE/SAE, all the missing PROMIS-SF v2.0 Physical Function 10b 
score afterward will be substituted with the worst possible scores before being used in descriptive 
summary and statistical models. 
3.
Death: using Treatment-policy strategy: regardless of these intercurrent events occurred. If a patient
died, the PROMIS-SF v2.0 Physical Function 10b scores up to death will be used for analysis. 
Line plot of mean and mean change from baseline over time with the associated standard error will be 
provided. A cumulative distribute plot will be presented to show the difference of patients achieving 
meaningful change in PROMIS-SF v2.0 Physical Function 10b score between two treatment groups. 
A by-patient listing will also be provided. 
The analysis will be conducted for FAS and PPS. 
12.3.3.7. Mean Change from Baseline in Fatigue Subscale of PROMIS 
Fatigue will be measured in the study using the 13-item fatigue scale of the FACIT Measurement System, 
each item is scored on a 5-point rating scale ranging from 1 to 5 depicting “not at all” to “very much”, 
with higher scores indicating better functioning. The questionnaire is designed for self-completion by 
patients and will be administered at baseline, Week 9, Week 17, Week 28 and Week 52(or EOT).  
PROMIS items are not scored as sums, but rather on a standardized T-score metric (Appendix 19.6) using 
IRT. The standardized norm-based T-scores will be used in the summary. The mean change from 
Baseline in the PROMIS-SF v1.0 Fatigue 13a score over time will be summarized and analyzed using the 
FAS and PPS Population. The analysis window is defined in Appendix 19.3.1.  
A mixed model for repeated measures (MMRM) with treatment, visit, treatment*visit, and stratification 
factors as fixed effects, the baseline score value and baseline*visit interaction as covariate will be used to 
assess treatment difference. The LSM and the corresponding 95% confidence intervals for the differences 
between roxadustat and the placebo group (roxadustat – placebo) will be presented along with the p-
values for the treatment differences resulting from the model. The LSM for the difference will be 
considered clinically meaningful if it exceeds the distribution-based minimal clinically important 
difference (MCID) and will be marked in the results, see Section 19.8.1 for details of MCID. An 
unstructured variance-covariance structure will be used to model the within-patient errors. This variance-
covariance matrix will be estimated across treatment groups. If the model fails to converge, then the 
covariance structure that converges and with the highest REML log likelihood will be used.  
Missing value will be handled by the MMRM model, utilizing data from all visits and all patients. 
A sensitivity analysis will be conducted using Analysis of Covariance (ANCOVA) model with 
Last Observation Carries Forward (LOCF) imputation, see Section 19.8.2 for details. 
Week 9 and week 52 are the analysis endpoint for 28-week and 52-week analysis respectively, the p-
value obtained will be reported. 
This analysis will take into account the potential intercurrent events as follows: 
1.
Treatment discontinuation due to reasons other than AE/SAE: using Treatment-policy strategy:
regardless of these intercurrent events occurred; 


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2. Treatment discontinuation due to AE/SAE: using Hypothetical strategy: A scenario is envisaged in 
which the patient suffers from the worst quality of life after discontinuation treatment due to AE/SAE. If 
a patient discontinued treatment due to AE/SAE, all the missing PROMIS-SF v1.0 Fatigue 13a score 
afterward will be substituted with the worst possible scores before being used in descriptive summary and 
statistical models. 
3. Death: using Treatment-policy strategy: regardless of these intercurrent events occurred. If a patient 
died, the PROMIS-SF v1.0 Fatigue 13a scores up to death will be used for analysis. 
Line plot of mean and mean change from baseline over time with the associated standard error will be 
provided. A cumulative distribute plot will be presented to show the difference of patients achieving 
meaningful change in PROMIS-SF v1.0 Fatigue 13a score between two treatment groups. A by-patient 
listing will also be provided. 
The analysis will be conducted for FAS and PPS.  
12.3.3.8. Mean Change from Baseline in EQ-5D assessment  
The EQ-5D questionnaire is designed for self-completion by patients and will be administered at baseline, 
Week 9, Week 17, Week 28 and Week 52(or EOT). The EQ-5D-5L descriptive system, which will be 
applied in the study, comprises the following 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problem, 
moderate problems, severe problems, and unable to/extreme problems. The questionnaire also includes a 
visual analogue scale, where the patient will be asked to rate current health status on a scale of 0-100, 
with 0 being the worst imaginable health state and 100 being the best imaginable health. 
Descriptive statistics (frequency counts per answer) by treatment group will be presented for each of the 
EQ-5D dimension at each study visit.  
The mean change from Baseline in EQ-5D-5L VAS score will be also summarized and analyzed. Baseline 
is defined as the last assessment before first intake of dose of study treatment. The analysis windows are 
defined in Appendix 19.3.1. 
A mixed model for repeated measures (MMRM) with treatment, visit, treatment*visit, and stratification 
factors as fixed effects, the baseline score value and baseline*visit interaction as covariate will be used to 
assess treatment difference. The analysis will include the patients with both a baseline and post-baseline 
value at the specific visit. The least-squares mean (LSM) and the corresponding 95% confidence intervals 
for the differences between roxadustat and the placebo group (roxadustat – placebo) will be presented 
along with the p-values for the treatment differences resulting from the model. An unstructured variance-
covariance structure will be used for the within-patient variation. This variance-covariance matrix will be 
estimated across treatment groups. If the model fails to converge, then the covariance structure that 
converges and with the highest REML log likelihood will be used.  
Missing value of this endpoint will be handled by the MMRM model, utilizing data from all visits and all 
patients.  
Week 9 and week 52 are the analysis endpoint for 28-week and 52-week analysis, respectively. The p-
value obtained will be reported. 
This analysis will take into account the potential intercurrent events as follows:  
1. Treatment discontinuation due to reasons other than AE/SAE: using Treatment-policy strategy: 
regardless of these intercurrent events occurred; 
2. Treatment discontinuation due to AE/SAE: using Hypothetical strategy: A scenario is envisaged in 
which the patient suffers from the worst quality of life after discontinuation treatment due to AE/SAE. If 


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a patient discontinued treatment due to AE/SAE, all the missing EQ-5D-5L VAS scores afterward will be 
substituted with the worst possible scores before being used in descriptive summary and statistical 
models. 
3. Death: using Treatment-policy strategy: regardless of these intercurrent events occurred. If a patient 
died, the EQ-5D-5L VAS scores up to death will be used for analysis.  
Line plot of mean and mean change from baseline over time on EQ-5D assessment will be provided. A 
cumulative distribute plot will be presented to show the difference of patients achieving meaningful 
change in EQ-5D-5L VAS score between two treatment groups. A by-patient listing will also be provided. 
The analysis will be conducted for FAS and PPS. 
12.3.4. 
Analysis of Exploratory Efficacy Endpoints  
P values generated from treatment comparison for exploratory endpoints are exploratory, no multiplicity 
adjustment will be needed. Nominal p-values are used primarily as measures of strength of association 
rather than formal criteria to claim statistical significance. The nominal p-values will also be explained in 
table footnotes. All analysis will be performed using the FAS. 
12.3.4.1. Time to transfusion independence (TI)  
Time to transfusion independence (in weeks) is measured from the day of first study drug to the first day 
of TI response anytime during the study or a censor date. Section 12.3.3.1 for the detail of definition of TI 
response anytime during the study. If a patient has more than one at least 56-day period with transfusion 
free, that is, more than one TI response period, only the first will be used for analysis. 
• for those who have a TI response period, time to transfusion independence will be calculated as 
duration = first day of TI response - day of first study drug +1 where the first day of TI response is 
defined as the first day of at least 56-day transfusion-free period 
• for those who do not have a TI response period, time to transfusion independence will be 
calculated as duration = date of the end of study or treatment discontinuation due to AE/SAE or 
death, whichever comes earlier - day of first study drug + 1. 
Median time to transfusion independence will be estimated using Kaplan-Meier (K-M) method and its 
associated 2-sided 95% CIs for each treatment group will be calculated using the method of Brookmeyer 
and Crowley. The estimated survival probability and its associated 2-sided 95% CIs for each treatment 
group up to 52 weeks by every 4-weeks will be estimated by Kaplan-Meier product limit method. Kaplan-
Meier curves will also be presented by treatment group. 
Sample SAS codes are presented as below: 
PROC LIFETEST DATA=<input dataset> PLOTS=SURVIVAL; 
            TIME value*censor (1); 
STRATA treatment; 
SURVIVAL OUT=xx; 
RUN; 
Treatment comparison will be performed using the stratified log-rank test stratified by randomization 
factors. 
Sample SAS codes are presented as below: 


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PROC LIFETEST DATA=<input dataset>; 
      TIME value*censor (1); 
      STRATA <stratum_var>/GROUP=treatment; 
RUN; 
Time to transfusion independence will be compared between treatment groups using the Cox regression 
model, controlling for baseline hemoglobin and the stratification factors. Two-sided 95% CI of the hazard 
ratio will be presented for the treatment difference.  
 Sample SAS codes are presented as below: 
PROC PHREG DATA=<input dataset>; 
      MODEL value*censor (1)= treatment base_hb <stratum_var>; 
RUN; 
Model checking: The proportional hazards assumption will be checked graphically using a log-
cumulative hazard plot against log-survival time. This plot will give approximately parallel lines if the 
proportional hazards assumption between treatment arms subgroups holds. If the proportional hazard 
assumption is violated, then stratified Cox Model (with stratification-factors in STRATA statement) will 
be used instead. 
12.3.4.2. Time to 50% reduction in pRBC transfusion  
Time to 50% reduction in pRBC transfusion (in weeks) is measured from the day of first study drug to the 
first day of response of 50% reduction of pRBC transfusion or a censor date. See Section 12.3.3.1 for the 
detail of definition of the response.  
• for those who have a response, time to 50% reduction in pRBC transfusion will be calculated as 
duration = first day of response - day of first study drug +1 
• for those who do not have a response, time to 50% reduction in pRBC transfusion will be 
calculated as duration = date of the end of study or treatment discontinuation due to AE/SAE or 
death, whichever comes earlier - day of first study drug + 1. 
Median time to 50% reduction in pRBC transfusion will be estimated using Kaplan-Meier (K-M) method 
and its associated 2-sided 95% CIs for each treatment group will be calculated using the method of 
Brookmeyer and Crowley. The estimated survival probability and its associated 2-sided 95% CIs for each 
treatment group up to 52 weeks by every 4-weeks will be estimated by Kaplan-Meier product limit 
method. Kaplan-Meier curves will also be presented by treatment group. 
Sample SAS codes are presented as below: 
PROC LIFETEST DATA=<input dataset> PLOTS=SURVIVAL; 
      TIME value*censor (1); 
STRATA treatment; 
SURVIVAL OUT=xx; 
RUN; 
Treatment comparison will be performed using the stratified log-rank test stratified by randomization 
factors. 
Sample SAS codes are presented as below: 


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PROC LIFETEST DATA=<input dataset>; 
      TIME value*censor (1); 
      STRATA <stratum_var>/GROUP=treatment; 
RUN; 
Time to 50% reduction in pRBC transfusion will be compared between treatment groups using the Cox 
regression model, controlling for baseline hemoglobin and the stratification factors. Two-sided 95% CI of 
the hazard ratio will be presented for the treatment difference. Sample SAS codes are presented as below: 
PROC PHREG DATA=<input dataset>; 
      MODEL value*censor (1)= treatment base_hb <stratum_var>; 
RUN; 
Model checking: The proportional hazards assumption will be checked graphically using a log-
cumulative hazard plot against log-survival time. This plot will give approximately parallel lines if the 
proportional hazards assumption between treatment arms subgroups holds. If the proportional hazard 
assumption is violated, then stratified Cox Model (with stratification-factors in STRATA statement) will 
be used instead. 
12.3.4.3. Maximum Duration of transfusion independence (TI)  
Duration of TI (in weeks) is measured from the first day of the TI response anytime during the study to 
the date of the first RBC transfusion after this period or a censor date. See Section 12.3.3.1 for the detail 
of definition of TI response. If a patient has more than one at least 56-day period with transfusion free, 
i.e., more than one TI response period, then the one with the maximum duration will be used for analysis.  
• for those who receive a subsequent RBC transfusion, the duration of TI will not be censored and 
will be calculated as duration = last day of TI response - first day of TI response +1 where the last 
day of response is defined as 1 day before the first subsequent RBC transfusion which is given at 
56 days or more after the response starts. 
• for those who do not receive a subsequent RBC transfusion, the end day of the TI response will be 
censored as in Section 12.3.3.1 and duration of the TI response will be calculated as duration = 
date of the end of study or treatment discontinuation due to AE/SAE or death, whichever comes 
earlier - first day of TI response + 1.  
A Frequency summary with regard to patients who had a transfusion after the TI response with the 
maximum duration of the TI response, patients who maintained transfusion independence until the 
censored date will be provided by treatment group.  
Median maximum duration of TI will be estimated using Kaplan-Meier (K-M) method and its associated 
2-sided 95% CIs for each treatment group will be calculated using the method of Brookmeyer and 
Crowley. The estimated survival probability and its associated 2-sided 95% CIs for each treatment group 
up to 52 weeks by every 4-weeks will be estimated by Kaplan-Meier product limit method. Kaplan-Meier 
curves will also be presented by treatment group. 
Sample SAS codes are presented as below, the ‘input dataset’ will consist of TI responders only: 
PROC LIFETEST DATA=<input dataset> PLOTS=SURVIVAL; 
           TIME value*censor (1); 
STRATA treatment; 


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SURVIVAL OUT=xx; 
RUN; 
Treatment comparison will be performed using the stratified log-rank test stratified by randomization 
factors. 
Sample SAS codes are presented as below: 
PROC LIFETEST DATA=<input dataset>; 
      TIME value*censor (1); 
      STRATA <stratum_var>/GROUP=treatment; 
RUN; 
Maximum Duration of TI will be compared between treatment groups using the Cox regression model, 
controlling for baseline hemoglobin and the stratification factors. Two-sided 95% CI of the hazard ratio 
will be presented for the treatment difference. Sample SAS codes are presented as below: 
PROC PHREG DATA=<input dataset>; 
      MODEL value*censor (1)= treatment base_hb <stratum_var>; 
RUN; 
Model checking: The proportional hazards assumption will be checked graphically using a log-
cumulative hazard plot against log-survival time. This plot will give approximately parallel lines if the 
proportional hazards assumption between treatment arms subgroups holds. If the proportional hazard 
assumption is violated, then stratified Cox Model (with stratification-factors in STRATA statement) will 
be used instead. 
Summary statistics for duration of response (in weeks) as well as a frequency summary of duration of 
Response by different time points (e.g. ≥ 8 weeks, ≥ 16 weeks, etc.) will also be provided. 
12.3.4.4. Proportion of patients who achieve a mean Hb increase of ≥ 1.0 g/dL and ≥ 1.5 g/dL 
(averaged over 8 weeks in those that achieved TI) compared to pre-transfusion Hb at 
baseline)  
Moving average (MA) of change from baseline in Hb will be calculated for any 8-week window (e.g., 
Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.), starting at Week 1 day 1 post-dose. 
Baseline Hb value is defined as the mean of screening central laboratory Hb value and week 1 Day 1 Hb 
value prior to treatment. For each post-baseline 8-week window, a minimum of 3 evaluable Hb 
assessments is required for 28-week analysis (only one assessments every 4 weeks after Week 31.); 
otherwise, the mean is set to missing in the corresponding window. A patient is considered a responder of 
this endpoint during the treatment period if  
•
Transfusion independent for ≥ 56 days consecutively;
•
The moving averages of change from baseline in Hb is ≥ 1.0 g/dL (or ≥ 1.5 g/dL) during the
treatment period.
The following summaries will be provided based on FAS: 
•
Analysis of average change from baseline in Hb by every 8-week period (e.g., 56 consecutive
days)
•
Number and percentage of TI responder and non-responder


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Baseline Hb, absolute Hb value and change from baseline at each scheduled post-baseline visit 
The following summaries will be provided for TI responders in FAS: 
• The proportion of patients who achieve a mean Hb increase of ≥ 1.0 g/dL averaged over any 8
weeks
• The proportion of patients who achieve a mean Hb increase of ≥ 1.5 g/dL averaged over any 8
weeks
The denominator for the proportions is FAS population. 
Similar methods will be used as in Section 12.3.1.1. 
Mean (±SE) Hb (g/dL) from Baseline to Week 28 and to Week 52 will be plotted by treatment groups. 
12.3.4.5. Impact of baseline endogenous erythropoietin levels on roxadustat treatment response 
and dose requirement 
TI response rate (RBC TI at least ≥ 8 weeks) will be analyzed by baseline endogenous EPO level (< 200 
mIU/mL OR > 200 mIU/mL and ≤ 400 mIU/mL) using the methods described in Section 12.3.1. A 
summary table will be provided. See Section 12.3.3.1 for the detail of definition of TI response. 
Average weekly exposure data will be analyzed by baseline endogenous EPO level and treatment group. 
The average weekly dose will be analyzed by baseline endogenous EPO level (< 200 mIU/mL OR > 200 
mIU/mL and ≤ 400 mIU/mL) and treatment group. 
In order to compare patients with baseline endogenous EPO level < 200 mIU/mL to patients with baseline 
endogenous EPO level > 200 mIU/mL and ≤ 400 mIU/mL), the ANCOVA with baseline Hb value as 
covariate and baseline endogenous EPO level as class category. 
RBC TI response analysis as primary efficacy endpoint will be repeated for each level of baseline EPO：
≤ 100, ≤ 200, ≤ 300 and, ≤ 400 mIU/mL. 
Proportion of patients who achieve a mean Hb increase of ≥ 1.0 g/dL and ≥ 1.5 g/dL (averaged over 8 
weeks in those that achieved TI) compared to pre-transfusion Hb at baseline will be summarized for each 
level of baseline EPO：< 200 mIU/mL OR > 200 mIU/mL and ≤ 400 mIU/mL. 
12.3.4.6. Potential Effect on Hepcidin and Iron Metabolism 
The effect on Hepcidin and Iron Metabolism will be assessed using the mean change from baseline over 
time in Hepcidin and Iron parameters. 
Hepcidin Levels 
Hepcidin levels will be measured at screening, week 1 day 1, week 5, week 13, week 21, week 25, week 
28, week 39 and week 52 (or EOT). 
Absolute value and mean change from baseline in hepcidin at each time point will be summarized using 
descriptive statistics. The analysis windows are defined in Appendix 19.3.1. The summary will include: 
•
Change from baseline in hepcidin
•
Change from baseline in hepcidin stratified by TI vs. Non-TI (TI will be defined by week 28 as for
the primary endpoint)
•
Correlation between change from baseline in hepcidin and change from baseline in Hb. A scatter
plot will be provided with CFB in Hepcidin on x-axis and CFB in Hb on y-axis. Different colors


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will be used to indicate two treatment groups. A fitted linear regression line will be added to the 
scatter plot as well as the spearman correlation coefficient and p-value.   
Treatment comparison will be based on a MMRM model with treatment group, visit, treatment*visit as 
fixed effect, baseline hepcidin value as covariate, controlling for stratification factors. The LSM and the 
corresponding 95% confidence intervals for the differences between roxadustat and the placebo group 
(roxadustat – placebo) will be presented along with the p-values for the treatment differences resulting 
from the model. Missing data will be handled by the MMRM model. 
Week 28 and week 52 are the analysis endpoint for 28-week and 52-week analysis respectively; the p-
values will be reported. 
The analysis will be conducted for FAS population. 
Iron Parameters  
Iron biomarkers will be measured at screening, week 1 Day 1, week 3, week 5, week 9, week 13, week 
17, week 21, week 25, week 28, week 39 and week 52 (or EOT). 
Absolute value and mean change from baseline in iron parameters (Transferrin, TIBC, UIBC, TSAT and 
Ferritin, serum iron) at each time point will be summarized using descriptive statistics. The analysis 
windows are defined in Appendix 19.3.1. 
Treatment comparison will be based on a MMRM model with treatment, visit, treatment*visit, and 
stratification factors as fixed effects, the baseline value as covariate. The LSM and the corresponding 
95% confidence intervals for the differences between roxadustat and the placebo group (roxadustat – 
placebo) will be presented along with the p-values for the treatment differences resulting from the model. 
Week 28 and week 52 are the analysis endpoint for 28-week and 52-week analysis respectively; the p-
values will be reported. 
The analysis will be conducted for FAS population. 
12.3.4.7. Effect on Cholesterol and Lipid Parameters  
The effect on cholesterol and lipid parameters will be assessment by mean change from baseline over 
time in cholesterol and lipid parameters. 
Absolute value and mean change from baseline in total cholesterol at each time point will be summarized 
using descriptive statistics. The definitions of analysis widows are defined in Appendix 19.3.1. 
The total cholesterol will be analyzed similarly using the MMRM method. The LSM and the 
corresponding 95% confidence intervals for the differences between roxadustat and the placebo group 
(roxadustat – placebo) will be presented along with the p-values for the treatment differences resulting 
from the model.  
Other Serum Lipid Panel (non-fasting) parameters includes LDL, HDL, LDL/HDL ratio and triglycerides 
(TG), summary of mean change from baseline over time will use the same method as that for total 
cholesterol. 
Week 28 and week 52 are the analysis endpoint for 28-week and 52-week analysis respectively; the p-
values for other visits are for reference only. 
For the analysis of triglycerides data, due to the nature of the skewness for the triglycerides data, the 
stratified non-parametric ANCOVA as that described in Section 12.3.3.3 with baseline value as the 
covariate will be used for the analyses. 


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12.4. 
Examination of Subgroups 
Subgroup analyses (based on the FAS) will be performed based on the following criteria using the same 
approach as for the primary efficacy endpoint: 
• by gender: male, female 
• by age: < 65, >= 65 years 
• by race: white, non-white 
• by baseline endogenous EPO level: ≤ 200 mIU/mL, > 200 and ≤ 400 mIU/mL (defined as an 
exploratory endpoint in Section 12.3.4.5)  
• by IPSS-R risk category: low risk / very low risk, intermediate risk  
• by RBC transfusion burden: 1 pRBC/8-weeks over 16 consecutive weeks, 2- 4 pRBC/8-weeks 
• by baseline iron repletion status ([TSAT < 20% or ferritin < 100 ng/mL] vs. others),  
• by baseline CRP group (CRP ≤ ULN vs. CRP > ULN) 
• by Prior ESA use: (ESA Naïve vs. ESA Experienced) 
• by region (Section 12.5) 
Subgroup analysis will also be performed based on anticoagulant use at baseline if applicable. For the 
mentioned subgroup analyses, un-stratified tests/models can be used to evaluate the treatment differences 
if the sample size within a level of a subgroup does not allow for a comparison. If the subgroup variable is 
the same as the stratified variable, the corresponding stratified variable will be dropped from analysis. If 
the strata contain few or no patients, the stratification variable will not be included in the analysis. 
Patients with missing baseline values used to define the subgroups will be considered in a subgroup 
category missing, otherwise data will be excluded from the respective subgroup analyses. 
12.5. 
Subgroup Analyses by Region 
As it is expected to have approximately 100 global sites in this study, sensitivity analyses for the primary 
and secondary endpoints will be performed adding region and region by treatment interaction term in the 
model in order to examine whether the treatment effect varies by region and if results adjusted by region 
are consistent with those from the corresponding primary analysis and secondary analyses. Sites will be 
pooled by country into geographic region (defined as North America, Europe and Asia-pacific) to enable 
these analyses. 
In addition, the consistency of the treatment effect across region will also be assessed by performing a 
subgroup-type analysis with respect to the primary and secondary endpoint, with region treated as 
subgroups. A listing of TI response rates will be provided by individual study site. 
For NDA filing in China, the above analyses by additional region subgroup (defined as East Asia, non-
East Asia) will also be provided. 


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13. 
PHARMACOKINETICS / PHARMACODYNAMICS ANALYSES 
The methods described in Appendix 19.2 will be used. 


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14. 
SAFETY ANALYSES 
All safety analyses will be conducted using the safety population. Percentages will be calculated based on 
the number of patients in the safety population. 
For open-label component, the summaries will be presented by dose level cohort. For OL high-
erythropoietin component, the summaries will be presented along with the cohorts from open-label 
component. For double-blind component, the summarizes will be presented by treatment group. 
14.1. 
Adverse Events 
A treatment-emergent AE (TEAE) is defined as an AE that begins on or after the first dose of study 
treatment and within 28 days of the end date of the last dose of study treatment. An adverse event with 
unknown onset date will be counted as TEAE unless the event is resolved prior to the first dose of study 
medication.  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA, version 
19.1). CTCAE Version 4.03 will serve as guidance for specific severity assessment criteria for AEs. Any 
adverse event recorded prior to the start of study treatment will be listed together with all other adverse 
events. Only treatment-emergent adverse events will be summarized. 
If a patient has more than one TEAE coded to the same preferred term, the patient will be counted only 
once for that preferred term. Similarly, if a patient has more than one TEAE within a system organ 
category, the patient will be counted only once in that system organ category.  
In this analysis, if a patient reports multiple occurrences of TEAEs within one system organ class or 
preferred term, the most closely related occurrence will be presented. TEAEs with unknown relationship 
to study treatment will be counted as “possibly related” in the summary table but will be listed with a 
missing relationship in data listing.  
In this analysis, if a patient reports multiple occurrences of TEAEs within one system organ class or 
preferred term, the most severe occurrence will be presented in the table summarized by maximum 
severity. TEAEs with unknown severity will be counted as “Severe” in the summary table but will be 
listed with a missing severity in data listing. 
The overview table by treatment and overall will be summarized showing the number and percentage of 
patients with at least one AE in any of the following categories:   
• TEAEs  
• drug related (Possibly Related and Related) TEAEs 
• all grade 3 or greater TEAEs 
• Serious TEAEs   
• TEAEs leading to discontinuation of study treatment 
• TEAEs leading to death 
• TEAE of special interest 
In summary, the following sets of adverse events will be summarized separately in separate tables by 
SOC (sorted alphabetically) and PT (sorted by descending) that present the number and percentage of 
patients with: 
• any TEAE (number of patients who have at least one adverse event) 


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• TEAE by maximum severity 
• TEAE with relationship to study medication suspected to be related to study drug 
• all grade 3 or greater TEAE 
• treatment-emergent serious AEs (TESAE) 
• TEAEs leading to discontinuation of study treatment, 
• TEAEs leading to death  
• TEAE of special interest 
• TESAE leading to discontinuation of study treatment 
AE of special interest consists of the following categories: Secondary hypothyroidism, Thyroid disorders 
(Hypothyroidism and Hyperthyroidism), Dermatitis Exfoliative Generalised, Deep vein thrombosis, 
Pulmonary embolism, Cardiovascular events (cardiac failure, arrythmia, myocardial infarction), Seizures, 
Serious infections.Number and percentage of patients with any TEAE of special interest will summarized 
up to 28 weeks, 52 weeks and 52 weeks and beyond. Exposure adjusted incidence rate (EAIR) of TEAE 
of special interest per 100 patient exposure years will also be presented. See Section 14.1.2 for EAIR 
calculation.  
In addition, most frequently occurring adverse events (PT ≥ 5% of patients in any dose 
cohort/treatment group) and most frequently occurring non-serious adverse events (PT ≥ 5% of patients 
in any dose cohort/treatment group) for each PT will be summarized in descending frequency according 
to its incidence in either dose cohort/treatment group. 
In addition, the incidence rate * 100 / PEY will be presented along with the number and percentage of 
patients in double-blind tables, where Patient-Exposure-Year (PEY) = (Last Dose Date - First Dose Date 
+ 1)/365.25. 
All AEs will be presented in a listing, including patient identifier, treatment group, system organ class, 
preferred term, start and stop dates, seriousness, severity, relationship to study treatment, Action taken 
with regard to study drug and outcome. Additionally, listings of SAEs, Death and AEs leading to 
permanent discontinuation of study drug and AEs of special interest will be presented. The listing of AEs 
prior to start of treatment will be provided for all patients enrolled. 
Listings of death report will be provided in the SAF with death date, primary cause of death and verbatim, 
system organ class and preferred term of AE leading to death. 
14.1.1. 
AE Subgroup Analysis 
The overview table of TEAE by the following subgroups will be provided:  
• by gender: male, female 
• by age: < 65, >= 65 years 
• by race: white, non-white 
• by baseline endogenous EPO level: ≤ 200 mIU/mL, > 200 and ≤ 400 mIU/mL (defined as an 
exploratory endpoint in Section 12.3.4.3)  
• by IPSS-R risk category: low risk / very low risk, intermediate risk  
• by RBC transfusion burden: 1 pRBC/8-weeks over 16 consecutive weeks, 2- 4 pRBC/8-weeks 


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• by region: North America, Europe and Asia-pacific 
In addition, for NDA filing in China, the overview table of TEAE, TEAE table and TESAE table by the 
following subgroups will be provided: 
• by additional race subgroup: Asian, non-Asian 
• by additional region subgroup: East Asia, non-East Asia 
14.1.2. 
Exposure Adjusted Incidence Rate 
Exposure adjusted incidence rate EAIR (per 100 patient years at risk) will be calculated regarding 
selected TEAEs of interest. 
The exposure adjusted incidence rate (per 100 patient years at risk) will be calculated as follows: 
100
 
 
risk
at 
 
years
-
Person
event
 with 
subjects
 
of
Number 
×
 
Where total cumulative time at risk is the sum of individual time at risk. 
1. The Time at Risk for a subject with the event of interest will be calculated (in years) as: 
(First event date – analysis Date of first dose + 1) / 365.25 
      Where ‘Analysis Date of first dose’ is defined as the date of initial dose of the study drug. 
2. The Time at Risk for a subject without the event of interest is calculated as  
(Censoring date – Date of first dose + 1) / 365.25      
Censoring date will be calculated as: 
Min (death date, last contact date if the subject is lost to FU, visit date of week 52 + 28, last dose 
date + 28)   
14.2. 
Disease Progression of AML 
The number and percentage of patients in double-blind component who progressed to AML will be 
presented in a frequency table using safety population. 
Listings by patient with progressive disease for OL high-erythropoietin component and double-blind 
component will also be provided. 
14.3. 
Clinical Laboratory Data 
Summary tables for clinical laboratory data will be performed for double-blind component only.  
The results of laboratory assessments, which include CBC, Serum chemistries (sodium, potassium, 
chloride, bicarbonate, BUN, creatinine, glucose, calcium, magnesium, phosphorus, lactate dehydrogenase 
(LDH), albumin) will be provided by a central laboratory. All summaries will be based on the standard 
units provided by the central laboratory.  
Descriptive statistics for laboratory values (in SI units) and changes from baseline at each assessment 
time point will be presented by treatment group for laboratory parameters collected in the study.  
To assess potentially clinically significant (PCS) laboratory abnormalities (Table 5), the number and 
percentage of patients with post-baseline lab values outside a pre-defined range (low or high) or limit of 
change will be tabulated. Laboratory test values will be considered PCS if they meet the criteria listed in 
the table. The number and percentage of patients with post-baseline PCS values will be tabulated. The 


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percentages are to be calculated relative to the number of patients with available non-PCS baseline values 
and at least one post-baseline assessment. The numerator is the total number of patients with at least one 
post-baseline PCS value. Shift tables may be presented.  
Patient incidence for each abnormality will be calculated based on patients with a baseline value and at 
least one post-baseline value for criteria requiring baseline or patients with at least one post-baseline 
value for criteria not requiring baseline. If differential dropout is observed between the two treatment 
arms, then the exposure adjusted incidence rate EAIR (per 100 patient years at risk) will be calculated 
regarding each abnormality. 
A supportive listing of patients with post-baseline PCS values will be provided including the patient ID, 
study center, baseline, and post-baseline values. Values from unscheduled time points will not be used in 
post-baseline analysis but will be listed. 
In addition, for serology testing and other lab test (e.g. PT, PTT, Vitamin B12 and folate) will be provided 
in data listings by patient. Local hemoglobin data will be listed along with prescribed dose adjustment for 
reference. 
Table 5: 
Range of Potentially Clinically Significant Lab Values 
Parameter 
SI Unit 
Lower Limit 
Higher Limit 
CHEMISTRY 
Alanine Aminotransferase 
(ALT) 
U/L 
  
≥3 * ULN 
Alkaline Phosphatase (ALP) 
U/L 
  
≥3 * ULN 
Aspartate Aminotransferase 
(AST) 
U/L 
  
≥3 * ULN 
Calcium 
mmol/L 
<0.8*LLN 
>1.2 * ULN 
Creatinine 
µmol/L 
  
> 1.5x Baseline Value 
Potassium 
mmol/L 
<0.75*LLN 
>1.2 * ULN 
Sodium 
mmol/L 
<0.9*LLN 
>1.1 * ULN 
Total Bilirubin 
µmol/L 
  
>1.5 * ULN 
Urea (BUN) 
mmol/L 
  
>1.5x Baseline Value 
CBC 
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 
14.3.1. 
Liver Function Tests 
The frequency of the following categories will be summarized and compared across dose level cohorts 
(for open-label component and OL high-erythropoietin component) or treatment groups (for double-blind 
component).  
• Aminotransferase (i.e. AST ≥ 3x ULN or ALT ≥ 3x ULN) or/and Total bilirubin (TBL) ≥ 2x ULN 
• ALT or AST > 8 x ULN 


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• ALT or AST > 5 x ULN for more than 2 weeks 
• ALT or AST > 3 x 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%).  
A scatter plot of the maximum aminotransferase (i.e., ALT or AST) level against maximum TBL at post-
baseline will also be presently with dotted reference lines at 3 x ULN for ALT or AST, and 2 x ULN for 
total bilirubin. In each plot, TBL will be in the vertical axis. Different dots will be used for roxadustat and 
placebo. 
Individual displays of abnormal Liver Enzymes (ALT or AST >= 3 x ULN) and Bilirubin parameters (>= 
2 x ULN) with corresponding other liver enzymes and bilirubin values during the treatment periods will 
be listed. The timepoints for subjects falling into Hy's Law Range (ALT or AST > 3 x ULN, and total 
bilirubin > 2 x ULN), Cholestasis Range (total bilirubin > 2 x ULN), and Temple's Corollary Range (ALT 
or AST > 3 x ULN) will be marked. 
14.4. 
Excessive Hematopoiesis 
The presence of potential EH will be defined if Hb increases by >2.0 g/dL within 4 weeks of treatment 
during the treatment period. A listing of the patients with potential EH will be provided. 
The following summaries will be presented for double-blind component: 
• Proportion of patients with potential excessive erythropoiesis. 
• Proportion of patients with Hb exceeds 12 g/dl. 
14.5. 
Vital Signs 
Blood Pressures and Heart Rate baselines are defined as the mean of values obtained from the last 2 
weeks of screening including Day 1 prior to the first dose. 
Descriptive statistics for vital signs and their changes from baseline at each visit and at the end of study 
will be presented. 
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 6 below. The number and percentage of patients with 
post-baseline PCS values will be tabulated by dose level cohort (for open-label component) /treatment 
group (for double-blind component). The percentages are to be calculated relative to the number of 
patients with baseline and at least one post-baseline assessment. The numerator is the total number of 
patients with at least one post-baseline PCS vital sign value. Shift tables may be presented.   
Patient incidence for each abnormality will be calculated based on patients with a baseline value and at 
least one post-baseline value for criteria requiring baseline or patients with at least one post-baseline 
value for criteria not requiring baseline. If differential dropout is observed between the two treatment 
arms, then the exposure adjusted incidence rate EAIR (per 100 patient years at risk) will be calculated 
regarding each abnormality. 
Line plots of mean and mean change from baseline of vital sign parameters over time with the associated 
standard error will be provided. 


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A supportive listing of patients with post-baseline PCS values will be provided including the patient ID, 
study center, baseline, and post-baseline values. Values from unscheduled time points will not be used in 
post-baseline analysis, but will be listed. 
Table 6: 
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 
Diastolic Blood 
Pressure (mmHg) 
High 
≥ 110 
Increase of ≥ 15 
Low 
≤ 45 
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% 
*Except for body weight, a post-baseline value is considered as a PCS value if it meets both criteria for 
observed value and change from baseline. 
14.6. 
Electrocardiogram (ECG) 
ECG findings are summarized in shift tables that include cross-tabulation of ‘Normal’, ‘Abnormal NCS’, 
and ‘Abnormal CS’. Baseline value is the last non-missing measurement on or prior to the first dose. 
Patients with a baseline value and at least one post-baseline value will be included in the summary. 
ECG data are presented in the data listing. 
14.7. 
ECOG Performance Status 
For ECOG performance status, the shift from baseline to the worst and best during the treatment will be 
displayed in cross tabulations. Baseline value is the last non-missing measurement on or prior to the first 
dose. Patients with a baseline value and at least one post-baseline value will be included in the summary. 
14.8. 
Pregnancy Test 
Findings from the pregnancy test will only be listed if applicable. 


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15. 
DATA SAFETY MONITORING BOARD  
Safety data and dosing decisions will be monitored on an ongoing basis. In addition, ongoing review of 
safety data will be completed by an independent Data Safety Monitoring Board (DSMB) on a pre-defined 
periodic basis. The role and function of the DSMB will be defined in a DSMB charter.  


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16. 
INTERIM ANALYSIS 
A preliminary analysis of the open-label component was conducted at the end of the open-label 
component of the study In the double-blind component, the primary efficacy analysis will be conducted 
when all randomized patients have completed 28 weeks of treatment or early discontinued. A table of 
content (ToC) lists a subset of tables, figures, and listings for the Week 28 primary analysis in Appendix 
19.9. All other planned analyses outlined in this SAP will not be conducted until the end of study. The 
Week 28 analysis will be conducted by a small unblinded group not directly involved in the day-to-day 
study conduct. The study team will remain blinded until the final database lock and study unblinding. A 
detailed Data Access Plan summarizes the maintenance of blinding for the rest of the study. 
No other formal interim analysis is planned.   


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17. 
CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES 
3. Exploratory analyses on time to transfusion independence and time to 50% reduction in pRBC 
transfusion are added in this SAP due to clinical interest, although they are not in the protocol. 
4. The 52 weeks analysis on the primary endpoint is regarded as a secondary endpoint and been 
included in the sequential gatekeeping procedure.  
5. Based on results from prior roxadustat studies, measuring HRQoL 2-4 weeks after Hb “peaks” or 
stabilizes is shown to be most informative. In order to capture the treatment effect on Physical 
Function/fatigue before it wears off, Week 9 will be used as the primary time-point for HRQoL 
hypothesis testing in the sequential gatekeeping procedure. 
6. Based on the re-estimated sample size of 120, 140 patients were enrolled in the double-blind 
component of the study. 


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18. 
REFERENCE 
Stokes, Davis, Koch (2000) Categorical Data Analysis Using the SAS System, Page 174-179. 
Rombach, I., Rivero-Arias, O., Gray, A. M., Jenkinson, C., & Burke, Ó. (2016). The current practice of 
handling and reporting missing outcome data in eight widely used PROMs in RCT publications: a review 
of the current literature. Quality of life research: an international journal of quality of life aspects of 
treatment, care and rehabilitation, 25(7), 1613–1623. https://doi.org/10.1007/s11136-015-1206-1 
ICH (International Conference on Harmonization) Harmonized Tripartite Guideline E9 (R1). Statistical 
Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials, Final 
Version adopted on 20 November 2019  
Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in Patients with Lower-Risk Myelodysplastic 
Syndromes. N Engl J Med. 2020;382(2):140-151. doi:10.1056/NEJMoa1908892 
Ge, M., Durham, L. K., Meyer, R. D., Xie, W., & Thomas, N. (2011). Covariate-Adjusted Difference in 
Proportions from Clinical Trials Using Logistic Regression and Weighted Risk Differences. Drug 
Information Journal, 45(4), 481–493. 


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19. 
APPENDIX 
19.1. 
Dose Adjustment Rules for Patients who have TI for ≥ 56 Days  
A modified dose adjustment algorithm will apply to patients who have attained TI ≥ 56 days 
(Maintenance Phase). The down titration of the dose is allowed at any time. 
 
Dose Adjustment for Excessive Hematopoiesis:  
At any time during the Treatment Period if Hb increases by > 2.0 g/dL within 4 weeks, 
the dose should be reduced by one dose step.  
 
19.2. 
Pharmacokinetics / Pharmacodynamics Analyses 
Blood samples will be collected at the study site for determination of roxadustat plasma 
concentrations and erythropoietin levels at 1-3 and 3-5 hours after dosing at clinic on 
Day 1 (Week 1) as well as 4-6 hours at Week 5 and 8-10 hours at Week 21 after self-
administration at home or at the clinic.  
Population PK/PD Analysis will be done outside of the SAP, which will focus on 
safety and efficacy. 
 
 
Change in Hb 
over past 4 weeks (g/dL) 
Hemoglobin Values  
(g/dL) 
<10.5 
10.5 to 12.9 
 >13.0   
≥13.5  
< -1.0 (or had RBC
transfusion 
within 
4 
weeks)  
 
↑ 
↑ 
No change 
Hold, 
then 
resume 
dosing when:  
Hb <12 g/dL, at a dose 
that is reduced by one 
dose steps  
Patients are to return 
weekly to monitor Hb 
until dosing can be 
resumed  
-1.0 to 1.0 
↑ 
No change 
↓ 
 >1.0 
No change 
↓ 
↓ 


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19.3. 
Data Handling Conventions  
19.3.1. 
Analysis Windows 
Tables below present the visits assigned for efficacy and safety analyses corresponding to the range of 
treatment days (window) during which an actual visit may have occurred.  
The analysis windows will be only applied to those assessments up to the day before the first week of 
follow-up visit. Assessments obtained afterwards are considered follow-up assessments. For follow-up 
assessments, only follow-up assessments on scheduled follow-up visits (i.e. nominal follow-up visits) will 
be summarized unless otherwise specified.  
If more than one assessment is available in the same window, the last assessment is used for analysis. 
Assessments that do not fall in any windows will not be included in analyses unless otherwise specified. 
However, all post-baseline assessments will be used for PCS value determination and all assessments will 
be presented in the data listings. 
Table 7.1 Analysis Visit Windows (General) 
Analysis Visit 
Visit Scheduled  
Daya 
Window 
Baseline 
Day 1 
Up to Day 1 Pre-Dose 
Week 3 
Day 7*(Week # -1)+1 
[Day 1 Post-Dose, Scheduled Day +7) 
Weeks 5, 7, 9, 11…27 
Day 7*(Week # -1)+1 
[Scheduled Day -7, Scheduled Day +7) 
Week 28b 
Day 7*(Week # )+1 
[Scheduled Day -7, Scheduled Day +7) 
Weeks 31 
Day 7*(Week # -1)+1 
[Scheduled Day -7, Scheduled Day +14) 
Week 35, 39, 43 
Day 7*(Week # -1)+1 
[Scheduled Day -14, Scheduled Day +14) 
Week 47 
Day 7*(Week # -1)+1 
[Scheduled Day -14, Scheduled Day +21) 
Week 52c 
Day 7*(Week # )+1 
[Scheduled Day -21, Up to Week 4 Follow up) 
a: Relative to the first study medication date.  For example, Day 1 = the first dose date of study 
medication. 
b: Week 28 visit should be conducted at the end of 28 weeks of treatment (2 weeks after Week 27 Visit). 
c: Week 52 Visit should be scheduled at the end of 52 weeks treatment (6 weeks after Week 47 visit). 
Table 7.2 Analysis Visit Windows for Lipid Parameters  
Derived 
Visit 
Visit Scheduled  
Daya 
Window 
Baseline 
Day 1(first dose day) 
Up to Day 1 Pre-Dose 
Week 5 
Day 7 * (Week # -1) +1 
[Day 1 Post-dose, Scheduled Day + 56) 
Week 21 
Day 7 * (Week # -1) +1 
[Scheduled Day - 56, Scheduled Day + 28) 
Week 28b 
Day 7 * (Week # ) +1 
[Scheduled Day - 28, Scheduled Day + 35) 
Week 39 
Day 7 * (Week # -1) +1 
[Scheduled Day - 35, Scheduled Day + 49) 
Week 52c 
Day 7 * (Week # ) +1 
[Scheduled Day -49, Up to Week 4 follow-up) 
a: Relative to the first study medication date.  For example, Day 1 = the first dose date of study 
medication. 
b: Week 28 visit should be conducted at the end of 28 weeks of treatment (2 weeks after Week 27 Visit). 
c: Week 52 Visit should be scheduled at the end of 52 weeks treatment (6 weeks after Week 47 visit). 


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Table 7.3 Analysis Visit Windows for Serum Iron, Ferritin, TIBC, UIBC, TSAT, Transferrin, Vital 
Sign, Serum Chemistry  
Derived Visit 
Visit Scheduled  
Daya 
Window 
Baseline 
Day 1(first dose day) 
Up to Day 1 Pre-Dose 
Week 5 
Day 7 * (Week # -1) +1 
[Day 1 post-dose, Scheduled Day + 14) 
Weeks 9, 13, 17, 21 
Day 7 * (Week # -1) +1 
[Scheduled Day - 14, Scheduled Day + 14) 
Week 25 
Day 7 * (Week # -1) +1 
[Scheduled Day - 14, Scheduled Day + 14) 
Week 28b 
Day 7 * (Week # ) +1 
[Scheduled Day - 14, Scheduled Day + 35) 
 
Week 39 
Day 7 * (Week # -1) +1 
[Scheduled Day - 35, Scheduled Day + 49) 
Week 52c 
Day 7 * (Week # ) +1 
[Scheduled Day - 49, Up to Week 4 follow-up) 
a: Relative to the first study medication date.  For example, Day 1 = the first dose date of study 
medication. 
b: Week 28 visit should be conducted at the end of 28 weeks of treatment (2 weeks after Week 27 Visit). 
c: Week 52 Visit should be scheduled at the end of 52 weeks treatment (6 weeks after Week 47 visit). 
Table 7.4 Analysis Visit Windows for Hepcidin  
Derived Visit 
Visit Scheduled  
Daya 
Window 
Baseline 
Day 1(first dose day) 
Up to Day 1 Pre-Dose 
Week 5 
Day 7 * (Week # -1) +1 
[Day 1 post-dose, Scheduled Day + 28) 
Week 13 
Day 7 * (Week # -1) +1 
[Scheduled Day - 28, Scheduled Day + 28) 
Week 21 
Day 7 * (Week # -1) +1 
[Scheduled Day - 28, Scheduled Day + 14) 
Week 25 
Day 7 * (Week # -1) +1 
[Scheduled Day - 14, Scheduled Day + 14) 
Week 28b 
Day 7 * (Week # ) +1 
[Scheduled Day - 14, Scheduled Day + 35) 
 
Week 39 
Day 7 * (Week # -1) +1 
[Scheduled Day - 35, Scheduled Day + 49) 
Week 52c 
Day 7 * (Week # ) +1 
[Scheduled Day - 49, Up to Week 4 follow-up) 
a: Relative to the first study medication date.  For example, Day 1 = the first dose date of study 
medication. 
b: Week 28 visit should be conducted at the end of 28 weeks of treatment (2 weeks after Week 27 Visit). 
c: Week 52 Visit should be scheduled at the end of 52 weeks treatment (6 weeks after Week 47 visit). 
Table 7.5 Analysis Visit Windows for ECG  
Derived Visit 
Visit Scheduled  
Daya 
Window 
Baseline 
Day 1(first dose day) 
Up to Day 1 Pre-Dose 
Week 28b 
Day 7 * (Week # ) +1 
[Day 1 post-dose, Scheduled Day + 84) 
 
Week 52c 
Day 7 * (Week # ) +1 
[Scheduled Day - 84, Up to Week 4 follow-up) 
a: Relative to the first study medication date.  For example, Day 1 = the first dose date of study 
medication. 
b: Week 28 visit should be conducted at the end of 28 weeks of treatment (2 weeks after Week 27 Visit). 
c: Week 52 Visit should be scheduled at the end of 52 weeks treatment (6 weeks after Week 47 visit). 


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Table 7.6 Analysis Visit Windows for CBC  
(Only in Subjects Enrolled before Effective Day of Protocol Amendment 3) 
Analysis Visit 
Visit Scheduled  
Daya 
Window 
Baseline 
Day 1 
Up to Day 1 Pre-Dose 
Week 2 
Day 7*(Week # -1)+1 
[Day 1 Post-Dose, Scheduled Day +3] 
Week 3,4 
Day 7*(Week # -1)+1 
[Scheduled Day -3, Scheduled Day +3] 
Week 5 
Day 7*(Week # -1)+1 
[Scheduled Day -3, Scheduled Day +7) 
Weeks 7, 9, 11…27 
Day 7*(Week # -1)+1 
[Scheduled Day -7, Scheduled Day +7) 
Week 28b 
Day 7*(Week # )+1 
[Scheduled Day -7, Scheduled Day +7) 
Weeks 31 
Day 7*(Week # -1)+1 
[Scheduled Day -7, Scheduled Day +14) 
Week 35, 39, 43 
Day 7*(Week # -1)+1 
[Scheduled Day -14, Scheduled Day +14) 
Week 47 
Day 7*(Week # -1)+1 
[Scheduled Day -14, Scheduled Day +21) 
Week 52c 
Day 7*(Week # )+1 
[Scheduled Day -21, Up to Week 4 Follow up) 
a: Relative to the first study medication date.  For example, Day 1 = the first dose date of study 
medication. 
b: Week 28 visit should be conducted at the end of 28 weeks of treatment (2 weeks after Week 27 Visit). 
c: Week 52 Visit should be scheduled at the end of 52 weeks treatment (6 weeks after Week 47 visit). 
Table 7.7 Analysis Visit Windows for EQ-5D-5L, PROMIS Physical Function and PROMIS Fatigue 
Function 
Derived Visit 
Visit Scheduled  
Daya 
Window 
Baseline 
Day 1(first dose day) 
Up to Day 1 Pre-Dose 
Week 9 
Day 7 * (Week # -1) +1 
[Day 1 post-dose, Scheduled Day + 28) 
Weeks 17 
Day 7 * (Week # -1) +1 
[Scheduled Day - 28, Scheduled Day + 42) 
Week 28b 
Day 7 * (Week # ) +1 
[Scheduled Day - 42, Scheduled Day + 84) 
 
Week 52c 
Day 7 * (Week # ) +1 
[Scheduled Day - 84, Up to Week 4 follow-up) 
a: Relative to the first study medication date.  For example, Day 1 = the first dose date of study 
medication. 
b: Week 28 visit should be conducted at the end of 28 weeks of treatment (2 weeks after Week 27 Visit). 
c: Week 52 Visit should be scheduled at the end of 52 weeks treatment (6 weeks after Week 47 visit). 
Table 7.8 Analysis Visit Windows for ECOG 
Derived Visit 
Visit Scheduled  
Daya 
Window 
Baseline 
Day 1(first dose day) 
Up to Day 1 Pre-Dose 
Week 5 
Day 7 * (Week # -1) +1 
[Day 1 post-dose, Scheduled Day + 28) 
Week 13 
Day 7 * (Week # -1) +1 
[Scheduled Day - 28, Scheduled Day + 14) 
Weeks 17 
Day 7 * (Week # -1) +1 
[Scheduled Day - 14, Scheduled Day + 28) 
Weeks 25 
Day 7 * (Week # -1) +1 
[Scheduled Day - 28, Scheduled Day + 14) 
Week 28b 
Day 7 * (Week # ) +1 
[Scheduled Day - 14, Scheduled Day + 84) 
 
Week 52c 
Day 7 * (Week # ) +1 
[Scheduled Day - 84, Up to Week 4 follow-up) 
a: Relative to the first study medication date.  For example, Day 1 = the first dose date of study 
medication. 


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b: Week 28 visit should be conducted at the end of 28 weeks of treatment (2 weeks after Week 27 Visit). 
c: Week 52 Visit should be scheduled at the end of 52 weeks treatment (6 weeks after Week 47 visit). 
19.3.2. 
Missing Date of Study Medication 
When the last date of study medication during the study treatment period 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. 
19.3.3. 
Missing Severity Assessment for Adverse Events 
If severity is missing for an AE started prior to the first study medication, then a severity of “Mild” will 
be assigned. If the severity is missing for an AE started on or after the first study medication dosing, then 
a severity of “Severe” will be assigned. The imputed values for severity assessment will be used for 
incidence summary, while the actual missing values will be presented in data listings.  
19.3.4. 
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 
“possibly 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.  
19.3.5. 
Missing Date Information for Adverse Events 
The following imputation rules only apply to the case where the start date is incomplete (i.e., partial 
missing) for adverse events. 
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 prior to the year of first day on study medication, then December 31 will be assigned to the 
missing fields. 
If the year is after 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 before the year and month of first day on study medication, then the last day of 
the month will be assigned to the missing day. 
If the month and year are after 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.  
 


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19.3.6. 
Missing Date Information for Prior or Concomitant Medications 
For prior or concomitant medications, including rescue medications, incomplete (i.e., partial missing) 
start date and/or stop date will be imputed. When the start date and the stop date are both incomplete for a 
patient, impute the start date first. 
Incomplete Start Date 
The following rules will be applied to impute the missing numerical fields.  If the stop date is complete 
and the imputed start date is after the stop date, then the start date will be imputed using the stop date. 
Missing day and month 
If the year of the incomplete start date is the same as the year of the first dose date of study medication, 
then the day and month of the first dose date will be assigned to the missing fields.  
If the year of the incomplete start date is 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. 
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. 


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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. 
19.3.7. 
Missing Start Date for Study Disease (Myelodysplastic Syndrome) 
When start date of study disease (Myelodysplastic syndrome) is incomplete, the following imputation 
rules will be adopted:  
Missing day and month 
January 1 will be assigned to the missing fields. 
Missing month only 
January will be assigned to the missing month. 
Missing day only  
The first day of the month will be assigned to the missing day. 
 
 


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19.4. 
EQ-5D 5L v2 
 


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EQ-5D 5L v2 
 
 


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19.5. 
PROMIS Physical Function 10b Short Form   
 
 
Instructions: You can use the following conversion table to translate the total raw score into a T-score 
for each participant. These conversions are accurate ONLY when all questions on the short form have 
been answered. 


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PROMIS-SF v2.0 Physical Function 10b Scoring Table 
 


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19.6. 
Fatigue – Short Form 13a  
 
 
 
Instructions: You can use the following conversion table to translate the total raw score into a T-score 
for each participant. These conversions are accurate ONLY when all questions on the short form have 
been answered. 


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PROMIS-SF v1.0 Fatigue 13a Scoring Table 
 
19.7. 
An Adjusted Difference in Proportions using Logistic Regression 
The method was proposed by Ge et al. (2011). Please ensure the model built in this macro is the same 
with logistic regression model which is used for odds ratio calculation. 
%macro LR ( 
data=, /* input data set */ 
var1=, /* continuous covariates in the logistic regression */ 
var2=, /* categorical covariates in the logistic regression */ 
p1=, /* number of continuous covariates in the logistic regression */ 
p2=, /* number of categorical covariates in the logistic regression */ 
resp=, /* binary response variable in the logistic regression */ 
ntrt= ); /* position of the treatment variable in the categorical covariates */ 
/* delete the observations with missing values in either numeric or categorical covariates */ 


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data newdata; 
set &data; 
if cmiss(of &var1 &var2)>0 then delete; 
run; 
/* extract the design matrix and variance-covariance matrix of the regression and store them in 
data1 and parms respectively */ 
/* cases when there is no continuous covariates */ 
%if &p1=0 %then 
%do; 
proc transreg data=newdata dummy noprint; 
model identity(&resp) = class(&var2/zero=first); 
output out = data1(drop=_: &var2 &resp) replace; 
run; 
proc logistic data=newdata desc covout outest=parms(drop=_:) 
noprint; 
class &var2 / param=ref ref=first; 
model &resp = &var2; 
run; 
%end; 
/* cases when both categorical and continuous covariates exist */ 
%else 
%do; 
proc transreg data=newdata dummy noprint; 
model identity(&resp) = class(&var2/zero=first) identity(&var1); 
output out = data1(drop=_: &var2 &resp) replace; 
run; 
proc logistic data=newdata desc covout outest=parms(drop=_:) 
noprint; 
class &var2 / param=ref ref=first; 
model &resp = &var2 &var1; 
run; 
%end; 
/* estimate the proportion difference and standard error to construct the 95% confidence 
interval */ 


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proc iml; 
use parms; 
read all into params; 
close parms; 
use data1; 
read all into xmat; 
close data1; 
p = nrow(params)-2; 
cov = params[2:(p+2),]; 
psize = nrow(xmat); 
ntrt = &ntrt+1; 
xt = xmat; 
xt[,ntrt] = J(psize,1,1); 
axT = xt*params[1,]`; 
xc = xmat; 
xc[,ntrt] = J(psize,1,0); 
axC = xc*params[1,]`; 
pderT = J(psize,1,0); 
pderC = J(psize,1,0); 
pderivT = J(psize,(p+1),0); 
pderivC = J(psize,(p+1),0); 
gt = J(1,(p+1),0); 
gc = J(1,(p+1),0); 
do k=1 to psize; 
pderT[k] = exp(axT[k])/(1+exp(axT[k])); 
pderC[k] = exp(axC[k])/(1+exp(axC[k])); 
pderivT[k,] = pderT[k]*(1-pderT[k])*xt[k,]; 
pderivC[k,] = pderC[k]*(1-pderC[k])*xc[k,]; 
end; 
difb=sum(pderT-pderC)/psize; 
pT=sum(pderT)/psize; 
pC=sum(pderC)/psize; 
do k=1 to (p+1); 
gt[k] = sum(pderivT[,k])/psize; 


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gc[k] = sum(pderivC[,k])/psize; 
end; 
se=sqrt(gt*cov*gt`+ gc*cov*gc`-2*gt*cov*gc`); 
upperb=difb+1.96*se; 
lowerb=difb-1.96*se; 
store difb se pT pC lowerb upperb; 
create difb var {"difb" "se" "pT" "pC" "lowerb" "upperb"}; **output statistics; 
append; 
close difb; 
quit; 
%mend; 
/* print out the LR estimation results */ 
19.8. 
PRO Appendix for PROMIS 
19.8.1. 
Distribution-based Minimal Clinically Important Difference (MCID) 
The distribution-based minimal clinically important difference (MCID), ½ SD and 1 SEM will be 
provided based on the pooled PROMIS Physical Function scores and Fatigue scores of two treatment 
arms at baseline for the FAS and the PPS, respectively. 
½ SD = 1/2 * Standard Deviation of the pooled norm-based T-scores of two treatment arms at baseline 
1 SEM = [(1 – Cronbach’s alpha) ^ (1/2)] * SD 
Where SD is the same as the definition for ½ SD and Cronbach’s alpha refers to the Standardized 
Cronbach’s alpha calculated using the following SAS code. For example, when calculating Cronbach’s 
alpha for PROMIS Physical Function, the individuals’ 10 item scores that constituted the Physical 
Function score will be used in the VAR clause. 
Sample SAS code： 
   ODS OUTPUT CronbachAlpha=CronbachAlpha; 
   PROC CORR DATA = PF NOMISS ALPHA; 
   VAR pfa11 pfa56 pfa21 pfa53 pfa9 pfb28r1 pfa1 pfa6 pfb3 pfb44; 
   RUN; 
19.8.2. 
Sensitivity Analysis of PROMIS 
Sensitivity analysis will be conducted using Analysis of Covariance (ANCOVA) model for PROMIS 
Physical Function T-scores and Fatigue T-scores using Last Observation Carries Forward (LOCF) 
imputation for the FAS and the PPS, respectively. The LOCF imputation should be performed after any 
data handling for the intercurrent events as described in Section 12.3.3.6 and Section 12.3.3.7. 
 


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An ANCOVA model with treatment and stratification factors as fixed effects, the baseline score value as 
covariate will be used to assess treatment difference. The LSM and the corresponding 95% confidence 
intervals for the differences between roxadustat and the placebo group (roxadustat – placebo) will be 
presented along with the p-values for the treatment differences resulting from the model. The LSM for the 
difference will be considered clinically meaningful if it exceeds the MCID and will be marked in the 
results, see Section 19.8.1 for details of MCID. 
19.9. 
Scope of Week 28 Primary Analysis 
The following tables, figures and listing will be provided in Week 28 Primary Analysis for the double 
blind component. The date when last patient in the double blind component finished Week 28 visit is the 
cutoff date for Week 28 database lock. For efficacy TFLs, only primary endpoint at Week 28 will be 
analyzed. Data for adverse events up to the cutoff date for Week 28 database lock will be summarized. 
For other safety TFLs, data up to last subject’s Week 28 will be included. 
Table 
Table 14.1.1.2 Subject Accountability and Disposition Double Blind Component (All Subjects) 
Table 14.1.2.2 Important Protocol Deviations Double Blind Component (Full Analysis Set) 
Table 14.1.3.1.2 Demographics and Baseline Characteristics Double Blind Component (Safety Analysis 
Set) 
Table 14.1.3.1.3 Demographics and Baseline Characteristics Double Blind Component (Per Protocol Set) 
Table 14.1.3.1.4 Demographics and Baseline Characteristics Double Blind Component (Full Analysis 
Set) 
Table 14.1.4.2 Medical History Double Blind Component (Full Analysis Set) 
Table 14.1.5.1.2 Exposure and Compliance Double Blind Component (Safety Analysis Set) 
Table 14.1.5.2.2 Dose Modification Double Blind Component (Safety Analysis Set) 
Table 14.1.6.2b Prior ESA Use and ESA Refractory Double Blind Component (Safety Analysis Set) 
Table 14.2.1.2 Primary Efficacy Endpoint Double Blind Component (Full Analysis Set) 
Table 14.2.2.1 Sensitivity Analysis I Double Blind Component (Per Protocol Set) 
Table 14.2.2.2.1 Sensitivity Analysis III Double Blind Component (Full Analysis Set) 
Table 14.2.5.1.3 Primary Efficacy Endpoint by Randomization Endogenous EPO Level Double Blind 
Component (Full Analysis Set) 
Table 14.2.5.1.4 Primary Efficacy Endpoint by Randomization IPSS-R Risk Category Double Blind 
Component (Full Analysis Set) 
Table 14.2.5.1.5 Primary Efficacy Endpoint by Randomization RBC Transfusion Burden Double Blind 
Component (Full Analysis Set) 
Table 14.2.5.1.11 Primary Efficacy Endpoint by Prior ESA Use Double Blind Component (Full Analysis 
Set) 
Table 14.3.1.1.2 Overall Summary of Treatment-Emergent Adverse Events Double Blind Component 
(Safety Analysis Set) 
Table 14.3.1.2.2 TEAEs by System Organ Class and Preferred Term Double Blind Component (Safety 
Analysis Set) 


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Table 14.3.1.3.1 TEAEs by System Organ Class and Preferred Term and Maximum Severity Double 
Blind Component (Safety Analysis Set) 
Table 14.3.1.4 TEAEs Related to Study Treatment Double Blind Component (Safety Analysis Set) 
Table 14.3.1.5 TEAEs with CTCAE with Grade 3 or Higher Double Blind Component (Safety Analysis 
Set) 
Table 14.3.1.6.2 Serious TEAEs Double Blind Component (Safety Analysis Set) 
Table 14.3.1.7 TEAEs Leading to Discontinuation of Study Treatment Double Blind Component (Safety 
Analysis Set) 
Table 14.3.1.8 TEAEs Leading to Death Double Blind Component (Safety Analysis Set) 
Table 14.3.1.9 Most Frequently Occurring TEAEs Double Blind Component (Safety Analysis Set) 
Table 14.3.1.11 Most Frequently Occurring Non-Serious TEAEs Double Blind Component (Safety 
Analysis Set) 
Table 14.3.1.12 TEAEs of Special Interest Double Blind Component (Safety Analysis Set) 
Table 14.3.1.13 TEAEs of Special Interest by SMQ Double Blind Component Double Blind Component 
(Safety Analysis Set) 
Table 14.3.1.14 Serious TEAEs Leading to Discontinuation of Study Treatment Double Blind 
Component (Safety Analysis Set) 
Table 14.3.2 Disease Progression to AML Double Blind Component (Safety Analysis Set) 
 
Figure 
Figure 14.2.1.1 Cumulative Number of PEW of TI at Week 28 Double Blind Component (Full Analysis 
Set) 
Figure 14.2.1.2 Subject Exposure over Time up to Week 28 Double Blind Component (Full Analysis Set) 
Figure 14.2.6.1 Mean (±SE) Hb (g/dL) from Baseline to Week 28 Double Blind Component (Full 
Analysis Set) 
Figure 14.2.6.2 Mean (±SE) Hb Change (g/dL) from Baseline to Week 28 Double Blind Component (Full 
Analysis Set) 
Figure 14.2.11.1 Swimming Plot of RBC Transfusion During the First 28 Weeks of Treatment Double 
Blind Component (Full Analysis Set) 
Figure 14.2.10.2 Consort Diagrams Double Blind Component (Safety Analysis Set) 
Listing 
Listing 16.2.2.1.2 Subject Accountability and Disposition Double Blind Component (All Subjects) 
Listing 16.2.2.2.2 Inclusion Criteria Not Met/Exclusion Criteria Met Double Blind Component (All 
Subjects) 
Listing 16.2.2.3.2 Analysis Populations Double Blind Component (All Subjects) 
Listing 16.2.2.3.3 Subjects Randomized from Incorrect Strata Double Blind Component (Full Analysis 
Set) 
Listing 16.2.2.4.2 Important Protocol Deviations Double Blind Component (All Subjects) 


Protocol: FGCL-4592-082  
Statistical Analysis Plan 
Version 1.0, 2023-04-10  
 
 
FibroGen, Inc                             CONFIDENTIAL                              Page 76 of 76  
Listing 16.2.3.1.2 Demographics Double Blind Component (Safety Analysis Set) 
Listing 16.2.3.2.2.1 Baseline Characteristics I Double Blind Component (Safety Analysis Set) 
Listing 16.2.3.2.2.2 Baseline Characteristics II Double Blind Component (Safety Analysis Set) 
Listing 16.2.4.1.2 Medical History Double Blind Component (Full Analysis Set) 
Listing 16.2.4.2.2b Prior ESA Use and ESA Refractory Double Blind Component (Safety Analysis Set) 
Listing 16.2.5.2.2 Exposure Double Blind Component (Safety Analysis Set) 
Listing 16.2.5.3.2 Treatment Compliance Double Blind Component (Safety Analysis Set) 
Listing 16.2.6.1.2 RBC Transfusion Double Blind Component (Safety Analysis Set) 
Listing 16.2.7.1.2 Adverse Events Double Blind Component (Safety Analysis Set) 
Listing 16.2.7.2.2 Serious Adverse Events Double Blind Component (Safety Analysis Set) 
Listing 16.2.7.3.2 AEs Leading to Death Double Blind Component (Safety Analysis Set) 
Listing 16.2.7.4.2 AEs Leading to Permanent Discontinuation of Study Drug Double Blind Component 
(Safety Analysis Set) 
Listing 16.2.7.5.2 Listing of Death Double Blind Component (Safety Analysis Set) 
Listing 16.2.7.6.2 Treatment-Emergent Adverse Events in Subjects with any Liver Abnormalities Double 
Blind Component (Safety Analysis Set) 
Listing 16.2.7.7.1 AEs of Special Interest Double Blind Component (Safety Analysis Set) 


Signature Page for VV-CLIN-013690 v2.0
Signature Page for VV-CLIN-013690 v2.0
Approval Task
20-Apr-2023 19:38:02 GMT+0000
Approval Task
20-Apr-2023 20:51:58 GMT+0000
Approval Task
20-Apr-2023 21:15:57 GMT+0000
Approval Task
20-Apr-2023 21:20:13 GMT+0000
Approval Task
20-Apr-2023 21:41:24 GMT+0000
Approval Task
20-Apr-2023 22:00:32 GMT+0000
Approval Task
21-Apr-2023 00:06:03 GMT+0000