A Phase 3, Randomized, Double-Blind, Placebo Controlled Study of the Efficacy and Safety of Roxadustat for the Treatment of Anemia in Chronic Kidney Disease Patients Not on Dialysis
Phase: PHASE3
Conditions: Anemia in Chronic Kidney Disease in Non-dialysis Patients
Sponsor: Astellas Pharma Europe B.V.

A Phase 3, Randomized, Double-Blind, Placebo Controlled 
Study of the Efficacy and Safety of Roxadustat for the 
Treatment of Anemia in Chronic Kidney Disease Patients 
not on Dialysis
ISN/Protocol 1517-CL-0608
ClinicalTrials.gov Identifier: NCT01887600
Date of Protocol: Version 2.1, dated 21 Jun 2016
Sponsor: Astellas Pharma Europe B.V.
Sylviusweg 62
2333 BE Leiden
The Netherlands

Sponsor: APEB
ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
- CONFIDENTIAL -
21 Jun 2016
Astellas
Page 1 of 161
Version 2.1. Incorporating Non-substantial Amendment 1
A Phase 3, Randomized, Double-Blind, Placebo Controlled Study 
of the Efficacy and Safety of Roxadustat for the Treatment of 
Anemia in Chronic Kidney Disease Patients not on Dialysis
Protocol for Phase 3 Study of Roxadustat (ASP1517/FG-4592)a
ISN/Protocol 1517-CL-0608
Version 2.1
Incorporating Non-substantial Amendment 1 [See Attachment 1]
21 June 2016
EudraCT No: 2012-005180-27
Sponsor:
Astellas Pharma Europe B.V.
Sylviusweg 62
2333 BE Leiden
The Netherlands
Protocol History:
Version 1.0 [11 Dec 2012]
Version 2.0 Incorporating Substantial Amendment 1 [17 Dec 2014]
                                                
a The originator of the compound under study is FibroGen Inc and the code name used by FibroGen Inc is 
FG-4592. Astellas is the development partner and uses the code name ASP1517. The sponsor of this study is 
Astellas. The compound has received the International Nonproprietary Name (INN) roxadustat.

Sponsor: APEB
ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
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Version 2.1. Incorporating Non-substantial Amendment 1
TABLE OF CONTENTS
I.
SIGNATURES ······················································································ 8
II.
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL····························10
III.
LIST OF ABBREVIATIONS AND KEY TERMS··········································11
IV.
SYNOPSIS··························································································16
V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS·································28
1
INTRODUCTION·················································································33
1.1
Background ····················································································33
1.1.1
Epidemiology of Chronic Kidney Disease and End Stage Renal Disease········33
1.1.2
Anemia Associated with CKD·························································33
1.1.3
Treatment of Anemia ···································································34
1.2
Non-clinical and Clinical Data ······························································35
1.2.1
Mechanism of Action of Roxadustat··················································35
1.2.2
Clinical Experience with Roxadustat ·················································37
1.2.2.1
Pharmacokinetics and Pharmacodynamics ·····································37
1.2.2.2
Efficacy ·············································································38
1.2.2.3
Summary············································································40
1.3
Summary of Key Safety Information for Study Drugs ···································40
1.4
Risk-Benefit Assessment·····································································41
2
STUDY OBJECTIVE(S), DESIGN AND ENDPOINTS ··································42
2.1
Study Objectives ··············································································42
2.1.1
Primary Objective ·······································································42
2.1.2
Secondary Objectives···································································42
2.2
Study Design and Dose Rationale···························································42
2.2.1
Study Design·············································································42
2.2.1.1
General··············································································42
2.2.1.2
Study Population···································································43
2.2.1.3
Description of Study ······························································43
2.2.1.4
Randomization and Blinding ·····················································44
2.2.1.5
Comparator ·········································································44
2.2.2
Dose Rationale···········································································45
2.3
Endpoints·······················································································46
2.3.1
Primary Endpoint········································································46

Sponsor: APEB
ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
- CONFIDENTIAL -
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Page 3 of 161
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2.3.2
Secondary Endpoints····································································46
2.3.3
Other Endpoints ·········································································47
2.3.3.1
Additional Secondary Evaluation of Efficacy··································47
2.3.3.2
Safety Endpoints···································································48
3
STUDY POPULATION··········································································49
3.1
Inclusion Criteria··············································································49
3.2
Exclusion Criteria·············································································50
3.3
Discontinuation Criteria for Individual Subjects ··········································52
4
STUDY DRUGS ···················································································53
4.1
Description of Study Drugs ··································································53
4.1.1
Test Drug(s)··············································································53
4.1.2
Comparative Drug·······································································53
4.1.3
Drug(s) for Pre-investigational Period················································53
4.2
Packaging and Labeling······································································53
4.3
Study Drug Handling ·········································································54
4.4
Blinding ························································································55
4.4.1
Blinding Method·········································································55
4.4.2
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking ··················································································55
4.4.3
Breaking the Treatment Code for Emergency ·······································55
4.4.4
Breaking the Treatment Code by the Sponsor ·······································56
4.5
Assignment and Allocation ··································································56
5
TREATMENTS AND EVALUATION························································56
5.1
Dosing and Administration of Study Drugs and Other Medications····················57
5.1.1
Dose/Dose Regimen and Administration Period ····································57
5.1.2
Changes in Study Drug Dose ··························································58
5.1.3
Previous and Concomitant Medication (Drugs and Therapies)····················59
5.1.3.1
Previous Medication (Drugs and Therapies) ···································59
5.1.3.2
Concomitant Medication (Drugs and Therapies) ······························60
5.1.4
Treatment Compliance··································································62
5.1.5
Rescue Therapy Guidelines ····························································62
5.1.6
Emergency Procedures ·································································63
5.1.7
Restrictions During the Study··························································63
5.2
Demographics and Baseline Characteristics ···············································64

Sponsor: APEB
ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
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21 Jun 2016
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5.2.1
Demographics············································································64
5.2.2
Medical History··········································································64
5.2.3
Renal Ultrasound ········································································64
5.2.4
Diagnosis of the Target Disease, Severity, and Duration of Disease··············64
5.2.5
Further Laboratory Testing Prior to Randomization ································65
5.3
Efficacy Assessment··········································································65
5.3.1
Primary Efficacy Assessment··························································65
5.3.2
Additional Efficacy Assessment·······················································65
5.3.2.1
Blood Pressure ·····································································65
5.3.2.2
Serum Lipid Panel·································································66
5.3.3
Additional Assessments ································································66
5.3.3.1
Health Related Quality of Life ···················································66
5.3.3.2
Hospitalizations····································································67
5.4
Safety Assessment ············································································67
5.4.1
Vital Signs················································································67
5.4.1.1
Blood pressure ·····································································68
5.4.1.2
Heart rate ···········································································68
5.4.1.3
Respiratory rate ····································································68
5.4.2
Adverse Events ··········································································68
5.4.2.1
Adverse Events of Possible Hepatic Origin ····································69
5.4.3
Laboratory Assessments································································69
5.4.3.1
Abnormal Liver Function Tests··················································69
5.4.3.2
HemoCue ···········································································69
5.4.3.3
Urinalysis···········································································69
5.4.3.4
Central Laboratory·································································69
5.4.4
Physical Examination···································································72
5.4.5
Electrocardiogram (ECG) ······························································72
5.4.6
Exploratory Assessments·······························································72
5.5
Adverse Events and Other Safety Aspects ·················································73
5.5.1
Definition of Adverse Events (AEs) ··················································73
5.5.2
Definition of Serious Adverse Events (SAEs) ·······································74
5.5.3
Criteria for Causal Relationship to the Study Drug ·································76
5.5.4
Criteria for Defining the Severity of an Adverse Event ····························76
5.5.5
Reporting of Serious Adverse Events (SAEs) ·······································77
5.5.6
Follow-up to Adverse Events ··························································78

Sponsor: APEB
ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
- CONFIDENTIAL -
21 Jun 2016
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Page 5 of 161
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5.5.7
Monitoring of Common Serious Adverse Events ···································79
5.5.8
Procedure in Case of Pregnancy·······················································79
5.5.9
Supply of New Information Affecting the Conduct of the Study··················80
5.5.10
Emergency Procedures and Management of Overdose ·····························80
5.6
Test Drug Concentration ·····································································80
5.6.1
Blood Sample for Roxadustat Pharmacokinetic Analysis ··························81
5.7
Other Measurements, Assessments, or Methods ··········································81
5.7.1
Hepcidin in Serum ······································································82
5.7.2
Archival of Serum Samples for Biomarker Analysis ·······························82
5.7.3
Archival of Urine Samples for Biomarker Analysis ································82
5.7.4
Optional Genotyping Sample ··························································82
5.8
Total Amount of Blood·······································································82
6
TERMINATION OF THE CLINICAL STUDY ············································83
7
STATISTICAL METHODOLOGY ···························································83
7.1
Sample Size····················································································83
7.2
Analysis Set····················································································83
7.2.1
Full Analysis Set (FAS) ································································84
7.2.2
Per Protocol Set (PPS)··································································84
7.2.3
Safety Analysis Set (SAF)······························································84
7.2.4
Pharmacokinetic Analysis Set (PKAS) ···············································84
7.3
Demographics and Other Baseline Characteristics········································84
7.4
Analysis of Efficacy ··········································································84
7.4.1
Analysis of Primary Endpoint ·························································84
7.4.1.1
Primary Analysis···································································85
7.4.1.2
Secondary Analysis································································86
7.4.1.3
Subgroup Analysis·································································86
7.4.2
Secondary Endpoints····································································86
7.4.2.1
Primary Analysis···································································86
7.4.2.2
Secondary Analysis································································88
7.4.3
Analysis of Additional Efficacy Endpoints ··········································88
7.5
Analysis of Safety·············································································88
7.5.1
Adverse Events ··········································································88
7.5.2
Clinical Laboratory Parameters························································89
7.5.3
Vital Signs················································································89

Sponsor: APEB
ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
- CONFIDENTIAL -
21 Jun 2016
Astellas
Page 6 of 161
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7.5.4
ECG·······················································································89
7.5.5
ESA ·······················································································90
7.6
Analysis of Pharmacokinetics ·······························································90
7.7
Analysis of Pharmacodynamics ·····························································90
7.8
Protocol Deviations and Other Analyses···················································90
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)····················90
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········91
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ····················91
8.1
Procedure for Clinical Study Quality Control ·············································91
8.1.1
Data Collection ··········································································91
8.1.2
Specification of Source Documents···················································91
8.1.3
Clinical Study Monitoring······························································92
8.1.4
Direct Access to Source Data/Documents············································92
8.1.5
Data Management ·······································································92
8.1.6
Protocol Deviations ·····································································93
8.1.7
End of Trial in All Participating Countries···········································93
8.2
Ethics and Protection of Subject Confidentiality··········································93
8.2.1
Institutional Review Board (IRB) Independent Ethics Committee (IEC) / 
Competent Authorities (CA) ···························································93
8.2.2
Ethical Conduct of the Study···························································94
8.2.3
Informed Consent of Subjects ·························································94
8.2.3.1
Subject Information and Consent················································94
8.2.3.2
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information·····························95
8.2.4
Subject Confidentiality ·································································95
8.3
Administrative Matters ·······································································96
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study ·····96
8.3.2
Documents and Records Related to the Clinical Study·····························96
8.3.3
Protocol Amendment and/or Revision················································97
8.3.4
Insurance of Subjects and Others······················································98
8.3.5
Investigator Indemnity··································································98
8.3.6
Signatory Investigator for Clinical Study Report····································99

Sponsor: APEB
ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
- CONFIDENTIAL -
21 Jun 2016
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Page 7 of 161
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9
QUALITY ASSURANCE········································································99
10
STUDY ORGANIZATION······································································99
10.1
Independent Data and Safety Monitoring Board (DSMB) ·······························99
10.2
Independent Event Review Committee (IERC) ···········································99
10.3
Other Study Organization ····································································99
11
REFERENCES ·················································································· 100
12
APPENDICES ··················································································· 103
12.1
Appendix 1:  List of Prohibited Concomitant Medication ····························· 103
12.2
Appendix 2:  Liver Safety Monitoring and Assessment································ 104
12.3
Appendix 3:  Instructions for Subjects Moving from Protocol v1.0 to Protocol 
v2.0 ··························································································· 107
12.4
Appendix 4:  Instructions for Subjects Requiring Dialysis ···························· 109
12.4.1
Dosing ·················································································· 109
12.4.2
Dose Adjustment ······································································ 109
12.4.3
Rescue Therapy – ESA Use·························································· 109
12.4.4
Health Related Quality of Life······················································· 109
12.4.5
Timing of Study Assessments ······················································· 109
12.5
Appendix 5:   Short Form-36 Health Survey (SF-36) ·································· 110
12.6
Appendix 6:  Functional Assessment of Cancer Therapy –  Anemia (FACT-an) ··· 116
12.7
Appendix 7:  Euroqol Questionnaire (EQ-5D-5L) ······································ 119
12.8
Appendix 8:   Patients’ Global Impression of Change (PGIC) Scale ················· 122
12.9
Appendix 9:  Work Productivity and Activity Impairment Questionnaire: 
Anaemic Symptoms V2.0 (WPAI:ANS)················································· 123
13
ATTACHMENT 1:  NON-SUBSTANTIAL AMENDMENT 1························· 127
14
SPONSOR’S SIGNATURES·································································· 161

Sponsor: APEB
ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
- CONFIDENTIAL -
21 Jun 2016
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Page 8 of 161
Version 2.1. Incorporating Non-substantial Amendment 1
I.
SIGNATURES
1.
SPONSOR’S SIGNATURES
Required signatures (e.g., Protocol authors, sponsor’s reviewers and contributors) are located 
in Section 14 Sponsor’s Signatures; e-signatures (when applicable) are located at the end of 
this document.

Sponsor: APEB
ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
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21 Jun 2016
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2.
INVESTIGATOR’S SIGNATURE
A Phase 3, Randomized, Double-Blind, Placebo Controlled Study of the Efficacy 
and Safety of roxadustat for the Treatment of Anemia in Chronic Kidney 
Disease Patients not on Dialysis
ISN/Protocol 1517-CL-0608 
Version 2.1/ Incorporating Non-substantial Amendment 1
21 June 2016
I have read all pages of this clinical study protocol for which Astellas is the sponsor. I agree 
to conduct the study as outlined in the protocol and to comply with all the terms and 
conditions set out therein. I confirm that I will conduct the study in accordance with ICH 
GCP guidelines and applicable local regulations. I will also ensure that sub-investigator(s) 
and other relevant members of my staff have access to copies of this protocol and the ICH 
GCP guidelines to enable them to work in accordance with the provisions of these 
documents.
Principal Investigator:
Signature:
<Insert name and qualifications of the Investigator>
Printed Name:
Date (DD Mmm YYYY)
Address:

Sponsor: APEB
ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
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III.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase (GPT)
ANOVA
Analysis of variance
AnS
Anemia Subscale
anti-HCV Ab
Anti-hepatitis C virus antibody
APEB
Astellas Pharma Europe BV
ASP1517
= FG-4592 (codename of investigational product) or roxadustat (international 
nonproprietary name)
AST
Aspartate Aminotransferase (GOT)
AT
Aminotransferases
BL
Baseline
BP
Blood Pressure
CA
Competent Authority 
CBC
Complete Blood Count
CHr
Hemoglobin content of reticulocytes
CI
Confidence Interval
CKD
Chronic Kidney Disease
Cmax
Maximum concentration
CMH
Cochran-Mantel-Haenszel
Cr
Creatinine
CRF
Case Report Form
CRO
Contract Research Organization
CYP
Cytochrome P450
DBP
Diastolic Blood Pressure
DD-CKD
Dialysis-dependent chronic kidney disease
DNA
Deoxyribonucleic Acid
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
eCRF
Electronic CRF
EDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate
EOS
End of Study
EPO
Erythropoietin
EQ-5D 5L
Health Related Quality of Life Questionnaire consisting of Five Levels
ESA
Erythropoiesis-Stimulating Agent
ESRD
End Stage Renal Disease
EOT
End of Treatment
FACT-An
Functional Assessment of Cancer Therapy-Anemia
FACT-G
Functional Assessment of Cancer Therapy-General
FAS
Full Analysis Set
FG-4592
= ASP1517 (codename of investigational product) or roxadustat (international 
nonproprietary name)
GCP
Good Clinical Practice

Sponsor: APEB
ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
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Abbreviations
Description of abbreviations
GDS
Global Data Science
Hb
Hemoglobin
HbA1c
Hemoglobin A1c Glycated hemoglobin
HBsAg
Hepatitis B Surface Antigen
HD
Hemodialysis
HDF
Hemodiafiltration
HDL
High density lipoprotein
HIF
Hypoxia-inducible Factor
HIF-PH
Prolyl Hydroxylase
HIF-PHI
Prolyl Hydroxylase Inhibitor
HIV
Human Immunodeficiency Virus
HR
Heart Rate
HRQoL
Health-Related Quality of Life
hs-CRP
High Sensitivity C-reactive protein
ICF
Informed Consent Form
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IERC
Independent Event Review Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISN
International Study Number
IUD
Intrauterine device
IUS
Intrauterine system
IV
Intravenous
KDOQI
Kidney Disease Outcomes Quality Initiative
LDL
Low density lipoprotein
LA-CRF
Liver Abnormality Case Report Form
LFT
Liver Function Test
LOCF
Last Observation Carried Forward
MACE
Major cardiovascular adverse events: myocardial infarction, stroke, death from 
all causes
MACE+
Myocardial infarction, stroke, death from all causes, chronic heart failure 
requiring hospitalization, unstable angina requiring hospitalization
MAP
Mean Arterial Pressure
MDRD
Modification of Diet in Renal Disease
MMRM
Mixed Model of Repeated Measures
MRI
Magnetic resonance imaging
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria for Adverse Events
NDD-CKD
Non dialysis-dependent chronic kidney disease
PF
Physical Functioning
PGIC
Patients’ Global Impression of Change
PKAS
Pharmacokinetic Analysis Set
PPD
Population pharmacodynamic
PPK
Population pharmacokinetics
PPK/PD
Population pharmacokinetic/pharmacodynamic
PPS
Per Protocol Set

Sponsor: APEB
ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
- CONFIDENTIAL -
21 Jun 2016
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Abbreviations
Description of abbreviations
PWB
Physical Wellbeing
QoL
Quality of Life
QTc
QT Interval corrected for heart rate
RBC
Red Blood Cell
RRT
Renal Replacement Therapy
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SF-36
Short Form 36
SMD
Study Medication Diary
SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
SST
Serum Separator Tube
sTfR
Soluble Transferrin Receptor
SUSAR
Suspected Unexpected Serious Adverse Reactions
SWB
Social Wellbeing
t½
Apparent Terminal Elimination Half-life
TBL
Total Bilirubin 
TEAE
Treatment-Emergent Adverse Event
TIBC
Total Iron-Binding Capacity
TIW
Thrice Weekly
TSAT
Transferrin Saturation (also known as FeSAT, iron saturation)
ULN
Upper Limit of Normal
USRDS
United States Renal Data System
VAS
Visual Analogue Scale
VT
Vitality
WBC
White Blood Cell
WPAI:ANS
Work Productivity and Activity Impairment questionnaire: Anemic Symptoms

Sponsor: APEB
ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
- CONFIDENTIAL -
21 Jun 2016
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List of Key Study Terms
Terms
Definition of terms
Adverse Event
An adverse event (AE) is as any untoward medical occurrence in a subject 
administered the study drug, roxadustat or placebo, or who has undergone 
study procedures and which does not necessarily have a causal relationship 
with this treatment. AE collection starts after obtaining signed informed 
consent and continues until the End of Study visit.  AEs will not be collected 
during the period between first screen where subject has failed screening and 
first rescreening visit.
Baseline
1) Observed values/findings which are regarded as calibrated zero status in 
the present study; 2) Time when ‘Baseline’ is observed.
Baseline Hemoglobin 
(Hb) value
Mean of 4 Hb values: the last 3 Hb values during screening and the Hb value 
at the day of randomization, all assessed by the central laboratory.
Discontinuation
The act of concluding participation in either the study treatment or the study, 
prior to completion of all protocol-required elements, in a trial by an enrolled 
subject. Four categories of discontinuation are distinguished: a) dropout: 
Active discontinuation by a subject (also a noun referring to such a 
discontinued subject); b) investigator-initiated discontinuation (e.g., for 
cause); c) loss to follow-up: cessation of participation without notice or 
action by the subject; d) sponsor-initiated discontinuation. Note that subject 
discontinuation does not necessarily imply exclusion of subject data from 
analysis. “Termination” has a history of synonymous use, but is now 
considered non-standard.
Enroll
To register or enter into a clinical trial; transitive and intransitive. Informed 
consent precedes enrollment, which precedes or is contemporaneous with 
randomization.
Extended treatment 
period
Period of time that patient is treated from end of primary treatment period 
(52 weeks) up to 104 weeks
Hb response

Hb 11.0 g/dL and a Hb increase from baseline (BL) by 1.0 g/dL in 
any subject with BL Hb> 8.0 g/dL, OR 

an increase from BL by 2.0 g/dL in any subject with 
BL Hb ≤8.0 g/dL 
at 2 consecutive visits separated by at least 5 days during the first 24 weeks 
of treatment without rescue therapy (i.e., red blood cell [RBC] transfusion, 
erythropoiesis-stimulating agent (ESA), or IV iron) prior to Hb response. 
Investigational period
Period of time where major interests of protocol objectives  are observed, 
and where the test drug or placebo (sometimes without randomization) is 
usually given to a subject, and continues until the last assessment after 
completing administration of the test drug or placebo.
Post study follow-up
Period of time from end of study (EOS) visit to projected week 108 or until 
the last subject randomized reaches EOS, whichever comes first. This period 
is only applicable to subjects who prematurely discontinued treatment. These 
subjects will be followed up on a 6-monthly frequency for vital status, SAEs, 
cardiovascular and thromboembolic AEs.

Sponsor: APEB
ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
- CONFIDENTIAL -
21 Jun 2016
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Page 15 of 161
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Terms
Definition of terms
Primary treatment 
period
Period of time that subject is treated from first treatment up to 52 weeks
Randomization
Action to allocate a subject to the treatment group or treatment cohort. 
Subjects will be randomized to roxadustat or placebo at day 1.
Rescreening
Process of repeating screening. If a subject fails screening they may be re-
screened once if deemed appropriate; all screening procedures will be 
repeated.  Renal ultrasound only to be repeated if not within 12 weeks prior 
to randomization.
Rescreening failure
Subject who is rescreened, but did not fulfill protocol inclusion and/or 
exclusion criteria for a second time and failed to receive randomized 
treatment, or decided not to participate anymore (withdrew consent) prior to 
the treatment period.  
Screening
1) Process for retrieving candidates for the study. 2) Process for checking the 
eligibility of subjects usually done during the “pre-investigational period”
Screening failure
Screened subject, but did not fulfill protocol inclusion and/or exclusion 
criteria and failed to receive randomized treatment, or decided not to 
participate anymore (withdrew consent) prior to the treatment period.
Serious Adverse 
Event
An adverse event is considered “serious” if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: results in 
death, is life threatening, results in persistent or significant 
disability/incapacity or substantial disruption of the ability to conduct normal 
life functions, results in congenital anomaly, or birth defect, requires 
in-subject hospitalization or leads to prolongation of hospitalization, or a 
medically important event.
Study period
Period of time from first subject screened to end of the last scheduled visit of 
the last subject randomized
Subject
An individual who participates in a clinical trial, either as a recipient of the 
investigational product(s) or as a control.
Treatment Period
Period of time from first study drug intake until last study drug intake.  
Minimum 52 weeks to a maximum of 104 weeks or until the last subject 
randomized to treatment has completed 40 weeks of treatment (or at the 
forecasted week 40 date if this subject discontinues treatment early)
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.

Sponsor: APEB
ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
- CONFIDENTIAL -
21 Jun 2016
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Page 16 of 161
Version 2.1. Incorporating Non-substantial Amendment 1
IV.
SYNOPSIS
Title of Study
A Phase 3, Randomized, Double-Blind, Placebo Controlled Study of the 
Efficacy and Safety of roxadustat for the Treatment of Anemia in Chronic 
Kidney Disease Patients not on Dialysis [ISN/Protocol 1571-CL-0608]
Planned Study 
Period
From 1Q2013 to 4Q2017
Study Objective(s)
The primary objective of this study is to evaluate the efficacy of roxadustat
in the treatment of anemia in non-dialysis Chronic Kidney Disease (CKD)
subjects.
The secondary objectives in this study are to:

Evaluate the safety of roxadustat in the treatment of anemia in non-
dialysis CKD subjects.

Evaluate health-related quality of life (HRQoL) benefit of treatment 
with roxadustat in subjects with CKD anemia.

Evaluate the need for anemia rescue therapy with roxadustat treatment 
in subjects with CKD anemia: red blood cell (RBC) transfusion, or 
erythropoiesis-stimulating agent (ESA), or IV iron.
Planned Total 
Number of Study 
Centers and Location
Approximately 200 centers globally
Design and 
Methodology
This is a phase 3, multi-center, randomized, double-blind, 
placebo-controlled study. The study population consists of subjects with 
CKD as defined by CKD stages 3, 4, and 5 (estimated glomerular filtration 
rate [eGFR] < 60 mL/min/1.73 m2) who are anemic and not receiving
dialysis.
The study will consist of 3 study periods as follows:

Screening period: up to 6 weeks.

Treatment period: minimum 52 weeks (primary treatment period) up to 
a maximum of 104 weeks (extended treatment period) or until the last 
subject randomized to treatment has completed 40 weeks of treatment 
(or at the forecasted week 40 date if this subject discontinues treatment 
early). Treatment period for last patient randomized is 52 weeks.

Post-Treatment Follow-Up period: 4 weeks.
Subjects that have discontinued treatment prior to their projected week 
104 will continue to be followed for vital status and serious adverse events 
(SAEs), cardiovascular and thromboembolic adverse events (AEs) in post 
study follow up.
Subjects are randomized to 1 of 2 treatment arms. The randomization will 
result in a 2:1 ratio of subjects receiving roxadustat or placebo, respectively. 
Study treatment administration is implemented in a double-blind, placebo
controlled manner. 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.
Proper randomization of treatments and preserving the treatment blind are 
maintained by Interactive Response Technology (IRT).
The initial study drug dose (per dose amount) is based on the tiered, 
weight-based dosing scheme shown in Table 1.

Sponsor: APEB
ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
- CONFIDENTIAL -
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Version 2.1. Incorporating Non-substantial Amendment 1
Table 1
Initial Study Drug (Roxadustat/Placebo) Dosing
Study Drug
(Dose Frequency)
Weight
(≥45 to ≤70 kg)
Weight
(> 70 to ≤160 kg)
Roxadustat/ Placebo 
(TIW)
70 mg
100 mg
Study drug will be dosed thrice weekly (TIW) during the treatment period. 
Initially subjects will be dosed for hemoglobin (Hb) correction, until
subjects achieve central Hb values of ≥11.0 g/dL and Hb increase from BL
≥1.0 g/dL at 2 consecutive study visits, separated by at least 5 days
(correction period).
During the Treatment period, subjects will attend weekly study visits from 
day 1 to week 2, followed by every other week study visits from weeks 4 to 
24 and thereafter every 4 weeks until end of treatment (EOT).
Subjects will be treated with roxadustat or placebo for at least 52 weeks and 
will continue taking the double-blind treatment as they were assigned until a 
maximum of 104 weeks. Depending on the rate of recruitment, the 
maximum treatment period will be 104 weeks for subjects who were 
randomized early into the study.

The last subject randomized will stop treatment at the minimum of 
52 weeks. 

When the last subject randomized reaches 40 weeks of treatment (or 
the forecasted week 40 date, if the last subject randomized 
discontinues treatment early) 
o
Subjects beyond 52 weeks treatment will stop treatment at 
this point. 
o
Subjects that have not yet reached 52 weeks treatment will 
continue until they reach 52 weeks treatment
Correction Period
The aim of the Correction period is to correct Hb levels to ≥11.0 g/dL with 
an increase from BL ≥1.0 g/dL at 2 consecutive visits. This period is 
variable in length for each subject, depending on when a subject achieves 
central Hb ≥11.0 g/dL and an Hb increase from BL ≥1.0 g/dL as measured 
by Hb values at 2 consecutive study visits separated by at least 5 days.  
Once 2 consecutive Hb values reach 11.0 g/dL or higher, the subject will 
enter into the Maintenance period.
Maintenance Period
The aim of the Maintenance period is to treat to a Hb target level of 
11.0 g/dL by maintaining the Hb levels between Hb 10.0 g/dL and 
12.0 g/dL.
Dose Adjustments
All dose adjustments will follow pre-specified dose adjustment rules, see
Table 2, and are made based on Hb values using the HemoCue® device, a 
point-of-care device. 

Sponsor: APEB
ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
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Page 18 of 161
Version 2.1. Incorporating Non-substantial Amendment 1
Table 2
Dose Adjustment Rules
Correction 
Period
Maintenance Period
Change in Hb 
over past 
4 weeks 
(g/dL)a
(When Hb 
correction 
has not been 
reached)
Hb 
< 10.5 g/dL
Hb 10.5 to 
< 12.0 g/dL
Hb 12.0 to 
< 13.0 g/dL
< -1.0
↑
↑
↑
No change
-1.0 to 1.0
↑
↑
No change
↓
> 1.0
No change
No change
↓
↓
a
Subtract 4 weeks’ previous Hb value from the present Hb value to calculate the 
change

All dose adjustments are made based on Hb values using HemoCue, a 
point-of-care device. 

If the dose adjustment is ‘No change’ per Table 2, the next dose 
adjustment review is 4 weeks after that visit.

Dose increases by 1 dose step (↑) and reductions by 1 dose step (↓) are 
pre-set per the dose steps.

The dose steps are as follows: 20, 40, 50, 70, 100, 150, 200, 250 and 
300 mg.  

The maximum dose is the dose step corresponding to 3.0 mg/kg per 
administration or 300 mg, whichever is lower. The default weight is 
initially set as weight measured at day 1. At study visits where weight is 
collected, the maximum allowed dose step and the default weight for a 
subject will be adjusted if the weight change is ≥ 5% compared to the 
previous default weight collected in the study.  For randomized subjects 
who require chronic dialysis during the treatment period, the maximum 
dose step is the dose step corresponding to 3.0 mg/kg per administration 
or 400 mg, whichever is lower.

At week 4 only, in a subject whose BL Hb level was < 8.0 g/dL, if the 
dose adjustment is to increase, then dose increase could be made with 
either a 1 or 2 step increase per investigator’s discretion to minimize the 
probability of requiring rescue therapy treatment. 

Contact the Medical Monitor if dose adjustments would lead to doses 
outside the limits of the dose step range; i.e., lower than 20 mg or higher 
than 300 mg.

If there is a safety concern, investigators may deviate from the dose 
adjustment rules. This should be discussed with the Medical Monitor 
and documented in the source documentation.
At any time when Hb ≥13.0 g/dL

Stop dosing

Resume dosing when Hb < 12.0 g/dL at a dose that is reduced by 2 steps

Next dose adjustment review is 4 weeks after dose resumption and in 
4-weekly intervals thereafter.

Sponsor: APEB
ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
- CONFIDENTIAL -
21 Jun 2016
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Page 19 of 161
Version 2.1. Incorporating Non-substantial Amendment 1
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 1 dose step
Note: Only 1 dose reduction for excessive hematopoiesis is recommended 
within a period of 4 weeks. If a blood transfusion or ESA treatment has 
been performed within 2 weeks of meeting the criteria for excessive 
hematopoiesis, it is recommended not to perform a dose reduction for 
excessive hematopoiesis.
After a dose adjustment due to excessive hematopoiesis, the subject’s next 
dose adjustment review will occur 4 weeks later, and in 4-weekly intervals 
thereafter.
Follow up Period
After the Treatment Period, subjects proceed to the 4-week Post-Treatment 
Follow-up period.  
Post Study Follow-up
Subjects that have discontinued treatment prior to their projected week 104 
will complete the EOT visits (EOT visit and EOT + 2 weeks visit) and the 
EOS visit. Thereafter, these subjects will continue to be followed up on a 
6-monthly frequency for vital status and SAEs, cardiovascular and 
thromboembolic AEs until their projected date of completion (i.e., projected 
week 108 date) or, if earlier, until the last subject randomized reaches EOS, 
or until consent withdrawn.
Data Safety Monitoring Board/Independent Event Review Committee
A Data Safety Monitoring Board (DSMB) will review pre-specified safety 
data periodically in collaboration with the sponsor to ensure subject 
safety. The DSMB will review safety data in a blinded and unblinded 
manner while the sponsor remains blinded.
An Independent Event Review Committee (IERC) will adjudicate all pre-
specified cardiovascular and cerebrovascular events in a blinded manner to 
ensure consistent safety assessment.  Details will be specified in an IERC 
charter. 
Population Pharmacokinetic Analysis
Blood samples for population pharmacokinetics (PPK) will be collected at 6 
different time points and can be collected over 1 to 3 visits in weeks 2 to 8 
of treatment.
Number of Subjects 
Planned
450-600 subjects will be randomized.

Sponsor: APEB
ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
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21 Jun 2016
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Page 20 of 161
Version 2.1. Incorporating Non-substantial Amendment 1
Selection Criteria
Inclusion Criteria
Subject is eligible for the study if all of the following apply:
1.
Institutional Review Board (IRB)-/Independent Ethics Committee 
(IEC)-approved written Informed Consent and privacy language as per 
national regulations must be obtained from the subject or legally 
authorized representative prior to any study-related procedures 
(including withdrawal of prohibited medication, if applicable).
2.
Subject age is ≥18 years.
3.
Subject has a diagnosis of chronic kidney disease, with Kidney Disease 
Outcomes Quality Initiative (KDOQI) Stage 3, 4 or 5, not receiving 
dialysis; with an eGFR <60 mL/min/1.73 m2 estimated using the 
abbreviated 4-variable Modification of Diet in Renal Disease (MDRD) 
equation.
4.
The mean of the subject’s three most recent Hb values during the 
Screening period, obtained at least 4 days apart, must be ≤10.0 g/dL, 
with a difference of ≤1.0 g/dL between the highest and the lowest 
values. The last Hb value must be within 10 days prior to 
randomization.
5.
Subject has a ferritin level ≥30 ng/mL (≥67.4 pmol/L) at screening. 
6.
Subject has a transferrin saturation (TSAT) level ≥5% at screening.
7.
Subject has a serum folate level ≥lower limit of normal at screening. 
8.
Subject has a serum vitamin B12 level ≥lower limit of normal at 
screening. 
9.
Subject’s alanine aminotransferase (ALT), aspartate aminotransferase 
(AST) levels are ≤3 x upper limit of normal (ULN), and total bilirubin 
(TBL) ≤1.5 x ULN.
10. Subject’s body weight is 45.0 kg up to a maximum of 160.0 kg.
11. Female subject is either:
Of non-child bearing potential:
post-menopausal (defined as at least 1 year without any 
menses) prior to screening, or 
documented surgically sterile
or if of child bearing potential
agree not to try to become pregnant during the study and for 
28 days after the final study drug administration.
must have a negative serum pregnancy test at screening, and
if heterosexually active, agree to consistently use a highly 
effective form of birth control* starting at screening and 
throughout the study period, and continued for 28 days after 
the last study treatment administration.
12. Male subject and their female spouse/partner(s) who are of 
childbearing potential must be using highly effective contraception 
starting at screening and continue throughout the study period, and for 
12 weeks after final study treatment administration.
* Highly effective forms of birth control include:

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
Consistent and correct usage of established oral contraception.

Injected or implanted hormonal methods of contraception.

Established intrauterine device (IUD) or intrauterine system 
(IUS).

Barrier methods of contraception: condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository (if allowed by local 
regulations).

Any male partner that has undergone effective surgical 
sterilization.

Any female partner that has undergone effective surgical 
sterilization, if applicable.
13. Subject agrees not to participate in another interventional study from 
the time of signing informed consent until the End of Study visit 
(EOS).
Exclusion Criteria
Subject will be excluded from participation if any of the following apply:
1.
Subject has received any ESA treatment within 12 weeks prior to 
randomization.
2.
Subject has had more than one dose of IV iron within 12 weeks prior to 
randomization.
3.
Subject has received a RBC transfusion within 8 weeks prior to 
randomization. 
4.
Subject has a known history of myelodysplastic syndrome or multiple 
myeloma.
5.
Subject has a known hereditary hematologic disease such as 
thalassemia or sickle cell anemia, pure red cell aplasia, or other known 
causes for anemia other than CKD.
6.
Subject has a known hemosiderosis, hemochromatosis, coagulation 
disorder, or hypercoagulable condition.
7.
Subject has chronic inflammatory disease that could impact 
erythropoiesis (e.g., systemic lupus erythematosus, rheumatoid 
arthritis, celiac disease) even if it is currently in remission.
8.
Subject is anticipated to have elective surgery that is expected to lead 
to significant blood loss or anticipated elective coronary 
revascularization.
9.
Subject has active or chronic gastrointestinal bleeding. 
10. Subject has received any prior treatment with roxadustat or a hypoxia-
inducible factor Prolyl Hydroxylase Inhibitor (HIF-PHI).
11. Subject has been treated with iron-chelating agents within 4 weeks 
prior to randomization.
12. Subject has a history of chronic liver disease (e.g., cirrhosis or fibrosis 
of the liver).
13. Subject has a known New York Heart Association Class III or IV 
congestive heart failure.

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14. Subject has had a myocardial infarction, acute coronary syndrome, 
stroke, seizure, or a thrombotic/thromboembolic event (e.g., pulmonary 
embolism) within 12 weeks prior to randomization.
15. Uncontrolled hypertension in the opinion of the investigator or two or 
more blood pressure values of systolic BP (SBP) ≥160 mmHg or 
diastolic BP (DPB) ≥95 mmHg confirmed by repeat measurement 
within 2 weeks prior to randomization. 
16. Subject has a diagnosis or suspicion (e.g., complex kidney cyst of 
Bosniak Category 2F or higher) of renal cell carcinoma on renal 
ultrasound within 12 weeks prior to randomization.
17. Subject has a history of malignancy, except the following: cancers 
determined to be cured or in remission for ≥5 years, curatively 
resected basal cell or squamous cell skin cancers, cervical cancer in 
situ, or resected colonic polyps.
18. Subject is positive for any of the following: Human Immunodeficiency 
Virus (HIV); hepatitis B surface antigen (HBsAg); or anti-hepatitis C 
virus antibody (anti-HCV Ab).
19. Subject has an active clinically significant infection manifested by 
White Blood Count (WBC) > ULN, and/or fever, in conjunction with 
clinical signs or symptoms of infection within one week prior to 
randomization. 
20. Subject has a known untreated proliferative diabetic retinopathy, 
diabetic macular edema, macular degeneration and retinal vein 
occlusion.
21. Subject has had any prior organ transplant (that has not been 
explanted), or a scheduled organ transplantation.
22. Subject has participated in any interventional clinical study or has been 
treated with any investigational drugs within 30 days or 5 half lives or 
limit set by national law, whichever is longer, prior to the initiation of 
Screening.  
23. Subject has an anticipated use of dapsone in any dose amount or
chronic use of acetaminophen (paracetamol) > 2.0 g/day during the 
treatment or follow-up period of the study.
24. Subject has a history of alcohol or drug abuse within 2 years prior to 
randomization.
25. Female subject
must agree not to breastfeed starting at screening or during the study 
period, and continued for 28 days after the final study treatment 
administration.
must not donate ova starting at screening and throughout the study 
period and continued for 28 days after final study drug 
administration.
26. Male subject
must not donate sperm starting at screening and throughout the 
study period and for 12 weeks after final study drug administration.
27. Any medical condition that in the opinion of the investigator may pose 
a safety risk to a subject in this study, which may confound efficacy or 
safety assessment, or may interfere with study participation.

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Discontinuation 
Criteria 
Subjects should be discontinued from study treatment for any of the 
following reasons:
Subject no longer consents to participate in the treatment period of the 
study.
Physician decision that it is in the best interest of the subject to be 
discontinued from the study treatment.
Significant noncompliance with study procedures, as determined by 
principal investigator and/or sponsor.
Pregnancy in a study subject.
Subject requires a third course of ESA rescue therapy.
Subject receives an organ transplant
If a subject has discontinued treatment prior to their projected week 104 the 
subject will complete the EOT visits (EOT visit and EOT + 2 weeks visit) 
and the EOS visit. Thereafter, this subject will continue to be followed up 
on a 6-monthly frequency for vital status and SAEs, cardiovascular and 
thromboembolic AEs until their projected date of completion (i.e.,
projected week 108 date) or, if earlier, until the last subject randomized 
reaches EOS, or until consent withdrawn.
Subjects should be withdrawn from the study for any of the following 
reasons:

Subject no longer consents to participate in the study. 

Subject is lost to follow-up despite reasonable efforts by the investigator 
to contact the subject.

Death of the study subject
The Sponsor may decide to prematurely stop the study, e.g., for safety 
considerations.
Test Drug Dose:
Mode of 
Administration:
Duration of 
Treatment:
Roxadustat (=ASP1517 / FG-4592)
Tablets for oral administration
Strengths of 20, 50 and 100 mg
Maximum of 104 weeks of treatment
Reference Therapy
Dose:
Mode of 
Administration:
Duration of 
Treatment:
Placebo
Tablets for oral administration matching the roxadustat tablets in 
appearance and size
Strengths of 20, 50 and 100 mg
Maximum of 104 weeks of treatment
Prohibited 
Medication 
The intake or administration of the following previous medication is 
prohibited:

Any ESA within 12 weeks prior to randomization.

IV iron (more than 1 dose) within 12 weeks prior to randomization.

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
RBC transfusion within 8 weeks prior to randomization.

Iron-chelating drugs within 4 weeks prior to randomization.

Any investigational drug within 30 days or 5 half-lives or limit set by 
national law (whichever is longer), prior to the initiation of Screening.
Roxadustat or another HIF-PHI at any time.
The following medications are prohibited during the period identified:

Iron-chelating agents (e.g., deferoxamine, deferiprone, or deferasirox
therapy) from 4 weeks prior to randomization until EOS visit.

Androgens from randomization until EOS visit.

Dapsone in any dose amount or chronic use of acetaminophen 
(paracetamol) > 2.0 g/day from randomization until EOS visit.
Any HIF-PHIother than roxadustat, as allocated by randomization, until 
EOS visit.
Rescue therapy guidelines (Section 5.5.5) are provided to optimize 
standardization of the use of rescue therapy by investigators and to ensure 
safety of the individual study subjects. Rescue medication or procedures 
include RBC transfusion, ESA, and IV iron.
Efficacy
There are 2 separate regionally based primary efficacy endpoints in this 
study depending upon whether the data are being filed to support 
submission to the US FDA or to Ex-US health authorities, such as the EMA.
The EU (EMA) primary efficacy endpoint is Hb response.
Hb response is defined as:

Hb 11.0 g/dL and a Hb increase from BL by 1.0 g/dL in any subject 
with BL Hb > 8.0 g/dL, OR 

an increase from BL by 2.0 g/dL in any subject with BL Hb ≤
8.0 g/dL
at 2 consecutive visits separated by at least 5 days during the first 24 weeks 
of treatment without rescue therapy (i.e., RBC transfusion, ESA, or IV iron) 
prior to Hb response.
The US (FDA) primary efficacy endpoint is the change in Hb from BL to 
the average level during the evaluation period (defined as Week 28 until 
Week 52) regardless of rescue therapy.
The key secondary efficacy endpoints in this study are:

Hb maintenance: Hb change from BL to the average Hb of weeks 28-
36, without having received rescue therapy within 6 weeks prior to and 
during this 8-week evaluation period.

Change from BL in low–density lipoprotein (LDL) cholesterol to the 
average value of LDL cholesterol in weeks 12-28.

Use and time to use of rescue therapy (composite of RBC transfusions, 
ESA use, and IV iron) in the first 24 weeks of treatment.

Change from BL in Short Form (SF)-36 Physical Functioning (PF) 
subscore to the average SF-36 PF subscore in weeks 12-28.

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
Change from BL in SF-36 Vitality (VT) subscore to the average SF-36 
VT subscore in weeks 12-28.

Blood pressure effect

Change from BL in Mean Arterial Pressure (MAP) to the 
average MAP in weeks 20-28.  

Occurrence, and time to occurrence of hypertension (defined as 
either SBP > 170 mmHg AND an increase from BL 
≥20 mmHg or as DBP > 110 mmHg, AND an increase from 
BL ≥15 mmHg). 
Additional secondary endpoints for assessment of efficacy include 
endpoints for Hb correction and maintenance, hospitalizations, rescue 
therapy use, change in cholesterol levels, BP effect, HRQoL, hepcidin, iron, 
hemoglobin A1c glycated hemoglobin (HbA1c) and rate of eGFR decline.
Safety
Safety will be assessed by evaluating the following:

Occurrence of AEs, SAEs, and clinically significant changes in 
laboratory values from BL.

Changes from BL in vital signs, electrocardiogram (ECG) findings, and 
clinical laboratory values.

Various region-specific pooled analyses of pre-specified adjudicated 
cardiovascular and cerebrovascular events (such as major 
cardiovascular adverse events [MACE; i.e., myocardial infarction, 
stroke, death from all causes], MACE+ [i.e., MACE, hospitalization for 
chronic heart failure, hospitalization for unstable angina] and other 
events) will be conducted; these analyses will be detailed in 
region-specific pooled safety analysis plans.
Statistical Methods
A total of 450-600 planned subjects will be randomized to receive 
roxadustat or placebo in a double-blind fashion in a 2:1 ratio. 
Sample Size
EU (EMA) 
Three hundred subjects for the roxadustat treatment group and 150 subjects 
for the placebo treatment group will provide > 95% test power to 
demonstrate a statistical significant difference between roxadustat and 
placebo in the EU (EMA) primary endpoint, assuming that the proportion of 
subjects with response in the roxadustat group is at least 65% and in the 
placebo group is at most 25%. 
USA (FDA)
A sample size of 450 will have > 99% power to detect a 1.0 g/dL difference 
in mean Hb values between the 2 treatment groups, assuming that the 
common standard deviation is 1.2 g/dL using an analysis of variance 
(ANOVA) test with a 0.05 2-sided significance level.
Most importantly, this sample size is required for a meta-analysis of pre-
specified cardiovascular and cerebrovascular events pooling studies. Four 
hundred and fifty subjects is the minimum number of subjects that will be 
randomized. In case this sample size is not sufficient to achieve the required 
number of pre-specified cardiovascular and cerebrovascular events, then the 
number of randomized subjects will be increased up to 600. The 
justification of the required number of events for this safety endpoint will be 
detailed in a pooled cardiovascular safety analysis plan.

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Analysis Sets
The following analysis sets are defined and will be used for the statistical 
analysis:

Full Analysis Set (FAS)

Per Protocol Set (PPS)

Safety Analysis Set (SAF)

Pharmacokinetic Analysis Set (PKAS).
Efficacy
EU (EMA)
The proportion of responders in the EU (EMA) primary efficacy endpoint 
will be compared using a Cochran–Mantel–Haenszel (CMH) test adjusting 
for the stratification factors comparing pooled roxadustat to pooled placebo. 
The EU (EMA) primary hypothesis to be tested for the primary efficacy 
analysis is:
H0: Hb responder rate in the roxadustat group = Hb responder rate in the 
Placebo group
versus
H1:  Hb responder rate in the roxadustat group ≠ Hb responder rate in the 
Placebo group.
H0 tested at the alpha = 0.05 level of significance and will be rejected if the 
P < 0.05 from the test.
The CMH adjusted odds ratio (pooled roxadustat versus pooled placebo) 
and its 95% confidence interval (CI) will be provided. In addition, a 95% CI 
will be calculated for the proportion of each roxadustat and placebo based 
on the exact method of Clopper-Pearson.
US (FDA)
The Hb change from BL to the average Hb of weeks 28-52 will be analyzed 
using a Mixed Model of Repeated Measurements (MMRM) with 
unstructured covariance matrix model. The model will contain terms for 
treatment arm, BL measurement, visit, visit x treatment arm, and other 
stratification factors.
The primary hypothesis to be tested for the US FDA primary efficacy 
analysis is:
H0: Hb mean change from BL to the average level from week 28 to week 
52 in the roxadustat group = Hb mean change from BL in the placebo 
group 
versus
H1: Hb mean change from BL to the average level of week 28 to week 52 in 
the roxadustat group ≠ Hb mean change from BL in the placebo group.

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Secondary
Once the primary hypothesis has been rejected for the EU (EMA) primary 
endpoint, the key secondary endpoints will be tested using a fixed sequence 
testing procedure as follows. 
1. Change from BL in Hb to the average Hb in weeks 28-36, without 
having received rescue therapy within 6 weeks prior to and during this 
8-week evaluation period (superiority of pooled roxadustat versus 
pooled placebo).
2. Change from BL in LDL cholesterol to the average value of LDL 
cholesterol in weeks 12-28 (superiority of pooled roxadustat versus 
pooled placebo).
3. Use and time to use of rescue therapy within the first 24 weeks of 
treatment (noninferiority of pooled roxadustat versus pooled placebo).
4. Change from BL in SF-36 PF subscore to the average SF-36 PF 
subscore in weeks 12–28 (superiority of pooled roxadustat versus 
pooled placebo) for all subjects and in the subgroup with BL PF 
subscore < 35.
5. Change from BL in SF-36 vitality subscore to the average SF-36 VT 
subscore in weeks 12–28 (superiority of pooled roxadustat versus 
pooled placebo) for all subjects and in the subgroup with BL vitality PF 
subscore < 50.
6. Change from BL in MAP to the average MAP in weeks 20–28 
(noninferiority of pooled roxadustat versus pooled placebo). 
7. Occurrence and time to occurrence of hypertension (noninferiority of 
pooled roxadustat versus pooled placebo).
Safety
Safety analyses will be performed using the Safety Analysis Set (SAF).  
Safety parameters include AEs, laboratory parameters (with special 
emphasis on excessive Hb response and Liver Function Tests (LFTs), vital 
signs, renal ultrasound findings and ECG parameters.  
The number and percentage of subjects reporting Treatment-Emergent 
Adverse Events (TEAEs) in each treatment group will be tabulated. 
Descriptive statistics will be presented for laboratory, vital signs values and 
ECG parameters by visit and for the changes from BL to each visit. 
The statistical method for analysis of the CSE pooling studies will be 
detailed in a pooled cardiovascular safety analysis plan.
Pharmacokinetics
Population pharmacokinetic data will be generated for roxadustat from a 
timed blood sampling scheme. All details of the PPK analysis will be 
described in a separate analysis plan and a separate PPK modeling report 
will be written.
Pharmacodynamics
Pharmacodynamic data may be submitted to population pharmacodynamic 
(PPD) or population pharmacokinetic/pharmacodynamic (PPK/PD) 
modeling. When deemed necessary, data from this study may be combined 
with data from other studies. Results will be reported in a separate PPK/PD 
modeling report.

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V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS
Figure 1
Flow Chart

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Table 1
Schedule of Assessments
Study Period:
Screening
Treatmenta
Follow-up
Post study 
Follow-up
Up to 6 Weeks
Day 1b
Weekly
(wks 1 to 2)
± 2 days
Every 2 Weeks
(wks 4 to 24) ± 2 days
Every 4 Weeks (wks 
28 to 100)  ± 3 days
EOT
(wk 104) 
± 3 days
EOT 
+ 2 wks
± 3 days
EOS
(EOT + 4 wks)
± 3 days
Unscheduled 
Visits
Every 6 months 
until projected 
wk 108
Visit / Week:
S1
S2
S3
Written informed consent
X
Randomization
X
Eligibility criteria
X
X
Demographics and medical history 
including tobacco use
X
Weight
X
X
wks 12, 24
wks 36, 52, 76
X
X
Oc
Physical examination
X
X
wks 12d 24d
wks 36d, 52d, 76d
X
Xc
Oc, d
Blood pressuree, heart ratee, respiratory 
rateg
X
X
X
X
X
X
X
X
X
Oc
CBC with WBC differential, red cell 
indices and platelet count
X
X
X 
wks 4, 8, 12, 20
wk 28 and every 
following 8 wks
X
X
Oc
Reticulocyte count, Hemoglobin content of 
reticulocytes (CHr)
X
X
X
wks 4, 6, 8, 12, 16, 20
wk 28 and every 
following 8 wks
X
X
Oc
Hemoglobinh
X
X
X
X
X
Oc
HemoCue® assessmenti
X
X
X
X
Oc
Serum chemistry (incl LFT)
X
X
wks 4, 8, 12, 20
wk 28 and every 
following 8 wks
X
X
X
Oc
LFTsj
wk 2
wks 6, 16
Oc
Serum Lipid panel (fasting whenever  
possible)
X
X
wks 4, 8, 12, 20
wks 28, 36, 44, 52, 68, 
84
X
X
Oc
Serum iron, ferritin, TIBC, TSAT
X
X
wks 4, 8, 12, 20
wk 28 and every 
following 8 wks
X
X
Oc
HbA1c
X
X
wk 12
wks 28, 36, 44, 60, 84
X
X
Oc
Vitamin B12, folate
X
HIV Immunoassay, HBsAg, anti-HCV 
antibody
X
Table continued on next page

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Study Period:
Screening
Treatmenta
Follow-up
Post study 
Follow-up
Up to 6 Weeks
Day 1b
Weekly
(wks 1 to 2)
± 2 days
Every 2 Weeks
(wks 4 to 24) ± 2 days
Every 4 Weeks (wks 
28 to 100)  ± 3 days
EOT
(wk 104) 
± 3 days
EOT 
+ 2 wks
± 3 days
EOS
(EOT + 4 wks)
± 3 days
Unscheduled 
Visits
Every 6 months 
until projected 
wk 108
Visit / Week:
S1
S2
S3
Serum Pregnancy testk
X
wks 12, 24
wks 36, 48, 60, 72, 84, 
96
X
Oc
eGFR (Cr Clear Modified Diet 
Abbreviated)l
X
X
wk 20
wks 36, 52, 68, 84
X
X
Oc
Special laboratory analytes (hepcidin, 
sTfR, hs-CRP)
X
wks 4, 12, 20
wks 36, 52
X
X
Archival serum/plasma samples for 
biomarkers
X
wks 4, 12, 20
wks 52, 76
X
X
Blood sample for population 
pharmacokinetics
wks 2 to 8m
Genotypingn
X
Urinary testingo
X
wks 12, 24
wks 36, 52, 64, 76, 88
X
Oc
Quality of Life Questionnairesp
X
wks 8, 12
wks 28, 36, 52, 76
X
Oc
12-lead ECG
X
X
wks 12, 24
wks 36, 52, 76
X
Oc
Renal ultrasoundq
X
Oc
Dose adjustment reviewr
X
X
Oc
Hospitalization recordings
X
X
X
X
X
X
X
X
X
X
X
X
Adverse event recording
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication recording
X
X
X
X
X
X
X
X
X
X
X
Procedure and non-drug therapy recording
X
X
X
X
X
X
X
X
X
X
X
Study drug dispensingt
Xu
X
X
X
Oc
Vital Status, SAEs, cardiovascular and 
thromboembolic AEs 
X
AE: adverse events; CBC: complete blood count; CHr: hemoglobin content of reticulocytes; Cr: creatinine; ECG: electrocardiogram; eGFR: estimated glomerular filtration rate; EOT:
End of Treatment; EOS: End of Study; HbA1c: hemoglobin A1c glycated hemoglobin; HBsAg: hepatitis B surface antigen; HCV: hepatitis C virus; HIV: Human Immunodeficiency 
Virus; hs-CRP: high sensitivity C-reactive protein; LFT: liver function test; O: optional test/assessment (see below for footnotes); S1/S2/S3: screening visit 1, 2 and 3; SAE: serious 
adverse event; sTfR: soluble transferrin receptor; TIBC: total iron binding capacity; TSAT: Transferrin Saturation (also known as FeSAT, iron saturation); WBC: white blood cell; 
wk(s): week(s); X: mandatory test/assessment.
Note:  see Appendix 3   Instructions for Subjects Moving from Protocol v1.0 to Protocol v2.0
Note:  see Appendix 4:  Instructions for Subjects Requiring Dialysis
Table footnotes continued on next page

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a In case of premature discontinuation or withdrawal during the treatment period, the subject should complete the EOT visits (EOT visit and EOT + 2 weeks visit) and the EOS visit.
Thereafter, this subject will continue to be followed up at a 6-monthly frequency for vital status and SAEs, cardiovascular and thromboembolic AEs until their projected date of 
completion (i.e., projected week 108 date) or, if earlier, until the last subject randomized reaches EOS, or until consent is withdrawn.
b All study assessments to be performed prior to first study drug administration
c The study drug dosing is to be reviewed and if needed new or additional study drug is to be dispensed.
d Targeted physical examination only (e.g., respiratory and cardiovascular).
e Blood pressure (BP) measured singly during the screening period, and in triplicate at all other visits. It is recommended during the treatment period, BP measurement should occur 
prior to study drug administration if study medication is taken on same day of visit; except for visits where subjects are instructed to take study medication at home for 
pharmacokinetic sampling purpose. For subjects requiring dialysis, BP will be recorded prior to, and after dialysis (hemodialysis [HD]/hemodiafiltration [HDF] subjects only).   
f Heart rate (HR) measured singly during the screening period, and in triplicate at all other visits. It is recommended during the treatment period, HR measurement should occur prior to 
study drug administration if study medication is taken on the same day of visit; except for visits where subjects are instructed to take study medication at home for pharmacokinetic
sampling purposes.  For subjects requiring dialysis, HR will be recorded prior to, and after dialysis (HD/HDF subjects only).
g Respiratory rate measured singly during all visits.  It is recommended during the treatment period, respiratory rate measurement should occur prior to study drug administration 
except for visits where subjects are instructed to take study medication at home for pharmacokinetic sampling purposes. For subjects requiring dialysis, respiratory rate will be 
recorded prior to dialysis (HD/HDF subjects only).
h Hemoglobin (Hb) should be collected at all the visits where CBC is not collected.
i If during an unscheduled visit Hb needs to be assessed, this should always be done with the HemoCue AND central laboratory Hb assessment. Hb will be assessed by HemoCue on 
the blood sample collected for central laboratory Hb assessment.
j Liver Function Tests (LFTs) to be collected at visits where full Serum Chemistry is not collected 
k Collect from female subjects of child bearing potential only.
l Calculated by the Central Laboratory 
m Sampling roxadustat will be done at 6 time points over 1 to 3 visits (see Section 5.6).  At each pharmacokinetic visit, an additional sample will be collected for albumin and alpha-
acid glycoprotein determination.
n Optional assessment.  A separate informed consent form must be signed before a genotyping sample is collected.  Sample collection can be done at any timepoint throughout the 
treatment period of the study.
o Ideally, the sample should be from the first morning void. Urinary testing includes qualitative testing with dipstick testing (for protein, pH, glucose) and quantitative assessment of 
albumin and Cr for calculation of albumin/Cr ratio. At day 1, weeks 24, 52 and 76 and EOT a urine sample will be archived for potential future biomarker analysis.
p The Quality of Life (QoL) Questionnaires used are SF-36, FACT-An, EQ-5D 5L, PGIC and WPAI:ANS. The PGIC questionnaire is not completed at day 1. Questionnaires are to be 
completed by the subject preferably prior to any study assessments. When subjects need dialysis therapy, QoL questionnaires will be completed on the day of first dialysis (preferably 
before the dialysis is started), 4 weeks later and 12 weeks later.
q Renal ultrasound examination within 12 weeks of randomization. Not required if result of a previous renal ultrasound (or other imaging modality such as CT scan or magnetic 
resonance imaging [MRI]) within 12 weeks prior to randomization is available and rules out renal cell carcinoma.  If other imaging modality, a conclusive report on the kidney should 
be available.
Table footnotes continued on next page

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r Dose adjustment review from week 4 onward, and every 4 weeks thereafter until EOT (except in the event of excessive hematopoiesis or Hb ≥13.0 g/dL).  If next dose adjustment 
interval falls on a non-visit study week, the dose adjustment review should be performed at the next scheduled visit.
s Telephone or in-person follow-up call with subject
t For subjects requiring dialysis, it is recommended for HD/HDF subjects that study drug is administered any time after completion of dialysis (if dosing is scheduled on a dialysis day).
u Intake of initial study drug on day of randomization.

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1
INTRODUCTION
1.1
Background
1.1.1
Epidemiology of Chronic Kidney Disease and End Stage Renal Disease
Chronic Kidney Disease (CKD) is a growing worldwide public health challenge associated 
with significant morbidity and mortality, yet it is under-diagnosed and under-treated.  It is 
characterized by progressive loss of kidney function, ultimately resulting in premature death 
or renal replacement therapy (RRT) (kidney transplant or dialysis).  In 2007, CKD affected 
13% of the US adult population (approximately 29 million U.S. adults) and its prevalence is 
growing rapidly [Coresh et al, 2007]. In Europe, the average prevalence of CKD regardless 
of age lies between 5 and 11% [Zoccali et al, 2010]. All-cause mortality risk increases 
exponentially as CKD stages advance [Tonelli et al, 2006]. 
The number of patients suffering from End Stage Renal Disease (ESRD) also continues to 
increase worldwide.  The US has 1 of the highest prevalence rates of ESRD in the world: in 
2010, the US had over 1700 ESRD patients per million population, a 23% increase compared 
to 10 years prior (United States Renal Data System (USRDS), 2011).  In 2009 (point 
prevalence Dec 31), there were approximately 570,000 ESRD patients in the US, of whom 
370,000 were receiving hemodialysis (HD), 27,000 were receiving peritoneal dialysis, and 
173,000 had a functioning kidney transplant (USRDS, 2011). In Europe, over the period 
1992–2005, the overall crude prevalence of RRT for ESRD increased from 480 to 807 
patients per million population [Zoccali et al, 2010].
The average expected remaining lifetime of a dialysis patient in the US is 5.9 years, 
compared to 16.4 years for a transplant patient, and 25.2 years for someone of comparable 
age in the general population (USRDS, 2009).  The prevalence of ESRD is projected to grow 
to 774,000 by the year 2020 (USRDS, 2009). Data from selected countries in Europe indicate 
that the 5-year mortality rates in incident RRT patients are 52% in all patients, and 21%, 32% 
and 73% for patients 0 to 14, 15 to 64 and over 65 years of age, respectively [Zoccali et al, 
2010].
1.1.2
Anemia Associated with CKD
Anemia is a common complication in patients with CKD, and although its pathogenesis is 
multi-factorial, the decreased production of erythropoietin (EPO), a hormone produced 
primarily in the kidneys, is considered an important etiologic factor.  The impaired ability of 
the body to absorb and utilize iron is likely another etiologic factor.  
Anemia is first seen in early stages of CKD, and its prevalence increases as CKD progresses.  
Anemia is present in 17% of patients with late Stage 3 CKD; this increases to 25% in patients 
with Stage 4 CKD, and 49% in patients with Stage 5 CKD who have not yet progressed to 
requiring dialysis [Coresh et al, 2007; Go et al, 2004).  Over 90% of patients undergoing 
dialysis are anemic. Half of new dialysis patients (50.1%) had hemoglobin (Hb) levels below 
10 g/dL and approximately 28 % had Hb below 9 g/dL [USRDS, 2003]. Some studies from 
Europe provide data on anemia rates in patients who have been under care of nephrologists. In 

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1999 Jungers prospectively studied 403 consecutive ambulatory pre-dialysis patients and found 
that 60% of patients with a creatinine (Cr) clearance of < 20 mL/min/1.73 m2 were anemic (Hb 
< 11 g/dL) [Jungers et al, 2002]. Between 2003 and 2005, Thilly studied pre-dialysis anemia
care in 6271 incident dialysis patients. The average level of pre-dialysis Hb was 10.3 g/dl and 
63.6% of the patients had a Hb value lower than 11 g/dl [Thilly et al, 2008].
The clinical consequences of anemia in patients with CKD have been studied extensively.  
Because the main impact of anemia on organ function is reduced oxygen delivery to tissues, 
it affects almost every organ system.  
Anemia contributes to the excess morbidity and mortality in CKD and ESRD.  In patients 
with CKD, the severity of anemia correlates directly with the risk of hospitalization, 
cardiovascular disease, and death [Collins et al, 1998]. Patients with the lowest Hb have 
worse outcomes, as was discussed in the post hoc analysis of mortality by Hb quintiles for 
the Normal Hematocrit and Correction of Hemoglobin and Outcomes in Renal Insufficiency 
studies in the FDA briefing document for the October 2007 Cardiovascular and Renal 
Advisory Committee [Unger, 2007]. Similar data are found in the USRDS mortality data 
stratified by Hb. All-cause mortality stratified by Hb (1993–1996) showed significantly 
higher first-year death rates in patients with Hb levels < 9 and 9 to < 10 g/dL, compared to 
11 to < 12 g/dL. This trend continued to worsen, as reflected in 1998–1999 data, where the 
death rate rose by approximately 75% compared to the 1993–1996 period [USRDS, 2000;
USRDS, 2002]. This increase coincides with the introduction of the Kidney Disease 
Outcomes Quality Initiative (KDOQI) guidelines in 1997. The relative risk of all-cause
mortality for patients with Hb < 9 g/dL is twice that of patients with Hb > 12 g/dL [USRDS, 
2002]. The relative risk of cardiovascular hospitalization increased significantly to 1.26 in 
patients with Hb levels < 9 g/dL compared to those with Hb at 11 to 12 g/dL [USRDS, 2001].
Multiple studies have shown that treatment of anemia reduces blood transfusions and 
improves health-related quality of life (HRQoL) [NKF KDOQI, 2007]. 
1.1.3
Treatment of Anemia
In less severe anemia first-line therapy consists of iron monotherapy (oral or IV). However,
therapy with erythropoiesis-stimulating agents (ESAs) in combination with iron 
supplementation is a major alternative to transfusion in managing more severe anemia 
associated with CKD.  Anemic patients with CKD or ESRD will require life-long treatment. 
For those patients not resistant to ESAs, parenteral administration of exogenous recombinant 
human EPO (epoetin alfa or beta) or pegylated analogues has been a widely accepted 
approach for treatment of anemia in patients with CKD [Eschbach et al, 1987; Eschbach et al, 
1989; Winearls et al, 1986], despite the documented safety risks such as hypertension and 
thrombosis.  

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Although the treatment of anemia in CKD and ESRD is thought to contribute positively to a 
patient’s quality of life (QoL), functional well-being and physical performance, several 
studies in ESRD and CKD non-dialysis patients have shown higher mortality or trends in that 
direction in the higher-dosed ESA-treated cohorts when the protocol objective was to treat to
high target Hb levels [Besarab et al, 1998; Drueke et al, 2006; Singh et al, 2006].  
An ESA dose relationship to mortality has been reported in a review of the USRDS database 
[Zhang et al, 2004] of ESRD patients who received higher ESA doses. A treatment option 
that avoids supraphysiologic levels of circulating plasma EPO levels may be a safer 
alternative. Additionally, ESA therapy for anemia in ESRD patients on HD usually requires 
concomitant IV iron supplementation. 
There is currently an unmet medical need for an oral treatment that will correct anemia in 
CKD non-dialysis and dialysis patients to a target Hb level that is safe and well tolerated.  
Roxadustat is an oral medication that could potentially deliver effective treatment for 
CKD-related anemia with less need for iron supplementation and without producing 
supraphysiologic levels of circulating EPO. 
1.2
Non-clinical and Clinical Data
1.2.1
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 2]. Hypoxia-inducible factor (HIF) is a transcription factor that is believed 
to be the key element in the body’s oxygen sensing mechanism [Semenza, 2000]. HIF 
regulates expression of genes that modulate both the acute and chronic response to hypoxia, 
and HIF-responsive genes regulate processes as diverse as erythropoiesis, iron metabolism, 
oxidation, cellular metabolism, glycolysis, vasculogenesis, cell cycle progression, and 
apoptosis. Chronic hypoxia and intermittent hypoxia induce different sets of genes associated 
with HIF transcriptional activity [Fan et al, 2005]. HIF is a heterodimeric transcription factor 
family comprising 3 oxygen-sensitive isoforms (HIF-1, HIF-2and HIF-3), and a 
constitutively expressed HIF-1subunit, with each heterodimeric isoform responsible for the 
induction of specific sets of genes [Greijer et al, 2005; Hu et al, 2003].  For example, HIF-1
has been shown to regulate vascular endothelial growth factor  expression [Gray et al, 2005;
Buchler et al, 2003], while HIF-2is critical for the induction of the EPO gene and 
erythropoiesis [Warnecke et al, 2004; Scortegagna et al, 2005].

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Figure 2
HIF-PHI Mechanism of Action
Source: Epstein, et al.  Cell, 2001 Oct 5; 107(1)
HIF target genes are expressed when the active heterodimer binds to a conserved 
deoxyribonucleic acid (DNA) motif found within all HIF target genes, termed the hypoxia 
response element, and in cooperation with other 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-isoforms are constitutively produced, their accumulation under normoxic 
conditions is prevented by recruitment and binding by the Von Hippel-Lindau protein, which 
targets HIF-isoforms for degradation through the ubiquitin-proteasome pathway. The 
molecular mechanism for oxygen-dependent degradation of HIF-is based on the 
hydroxylation of specific proline residues, as catalyzed by a family of HIF prolyl 
hydroxylases (HIF-PH) that utilize molecular oxygen as the substrate for hydroxylation. 
Thus, HIF-PH constitutes the body’s main oxygen sensor by regulating the prevalence and 
activity of nuclear HIF protein. Under hypoxic conditions, HIF-PHs are inactive and lead to 
initiation of the HIF-responsive transcriptional cascade [Wang et al, 1995; Semenza, 1998].  
Roxadustat is a potent and reversible HIF-PH inhibitor 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 [Peyssonnaux et al, 2008]. Thus, roxadustat pharmacologically 
stimulates erythropoiesis via the HIF pathway and in a manner consistent with the body’s 
normal homeostatic response to anemia, but under normoxic conditions.

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Roxadustat also has the potential to effectively treat anemias caused by inflammation-
induced functional iron deficiency, which are typically hyporesponsive to ESAs. In these 
conditions, iron availability for erythropoiesis is reduced due to a number of inflammatory 
mediators.  Because HIF-PH inhibitors such as roxadustat alter expression not only of the 
EPO gene but also of genes regulating iron metabolism, it is postulated that roxadustat may 
be effective in treating these anemias as well [Langsetmo et al, 2005].
Chronic hypoxia and intermittent hypoxia induce different sets of genes associated with HIF 
transcriptional activity, presumably because intermittent stimulation allows the restoration of 
HIF degradation, turnover, and inactivation. Transient activation of HIF thereby precludes 
sustained gene expression and the induction of genes that are expressed late after HIF 
activation, as well as expression of additional genes that are secondary to activation of 
HIF-dependent genes. Both non-clinical and clinical studies of roxadustat have successfully 
used the intermittent dosing paradigm to induce selective erythropoiesis and to optimize the 
Hb dose response. Furthermore, roxadustat was selected for development over other HIF-PH-
inhibiting candidate molecules based on an optimal biodistribution profile that enhances its 
selective actions. The specific tissues where roxadustat enters the cytoplasm and triggers 
gene expression reside in the main target organs for erythropoiesis: the kidney (EPO 
production), the bone marrow (increase in EPO receptors), the duodenum (transepithelial iron 
transport), and the liver (EPO production and down-regulation of hepcidin production); 
roxadustat distributes preferentially to these organs.
1.2.2
Clinical Experience with Roxadustat
Roxadustat is currently being studied in dialysis and non dialysis CKD subjects with anemia. 
Numerous Phase 1 and 2 clinical studies have been completed, in the United States, Europe, 
and Asia. Information from these studies is provided in the Investigator’s Brochure. As of 
14 September 2014, an estimated total of 1,485 subjects have been exposed to roxadustat in 
the clinical development program, comprising 571 healthy subjects and an estimated 
483 subjects with non dialysis-dependent chronic kidney disease (NDD-CKD) and 
431 subjects with dialysis-dependent chronic kidney disease (DD-CKD). In completed 
studies, subjects with CKD have received up to 24 weeks of roxadustat, in doses of up to 
3.0 mg/kg. In completed Phase 1 studies, healthy subjects received single doses of roxadustat 
up to 4.0 mg/kg and repeat doses up to 3.75 mg/kg 3 times a week for 4 weeks. In a 
completed thorough QT study in healthy subjects, single doses up to 5 mg/kg were 
administered, without evidence of QT prolongation. The clinical data collected thus far 
suggest that roxadustat is generally safe and well tolerated in healthy adult subjects, and in 
DD-CKD and NDD-CKD subjects with anemia who have been treated in the completed and 
ongoing studies.
1.2.2.1 Pharmacokinetics and Pharmacodynamics
The pharmacokinetics and pharmacodynamics of roxadustat were characterized in studies in 
healthy subjects and in dialysis and non-dialysis CKD patients.  Roxadustat showed generally 
dose proportional pharmacokinetics (except at the lowest dose of 0.3 mg/kg); t1/2 was 12 to 

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14 hours in healthy subjects, and 15 to 19 hours in dialysis patients (after single doses of 
1 and 2 mg/kg). The exposure was higher in dialysis patients compared to healthy subjects.
With an intermittent dose regimen once per week (QW), twice per week (BIW) or 3 times per 
week (TIW), no or limited accumulation in mean area under the plasma concentration or Cmax
was observed. Furthermore no evidence was found for time-dependent pharmacokinetics (no 
auto-induction or inhibition). Roxadustat is highly protein bound and the pharmacokinetics
of roxadustat is not affected by dialysis. Metabolites found in urine suggested phase 2 
metabolism as the major metabolic pathway. In plasma, parent roxadustat is the main 
component. The inhibitory potential of roxadustat on cytochrome P450 (CYP) enzymes, 
based on in vitro studies is limited, and the lowest inhibition constant value was observed for 
CYP 2C8 (16 μM). In a clinical drug-drug interaction study with rosiglitazone, a probe drug 
for CYP 2C8, roxadustat did not show any inhibitory potential on CYP 2C8 in vivo.
Additional drug-drug interaction studies were performed with statins and phosphate binders. 
Roxadustat increases the AUCinf of simvastatin 1.9-fold, of rosuvastatin 2.9-fold and of 
atorvastatin 2.0-fold. The AUCinf of roxadustat is decreased 2.9-fold and 1.8-fold 
respectively by simultaneous administration with the phosphate-binders sevelamer carbonate 
and calcium acetate. Administration of roxadustat at least 1 hour before or 1 hour after the 
phosphate binder minimized the interactions.
In healthy adult male subjects (Study 
), roxadustat administered orally as 
a single dose up to 4.0 mg/kg, and QW, BIW, or TIW for 4 weeks at doses up to 3.75 mg/kg, 
was pharmacodynamically active as evidenced by dose-dependent transient increases in 
endogenous EPO (starting from single doses of 0.3 mg/kg), increases in reticulocytes 
(starting from doses of 2 mg/kg), and Hb responses (starting at 3 mg/kg).  The mean peak 
level of plasma EPO following the day 26 dose of 2.0 mg/kg TIW (the high therapeutic dose 
studied) was 326.3 ± 197.0 mIU/mL.
In pharmacodynamic studies conducted with roxadustat in CKD patients not on dialysis 
(Study 
), the mean maximum EPO increase from baseline (BL) ranged from 
82-443 and 492-554 mIU/mL after a single 1 and 2 mg/kg dose, respectively. In dialysis 
patients (Study
), comparable dose-dependent increases in EPO levels were 
observed, both pre-dialysis and post-dialysis. These increases in endogenous EPO were 
transient and the effect disappeared within approximately 48 hours.
In contrast, EPO levels associated with therapeutic ESA dosing range from 1,500 to over 
10,000 mIU/mL [Besarab et al, 2009]. In a clinical study with dialysis patients, the reported 
mean administered individual ESA dose was 8,000 IU, which would correspond to plasma 
EPO Cmax levels exceeding 3,000 mIU/mL [Fishbane & Besarab 2007]. This is 
approximately 10-fold higher than the physiologic range. 
1.2.2.2 Efficacy
Data from a 4-week treatment study in anemic CKD patients not on dialysis (Study 
) showed that roxadustat promoted erythropoiesis at lower doses in CKD 
patients than in healthy subjects. In contrast to the classical paradigm suggesting that anemia 

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in CKD patients is caused by the inability of these patients to produce EPO, the results of this 
study suggest that the EPO production in this patient population is sufficient to achieve a 
robust erythropoiesis. With roxadustat 0.7 mg/kg TIW dosing, mean maximum Hb increased 
by 1.0 g/dL over a 6-week period in anemic CKD patients who completed 4 weeks of dosing; 
more robust mean Hb increases of 2.0 to 2.3 g/dL occurred at roxadustat doses of 1.5 and 
2.0 mg/kg TIW, respectively. Hb responder (Hb increase of ≥1.0 g/dL) rates were 62%, 
60%, 91%, and 100% in the roxadustat0.7, 1.0, 1.5, and 2.0 mg/kg TIW cohorts, respectively.  
The Hb responses were also robust at the higher roxadustat doses (1.5 to 2.0 mg/kg) in the 
BIW dosing groups.  With the additional criterion that Hb achieve a level of ≥11.0 g/dL as 
well as increasing by ≥1.0 g/dL, the Hb responder rate with roxadustat2.0 mg/kg was 89% 
and 91% in BIW and TIW dosing, respectively.  The rapid rates of rise in Hb with roxadustat
treatment were not accompanied by elevations in blood pressure (BP), as has been reported 
with ESA treatment [Eschbach et al, 1989].
Data from a 16- to 24-week treatment study in CKD patients not on dialysis (Study FGCL-
4592-041) showed absolute and weight-based doses of roxadustat, administered TIW and 
BIW, effectively corrected Hb levels in these patients. For cohorts that have completed 
treatment, corrected Hb levels were maintained within target range for the 16- or 24-week 
treatment period. The median time to Hb response was 28 days for subjects who received 
adequate weight-based or absolute starting doses of roxadustat and longer for those who 
received a lower absolute starting dose.  Dose-response trends suggested that starting doses 
of 1.0−1.6 mg/kg roxadustat administered TIW are appropriate to correct Hb levels during 
4 weeks of treatment in non-dialysis CKD patients. Dosing frequency reduction, once Hb 
correction is achieved, appears to be feasible to maintain Hb in the target range.
Data from a 6- and 19-week treatment study in ESRD patients on dialysis showed the 
feasibility of converting patients from a stable ESA dose to roxadustat (Study 
FGCL-4592-040).  In the 6-week dose range portion of this conversion study (during which 
roxadustat doses were mostly fixed upon switching from stable doses of epoetin alfa), dose 
response was observed.  The 1.0 mg/kg roxadustat dose was comparable to the epoetin alfa 
control, which had a small decline in Hb levels from BL and a lower percent Hb responder 
rate compared to the higher doses of roxadustat. The 1.5 and 2.0 mg/kg roxadustat dose arms 
resulted in a Hb increase of about 1 g/dL from BL and an 89% response rate, more than 
double that of the epoetin alfa arm, despite the absence of IV iron supplementation.  
Regression slope analyses of Hb values over time showed that the estimated rate of Hb rise 
was positive and statistically significant for the 1.5 and 2.0 mg/kg dose cohorts, with a Hb 
increase of 0.22 g/dL (p=0.0040) and 0.18 g/dL (p=0.0146) per week, respectively. In the 
19-week portion of the study, during which dose-titration was allowed, Hb maintenance was 
demonstrated to be durable in roxadustat treatment arms (combined) over a 19-week period.  
For further information refer to the most recent version of the Investigator’s brochure.

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1.2.2.3 Summary
In summary, roxadustat is an orally active HIF-PH inhibitor with potent erythropoietic 
effects.  Repeated intermittent dosing of roxadustat results in intermittent activation of HIF, 
intermittent induction of endogenous EPO and a dose-dependent erythropoiesis. The clinical 
data collected thus far suggest that roxadustat is generally safe and well tolerated in healthy 
adult subjects, and in dialysis and non-dialysis CKD patients with anemia who have been 
enrolled and treated in completed and ongoing clinical studies. Roxadustat leads to a robust 
dose-related erythropoietic response in patients with CKD-associated anemia. Roxadustat
dosing induces a transient elevation in endogenous EPO level that is close to the physiologic 
range, but much lower than the plasma EPO level associated with IV ESA dosing, suggesting 
a coordinated erythropoiesis mechanism that is different from that of ESA therapy.
1.3
Summary of Key Safety Information for Study Drugs
The overall frequency and type of treatment-emergent adverse events (TEAEs) and serious 
adverse events (SAEs) observed in the clinical studies conducted with roxadustat reflect
events that would be expected to occur in CKD patients. The most commonly reported 
adverse events (AEs) in healthy subjects were headache, pharyngolaryngeal pain, and nasal 
congestion. The most commonly reported AEs (> 5%) in CKD patients not on dialysis were 
diarrhea, nausea, urinary tract infection, nasopharyngitis, peripheral edema, hyperkalemia, 
headache, and hypertension. The most commonly reported AEs (> 3%) in CKD patients on 
dialysis were diarrhea, nausea, hypertension, and upper respiratory tract infection.  The only 
expected non-serious adverse drug reaction is heart rate (HR) increase.
Safety analyses did not reveal any association between the rates of occurrence of 
cardiovascular events with roxadustat, or any effect on adverse event rates related to either 
increasing Hb levels or on the rate of change of Hb levels. 
AEs commonly reported with ESA use have been reported at lower rates such as 
hypertension (1% in Study 
, and 6.9% in Study FGCL-4592-041) and 
thrombosis (overall incidence < 1 %). No increased cancer risk has been noted with 
roxadustat treatment. However, the study program was not powered to detect absence of 
cancer risk.
Liver enzymes were monitored closely throughout the phase 2 roxadustat clinical 
development program. Increases in liver enzymes were infrequently seen, and were generally 
mild and transient in nature. No case of Hy’s Law was observed throughout the program.  An 
independent data and safety monitoring committee concluded that there was no concern for 
hepatotoxicity with roxadustat.
A number of pancreatitis events were noted during the phase 2 roxadustat clinical 
development program, the majority of which have been associated with gallstones or biliary 
sludge; one of which was due to a pancreatic duct stricture, and another case had multiple 
risk factors for pancreatitis. Only 1 of the pancreatitis cases was considered as possibly 
related by the investigator. Amylase levels were routinely measured in the FGCL-4592-040 

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study and mean levels were not found to be elevated during the course of the study. A higher 
incidence of pancreatitis in patients with type 2 diabetes mellitus, and CKD, has been well 
described in the literature.
For further information refer to the most recent version of the Investigator’s Brochure.
1.4
Risk-Benefit Assessment
Based upon the results of the studies described above the benefit of roxadustat is the 
correction of anemia and relief of signs and symptoms of anemia resulting in an increased 
QoL, improved physical functioning and performance. Treatment with roxadustat triggers a 
pharmacodynamic response which translates into correction of anemic Hb levels and 
maintenance of these corrected Hb levels.
Patients treated with placebo may be at risk of achieving insufficient efficacy as expressed by 
Hb levels not improving significantly or worsening as compared to BL. As a result they may 
have no improvement in QoL, impairment of physical functioning and performance. 
An established dose adjustment algorithm, very similar to the one used in phase 2, will be 
used during the study to titrate roxadustat doses to enable patients to achieve and maintain 
Hb levels within target range, while allowing investigators to closely monitor the rate of rise 
of Hb levels.  Roxadustat doses may be held and/or the use of therapeutic phlebotomy is 
allowed in the event of excessive hematopoiesis. In case of insufficient response to study 
drug (placebo or roxadustat) rules for the use of rescue medication/procedures such as IV 
iron, ESAs or red blood cell transfusion are in place in order to assure safety of the affected
study subjects. 
In pharmacokinetic studies there was no evidence of drug accumulation with the proposed 
clinical regimen of up to 3 times weekly dosing. The overall frequency and nature of AEs 
and SAEs observed in clinical studies thus far generally reflect events what would be 
expected to occur in the dialysis and non-dialysis CKD patient populations, and did not 
reveal any particular safety concern.
A drug interaction with statins is a potential risk. To mitigate this risk, recommendations for 
maximum statin doses are included in the study protocol. There is a potential risk that the 
drug interaction between phosphate-binders and roxadustat could decrease the efficacy of 
roxadustat, which will be mitigated by Hb-based dose adjustments. There is also a potential 
risk that a subject who suddenly discontinues or decreases the dose of a phosphate binder 
might be exposed to increased concentrations of roxadustat, although there are no data 
evaluating this potential effect. Although drug interaction of roxadustat with phosphate 
binders is an identified effect, it is unclear whether this interaction poses a true risk to 
subjects since the pharmacokinetics of discontinuing phosphate binder or changing the 
phosphate binder dose has not been investigated. Subjects who suddenly discontinue or 
decrease the dose of a phosphate-binder are advised to discuss changes in their use of 
phosphate binders with the investigator. As a further risk mitigation, this study protocol 
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The safety of treatment with roxadustat and placebo in this study will be carefully monitored 
including AEs and serious adverse events (SAEs), and laboratory parameters including 
electrolytes, liver enzymes, and iron indices. Emphasis will be placed on cardiovascular and
cerebrovascular events, which are not uncommon in the study population; an independent 
expert panel will assess and adjudicate all significant occurrences of such events.  In 
addition, an independent Data Safety Monitoring Board (DSMB) will perform regular, 
periodic assessments of blinded and unblinded data to detect any potential safety signals that 
may arise during the study and advise the sponsor accordingly. 
Based on the clinical and non-clinical experimental results to date, it can be expected that the 
orally administered roxadustat will be efficacious and safe in the treatment of anemia of 
CKD. The risk mitigation measures applied in this protocol are deemed to sufficiently assure 
that major risks for the patient can be avoided. The benefit-risk for the participation of 
patients in this study is therefore considered to be acceptable.
2
STUDY OBJECTIVE(S), DESIGN AND ENDPOINTS
2.1
Study Objectives
2.1.1
Primary Objective
The primary objective of this study is to evaluate the efficacy of roxadustat in the treatment 
of anemia in non-dialysis CKD subjects.
2.1.2
Secondary Objectives
The secondary objectives in this study are to:
●
Evaluate the safety of roxadustat in the treatment of anemia in non-dialysis CKD 
subjects.
●
Evaluate HRQoL benefit of roxadustat treatment in subjects with CKD anemia.
●
Evaluate the need for anemia rescue therapy with roxadustat in subjects with CKD 
anemia: RBC transfusion, ESA, or IV iron.
2.2
Study Design and Dose Rationale
2.2.1
Study Design
2.2.1.1 General
This is a phase 3, multi-center, randomized, double-blind, placebo controlled study in anemic 
subjects with Stage 3, 4 or 5 CKD who are not on dialysis. This study is planned to recruit 
subjects from approximately 200 study centers, globally.
The study is planned to provide key efficacy and safety data for the approval of roxadustat in 
the treatment of anemia associated with CKD. Another study with similar design will be 
conducted by FibroGen Inc, in study centers across North America, Latin America and Asia 
Pacific.

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2.2.1.2 Study Population
The study population consists of subjects with CKD stages 3, 4, and 5 (estimated glomerular 
filtration rate [eGFR] < 60 mL/min/1.73 m2) who are anemic and not receiving dialysis. Anemia 
is defined by mean Hb ≤10.0 g/dL upon repeated screening measurements. Subjects do not need 
to be iron replete at BL; inclusion is permitted if ferritin ≥30 ng/mL (≥ 67.4 pmol/L) and 
Transferrin Saturation (TSAT) ≥ 5%. Anemia of non-renal origin is to be excluded. Washout 
periods of at least 12 weeks for any prior ESA or IV iron treatment or at least 8 weeks for any 
RBC transfusion prior to randomization have been mandated in order to exclude a potential 
impact of these extraneous anemia treatments on the assessment of efficacy.
2.2.1.3 Description of Study
Subjects will take roxadustat or placebo orally as a combination of tablets of different 
strengths. All tablets for subjects receiving roxadustat will contain active ingredient whereas 
all tablets for subjects receiving placebo will contain just placebo. The study will consist of 
3 study periods as follows:
●
Screening period: up to 6 weeks.
●
Treatment period: minimum 52 weeks (primary treatment period) up to a maximum of 
104 weeks (extended treatment period) or until the last subject randomized to treatment 
has completed 40 weeks of treatment (or at the forecasted week 40 date if this subject 
discontinues treatment early). Treatment period for last patient randomized is 52 weeks.
●
Post-treatment follow-up period: 4 weeks.
Refer to the study schema in [Figure 1].
Subjects that have discontinued treatment prior to their projected week 104 will continue to 
be followed for vital status and SAEs, cardiovascular and thromboembolic AEs in post study 
follow up.
2.2.1.3.1
Screening Period
During the screening period, subjects’ eligibility for study participation will be assessed.
2.2.1.3.2
Treatment Period
After subjects have been confirmed eligible for study participation, they will be randomized
to receive 1 of 2 treatment arms. The randomization will result in a 2:1 ratio of subjects 
receiving roxadustat or placebo, respectively. 
The initial study drug dose (per dose amount) is based on a tiered, weight-based dosing 
scheme shown in [Table 2].
Table 2
Initial Study Drug (Roxadustat/ Placebo) Dosing
Study Drug
(Dose Frequency)
Weight
(≥45 to ≤70 kg)
Weight
(> 70 to ≤160 kg)
Roxadustat/Placebo (TIW)
70 mg
100 mg

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Study drug will be dosed initially for Hb correction, until subjects achieve central Hb value 
of ≥11.0 g/dL and Hb increase from BL of ≥1.0 g/dL at 2 consecutive study visits separated 
by at least 5 days (correction period).  
Once Hb correction is reached the subject will enter the maintenance period. The aim of the 
maintenance period is to treat to a Hb level of 11.0 g/dL by maintaining the Hb levels
between 10.0 g/dL and 12.0 g/dL. During the treatment period, subjects will attend weekly 
study visits from day 1 to week 2, followed by every other week study visits from weeks 4 to 
24 and thereafter every 4 weeks until the end of treatment (EOT).  Subjects will be treated 
with roxadustat or placebo for at least 52 weeks and will continue taking the double-blind 
treatment as they were assigned until a maximum of 104 weeks. Depending on the rate of 
recruitment, the maximum treatment period will be 104 weeks for subjects who were 
randomized early into the study.
●
The last subject randomized will stop treatment at the minimum of 52 weeks. 
●
When the last subject randomized reaches 40 weeks of treatment (or the forecasted 
week 40 date, if the last subject randomized discontinues treatment early) 
o
Subjects beyond 52 weeks treatment will stop treatment at this point. 
o
Subjects that have not yet reached 52 weeks treatment will continue until they reach 
52 weeks treatment.
For details on study drug dosing, see [Section 5.1].
2.2.1.3.3
Follow-up Period
After the Treatment period, subjects proceed to the 4-week post-treatment follow-up period.
2.2.1.3.4
Post-study Follow-up Period (Only for Subjects Prematurely Discontinued 
from Treatment)
Subjects that have stopped treatment prior to their projected week 104 will complete the EOT 
visits (EOT visit and EOT + 2 weeks visit) and the end of study (EOS) visit. Thereafter, these 
subjects will continue to be followed up on a 6-monthly frequency for vital status and SAEs,
cardiovascular and thromboembolic AEs until their projected date of completion (i.e.,
projected week 108 date) or, if earlier, until the last subject randomized reaches EOS, or until 
consent withdrawn.
2.2.1.4 Randomization and Blinding
A randomized double-blind design has been chosen in order to ensure a balanced allocation 
of study subjects to the treatment arms and to minimize bias in therapeutic management and 
in outcomes assessment. For more details on blinding, please refer to [Section 4.4].
2.2.1.5 Comparator
Placebo has been chosen as comparator to adequately assess the efficacy, safety and benefit 
of achieving Hb correction and maintenance in anemic subjects treated with roxadustat.  
Scientifically, efficacy and benefit of a new investigational medicinal product is most 
convincingly established by demonstrating superiority in a placebo-controlled trial.

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2.2.2
Dose Rationale
Starting doses of roxadustat in the correction setting were studied in 3 ways in the phase 2 
program: 
●
using a strict weight-based dosing approach by dosing in mg/kg that was useful in the 
proof of concept stage;
●
using a tiered weight-based approach where a subject’s starting dose was selected based 
on categorizing the subject’s body weight as low (45 to 60 kg), medium (> 60 to 90 kg), 
or high (> 90 to 140 kg);
●
and using an absolute starting dose regardless of body weight.  
The tiered weight-based approach has been chosen for the development of roxadustat in 
phase 3 program to provide the best opportunity for managing subjects’ controlled correction 
to target Hb values. 
Based upon simulations derived from a pharmacokinetic-pharmacodynamic model built from 
phase 2 data a tiered weight-based approach with starting doses of 70 mg given 3 times a 
week (TIW) for patients weighing up to 70 kg and 100 mg given TIW for patients weighing 
more than 70 kg has been chosen for the development of roxadustat. This approach is a 
variation of the tiered weight-based starting approach used in phase 2 and provides the best 
opportunity for managing subjects’ controlled individualized correction to target Hb values 
by achieving a steady Hb increase associated with moderate rates of Hb overshoots.
Based on the phase 2 data, it can be expected that subjects who receive these starting doses to 
correct anemia will require in the maintenance period a total weekly dose reduction in the 
order of 22% to 35% after achieving response. This dose reduction will be achieved by 
adjustment of the single dose. The phase 2 studies evaluated the need for dose adjustments 
for correcting and maintaining Hb. Dose adjustments were allowed at regular 4-week 
intervals to maintain, increase, or decrease the dose according to pre-specified rules. 
Prespecified dosing steps were used to correct and maintain Hb levels within treatment 
thresholds based on absolute Hb levels and change of Hb in the previous 4 weeks. Additional 
rules for dose adjustment were provided to minimize excessive hematopoiesis. These dose 
adjustment rules were successful in Hb correction and Hb maintenance and will be adopted 
in this study with minor modifications.
The maximum allowed dose in this study is set at 3.0 mg/kg or 300 mg, whichever is lower.
For randomized subjects who require chronic dialysis during the treatment period, the 
maximum dose step is the dose step corresponding to 3.0 mg/kg per administration or 
400 mg, whichever is lower. The highest dose tested in healthy subjects is 5 mg/kg single 
dose and 3.75 mg/kg TIW; the highest dose tested in phase 2 studies was 3.0 mg/kg. The 
doses were safe and well tolerated with transient dose dependent HR increases observed. No 
maximum tolerated dose was reached in the clinical development of roxadustat based on the 
observed pharmacodynamic response (plasma EPO levels) and the predicted relation between 
EPO levels and Hb response; therefore exploration of higher doses was not conducted. 
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expected that the majority of the subjects will show adequate Hb response (correction and 
maintenance) at substantially lower doses than the maximum allowed dose.
The treatment period, of a minimum of 52 weeks, will provide sufficient data on the long 
term treatment of anemic CKD subjects with roxadustat.
2.3
Endpoints
2.3.1
Primary Endpoint
For EU (EMA) the primary efficacy endpoint is Hb response.
Hb response is defined as:
●
Hb ≥11.0 g/dL and a Hb increase from BL by ≥1.0 g/dL in any subject with 
BL Hb > 8.0 g/dL, OR
●
an increase from BL by ≥2.0 g/dL in any subject with BL Hb ≤8.0 g/dL
at 2 consecutive visits separated by at least 5 days during the first 24 weeks of treatment 
without rescue therapy (i.e., RBC transfusion, ESA, or IV iron) prior to Hb response.
For US (FDA) the primary efficacy endpoint is the change in Hb from BL to the average 
level during the evaluation period (defined as week 28 until week 52) regardless of rescue
therapy.
2.3.2
Secondary Endpoints
The key secondary efficacy endpoints in this study are:
●
Hb maintenance: Hb change from BL to the average Hb of weeks 28-36, without having 
received rescue therapy within 6 weeks prior to and during this 8-week evaluation period
●
Change from BL in low–density lipoprotein (LDL) cholesterol to the average value 
of LDL cholesterol in weeks 12-28
●
Use and time to use of rescue therapy (composite of RBC transfusions, ESA use, and IV 
iron) in the first 24 weeks of treatment.
●
Change from BL in Short Form (SF)-36 Physical Functioning (PF) subscore to the 
average SF-36 PF subscore in weeks 12-28
●
Change from BL in SF-36 Vitality (VT) subscore to the average SF-36 VT subscore in 
weeks 12-28 
●
Blood pressure effect
o
Change from BL in Mean Arterial Pressure (MAP) to the average MAP in
weeks 20-28
o
Occurrence and time to occurrence of hypertension (defined as either systolic 
blood pressure [SBP] > 170 mmHg AND an increase from BL ≥20 mmHg or as
DBP > 110 mmHg, AND an increase from BL of ≥15 mmHg)

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2.3.3
Other Endpoints
2.3.3.1 Additional Secondary Evaluation of Efficacy
Hb correction and maintenance:
●
Hb averaged over weeks 28-36, without use of rescue therapy within 6 weeks prior to 
and during this evaluation period
●
Time to achieve the first Hb response as defined by primary endpoint
●
Hb change from BL to each post-dosing time point
●
Hb level averaged over weeks 44-52, without use of rescue therapy within 6 weeks prior 
to and during this evaluation period
●
Hb change from BL to the average Hb value of weeks 28-36 and weeks 44-52, regardless 
of the use of rescue therapy 
●
Proportion of Hb values within 10.0-12.0 g/dL in weeks 28-36, without use of rescue
therapy within 6 weeks prior to and during this 8-week evaluation period.
Hospitalizations
●
Occurrence of hospitalization
●
Number of days of hospitalization.
Rescue therapy use 
●
Having received RBC transfusions
●
Number of RBC packs per subject
●
Volume of RBC transfused per subject
●
Having received IV iron therapy
●
Number of ESA-week dose per subject: 1-3 doses of epoetin alfa or beta or biosimilar 
thereof (in EU) administered within 1 week = 1 ESA-week; 1 darbepoetin SQ or IV 
dose = 2 ESA-week; 1 Mircera IV or SQ dose = 4 ESA-week.
Changes in cholesterol levels
●
Change from BL to each post-dosing study visit in 
o
Total cholesterol 
o
LDL/High-density Lipoprotein (HDL) ratio
o
Non-HDL cholesterol
o
Apolipoproteins A1 and B, and ApoB/ApoA1 ratio
●
Occurrence of mean LDL cholesterol < 100 mg/dL (mean LDL calculated over 
weeks 12-28 of treatment).
Blood pressure effect
●
Occurrence of achieved antihypertensive treatment goal in CKD subjects (SBP 
< 130 mmHg and DBP < 80 mmHg) based on the mean SBP and mean DBP calculated 
over weeks 12-28 of treatment with study drug.

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HRQoL and Euroqol Questionnaire – 5 Dimensions 5 Levels (EQ-5D 5L) benefits of 
roxadustat in subjects with CKD anemia
●
Change from BL to the average value of weeks 12-28 in
o
Physical Component Score of SF-36
o
Anemia Subscale (“Additional Concerns”) of Functional Assessment of Cancer 
Therapy-Anemia (FACT-An) Score
o
Total FACT-An Score
o
EQ-5D 5L visual analogue scale (VAS) Score
o
Patients’ Global Impression of Change (PGIC) (qualitatively by assessment)
Hepcidin and Iron, Hemoglobin A1c glycated hemoglobin (HbA1c), and CKD progression
●
Changes from BL to each study visit in:
o
Serum hepcidin
o
Serum ferritin
o
TSAT
o
HbA1c level
o
Fasting blood glucose
o
eGFR (including eGFR slope over time)
o
Urine albumin/Cr ratio
●
Serum Cr having doubled during the study
●
Occurrence of ESRD, i.e., dialysis initiation
2.3.3.2 Safety Endpoints
Safety will be assessed by evaluating the following:
●
Occurrence of AEs, SAEs and clinically significant changes in laboratory values from BL
●
Changes from BL in vital signs, electrocardiogram (ECG) findings and clinical laboratory 
values
●
For the purpose of EU regulatory filing and other submissions: Adjudicated MACE+ 
events (i.e., myocardial infarction, stroke, death from all causes, hospitalization for 
chronic heart failure, hospitalization for unstable angina) and other pre-specified events 
will be pooled and analyzed across multiple studies in the global phase 3 program.  This 
analysis will be described in a separate pooled safety statistical analysis plan.  
●
For the purpose of US FDA regulatory filing: Adjudicated MACE i.e., myocardial 
infarction, stroke, death from all causes, will be pooled across multiple studies in the 
global phase 3 program to serve as primary safety endpoint.  
The adjudicated MACE events in this study will be part of this pooled analysis, but will not 
be a self-contained endpoint within this individual study.  

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3
STUDY POPULATION
The study population consists of subjects with CKD as defined by CKD stages 3, 4 and 5 
(eGFR < 60 mL/min/1.73 m2) who are anemic and not receiving dialysis.
Waivers to the selection criteria will not be allowed.
3.1
Inclusion Criteria
Subject is eligible for the study if all of the following apply:
1. Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written 
Informed Consent and privacy language as per national regulations must be obtained from 
the subject or legally authorized representative prior to any study-related procedures 
(including withdrawal of prohibited medication, if applicable).
2. Subject age is ≥18 years.
3. Subject has a diagnosis of chronic kidney disease, with Kidney Disease Outcomes Quality 
Initiative (KDOQI) Stage 3, 4 or 5, not receiving dialysis; with an eGFR
<60 mL/min/1.73 m2 estimated using the abbreviated 4-variable Modification of Diet in 
Renal Disease (MDRD) equation.
4. The mean of the subject’s three most recent Hb values during the Screening period, 
obtained at least 4 days apart, must be ≤10.0 g/dL, with a difference of ≤1.0 g/dL 
between the highest and the lowest values. The last Hb value must be within 10 days prior 
to randomization.
5. Subject has a ferritin level ≥30 ng/mL (≥67.4 pmol/L) at screening.
6. Subject has a transferrin saturation (TSAT) level ≥5% at screening.
7. Subject has a serum folate level ≥lower limit of normal at screening.
8. Subject has a serum vitamin B12 level ≥lower limit of normal at screening. 
9. Subject’s alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels are
≤3 x upper limit of normal (ULN), and total bilirubin (TBL) is ≤1.5 x ULN.
10. Subject’s body weight is 45.0 kg up to a maximum of 160.0 kg.
11. Female subject is either:

Of non-child bearing potential:
o
post-menopausal (defined as at least 1 year without any menses) prior to 
screening, or
o
documented surgically sterile

or if of child bearing potential
o
agree not to try to become pregnant during the study and for 28 days after the 
final study drug administration.
o
must have a negative serum pregnancy test at screening, and

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o
if heterosexually active, agree to consistently use a highly effective form of 
birth control* starting at screening and throughout the study period, and 
continued for 28 days after the last study treatment administration.
12. Male subject and their female spouse/partner(s) who are of childbearing potential must be 
using highly effective contraception starting at screening and continue throughout the 
study period, and for 12 weeks after final study treatment administration.
* Highly effective forms of birth control include:

Consistent and correct usage of established oral contraception.

Injected or implanted hormonal methods of contraception.

Established intrauterine device (IUD) or intrauterine system (IUS).

Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository (if allowed 
by local regulations).

Any male partner that has undergone effective surgical sterilization.

Any female partner that has undergone effective surgical sterilization, if 
applicable.
13. Subject agrees not to participate in another interventional study from the time of signing 
informed consent until the End of Study visit (EOS).
3.2
Exclusion Criteria
Subject will be excluded from participation if any of the following apply:
1. Subject has received any ESA treatment within 12 weeks prior to randomization.
2. Subject has had more than one dose of IV iron within 12 weeks prior to randomization.
3. Subject has received a RBC transfusion within 8 weeks prior to randomization.
4. Subject has a known history of myelodysplastic syndrome or multiple myeloma.
5. Subject has a known hereditary hematologic disease such as thalassemia or sickle cell 
anemia, pure red cell aplasia, or other known causes for anemia other than CKD.
6. Subject has a known hemosiderosis, hemochromatosis, coagulation disorder, or 
hypercoagulable condition.
7. Subject has chronic inflammatory disease that could impact erythropoiesis (e.g., systemic 
lupus erythematosus, rheumatoid arthritis, celiac disease) even if it is currently in 
remission.
8. Subject is anticipated to have elective surgery that is expected to lead to significant blood 
loss or anticipated elective coronary revascularization.
9. Subject has active or chronic gastrointestinal bleeding.
10. Subject has received any prior treatment with roxadustat or a hypoxia-inducible factor 
Prolyl Hydroxylase Inhibitor (HIF-PHI).

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11. Subject has been treated with iron-chelating agents within 4 weeks prior to randomization.
12. Subject has a history of chronic liver disease (e.g., cirrhosis or fibrosis of the liver)
13. Subject has a known New York Heart Association Class III or IV congestive heart failure.
14. Subject has had a myocardial infarction, acute coronary syndrome, stroke, seizure, or a 
thrombotic/thromboembolic event (e.g., pulmonary embolism) within 12 weeks prior to 
randomization.
15. Uncontrolled hypertension in the opinion of the investigator or two or more blood pressure 
values of systolic BP (SBP) ≥160 mmHg or diastolic BP (DBP) ≥95 mmHg confirmed by 
repeat measurement within 2 weeks prior to randomization.
16. Subject has a diagnosis or suspicion (e.g., complex kidney cyst of Bosniak Category 2F or 
higher) of renal cell carcinoma on renal ultrasound within 12 weeks prior to 
randomization.
17. Subject has a history of malignancy, except the following: cancers determined to be cured 
or in remission for ≥5 years, curatively resected basal cell or squamous cell skin cancers, 
cervical cancer in situ, or resected colonic polyps.
18. Subject is positive for any of the following: Human Immunodeficiency Virus (HIV); 
hepatitis B surface antigen (HBsAg); or anti-hepatitis C virus antibody (anti-HCV Ab).
19. Subject has an active clinically significant infection manifested by White Blood Count 
(WBC) > ULN, and/or fever, in conjunction with clinical signs or symptoms of infection
within one week prior to randomization.
20. Subject has a known untreated proliferative diabetic retinopathy, diabetic macular edema, 
macular degeneration and retinal vein occlusion.
21. Subject has had any prior organ transplant (that has not been explanted) or a scheduled 
organ transplantation.
22. Subject has participated in any interventional clinical study or has been treated with any 
investigational drugs within 30 days or 5 half lives or limit set by national law, whichever 
is longer, prior to the initiation of Screening.  
23. Subject has an anticipated use of dapsone in any dose amount or chronic use of 
acetaminophen (paracetamol) > 2.0 g/day during the treatment or follow-up period of the 
study.
24. Subject has a history of alcohol or drug abuse within 2 years prior to randomization.
25. Female subject:
●
must agree not to breastfeed starting at screening or during the study period, and 
continued for 28 days after the final study treatment administration.
●
must not donate ova starting at screening and throughout the study period and 
continued for 28 days after final study drug administration. 

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26. Male subject must not donate sperm starting at screening and throughout the study period 
and for 12 weeks after final study drug administration.
27. Any medical condition that in the opinion of the investigator may pose a safety risk to a 
subject in this study, which may confound efficacy or safety assessment, or may interfere 
with study participation.
3.3
Discontinuation Criteria for Individual Subjects
Discontinuation is the act of concluding participation in either the study treatment or the 
study, prior to completion of all protocol-required elements, in a trial by an enrolled subject. 
The subject is free to withdraw from the study treatment and/or study for any reason and at 
any time without giving reason for doing so and without penalty or prejudice. The 
investigator is also free to terminate a subject's involvement in the study at any time if the 
subject's clinical condition warrants it.
If a subject is discontinued from the study with an ongoing AE or an unresolved laboratory 
result that is significantly outside of the reference range, the investigator will attempt to 
provide follow-up until the condition stabilizes or no longer is clinically significant. Subjects 
should be discontinued from the study treatment for any of the following reasons:
●
Subject no longer consents to participate in the treatment phase of the study 
●
Physician decision that it is in the best interest of the subject to be discontinued from the 
study treatment
●
Significant noncompliance with study procedures, as determined by principal 
investigator and/or sponsor
●
Pregnancy in a study subject
●
Subject requires a third course of ESA rescue therapy (for details, see [Section 5.1.5])
●
Subject receives an organ transplant
If a subject has discontinued treatment prior to their projected week 104, subject will 
complete the EOT visits (EOT visit and EOT + 2 weeks visit) and the EOS visit. Thereafter, 
this subject will continue to be followed up on a 6-monthly frequency for vital status and 
SAEs, cardiovascular and thromboembolic AEs until their projected date of completion (i.e.,
projected week 108 date) or, if earlier, until the last subject randomized reaches EOS, or until 
consent withdrawn.
●
Subjects should be withdrawn from the study for any of the following reasons:
●
Subject no longer consents to participate in the study
●
Subject is lost to follow-up despite reasonable efforts by the investigator to contact the 
subject
●
Death of the study subject
●
The Sponsor may decide to prematurely stop the study, e.g., for safety considerations

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Discontinued and withdrawn subjects will complete the EOT visits (EOT visit and EOT + 2
weeks visit) and the end of study (EOS) visit procedures. The appropriate documentation 
must be entered on the electronic case report form (eCRF).
Women of childbearing potential who withdraw from this study must continue contraception 
for at least 28 days following the last study drug administration. Male subjects with partners 
of childbearing potential must agree to use a medically acceptable method of contraception 
during the study and for at least 12 weeks following the last study drug administration. 
4
STUDY DRUGS
4.1
Description of Study Drugs
4.1.1
Test Drug(s)
Roxadustat is supplied as red coated, oval tablets for oral administration, in strengths of 20, 
50 and 100 mg. All ingredients used for the manufacture of roxadustat tablets comply with 
US and EU compendial or regulatory standards. Tablet strengths are different in size and 
debossing reflects the strength (i.e., 20, 50 or 100 mg).
The excipients include lactose monohydrate, microcrystalline cellulose, povidone, 
croscarmellose sodium, magnesium stearate, and colorant Red Opadry II.
More details can be found in the Investigator’s Brochure.
4.1.2
Comparative Drug
Placebo tablets are identical in appearance to roxadustat tablets.
The matching placebo drug product is supplied as red coated, oval tablets for oral 
administration marked as 20, 50 and 100 mg. All ingredients used for manufacture of the 
placebo tablets comply with US and EU compendial or regulatory standards.  Size and 
debossing are identical to roxadustat, matching the appearance of the different strengths (i.e.,
20, 50 or 100 mg) of the roxadustat tablets.
More details can be found in the Investigator’s Brochure.
4.1.3
Drug(s) for Pre-investigational Period
Not applicable.
4.2
Packaging and Labeling
All medication used in this study will be prepared, packaged and labelled under the 
responsibility of a qualified person at Astellas Pharma Europe BV (APEB) or sponsor’s 
designee in accordance with APEB or sponsor’s designee Standard Operating Procedures 
(SOPs), Good Manufacturing Practice guidelines, International Conference on 
Harmonization for Good Clinical Practice (ICH GCP) guidelines, and applicable local    
laws/regulations. A Qualified Person of APEB or sponsor’s designee will perform the final 
release of the medication according to Directive 2003/94/EC Annex 13.

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Study drug tablets are presented in white High-density Polyethylene bottles with a black 
lining, for optimal light protection, and closed with a foil induction seal and a white, child 
resistant cap. Due to the light sensitive nature of roxadustat and to minimize exposure of the 
active pharmaceutical ingredients to light, tablets should remain in the original packaging 
until time of administration and be administered as intact tablets only.
4.3
Study Drug Handling
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries 
from the sponsor are received by a responsible person at the study site (e.g., pharmacist), and
that:
●
such deliveries are recorded
●
study drug is handled and stored safely and properly
●
study drug is only dispensed to study subjects in accordance with the protocol
●
any unused study drug is returned to the sponsor or designee standard procedures for the 
alternative disposition of unused study drug are followed if agreed by the sponsor.
Drug inventory and accountability records for the study drugs will be kept by the 
investigator/pharmacist. Study drug accountability throughout the study must be documented. 
The following guidelines are therefore pertinent:
●
The investigator agrees not to supply study drug to any persons except the subjects 
randomized in this study.
●
The investigator/pharmacist will keep the study drug in a pharmacy or other locked and 
secure storage facility under controlled storage conditions, where access is limited to 
appropriately qualified staff and authorized by the investigator to dispense this study 
drug.
●
A study drug inventory will be maintained by the investigator/pharmacist. The inventory 
will include details of material received and a clear record of when they were dispensed 
and to which subject.
●
At the conclusion or termination of this study, the investigator/pharmacist agrees to 
conduct a final drug supply inventory and to record the results of this inventory on the 
Drug Accountability Record. It must be possible to reconcile delivery records with those 
of used and returned medication. Any discrepancies must be accounted for. Appropriate 
forms for deliveries and returns must be signed by the person responsible.
●
Used or unused study drug is returned to the sponsor or designee at the end of the study 
or upon expiration.  Only if agreed by the sponsor, can standard procedures for the 
alternative disposition of the unused study drug be followed, after drug accountability 
has been conducted by the sponsor or representative. A copy of the standard institutional 
procedure for destroying investigational drugs will be provided to the sponsor or 
designee upon request. 

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4.4
Blinding
4.4.1
Blinding Method
Study drug administration is implemented in a double-blind, placebo-controlled manner. 
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.
Randomization of treatments and preservation of the treatment blind are maintained by an 
Interactive Response Technology (IRT). The randomization code will remain confidential 
until completion of the study.
4.4.2
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking
The randomization schedule will be generated under the responsibility of the Global Data 
Science (GDS) Department, Astellas Pharma Europe B.V. (see Section 4.5).  The vendor of 
the IRT used in this study will receive the randomization schedule and perform the random 
assignments of medication numbers to study treatments. These files will be held securely and 
will be released to the study biostatistician only after database hard lock has taken place and 
a decision has been taken to unblind the study.
Procedures for emergency unblinding of individual subjects, in the event that knowledge of 
the treatment assigned is required for the correct management of a medical emergency, are 
described in [Section 4.4.3]. Emergency unblinding of a few individual subjects does not, in 
general, affect the continued blinding of other subjects in the study or the scientific integrity 
of the study.
The Independent DSMB see [Section 10.1], will have access to group-unblinded and/or fully 
unblinded DSMB reports. They will also be authorized to access the unblinded treatment for 
single subjects or for single treatment groups via the IRT. The DSMB will not disclose this 
information to any other staff involved in this study.
4.4.3
Breaking the Treatment Code for Emergency
For each randomized subject, individual code breaks will be accessible in the event of a 
medical emergency requiring knowledge of the treatment assigned to the subject. The code is 
accessible through the IRT. The time and date of any code break will automatically be 
documented in the IRT. 
Only the responsible investigator or delegates duly registered in the study file as 
sub-investigators can break the code via the IRT. Subjects or other study personnel will not 
be made aware of the treatment given to any subject unless a medical emergency necessitates 
such disclosure. Any breaking of the treatment code by the investigational staff must be 
reported immediately to the 24-hour contact for SAEs [see Section II] and must include an 
explanation for breaking the code. The sponsor should be contacted to discuss the case, if 
possible, prior to unblinding.  The date of breaking the blind, person who requested the blind 

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to be broken, person who broke the blind, the reason for breaking the blind, and the person 
informed at the sponsor will be captured in the eCRF.
Unplanned unblinding may result in the discontinuation of subject participation from the 
study.
4.4.4
Breaking the Treatment Code by the Sponsor
The sponsor’s personnel from the Drug Safety and Pharmacovigilance Department may
break the treatment code for subjects who experience a Suspected Unexpected Serious 
Adverse Reaction (SUSAR), in order to determine if the individual case or a group of cases 
requires expedited regulatory reporting. Individual Emergency Code will be provided to the 
limited staff who are empowered to break the codes for all SUSAR cases for reporting 
purposes.
4.5
Assignment and Allocation
Assignment to treatment groups will be done using the randomization scheme prospectively 
prepared by
on behalf of the sponsor, under the responsibility of the GDS
Department of APEB. Automated randomization and treatment assignments will be provided 
by an IRT.
A total of 450-600 planned subjects will be randomized to receive 1 of the 2 treatment arms 
in a 2:1 ratio as follows:
●
Roxadustat (planned 300-400 subjects)
●
Placebo (planned 150-200 subjects)
Randomization will be stratified by the following 4 factors: 
●
Region (region A versus region B)*
* assignment to region will be determined based on health care system comparability
●
Screening Hb values ( ≤8.0 g/dL versus > 8.0 g/dL)
●
History of cardiovascular, cerebrovascular or thromboembolic diseases (Yes versus No)
●
eGFR (< 30 mL/min/1.73 m2 versus ≥ 30 mL/min/1.73 m2)
5
TREATMENTS AND EVALUATION
Subjects must provide a signed Informed Consent Form (ICF) and be registered in IRT
before any screening tests or assessments are performed. Participating study sites are required 
to document all screened candidates who provided Informed Consent. If a subject is later 
excluded from the study, the reasons for exclusion will be documented in the subject’s source 
documents in the eCRF.
Registration of subjects into the study, assignment of subject identification numbers, and 
randomization will take place using a centralized IRT technology. After obtaining consent, 
and prior to the start of screening assessments, the investigator will register the subject in 
IRT, which starts the 42 day Screening Period, and a subject identification number will be 
assigned. No screening tests or assessments should be performed prior to registration and 

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assignment of a unique subject identification number by IRT. Any subject identification 
numbers that are assigned will not be reused even if the subject does not receive treatment.
If a subject’s laboratory parameter results do not meet the inclusion criteria or meet the 
exclusion criteria at Screening, the laboratory parameter assessment may be repeated once 
within the 42-day screening period. This includes an additional (4th) Hb value that may be 
collected if necessary. The mean of 3 most recent Hb values during the 42-day screening 
period, obtained at least 4 days apart, will be used to assess the subject’s eligibility. 
If a subject fails screening, they will be registered in IRT as a screen failure and considered 
out of the study. However, the subject may be re-screened once (immediately or later) if 
deemed appropriate by the investigator. When a subject will be re-screened, the subject must 
be re-consented, a new 42-day screening period starts and all screening procedures must be 
repeated. Subject must also be registered in IRT as re-screened under the same subject 
number as first screening.
Subjects confirmed not eligible after screening or, if applicable, after re-screening, should be 
registered in IRT as a screen/re-screen failure.
5.1
Dosing and Administration of Study Drugs and Other Medications
5.1.1
Dose/Dose Regimen and Administration Period
Following the screening period, eligible subjects will enter the treatment period upon 
randomization. Subjects will be randomized via IRT to receive roxadustat or placebo. The 
initial study drug dose is based on the tiered, weight-based dosing scheme [refer to Table 2].  
The first study drug administration should be on the day of randomization, i.e., day 1, after 
all study assessments have been completed.
Scheduled Visits
During the Treatment period, subjects will attend weekly study visits from day 1 to week 2, 
followed by every other week study visits from weeks 4 to 24 and thereafter every 4 weeks 
until the EOT.
Study drug will be dispensed to subjects at each study visit during the treatment period with 
instructions for self-administration of the tablets on each dosing day, according to the dosing 
schedule. The study drug tablets are to be swallowed whole with room-temperature drinking 
water. 
All subjects will administer study drug TIW and study drug doses must be administered at 
least 2 days apart, and no more than 4 days apart. Investigators and subjects should make 
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Dosing Instructions for Subjects Moving from Protocol v1.0 to Protocol v2.0
Subjects who entered the study under protocol v1.0 should, upon signing the updated 
informed consent, adapted their dose frequency and dose amount according to the 
instructions in Appendix 3:  Instructions for Subjects Moving from Protocol v1.0 to 
Protocol v2.0.
There were no adaptations to dose frequency or dose amount for subjects moving from 
Protocol v2.0 to Protocol v2.1.
5.1.2
Changes in Study Drug Dose
Dose adjustments are permitted from week 4 onward, and every 4 weeks thereafter. All dose 
adjustments are made to maintain study subjects’ Hb level within the predefined target range 
and are based on Hb values using the HemoCue® device, a point-of-care device.
Dose adjustments will follow unique dose adjustment rules [Table 3].
Table 3
Dose Adjustment Rules
Correction Period
Maintenance Period
Change in Hb over 
past 4 weeks 
(g/dL)a
(When Hb 
correction has not 
been reached)
Hb <10.5 g/dL
Hb 10.5 to <12.0 
g/dL
Hb 12.0 to <13.0 
g/dL
< -1.0
↑
↑
↑
No change
-1.0 to 1.0
↑
↑
No change
↓
> 1.0
No change
No change
↓
↓
a Subtract 4 weeks’ previous Hb value from the present Hb value to calculate the change.
●
All dose adjustments are made based on Hb values using HemoCue, a point-of-care 
device. 
●
If the dose adjustment is ‘No change’ per Table 3, the next dose adjustment review is 
4 weeks after that visit.
●
Dose increases by 1 dose step (↑) and reductions by 1 dose step (↓) are pre-set per the 
dose steps.
●
The dose steps are as follows: 20, 40, 50, 70, 100, 150, 200, 250 and 300 mg.  
●
The maximum dose is the dose step corresponding to 3.0 mg/kg per administration or 
300 mg, whichever is lower. The default weight is initially set as weight measured at day 
1. At study visits where weight is collected, the maximum allowed dose step and the 
default weight for a subject will be adjusted if the weight change is ≥ 5% compared to 
the previous default weight collected in the study.  For randomized subjects who require 
chronic dialysis during the treatment period, the maximum dose step is the dose step 
corresponding to 3.0 mg/kg per administration or 400 mg, whichever is lower.
●
At week 4 only, in a subject whose BL Hb level was < 8.0 g/dL, if the dose adjustment is 
to increase, then dose increase could be made with either a 1 or 2 step increase per 
investigator’s discretion to minimize the probability of requiring rescue therapy 
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●
Contact the Medical Monitor if dose adjustments would lead to doses outside the limits 
of the dose step range; i.e., lower than 20 mg or higher than 300 mg.
●
If there is a safety concern, investigators may deviate from the dose adjustment rules. 
This should be discussed with the Medical Monitor and documented in the source 
documentation.
At Any Time when Hb ≥ 13.0 g/dL
●
Stop dosing
●
Resume dosing when Hb < 12.0 g/dL at a dose that is reduced by 2 steps
●
Next dose adjustment review is 4 weeks after dose resumption and in 4-weekly intervals 
thereafter.
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 1 dose step.
Note: Only 1 dose reduction for excessive hematopoiesis is recommended within a period of 
4 weeks. If a blood transfusion or ESA rescue treatment has been performed within 2 weeks 
of meeting the criteria for excessive hematopoiesis, it is recommended not to perform a dose 
reduction for excessive hematopoiesis. 
After a dose adjustment due to excessive hematopoiesis, the subject’s next dose adjustment 
review will occur 4 weeks later, and in 4-weekly intervals thereafter. If the dose adjustment 
interval falls on a non-visit study week, the dose adjustment review should be performed at 
the next scheduled clinic visit.
5.1.3
Previous and Concomitant Medication (Drugs and Therapies)
5.1.3.1 Previous Medication (Drugs and Therapies)
Previous medications are any prescription or over-the-counter preparations, including herbal 
products and “natural remedies”, used by a subject prior to Screening.  
If not specified differently, intake of any previous medication within 4 months prior to 
randomization should be documented in the eCRF. The medication name, start and stop date, 
route, dose, frequency and indication for each medication will be entered in the eCRF.
The last treatment course of any previous treatment type received for anemia (medication or 
procedures such as ESAs, iron (IV or oral), and RBC transfusions) within 12 months prior to 
randomization will be documented in the eCRF. The medication name, start and stop date,
route, dose, frequency and indication for each medication will be entered in the eCRF.
The following previous medication is not permitted:
●
Any ESA within 12 weeks prior to randomization
●
IV iron (more than 1 dose) within 12 weeks prior to randomization
●
RBC transfusion within 8 weeks prior to randomization
●
Iron-chelating drugs within 4 weeks prior to randomization

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●
Any investigational drug within 30 days or 5 half-lives or limit set by national law 
(whichever is longer), prior to the initiation of Screening
●
Roxadustat or another HIF-PHI at any time.
5.1.3.2 Concomitant Medication (Drugs and Therapies)
Concomitant medications are any prescription or over-the-counter preparations, including 
herbal products and “natural remedies”, used by a subject from informed consent to EOS 
visit. The medication/therapy name, start and stop date, route (if applicable), dose and 
frequency and indication for each medication/therapy will be entered in the eCRF.
For all concomitant medication use, from screening visit to EOS visit, the study site must 
provide an indication for its use. If the stated indication is a non-specific condition, e.g., 
“rash”, documentation of the condition, as specific as possible, should be maintained in the 
subject’s clinical study records as source documentation.
Statins and Other Substrates for OATP 1B1
There is a risk that roxadustat will increase the plasma levels of statins and other drugs that 
are substrates of OATP 1B1, based on results from drug-drug interaction studies.  Because 
statin dose has been known to be associated with  the risk for side effects such as  myopathy, 
(e.g., myalgia, myositis and rhabdomyolysis), the investigator is advised to consider this 
potential interaction between roxadustat and statins when deciding on the appropriate dose of
statins based on efficacy and safety of statin therapy. Switching to a non-interacting statin 
(e.g., pravastatin) may be considered. Furthermore, it is recommended not to exceed the 
proposed maximum daily dose of statins as outlined in [Table 4].
The investigator is also advised to consider this potential interaction between roxadustat and 
other drugs that are substrates for OATP 1B1 when deciding on the appropriate posology of 
these drugs. Examples of these drugs are atrasentan, bosentan, ezetimibe, repaglinide, 
glyburide, SN-38 (active metabolite of irinotecan), rifampin, valsartan and olmesartan. It is 
recommended to refer to the Summary of Product Characteristics (SmPC) of these drugs for 
further details and guidance.
Table 4
Proposed Maximum Daily Dose of Statins Not to Be Exceeded
Statin
Proposed maximum dose (mg/day)
Simvastatin
20
GFR < 30 mL/min: 5
Atorvastatin
40
Rosuvastatin
10
Severe renal impairment: no recommendation as 
contraindicated in this case
Fluvastatin
40
GFR < 30 mL/min: 20
Pravastatin
40
Pitavastatin
2
GFR < 30 mL/min: 1

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Phosphate Binders and Other Multivalent Cation-containing Drugs and Mineral 
Supplements
Results from a drug-drug interaction study demonstrated a significant reduction in roxadustat 
plasma exposure when a single dose of roxadustat was administered simultaneously with the 
phosphate binders sevelamer carbonate or calcium acetate. 
Subjects should take roxadustat in a consistent manner relative to their phosphate binder 
intakes, and discuss with the investigator before changing their phosphate binder dose or 
dosing time.  To reduce the effect of phosphate binders on roxadustat exposure, subjects 
should be advised that roxadustat be taken at least 1 hour before or 1 hour after their 
phosphate binder.
It is anticipated that other multivalent cation-containing drugs and mineral supplements (e.g., 
iron, calcium, magnesium, aluminum), sucralfate or magnesium- or aluminum-containing 
antacids would produce a similar interaction; therefore, administration of roxadustat between 
-1 hour and +1 hour of intake of these preparations is not recommended.
Anti-hypertensive Medications
To avoid confounding effects on study endpoints, changes to anti-hypertensive medications 
should be kept to a minimum during the course of the study, and only if deemed medically 
necessary by the investigator. Changes to anti-hypertensive medications will be documented 
in the eCRF.
Supplemental Vitamin B12, Folate
Vitamin B12 and folate can be taken without restriction at any time during the study.
Supplemental Iron and ESA Use
Oral iron is recommended as the first-line treatment for iron supplementation and can be 
taken without any restriction. However, IV iron and ESA use is restricted to use as rescue 
therapy, see rescue therapy guidelines, [Section 5.1.5].  Administration of roxadustat between 
-1 hour and +1 hour of intake of oral iron is not recommended.
Prohibited Medications
The following medications are prohibited during the period identified:
●
Iron-chelating agents (e.g., deferoxamine, deferiprone, or deferasirox therapy) from 
4 weeks prior to randomization until EOS visit
●
Androgens from randomization until EOS visit
●
Dapsone in any dose amount or chronic use of acetaminophen (paracetamol) > 2.0 g/day 
from randomization until EOS visit
●
Any hypoxia-inducible factor HIF-PHI other than roxadustat, as allocated by 
randomization, until EOS visit.
Use of herbal medicine is not prohibited but strongly discouraged during the course of the 
study.

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5.1.4
Treatment Compliance
The quantity of study drug dispensed to and returned by the subject will be counted and 
recorded in the eCRF [see Section 5.1.1]. If the subject is not compliant with study drug 
intake, the investigator should discuss this with the subject. Deviations from the prescribed 
dose should be entered into the eCRF and require notification to the Sponsor (see 
Sections 7.8 and 8.1.6).
5.1.5
Rescue Therapy Guidelines
Rescue therapy guidelines are provided to optimize standardization of the use of rescue 
therapy by investigators and to ensure safety of the individual study subjects. Use of rescue 
therapy and reason for rescue therapy should be recorded in the eCRF. If subjects meet the 
criteria for ESA rescue therapy whilst on dialysis, ESAs will be administered IV or SC 
according to the Package Insert or SmPC of the respective ESA for dialysis patients.
RBC Transfusion
In the event of acute or severe blood loss, RBC transfusion is allowed if clinically indicated.  
In a situation where there is no obvious blood loss, RBC transfusion will be permitted if the
subject has moderate to severe symptom(s) from his/her anemia, e.g., dyspnea at rest or on 
mild exertion, and the investigator is of the opinion that the blood transfusion is a medical 
necessity. Study drug may be continued even if a blood transfusion had been administered.
ESA
If a subject’s Hb level has not sufficiently responded to 2 or more dose increases or 
maximum dose (by body weight) of the study drug and the investigator considers the 
initiation of an ESA (i.e., EPO analogue) rescue as a medical necessity, the investigator 
should consider initiating the use of an approved ESA only if all of the following criteria are 
met:
●
The subject’s Hb level has not sufficiently responded to 2 or more dose increases in 
previous 8 weeks or maximum dose (by body weight) of the study drug; and
●
The subject’s Hb is < 8.0 g/dL; and
●
Reducing the risk of alloimmunization in transplant eligible subjects and/or reduction of 
other RBC transfusion-related risks is a goal.
The subject may continue on study, however, the subject is not allowed to be administered 
both ESA and study drug during the same time period. The course of ESA (i.e., the amount 
that may be administered) will be limited by duration of therapy and effect on Hb, including 
that 1 course of ESA treatment will not exceed 4 weeks in duration, and that ESA rescue will 
be stopped as soon as Hb ≥9 g/dL. Treatment with study drug may be resumed as soon as 
possible after the following intervals:
●
At least 2 days after stop of Epoetin alfa or Epoetin beta, or biosimilar thereof
●
At least 1 week after stop of darbepoetin alfa 
●
At least 2 weeks after stop of methoxy polyethylene glycol-epoetin beta.

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If a subject requires a third course of rescue with ESAs, the subject must be discontinued. 
The subject will complete the EOT visits (EOT visit and EOT + 2 weeks visit) and the EOS 
visit, and will continue to be followed up on 6-monthly frequency for vital status and SAEs, 
cardiovascular and thromboembolic AEs until their projected date of completion or, if earlier, 
until the last subject randomized reaches EOS. 
For instructions on ESA rescue treatments for subjects moving from protocol v1.0 to 
protocol v2.0, see Appendix 3
Intravenous Iron 
Oral iron is recommended for dietary supplementation to support erythropoeisis and as the 
first-line for prevention and treatment of iron deficiency, unless the subject is intolerant to 
this route of treatment.  The recommended daily oral dose is 200 mg of elemental iron.
The investigator may initiate the use of IV iron supplement if: 
●
The subject’s Hb level has not sufficiently responded to 2 or more dose increases of 
study drug while taking oral iron (unless not tolerated), and
●
Hb < 8.5 g/dL, and
●
Ferritin < 100 ng/mL, or TSAT < 20%.
If IV iron rescue criteria are met, the dose in a single administration (day) should be no more 
than 250 mg. Study treatment may continue during IV iron administration. At 4 to 8 weeks 
after the single dose of IV iron, a repeat dose of IV iron can be administered if the Hb 
remains < 9.0 g/dL and the subject still meets iron deficiency criteria (ferritin < 100 ng/mL or 
TSAT < 20%). After this 8-week period, full IV iron rescue criteria would need to be met 
again in order to qualify a subject for a second course of IV iron at a later point in the trial.
In Case of Excessive Hematopoiesis
If a blood transfusion or ESA has been performed within 2 weeks of meeting the criteria for 
Excessive Hematopoiesis, it is recommended not to perform a dose reduction of the study 
drug for excessive hematopoiesis.
5.1.6
Emergency Procedures
Therapeutic Phlebotomy
If there are clinical concerns for a subject’s high Hb levels, the investigator may decide to 
perform a therapeutic phlebotomy instead of, or in addition to, a dose hold. This should be 
documented and discussed with the study medical monitor.
5.1.7
Restrictions During the Study
Subjects are not permitted to consume more than 3 alcohol-containing drinks per day during 
the treatment or follow-up periods.
Female subjects of childbearing potential must agree to not try to become pregnant during the 
study and for 28 days after the final study drug administration, AND must have a negative 

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serum pregnancy test at Screening AND, if heterosexually active, must agree to use highly 
effective contraception as stated in the inclusion criteria.
Contraception must be practiced from start of screening until 28 days (female subjects), and 
until 12 weeks (male subjects with female partners of childbearing potential) after the last 
dose of study drug. If a subject discontinues prematurely, contraception must be practiced 
for 28 days (female subjects) and 12 weeks (male subjects) following final administration of 
study drug.
Pregnancy, spontaneous or therapeutic abortion, or events related to pregnancy must be 
reported [see Section 5.5.8 Procedure in Case of Pregnancy].
5.2
Demographics and Baseline Characteristics
5.2.1
Demographics
Demographic data recorded during Screening, including date of birth or age (depending on 
local regulations; if full date of birth cannot be recorded only year of birth will be recorded), 
sex, race, height, and body weight will be recorded in the eCRF.
5.2.2
Medical History
A detailed medical history, including detailed cardiovascular history, other than the target 
disease for each subject will be obtained at screening. All relevant past and present 
conditions as well as prior surgical procedures, and previous and current tobacco use will be 
recorded in the subject’s eCRF. Additionally, family history of cardiovascular diseases in 
first degree relatives (occurring before the age of 60) will be obtained.
5.2.3
Renal Ultrasound
A renal ultrasound examination must be performed within 12 weeks prior to randomization.
This can be replaced by a pre-existing examination (or other renal imaging modality such as 
CT or magnetic resonance imaging (MRI) scan if conducted within 12 weeks prior to 
randomization and it conclusively excludes the presence of renal cell carcinoma).
Examination results must be available prior to randomization. Sites are reminded to schedule 
the renal ultrasound, following the screening visit, once the subjects are confirmed eligible 
for the study, for subjects only that have not had a renal ultrasound in the specified period.
The date and assessment of presence of suspicion of renal cell carcinoma will be collected in 
the eCRF.
5.2.4
Diagnosis of the Target Disease, Severity, and Duration of Disease
A detailed anemia and CKD history for each subject will be obtained at Screening and 
recorded in the eCRF. This includes date of diagnosis and symptoms for anemia, date of 
diagnosis, CKD stage and etiology for CKD and non-drug therapy history and medication 
history for anemia in the last 12 months prior to randomization.
Chronic Kidney Disease stages 3, 4 and 5 is defined as eGFR < 60 mL/min/1.73 m2 for 
≥3 months, with or without kidney damage and not requiring dialysis. This is in line with 
the diagnosis criterion for CKD as defined by KDOQI. A reduction in kidney function to this 

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level or lower represents loss of half or more of the adult level of normal kidney function, 
which may be associated with a number of complications. Documentation of reduced eGFR 
should be available in the subject’s source documentation. In addition, calculation of eGFR 
will be performed by the central laboratory on day 1 to confirm the degree of CKD.
eGFR will be calculated using the following MDRD equation: eGFR (mL/min per 1.73 m2) = 
175 × Serum Cr –1.154 × age–0.203 × (0.742 if female) × (1.21 if black).
Anemia will be measured by repeated Hb measurements (central laboratory assessment) 
during screening; the mean of the 3 most recent Hb values during the Screening period, 
obtained at least 4 days apart, must be ≤10.0 g/dL, with a difference of ≤1.0 g/dL between 
the highest and the lowest values. The last Hb value must be within 10 days prior to 
randomization.
Exclusion of other causes of anemia should be based upon assessments of:
●
Complete blood count (CBC), which will include Hb concentration, red cell indices, 
white blood cell count and differential, platelet count and reticulocyte count
●
Serum ferritin level
●
TSAT
●
Serum vitamin B12 and folate levels.
For more details on the laboratory tests please refer to [Section 5.4.3.4 Central Laboratory].
5.2.5
Further Laboratory Testing Prior to Randomization
Other laboratory tests mandatory prior to randomization of a subject include enzyme-linked 
immunosorbent assay for HIV, HBsAg and anti-HCV Ab and serum pregnancy test for 
women of childbearing potential only, serum chemistry and serum lipid panel.
For more details on the laboratory tests please refer to [Section 5.4.3.4 Central Laboratory].
5.3
Efficacy Assessment
5.3.1
Primary Efficacy Assessment
Efficacy assessment of treatment with study drug will be based primarily upon Hb as 
assessed by central laboratory from intravenous blood sampling.
For the exact timing of Hb assessments refer to the Schedule of Assessments [Table 1]. For 
further details on central laboratory assessments, refer to [Section 5.4.3.4].
The use of rescue medication (as recorded in the eCRF) will be utilized for the evaluation of 
the primary efficacy assessment.
5.3.2
Additional Efficacy Assessment
See additional information in Appendix 4:  Instructions for Subjects Requiring Dialysis.
5.3.2.1 Blood Pressure
Blood pressure will be assessed as per schedule of assessment, SBP and DBP will be 
measured and MAP will be calculated. For measurement of BP, refer to [Section 5.4.1.1].

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5.3.2.2 Serum Lipid Panel
Blood sampling for serum lipids should be done in a fasted condition, wherever possible. The 
following parameters will be assessed (central laboratory): Total cholesterol, 
LDL-cholesterol, HDL-cholesterol, triglycerides, apolipoproteins A1 and B and 
ApoB/ApoA1 ratio.
5.3.3
Additional Assessments
See additional information in Appendix 4:  Instructions for Subjects Requiring Dialysis.
5.3.3.1 Health Related Quality of Life
All study subjects will be required to complete QoL questionnaires as indicated in the 
Schedule of Assessments [Table 1]: SF-36, FACT-An, EQ-5D 5L, PGIC and Work 
Productivity and Activity Impairment questionnaire Anemic Symptoms (WPAI:ANS).  See 
Appendices 5, 6, 7, 8 and 9.
5.3.3.1.1
Short Form-36 Health Survey (SF-36)
The SF-36 is a QoL instrument designed to assess generic health concepts relevant across 
age, disease, and treatment groups. It is aimed at both adults and adolescents aged 18 years 
and older. The SF-36 consists of 8 domains of health status: Physical functioning (10 items), 
Role-physical (4 items), Bodily pain (2 items), General health (5 items), Vitality (4 items), 
Social functioning (2 items), Role emotional (3 items) and Mental health (5 items). Two 
component scores, the Physical Component Summary and the Mental Component Summary 
can also be calculated. For both the SF-36 domain scores and summary scores, higher scores 
indicate better health status.  The SF-36 has a recall period of the ‘past four weeks’.
5.3.3.1.2
Functional Assessment of Cancer Therapy –Anemia (FACT-An)
The Functional Assessment of Cancer Therapy- General (FACT-G) Version 4 contains 
27 items that cover 4 dimensions of well-being: physical (PWB)—7 items, functional 
well-being (FWB)—7 items, social/family (SWB)—7 items each, and emotional well-being 
(EWB)—6 items. A subscale of 13 fatigue specific items (the Fatigue Subscale) plus 
7 additional items related to anemia were developed for use in conjunction with the FACT-G 
(Cella, 1997). The 13 fatigue items plus the 7 additional items related to anemia comprise 
the Anemia Subscale (AnS). Administration of the FACT-G plus the AnS is referred to as the 
FACT-An. The FACT-An has a recall period of the ‘past seven days’. Respondents are 
asked to provide responses, (i.e., ‘Not at all’, ‘A little bit’, ‘Somewhat’, ‘Quite a bit’ and 
‘Very much’), to a list of statements which are either positively or negatively phrased. For 
all FACT-An scales, a higher score indicates better QoL. 
5.3.3.1.3
Euroqol Questionnaire – 5 Dimensions 5 Levels (EQ-5D 5L)
The EQ-5D 5L is a self-reported questionnaire. The EQ-5D is being used as a measure of 
respondents' HRQoLand utility values. The EQ- 5D consists of the EQ-5D descriptive 
system and the EQ VAS. The EQ-5D descriptive system comprises 5 dimensions of health: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension 

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has 5 levels: no problems, slight problems, moderate problems, severe problems, extreme 
problems. The VAS records the respondent's self-rated health status on a graduated (0–100) 
scale, where the endpoints are labeled ‘Best imaginable health state’ and ‘Worst imaginable 
health state’ with higher scores for higher HRQoL. EQ-5D health states, defined by the 
EQ-5D descriptive system, may be converted into a single summary index by applying a 
formula that essentially attaches values (also called weights) to each of the levels in each 
dimension. The index can be calculated by deducting the appropriate weights from 1, the 
value for full health (i.e., state 11111).
5.3.3.1.4
Patients’ Global Impression of Change (PGIC) Scale
The PGIC is a subject-rated instrument that measures change in subjects’ overall status on a 
7-point scale ranging from 1 (very much improved) to 7 (very much worse).
5.3.3.1.5
Work Productivity and Activity Impairment Questionnaire: Anemic 
Symptoms (WPAI:ANS)
The objective of the WPAI:ANS version 2 is to measure work and activity impairment 
during the past 7 days due to anemia. It is self-assessed. The 2 domains covered by the 
questionnaire are work and daily activities. The WPAI: ANS consists of 6 questions, 
including asking if the subject is working, how many hours the person missed work due to 
anemic symptoms, how many hours the subject actually worked and how the anemic
symptoms impacted the productivity and ability to do daily activities.
5.3.3.2 Hospitalizations
Details on hospitalizations will be collected at each study visit as indicated in the schedule of 
assessments. Reason, admission and discharge dates and type and reason for hospitalization 
will be recorded in the eCRF.
Details of hospitalizations will also be collected at Post-study Follow-Up visits in subjects 
who prematurely discontinued treatment (only if they have taken at least 1 dose of study 
drug), until the projected date of the EOS visit (week 108) or, if earlier, until the last subject 
randomized reaches EOS. 
5.4
Safety Assessment
See [Section 5.5 Adverse Events and other Safety Aspects].
Please review the requirements related to the evaluation, reporting and analysis of liver
abnormalities information found in Appendix 2:  Liver Safety Monitoring and Assessment. 
In the event of a confirmed, severe hepatic abnormality as defined in Appendix 2   Liver 
Safety Monitoring and Assessment, it is the investigators responsibility to ensure contact 
with the sponsor/delegated contract research organization (CRO) by telephone or fax 
immediately (i.e., within 24 hours of awareness).
5.4.1
Vital Signs
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5.4.1.1 Blood pressure
Blood pressure measurement will be done with the subject comfortably seated in a chair, with 
the legs uncrossed, and the back and arm supported, such that the middle of the cuff on the 
upper arm is at the level of the right atrium (the midpoint of the sternum). The subject will 
be instructed to relax as much as possible and to not talk during the measurement procedure; 
ideally, 5 minutes should elapse before the first reading is taken. Preferably measurement 
will be done with an electronic automated oscillometric device. The same device should
preferably be used for the subject during the course of the study, timing as indicated in the 
schedule of assessments.
Blood pressure (systolic and diastolic) will be measured singly on each of the 3 visits during 
the screening period, and in triplicate with at least 2 minute intervals for all other visits. The 
same arm should be used consistently for measurements throughout the study.  All values 
will be reported in the eCRF.
5.4.1.2 Heart rate
Measurement of HR will be done at rest in a sitting position wherever possible. It can be 
performed with an oscillometric device as used for BP measurement [see Section 5.4.1.1], by 
using any other suitable device or manually (wrist HR within 1 minute). The same 
methodology and device should preferably be used for the subject throughout the study, 
timing as indicated in the schedule of assessments.
HR will be measured singly on each of the 3 visits during the screening period, and in 
triplicate with at least 2 minute intervals for all other visits. All values will be reported in the 
eCRF.
5.4.1.3 Respiratory rate
Measurement of respiratory rate will be done at rest in a sitting position wherever possible. It 
can be performed with any suitable device or manually (number of breathing cycles within 
1 minute). The same methodology and device should preferably be used for the subject
throughout the study, timing as indicated in the schedule of assessments. Respiratory rate 
will be measured singly during all visits and reported in the eCRF.
5.4.2
Adverse Events
Adverse Events (AEs) will be collected at all study visits (see Section 5.5 for detailed 
information regarding AE collection and data handling). AE collection starts after obtaining 
signed informed consent and continues until the EOS visit.  For subjects who continue in the 
post study follow-up period, SAEs and cardiovascular and thromboembolic AEs will be 
collected.  AEs will not be collected during the period between first screen where subject has 
failed screening and first rescreening visit.
The description of the collection and adjudication of prespecified cardiovascular and 
cerebrovascular events will be detailed in a separate adjudication charter. For submission of 
documentation for events that require adjudication, the ICON SQUARE system will be used.
A site manual for the submission of packages for events requiring adjudication will be 

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provided to each site and a dedicated staff member (and 1 back-up person) will be required to 
review the manual prior to getting access to the system.
5.4.2.1 Adverse Events of Possible Hepatic Origin
Subjects with AEs of hepatic origin accompanied by liver function test (LFT) abnormalities 
should be carefully monitored. See Appendix 2 (Liver Safety Monitoring and Assessment)
for detailed information on liver abnormalities, monitoring and assessment, if the AE for a 
subject enrolled in the study and receiving study drug is accompanied by increases in LFTs 
(e.g., AST, ALT, bilirubin) or is suspected to be due to hepatic dysfunction.
In the event of a confirmed, severe hepatic abnormality as defined in Appendix 2 (Liver 
Safety Monitoring and Assessment) it is the investigator’s responsibility to ensure contact 
with the Medical Monitor of the Sponsor/delegated Contract Research Organization by 
telephone or fax immediately (i.e., within 24 hours of awareness) for further follow-up.
5.4.3
Laboratory Assessments
5.4.3.1 Abnormal Liver Function Tests
If laboratory testing for a subject enrolled in a study and receiving study drug reveals an 
increase of serum aminotransferases (AT) to > 3 x ULN, or bilirubin > 2 x ULN, at least all 
4 of the usual serum measures (ALT, AST, alkaline phosphatase [ALP], and TBL)  should be 
repeated within 48 - 72 hours of notification of the test results. See Appendix 2 (Liver Safety
Monitoring and Assessment) for additional information on monitoring and assessment of 
abnormal LFTs.
5.4.3.2 HemoCue
Hb values obtained by HemoCue are used to allow “real-time” dose adjustments for all 
subjects.  Date and results of HemoCue measurement will be collected in the eCRF at visits
specified in the Schedule of Assessments [Table 1]. The HemoCue assessment of Hb will be 
performed on the venous blood sample collected for Central Laboratory Hb assessment.
5.4.3.3 Urinalysis
Dipstick analysis will be performed for protein, pH and glucose.  A quantitative assessment 
of albumin and Cr for the calculation of albumin/Cr ratio will be performed by the Central 
Laboratory.  Ideally, the sample should be from the first morning void.
5.4.3.4 Central Laboratory
All safety related tests of blood specimens will be performed by a central laboratory. 
Central laboratory results should be reviewed by the investigator or another qualified study 
staff member. Subject management is dependent upon close review of the laboratory data.
Any changes in laboratory values are to be evaluated by the investigator. Clinically relevant 
changes will be recorded as AEs in the eCRF.
Unscheduled and repeat laboratory tests will also be performed by the central laboratory.  
However, in no case should prudent or necessary testing be delayed if it is not possible to 

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send a sample to the central laboratory or if the turnaround time from the central laboratory is 
not sufficiently rapid for clinical management of the subject. In such emergency/urgent 
situations local laboratory test results may be used to make clinical judgments that affect the 
safety of the study subject. 
A Central Laboratory Manual with instructions on specimen collection, processing, storage, 
and shipping to the central laboratory will be provided to all participating sites before they
start the study. 
To maintain a blinded allocation to study treatment, the results of hepcidin, the level of 
hemoglobin content of reticulocytes (CHr) and the quantity of Soluble Transferrin Receptor 
(sTfR) will be reported to sites and the Sponsor after completion of the study.
Below is a table of the laboratory tests that will be performed during the conduct of the study
[Table 5].  The exact timing of all assessments can be found in the Schedule of Assessments
[Table 1].
Table 5
Laboratory Tests
Parameters to be analyzed
Hematology
CBC with WBC differential
Hemoglobin (Hb)
Hematocrit (Hct)
Erythrocytes (RBC)
Mean corpuscular volume
Mean corpuscular Hb 
Mean corpuscular Hb concentration
Leukocytes (WBC) 
Differential WBC

Neutrophils

Lymphocytes

Monocytes

Eosinophils
Basophils
Platelet count
Reticulocyte count
CHr
Table continued on next page

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Parameters to be analyzed
Biochemistry
Serum Chemistry
Sodium
Potassium
Calcium
Chloride
Glucose (fasted condition wherever possible)
Cr
Magnesium
Bicarbonate
Phosphorus
Uric Acid
Albumin
Total protein
Lactate dehydrogenase
Blood urea nitrogen
Lipase
Pregnancy test (for females of child bearing potential only)
Liver Function Tests:

AST

ALT

Bilirubin (Total and direct)

Gamma Glutamyl Transferase ALP
Lipid Panel (in fasted condition wherever possible):

Total Cholesterol

LDL

HDL

Triglyceride

Apolipoprotiens A1 and B and ApoB/ApoA1 ratio
Iron
Ferritin
Total Iron-Binding Capacity (TIBC)
TSAT (=FESAT)
Covariate for pharmacokinetic markers

Albumin

α1-AGP
HbA1c
Vitamin B12Folate
Serology (Immunology):
HIV Immunoassay
HBsAg 
Anti-HCV Antibody Tests
Special Laboratory Analytes:
Hepcidin  
sTfR (blinded)
High sensitivity C-reactive protein (hs-CRP) (blinded)
Table continued on next page

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Parameters to be analyzed
Serum 
Archival Serum samples for biomarkers
Plasma
Level of roxadustat and potentially metabolites
Whole Blood
Genotyping
Urinalysis
Qualitative

Protein

pH

Glucose
Quantitative

Cr

Albumin
Archival of urine samples for
biomarkers
5.4.4
Physical Examination
A comprehensive physical examination will be conducted during the screening visit, day 1 
and at EOT visit and recorded in the source documents. This examination will include 
general appearance and the following body regions and systems: head, eyes, ears, neck and 
throat, lungs, heart, chest and back, abdomen, genitourinary, extremities, skin, and any other, 
if deemed necessary.
A targeted examination (e.g., respiratory and cardiovascular) will be conducted throughout 
the study as described in Schedule of Assessments, and recorded in the source documents.
Only the date of the physical examination will be recorded in the eCRF. Any clinically 
relevant adverse change will be recorded as an AE in the eCRF [see Section 5.5.1].
5.4.5
Electrocardiogram (ECG)
Local 12-lead ECGs will be performed on all subjects at specific time points as described in 
Schedule of Assessments. A single ECG will be taken with the subject in the supine 
position, after the subject has been lying quietly for 5 minutes. Any abnormalities must be 
evaluated in clinical context (based on subject’s medical history and concomitant medication) 
and the investigator should determine if it is clinically significant. Clinically significant 
abnormalities should be reported as an AE.
Only the visit, ECG date, HR, PR interval, QRS interval, QT interval, overall interpretation
and relevant comments will be recorded in the eCRF. The RR interval will be calculated in 
the eCRF using the HR.  ECG recording will be kept as source documents.
5.4.6
Exploratory Assessments
Exploratory assessments in this study include the following parameters:
●
hs-CRP
●
Relevant selected biomarkers may be assessed from archived serum/plasma samples
●
WPAI

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●
PGIC
5.5
Adverse Events and Other Safety Aspects
Safety will be assessed throughout the study. A complete BL profile of each subject will be 
established through medical history, clinical laboratory values, vital signs, physical 
assessments, and ECGs. During the course of the study, vital signs, complete and targeted 
physical assessments, laboratory tests, and ECGs will be performed at several intervals.  Any 
medically significant changes from BL 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.
AEs, SAEs and ongoing concomitant medication usage will be monitored and recorded 
throughout the study.
5.5.1
Definition of Adverse Events (AEs)
An adverse event (AE) is defined as any untoward medical occurrence in a subject 
administered a study drug or has undergone study procedures and which does not necessarily 
have a causal relationship with this treatment.  An AE can therefore be any unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated with 
the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
Some countries may have additional local requirements for events that are required to be 
reported as AEs or in an expedited manner similar to an SAE. In these cases, it is the 
investigator’s responsibility to ensure these AEs or other reporting requirements are followed 
and the information is appropriately recorded in the (e)CRF accordingly.
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 1 of the 
following criteria:
●
Induces clinical signs or symptoms
●
Requires active intervention
●
Requires interruption or discontinuation of study medication
●
The abnormality or investigational value is clinically significant in the opinion of the 
investigator.
AEs present prior to study drug administration will be considered as ‘non-treatment 
emergent’.  Baseline conditions that worsen during the study will be recorded as adverse 
events.  Adverse events with a start date after subjects have completed EOS procedures will 
not be captured.

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For AEs that resolve during the subject’s participation in the study, a resolution date will be 
documented in the eCRF. AEs will be followed until resolved, stable, or until the subject’s 
last study visit or lost to follow up. AEs ongoing at the EOS visit will be followed up for as 
long as necessary to adequately evaluate the subject’s safety or until the event stabilizes.
Data to be recorded in the eCRF include a description of the event, date of onset, onset status 
(onset before/after first dose of double-blind medication), end of the event, severity, SAE, 
seriousness criteria, action with respect to study medication, treatment required, relationship 
to study drug and outcome of the event. 
The study period during which all AEs and SAEs must be reported begins after informed 
consent is obtained and ends 28 days after the last dose of study drug or through to EOS, 
except for pregnancy reporting [see Section 5.5.8]. For subjects that continue into the post 
study follow-up period, SAEs, cardiovascular and thromboembolic AEs will be captured 
until their projected date of completion of the follow-up period (i.e., projected week 108) or 
until the last subject randomized reaches EOS, whichever comes first.
During the AE reporting period, study site personnel will query each subject at each visit to 
actively solicit any AE occurring since the previous visit. All AEs will be collected in 
response to a general question about the subject’s well-being and any possible changes from 
the BL or previous visit, but shall not be specifically solicited. There will be no directed 
questioning for any specific AE. This does not preclude the site from collecting and 
recording any AEs reported by the subject to site personnel at any other time. 
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 until 28 days after the last dose of study drug or 
through to EOS visit, will be recorded as AEs; recurrence or worsening of medical history 
problems requiring new or changes in concomitant medication, will also be recorded as AEs.  
Abnormal, clinically significant laboratory results, physical examination findings, and ECGs 
will be recorded as AEs if they are deemed by the investigator to meet criteria.
5.5.2
Definition of Serious Adverse Events (SAEs)
An adverse event is considered “serious” if, in the view of either the investigator or sponsor, 
it results in any of the following outcomes:
●
Results in death,
●
Is life threatening (an adverse event is considered “life-threatening” if, in the view of 
either the investigator or sponsor, its occurrence places the subject at immediate risk of 
death. It does not include an adverse event that, had it occurred in a more severe form, 
might have caused death),
●
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions, 
●
Results in congenital anomaly or birth defect,

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●
Requires inpatient hospitalization or leads to prolongation of hospitalization 
(hospitalization for treatment/observation/examination caused by AE is to be considered 
as serious). 
●
Other medically important events.
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent 1 of the other outcomes listed in the definition 
above. These events, including those that may result in disability/incapacity, should also 
usually be considered serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that 
do not result in hospitalization; or development of drug dependency or drug abuse.
Additionally, Astellas requests that all medical events listed in Appendix 2 (Liver Safety 
Monitoring and Assessment) be reported by the Investigator as SAEs, even if none of the 
above criteria apply.
Safety events of interest (“Special Situations”) on the Sponsor medicinal products 
administered to the subject 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:
●
Overdose of the medicinal product
●
Suspected abuse/misuse of the medicinal product
●
Inadvertent or accidental exposure to the medicinal product
●
Medication error involving the medicinal product (with or without subject/patient 
exposure to the sponsor medicinal product, e.g., name confusion).
●
Drug-drug interactions
Concerning other special situations: lack of efficacy is not to be recorded or reported as an 
AE in this study, as the study end point monitors the effect of the study drug. Due to the 
method of oral administration of roxadustat the risk of transmission of infectious agents is 
limited for which these events do not need to be reported. Off-label use of roxadustat can be 
excluded for reporting as the product is under development.
All of the events of interest noted above should be recorded on a SAE Worksheet and within 
the timelines of reporting SAEs, thus within 24 hours of becoming aware of this event.  The 
above special situations will not be captured on the AE form in the eCRF, instead they will 
be captured in the dosing and accountability forms within the eCRF. 
If special situation also induces an adverse event, this AE should be recorded on the AE page 
of the eCRF. Note, the seriousness criteria described in this section do not apply for the 
above special situations themselves but only for their potentially induced adverse events. 
This means that on the SAE Worksheet the seriousness criteria for a special situation only 
should be left blank.

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The sponsor has a list of events that they classify as “always serious” events.  If an adverse 
event is reported that is considered to be an event per this classification as “always serious”, 
additional information on the event may be requested.
If a subject becomes pregnant during treatment, this should be reported as if it were a SAE. 
Refer to Section 5.5.8  Procedure in Case of Pregnancy.
5.5.3
Criteria for Causal Relationship to the Study Drug
Adverse events that fall under either "Possible" or "Probable" should be defined as "adverse 
events whose relationship to the study drugs could not be ruled out".
Table 6
Criteria for Causal Relationship to Study Drug
Causal relationship to 
the study drug
Criteria for causal relationship
Not Related
A clinical event, including laboratory test abnormality, with a temporal  
relationship to drug administration which makes a causal relationship 
improbable, and/or in  which other drugs, chemicals or underlying disease 
provide plausible explanations.
Possible
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, but which could also be 
explained by concurrent disease or other drugs or chemicals. Information 
on drug withdrawal may be lacking or unclear.
Probable
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, unlikely to be attributed to 
concurrent disease or  other drugs or chemicals, and which follows a 
clinically reasonable response on re- administration (rechallenge) or 
withdrawal (dechallenge).
5.5.4
Criteria for Defining the Severity of an Adverse Event
Severity of AEs will be graded according to National Cancer Institute - Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03. For terms not 
specified as part of NCI-CTCAE Version 4.03, the following guideline should be used to 
determine grade:
Table 7
Criteria for Defining the Severity of an Adverse Event
Grade
Description
1 - Mild
Mild; asymptomatic or mild symptoms, clinical or diagnostic observations 
only; intervention not indicated.
2 - Moderate
Moderate; minimal, local or non-invasive intervention indicated.
3 - Severe
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated.
4 – Life threatening
Life-threatening consequences; urgent intervention indicated.
5 - Death
Death related to AE.

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5.5.5
Reporting of Serious Adverse Events (SAEs)
In the case of a SAE, the investigator must contact the delegated CRO by telephone or fax 
immediately (within 24 hours of awareness).
The investigator should complete and submit a SAE Worksheet containing all information 
that is required by the Regulatory Authorities to delegated CRO by fax immediately (within 
24 hours of awareness). Toll free fax number for each country is provided on the fax 
coversheet of the SAE Worksheet. In case of fax failure the SAE Worksheet should be 
emailed to the delegated CRO.
If the faxing of a SAE Worksheet is not possible or is not possible within 24 hours, the drug 
safety contact should be informed by phone.  
The contact details of the delegated CROs are:
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
Sponsor's Medical Monitor or his/her designee (see Section II Contact Details of Key 
Sponsor’s Personnel). 
After checking for completeness and accuracy, the delegated CRO will send the SAE 
Worksheet and (when present) source documents (within 24 hours of receipt) to the Sponsor.
Follow-up information for the event should be sent promptly (preferable within 7 days of the 
initial notification).
Full details of the SAE should also be recorded on the medical records and in the eCRF.  The 
investigator must ensure that the information on the SAE Worksheet matches the information 
on the AE pages within the eCRF.

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The following minimum information is required to be completed on the SAE form:
●
ISN/Study number
●
Subject number, sex and age
●
Date of report
●
A description of the SAE (event, seriousness of the event)
●
Causal relationship to the study drug
All SAEs, including death, should be reported up to EOS visit or up to 28 days after the last 
intake of study medication, whichever is last. Any hospitalizations and/or death during the 
Post-Study follow-up period should also be reported as an SAE.
The sponsor or sponsor's designee will submit expedited safety reports (i.e., IND Safety 
Reports) to the regulatory agencies as necessary, and will inform the investigators of such 
regulatory reports. Investigators must submit safety reports as required by their IRB/IEC
within timelines set by regional regulations (i.e., EU). Documentation of the submission to 
and receipt by the IRB/IEC of expedited safety reports should be retained by the site.
The delegated CRO will notify all investigators responsible for ongoing clinical studies with 
the study drug of all SAEs which require submissions per local requirements of 
IRB/IEC/head of the study site.
The investigators should provide written documentation of IRB/IEC notification for each 
report to the Sponsor.
You may contact the sponsor's Medical Monitor for any other problem related to the safety, 
welfare, or rights of the study subject.
For SUSARs from a blinded trial, unblinded Council for International Organizations of 
Medical Sciences-I report will be submitted to the authorities and IRB/IEC where required.
5.5.6
Follow-up to Adverse Events
All adverse events occurring during or after the subject has discontinued the study are to be
followed up until resolved or judged to be no longer clinically significant, or until they 
become chronic to the extent that they can be fully characterized.
If during adverse event follow-up, the adverse event progresses to an "SAE", or if a subject 
experiences a new SAE, the investigator must immediately report the information to the 
sponsor. 
Please refer to Appendix 2 (Liver Safety Monitoring and Assessment) for detailed 
instructions on liver abnormality follow-up responsibilities related to history of symptoms, 
concomitant drug use, alcohol use, and recreational drug use.

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5.5.7
Monitoring of Common Serious Adverse Events
Common serious adverse events are SAEs commonly anticipated to occur in the study 
population independent of drug exposure.  SAEs classified as “common” are progression to 
end stage renal disease.  This does NOT change your reporting obligations or prevent the 
need to report an AE meeting the definition of an SAE as detailed above.  The purpose of this 
is to alert you that some events reported as SAEs may not require expedited reporting to the 
regulatory authorities based on the classification of “common serious adverse events”.  The 
Sponsor will monitor these events throughout the course of the study for any change in 
frequency.  Any changes will be communicated to the participating investigational sites. 
Investigators must report individual occurrences of these events as stated in Section 5.5.5
Reporting of Serious Adverse Events (SAEs).
5.5.8
Procedure in Case of Pregnancy
If a female subject or female partner of a male subject becomes pregnant during the subject’s 
treatment period or within 12 weeks from the discontinuation of dosing, the investigator 
should report the information to the delegated CRO as if it is an SAE. Besides completion of 
the SAE Worksheet, a separate Pregnancy Form should be completed: part A at time of 
pregnancy reporting and part B when outcome of pregnancy is known. The expected date of 
delivery or expected date of the end of the pregnancy, last menstruation, estimated fertility 
date, pregnancy result and neonatal data etc., should be included in this information.
Additional details should be provided in part C during the pregnancy and/or after the 
delivery.
The investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE and will report the outcome to the sponsor.
When the outcome of the pregnancy falls under the criteria for SAEs [spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly (including anomaly in a 
miscarried fetus)], the investigator should respond in accordance with the report procedure 
for SAEs. Additional information regarding the outcome of a pregnancy (which is 
categorized as an SAE) is mentioned below.
●
"Spontaneous abortion" includes abortion and missed abortion.
●
Death of an infant within 1 month after birth should be reported as an SAE regardless of 
its relationship with the study drug. 
●
If an infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by 
the investigator.
●
In the case of a delivery of a living newborn, the "normality" of the infant is evaluated at 
the birth.
●
"Normality" of the miscarried fetus is evaluated by visual examination unless test results 
which indicate a congenital anomaly are obtained prior to miscarriage.

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5.5.9
Supply of New Information Affecting the Conduct of the Study
When new information becomes available, necessary for conducting the clinical study 
properly, the sponsor will inform all investigators involved in the clinical study as well as the 
regulatory authorities, as applicable/needed.  Investigators should inform the IRB/IEC of 
such information when needed.
5.5.10
Emergency Procedures and Management of Overdose
In the event of suspected roxadustat overdose, the subject should receive supportive care and 
monitoring.  If clinically indicated, phlebotomy will be performed [see Section 5.1.5].  The 
Sponsor’s Medical Monitor should be contacted as applicable.
5.6
Test Drug Concentration
For purpose of evaluation of population pharmacokinetics, blood samples will be obtained 
from all subjects. The intention is to collect 6 blood samples per subject at the following 
time points:
A: up to 2 hours prior to dosing
B: 1 to 2  hours  after dosing
C: 2 to 3 hours after dosing, at least 60 minutes after sample B
D: 3 to 5 hours after dosing, at least 60 minutes after sample C 
E: 4 to 6 hours after dosing, at least 60 minutes after sample D
F: 6 to 10 hours after dosing, at least 2 hours after sample E
The blood samples can be collected over 1 to 3 visits, between weeks 2 and 8 of the treatment 
period:
●
samples A, B and C should be collected during the same visit 
●
samples D and E should be collected on the same visit
●
sample F can be collected during the same visit as samples D and E OR during a separate 
visit. Sample F should be collected as late as possible during the pharmacokinetic visit 
(last assessment of the visit)
●
The investigator is free to choose at which study visits, between weeks 2 and 8 of 
treatment, to draw the samples and in which order. The study site will inform the 
subjects on timing and process of the sampling. Based on preference of the study site, 
there is a choice of 3 sampling schedules to perform the pharmacokinetic samples 
collection, see [Table 8].
●
During weeks 1 to 8 subjects will be instructed to record the date and time of study drug 
intake in the Study Medication Diary (SMD), except for the visit(s) when the study drug 
is taken in the clinic. The information will be used to record the date and time of 
roxadustat intake on the day prior to pharmacokinetic sampling and on the day of 
pharmacokinetic sampling in the eCRF. The date and time of each pharmacokinetic
sample and the actual study drug dose taken on the day of sampling will be recorded in 
the eCRF.

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Table 8
Example of Sampling Schedules for Population Pharmacokinetics
Schedulea
Pharmacokinetic Visit 1
Pharmacokinetic Visit 2
Pharmacokinetic Visit 3
1
Collect sample A
Take study drug in clinic
Collect samples B to F
None
None
2a
Collect sample A
Take study drug in clinic
Collect samples B and C
Take study drug at home
Collect samples D to F
None
3a
Collect sample A
Take study drug in clinic
Collect samples B and C
Take study drug at home
Collect sample D and E
Take study drug at home
Collect sample F
a
The order of the pharmacokinetic visits for schedule 2 and 3 is a decision for the investigator
5.6.1
Blood Sample for Roxadustat Pharmacokinetic Analysis
Samples of venous blood (3 mL) for bioanalysis of roxadustat will be collected into 
appropriately labeled tubes containing sodium-heparin as anticoagulant. Immediately after 
collection, blood samples will be kept on melting ice until ready for centrifugation, which 
must be done within 30 minutes of collection. Blood samples will be centrifuged at 1500 g 
for 10 minutes at room temperature in order to obtain plasma. Plasma will be harvested and 
transferred into an appropriately labeled 3.6 mL polypropylene storage tube and stored 
at -20°C or below, within 30 minutes of centrifugation.
Samples will be stored frozen at the site until shipment.
Samples will be sent to the central laboratory packed with sufficient dry ice to keep the 
samples frozen. Further details will be provided in the laboratory manual.
5.7
Other Measurements, Assessments, or Methods
Serum levels of albumin and α1-AGP will be included as covariate in the pharmacokinetic
analysis, since both albumin and α1-AGP is involved in plasma protein binding of 
roxadustat. 
Serum albumin and α1-AGP will be analyzed by the central laboratory using a standardized 
assay. To perform the analysis, 2 mL blood samples will be collected on the same day as 
pharmacokinetic sampling is performed (1-3 visits). If 1 or more pharmacokinetic samples 
are taken at a visit, 1 α1-AGP sample should be taken at that visit as well.
After blood sampling, serum separator tube (SST), samples should be kept in an upright 
position for at least 30 minutes at room temperature to allow blood clotting. The tubes 
should not be refrigerated or opened during this time. After this clotting period, the SST will 
be centrifuged for 10 minutes at 1500 g at room temperature within the next 30 minutes (i.e.,
within 1 hour of sampling). Serum from each tube will be harvested and transferred into a 
properly labeled polypropylene tube and stored at –20°C or below until shipment to the 
central laboratory where they will be analyzed.

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5.7.1
Hepcidin in Serum
For the determination of hepcidin, serum samples will be drawn at the visits as indicated in 
[Table 1]. All details on the processing of the samples, storage and shipment conditions will 
be provided in the laboratory manual.  Results will be blinded to site personnel and the 
Sponsor.
5.7.2
Archival of Serum Samples for Biomarker Analysis
Serum samples will be drawn at the visits as indicated in [Table 1]. The processed samples 
will be stored and archived for potential future analysis of relevant biomarkers, linked with 
the efficacy or safety of the study drugs, prognosis and outcomes. These archival samples 
will be destroyed (if not used in total), maximally 5 years after the last subject completed the 
study. All details on the processing of the samples, storage and shipment conditions will be 
provided in the laboratory manual.
5.7.3
Archival of Urine Samples for Biomarker Analysis
Urine samples will be drawn at the timepoints as indicated in [Table 1]. The processed
samples will be stored and archived for potential future analysis of relevant biomarkers. All
details on the processing of the samples, storage and shipment conditions will be provided in
the laboratory manual.
5.7.4
Optional Genotyping Sample 
It is now known that roxadustat is a substrate of various transporters as well as metabolizing 
enzymes. Some of these proteins are polymorphic resulting in different phenotypes in the 
standard human population. In order to clarify and explain the possible differences observed 
in the study subjects, exploratory (and optional) genotyping sampling will be included in this 
study.
If a separate (optional) informed consent is signed by the subject, a 5 mL whole blood sample 
for genotyping can be done at any time during the study.  The sample will be collected into 
pre-labeled polypropylene collection tubes containing ethylenediaminetetraacetic acid 
(anticoagulant) as anti-coagulant. The sample will be taken via venipuncture or cannulation 
of a forearm vein. The genotyping tube will not require any further processing. Genotyping 
samples will be stored at -20°C or lower until they are shipped to the delegated CRO and 
analyzed under the responsibility of Bioanalysis-Europe of APEB. All details on the 
processing of the samples, storage and shipment conditions will be provided in the laboratory 
manual. The genotyping samples (whole blood and isolated DNA) will be managed in 
strictly secured condition and they will be destroyed after completion of the study according 
to relevant guidance and procedures.
5.8
Total Amount of Blood
The maximum total amount of blood to be collected per subject during the study period, if 
subject completes 104 weeks of treatment, allowing full rescreening and unscheduled visits is 
estimated to be 420 mL.  

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6
TERMINATION OF THE CLINICAL STUDY
1.
When the sponsor is aware of information on matters concerning the quality, efficacy, 
and safety of the study drugs, as well as other important information that may affect 
proper conduct of the clinical study, the sponsor may discontinue the clinical study and 
send a written notice of the discontinuation along with the reasons to the investigator.
2.
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the sponsor of the discontinuation and the reason for it.
7
STATISTICAL METHODOLOGY
7.1
Sample Size
The study is sufficiently powered for both regionally-based primary efficacy endpoints.  A 
minimum of 450 subjects are planned to be randomized to receive roxadustat or placebo (2:1 
with approximately 300 roxadustat versus 150 placebo) in a double-blind manner in order to 
support the primary endpoint(s) of the study.
EU (EMA)
Three hundred subjects for the roxadustat treatment group and 150 subjects for the placebo 
treatment group will provide > 95% test power to demonstrate a statistically significant 
difference between roxadustat and placebo in the primary endpoint assuming that the 
proportion of subjects with response in the roxadustat group is at least 65% and in the 
placebo group is at most 25%. 
USA (FDA)
A sample size of 450 will have > 99% power to detect a 1.0 g/dL difference in mean Hb 
values between the 2 treatment groups, assuming that the common standard deviation is 
1.2 g/dL using an analysis of variance (ANOVA) test with a 0.05 2-sided significance level.
Most importantly, this sample size is required for a meta-analysis of composite safety 
endpoint by pooling studies. Four hundred and fifty subjects is the minimum number of 
subjects that will be randomized. In case this sample size is not sufficient to achieve the 
required number of MACE/MACE+ events, then the number of randomized subjects will be 
increased up to 600. The justification of the required number of events for this safety 
endpoint will be detailed in the pooled cardiovascular safety analysis plan. 
7.2
Analysis Set
The following analysis sets are defined and will be used for the statistical analysis:
●
Full Analysis Set (FAS)
●
Per Protocol Set (PPS)
●
Safety Analysis Set (SAF) 
●
Pharmacokinetic Analysis Set (PKAS).

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7.2.1
Full Analysis Set (FAS)
All randomized subjects who received at least 1 dose of study drug and have at least 1 post-
dose Hb assessment. All efficacy data will be analyzed using the full analysis set.
7.2.2
Per Protocol Set (PPS)
All FAS subjects who received at least 2 weeks of study treatment with valid corresponding 
Hb measurements and without major protocol deviations. Criteria for PPS exclusion will be 
defined in the Statistical Analysis Plan (SAP). The primary and secondary efficacy 
endpoints will also be analyzed using the per protocol set.
7.2.3
Safety Analysis Set (SAF)
All subjects that received any dose of study drug will be included in the safety population. 
All safety data will be analyzed using the safety population.
7.2.4
Pharmacokinetic Analysis Set (PKAS)
The PKAS consists of all randomized subjects who meet the following criteria: 
●
Received at least 1 dose of study drug, and 
●
At least 1 quantifiable plasma concentration of roxadustat was obtained and dosing and 
sampling history has been recorded.
Additional details of the population pharmacokinetics (PPK) analysis set will be described in 
a separate document.
The PKAS will be used for all tables and graphical summaries of the pharmacokinetic data.
7.3
Demographics and Other Baseline Characteristics 
Demographic (age, race, sex) and BL characteristics, including stratification factors, and 
subject disease characteristics will be summarized for the Safety, FAS and PPS populations.  
Descriptive statistics will be calculated for continuous endpoints (e.g., age, weight, BL Hb, 
body mass index and BL eGFR) and frequency counts and percentages will be tabulated for 
categorical endpoints (e.g., sex, race, BL Hb category, region, BL eGFR category and history 
of cardiovascular disease or cerebrovascular disease) by study treatment arm, pooled 
roxadustat group, pooled placebo and overall.
7.4
Analysis of Efficacy 
7.4.1
Analysis of Primary Endpoint
There are 2 separate regionally based primary efficacy endpoints in this study depending 
upon whether the data are being filed to support submission to the EU EMA or to ex-EU
health authorities, such as the US FDA.
EU (EMA)
The primary efficacy endpoint for EU (EMA) is a binary response endpoint (Hb response)
defined as:

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●
Hb ≥11.0 g/dL and a Hb increase from BL by ≥1.0 g/dL in any subject with 
BL Hb > 8.0 g/dL, 
or
●
an increase from BL by ≥2.0 g/dL in any subject with BL Hb ≤8.0 g/dL
at 2 consecutive visits separated by at least 5 days during the first 24 weeks of treatment 
without having received rescue therapy (i.e., RBC transfusion, ESA, or IV iron) prior to Hb
response.
Subjects in FAS who either discontinue or receive rescue therapy before Hb response will be 
regarded as non-responders.  
US (FDA)
The primary efficacy endpoint for US (FDA) is a quantitative endpoint defined as:
The change in Hb from BL to the average level during the evaluation period (defined as 
week 28 until week 52)
Hb results obtained from the central laboratory will be used for all efficacy analyses. 
Baseline Hb is defined as the mean of the 4 central laboratory Hb values prior to the first 
dose of study drug. 
7.4.1.1 Primary Analysis
EU (EMA)
The EU (EMA) primary efficacy endpoint will be analyzed using the FAS.  
The proportion of responders in the EU (EMA) primary efficacy endpoint will be compared 
using a Cochran–Mantel–Haenszel (CMH) test adjusting for the stratification factors 
comparing pooled roxadustat to pooled placebo.  The EU (EMA) primary hypothesis to be 
tested for the primary efficacy analysis is:
H0: Hb responder rate in the roxadustat group = Hb responder rate in the Placebo 
group
versus
H1:  Hb responder rate in the roxadustat group ≠ Hb responder rate in the Placebo 
group
H0 tested at the alpha=0.05 level of significance and will be rejected if the p<0.05 from the 
test.
The CMH adjusted odds ratio (pooled roxadustat versus pooled placebo) and its 95% 
confidence interval (CI) will be provided. In addition, a 95% CI will be calculated for the 
proportion of each roxadustat and placebo based on the exact method of Clopper-Pearson.
US (FDA)
The US (FDA) primary efficacy endpoint will be analyzed using all randomized subjects 
(intent-to-treat principle).

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The Hb change from BL to the average Hb of weeks 28-52 will be analyzed using a Mixed 
Model of Repeated Measurements (MMRM) with unstructured covariance matrix model. 
The model will contain terms for treatment arm, BL measurement, visit, visit x treatment 
arm, and other stratification factors.
The primary hypothesis to be tested for the US (FDA) primary efficacy analysis is:
H0: Hb mean change from BL to the average level from Week 28 to Week 52 in the 
roxadustat group = Hb mean change from BL in the placebo group 
versus:
H1: Hb mean change from BL to the average level of Week 28 to Week 52 in the 
roxadustat group ≠ Hb mean change from BL in the placebo group. 
7.4.1.2
Secondary Analysis
The 2 primary efficacy analyses will be repeated using the PPS.
As a sensitivity analysis, the analysis of the EU (EMA) primary endpoint will be repeated 
using all Hb values during the first 24 weeks regardless of whether rescue therapy was used.
A sensitivity analysis on the 2 primary efficacy endpoints will be performed on the subgroup 
of patients being randomized after the implementation of protocol v2.0. 
7.4.1.3 Subgroup Analysis
The analysis of the primary endpoint and selected secondary endpoints will be repeated 
separately by gender, age group, region, BL Hb categories iron repletion at BL, diabetes and 
eGFR categories. Other subgroups analysis might be added to the SAP.
7.4.2
Secondary Endpoints 
7.4.2.1 Primary Analysis
Once the primary hypothesis has been rejected for the EU (EMA) primary efficacy endpoint 
[see Section 7.4.1.1], the key secondary endpoints below will be tested using a fixed 
sequence testing procedure, as depicted in [Table 9], in order to maintain the overall 2-sided 
type I error rate at 0.05. If P-value from a test is < 0.05, the claim of superiority (or 
noninferiority for tests 6 and 7) will be considered successful and the test will progress to the 
next comparison in sequence. The analysis set for the analysis of the secondary endpoints 
will be the PPS for the noninferiority tests and the FAS for the superiority tests.

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Table 9
Secondary Endpoints Fixed Sequence Testing Procedure
Test 
Endpoint
Test (superiority unless otherwise specified)
1
Hb change from BL
*Pooled roxadustat versus pooled placebo
2
LDL change from BL
*Pooled roxadustat versus pooled placebo
3
Use and time to use of rescue 
therapy
*Pooled roxadustat versus pooled placebo
4
SF-36 PF subscore change from BL
*Pooled roxadustat versus pooled placebo
5
SF-36 vitality subscore change from 
BL
*Pooled roxadustat versus pooled placebo
6
MAP change from BL
Noninferiority of pooled roxadustat versus 
pooled placebo
7
Occurrence and time to occurrence 
of hypertension 
Noninferiority of pooled roxadustat versus 
pooled placebo 
*Subjects randomized to roxadustat QW, BIW and TIW prior to implementation of protocol v2.0 will be pooled 
together. Subjects randomized to placebo will also be pooled together.
●
Change from BL in the average Hb of weeks 28-36, without having received rescue 
therapy within 6 weeks prior to and during this 8-week evaluation period (superiority of 
pooled roxadustat versus pooled placebo) will be analyzed using a MMRM with 
unstructured covariance matrix model. The model will contain terms for treatment arm, 
BL measurement, visit, visit x treatment arm and other stratification factors.
●
Change from BL in LDL cholesterol to the average value of LDL cholesterol of 
weeks 12-28 will be compared (superiority of pooled roxadustat versus pooled placebo) 
using a MMRM model with unstructured covariance containing terms for treatment arm, 
BL measurement, visit, visit x treatment arm, and other stratification factors. 
●
Use and time to use of rescue therapy (composite of RBC transfusion, ESA use and IV 
iron) in the first 24 weeks of treatment will be reported and compared using stratified 
Cox Proportional Hazards regression adjusting for stratification factors. Hazard ratio 
and its 95% will be calculated for the frequency of pooled roxadustat as relative to 
pooled placebo.  Superiority will be declared if the lower bound of the 2-sided 95% CI is 
higher than 1.0.
●
Change from BL in SF-36 PF subscore to the average in weeks 12-28 will be compared 
(superiority of pooled roxadustat versus pooled placebo) for all subjects and in the subset 
of subjects with BL PF subscore below 35, using a MMRM model with unstructured 
covariance containing terms for treatment arm, BL measurement, visit, visit x treatment 
arm, and other stratification factors.
●
Change from BL in SF-36 vitality subscore to the average SF-36 vitality subscore in 
weeks 12-28 will be compared (superiority of pooled roxadustat versus pooled placebo) 
for all subjects and in the subset of subjects with BL vitality subscore below 50, using a
MMRM model with unstructured covariance containing terms for treatment arm, BL
measurement, visit, visit x treatment arm, and other stratification factors.

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●
Change from BL in MAP to the average MAP in weeks 20–28 will be compared 
(noniferiority of pooled roxadustat versus pooled placebo) using a MMRM model with 
unstructured covariance containing terms for treatment arm, BL measurement, visit, visit 
x treatment arm, and other stratification factors.  Noninferiority will be declared if the 
upper bound of the 2-sided 95% CI of the difference between roxadustat and placebo is 
below 2 mmHg.
●
Occurrence and time to occurrence of hypertension will be reported and compared 
(noninferiority of pooled roxadustat versus pooled placebo) using stratified Cox 
Proportional Hazards regression adjusting for stratification factors. Hazard ratio and its 
95% will be calculated for the frequency of pooled roxadustat as relative to pooled 
placebo. Noninferiority will be declared if the upper bound of the 2-sided 95% CI does 
not exceed 1.3. Once this hypothesis is rejected, superiority will be checked but not as 
part of the sequence testing procedure.
7.4.2.2 Secondary Analysis
Each of the key secondary endpoints will be repeated separately by gender, age group, 
region, BL Hb categories, iron repletion at BL, diabetes and eGFR categories. Subgroup 
analyses will be detailed in the SAP.
7.4.3
Analysis of Additional Efficacy Endpoints 
Statistical methods for the additional endpoints detailed in [Section 2.3.3.1] will be detailed 
in the SAP.
7.5
Analysis of Safety
Safety analyses will be performed using the SAF. Safety parameters include AEs, laboratory 
parameters (with special emphasis on excessive Hb response and LFTs), vital signs, renal 
ultrasound findings and ECG parameters. For each safety parameter, unless otherwise 
specified, the last assessment made prior to the first dose of study drug will be used as the BL
for all analyses. All safety analyses will be presented by treatment group; roxadustat and 
placebo. Further details will be described in the SAP.
7.5.1
Adverse Events
AEs will be coded using MedDRA. 
An AE (classified by preferred term) started during the double-blind treatment period will be 
considered a TEAE if it was not present prior to the first dose of study drug, or it was present 
prior to the first dose of study drug but increased in severity during the double-blind 
treatment period. An AE that occurs more than 28 days after the last dose of study 
medication will not be counted as a TEAE.
The number and percentage of subjects reporting TEAEs in each treatment group will be 
tabulated by SOC and preferred term; by SOC, preferred term, and severity; and by SOC, 
preferred term, and relationship to study medication. If more than 1 event occurs with the 
same preferred term for the same subject, the subject will be counted only once for that 

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preferred term using the most severe and most related occurrence for the summarization by 
severity and by relationship to the study medication. 
The overall distribution of TEAEs by severity and relationship to study medication will be 
summarized by treatment group.
The proportion of subjects with Treatment-Emergent Serious AEs, fatal SAEs (i.e., events 
that caused death), and AEs leading to discontinuation of study drug will be summarized by 
SOC, preferred term and treatment group.
TEAEs will also be reported in terms of cumulative incidence versus time and as an 
incidence rate per subject-exposure-year.
For the purpose of EU regulatory filing and other submissions: Adjudicated MACE+ events 
(i.e., myocardial infarction, stroke, death from all causes, hospitalization for chronic heart 
failure, hospitalization for unstable angina) and other pre specified events will be pooled and 
analyzed across multiple studies in the global Phase 3 program.  This analysis will be 
described in a separate pooled safety statistical analysis plan.  For the purpose of US FDA 
regulatory filing: Adjudicated major cardiovascular adverse events (MACE; i.e., myocardial 
infarction, stroke, death from all causes) will be pooled across multiple studies in the global 
Phase 3 program to serve as primary safety endpoint.  The adjudicated MACE events in this 
study will be part of this pooled analysis, but will not be a self-contained endpoint within this 
individual study.  
Adjudicated safety data will be reported in a separate report.   
Listings will be presented of subjects with SAEs, subjects with AEs leading to 
discontinuation and subjects who died.
7.5.2
Clinical Laboratory Parameters
Descriptive statistics for laboratory values (in International System of Units [SI]) and 
changes from BL at each assessment time point and for the maximum and minimum value on 
treatment will be presented by treatment group for all laboratory parameters. Presence of 
Potentially Clinically Significant laboratory values will be reported using similar statistics as 
mentioned for TEAEs.
7.5.3
Vital Signs
Descriptive statistics for vital signs (e.g., systolic and diastolic BP, HR) and their changes 
from BL at each visit and the end of study and for the maximum and minimum value on 
treatment will be presented by treatment group.
7.5.4
ECG
Descriptive statistics for ECG parameters (Heart Rate, PR interval, QRS interval, QT interval 
and QTc [QT interval corrected for heart rate] interval) at BL, and changes from BL, at each 
assessment time point and for the maximum and minimum value on treatment will be 
presented by treatment group. QTc interval will be calculated using both Bazett (QTcB = 
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will be replaced with 60/HR in the correction formula. Presence of Potentially Clinically 
Significant ECG values will be reported using similar statistics as mentioned for TEAEs.
7.5.5
ESA
A variety of sensitivity analyses may be performed to evaluate subjects who did or did not 
receive rescue with ESAs, and excluding CV events occurring during the interval after 
receipt of rescue.
7.6
Analysis of Pharmacokinetics
Plasma concentration data of roxadustat will be subjected to population pharmacokinetic
analysis. The aim of this analysis is to describe the pharmacokinetic behavior of roxadustat
in the target population and to evaluate the effects of selected covariates on the 
pharmacokinetics of roxadustat. The results of the population pharmacokinetic analysis will 
not be reported in the Clinical Study Report but in a separate population pharmacokinetic
modeling report.
7.7
Analysis of Pharmacodynamics
Pharmacodynamic data may be submitted to population pharmacodynamic (PPD) or 
population pharmacokinetic/pharmacodynamic (PPK/PD) modeling. When deemed 
necessary, data from this study may be combined with data from other studies. Results will 
be reported in a separate PPK/PD report.
7.8
Protocol Deviations and Other Analyses  
Protocol deviations requiring notification to the Sponsor as defined in Section 8.1.6 Protocol 
Deviations will be summarized for all randomized subjects by treatment group and total as 
well as by site. A data listing will be provided by site and subject. 
The protocol deviation criteria will be uniquely identified in the summary table and listing. 
The unique identifiers will be as follows:
PD1 - Entered into the study even though they did not satisfy entry criteria, 
PD2 - Developed discontinuation criteria during the study and was not discontinued from 
study treatment,
PD3 - Received wrong treatment or incorrect dose,
PD4 - Received prohibited concomitant treatment. 
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)
The study will have no interim analysis with statistical inference. Safety data and dosing 
decisions will be monitored on an ongoing basis. Ongoing review of safety data will be 
completed by an independent DSMB [see Section 10.1].

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7.10
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
Main analysis of the efficacy endpoints with repeated measures over time will follow the 
MMRM methodology.  In addition, as a sensitivity analysis, a Last Observation Carried 
Forward (LOCF) method will be fitted.
Visit time windows will be detailed in the SAP.
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS
8.1
Procedure for Clinical Study Quality Control
8.1.1
Data Collection
The investigator or site designee is responsible to ensure that all data in the eCRFs and 
queries are accurate and complete and that all entries are verifiable with source documents.
These documents should be appropriately maintained by the site.
The investigator or site designee will enter data into an eCRF using an Electronic Data 
Capture (EDC) system.
In the interest of collecting data in the most efficient manner, the investigator or site designee 
should record data onto the eCRF as soon as possible after the subject visit. The SMD and 
the questionnaires will be completed by the subject. The investigator or designee should 
review the diaries and questionnaires for correct completion whilst the subject is at the site. 
The investigator or site designee will enter only the relevant information from the medication 
diary (i.e., study medication intake data related to pharmacokinetic sampling) and all 
questionnaire date directly into the EDC system. (e)CRFs, diaries and questionnaires and any 
supporting documents should be available for review or retrieval at any given time. 
The monitor should verify the data in the eCRFs with source documents and confirm that 
there are no inconsistencies between them. 
Laboratory tests are performed at the central laboratory and specialist laboratory.
Laboratory results will be provided to the investigator who will print and retain the 
laboratory results and sign abnormalities for their clinical relevance. Laboratory data will be 
transferred electronically to the Data Management Center at predefined intervals during the 
study.
The laboratory may provide the Data Manager with a complete and clean copy of the data.
8.1.2
Specification of Source Documents
Source data must be available at the site to document the existence of the study subjects and 
substantiate the integrity of study data collected. Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject.  

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The following information should be included in the source medical records:
●
Demographic data (date of birth, sex, race, height and body weight)
●
Inclusion and exclusion criteria details
●
Participation in study and signed and dated informed consent forms 
●
Visit dates
●
Medical history and physical examination details
●
Key efficacy and safety data
●
Adverse events and concomitant medication 
●
Results of HemoCue device Hb assessments on all visits
●
Decision on study drug dosage on all visitsResults of relevant examinations (e.g., ECG 
charts, Ultrasound reports)
●
Laboratory printouts (such as Central Laboratory assessments, including certification by 
the investigator of abnormal laboratory data being clinically relevant or not)
●
Dispensing and return of study drug details
●
Reason for premature discontinuation from study treatment (if applicable)
●
Subject number 
●
Method of contraception for subjects or subject’s partner of childbearing potential.
8.1.3
Clinical Study Monitoring
The sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that 
subject's human rights, safety and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP, and study data reported by the 
investigator/sub-investigator are accurate and complete and that they are verifiable with 
study-related records such as source documents. The sponsor is responsible for assigning 
study monitor(s) to this study for proper monitoring. They will monitor the study in 
accordance with planned monitoring procedures. 
8.1.4
Direct Access to Source Data/Documents
The investigator and the study site must accept monitoring and auditing by the sponsor or 
delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities. 
In these instances, they must provide all study-related records, such as source documents 
[refer to Section 8.1.2 "Specification of Source Documents"] when they are requested by the 
sponsor monitors and auditors, the IRB/IEC or regulatory authorities. The confidentiality of 
the subject's identities shall be well protected consistent with local and national regulations 
when the source documents are subject to direct access.
8.1.5
Data Management
Data management will be coordinated by the GDS Department of the sponsor in accordance 
with the SOPs for data management. All study specific processes and definitions will be 
documented by Data Management. eCRF completion will be described in the eCRF 
Completion Guidelines Coding of medical terms and medications will be performed using 
MedDRA and World Health Organization Drug Reference list respectively. 

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8.1.6
Protocol Deviations 
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The investigator is responsible for ensuring 
the study is conducted in accordance with the procedures and evaluations described in this 
protocol and must protect the rights, safety, and welfare of subjects. The investigator should 
not implement any deviation from, or changes of, the protocol, unless it is necessary to 
eliminate an immediate hazard to trial subjects.  
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited.
For the purposes of this protocol, deviations requiring notification to Sponsor are defined as 
any subject who: 
●
Entered into the study even though they did not satisfy entry criteria. 
●
Developed discontinuation criteria during the study and was not discontinued from study 
treatment
●
Received wrong treatment or incorrect dose. 
●
Received prohibited concomitant treatment. 
When a deviation from the protocol is identified for an individual subject, the investigator or 
designee must ensure the Sponsor is notified. The Sponsor will follow-up with the 
investigator, as applicable, to assess the deviation and the possible impact to the safety and / 
or efficacy of the subject to determine subject continuation in the study. 
If a deviation impacts the safety of a subject, the investigator must contact the Sponsor 
immediately.
The investigator will also assure that deviations meeting IRB/IEC and applicable regulatory 
authorities’ criteria are documented and communicated appropriately.  All documentation 
and communications to the IRB/IEC and applicable regulatory authorities will be provided to 
the Sponsor and maintained within the Trial Master File.  
NOTE:  Other deviations outside of the categories defined above that are required to be 
reported by the IRB/IEC in accordance with local requirements will be reported, as 
applicable. 
8.1.7
End of Trial in All Participating Countries
The end of trial in all participating countries is defined as the Last Subject’s Last Visit.
8.2
Ethics and Protection of Subject Confidentiality 
8.2.1
Institutional Review Board (IRB) Independent Ethics Committee (IEC) / 
Competent Authorities (CA)
The clinical study may only begin after receipt of a written approval from the IRB/ IEC. 
Documents to be submitted to the IRB/IEC may differ per committee but should at least 

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include the final study protocol, subject information, informed consent and the Investigator’s 
Brochure, containing information on the study drug.
This protocol and the required supporting documents will be submitted to the Competent 
Authority (CA) according to the national laws. Prior to starting the study, approval must be 
obtained in writing, where applicable. The original or at least a photocopy of this statement 
must be forwarded to the sponsor.
The investigator shall make accurate and adequate written progress reports to the 
IRB/IEC/CA at appropriate intervals, not exceeding 1 year. The investigator shall make an 
accurate and adequate final report to the IRB/IEC/CA for APEB sponsored studies within 
1 year after last subject out or termination of the study.
8.2.2
Ethical Conduct of the Study
The investigator(s) and all parties involved in this study should conduct the study in 
adherence to ICH GCP Guidelines and the applicable laws and regulations.
8.2.3
Informed Consent of Subjects
8.2.3.1 Subject Information and Consent
Prior to execution of the clinical study, the investigator should prepare the written informed 
consent form and other written information in collaboration with the delegated CRO/sponsor
and revise the information whenever necessary. The written informed consent form and any 
other written information should be submitted to the sponsor and be subject to prior approval 
by the IRB/IEC.
●
The investigator/sub-investigator is responsible for explaining the nature and purpose of 
the study as well as other study-related matters to subjects, using the written information, 
and for obtaining their full understanding and written consent to participate in the study 
of their own free will.
●
The investigator or delegate who provided explanations (including collaborators who 
gave supportive information, if applicable) and the subject should sign and date the 
written information, or write down his/her name, and date the form.
●
Informed consent must be obtained by the time that the first observations / examinations 
of the screening period are performed. Guardian consent should be obtained from the 
proxy consenter, before start of pre-investigational period.
●
The investigator or other responsible personnel must give a copy of the signed consent 
form to the subject and store the original appropriately in accordance with the rules at the 
study site concerned. 
●
The investigator or other responsible personnel should note the following when 
obtaining consent from subjects:
o
No subject may be subjected to undue influence, such as compulsory enrollment 
into a study.

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o
The language and expressions used in the written information should be as plain 
and understandable as possible. Subjects should be given the opportunity to ask 
questions and receive satisfactory answers to the inquiry, and should have adequate 
time to decide whether or not to participate in the study. Written information 
should not contain any language or contents that causes the subject to waive or 
appears to waive any legal rights, or that releases/mitigates or appears to 
release/mitigate the study site, the investigator/sub-investigator, collaborators, or 
the sponsor from liability for negligence.
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor upon request.
8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information
1.
The investigator/sub-investigator will immediately inform the subject orally whenever 
new information becomes available that may be relevant to the subject's consent or may 
influence the subject's willingness to continue participation in the study (e.g., report of 
serious adverse drug reactions). The communication should be documented in the
subject's medical records, and it should be confirmed whether the subject is willing to 
remain in the study or not. 
2.
If the investigator recognizes the necessity to revise the written information in the terms 
and conditions applicable to paragraph 1, the written information should be revised 
immediately based upon the newly available information, and be re-approved by the 
IRB/IEC. 
3.
The investigator/sub-investigator must obtain written informed consent to continue 
participation with the revised written information defined in paragraph 2, even if subjects 
are already informed of the relevant information orally. The investigator or other 
responsible personnel who provided explanations (including collaborators who gave 
supportive information, if applicable) and the subject should sign and date the informed 
consent form, or write down his/her name and date the form. The investigator or other 
responsible personnel should give a copy of the signed informed consent form to the 
subject who had given consent with the written information and store the original 
appropriately as done for the previous informed consent. 
8.2.4
Subject Confidentiality
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Such medical information may be 
given only after approval of the subject to the subject's physician or to other appropriate 
medical personnel responsible for the subject's well-being.
The sponsor, its board members, and its personnel shall not disclose any confidential 
information on subjects obtained during the performance of their duties in the clinical study 
without justifiable reasons.

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Even though any individuals involved in the study, including the study monitors and auditors, 
may get to know matters related to subject's privacy due to direct access to source 
documents, or from other sources, they may not leak the content to third parties. 
The sponsor affirms the subject's right to protection against invasion of privacy. Only a 
subject identification number and/or initials will identify subject data retrieved by the 
sponsor. However, the sponsor requires the investigator to permit the sponsor, sponsor's 
representative(s), the IRB/IEC and when necessary, representatives of the regulatory health 
authorities to review and/or to copy any medical records relevant to the study.
The sponsor will ensure that the use and disclosure of protected health information obtained 
during a research study complies with the federal and/or regional legislation related to the 
privacy and protection of personal information (i.e., HIPAA).
8.3
Administrative Matters
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the Investigator's Brochure and other pertinent information is confidential and remains 
the property of the sponsor. Details should be disclosed only to the persons involved in the 
approval or conduct of the study. The investigator may use this information for the purpose 
of the study only. It is understood by the investigator that the sponsor will use the 
information obtained during the clinical study in connection with the development of the 
drug and therefore may disclose it as required to other clinical investigators or to regulatory 
agencies. In order to allow for the use of the information derived from this clinical study, the 
investigator understands that he/she has an obligation to provide the sponsor with all data 
obtained during the study.
Publication of the study results is discussed in the Clinical Study Agreement.
8.3.2
Documents and Records Related to the Clinical Study
The sponsor will provide the investigator and/or institution with the following:
For EU:
●
Study protocol (and amendments, as applicable)
●
Investigator’s Brochure (and amendments, as applicable)
●
Investigational Medicinal Product Dossier (IEC only if applicable per local regulations)
●
CRFs and SAE Worksheet
●
Investigator’s File
●
Study drug with all necessary documentation
●
Study contract
●
Approval of regulatory authority and all documents related to submission.
In order to start the study, the investigator and/or study site is required to provide the 
following documentation to the sponsor: 

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For EU:
●
Financial disclosure in compliance with federal regulation 21CFR Part 54
●
Signed and dated FDA form 1572, if conducted under a U.S. IND
●
If the investigator submits to the IEC: Submission letter to the IEC
●
Signed confidentiality agreement
●
Signed Investigator's Statement in this protocol
●
Executed Study Contract
●
IEC/IRB approval of the protocol, protocol amendments (if applicable) and ICF (and 
separate authorization form, if appropriate), stating clearly the sponsor's name, study 
number and study drug, including a membership list with names and qualifications
●
Current Curricula Vitae of all investigators (signed and dated, brief and in English.)
●
Laboratory normal reference ranges (if applicable, signed and dated by the responsible 
laboratory employee)
●
Medical/Laboratory/Technical procedures/tests certifications or accreditations or 
established quality control or other validation, where required.
At the end of the study, the sponsor is responsible for the collection of:
●
Study documentation,
●
Unused study drug
The investigator will archive all study data (e.g., Subject Identification Code List, source 
data, and Investigator's File) and relevant correspondence. Essential documents should be 
retained until at least 2 years after the last approval of a marketing application in an ICH 
region and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents should be retained for a longer 
period however if required by the applicable regulatory requirements or by an agreement 
with the sponsor.  It is the responsibility of the sponsor to inform the investigator/institution 
when these documents no longer need to be retained.  The investigator agrees to obtain the 
sponsor's agreement prior to disposal, moving, or transferring of any study-related records. 
The sponsor will archive and retain all documents pertaining to the study according to ICH 
GCP.
Data generated by the methods described in the protocol will be recorded in the subjects' 
medical records and/or study progress notes. All data will be entered on eCRFs supplied for 
each subject. 
8.3.3
Protocol Amendment and/or Revision
Any changes to the study that arise after approval of the protocol must be documented to the 
regulatory authority, and the IRB/IEC (if applicable). Amendments to this protocol must be 
signed by the sponsor and the investigator. Written verification of IRB/IEC approval will be 
obtained before any amendment is implemented which affects subject safety or the 
evaluation of safety, and/or efficacy. Modifications to the protocol that are administrative in 

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nature do not require IRB/IEC approval, but will be submitted to the IRB/IEC for their 
information, if required by local regulations.
If there are changes to the Informed Consent, written verification of IRB/IEC approval must 
be forwarded to the sponsor.  An approved copy of the new Informed Consent must also be 
forwarded to the sponsor.
8.3.4
Insurance of Subjects and Others
The Sponsor has covered this study by means of an insurance of the study according to 
national requirements. The name and address of the relevant insurance company, the 
certificate of insurance, the policy number and the sum insured are provided in the 
Investigator's File. 
8.3.5
Investigator Indemnity 
The sponsor agrees to, and does hereby, indemnify, defend and hold the investigator 
harmless from and against all claims, demands, actions, and proceedings which may be 
brought or asserted against the investigator to recover damages and losses for or attributable 
to bodily injury, sickness, disease, or death arising from or alleged to arise from or be 
reasonably attributable to this study.
Notwithstanding the foregoing, the sponsor does not, however, agree to indemnify, defend or 
hold the investigator harmless from claims, demands, actions, proceedings or damages 
resulting or claimed to have resulted from:
●
Failure of the investigator to evaluate or properly interpret available information that is 
relevant to this study, and for independent decisions made as the result of such failure;
●
Failure of the investigator to adhere to all provisions of the protocol for this study and to 
written recommendations and written instructions delivered to the investigator by the 
sponsor concerning the administration and use of drug substances, including the placebo, 
involved in this study;
●
Failure of the investigator to render professional service or to conduct this study in a 
normal, prudent manner.
A condition of this indemnity obligation is that, whenever the investigator has information 
from which it may be reasonably concluded that an incident of bodily injury, sickness, 
disease or death has occurred, the investigator shall immediately give notice to the sponsor of 
all pertinent data surrounding any such incident, and, in the event a claim is made or a suit is 
brought, the investigator shall assist the sponsor and cooperate in the gathering of 
information with respect to the time, place, and circumstances and in obtaining the names 
and addresses of the injured parties and available witnesses. The investigator shall not, 
except at his own cost, voluntarily make any payment or incur any expense in connection 
with any such claim or suit without the prior written consent of the sponsor.

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8.3.6
Signatory Investigator for Clinical Study Report
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study 
report which forms part of a marketing authorization application be signed by a Coordinating 
(principal) Investigator. The Coordinating Investigator will have the responsibility to review 
the final study results to confirm to the best of his/her knowledge it accurately describes the 
conduct and results of the study. A Coordinating Investigator will be selected from the 
participating investigators by Astellas prior to database lock.
9
QUALITY ASSURANCE
The sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that trials are conducted and data are generated, documented 
(record), and reported in compliance with the protocol, GCP, and applicable regulatory 
requirement(s).
The sponsor or sponsor's designee may arrange to inspect/audit the clinical study at any or all 
investigational sites. The auditor is independent from the clinical monitoring and project 
management team at the sponsor. The audit may include on-site review of regulatory 
documents, case report forms, and source documents. Direct access to these documents will 
be required by the auditors.
10
STUDY ORGANIZATION
10.1
Independent Data and Safety Monitoring Board (DSMB)
A DSMB will review pre-specified safety data periodically in collaboration with the sponsor
to ensure subject safety. The DSMB will review safety data in a blinded and unblinded 
manner while the sponsor remains blinded.
A separate DSMB charter will establish the process, meeting frequency and scope of 
responsibilities.  
10.2
Independent Event Review Committee (IERC)
An IERC will adjudicate all relevant cardiovascular and cerebrovascular events in a blinded 
manner to ensure consistent safety assessment. Details will be specified in an IERC Charter.
10.3
Other Study Organization
Not applicable.

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11
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Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, Schwab SJ, Goodkin 
DA. The effects of normal as compared with low hematocrit values in patients with cardiac 
disease who are receiving hemodialysis and epoetin. N Engl J Med. 1998;339(9):584-90.  
Besarab A, Frinak S and Yee J. "What is so bad about a hemoglobin level of 12 to 13 g/dL for chronic 
kidney disease patients anyway?" Advances in Chronic Kidney Disease 16.2(2009):131-42.
Büchler P, Reber HA, Büchler M, Shrinkante S, Büchler MW, Friess H, Semenza GL, Hines OJ. 
Hypoxia-inducible factor 1 regulates vascular endothelial growth factor expression in human 
pancreatic cancer. Pancreas 26.1(2003):56-64.
Cella D.The Functional Assessment of Cancer Therapy-Anemia (FACT-An) Scale: a new tool for the 
assessment of outcomes in cancer anemia and fatigue. Semin Hematol. 1997 Jul;34(3 Suppl 
2):13-9
Collins AJ, Ma JZ, Xia A, Ebben J. Trends in anemia treatment with erythropoietin usage and patient 
outcomes. Am J Kidney Dis 1998;32(supl4):133-S141.
Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, Van Lente F, Levey AS. Prevalence 
of Chronic Kidney Disease in the United States. JAMA. 2007;298(17):2038-2047. 
Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A. 
Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl 
J Med. 2006;355(20):2071-2084.
Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. Correction of the Anemia of End-
Stage Renal Disease with Recombinant Human Erythropoietin. N Engl J Med 1987; 316:73-78.
Eschbach JW, Adamson JW. Guidelines for recombinant human erythropoietin therapy. Am J Kidney 
Dis. Aug 1989;14;(2 Supl 1):2-8. 
Eschbach JW, Abdulhadi MH, Browne JK, Delano BG, Downing MR, Egrie JC, Evans RW, 
Friedman EA, Graber SE, Haley NR, et al. Recombinant human erythropoietin in anemic 
patients with endstage renal disease. Results of a phase III multicenter clinical trial. Annals of 
Internal Medicine 1989;111(12):992-1000.
Fan C, Iacobas DA, Zhou D, Chen Q, Lai JK, Gavrialov O, Haddad GG. Gene expression and 
phenotypic characterization of mouse heart after chronic constant or intermittent hypoxia. 
Physiol Genomics 2005;22(3):292-307.
Fishbane  S, Besarab A. Mechanism of increased mortality risk with erythropoietin treatment to 
higher hemoglobin targets.  Clinical Journal of the American Society of Nephrology 
2007;2(6):1274-82.
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu C. Chronic Kidney Disease and the Risks of 
Death, Cardiovascular Events, and Hospitalization. N Engl J Med 2004;351:1296-1305.

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Gray MJ, Zhang J, Ellis LM, Semenza GL, Evans DB, Watowich SS, Gallick GE. HIF-1alpha, 
STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates 
Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas. 
Oncogene 2005;24(19):3110-19.
Greijer AE, van der Groep P, Kemming D, Shvarts A, Semenza GL, Meijer GA, van de Wiel MA, 
Belien JA, van Diest PJ, van der Wall E. Up-regulation of gene expression by hypoxia is 
mediated predominantly by hypoxia-inducible factor 1 (HIF-1). J Pathol 2005;206(3):291-304.
Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC. Differential roles of hypoxia-inducible factor 
1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol 2003 
23(24):9361-74.
Jungers PY, Robino C, Choukroun G, Nguyen-Khoa T, Massy ZA. Incidence of anaemia, and use of 
epoetin therapy in pre-dialysis patients: a prospective study in 403 patients. Nephrol Dial 
Transplant 2002;17(9):1621-7.
Langsetmo I, Stephenson R, Jacob C, Zhang W, Klaus S, Lin A et al. Effect of FG-4592 in a Rat 
Model of Anemia of Chronic Disease. 301_05_3510_047 (ACD6). 2005.
National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI). KDOQI 
Clinical Practice Guideline and Clinical Practice Recommendations for Anemia in Chronic 
Kidney Disease: 2007 Update of Hemoglobin Target 
(http://www.kidney.org/professionals/KDOQI/guidelines_anemiaUP/guide1.htm )
National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI). 
http://www.kidney.org/professionals/kdoqi/
Peyssonnaux C, Nizet V, Johnson RS. Role of the hypoxia inducible factors HIF in iron metabolism. 
Cell Cycle 2008;7(1): 28-32.
Scortegagna M, Ding K, Zhang Q, Oktay Y, Bennett MJ, Bennett, Shelton JM, Richardson JA, Moe 
O, Garcia JA. HIF-2alpha regulates murine hematopoietic development in an erythropoietin-
dependent manner. Blood 2005;105(8):3133-40.
Semenza GL. Hypoxia-inducible factor 1: master regulator of O2 homeostasis. Curr.Opin.Genet.Dev. 
1998;8(5);588-94.
Semenza, GL. HIF-1: mediator of physiological and pathophysiological responses to hypoxia. 
J.Appl.Physiol 2000;88(4):1474-80.
Singh H, Reed J, Noble S, Cangiano JL, Van Wyck DB. Effect of Intravenous Iron Sucrose in 
Peritoneal Dialysis Patients Who Receive Erythropoiesis-Stimulating Agents for Anemia: A 
Randomized, Controlled Trial. Clin J Am Soc Nephrol 2006;1:475-482.
Temple R. Hy’s law: predicting serious hepatotoxicity.  Pharmacoepidermiol Drug Saf 2006 
Apr;15(4):241-3.
Thilly N, Stengel B, Boini S, Villar E, Couchoud C Frimat L. Evaluation and determinants of 
underprescription of erythropoiesis stimulating agents in pre-dialysis patients with anaemia. 
Nephron Clin Pract. 2008;108(1):67-74.

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Tonelli M, Wiebe N, Culleton B, House A, Rabbat C, Fok M, McAlister F, Garg AX. Chronic Kidney 
Disease and Mortality Risk: A Systematic Review. JASN 2006;17:(7): 2034-2047.
Unger E. F. FDA Department of Health and Human Services. Joint Meeting of the Cardiovascular 
and Renal Drugs Advisory Committee and the Drug Safety and Risk Management Advisory 
Committee. 2007.
Unger E. F. FDA Perspectives on ESAs for Anemia of Chronic Renal Failure: Hemoglobin Target 
and Dose Optimization. 2007. 
United States Renal Data System (USRDS). Annual Data Report 2000 
(http://www.usrds.org/atlas00.aspx)
United States Renal Data System (USRDS). Annual Data Report 2001 
(http://www.usrds.org/atlas01.aspx)
United States Renal Data System (USRDS). Annual Data Report 2002 
(http://www.usrds.org/atlas02.aspx)
United States Renal Data System (USRDS). Annual Data Report 2009 
(http://www.usrds.org/atlas09.aspx)
United States Renal Data System (USRDS). Annual Data Report 2011 
(http://www.usrds.org/atlas11.aspx)
Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS 
heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 1995;92(12):5510-14.
Warnecke C, Zaborowska Z, Kurreck J, Erdmann VA, Frei U, Wiesener M, Eckardt KU. 
Differentiating the functional role of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha 
(EPAS-1) by the use of RNA interference: erythropoietin is a HIF-2alpha target gene in Hep3B 
and Kelly cells. The FASEB Journal 2004;18(12):1462-64.
Winearls CG, Oliver DO, Pippard MJ, Reid C, Downing MR, Cotes PM. Effect of human 
erythropoietin derived from recombinant DNA on the anaemia of patients maintained by 
chronic haemodialysis. Lancet 1986;2(8517):1175-8.
Zhang Y, Thamer M, Stefanik K, Kaufman J, Cotter DJ. Epoetin Requirements Predict Mortality in 
Hemodialysis Patients. Am J Kidney Dis 2004;44(5):866-876.
Zoccali C, Kramer A, Jager KJ. Chronic kidney disease and end-stage renal disease – a review 
produced to contribute to the report ‘the status of health in the European union: towards a 
healthier Europe’. NDT Plus 2010;3(3):213-24.

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12
APPENDICES 
12.1
Appendix 1:  List of Prohibited Concomitant Medication
●
Iron-chelating agents (e.g., deferoxamine, deferiprone, or deferasirox therapy) from 
4 weeks prior to randomization until EOS visit.
●
Androgens from the day of randomization until EOS visit.
●
Dapsone in any dose amount from the day of randomization until EOS visit.
●
Chronic use of acetaminophen (paracetamol) > 2.0 g/day from the day of randomization 
until EOS visit.
●
Any hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) other than 
roxadustat, as allocated by randomization, until EOS visit.

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12.2
Appendix 2: Liver Safety Monitoring and Assessment
If laboratory testing for a subject randomized in study and receiving study drug reveals an 
increase of serum AT to > 3× ULN, or bilirubin > 2× ULN, at least all 4 of the usual serum 
hepatic measures (ALT, AST, ALP, and TBL)  should be repeated. Testing should be repeated 
within 48 – 72 hours of notification of the test results. For studies for which a central 
laboratory is used, alerts will be generated by the central lab regarding moderate and severe
liver abnormality, to inform the investigator, study monitor and study team. Subjects should be 
asked if they have any symptoms suggestive of hepatobiliary dysfunction.
Definition of Liver Abnormalities
Confirmed abnormalities will be characterized as moderate and severe where ULN:
ALT or AST
Total Bilirubin
Moderate
>3× ULN
or
> 2× ULN
Severe*
>3× ULN
and
> 2× ULN
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following:
●
ALT or AST > 8× ULN
●
ALT or AST > 5× ULN for more than 2 weeks
●
ALT or AST > 3× ULN and International Normalized ratio (INR) > 1.5 (if INR testing 
is applicable/evaluated)
●
ALT or AST > 3× ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring 
and follow-up.
Follow-up Procedures
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, 
physical examination and laboratory tests. The site should complete the Liver Abnormality 
Case Report Form (LA-CRF) or an appropriate document.  Subjects with confirmed 
abnormal liver function testing should be followed as described below.
Confirmed moderately abnormal LFTs should be repeated 2-3 times weekly then weekly or 
less if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic.  
Severe hepatic liver function abnormalities as defined above, in the absence of another 
etiology, may be considered an important medical event and reported as a SAE.  The sponsor
should be contacted and informed of all subjects for whom severe hepatic liver function 
abnormalities possibly attributable to study drug are observed.

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To further assess abnormal hepatic laboratory findings, the investigator is expected to:
●
Obtain a more detailed history of symptoms and prior or concurrent diseases.  Symptoms 
and new onset-diseases should be recorded as ’adverse events’ on the AE page of CRF. 
Illnesses and conditions such as hypotensive events, and decompensated cardiac disease 
that may lead to secondary liver abnormalities should be noted. Non-alcoholic 
steatohepatitis is seen in obese hyperlipoproteinemic, and/or diabetic subjects and may 
be associated with fluctuating aminotransferase levels.  The investigator should ensure 
that the medical history form captures any illness that pre-dates study enrollment that 
may be relevant in assessing hepatic function. 
●
Obtain a history of concomitant drug use (including non-prescription medication, 
complementary and alternative medications), alcohol use, recreational drug use, and 
special diets.  Medications, including dose, should be entered on the concomitant 
medication page of CRF.  Information on alcohol, other substance use, and diet should 
be entered on the LA-CRF or an appropriate document.
●
Obtain a history of exposure to environmental chemical agents
●
Based on the subject’s history,  other testing may be appropriate including: 
o
acute viral hepatitis (A,B, C, D, E or other infectious agents). 
o
ultrasound or other imaging to assess biliary tract disease
o
other laboratory tests including INR, direct bilirubin
●
Consider gastroenterology or hepatology consultations
●
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document.
Study Discontinuation
In the absence of an explanation for increased LFTs, such as viral hepatitis, pre-existing or 
acute liver disease or exposure to other agents associated with liver injury, the subject may be 
discontinued from the study.  The investigator may determine that it is not in the subject’s 
best interest to continue study enrollment.  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%). 
*Hy’s Law Definition-Drug induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10-50% mortality 
(or transplant). “The 2 “requirements” for Hy’s Law are: 1) Evidence that a drug can cause 
hepatocelluary-type injury, generally shown by an increase in transaminase elevations higher 
3 times the upper limit of normal (“2 x ULN elevations are too common in treated and 
untreated subjects too be discriminating”). 2) Cases of increased bilirubin (at least 2 x ULN) 
with concurrent transaminase elevations at least 3 x ULN and no evidence of intra- or extra-

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hepatic bilirubin obstruction (elevated alkaline phosphatase) or Gilbert’s syndrome.  [Temple 
R. Hy’s law: predicting serious hepatotoxicity.  Pharmacoepidermiol Drug Saf 2006 
Apr;15(4):241-3.]”
In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, drug should be discontinued.
Reference
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” issued by 
FDA on July 2009.  

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12.3
Appendix 3:  Instructions for Subjects Moving from Protocol v1.0 to 
Protocol v2.0
Visit Schedule
Subjects who have entered the study under protocol v1.0, upon signing the updated informed 
consent, adapted their visit frequency according to Table 1, Schedule of Assessments.  For 
example, if the subject signs the informed consent for protocol v2.0 at scheduled week 3 
(according to protocol v1.0), subject will attend clinic at week 4, week 6 and all subsequent 
visits as per Schedule of Assessments.
Dosing Instructions for Subjects Moving from Protocol v1.0 to Protocol v2.0 Dosing
Study drug will be dosed TIW throughout the Treatment Period, unless otherwise specified.
Subjects who have entered the study under protocol version 1.0 should, upon signing the 
updated informed consent, adapt their dose frequency and dose amount. At this visit it is first 
determined if the subject would need a dose titration according to the dose adjustment rules 
as per Section 5.1.2  Once that is established, patients are converted per the below 
instructions. The dose assigned must not exceed the maximum allowed dose of 3.0 mg/kg 
bodyweight or 300 mg per administration, whichever is lower.  For subjects on permanent 
dialysis dose assigned must not exceed 3.0 mg/kg (based on dry weight in HD subjects and 
weight minus abdominal fluid based on last filling in peritoneal dialysis subjects) or 400 mg 
per administration, whichever is lower.
a) Subjects in the correction period or maintenance period on TIW dosing, will continue 
on TIW dosing for the remainder of the treatment period. If needed their dose will be
adjusted according to the conversion table below, at the visit when the updated 
informed consent is signed.
Current TIW dose (mg)
20
40
50
70
100
120
150
200
250
300
350
400
If no dose titration needed
20
40
50
70
100
100
150
200
250
300
300
300
If up titration needed*
40
50
70
100
150
150
200
250
300
300
300
300
If down titration needed*
#
20
40
50
70
100
100
150
200
250
300
300
b) Subjects in the maintenance period on BIW dosing will change to TIW dosing 
immediately, per the conversion table below, at the visit when the updated informed 
consent is signed.
Current BIW maintenance dose (mg)
20
40
50
70
100
120
150
200
250
300
350
400
If no dose titration needed
20
20
40
50
70
70
100
150
150
200
250
250
If up titration needed*
20
40
40
70
70 
100
150
150
200
250
250 300
If down titration needed*
#
20
20
40
50
70
70
100
150
150
200
200

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c) Subjects in the maintenance period on QW dosing will change to TIW dosing 
immediately, per the conversion table below, at the visit when the updated informed 
consent is signed.
Current QW maintenance dose (mg)
20
40
50
70
100
120
150
200
250
300
350
400
If no dose titration needed
20
20
20
20
40
40
50
70
70
100
100
150
If up titration needed*
20 
20
20
40
40
50
70
70 
100
100
150
150
If down titration needed*
#
#
20
20
20
40
40
50
70
70
100
100
* Up or down titrations were only applicable when the criteria for dose adjustment has been met
# Contact the medical monitor if down titration is needed
Note:  There are no adaptations to dose frequency or dose amount for subjects moving from 
Protocol v2.0 to Protocol v2.1.
ESA Rescue Therapy
Protocol v2.0 allows subjects to receive ESA rescue treatment twice. If a third ESA treatment 
is required the subject will be discontinued from the study treatment.
If, upon implementation of protocol v2.0, a subject has already received 3 or more ESA 
treatments (under protocol v1.0) they can initially continue in the study.  The subject will
however, be discontinued from study treatment if a further ESA rescue treatment is required.

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12.4
Appendix 4:  Instructions for Subjects Requiring Dialysis
Subjects who initiate temporary or permanent dialysis treatment are allowed to continue in 
the study. All modes of dialysis, i.e., HD, hemodiafiltration (HDF) and peritoneal dialysis 
are allowed.
12.4.1
Dosing
●
Subjects should continue with the same dose and dose frequency of study drug as 
they were on prior to dialysis initiation.
●
For HD/HDF subjects it is recommended that study drug is administered any time 
after completion of dialysis (if dosing is scheduled on a dialysis day) to avoid 
potential bias on certain study assessments.
12.4.2
Dose Adjustment
●
The dose adjustment rules remain unchanged (see Section 5.1.2). 
●
The maximum allowed dose in subjects on permanent dialysis is 3.0 mg/kg (based on 
dry weight in HD subjects and weight minus abdominal fluid based on last filling in 
peritoneal dialysis subjects) or 400 mg per administration, whichever is lower. 
12.4.3
Rescue Therapy – ESA Use
If subjects meet the criteria for ESA rescue therapy whilst on dialysis, ESAs will be 
administered IV or SC according to the Package Insert or SmPC of the respective ESA for 
dialysis patients.
12.4.4
Health Related Quality of Life
Additional questionnaires will be completed on day of first dialysis, 4 weeks later and 
12 weeks later, prior to initiation of the procedure.
12.4.5
Timing of Study Assessments
●
If a study visit occurs on a dialysis day, all study assessments should be performed 
before start of dialysis. 
●
BPand HR should be measured in triplicate prior to and after end of dialysis 
(HD/HDF subjects only). 

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12.5
Appendix 5:   Short Form-36 Health Survey (SF-36)
Your Health and Well-Being
This survey asks for your views about your health.  This information will 
help keep track of how you feel and how well you are able to do your 
usual activities. Thank you for completing this survey!
For each of the following questions, please tick the one box that best 
describes your answer.
1.
In general, would you say your health is:
Excellent
Very good
Good
Fair
Poor





  
1
  
2
  
3
  
4
  
5
2.
Compared to one year ago, how would you rate your health in 
general now?
Much better
now than one
year ago
Somewhat
better
now than one
year ago
About the
same as
one year ago
Somewhat
worse
now than one
year ago
Much worse
now than one
year ago





  
1
  
2
  
3
  
4
  
5

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3.
The following questions are about activities you might do during a 
typical day.  Does your health now limit you in these activities?  If so, 
how much? 
Yes,
limited
a lot
Yes,
limited
a little
No, not
limited
at all



a
Vigorous activities, such as running, lifting 
heavy objects, participating in strenuous sports ......................
1 .............
2 .............
3
b
Moderate activities, such as moving a table, pushing 
a vacuum cleaner, bowling, or playing golf.............................
1 .............
2 .............
3
c
Lifting or carrying groceries....................................................
1 .............
2 .............
3
d
Climbing several flights of stairs.............................................
1 .............
2 .............
3
e
Climbing one flight of stairs ....................................................
1 .............
2 .............
3
f
Bending, kneeling, or stooping................................................
1 .............
2 .............
3
g
Walking more than a mile........................................................
1 .............
2 .............
3
h
Walking several hundred yards................................................
1 .............
2 .............
3
i
Walking one hundred yards .....................................................
1 .............
2 .............
3
j
Bathing or dressing yourself....................................................
1 .............
2 .............
3

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4.
During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of your physical health?
All of
the time
Most of
the time
Some of
the time
A little of
the time
None of
the time




a
Cut down on the amount of
time you spent on work or 
other activities..................................
1.............
2..............
3..............
4 .............
5
b
Accomplished less than you 
would like ........................................
1.............
2..............
3..............
4 .............
5
c
Were limited in the kind of 
work or other activities....................
1.............
2..............
3..............
4 .............
5
d
Had difficulty performing the
work or other activities (for 
example, it took extra effort) ...........
1.............
2..............
3..............
4 .............
5
5.
During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of any emotional problems (such as feeling depressed or 
anxious)?
All of
the time
Most of
the time
Some of
the time
A little of
the time
None of
the time




a
Cut down on the amount of
time you spent on work or 
other activities..................................
1.............
2..............
3..............
4 .............
5
b
Accomplished less than you 
would like ........................................
1.............
2..............
3..............
4 .............
5
c
Did work or other activities
less carefully than usual...................
1.............
2..............
3..............
4 .............
5

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6.
During the past 4 weeks, to what extent has your physical health or 
emotional problems interfered with your normal social activities with 
family, friends, neighbours, or groups?
Not at all
Slightly
Moderately
Quite a bit
Extremely





 
1
 
2
 
3
 
4
 
5
7.
How much bodily pain have you had during the past 4 weeks?
None
Very mild
Mild
Moderate
Severe
Very severe






 
1
 
2
 
3
 
4
 
5
 
6
8.
During the past 4 weeks, how much did pain interfere with your 
normal work (including both work outside the home and housework)?
Not at all
A little bit
Moderately
Quite a bit
Extremely





 
1
 
2
 
3
 
4
 
5

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9.
These questions are about how you feel and how things have been with 
you during the past 4 weeks.  For each question, please give the one 
answer that comes closest to the way you have been feeling.  How much 
of the time during the past 4 weeks…
10.
During the past 4 weeks, how much of the time has your physical health 
or emotional problems interfered with your social activities (like 
visiting with friends, relatives, etc.)?
All of
the time
Most of
the time
Some of
the time
A little of
the time
None of
the time





 
1
 
2
 
3
 
4
 
5
All of
the time
Most of
the time
Some of
the time
A little of
the time
None of
the time





a Did you feel full of life? .................
1.............
2.............
3.............
4.............
5
b Have you been very nervous?.........
1..............
2.............
3..............
4.............
5
c Have you felt so down in the 
dumps that nothing could 
cheer you up?..................................
1.............
2.............
3.............
4.............
5
d Have you felt calm and  
peaceful? .........................................
1..............
2.............
3..............
4.............
5
e Did you have a lot of energy?.........
1.............
2.............
3.............
4.............
5
f Have you felt downhearted  
and low?..........................................
1..............
2.............
3..............
4.............
5
g Did you feel worn out? ...................
1..............
2.............
3..............
4.............
5
h Have you been happy?....................
1..............
2.............
3..............
4.............
5
i Did you feel tired? ..........................
1.............
2.............
3.............
4.............
5

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11.
How TRUE or FALSE is each of the following statements for you?
Definitely
true
Mostly
true
Don’t
know
Mostly
false
Definitely
false




a
I seem to get ill more
easily than other people ..................
1.............
2.............
3...............
4..............
5
b
I am as healthy as 
anybody I know ..............................
1.............
2.............
3...............
4..............
5
c
I expect my health to 
get worse.........................................
1.............
2.............
3...............
4..............
5
d
My health is excellent.....................
1.............
2.............
3...............
4..............
5
Thank you for completing these questions!

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12.6
Appendix 6:  Functional Assessment of Cancer Therapy – Anemia 
(FACT-an)

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Version 2.1 Incorporating Non-substantial Amendment 1

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Version 2.1 Incorporating Non-substantial Amendment 1

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12.7
Appendix 7:  Euroqol Questionnaire (EQ-5D-5L)

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Version 2.1 Incorporating Non-substantial Amendment 1

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Version 2.1 Incorporating Non-substantial Amendment 1

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12.8
Appendix 8:   Patients’ Global Impression of Change (PGIC) Scale
PATIENT OVERALL IMPRESSION OF CHANGE 
(UK English version of PGIC)
Since the start of the study, my general state of health is:
tick () one box only:
[1] 
Very Much Improved
[2] 
Much Improved
[3] 
Minimally Improved
[4] 
No Change
[5] 
Minimally Worse
[6] 
Much Worse
[7] 
Very Much Worse
(UK/English)

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12.9
Appendix 9:  Work Productivity and Activity Impairment 
Questionnaire: Anaemic Symptoms V2.0 (WPAI:ANS)
The following questions ask about the effect of your anaemic symptoms on your ability to work and perform 
normal daily activities. Please fill in the blanks or circle a number, as indicated.
1.
Are you currently employed (working for pay)? ______NO
______YES
If NO, tick “NO” and skip to question 6.
The next questions refer to the past seven days, not including today.
2.
During the past seven days, how many hours did you miss from work because of problems associated with 
your anaemic symptoms? Include hours you missed on sick days, times you went in late, left early, etc., 
because of your anaemic symptoms . Do not include time you missed to participate in this study.
______HOURS
3.
During the past seven days, how many hours did you miss from work because of any other 
reason, such as annual leave, holidays, time off to participate in this study?
______HOURS
4.
During the past seven days, how many hours did you actually work?
______HOURS (If “0”, skip to question 6)
5. During the past seven days, how much did your anaemic symptoms affect your productivity while you were 
working? 
Think about days you were limited in the amount or kind of work you could do, days you accomplished less 
than you would like, or days you could not do your work as carefully as usual. If anaemic symptoms
affected your work only a little, choose a low number. Choose a high number if anaemic symptoms affected 
your work a great deal. 
Consider only how much anaemic symptoms affected 
productivity while you were working.
Anaemic symptoms
had no effect on my 
work
Anaemic symptoms
completely 
prevented me from 
working
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER

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6. During the past seven days, how much did your anaemic symptoms affect your ability to perform your 
normal daily activities, other than work at a job? 
By normal activities, we mean the usual activities you perform, such as working around the house, 
shopping, childcare, exercising, studying, etc. Think about times you were limited in the amount or kind of 
activities you could perform and times you accomplished less than you would like. If anaemic symptoms
affected your activities only a little, choose a low number. Choose a high number if anaemic symptoms
affected your activities a great deal. 
Consider only how much anaemic symptoms affected your ability
to do your normal daily activities, other than work at a job.
Anaemic symptoms
had no effect on my 
daily activities
Anaemic symptoms
completely 
prevented me from 
doing my daily 
activities
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and activity 
impairment instrument. PharmacoEconomics 1993; 4(5): 353-65.

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Appendix 3:  Protocol Instructions Subjects Moving from Protocol v1.0 to Protocol v2.0
Visit Schedule
Subjects who have entered the study under protocol v1.0 should, upon signing the updated 
informed consent, adapt their visit frequency according to Table 1, Schedule of Assessments.  
Dosing Instructions for Subjects Moving from Protocol v1.0 to Protocol v2.0
Study drug will be dosed TIW throughout the Treatment Period, unless otherwise specified.
Subjects who have entered the study under protocol version 1.0 should, upon signing the 
updated informed consent, adapt their dose frequency and dose amount. At this visit it is first 
determined if the subject would need a dose titration according to the dose adjustment rules. 
Once that is established, patients are converted per the below instructions. The dose assigned 
must not exceed the maximum allowed dose of 3.0 mg/kg bodyweight or 300 mg per 
administration, whichever is lower. For subjects on permanent dialysis, the dose assigned 
must not exceed 3.0 mg/kg (based on dry weight in HD subjects and weight minus abdominal 
fluid based on last filling in peritoneal dialysis subjects) or 400 mg per administration, 
whichever is lower.
Subjects in the correction period or maintenance period on TIW dosing will continue on TIW 
dosing for the remainder of the treatment period. If needed, their dose will be adjusted 
according to the conversion table below, at the visit when the updated informed consent is 
signed.
Current TIW dose (mg)
20
40
50
70
100
120
150
200
250
300
350
400
If no dose titration needed
20
40
50
70
100
100
150
200
250
300
300
300
If up titration needed*
40
50
70
100
150
150
200
250
300
300
300
300
If down titration needed*
#
20
40
50
70
100
100
150
200
250
300
300
a) Subjects in the maintenance period on BIW dosing will change to TIW dosing 
immediately, per conversion table below, at the visit when the updated informed consent 
is signed. 
Current BIW maintenance dose (mg)
20
40
50
70
100
120
150
200
250
300
350
400
If no dose titration needed
20
20
40
50
70
70
100
150
150
200
250
250
If up titration needed*
20
40
40
70
70 
100
150
150
200
250
250 300
If down titration needed*
#
20
20
40
50
70
70
100
150
150
200
200
b) Subjects in the maintenance period on QW dosing will change to TIW dosing 
immediately, per conversion table below, at the visit when the updated informed consent 
is signed.
Current QW maintenance dose (mg)
20
40
50
70
100
120
150
200
250
300
350
400
If no dose titration needed
20
20
20
20
40
40
50
70
70
100
100
150
If up titration needed*
20 
20
20
40
40
50
70
70 
100
100
150
150
If down titration needed*
#
#
20
20
20
40
40
50
70
70
100
100
* Up or down titrations are only applicable when the criteria for dose adjustment has been met;
#  Contact the medical monitor if down titration is needed

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ESA Rescue Therapy
Protocol v2.0 allows subjects to receive ESA rescue treatment twice.  If a third ESA 
treatment is required subject will be discontinued from the study treatment.
If, upon implementation of protocol v2.0, a subject has already received 3 or more ESA 
treatments (under protocol v1.0) they can initially continue in the study. The subject will, 
however, be discontinued from study treatment if a further ESA rescue treatment is required.

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13
ATTACHMENT 1:  NON-SUBSTANTIAL AMENDMENT 1
I.  The purpose of this amendment is:
Non-Substantial Changes
1.
Update contact details of key sponsor personnel
DESCRIPTION OF CHANGE:
Update the sponsor personnel to be contacted for SAE to the Product Safety & 
Pharmacovigilance group and the affiliation of the medical monitor and clinical research 
contact.  
RATIONALE:
To provide the most up-to-date information for the key sponsor personnel. 
2.
Update abbreviation list
DESCRIPTION OF CHANGE:
Add ANOVA, DD-CKD, IUD, IUS, MRI, NDD-CKD, PPD, PPK/PD and SmPC to the 
abbreviation list. Delete ANCOVA, APEBV, APGD, BIW, CHOIR, CIOMS, CL/F, 
Composite Safety Endpoint, DSP, (e)CTD, EDTA, ELISA, EU, EWB, FDA, FWB, GGT, 
GMP, hCG, Hct, IB, IMPD, IND, INN, ka, kg, Ki, LLN, LSO, MedDRA, mg, min, mL, 
MTD, NASH, NONMEM, PCS, PD, PHI, PK, pmp, QW, SOC, SQ, TESAE, tmax, V/F, 
VHL, WHODRL and Wk from the abbreviation list.
RATIONALE:
Complete abbreviation list.
3.
Update post study follow-up
DESCRIPTION OF CHANGE:
Update wording to include follow-up of SAEs, cardiovascular and thromboembolic AEs 
during the post study follow-up and to remove the word ‘hospitalizations’.
RATIONALE:
The additional wording is to provide clarification on events that are required for collection 
during the post study follow-up period.  Information about hospitalizations is already stated 
in Section ‘5.3.3.2 Hospitalizations’ and is therefore removed from the description of the 
post study follow-up.
4.
Update planned study period
DESCRIPTION OF CHANGE:
Update the planned study period.

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RATIONALE:
To reflect current recruitment and completion timelines of the study.
5.
Clarify study population description 
DESCRIPTION OF CHANGE:
Update the study population description.
RATIONALE:
To reflect inclusion criterion 3.
6.
Clarify follow-up of discontinued subjects with ongoing adverse event or 
unresolved laboratory result
DESCRIPTION OF CHANGE:
Add wording relating to follow-up of subjects who have discontinued from the study. 
RATIONALE:
To provide additional clarity to investigators to ensure that discontinued subjects who have 
ongoing adverse events or unresolved laboratory results are followed up until condition 
stabilizes or is no longer clinically significant.
7.
Update dose adjustment rules
DESCRIPTION OF CHANGE:
Remove the wording attached to criteria for moving subjects from correction period to 
maintenance period.
RATIONALE:
Primary efficacy text is incorrectly placed under the dose adjustment rules.
8.
Clarify description of EOT visits
DESCRIPTION OF CHANGE:
Add description of EOT visit to include EOT visit and EOT + 2 weeks visit.
RATIONALE:
To provide clarity that EOT visits relate to 2 visits, 2 weeks apart.
9.
Update to the order of the secondary efficacy endpoints 
DESCRIPTION OF CHANGE:
Update of the order of the secondary endpoints for the fixed sequence testing procedure.  
Change from BL in MAP and occurrence and time to occurrence of hypertension are moved 
down, and change from BL in SF-36 PF and VT are moved up. 

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RATIONALE:
To adapt the order of statistical testing of key secondary endpoints on QoL related to the 
secondary objective of the study which are considered more important than the blood 
pressure endpoints.
10. Modify unscheduled visits  
DESCRIPTION OF CHANGE:
Change the mandatory collection of Hb assessment and vital signs at unscheduled visits to 
optional.
RATIONALE:
To update the protocol so that the collection of Hb and vital signs is optional at unscheduled 
visits leaving the decision as to which assessments are relevant with the investigator.  When 
testing Hb, both the HemoCue assessment (used for dose decisions) and central lab Hb (used 
for statistical analysis) should be tested. However, unscheduled visits can be planned for 
other purposes without there being a need for Hb and vital signs assessment.
11. Update the schedule of assessments
DESCRIPTION OF CHANGE:
Updates to the Schedule of Assessments to reflect changes made in this Amendment and to 
add clarifications to the footnotes.
RATIONALE:
To provide up to date and accurate information.
12. Update pharmacokinetic and pharmacodynamics information on roxadustat and 
clarify concomitant medication (drug and therapies)
DESCRIPTION OF CHANGE:
Update the pharmacokinetic and pharmacodynamic information based on the results of the 
drug-drug interaction studies performed with statins and phosphate binders and 
add additional clarifications and advice regarding potential drug-drug interaction with 
roxadustat including drugs that are substrates of OATP 1B1 and multivalent cation-
containing drugs and mineral supplements.  
RATIONALE:
To replace the interim results with the final results of the completed drug-drug interaction 
studies and update advice provided based on final results.

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13. Clarify liver enzyme and pancreatitis event monitoring in roxadustat clinical 
program
DESCRIPTION OF CHANGE:
Add the development phase during which liver enzymes and number of pancreatitis events 
are closely monitored during the roxadustat clinical development program.
RATIONALE:
To add clarity to the summary of key information.
14. Remove additional secondary evaluation of efficacy
DESCRIPTION OF CHANGE:
Remove an additional secondary efficacy evaluation endpoint relating to Hb correction and 
maintenance.
RATIONALE:
To remove an endpoint that is not well defined as it is confounding the treatment effect with 
the endpoint by subgroup defined as the patients who reach 11 or higher Hb values.
15. Clarify discontinuation criteria
DESCRIPTION OF CHANGE:
Add wording stating investigator responsibility if a subject is discontinued from the study 
with an ongoing AE or an unresolved laboratory result.
RATIONALE:
To add clarity to the discontinuation procedure.
16. Update information related to roxadustat study drug handling
DESCRIPTION OF CHANGE:
Remove bullet point relating to storage of tablets. 
RATIONALE:
Storage information for roxadustat is included in the Pharmacy Manual.
17. Update information on dosing instructions
DESCRIPTION OF CHANGE:
Add dosing instructions for patients moving from protocol v1.0 or v2.0 to protocol v 2.1.
RATIONALE:
To confirm that no adaptation to dose of study medication is required under this amendment.

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18. Update the rescue therapy guidelines of ESAs
DESCRIPTION OF CHANGE:
Add a procedure for subjects meeting ESA rescue therapy while on dialysis.
RATIONALE:
To add the same procedure from Appendix 12.4 to Section 5.1.5 for the administration of 
ESAs while on dialysis.
19. Update the Modification of Diet in Renal Disease equation
DESCRIPTION OF CHANGE:
Update the Modification of Diet in Renal Disease equation for calculating eGFR.
RATIONALE:
To align with central laboratory equation.  There is no impact on entry criteria of the subjects 
or impact on the safety of subjects.
20. Update blood pressure and heart rate measurements
DESCRIPTION OF CHANGE:
Remove wording related to calculation of blood pressure and heart rate within the eCRF.
RATIONALE:
Blood pressure and heart rate are calculated as an average of all 3 readings taken at each 
timepoint and not calculated from the 2nd and 3rd readings as currently stated.  As blood 
pressure and heart rate are calculated within RAVE (eCRF) and not by the investigator, they
are not required to be stated in the protocol and the calculation wording is being removed.
21. Update adverse event reporting for cardiovascular adjudication
DESCRIPTION OF CHANGE: 
Provide a more detailed description of the process of collecting adverse events and 
submission of documentation for events requiring adjudication is added. 
RATIONALE:
To align with other roxadustat phase 3 studies.
22. Update definition of serious adverse events
DESCRIPTION OF CHANGE:
Remove wording ‘always serious’ events reporting may be expedited within the timelines as 
for SAEs.
RATIONALE:
Expedited reporting by investigators is not required for Adverse Events.  Investigators are 
not provided with an ‘always serious’ list and therefore cannot know if they are classified as 
SAEs and therefore require expedited reporting.  

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23. Update contact details for reporting of serious adverse events (SAEs)
DESCRIPTION OF CHANGE:
Add additional contact details for a delegated CRO.  
RATIONALE:
A second CRO, in addition to 
, is supporting the SAE reporting in countries 
within South America, Belarus, Estonia and Greece. Contact details of the second CRO, 
 is added.  
24. Clarify the procedure for supplying new information affecting the conduct of the 
study
DESCRIPTION OF CHANGE:
Clarify procedure for supplying new information that affects the conduct of the study.
RATIONALE:
To clarify that the regulatory authorities can be informed of new information relating to the 
proper conduct of the clinical study, which many not necessarily be included in Dear Doctor 
Letters or that will lead to a protocol amendment.
25. Update primary analysis of secondary efficacy endpoints
DESCRIPTION OF CHANGE: 
Removal of the non-inferiority test for time to use of rescue therapy (only the superiority test 
is to be performed).  Removal of the superiority test for both ‘time to occurrence of 
hypertension’ and ‘MAP change from BL’.  Alignment of wording with regards to the 
definition of noninferiority margin, where applicable.
RATIONALE:
To align with the assumption that roxadustat is expected to show superiority versus placebo 
for the time to use of rescue therapy.  For time to hypertension and MAP change from BL, 
the assumption is that roxadustat is not worse than placebo.
26. Update the secondary analysis of secondary efficacy endpoints 
DESCRIPTION OF CHANGE: 
Delete the analysis for the key secondary efficacy endpoints on the PPS.
RATIONALE:
To align with Section 7.4.2.1 which states that the PPS is used for the noninferiority tests and 
the FAS for the superiority tests.

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27. Removal of the sensitivity analysis
DESCRIPTION OF CHANGE: 
Delete the sensitivity analysis using ANCOVA with the LOCF method.
RATIONALE:
The LOCF method is potentially a biased method in favor of roxadustat.
28. Publication of clinical study
DESCRIPTION OF CHANGE:
Delete the information describing process of publication or data disclosure.  
RATIONALE:
Publication is included in individual site contracts.
29. Minor administrative-type changes
DESCRIPTION OF CHANGE: 
Minor administrative-type changes, e.g., typos, format, numbering, consistency and clarity 
throughout the protocol, are included.  
RATIONALE:
Update the protocol to correct formatting and to provide clarifications to ensure complete 
understanding of study procedures.

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Hct
Hematocrit
IB
Investigator’s Brochure
IMPD
Investigational Medicinal Product Dossier
IND
Investigational New Drug (Application)
INN
International Nonproprietary Name
ka
First order absorption rate constant
kg
Kilogram
Ki
Inhibition Constant
LLN
Lower Limit of Normal
LSO
Last Subject Out
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram 
min
Minute 
mL
Milliliter 
MTD
Maximum Tolerated Dose
NASH
Non Alcoholic SteatoHepatitis
NONMEM
Non linear Mixed Effects Modeling
PCS
Physical Component Scores
PD
Pharmacodynamic
PHI
Protected health information
PK
Pharmacokinetic
pmp
Per million population
QW
Once Weekly
SOC
System Organ Class
SQ
subcutaneous
TESAE
Treatment Emergent Serious Adverse Event
tmax
Time to Attain Cmax
V/F
Apparent volume of distribution
VHL
Von Hippel Lindau
WHODRL
World Health Organization Drug Reference list
Wk
Week
III List of Abbreviations and Key Terms, IV Synopsis, 2 Study Objective(s), Design, 
and Endpoints, 3 Study Population, 5 Treatments and Evaluation 
List of Key Study Terms, Design and Methodology, Discontinuation Criteria, 2.2.1.3 
Description of Study, 2.2.1.3.4 Post-study Follow-up Period (Only for Subjects Prematurely 
Discontinued from Treatment), 3.3 Discontinuation Criteria for Individual Subjects, 5.1.5 
Rescue Therapy Guidelines
WAS:
Subjects that have discontinued treatment prior to their projected week 104 will continue to 
be followed for vital status and hospitalizations in post study follow up.
IS AMENDED TO:
Subjects that have discontinued treatment prior to their projected week 104 will continue to 
be followed for vital status and SAEs, cardiovascular and thromboembolic AEs
hospitalizations in post study follow up.

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IV Synopsis, Planned Study Period
WAS:  
From 1Q2013 to 3Q2017
IS AMENDED TO:
From 1Q2013 to 34Q2017
IV Synopsis, 2 Study Objective(s), Design, and Endpoints and 3 Study Population
Design and Methodology, 2.2.1.2 Study Population
WAS:  
The study population consists of subjects with CKD as defined by CKD stages 3, 4, and 5 
(eGFR < 60 mL/min/1.73 m2) who are anemic and not in need of dialysis.
IS AMENDED TO:
The study population consists of subjects with CKD as defined by CKD stages 3, 4, and 5 
(estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2) who are anemic and 
not in need of receiving dialysis.
IV Synopsis and 5 Treatments and Evaluation
Design and Methodology, 5.1.2 Changes in Study Drug Dose
DELETED:

However, the decision to move from the correction period rules to the maintenance period 
rules is based upon 2 central laboratory Hb values taken at least 5 days apart with Hb ≥ 
11.0 g/dL and a Hb increase from BL by ≥1.0 g/dL if BL Hb > 8.0 g/dL, or an increase 
from BL by ≥ 2.0 g/dL if BL Hb ≤ 8.0 g/dL.
IV Synopsis, 2 Study Objective(s), Design, and Endpoints, 3 Study Population and 5 
Treatments and Evaluation
Design and Methodology, Discontinuation Criteria,2.2.1.3.4 Post-study Follow-up Period 
(Only for Subjects Prematurely Discontinued from Treatment),3.3  Discontinuation Criteria 
for Individual Subjects, and 5.1.5 Rescue Therapy Guidelines
WAS:
Subjects that have stopped treatment prior to their projected week 104 will complete the EOT 
visit and EOS visit.
IS AMENDED TO:
Subjects that have stopped treatment prior to their projected week 104 will complete the EOT 
visits (EOT visit and EOT + 2 weeks visit) and the EOS visit.

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IV Synopsis, 2 Study Objective(s),  Design and Endpoints
Efficacy, Statistical Methods (Secondary), 2.3.2 Secondary Endpoints
WAS:
The secondary efficacy endpoints in this study are:
●
Change from BL in Hb to the average Hb in weeks 28-36, without having received 
rescue therapy within 6 weeks prior to and during this 8-week evaluation period
●
Change from BL in LDL cholesterol to the average value of LDL cholesterol in weeks 
12-28
●
Blood pressure effect
o
Change from BL in Mean Arterial Pressure (MAP) to the average MAP in weeks 
20-28.  
o
Occurrence and time to occurrence of hypertension (defined as either SBP 
> 170 mmHg AND an increase from BL ≥20 mmHg or as DBP > 110 mmHg, 
AND an increase from BL of ≥15 mmHg on 2 consecutive visits) 
●Use and time to use of rescue therapy (composite of RBC transfusions, ESA use, and IV 
iron) in the first 24 weeks of treatment.
●Change from BL in SF-36 Physical Functioning (PF) subscore to the average SF-36 PF 
subscore in weeks 12-28
●Change from BL in SF-36 Vitality (VT) subscore to the average SF-36 VT subscore in 
weeks 12-28
IS AMENDED TO:
The key secondary efficacy endpoints in this study are:
●
Hb maintenance: Hb Cchange from BL in Hb to the average Hb inof weeks 28-36, 
without having received rescue therapy within 6 weeks prior to and during this 8-week 
evaluation period
●
Change from BL in low–density lipoprotein (LDL) cholesterol to the average value of
LDL cholesterol in weeks 12-28
●
Use and time to use of rescue therapy (composite of RBC transfusions, ESA use, 
and IV iron) in the first 24 weeks of treatment.
●
Change from BL in Short Form (SF)-36 Physical Functioning (PF) subscore to the 
average SF-36 PF subscore in weeks 12-28
●
Change from BL in SF-36 Vitality (VT) subscore to the average SF-36 VT 
subscore in weeks 12-28
●
Blood pressure effect
o
Change from BL in Mean Arterial Pressure (MAP) to the average MAP in weeks 
20-28 
o
Occurrence and time to occurrence of hypertension (defined as either systolic 
blood pressure [SBP] > 170 mmHg AND an increase from BL ≥ 20 mmHg or as 
DBP > 110 mmHg, AND an increase from BL of ≥ 15 mmHg on 2 consecutive 
visits) 
●
Use and time to use of rescue therapy (composite of RBC transfusions, ESA use, and 

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IV iron) in the first 24 weeks of treatment.
●
Change from BL in SF 36 Physical Functioning (PF) subscore to the average SF 36 PF 
subscore in weeks 12 28
●
Change from BL in SF 36 Vitality (VT) subscore to the average SF 36 VT subscore in 
weeks 12 28

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Flow Chart and Schedule of Assessments
Table 1: Schedule of Assessments
WAS:
Study Period:
Screening
Treatmenta
Follow-up
Post study 
Follow- up
Up to 6 Weeks
Day 1b
Weekly
(wks 1 to 2)
± 2 days
Every 2 Weeks
(wks 4 to 24) 
± 2 days
Every 4 Weeks (wks 
28 to 100)  ± 3 days
EOT
(wk 104) 
± 3 days
EOT 
+ 2 wks
± 3 days
EOS
(EOT
+ 4 wks)
± 3 days
Unscheduled 
Visits
Every 6 months 
until projected 
wk 108
Visit / Week:
S1
S2
S3
Written informed consent
X
Randomization
X
Eligibility criteria
X
X
Demographics and medical 
history including tobacco use
X
Weight
X
X
wks 12, 24
wks 36, 52, 76
X
X
Od
Physical examination
X
X
wks 12c 24c
wks 36c, 52c, 76c
X
Xc
Oc, d
Blood pressuree, heart ratee, 
respiratory rateg
X
X
X
X
X
X
X
X
X
X
CBC with WBC differential, 
red cell indices and platelet 
count
X
X
X 
wks 4, 8, 12, 20
wks 
X
X
Od
Reticulocyte count, 
Hemoglobin content of 
reticulocytes (CHr)
X
X
X
wks 4, 6, 8, 12, 16, 20
wk 28 and every 
following 8 wks
X
X
Od
Hemoglobinh
X
X
X
X
X
X
HemoCue® assessment i
X
X
X
X
X
Serum chemistry (incl LFT)
X
X
wks 4, 8, 12, 20
wk 28 and every 
following 8 wks
X
X
X
Od
LFTs j
wk 2
wks 6, 16
Od
Serum Lipid panel (fasting 
whenever  possible)
X
X
wks 4, 8, 12, 20
wks 28, 36, 44, 52, 
68, 84
X
X
Od
Serum iron, ferritin, TIBC, 
TSAT
X
X
wks 4, 8, 12, 20
wk 28 and every 
following 8 wks
X
X
Od
HbA1c
X
X
wk 12
wks 28, 36, 44, 60, 84
X
X
Od
Vitamin B12, folate
X

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Study Period:
Screening
Treatmenta
Follow-up
Unscheduled 
Visits
Post study 
Follow- up
Visit / Week:
Up to 6 Weeks
Day 1b
Weekly
(wks 1 to 2)
± 2 days
Every 2 Weeks
(wks 4 to 24) 
± 2 days
Every 4 Weeks (wks 
28 to 100)  ± 3 days
EOT
(wk 104) 
± 3 days
EOT 
+ 2 wks
± 3 days
EOS
(EOT
+ 4 wks)
± 3 days
Every 6 months 
until projected 
wk 108
S1
S2
S3
HIV Immunoassay, HBsAg, 
anti-HCV antibody
X
Serum Pregnancy testk
X
wks 12, 24
wks 36, 48, 60, 72, 
84, 96
X
Od
eGFR (Cr Clear Modified Diet 
Abbreviated) l
X
X
wk 20
wks 36, 52, 68, 84
X
X
Od
Special laboratory analytes 
(hepcidin, sTfR, hs-CRP)
X
wks 4, 12, 20
wks 36, 52
X
X
Archival serum/plasma samples 
for biomarkers
X
wks 4, 12, 20
wks 52, 76
X
X
Blood sample for population 
PK
wks 2 to 8m
Genotypingn
X
Urinary testingo
X
wks 12, 24
wks 36, 52, 64, 76, 88
X
Od
Quality of Life Questionnaires p
X
wks 8, 12, 28
wks 36, 52, 76
X
Od
12-lead ECG
X
X
wks 12, 24
wks 36, 52, 76
X
Od
Renal ultrasoundq
X
Od
Dose adjustment reviewr
X
X
Od
Hospitalization recordings
X
X
X
X
X
X
X
X
X
X
X
X
Adverse event recording
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication 
recording
X
X
X
X
X
X
X
X
X
X
X
Procedure and non-drug 
therapy recording
X
X
X
X
X
X
X
X
X
X
X
Study drug dispensingt
Xu
X
X
X
Od
Vital Status
X
S1/S2/S3 = screening visit 1, 2 and 3; EOT = End of Treatment; EOS = End of Study; wk(s) = week(s); X = mandatory test/assessment; O = optional test/assessment; see below for 
footnotes)
Note:  see Appendix 3: Instructions for Subjects Moving from Protocol v1.0 to Protocol v2.0
Note:  see Appendix 4: Instructions for Subjects Requiring Dialysis 
a In case of premature discontinuation or withdrawal during the treatment period, the subject should complete the EOT and EOS visits. Thereafter, this subject will continue to be 
followed up at a 6-monthly frequency for vital status and hospitalizations until their projected date of completion (i.e., projected week 108 date) or, if earlier, until the last subject 
randomized reaches EOS, or until consent withdrawn.

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b All study assessments to be performed prior to first study drug administration
c Targeted physical examination only (e.g., respiratory and cardiovascular).
d The study drug dosing is to be reviewed and if needed new or additional study drug is to be dispensed.
e Blood pressure (BP) measured singly during the screening period, and in triplicate at all other visits. It is recommended during the treatment period, blood pressure measurement 
should occur prior to study drug administration if study medication is taken on same day of visit; except for visits where subjects are instructed to take study medication at home for 
PK sampling purpose. For subjects requiring dialysis, BP will be recorded prior to, and after dialysis (hemodialysis [HD]/hemodiafiltration [HDF] subjects only).   
f Heart rate measured singly during the screening period, and in triplicate at all other visits. It is recommended during the treatment period, heart rate measurement should occur prior to 
study drug administration if study medication is taken on the same day of visit; except for visits where subjects are instructed to take study medication at home for PK sampling 
purposes.  For subjects requiring dialysis, HR will be recorded prior to, and after dialysis (HD/HDF subjects only).
g Respiratory rate measured singly during all visit.  It is recommended during the treatment period, respiratory rate measurement should occur prior to study drug administration except 
for visits where subjects are instructed to take study medication at home for PK sampling purposes. For subjects requiring dialysis, respiratory rate will be recorded prior to dialysis 
(HD/HDF subjects only).
h Hemoglobin (Hb) should be collected at all the visits where complete Blood Count (CBC) is not collected 
i Hb will be assessed by HemoCue on the blood sample, collected for Central Laboratory hemoglobin assessment
j Liver Function Tests (LFTs) to be collected at visits where full Serum Chemistry is not collected 
k Collect from female subjects of child bearing potential only.
l Calculated by the Central Laboratory. 
m Sampling roxadustat will be done at 6 time points over 1 to 3 visits. See section 5.6.  At each pharmacokinetic visit, an additional sample will be collected for albumin and alpha-acid 
glycoprotein determination.
n Optional assessment.  A separate informed consent form must be signed before genotyping sample is collected.  Sample collection can be done at any timepoint thought the treatment 
period of the study.
o Ideally, the sample should be from the first morning void. Urinary testing includes qualitative testing with dipstick testing (for protein, pH, glucose) and quantitative assessment of 
albumin and creatinine for calculation of albumin/creatinine ratio. At day 1, weeks 24, 52 and 76 and EOT a urine sample will be archived for potential future biomarker analysis.
p Quality of Life (QoL) Questionnaires used are SF-36, FACT-An, EQ-5D 5L, PGIC and WPAI:ANS. The PGIC questionnaire is not completed at Day 1. Questionnaires to be 
completed by the subject preferably prior to any study assessments. When subjects need dialysis therapy, QoL questionnaires will be completed on the day of first dialysis (preferably 
before the dialysis is started), 4 weeks later and 12 weeks later.
q Renal ultrasound examination within 12 weeks of randomization. Not required if result of a previous renal ultrasound (or other imaging modality such as CT scan or MRI) within 12 
weeks prior to randomization is available and rules out renal cell carcinoma.  If other imaging modality, a conclusive report on the kidney should be available.
r Dose adjustment review from week 4 onward, and every 4 weeks thereafter until EOT (except in the event of excessive hematopoiesis or Hb ≥13.0 g/dL).  If next dose adjustment 
interval falls on a non-visit study week, the dose adjustment review should be performed at the next scheduled visit.
s Telephone or in-person follow-up call with subject
t For subjects requiring dialysis, it is recommended for HD/HDF subjects that study drug is administered any time after completion of dialysis (if dosing is scheduled on a dialysis day).
u Intake of initial study drug on day of randomization.

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IS AMENDED TO:
  Study Period:
Screening
Treatmenta
Follow-up
Post study 
Follow-up
Up to 6 Weeks
Day 1b
Weekly
(wks 1 to 2)
± 2 days
Every 2 Weeks
(wks 4 to 24) 
± 2 days
Every 4 Weeks (wks 
28 to 100)  ± 3 days
EOT
(wk 104) 
± 3 days
EOT + 2 wks
± 3 days
EOS
(EOT 
+ 4 wks)
± 3 days
Unscheduled 
Visits
Every 6 months 
until projected 
wk 108
  Visit / Week:
S1
S2
S3
Written informed consent
X
Randomization
X
Eligibility criteria
X
X
Demographics and medical 
history including tobacco use
X
Weight
X
X
wks 12, 24
wks 36, 52, 76
X
X
Odc
Physical examination
X
X
wks 12cd 24 cd
wks 36 cd, 52 cd, 76 cd
X
Xc
Oc, d
Blood pressuree, heart ratee, 
respiratory rateg
X
X
X
X
X
X
X
X
X
XOc
CBC with WBC differential, 
red cell indices and platelet 
count
X
X
X 
wks 4, 8, 12, 20
wks wk 28 and every 
following 8 wks
X
X
Odc
Reticulocyte count, 
Hemoglobin content of 
reticulocytes (CHr)
X
X
X
wks 4, 6, 8, 12, 16, 20
wk 28 and every 
following 8 wks
X
X
Odc
Hemoglobinh
X
X
X
X
X
XOc
HemoCue® assessment i
X
X
X
X
XOc
Serum chemistry (incl LFT)
X
X
wks 4, 8, 12, 20
wk 28 and every 
following 8 wks
X
X
X
Odc
LFTs j
wk 2
wks 6, 16
Odc
Serum Lipid panel (fasting 
whenever  possible)
X
X
wks 4, 8, 12, 20
wks 28, 36, 44, 52, 
68, 84
X
X
Odc
Serum iron, ferritin, TIBC, 
TSAT
X
X
wks 4, 8, 12, 20
wk 28 and every 
following 8 wks
X
X
Odc
HbA1c
X
X
wk 12
wks 28, 36, 44, 60, 84
X
X
Odc
Vitamin B12, folate
X
HIV Immunoassay, HBsAg, 
anti-HCV antibody
X

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  Study Period:
Screening
Treatmenta
Follow-up
Unscheduled 
Visits
Post study 
Follow-up
  Visit / Week:
Up to 6 Weeks
Day 1b
Weekly
(wks 1 to 2)
± 2 days
Every 2 Weeks
(wks 4 to 24) 
± 2 days
Every 4 Weeks (wks 
28 to 100)  ± 3 days
EOT
(wk 104) 
± 3 days
EOT + 2 wks
± 3 days
EOS
(EOT 
+ 4 wks)
± 3 days
Every 6 months 
until projected 
wk 108
S1
S2
S3
Serum Pregnancy testk
X
wks 12, 24
wks 36, 48, 60, 72, 
84, 96
X
Odc
eGFR (Cr Clear Modified Diet 
Abbreviated) l
X
X
wk 20
wks 36, 52, 68, 84
X
X
Odc
Special laboratory analytes 
(hepcidin, sTfR, hs-CRP)
X
wks 4, 12, 20
wks 36, 52
X
X
Archival serum/plasma samples 
for biomarkers
X
wks 4, 12, 20
wks 52, 76
X
X
Blood sample for population
PKpharmacokinetics
wks 2 to 8m
Genotypingn
X
Urinary testingo
X
wks 12, 24
wks 36, 52, 64, 76, 88
X
Odc
Quality of Life Questionnairesp
X
wks 8, 12, 28
wks 28, 36, 52, 76
X
Odc
12-lead ECG
X
X
wks 12, 24
wks 36, 52, 76
X
Odc
Renal ultrasoundq
X
Odc
Dose adjustment reviewr
X
X
Odc
Hospitalization recordings
X
X
X
X
X
X
X
X
X
X
X
X
Adverse event recording
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication 
recording
X
X
X
X
X
X
X
X
X
X
X
Procedure and non-drug 
therapy recording
X
X
X
X
X
X
X
X
X
X
X
Study drug dispensingt
Xu
X
X
X
Odc
Vital Status, SAEs, 
cardiovascular and 
thromboembolic AEs
X
AE: adverse events; CBC: complete blood count; CHr: hemoglobin content of reticulocytes; Cr: creatinine; ECG: electrocardiogram; eGFR: estimated glomerular filtration 
rate; EOT=: End of Treatment; EOS=: End of Study; HbA1c: hemoglobin A1c glycated hemoglobin; HBsAg: hepatitis B surface antigen; HCV: hepatitis C virus; HIV: Human 
Immunodeficiency Virus; hs-CRP: high sensitivity C-reactive protein; LFT: liver function test; O=: optional test/assessment; (see below for footnotes); S1/S2/S3=: screening 
visit 1, 2 and 3; SAE: serious adverse event; sTfR: soluble transferrin receptor; TIBC: total iron binding capacity; TSAT: Transferrin Saturation (also known as FeSAT, 
iron saturation); WBC: white blood cell; wk(s) =:week(s); X =: mandatory test/assessment.
Note:  see Appendix 3: Instructions for Subjects Moving from Protocol v1.0 to Protocol v2.0

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Note:  see Appendix 4: Instructions for Subjects Requiring Dialysis 
a In case of premature discontinuation or withdrawal during the treatment period, the subject should complete the EOT visits (EOT visit and EOT + 2 weeks visit) and the EOS visits.
Thereafter, this subject will continue to be followed up at a 6-monthly frequency for vital status and hospitalizations SAEs, cardiovascular and thromboembolic AEs until their 
projected date of completion (i.e., projected week 108 date) or, if earlier, until the last subject randomized reaches EOS, or until consent is withdrawn.
b All study assessments to be performed prior to first study drug administration
c Targeted physical examination only (e.g., respiratory and cardiovascular). The study drug dosing is to be reviewed and if needed new or additional study drug is to be 
dispensed.
d The study drug dosing is to be reviewed and if needed new or additional study drug is to be dispensed. Targeted physical examination only (e.g., respiratory and cardiovascular).
e Blood pressure (BP) measured singly during the screening period, and in triplicate at all other visits. It is recommended during the treatment period, blood pressureBP measurement 
should occur prior to study drug administration if study medication is taken on same day of visit; except for visits where subjects are instructed to take study medication at home for 
PKpharmacokinetic sampling purpose. For subjects requiring dialysis, BP will be recorded prior to, and after dialysis (hemodialysis [HD]/hemodiafiltration [HDF] subjects only).   
f Heart rate (HR) measured singly during the screening period, and in triplicate at all other visits. It is recommended during the treatment period, heart rateHR measurement should 
occur prior to study drug administration if study medication is taken on the same day of visit; except for visits where subjects are instructed to take study medication at home for 
PKpharmacokinetic sampling purposes.  For subjects requiring dialysis, HR will be recorded prior to, and after dialysis (HD/HDF subjects only).
g Respiratory rate measured singly during all visits.  It is recommended during the treatment period, respiratory rate measurement should occur prior to study drug administration 
except for visits where subjects are instructed to take study medication at home for PKpharmacokinetic sampling purposes. For subjects requiring dialysis, respiratory rate will be 
recorded prior to dialysis (HD/HDF subjects only).
h Hemoglobin (Hb) should be collected at all the visits where complete Blood Count (CBC) is not collected.
i If during an unscheduled visit Hb will needs to be assessed by, this should always be done with the HemoCue on the blood sample, collected for AND Ccentral Llaboratory
hemoglobinHb assessment. Hb will be assessed by HemoCue on the blood sample collected for central laboratory Hb assessment.
j Liver Function Tests (LFTs) to be collected at visits where full Serum Chemistry is not collected 
k Collect from female subjects of child bearing potential only.
l Calculated by the Central Laboratory. 
m Sampling roxadustat will be done at 6 time points over 1 to 3 visits. See (see sSection 5.6).  At each pharmacokinetic visit, an additional sample will be collected for albumin and 
alpha-acid glycoprotein determination.
n Optional assessment.  A separate informed consent form must be signed before a genotyping sample is collected.  Sample collection can be done at any timepoint thought throughout 
the treatment period of the study.
o Ideally, the sample should be from the first morning void. Urinary testing includes qualitative testing with dipstick testing (for protein, pH, glucose) and quantitative assessment of 
albumin and creatinineCr for calculation of albumin/creatinineCr ratio. At day 1, weeks 24, 52 and 76 and EOT a urine sample will be archived for potential future biomarker 
analysis.
p The Quality of Life (QoL) Questionnaires used are SF-36, FACT-An, EQ-5D 5L, PGIC and WPAI:ANS. The PGIC questionnaire is not completed at Dday 1. Questionnaires are to 
be completed by the subject preferably prior to any study assessments. When subjects need dialysis therapy, QoL questionnaires will be completed on the day of first dialysis 
(preferably before the dialysis is started), 4 weeks later and 12 weeks later.
q Renal ultrasound examination within 12 weeks of randomization. Not required if result of a previous renal ultrasound (or other imaging modality such as CT scan or magnetic 

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resonance imaging [MRI]) within 12 weeks prior to randomization is available and rules out renal cell carcinoma.  If other imaging modality, a conclusive report on the kidney 
should be available.
r Dose adjustment review from week 4 onward, and every 4 weeks thereafter until EOT (except in the event of excessive hematopoiesis or Hb ≥13.0 g/dL).  If next dose adjustment 
interval falls on a non-visit study week, the dose adjustment review should be performed at the next scheduled visit.
s Telephone or in-person follow-up call with subject
t For subjects requiring dialysis, it is recommended for HD/HDF subjects that study drug is administered any time after completion of dialysis (if dosing is scheduled on a dialysis day).
u Intake of initial study drug on day of randomization.

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Version 2.1 Incorporating Non-substantial Amendment 1
1 Introduction
1.2.2.1 Pharmacokinetics and Pharmacodynamics
WAS:
Based on interim study results, roxadustat increases the Cmax and AUCinf of simvastatin 
1.9-fold; of rosuvastatin 4.5-fold and 2.9-fold, respectively; and of atorvastatin 1.3-fold and 
2.0-fold, respectively.  Based on interim study results, the Cmax and AUCinf of roxadustat are 
decreased by the phosphate-binders (sevelamer carbonate or calcium acetate).
IS AMENDED TO:
Additional drug-drug interaction studies were performed with statins and phosphate 
binders. Based on interim study results, rRoxadustat increases the Cmax and AUCinf of 
simvastatin 1.9 fold;, of rosuvastatin 4.5 fold and 2.9-fold, respectively; and of atorvastatin 
1.3 fold and 2.0 fold, respectively.  Based on interim study results, the Cmax and The AUCinf 
of roxadustat are is decreased 2.9-fold and 1.8-fold respectively by simultaneous 
administration with the phosphate binders (sevelamer carbonate or and calcium acetate). 
Administration of roxadustat at least 1 hour before or 1 hour after the phosphate 
binder minimized the interactions.
1 Introduction
1.3 Summary of Key Safety Information for Study Drugs
WAS:
Liver enzymes were monitored closely throughout the roxadustat clinical development 
program. 
AND
A number of pancreatitis events were noted during the roxadustat clinical development 
program,
IS AMENDED TO:
Liver enzymes were monitored closely throughout the phase 2 roxadustat clinical 
development program.
AND
A number of pancreatitis events were noted during the phase 2 roxadustat clinical 
development program,
2 Study Objective(s), Design and Endpoints
2.3.3.1 Additional Secondary Evaluation of Efficacy
DELETED:
●
Hb change from BL to the average Hb value of weeks 28 36 and weeks 44 52, without 
use of rescue therapy within 6 weeks prior to and during this evaluation period in a 
subject who has reached Hb ≥ 11.0 g/dL prior to week 28

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Version 2.1 Incorporating Non-substantial Amendment 1
3 Study Population
3.3 Discontinuation Criteria for Individual Subjects
ADDED:
If a subject is discontinued from the study with an ongoing AE or an unresolved 
laboratory result that is significantly outside of the reference range, the investigator 
will attempt to provide follow-up until the condition stabilizes or no longer is clinically 
significant.
4 Study Drugs
4.3 Study Drug Handling
DELETED:
●
Tablets should be protected from light, and stored at 15ºC to 30ºC (59ºF to 86ºF).
5 Treatments and Evaluation
5.1.1 Dose/Dose Regimen and Administration Period
ADDED:
There were no adaptations to dose frequency or dose amount for subjects moving from 
Protocol v2.0 to Protocol v2.1.
5 Treatments and Evaluation
5.1.3.2 Concomitant Medication (Drugs and Therapies)
WAS:
Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins)
There is a risk that roxadustat will increase the plasma levels of statins based on results from 
drug-drug interaction studies.  Because statin dose has been known to be associated with  the 
risk for side effects such as  myopathy, (e.g., myalgia, myositis and rhabdomyolysis), the 
investigator is advised to consider this potential interaction between roxadustat and statins 
when deciding on the appropriate dose of statins based on efficacy and safety of statin therapy. 
Switching to a non-interacting statin (e.g. pravastatin) may be considered. Furthermore, it is 
recommended not to exceed the proposed maximum daily dose of statins as outlined in [Table 
4].
Table 4: Proposed Maximum Daily Dose of Statins Not to Be Exceeded
Statin
Proposed maximum dose (mg/day)
Simvastatin
20
GFR < 30 mL/min: 5
Atorvastatin
40
Rosuvastatin
10

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Severe renal impairment: no recommendation as 
contraindicated in this case
Fluvastatin
40
GFR < 30 mL/min: 20
Pravastatin
40
Pitavastatin
2
GFR < 30 mL/min: 1
Phosphate Binders
Interim results from a drug-drug interaction study demonstrated a clinically significant 
reduction in roxadustat plasma exposure when a single dose of roxadustat was administered 
simultaneously with the phosphate binders sevelamer carbonate or calcium acetate. To reduce 
the effect of phosphate binders on roxadustat exposure, subjects should be advised that 
roxadustat be taken at least one hour before or one hour after their phosphate binder. 
AND
Supplemental Vitamin B12, Folate and Iron
Vitamin B12, folate and oral iron can be taken without restriction at any time during the study.
Supplemental Iron and ESA Use
Oral iron is recommended as the first-line treatment for iron supplementation and can be taken 
without any restriction. However, IV iron and ESA use is restricted to use as rescue therapy, 
see rescue therapy guidelines, [Section 5.1.5].
IS AMENDED TO:
Hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins)Statins and 
Other Substrates for OATP 1B1
There is a risk that roxadustat will increase the plasma levels of statins and other drugs that 
are substrates of OATP 1B1, based on results from drug-drug interaction studies.  Because 
statin dose has been known to be associated with  the risk for side effects such as  myopathy, 
(e.g., myalgia, myositis and rhabdomyolysis), the investigator is advised to consider this 
potential interaction between roxadustat and statins when deciding on the appropriate dose of 
statins based on efficacy and safety of statin therapy. Switching to a non-interacting statin (e.g.,
pravastatin) may be considered. Furthermore, it is recommended not to exceed the proposed 
maximum daily dose of statins as outlined in [Table 4].  
The investigator is also advised to consider this potential interaction between roxadustat 
and other drugs that are substrates for OATP 1B1 when deciding on the appropriate 
posology of these drugs. Examples of these drugs are atrasentan, bosentan, ezetimibe, 
repaglinide, glyburide, SN-38 (active metabolite of irinotecan), rifampin, valsartan and 
olmesartan. It is recommended to refer to the Summary of Product Characteristics 
(SmPC) of these drugs for further details and guidance.

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Table 4: Proposed Maximum Daily Dose of Statins Not to Be Exceeded
Statin
Proposed maximum dose (mg/day)
Simvastatin
20
GFR < 30 mL/min: 5
Atorvastatin
40
Rosuvastatin
10
Severe renal impairment: no recommendation as 
contraindicated in this case
Fluvastatin
40
GFR < 30 mL/min: 20
Pravastatin
40
Pitavastatin
2
GFR < 30 mL/min: 1
Phosphate Binders and Other Multivalent Cation-containing Drugs and Mineral 
Supplements
Interim rResults from a drug-drug interaction study demonstrated a clinically significant 
reduction in roxadustat plasma exposure when a single dose of roxadustat was administered 
simultaneously with the phosphate binders sevelamer carbonate or calcium acetate. 
Subjects should take roxadustat in a consistent manner relative to their phosphate binder 
intakes, and discuss with the investigator before changing their phosphate binder dose or 
dosing time.  To reduce the effect of phosphate binders on roxadustat exposure, subjects should 
be advised that roxadustat be taken at least one1 hour before or one1 hour after their phosphate 
binder. 
It is anticipated that other multivalent cation-containing drugs and mineral supplements 
(e.g., iron, calcium, magnesium, aluminum), sucralfate or magnesium- or aluminum-
containing antacids would produce a similar interaction; therefore, administration of 
roxadustat between -1 hour and +1 hour of intake of these preparations is not 
recommended.
AND
Supplemental Vitamin B12, Folate and Iron
Vitamin B12, and folate and oral iron can be taken without restriction at any time during the 
study.
Supplemental Iron and ESA Use
Oral iron is recommended as the first-line treatment for iron supplementation and can be taken 
without any restriction. However, IV iron and ESA use is restricted to use as rescue therapy, see 
rescue therapy guidelines, [Section 5.1.5].  Administration of roxadustat between -1 and +1 
hour of intake of oral iron is not recommended.

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5 Treatments and Evaluation
5.1.5  Rescue Therapy Guidelines
ADDED:
If subjects meet the criteria for ESA rescue therapy whilst on dialysis, ESAs will be 
administered IV or SC according to the Package Insert or SmPC of the respective ESA 
for dialysis patients.
5 Treatments and Evaluation
5.2.4  Diagnosis of the Target Disease, Severity, and Duration of Disease
WAS:
eGFR will be calculated using the following MDRD equation: eGFR (mL/min per 1.73 m2) = 
186.3 × Serum Cr –1.154 × age–0.203 × (0.742 if female) × (1.21 if black).
IS AMENDED TO:
eGFR will be calculated using the following MDRD equation: eGFR (mL/min per 1.73 m2) = 
186.3175 × Serum Cr –1.154 × age–0.203 × (0.742 if female) × (1.21 if black).
5 Treatments and Evaluation
5.4.1.1  Blood Pressure
WAS:
Blood pressure (systolic and diastolic) will be measured singly on each of the three visits 
during the screening period, and in triplicate with at least two minute intervals for all other 
visits. An average SBP and DBP will be calculated from the 2nd and 3rd readings 
automatically within the eCRF. The same arm should be used consistently for measurements 
throughout the study.
IS AMENDED TO:
Blood pressure (systolic and diastolic) will be measured singly on each of the three3 visits 
during the screening period, and in triplicate with at least two2 minute intervals for all other 
visits. An average SBP and DBP will be calculated from the 2nd and 3rd readings 
automatically within the eCRF. The same arm should be used consistently for measurements 
throughout the study.  All values will be reported in the eCRF.
5 Treatments and Evaluation
5.4.1.2  Heart Rate
WAS:
Heart rate will be measured singly on each of the three visits during the screening period, and 
in triplicate with at least two minute intervals for all other visits. All values will be reported 

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in the eCRF. An average will be calculated from the 2nd and 3rd readings automatically within 
the eCRF.
IS AMENDED TO:
Heart rate will be measured singly on each of the three3 visits during the screening period, 
and in triplicate with at least two2 minute intervals for all other visits. All values will be 
reported in the eCRF. An average will be calculated from the 2nd and 3rd readings 
automatically within the eCRF.
5 Treatments and Evaluation
5.4.2  Adverse Events
WAS:
See [Section 5.5 Adverse Events and Other Safety Aspects] for information regarding 
adverse event collection and data handling. Adverse event (AE) collection will begin at the 
time the informed consent form is signed and continue through to EOS visit and will be 
recorded in the eCRF.
The description of the collection and adjudication of pre-specified cardiovascular and 
cerebrovascular events will be detailed in a separate adjudication charter.
IS AMENDED TO:
See [Adverse Events (AEs) will be collected at all study visits (see Section 5.5 Adverse 
Events and Other Safety Aspects] for detailed information regarding adverse eventAE
collection and data handling. Adverse event (AE)). AE collection will begin at the time the
starts after obtaining signed informed consent form is signed and continue through 
tocontinues until the EOS visit.  For subjects who continue in the post study follow-up 
period, SAEs and cardiovascular and thromboembolic AEs will be recorded in the 
eCRFcollected.  AEs will not be collected during the period between first screen where 
subject has failed screening and first rescreening visit.
The description of the collection and adjudication of pre specifiedprespecified
cardiovascular and cerebrovascular events will be detailed in a separate adjudication charter. 
For submission of documentation for events that require adjudication, the ICON 
SQUARE system will be used.  A site manual for the submission of packages for events 
requiring adjudication will be provided to each site and a dedicated staff member (and 
1 back-up person) will be required to review the manual prior to getting access to the 
system.
5 Treatments and Evaluation
5.5.1 Definition of Adverse Events (AEs)
ADDED:
For subjects that continue into the post study follow-up period, SAEs, cardiovascular 
and thromboembolic AEs will be captured until their projected date of completion of 

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the follow-up period (i.e., projected week 108) or until the last subject randomized 
reaches EOS, whichever comes first.
5 Treatments and Evaluation
5.5.2 Definition of Serious Adverse Events (SAEs)
WAS:
The sponsor has a list of events that they classify as “always serious” events. If an adverse
event is reported that is considered to be an event per this classification as “always serious”,
additional information on the event may be requested as well as expedited reporting within 
the timelines as demanded for SAEs.
IS AMENDED TO:
The sponsor has a list of events that they classify as “always serious” events. If an adverse
event is reported that is considered to be an event per this classification as “always serious”,
additional information on the event may be requested.as well as expedited reporting within 
the timelines as demanded for SAEs.
5 Treatments and Evaluation
5.5.5 Reporting of Serious Adverse Events (SAEs)
WAS:
The investigator should complete and submit a SAE report form containing all information 
that is required by the Regulatory Authorities to delegated CRO by fax immediately (within 
24 hours of awareness). Toll free fax number for each country is provided on the fax 
coversheet of the SAE worksheet.  In case of fax failure the SAE worksheet should be 
emailed to the delegated CRO.
If the faxing of a SAE report form is not possible or is not possible within 24 hours, the drug 
safety contact should be informed by phone.  
The contact details of the delegated CRO are:
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
Sponsor's Medical Monitor or his/her designee on the 24-hours Astellas Pharmacovigilance 
contact details, see Section II Contact Details of Key Sponsor’s Personnel. 
After checking for completeness and accuracy, the delegated CRO will send the SAE 
Worksheet and (when present) source documents (within 24 hours of receipt) to the Sponsor.
Follow-up information for the event should be sent promptly (within 7 days) as necessary.
Full details of the SAE should also be recorded on the medical records and in the eCRF.  The 
investigator must ensure that the information on the SAE worksheet matches the information 
on the AE pages within the eCRF.

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IS AMENDED TO:
The investigator should complete and submit a SAE report form Worksheet containing all 
information that is required by the Regulatory Authorities to delegated CRO by fax 
immediately (within 24 hours of awareness). Toll free fax number for each country is 
provided on the fax coversheet of the SAE wWorksheet.  In case of fax failure the SAE 
wWorksheet should be emailed to the delegated CRO.
If the faxing of a SAE Worksheet report form is not possible or is not possible within 24 
hours, the drug safety contact should be informed by phone.  
The contact details of the delegated CROs are:
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
Sponsor's Medical Monitor or his/her designee on the 24 hours Astellas Pharmacovigilance 
contact details, (see Section II Contact Details of Key Sponsor’s Personnel). 
After checking for completeness and accuracy, the delegated CRO will send the SAE 
Worksheet and (when present) source documents (within 24 hours of receipt) to the Sponsor.
Follow-up information for the event should be sent promptly (preferable within 7 days as 
necessary of the initial notification).
Full details of the SAE should also be recorded on the medical records and in the eCRF.  The 
investigator must ensure that the information on the SAE wWorksheet matches the 
information on the AE pages within the eCRF.

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5 Treatments and Evaluation
5.5.6 Follow-up to Adverse Events
WAS:  
All adverse events occurring during the study are to be followed up until resolved or judged
to be no longer clinically significant, or until they become chronic to the extent that they can 
be fully characterized.
IS AMENDED TO:
All adverse events occurring during or after the subject has discontinued the study are to 
be followed up until resolved or judged to be no longer clinically significant, or until they 
become chronic to the extent that they can be fully characterized.
5 Treatments and Evaluation
5.5.9 Supply of New Information Affecting the Conduct of the Study
WAS:
When new information becomes available, including "Dear Doctor Letters" but not limited to 
that, necessary for conducting the clinical study properly will lead to a protocol amendment. 
The sponsor should inform regulatory authorities, as well as all investigators involved in the 
clinical study, and the head of the study site, who will then inform the IRB/IEC of such 
information, and when needed, should amend the subject information.
IS AMENDED TO:
When new information becomes available, including "Dear Doctor Letters" but not limited to 
that, necessary for conducting the clinical study properly, will lead to a protocol amendment.
Tthe sponsor shouldwill inform regulatory authorities, as well as all investigators involved in 
the clinical study, as well as the regulatory authorities, as applicable/needed.  
Investigators should and the head of the study site, who will then inform the IRB/IEC of 
such information, and when needed, should amend the subject information.
7 Statistical Methodology
7.4.2.1 Primary Analysis
WAS:
Once the primary hypothesis has been rejected for the EU (EMA) primary efficacy endpoint 
[see Section 7.4.1.1], the key secondary endpoints below will be tested using a fixed 
sequence testing procedure, as depicted in [Table 9], in order to maintain the overall two-
sided type I error rate at 0.05. If P value from a test is < 0.05, the claim of superiority (or 
non-inferiority for tests 7 and 8) will be considered successful and the test will progress to 
the next comparison in sequence. The analysis set for the analysis of the secondary endpoints 
will be the PPS for the non-inferiority tests and the FAS for the superiority tests.
Table 9: Secondary Endpoints Fixed Sequence Testing Procedure

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Test 
Endpoint 
Test (superiority unless otherwise 
specified)
1
Hb change from BL
*Pooled roxadustat versus pooled placebo
2
LDL change from BL
*Pooled roxadustat versus pooled placebo
3
MAP change from BL
*Pooled roxadustat versus pooled placebo
4
Occurrence and time to occurrence 
of hypertension 
Non-inferiority of pooled roxadustat versus 
pooled placebo 
5
Use and time to use of rescue 
therapy
Non-inferiority of pooled roxadustat versus 
pooled placebo
6
Occurrence and time to occurrence 
of hypertension 
*Pooled roxadustat versus pooled placebo 
7
use and time to use of rescue 
therapy
*Pooled roxadustat versus pooled placebo
8
SF-36 PF subscore change from 
BL
*Pooled roxadustat versus pooled placebo
9
SF-36 vitality subscore change 
from BL
*Pooled roxadustat versus pooled placebo
*Subjects randomized to roxadustat QW, BIW and TIW prior to implementation of protocol 
v2.0 will be pooled together. Subjects randomized to placebo will also be pooled together.
●
Change from BL in the average Hb of weeks 28-36, without having received rescue 
therapy within 6 weeks prior to and during this 8-week evaluation period (superiority of 
pooled roxadustat versus pooled placebo) will be analyzed using a MMRM with 
unstructured covariance matrix model. The model will contain terms for treatment arm, 
baseline measurement, visit, visit x treatment arm and other stratification factors. 
●
Change from BL in LDL cholesterol to the average value of LDL cholesterol of weeks 
12-28 will be compared (superiority of pooled roxadustat versus pooled placebo) using a 
MMRM model with unstructured covariance containing terms for treatment arm, 
baseline measurement, visit, visit x treatment arm, and other stratification factors. 
●
Change from BL in MAP to the average MAP in weeks 20–28 will be compared 
(superiority of pooled roxadustat versus pooled placebo) using a MMRM model with 
unstructured covariance containing terms for treatment arm, baseline measurement, visit, 
visit x treatment arm, and other stratification factors.
●
Occurrence and time to occurrence of hypertension will be reported and compared (non-
inferiority of pooled roxadustat versus pooled placebo) using stratified Cox Proportional 
Hazards regression adjusting for stratification factors. Hazard ratio and its 95% will be 
calculated for the frequency of pooled roxadustat as relative to pooled placebo. Non-
inferiority will be declared if the upper bound of the 2-sided 95% CI does not exceed 
1.3. Once this hypothesis is rejected, superiority will be checked.
●
Use and time to use of rescue therapy (composite of RBC transfusion, ESA use and IV 
iron) in the first 24 weeks of treatment will be reported and compared (non-inferiority of 
pooled roxadustat versus pooled placebo) using stratified Cox Proportional Hazards 
regression adjusting for stratification factors. Hazard ratio and its 95% will be calculated 
for the frequency of pooled roxadustat as relative to pooled placebo.  Non-inferiority 
will be declared if the upper bound of the 2-sided 95% CI does not exceed 1.3. Once this 
hypothesis is rejected, superiority will be checked.

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●
Change from BL in SF-36 PF subscore to the average in weeks 12-28 will be compared 
(superiority of pooled roxadustat versus pooled placebo) for all subjects and in the 
subset of subjects with BL PF subscore below 35, using a MMRM model with 
unstructured covariance containing terms for treatment arm, baseline measurement, visit, 
visit x treatment arm, and other stratification factors.
●
Change from BL in SF-36 vitality subscore to the average SF-36 vitality subscore in 
weeks 12-28 will be compared (superiority of pooled roxadustat versus pooled placebo) 
for all subjects and in the subset of subjects with BL vitality subscore below 50, using a 
MMRM model with unstructured covariance containing terms for treatment arm, 
baseline measurement, visit, visit x treatment arm, and other stratification factors.
The secondary efficacy endpoints will be analyzed using the FAS population as the primary 
analysis population.  
IS AMENDED TO:
Once the primary hypothesis has been rejected for the EU (EMA) primary efficacy endpoint 
[see Section 7.4.1.1], the key secondary endpoints below will be tested using a fixed 
sequence testing procedure, as depicted in [Table 9], in order to maintain the overall two2-
sided type I error rate at 0.05. If P value from a test is < 0.05, the claim of superiority (or 
non-inferiority for tests 7 6 and 8 7) will be considered successful and the test will progress 
to the next comparison in sequence. The analysis set for the analysis of the secondary 
endpoints will be the PPS for the non-inferiority tests and the FAS for the superiority tests.
Table 9: Secondary Endpoints Fixed Sequence Testing Procedure
Test 
Endpoint 
Test (superiority unless otherwise specified)
1
Hb change from BL
*Pooled roxadustat versus pooled placebo
2
LDL change from BL
*Pooled roxadustat versus pooled placebo
3
Use and time to use of rescue 
therapy
*Pooled roxadustat versus pooled 
placebo
34
MAPSF-36 PF subscore change 
from BL
*Pooled roxadustat versus pooled placebo
45
Occurrence and time to occurrence 
of hypertensionSF-36 vitality 
subscore change from BL
Non inferiority of pooled*Pooled 
roxadustat versus pooled placebo 
56
Use and time to use of rescue 
therapyMAP change from BL
Non inferiority of pooled roxadustat versus 
pooled placebo
67
Occurrence and time to occurrence 
of hypertension 
*PooledNon-inferiority of pooled
roxadustat versus pooled placebo 
7
use and time to use of rescue 
therapy
*Pooled roxadustat versus pooled placebo
8
SF 36 PF subscore change from 
BL
*Pooled roxadustat versus pooled placebo
9
SF 36 vitality subscore change 
from BL
*Pooled roxadustat versus pooled placebo
*Subjects randomized to roxadustat QW, BIW and TIW prior to implementation of protocol 
v2.0 will be pooled together. Subjects randomized to placebo will also be pooled together.

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●
Change from BL in the average Hb of weeks 28-36, without having received rescue 
therapy within 6 weeks prior to and during this 8-week evaluation period (superiority of 
pooled roxadustat versus pooled placebo) will be analyzed using a MMRM with 
unstructured covariance matrix model. The model will contain terms for treatment arm, 
baselineBL measurement, visit, visit x treatment arm and other stratification factors. 
●
Change from BL in LDL cholesterol to the average value of LDL cholesterol of weeks 
12-28 will be compared (superiority of pooled roxadustat versus pooled placebo) using a 
MMRM model with unstructured covariance containing terms for treatment arm, 
baselineBL measurement, visit, visit x treatment arm, and other stratification factors. 
●
Change from BL in MAP to the average MAP in weeks 20 28 will be compared 
(superiority of pooled roxadustat versus pooled placebo) using a MMRM model with 
unstructured covariance containing terms for treatment arm, baseline measurement, visit, 
visit x treatment arm, and other stratification factors.
●
Occurrence and time to occurrence of hypertension will be reported and compared (non
inferiority of pooled roxadustat versus pooled placebo) using stratified Cox Proportional 
Hazards regression adjusting for stratification factors. Hazard ratio and its 95% will be 
calculated for the frequency of pooled roxadustat as relative to pooled placebo. Non
inferiority will be declared if the upper bound of the 2 sided 95% CI does not exceed 
1.3. Once this hypothesis is rejected, superiority will be checked.
●
Use and time to use of rescue therapy (composite of RBC transfusion, ESA use and IV 
iron) in the first 24 weeks of treatment will be reported and compared (non inferiority of 
pooled roxadustat versus pooled placebo) using stratified Cox Proportional Hazards 
regression adjusting for stratification factors. Hazard ratio and its 95% will be calculated 
for the frequency of pooled roxadustat as relative to pooled placebo.  Non
inferioritySuperiority will be declared if the upperlower bound of the 2-sided 95% CI 
does not exceed is higher than 1.30. Once this hypothesis is rejected, superiority will be 
checked.
●
Change from BL in SF-36 PF subscore to the average in weeks 12-28 will be compared 
(superiority of pooled roxadustat versus pooled placebo) for all subjects and in the 
subset of subjects with BL PF subscore below 35, using a MMRM model with 
unstructured covariance containing terms for treatment arm, baselineBL measurement, 
visit, visit x treatment arm, and other stratification factors.
●
Change from BL in SF-36 vitality subscore to the average SF-36 vitality subscore in 
weeks 12-28 will be compared (superiority of pooled roxadustat versus pooled placebo) 
for all subjects and in the subset of subjects with BL vitality subscore below 50, using a 
MMRM model with unstructured covariance containing terms for treatment arm, 
baselineBL measurement, visit, visit x treatment arm, and other stratification factors.
●
Change from BL in MAP to the average MAP in weeks 20–28 will be compared 
(noninferiority of pooled roxadustat versus pooled placebo) using a MMRM model 
with unstructured covariance containing terms for treatment arm,BL
measurement, visit, visit x treatment arm, and other stratification factors.  
Non-inferiority will be declared if the upper bound of the 2-sided 95% CI of the 
difference between roxadustat and placebo is below 2 mmHg.
●
Occurrence and time to occurrence of hypertension will be reported and compared 

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(noninferiority of pooled roxadustat versus pooled placebo) using stratified Cox 
Proportional Hazards regression adjusting for stratification factors. Hazard ratio 
and its 95% will be calculated for the frequency of pooled roxadustat as relative to 
pooled placebo. Noninferiority will be declared if the upper bound of the 2-sided 
95% CI does not exceed 1.3.  Once this hypothesis is rejected, superiority will be 
checked but as part of the sequence testing procedure.
The secondary efficacy endpoints will be analyzed using the FAS population as the primary 
analysis population.  
7 Statistical Methodology
7.4.2.2 Secondary Analysis
WAS:
The key secondary efficacy endpoints will be analyzed using the PPS population as 
supportive analysis population.  
For the first key secondary endpoints analyzed using MMRM, an additional sensitivity 
analysis will be performed to handle missing data using an ANCOVA model with LOCF 
method using BL value and the stratification factors as covariates. 
Each of the key secondary endpoints will be repeated separately by gender, age group, 
region, BL Hb categories, iron repletion at BL, diabetes and eGFR categories. Subgroup 
analyses will be detailed in the SAP
IS AMENDED TO:
The key secondary efficacy endpoints will be analyzed using the PPS population as 
supportive analysis population.  
For the first key secondary endpoints analyzed using MMRM, an additional sensitivity 
analysis will be performed to handle missing data using an ANCOVA model with LOCF 
method using BL value and the stratification factors as covariates. 
Each of the key secondary endpoints will be repeated separately by gender, age group, 
region, BL Hb categories, iron repletion at BL, diabetes and eGFR categories. Subgroup 
analyses will be detailed in the SAP.
8 Operational and Administrative Considerations
8.3.1  Arrangement for Use of Information and Publication of the Clinical Study
DELETED:
The study will be considered for publication or presentation at (scientific) symposia and 
congresses. The investigator will be entitled to publish or disclose the data generated at their 
respective study site only after submission to the sponsor all transcripts, texts of 
presentations, and abstracts related to the study at least 90 days prior to the intended 
submission for publication or any other disclosure for APEB sponsored studies. This is 
necessary to confirm whether any inventive knowledge should be protected by a patent or not

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ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
CONFIDENTIAL
21 Jun 2016
Astellas
Page 160 of 161
Version 2.1 Incorporating Non-substantial Amendment 1
and to prepare and file a patent application accordingly.  In addition this is in no way 
intended to restrict publication of facts or opinions formulated by the investigator.  The 
sponsor will inform the investigator in writing of any objection or question arising within 
30 days of receipt of the proposed publication material.
12 Appendices
12.3: Appendix 3: Instructions for Subjects Moving from Protocol v1.0 to Protocol v2.0
ADDED:
Note:  There are no adaptations to dose frequency or dose amount for subjects moving 
from Protocol v2.0 to Protocol v2.1.
III.  Non-Substantial Amendment Rationale:
Rationale for Non-Substantial Designation
The revisions made to the protocol are considered non-substantial as they do not have a 
significant impact on the safety or the scientific value of the trial.
Changes for clarification have been made to reflect the latest available information regarding 
roxadustat (item 11, 12, 15), the sponsor and CRO personnel (1, 22), most accurate 
description of study procedures (5, 6, 7, 9, 10, 14, 16, 17, 18, 19, 20, 21, 23), and to reflect 
updates to Astellas’ protocol template and for minor administrative reasons (2, 27, 28).
Post study follow-up (3)
Clarification of the safety information that is of specific interest during the post study follow-
up period.
Update to the planned study period (4)
Minor extension of the complete study duration to reflect the current projection when the 
study will be completed without any change to the study period for individual subjects.
Update of analysis methods (8, 13, 24, 25, 26)
Adjustments and changes made for the analysis methods have no impact on the study 
objectives, primary endpoints or primary analyses.
The change in order of the key secondary endpoints used for the fixed sequence procedure 
has been made to reflect the importance of the Quality of Life endpoints (SF-26 Vitality and 
Physical Functioning subscores), which is line with the secondary objective of the study. 
The change in hypothesis testing for some of the key secondary endpoints has been made to 
align with the assumption that roxadustat is expected to be superior to placebo for the use of 
rescue therapy and not worse for the blood pressure endpoints (hypertension and MAP). 
Additional changes were made in order to clarify some methodology aspects that were not 
well defined (removal of the LOCF method in favor of other methods, removal of additional 
Hb endpoints).

Sponsor: APEB
ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
CONFIDENTIAL
21 Jun 2016
Astellas
Page 161 of 161
Version 2.1 Incorporating Non-substantial Amendment 1
14
SPONSOR’S SIGNATURES

 
S-1 
ELECTRONIC SIGNATURE PAGE 
Document Type :  
Document Control Number :  
Amendment Number :  
International Study Number :  
Departmental Study Number :  
Actual Version Number :  
Document Version :  
Nonclinical Initial SD Approved Date (UTC) :  
Date (UTC) 
Signed by 
Sign Off Meaning 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
*UTC: Coordinated Universal Time 
06/29/2016 09:23:48
Clinical Study Protocol
Study Statistician Approval
Study Manager Approval
06/27/2016 07:06:56
Reissue v2.1, 21Jun2016
Principal Reviewer Approval
N/A
06/27/2016 06:29:32
N/A
MGC1501445
06/29/2016 10:02:04
1517-CL-0608
2.0
Signature as Document Originator
N/A