Conditions: Anemia in Chronic Kidney Disease in Non-dialysis Patients
Keywords: anemia chronic kidney disease (CKD) Hemoglobin (Hb) non-dialysis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 594
Healthy volunteers: no

Brief summary:
This study was conducted to treat anemia in patients with chronic kidney disease. Anemia is a reduced number of red blood cells or hemoglobin. Hemoglobin is important for the transport of oxygen in your blood. The purpose of the study was to see if Roxadustat is both effective and safe as a treatment for anemia in patients with chronic kidney disease.

Detailed description:
The study consisted of three 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)
* Post-Treatment Follow-Up period: 4 weeks

Arms:
arm 1: Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline (BL) of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for at least 52 weeks up to a maximum of 104 weeks. arm 2: Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline (BL) of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received matching placebo for at least 52 weeks up to a maximum of 104 weeks.

Interventions: intervention 1: Roxadustat intervention 2: Placebo
Intervention descriptions: intervention 1: Roxadustat was administered initially according to the tiered weight-based dosing, where participants with weight from ≥ 45 to ≤ 70 kg received 70 mg and participants with \> 70 to ≤ 160 kg received 100 mg of roxadustat. Dose-titration based upon regular measurement of Hb levels was performed until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline (BL) of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. intervention 2: Placebo was administered initially according to the tiered weight-based dosing, where participants with weight from ≥ 45 to ≤ 70 kg received 70 mg and participants with \> 70 to ≤ 160 kg received 100 mg of roxadustat. Dose-titration based upon regular measurement of Hb levels was performed until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline (BL) of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL.

Protocol document:
Prot_000.pdf: 
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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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 -
21 Jun 2016
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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
- CONFIDENTIAL -
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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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
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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
Astellas
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
Astellas
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
- CONFIDENTIAL -
21 Jun 2016
Astellas
Page 9 of 161
Version 2.1. Incorporating Non-substantial Amendment 1
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
- CONFIDENTIAL -
21 Jun 2016
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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
- CONFIDENTIAL -
21 Jun 2016
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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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Page 13 of 161
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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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Page 14 of 161
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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 -
21 Jun 2016
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Page 17 of 161
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
- CONFIDENTIAL -
21 Jun 2016
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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
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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
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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.


Sponsor: APEB
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Version 2.1. Incorporating Non-substantial Amendment 1
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.


Sponsor: APEB
ISN/Protocol 1517-CL-0608
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Version 2.1. Incorporating Non-substantial Amendment 1
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.


Sponsor: APEB
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Version 2.1. Incorporating Non-substantial Amendment 1

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.


Sponsor: APEB
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Version 2.1. Incorporating Non-substantial Amendment 1

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.


Sponsor: APEB
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Version 2.1. Incorporating Non-substantial Amendment 1
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.


Sponsor: APEB
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Version 2.1. Incorporating Non-substantial Amendment 1
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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Version 2.1 Incorporating Non-substantial Amendment 1
V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS
Figure 1
Flow Chart


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Version 2.1 Incorporating Non-substantial Amendment 1
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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Version 2.1 Incorporating Non-substantial Amendment 1
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
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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.
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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 
every effort to keep dosing days and dosing times consistent throughout the study.


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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 = 
QT/(RR)1/2) and Fridericia (QTcF = QT/(RR)1/3) corrections; and if RR is not available, it 


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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
REFERENCES 
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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FG-4592/ASP1517
CONFIDENTIAL
21 Jun 2016
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Page 112 of 161
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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


Sponsor: APEB
ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
CONFIDENTIAL
21 Jun 2016
Astellas
Page 113 of 161
Version 2.1 Incorporating Non-substantial Amendment 1
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


Sponsor: APEB
ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
CONFIDENTIAL
21 Jun 2016
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Page 114 of 161
Version 2.1 Incorporating Non-substantial Amendment 1
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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EudraCT number 2012-005180-27
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Version 2.1 Incorporating Non-substantial Amendment 1
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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Version 2.1 Incorporating Non-substantial Amendment 1
12.6
Appendix 6:  Functional Assessment of Cancer Therapy – Anemia 
(FACT-an)


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Version 2.1 Incorporating Non-substantial Amendment 1


Sponsor: APEB
ISN/Protocol 1517-CL-0608
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FG-4592/ASP1517
CONFIDENTIAL
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Version 2.1 Incorporating Non-substantial Amendment 1


Sponsor: APEB
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EudraCT number 2012-005180-27
FG-4592/ASP1517
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Version 2.1 Incorporating Non-substantial Amendment 1
12.7
Appendix 7:  Euroqol Questionnaire (EQ-5D-5L)


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Version 2.1 Incorporating Non-substantial Amendment 1


Sponsor: APEB
ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
CONFIDENTIAL
21 Jun 2016
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Version 2.1 Incorporating Non-substantial Amendment 1


Sponsor: APEB
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Version 2.1 Incorporating Non-substantial Amendment 1
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


Sponsor: APEB
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Version 2.1 Incorporating Non-substantial Amendment 1
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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   Non-Substantial Amendment 1
21 Jun 2016
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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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Page 139 of 161
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 


Sponsor: APEB
ISN/Protocol 1517-CL-0608
- CONFIDENTIAL -
EudraCT 2012-005180-27
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21 Jun 2016
Astellas
Page 146 of 161
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.


Sponsor: APEB
ISN/Protocol 1517-CL-0608
EudraCT number 2012-005180-27
FG-4592/ASP1517
CONFIDENTIAL
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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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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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Version 2.1 Incorporating Non-substantial Amendment 1
(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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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).


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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

SAP_001.pdf: 
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 Statistical Analysis Plan:
Final Version 5.0, dated 02 Aug 2018
Sponsor: Astellas Pharma Europe B.V. (APEB)
Sylviusweg 62
2333 BE Leiden
The Netherlands


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STATISTICAL ANALYSIS PLAN
Final Version 5.0, dated 02 August 2018
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: 1517-CL-0608
EudraCT number: 2012-005180-27
Sponsor name
Astellas Pharma Europe B.V. (APEB)
Sylviusweg 62, 
2333 BE Leiden
The Netherlands
This confidential document is the property of the sponsor.  No unpublished information 
contained in this document may be disclosed without prior written approval of the sponsor.


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Table of Contents
1
INTRODUCTION·················································································18
2
FLOW CHART AND VISIT SCHEDULE···················································19
3
STUDY OBJECTIVES AND DESIGN························································23
3.1
Study Objectives ··············································································23
3.1.1
Primary Objective ·······································································23
3.1.2
Secondary Objectives···································································23
3.2
Study Design···················································································23
3.2.1
General ···················································································23
3.2.2
Study Population ········································································23
3.2.3
Description of  Study ···································································24
3.2.4
Comparator···············································································25
3.3
Randomization·················································································25
4
SAMPLE SIZE ····················································································26
5
ANALYSIS SETS ·················································································26
5.1
All Randomized ···············································································27
5.2
Full Analysis Set (FAS) ······································································27
5.3
Per Protocol Set (PPS)········································································27
5.4
Safety Analysis Set (SAF) ···································································28
5.5
Pharmacokinetics Analysis Set (PKAS)····················································28
5.6
Pharmacodynamic Analysis Set (PDAS)···················································28
6
ANALYSIS VARIABLES ·······································································28
6.1
Efficacy Endpoints············································································28
6.1.1
Primary Efficacy Endpoint·····························································29
6.1.1.1
Primary Efficacy Endpoint for EU (EMA) ·····································29
6.1.1.2
Primary Efficacy Endpoint for US (FDA)······································29
6.1.2
Key Secondary Efficacy Endpoints ···················································30
6.1.2.1
Hb change from BL 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····························································30
6.1.2.2
Change from BL in Low Density Lipoprotein (LDL) Cholesterol to 
the Average LDL Cholesterol of Weeks 12 to 28 ·····························30
6.1.2.3
Use and time to first use of rescue therapy (composite of RBC 
transfusions, ESA use, and IV iron) ·············································31


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6.1.2.4
Change from BL in SF-36 Vitality (VT) Sub-score to the Average VT 
Sub-score of Weeks 12 to 28·····················································31
6.1.2.5
Change from BL in SF-36 Physical Functioning (PF) Sub-score to the 
Average PF Sub-score of Weeks 12 to 28 ······································32
6.1.2.6
Change from BL in Mean Arterial Pressure (MAP) to the Average 
MAP Value of Weeks 20 to 28 ··················································32
6.1.2.7
Occurrence and time to first occurrence of hypertension ·····················32
6.1.2.8
Rate of progression of CKD measured by annualized eGFR slope over 
time··················································································33
6.1.3
Additional Secondary Efficacy Endpoints ···········································33
6.1.3.1
Hb level averaged over weeks 28 to 36, 44 to 52, and 96 to 104 
without use of rescue therapy within 6 weeks prior to and during this 
evaluation period.··································································34
6.1.3.2
Time to achieve the first Hb response as defined by primary endpoint. ····34
6.1.3.2.1
Time (weeks) to achieve the first Hb response, without rescue 
therapy, as defined by the primary endpoint································34
6.1.3.3
Hb change from BL to each post-dosing time point···························35
6.1.3.4
Hb change from BL to the average Hb value of weeks 28 to 36, 44 to 
52, and 96 to 104 regardless of the use of rescue therapy ····················35
6.1.3.5
Categorical analysis of Hb values ···············································35
6.1.3.6
Occurrence (number) of hospitalizations, number of days of 
hospitalization per patient- exposure -year and time to first 
hospitalization······································································37
6.1.3.7
Occurrence and time to first use of rescue therapy [composite of RBC 
transfusions, IV iron supplementation and ESA treatment] during the 
first 24 weeks·······································································38
6.1.3.8
Occurrence and time to first use of RBC transfusions, number of RBC 
packs per month, volume of RBC transfused per month······················38
6.1.3.9
Occurrence and time to first use of IV iron supplementation. Mean 
monthly IV iron (mg) per subject during day 1 to week 36, weeks 37-
52 and weeks 53-104 (monthly defined as a period of 4 weeks)·············38
6.1.3.10
Occurrence and time to first use of ESA. Number of ESA-Weeks per 
year ··················································································39
6.1.3.11
Change from BL to each post-dosing study visit in Total cholesterol, 
LDL/High-density Lipoprotein (HDL) ratio, Non-HDL cholesterol, 
Apolipoproteins A1 and B, ApoB/ApoA1 ratio································40
6.1.3.12
Occurrence of mean LDL cholesterol <100 mg/dL calculated over 
weeks 12 to 28 ·····································································41


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6.1.3.13
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 to 28··························41
6.1.3.14
Change from BL to the average value of weeks 12 to 28 in Quality of 
Life scores ··········································································41
6.1.3.14.1
Medical Outcomes Study 36-Item Short-Form Health Survey (SF-
36) ···············································································41
6.1.3.14.2
Functional Assessment of Cancer Therapy –Anemia (FACT-An)·······42
6.1.3.14.3
EQ-5D 5L·······································································43
6.1.3.14.4
Work Productivity and Activity Impairment (WPAI: ANS)··············44
6.1.3.15
Patients’ Global Impression of Change (PGIC)································45
6.1.3.16
Hepcidin and Iron, HbA1c and CKD progression parameters ···············45
6.1.4
Other exploratory variables: hs-CRP (High Sensitivity C-Reactive Protein) 
and sTFR (Soluble Transferrin Receptor) ············································48
6.2
Safety Variables···············································································49
6.2.1
Adverse Events ··········································································49
6.2.1.1
Treatment emergent adverse event (TEAE) ····································49
6.2.1.2
Standardized MedDRA Queries ·················································49
6.2.1.3
Time to occurrence of a TEAE (by type of AE group)························50
6.2.1.4
AE within 7 days···································································51
6.2.1.5
Definition of incidence rate·······················································51
6.2.1.6
Definitions of event rate ··························································52
6.2.2
Vital Signs················································································52
6.2.3
Clinical laboratory variables ···························································54
6.2.3.1
Potentially Clinically Significant (PCS) Laboratory Criteria·················54
6.2.3.2
Laboratory assessments···························································55
6.2.4
Physical Examination···································································55
6.2.5
12-lead Electrocardiogram (ECG)·····················································56
6.2.6
Vascular Access Thrombosis (VAT)··················································57
6.3
Pharmacokinetic Variables···································································57
6.4
Pharmacodynamic Variables ································································57
6.5
Other Variables················································································57
6.5.1
Eligibility criteria········································································57
6.5.2
Demographic and Baseline Characteristic Variables································57
6.5.3
Previous and concomitant medication ················································61
6.5.4
Variables related to study drugs ·······················································61


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7
STATISTICAL METHODOLOGY ···························································65
7.1
General Considerations·······································································65
7.2
Study Population ··············································································65
7.2.1
Disposition of Subjects ·································································65
7.2.2
Protocol Deviations ·····································································67
7.2.3
Demographic and Other Baseline Characteristics ···································67
7.2.4
Previous and Concomitant Medications ··············································68
7.3
Study Drugs····················································································68
7.3.1
Exposure··················································································68
7.3.2
Treatment Compliance··································································69
7.4
Analysis of Efficacy ··········································································69
7.4.1
Analysis of Primary Endpoint(s) ······················································70
7.4.1.1
EU (EMA) Primary Endpoint ····················································70
7.4.1.1.1
Primary Analysis of the EU (EMA) Primary Endpoint ···················70
7.4.1.1.2
Secondary Analyses (sensitivity) of the EU (EMA) Primary 
Endpoint ········································································71
7.4.1.1.3
Additional Analyses of the EU (EMA) Primary Endpoint················72
7.4.1.2
US (FDA) Primary Endpoint·····················································72
7.4.1.2.1
Primary Analysis of the US (FDA) Primary Endpoint ····················72
7.4.1.2.2
Sensitivity Analyses  of the US (FDA) Primary Endpoint················74
7.4.1.2.3
Additional Analyses of the US (FDA) Primary Endpoint·················79
7.4.2
Analysis of Key Secondary Endpoints················································79
7.4.2.1
Hb change from baseline 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 ·························································80
7.4.2.2
Change from BL in Low Density Lipoprotein (LDL) cholesterol to the 
average LDL cholesterol of weeks 12 to 28····································81
7.4.2.3
Use and time to first use rescue therapy during the treatment period 
[composite of RBC transfusions, IV iron supplementation and rescue 
ESA]·················································································82
7.4.2.4
Change from baseline in SF-36 VT subscore to the average in weeks 
12–28················································································82
7.4.2.5
Change from BL in SF-36 Physical Functioning (PF) sub-score to the 
average PF sub-score of weeks 12 to 28 ········································83
7.4.2.6
Change from BL in mean arterial pressure (MAP) to the average MAP 
value of weeks 20 to 28···························································84


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7.4.2.7
Time to first 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) ······························85
7.4.2.8
Rate of progression of CKD measured by annualized eGFR slope over 
time··················································································87
7.4.2.9
Additional Analyses of the Key Secondary Endpoints························88
7.4.3
Analysis of Additional Secondary Efficacy Endpoints ·····························89
7.4.3.1
Hb level averaged over weeks 28 to 36, 44 to 52, and 96 to 104 
without use of rescue therapy within 6 weeks prior to and during these 
8-week evaluation periods························································89
7.4.3.2
Time to achieve the first Hb response as defined by primary endpoint 
for EU (EMA)······································································89
7.4.3.3
Hb change from BL to each post-dosing time point···························90
7.4.3.4
Hb change from BL to the average Hb value of weeks 28 to 36, 44 to 
52, and 96 to 104 regardless of the use of rescue therapy ····················90
7.4.3.5
Categorical analysis for Hb values ··············································90
7.4.3.6
Occurrence (number) of hospitalizations,number of days of 
hospitalization per PEY and time to first hospitalization ·····················90
7.4.3.7
Occurrence and time to first use of rescue therapy during the First 24 
Weeks [composite of RBC transfusions, IV iron supplementation and 
rescue ESA] ········································································91
7.4.3.8
Occurrence and time to first use of RBC transfusions, number of RBC 
packs per subject, volume of RBC transfused per subject ····················91
7.4.3.9
Occurrence and time to first use of IV iron supplementation. Mean 
monthly IV iron (mg) per subject during day 1 to week 36, weeks 37-
52 and weeks 53-104 (monthly defined as a period of 4 weeks)·············91
7.4.3.10
Occurrence and time to first use of ESA. Number of ESA-Week per 
year ··················································································92
7.4.3.11
Change from BL to each post-dosing study visit in Total cholesterol, 
LDL/High-density Lipoprotein (HDL) ratio, Non-HDL cholesterol, 
Apolipoproteins A1 and B, ApoB/ApoA1 ratio································92
7.4.3.12
Occurrence of mean LDL cholesterol <100 mg/dL calculated over 
weeks 12 to 28 ·····································································92
7.4.3.13
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 to 28. ·························92
7.4.3.14
Health related Quality of Life Questionnaires Change from BL to the 
average value of weeks 12 to 28 ·················································93
7.4.3.15
Patients’ Global Impression of Change (PGIC)································93


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7.4.3.16
Hepcidin and Iron, HbA1c and CKD progression parameters ···············94
7.4.4
Analysis of Exploratory Variables: hs-CRP (High Sensitivity C-Reactive 
Protein) and sTFR (Soluble Transferrin Receptor)··································95
7.5
Analysis of Safety·············································································95
7.5.1
Adverse Events ··········································································95
7.5.1.1
Overview ···········································································95
7.5.1.2
Proportion of subjects with TEAEs by SOC/PT ·······························95
7.5.1.3
Event-rates per 100 patient-years················································96
7.5.1.4
Incidence rates and cumulative incidence ······································96
7.5.1.5
Sensitivity/Subgroup analyses ···················································97
7.5.1.6
AEs within 7 days ·································································98
7.5.2
Clinical Laboratory Evaluation ························································99
7.5.2.1
Liver function tests ······························································ 100
7.5.3
Vital Signs·············································································· 100
7.5.4
Electrocardiograms (ECGs)·························································· 100
7.5.5
Pregnancies············································································· 101
7.6
Analysis of PK··············································································· 101
7.7
Analysis of PD··············································································· 101
7.8
Subgroups of Interest ······································································· 101
7.9
Other Analyses ·············································································· 102
7.10
Interim Analysis (and Early Discontinuation of the Clinical Study)·················· 102
7.11
Handling of Missing Data, Outliers, Visit Windows, and Other Information ······· 102
7.11.1
Missing Data ··········································································· 102
7.11.2
Missing Dates·········································································· 103
7.11.3
Outliers ················································································· 105
7.11.4
Visits Windows········································································ 105
7.11.5
End of Safety Emergent Period······················································ 107
7.11.6
End of Efficacy Emergent Period ··················································· 107
8
DOCUMENT REVISION HISTORY······················································· 108
9
REFERENCES ·················································································· 117
10
APPENDICES ··················································································· 118
10.1
Appendix 1: SF-36 v2 ······································································ 118
10.2
Appendix 2: FACT-An (Version 4)······················································· 125
10.2.1
FACT-An Questionnaire ····························································· 125


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10.2.2
FACT-An Scoring Guidelines ······················································· 128
10.3
Appendix 3: EQ-5D 5L v2································································· 131
10.4
Appendix 4: WPAI:ANS V2.0 ···························································· 133
10.5
Appendix 5: Patient Overall Impression of Change ···································· 135
10.6
Appendix 6: Medication  WHO Drug Dictionary Codes······························· 136
10.7
Appendix 7: Inverse probability censoring weighted model··························· 137
10.8
Appendix 8: Signatures····································································· 138
List of In-Text Tables
Table 1
Schedule of Assessments·····································································20
Table 2
Initial Study Drug (Roxadustat/ Placebo) Dosing·········································24
Table 3
Criteria for excluding a subject from PPS·················································28
Table 4
Key Secondary Efficacy Endpoints·························································30
Table 5
Additional Secondary Efficacy Endpoints ·················································33
Table 6
Potentially Clinically Significant (PCS) Vital signs Criteria ····························53
Table 7
Potentially Clinically Significant (PCS) Laboratory Criteria ····························54
Table 8
ECG Parameters classification ······························································56
Table 9
Randomization arms under Protocol version 1.0··········································62
Table 10
Treatment arms under protocol version 2.0················································62
Table 11
Time periods of interest ······································································63
Table 12
Primary and sensitivity analyses for the EU (EMA) primary endpoint·················71
Table 13
Additional Analyses of the EU (EMA) Primary Endpoint ·······························72
Table 14
Primary and sensitivity analysis for the US (FDA) primary endpoint ··················75
Table 15
Additional Analyses of the US (FDA) Primary Endpoint································79
Table 16
Key Secondary Endpoints fixed sequence testing procedure ····························80
Table 17
Primary and sensitivity analysis for the Hb change form BL to the average Hb 
in weeks 28-36·················································································81
Table 18
Primary and sensitivity analysis for the LDL change from BL to the average 
LDL in weeks 12-28 ··········································································81
Table 19
Primary and sensitivity analysis for use and time to first use rescue therapy··········82
Table 20
Primary and sensitivity analysis for change from BL in SF-36 VT sub-score to 
the average in weeks 12 to 28 ·······························································83
Table 21
Primary and sensitivity analysis for change from BL in SF-36 Physical 
Functioning (PF) sub-score to the average PF sub-score of weeks 12 to 28 for 
all subjects ·····················································································84
Table 22
Primary and sensitivity analysis for the MAP change from BL to the average 
MAP in weeks 20-28 ·········································································85
Table 23
Primary and sensitivity analysis for the time to first occurrence of hypertension·····86
Table 24
Additional Analyses of the Key Secondary Endpoints ···································88
Table 25
Subgroups of interest ······································································· 101


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Table 26
Definitions of the Analysis Date of Diagnosis of Anemia, CKD and Targeted 
Medical History ············································································· 103
Table 27
Definitions of the Previous or Concomitant Medication Analysis Start Date ······· 103
Table 28
Definitions of the Previous or Concomitant Medication Analysis Stop Date········ 104
Table 29
Definitions of the Analysis Adverse Event Onset Date ································ 104
Table 30
Definitions of the Analysis Adverse Event End Date··································· 104
Table 31
Analysis Visit Windows···································································· 105
Table 32
Analysis Visit Windows for QoL ························································· 106
Table 33
Analysis Visit Windows for Lipid Panel ················································· 106


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I.
LIST of ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase (GPT)
ANCOVA
Analysis of Covariance
AnS
Anemia Subscale
anti-HCV Ab
Anti-hepatitis C Virus Antibody 
APEB
Astellas Pharma Europe B.V.
Apo
Apolipoproteins
ASC
Analysis Set Classifications 
ASP1517
FG-4592 (codename of investigational product) or roxadustat (international 
nonproprietary name)
AST
Aspartate Aminotransferase (GOT)
AT
Aminotransferase
ATC
Anatomical Therapeutic Chemical
BL
Baseline
BL Hb
Baseline Hemoglobin (please refer to key definitions for infoFrmation)
BMI
Body Mass Index
BP
Blood Pressure
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CHr
Reticulocyte Hemoglobin Content
CI
Confidence Interval
CKD
Chronic Kidney Disease
CMH
Cochran-Mantel-Haenszel
CRF
Case Report Form
CRO
Contract Research Organization
CRP
C Reactive Protein
CS
Classification Specifications
CSE
Composite Safety Endpoint
CSR
Clinical Study Report
CV
Coefficient of Variation
DBP
Diastolic Blood Pressure
dL
Deciliter
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram


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Abbreviations
Description of abbreviations
eCRF
Electronic CRF
EDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate
EH
Excessive Hematopoiesis
EOS
End of Study
EOT
End of Treatment
EQ-5D 5L
Health Related Quality of Life Questionnaire Consisting of Five Levels
ESA
Erythropoiesis Stimulating Agent
ESRD
End Stage Renal Disease
EU
European Union
EudraCT
Clinical trial database regulated by European Community
EWB
Emotional Well being
FACT-An
Functional Assessment of Cancer Therapy-Anemia
FACT-G
Functional Assessment of Cancer Therapy-General
FDA
Food and Drug Administration
FAS
Full Analysis Set
FG-4592
= ASP1517 (codename of investigational product) or roxadustat (international 
nonproprietary name)
FSI
First Subject In
FWB
Functional Well-being
g
gram
GDS
Global Data Science
GGT
Gamma Glutamyl Transferase
GM
Geometric Mean
Hb
Hemoglobin
HbA1c
Hemoglobin A1c; Glycated hemoglobin
HBsAG
Hepatitis B Surface Antigen
Hct
Hematocrit
HD
Hemodialysis
HDF
Hemodiafiltration
HDL
High-density Lipoprotein
HEENT
Head, Eyes, Ears, Neck and Throat
HIF
Hypoxia-inducible Factor
HIV
Human Immunodeficiency Virus
HR
Heart Rate
HRQoL
Health-Related Quality of Life
hs-CRP
High Sensitivity C-reactive protein


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Abbreviations
Description of abbreviations
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICH E3
Guidance for Industry Structure and Content of Clinical Study Reports
ICH E9
Statistical Principles for Clinical Trials
ICH E14
Guidance for Industry – Clinical Evaluation of QT/QTc
IEC
Independent Ethics Committee
IERC
Independent Event Review Committee
INN 
International Nonproprietary Name
INR
International Normalized Ratio
IPCW
Inverse Probability of Censoring Weighting
IRT
Interactive Response Technology
ISN
International Study Number
IV
Intravenous(ly)
Kg
Kilograms
LDL
Low-density Lipoprotein
LA-CRF
Liver Abnormality Case Report Form
LFT
Liver Function Tests
LLN
Lower Limit of Normal 
LOCF
Last Observation Carried Forward
LSO
Last Subject Out
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
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram 
MI
Myocardial Infarction
mL
Milliliters 
Mg
Microgram
MMRM
Mixed Model of Repeated Measures
MSAP
Meta-Analysis Statistical Analysis Plan
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria for Adverse Events
O
Optional 
PCS
Physical Component Score
PD
Protocol Deviation
PDAS
Pharmacodynamic Analysis Set


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Abbreviations
Description of abbreviations
PEY
Patient-exposure year
PF
Physical Functioning
PGIC
Patients’ Global Impression of Change
PK
Pharmacokinetic
PKAS
Pharmacokinetic Analysis Set
PPS
Per Protocol Set
PT
Preferred Term
PWB
Physical Well-being
QoL
Quality of Life
QRS 
QRS interval 
QTc
QT Interval corrected for heart rate
QTcB
QTc calculated according to Bazett’s formula
QTcF
QTc calculated according to Fridericia’s formula
RBC
Red Blood Cell
RR
Respiratory Rate
RR Interval
Interval between successive Rs of the ECG
r-HuEPO
Recombinant Human Erythropoietin
RRT
Renal Replacement Therapy
SAE
Serious AE
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
SBP
Systolic Blood Pressure
SD
Standard Deviation
SI
International System of Units 
SF-36
Short Form 36
SF-36 PCS
SF-36 Physical Component Score
SF-36 PF
SF-36 Physical Functioning
SF-36 MCS
SF-36 Mental Component Score
SF-36 VT
SF-36 Vitality
SMQ
Standardized MedDRA Query
SOC
System Organ Class
SOP
Standard Operating Procedure
SPA
Special Protocol Assessment
SQ
Subcutaneous
sTfR
Soluble Transferrin Receptor
SWB
Social Well-being


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Abbreviations
Description of abbreviations
TEAE
Treatment-Emergent Adverse Event
TIBC
Total Iron-Binding Capacity
TIW
Thrice Weekly
TLF
Tables, Listings and Figures
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
WHO-DRL
World Health Organization Drug Reference List
Wk(s)
Week(s)
WPAI:ANS
Work Productivity and Activity Impairment questionnaire: Anemic Symptoms


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List of Key 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
Baseline Hb is defined as the mean of four central laboratory Hb values: 
four latest Hb values prior or on the same date as first study drug intake
(pre-dose).
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.
Endpoint
Event or outcome that can be measured objectively to determine whether 
the intervention being studied is beneficial. Primary and secondary variables 
supporting objectives of the study are called endpoints.
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 two consecutive visits [dates] (with available data) separated by at least 5 
days during the first 24 weeks of treatment without rescue therapy (i.e., red 
blood cell [RBC] transfusion, ESA, or intravenous [IV] iron) prior to Hb 
response.
Intervention
The drug, device, therapy or process under investigation in a clinical trial 
which has an effect on outcome of interest in a study: e.g., health-related 
quality of life, efficacy, safety, pharmacoeconomics. 


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Terms
Definition of terms
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 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 discontinued treatment. These subjects will be 
followed up on a 6-monthly frequency for vital status and hospitalizations.
Primary treatment 
period
Period of time that subject is treated from first treatment up to 52 weeks
Pre-investigational 
period
Period of time before entering the investigational period, from the time of 
starting a subject enrolling into study until just before the test drug or 
comparative drug is given to a subject 
Randomization
Action to allocate a subject to the treatment group or treatment cohort. 
Subjects will be randomized to roxadustat or placebo at day 1.
Roxadustat
International Nonproprietary Name (INN) of ASP1517/FG-4592 
investigational product
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.  
Safety Emergent 
Period
Defined as the evaluation period from the Analysis date of first drug intake 
up to 28 days after the Analysis Last Dose
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.
Screening Hb value
Mean of subject’s three last Hb valued collected during the screening period 
and prior to the day of randomization.
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.


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Terms
Definition of terms
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.
Time to event
Time from a defined starting point (analysis date of first dose intake) to the 
time of occurrence of the event of interest.
Time to censoring
Time from a defined starting point (analysis date of first dose intake) to the 
time of end of observation period in case the event did not occur. 
Time to event analysis
Time to event analyses are statistical methods, such as survival analysis, 
that take into account 2 types of timing: the time to occurrence of an event 
(if an event occurred) and the time to censoring (if an event did not occur
during the time we observed the subject). For time to censoring, we only 
know the total number of days in which the event didn’t occur until the 
subject ceased to be followed (censored).
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.


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1
INTRODUCTION
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes detailed procedures 
for executing the statistical analysis of the primary and secondary endpoints and other data. 
The SAP is finalized and signed prior to any of the following: study unblinding, database 
hard lock, interim analysis, or accumulation of substantial amount of data in an open-label 
study to ensure lack of bias. For operational efficiency an earlier time is usually targeted and 
wherever possible, the SAP should be developed in parallel with protocol finalization. If the 
expected interval between First Subject In (FSI) and soft-lock is less than 12 weeks, then the 
SAP should be approved by 12 weeks prior to the planned date of soft-lock. If needed, 
revisions to the approved SAP may be made prior to database hard lock. Revisions will be 
version controlled.
This statistical analysis is coordinated by the responsible biostatistician of APEB. Any 
changes from the analyses planned in the SAP will be justified in the Clinical Study Report 
(CSR).
All details of the Pharmacokinetics Analysis Set (PKAS)_will be described in a separate 
analysis plan, and a separate PKAS modeling report will be written.
This SAP is based on protocol version 2.0, dated 17 December 2014 and on Case Report 
Form (CRF) version 17.0, dated 26 April 2017.
Prior to database hard lock, a final review of data and TLFs meeting will be held to allow a 
review of the clinical trial data and to verify the data that will be used for analysis set 
classification. If required, consequences for the statistical analysis will be discussed and 
documented. A meeting to determine analysis set classifications may also be held prior to 
database hard lock. 


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2
FLOW CHART AND VISIT SCHEDULE
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
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
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
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
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, SAEs, 
cardiovascular and
thromboembolic AEs
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 from Protocol: Instructions for Subjects Moving from Protocol v1.0 to Protocol v2.0 
Note:  see Appendix 4 from Protocol: 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 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.
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 from Protocol.  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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3
STUDY OBJECTIVES AND DESIGN
3.1
Study Objectives
3.1.1
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.
3.1.2
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 non-dialysis CKD 
anemia.
●
Evaluate the need for anemia rescue therapy with roxadustat in subjects with non-
dialysis CKD anemia: RBC transfusion, ESA, or IV iron.
3.2
Study Design
3.2.1
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. Study FGCL-4592-060 with similar design is
conducted by FibroGen Inc, in study centers across North America, Latin America and Asia 
Pacific.
3.2.2
Study Population
The study population consists of subjects with CKD stages 3, 4, and 5 
(eGFR < 60 mL/min/1.73 m2) who are anemic and not on 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.


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3.2.3
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 
three 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.
●
Study termination and post-study follow-up period
During the course of the study, visits and assessments will be performed as defined in the 
Schedule of Assessments.
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.
Screening Period
During the screening period, subjects’ eligibility for study participation will be assessed.
Treatment Period
The initial protocol Version 1.0 included a random allocation to 6 treatment arms in a 
2:2:2:1:1:1 ratio. These 6 arms included placebo or roxadustat as double-blind treatment in a 
2:1 ratio and each of these had 3 different dosing frequencies for the maintenance period. 
(TIW, BIW or QW). Following FDA’s recommendation, the protocol was amended with the 
removal of the dosing frequencies BIW and QW and keeping only the TIW dosing 
frequency. This SAP is based on protocol version 2.0 using the pooled placebo and pooled 
roxadustat arms as treatment groups for comparison. 
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
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 two consecutive study visits 
separated by at least 5 days (correction period).  


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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 four weeks until the end of treatment.  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) 
○
Subjects beyond 52 weeks treatment will stop treatment at this point. 
○
Subjects that have not yet reached 52 weeks treatment will continue until they 
reach 52 weeks treatment.
For details on study drug dosing, see Protocol, Section 5.1.
Follow-up Period
After the Treatment period, subjects proceed to the 4-week post-treatment follow-up period.
Post Study Follow-up (only for subjects prematurely discontinued from treatment)
Subjects that have stopped treatment prior to their projected week 104 will complete the EOT 
visit and EOS visit. Thereafter, these subjects will continue to be followed up on 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.
3.2.4
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.
3.3
Randomization
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.  
Randomization and treatment assignments will be performed via Interactive Response 
Technology (IRT) prepared on behalf of the Sponsor (under the responsibility of the Data 
Science (DS) Department of APEB). Specific procedures for randomization through the IRS 
are contained in the study procedures manual.


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A total of 450-600 planned subjects will be randomized to receive one 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 four factors: 
●
Region (region A versus region B)*
* assignment to region (see Section 6.5.2) 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).
Subjects randomized to roxadustat QW, BIW or TIW prior to implementation of protocol 
v2.0 will be pooled together. Subjects randomized to placebo will also be pooled together.
4
SAMPLE SIZE
A minimum of 450 and up to 600 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 are needed to achieve at least power of 95% to demonstrate a statistically 
significant difference with a 5% two-sided significance level  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 allow the study to have at least power of 99% to detect a 1.0 g/dL 
difference in mean Hb values between the two treatment groups, assuming that the common 
standard deviation is 1.2 g/dL using an analysis of variance (ANOVA) test with a 5% two-
sided significance level.
Most importantly, this sample size is required for a meta-analysis of composite safety 
endpoint by pooling studies. In case the minimum size of four hundred and fifty subjects is 
not large enough to achieve the required number of MACE/MACE+ events, an increase in 
the sample size up to 600 is regarded.
5
ANALYSIS SETS
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the analysis sets below will be used for the analyses.


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Detailed criteria for analysis sets will be laid out in Classification Specifications (CS) and the 
allocation of subjects to analysis sets will be determined prior to database hard lock. 
5.1
All Randomized
The All Randomized consists of all randomized subjects. 
Criterion for exclusion from All Randomized is defined as follows:
●
Not randomized
The selection of subjects for the All Randomized will be confirmed in the Analysis Set 
Classification (ASC) meeting.
The All Randomized will be used for summaries, selected primary and secondary analyses of 
efficacy endpoints, as well as selected demographic and baseline characteristics.
The All Randomized Set will exclude the 3 subjects from site 70051, which has been 
terminated prematurely due to GCP violations including data integrity issues. Consequently, 
these subjects will not be included in any of the analyses.
5.2
Full Analysis Set (FAS)
The Full Analysis Set (FAS) consists of all randomized subjects who received at least one 
dose of study drug and have at least one non-missing post-dose Hb assessment. Subjects will 
be assigned to their planned treatment provided by the IRS. 
Criteria for FAS exclusion is defined as follows:
●
No study drug taken, or
●
No Hb value post-dose
The selection of subjects for the FAS will be confirmed in the Analysis Set Classification 
(ASC) meeting.
The FAS will be used for summaries, selected primary and secondary analyses of efficacy 
endpoints, as well as selected demographic and baseline characteristics.
5.3
Per Protocol Set (PPS)
The Per-Protocol Set includes all FAS subjects who do not meet any of the reasons to 
exclude a complete subject from PPS listed in Table 3. This PPS will be used for all 
disposition, demography and baseline characteristics. 


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Table 3
Criteria for excluding a subject from PPS
Number
Reasons for exclusion from PPS
1
Subject who receives less than 2 weeks of study treatment.
2
Patient without a valid corresponding Hb. A valid corresponding Hb is defined as an Hb value from 
the central laboratory that is measured at least 2 weeks after the first dose and was either before the 
last study drug intake or at maximum three days after the last drug intake.
3
Prescribed study drug compliance during treatment < 75% during the first 24 weeks or until EOT, 
whatever comes first. 
4
Violation of inclusion or exclusion criteria which may affect the assessment of the efficacy of the 
study drug during the reference period or until EOT, whatever comes first.
5
Subjects where breaking of the randomization code occurs during the reference period or until EOT, 
whatever comes first.
6
Administration of wrong randomization study drug for more than one week during the reference 
period or until EOT, whatever comes first
7
Administration of prohibited concomitant medication affecting efficacy listed in Appendix 12.1 of the 
protocol during the first 24 weeks or until EOT, whatever comes first.
8
Administration of rescue therapy significantly deviating from the protocol during the first 24 weeks or 
until EOT, whatever comes first.
More information on the derivation of these criteria can be found in the Classification 
Specifications.
5.4
Safety Analysis Set (SAF)
The safety analysis set consists of all randomized subjects who received at least one dose of 
study drug. Subjects will be assigned to their actual treatment received during the trial. 
The SAF will be used to describe demographic and baseline characteristics and all safety and 
tolerability related variables.
5.5
Pharmacokinetics Analysis Set (PKAS)
The PKAS includes the subjects from the SAF population who meet the following criteria: 
●
Received at least one dose of roxadustat 
●
At least one quantifiable plasma concentration of roxadustat was obtained; dosing and 
sampling history has been recorded.
PKAS will be defined separately and all analyses will be reported in a separate report.
5.6
Pharmacodynamic Analysis Set (PDAS)
Not applicable in this study.
6
ANALYSIS VARIABLES
6.1
Efficacy Endpoints
The Efficacy Emergent Period will be defined as the evaluation period from the Analysis 
date of first dose intake up to 7 days after the Analysis date of Last Dose (defined in 
Section 6.5.4) or EOT Visit, whichever occurs first. This period will be used as reference 


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period for the time to event analyses related to efficacy endpoints, unless specified otherwise. 
More details on the derivation of the date of End of Efficacy Emergent Period are provided in 
Section 7.11.6
6.1.1
Primary Efficacy Endpoint
There are two 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.
6.1.1.1
Primary Efficacy Endpoint for EU (EMA)
The primary efficacy endpoint is a binary variable, Hb response (Yes/No), where Yes is 
defined as:
●
Hb ≥11.0 g/dL and Hb increase from baseline by ≥ 1.0 g/dL, for subjects with baseline 
Hb > 8.0 g/dL; or 
●
Hb increase from baseline by ≥ 2.0 g/dL, for subjects with baseline Hb ≤ 8.0 g/dL
at two consecutive visits [dates] (with available data) separated at least 5 days during the first 
24 weeks of treatment without having received rescue therapy (RBC transfusion, ESA, or IV 
iron) prior to Hb response.
Both scheduled and unscheduled Hb values from the central laboratory will be taken into 
account.
The first date of the two consecutive visits will be used as the date of response. Analysis 
visits will be used to define the week of response (see Table 31, Section 7.11.4).
Subjects who discontinued or received rescue therapy prior to the first Hb that fulfills the 
definition of response or before the second consecutive Hb value that fulfills the definition of 
response, will be classified as non-responders.
Baseline Hb is defined as the mean of four central laboratory Hb values: four latest Hb values 
prior or on the same date as first study drug intake (pre-dose).
Definition of rescue therapy is provided in Section 6.1.2.3
6.1.1.2
Primary Efficacy Endpoint for US (FDA)
Hb change from baseline (BL) to the average Hb of weeks 28 to 52 regardless of rescue 
therapy.
The central laboratory reported Hb values will be used for this analysis.
All available Hb values obtained from the central laboratory will be used (i.e., both scheduled 
and unscheduled Hb values). Hb values in analysis visit windows at weeks 28, 32, 36, 40, 44, 
48 and 52 will be used for the calculation of the average of weeks 28 to 52 (see Table 31 and 
Section 7.11.4 for the analysis windows definition and the differentiation between the 
MMRM and ANCOVA analyses). 


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In case a subject does not have any available Hb value within this evaluation period refer to 
Section 7.11.1 for imputation rules.
Baseline Hb is defined as the mean of four central laboratory Hb values: four latest Hb values 
prior or on the same date as first study drug intake.
6.1.2
Key Secondary Efficacy Endpoints
The key secondary efficacy endpoints in this study are listed in Table 4
Table 4
Key Secondary Efficacy Endpoints
Number
Endpoint
1
Hb change from BL 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.
2
Change from BL in Low Density Lipoprotein (LDL) cholesterol to the average LDL cholesterol of 
weeks 12 to 28.
3
Occurrence and time to first use of rescue therapy [composite of RBC transfusions, IV iron 
supplementation and rescue ESA]
4
Change from BL in SF-36 Vitality (VT) sub-score to the average VT sub-score of weeks 12 to 28.
5
Change from BL in SF-36 Physical Functioning (PF) sub-score to the average PF sub-score of 
weeks 12 to 28.
6*
Change from BL in mean arterial pressure (MAP) to the average MAP value of weeks 20 to 28.
7*
Occurrence and time to first 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 
8*
Rate of progression of CKD measured by annualized eGFR slope over time
*: These key secondary endpoints will not be included in the hierarchical testing procedure.
6.1.2.1
Hb change from BL 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
All available Hb values obtained from the central laboratory will be used (i.e., both scheduled 
and unscheduled Hb values). Hb values in analysis visit windows at weeks 28, 32 and 36 will 
be used for the calculation of the average of weeks 28 to 36 (see Table 31 and Section 7.11.4
for the analysis windows definition and the differentiation between the MMRM and 
ANCOVA analyses). 
In case a subject does not have any available Hb value within this evaluation period, or in 
case a subject requires rescue therapy within 6 weeks prior to and during this 8-week 
evaluation period, refer to Section 7.11.1 for imputation rules.
Baseline Hb is defined in Section 6.1.1.1
6.1.2.2
Change from BL in Low Density Lipoprotein (LDL) Cholesterol to the 
Average LDL Cholesterol of Weeks 12 to 28
The analysis will be done on all values (fasted and non fasted) of Day 1 and weeks 12 to 28.
All available LDL values will be used (regardless the fasting status), i.e., both scheduled and 
unscheduled LDL values. LDL values in analysis visit windows at weeks 12, 20 and 28 will 


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be selected for the calculation of the average LDL cholesterol of weeks 12-28 (see Table 33
and Section 7.11.4 for the analysis windows definition and the differentiation between the
MMRM and ANCOVA analyses).
For missing LDL imputation rules, refer to Section 7.11.1. Baseline LDL is defined as the 
LDL value on Day 1. If this value is missing, the latest value prior to first study drug 
administration will be used. 
This analysis will also be repeated for fasted values only as a sensitivity analysis.
6.1.2.3
Use and time to first use of rescue therapy (composite of RBC transfusions, 
ESA use, and IV iron) 
RBC transfusion is collected in the Blood Transfusions form of the eCRF. The use of ESAs 
and IV iron is collected in the Concomitant Medication form of the eCRF (entries where 
“Given as Anemia Therapy?” is ticked). These medications will be coded into the ATC and 
WHO-DRL dictionaries.
The following  WHO-DRL codes will be classified as ESA: '00909301001', '00928301001', 
'02198701001', '07973701001', ‘01703101001’. The following WHO-DRL code where route 
is INTRAVENOUS will be classified as IV IRON: '00023501001' and ‘90135401001’. The 
following WHO-DRL code will be classified as RBC transfusion: '01186901001'.
Only rescue medication that started during the study treatment and up to the end of Efficacy 
Emergent Period will be taken into account and considered as use of rescue. Medication 
started at End of Treatment visit will not be considered rescue for patients completed the 
treatment. Medication Onset Date is the date of the first use of rescue medication. 
For a subject with use of rescue therapy, the time to use of rescue therapy will be calculated 
(in years) as:
(First event date – Analysis date of first dose intake + 1) / 365.25
With ‘First event date’ defined as ‘Date of first dose of rescue medication’ during the 
Efficacy Emergent Period and ‘Analysis date of first dose intake’ defined in Section 6.5.4
For a subject without use of rescue therapy, the time to censoring is calculated as: 
[(Date of End of Efficacy Emergent Period – Analysis date of first dose intake + 1] / 365.25
With date of End of Efficacy Emergent Period defined in Section 7.11.6
6.1.2.4
Change from BL in SF-36 Vitality (VT) Sub-score to the Average VT Sub-
score of Weeks 12 to 28
For details on the calculation of the SF-36 VT scale subscore, see Section 6.1.3.14.1.
All available SF-36 VT values will be used i.e., both scheduled and unscheduled SF-36 VT 
values. SF-36 PF values in analysis visit windows at weeks 12 and 28 will be selected for the 
calculation of the average VT sub-score of weeks 12 to 28 (see Table 32 and Section 7.11.4
for the analysis windows definition and the differentiation between the MMRM and 
ANCOVA analyses).


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For missing SF-36 VT, refer to Section 7.11.1 for the imputation rules. Baseline assessment 
is the assessment from Day 1 visit.
6.1.2.5
Change from BL in SF-36 Physical Functioning (PF) Sub-score to the Average 
PF Sub-score of Weeks 12 to 28
For details on the SF-36 PF subscore, refer to Section 6.1.3.14.1 Similar rules as for 
Section 6.1.2.4 will be used for the calculation of the SF-36 VT scale sub-score.
6.1.2.6
Change from BL in Mean Arterial Pressure (MAP) to the Average MAP Value 
of Weeks 20 to 28
Blood pressure will be measured singly for the three visits during the screening period and in 
triplicate with a 2-minute interval for all other visits during the study. During the study, for 
systolic blood pressure (SBP) and diastolic blood pressure (DBP), the average will be 
calculated for each visit using the three readings. If less than three readings are available, all 
will be used in the calculation of the average.
MAP will be derived for each visit from the above averaged SBP and the DBP using the 
following equation: 
MAP = (2/3) * DBP + (1/3) * SBP
All available MAP values during the Safety Emergent Period will be used, i.e. both 
scheduled and unscheduled MAP values. MAP values in analysis visit windows at weeks 20, 
22, 24 and 28 will be selected for the calculation of the average MAP during weeks 20-28 
(see Table 31 and Section 7.11.4 for the analysis windows definition and the differentiation 
between the MMRM and ANCOVA analyses). 
For missing data imputation rules, refer to Section 7.11.1 Baseline assessment is the 
assessment on Day 1 (average of the three readings). If the baseline assessment is missing, 
then the latest available value prior to first drug administration will be used.
6.1.2.7
Occurrence and time to first occurrence of hypertension
Occurrence of an increase in blood pressure is a binary variable (Yes/No), defined as:
●
systolic blood pressure (SBP) increase from BL ≥20 mmHg AND SBP >170 mmHg, or 
●
diastolic blood pressure (DBP) increase from BL ≥15 mmHg AND DBP ≥110 mmHg.
The date of occurrence of hypertension is defined as the first date where SBP criterion or 
DBP criterion is met, whichever occurs first.
At each visit, SBP and DBP are calculated as the average from the 3 readings.. If less than 
three readings are available, the non-missing readings will be used in the calculation of the 
average.
Baseline assessment is the assessment from Day 1. If this value is missing, then the latest 
available value from the screening period will be used.
Only events starting during the Safety Emergent Period (defined in Section 6.2) will be taken 
into account.


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The time to occurrence of hypertension for a subject with the event of interest will be 
calculated (in years) as:
(First event date – Analysis date of first dose intake + 1) / 365.25Where ‘Analysis date of 
first dose intake’ is defined in Section 6.5.4, and where ‘First event date’ is the first date of 
occurrence of hypertension.The time to censoring for a subject without the event of interest is 
calculated as: (Date of last vital signs assessment during the Safety Emergent Period –
Analysis date of first dose intake + 1) / 365.25Refer to Sections 6.2 and 7.11.5 for more 
details regarding the Safety Emergent Period. 
6.1.2.8
Rate of progression of CKD measured by annualized eGFR slope over time
Any eGFR values obtained from start of dialysis treatment (acute or chronic)  will be 
excluded for the summaries and statistical analyses.
6.1.3
Additional Secondary Efficacy Endpoints
The additional secondary efficacy endpoints are listed in Table 5
Table 5
Additional Secondary Efficacy Endpoints
Number
Endpoint
Hb correction and maintenance
1
Hb level averaged over weeks 28 to 36, 44 to 52, and 96 to 104 without use of rescue therapy within 
6 weeks prior to and during this evaluation period.
2
Time to achieve the first Hb response as defined by primary endpoint.
3
Hb change from BL to each post-dosing time point.
4
Hb change from BL to the average Hb value of weeks 28 to 36, 44 to 52, and 96 to 104 regardless 
of the use of rescue therapy.
5
Proportion of Hb values within 10.0 to 12.0 g/dL and ≥10.0 g/dL in weeks 28 to 36, 44 to 52, and 96 
to 104 without use of rescue therapy within 6 weeks prior to and during these 8-week evaluation 
periods.
Hospitalizations
6
Occurrence (number) of hospitalizations,number of days of hospitalization per patient-year exposure 
and time to first hospitalization.
Rescue Therapy Use
7
Time to first use of rescue therapy (composite of RBC transfusions, ESA use, and IV iron) in the 
first 24 weeks of treatment.
8
Occurrence and time to first use of RBC transfusions, number of RBC packs per month  subject, 
volume of RBC transfused per month.
9
Occurrence and time to first use of ESA. Number of ESA-Weeks per year
10
Occurrence and time to first use of IV iron supplementation. Mean monthly IV iron (mg) per subject 
during day 1 to week 36, weeks 37-52 and weeks 53-104 (monthly defined as a period of 4 weeks).
Change in Cholesterol Levels, Apolipoproteins
11
Change from BL to each post-dosing study visit in Total cholesterol, LDL/High-density Lipoprotein 
(HDL) ratio, Non-HDL cholesterol, Apolipoproteins A1 and B, ApoB/ApoA1 ratio. 
12
Occurrence of mean LDL cholesterol <100 mg/dL calculated over weeks 12 to 28.
Blood Pressure Effect
13
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 to 28. 
Table continued on next page


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Number
Endpoint
HRQoL 
14
Change from BL to the average value of weeks 12 to 28 (SF-36 Physical Component Score (PCS), 
Anemia Subscale (“Additional Concerns”) of Functional Assessment of Cancer Therapy 
(FACT-An) Score, Total FACT-An Score, EQ-5D 5L VAS Score and Work Productivity and 
Activity Impairment (WPAI:ANS).
15
Patient Global Impression of Change (PGIC).
Hepcidin, Iron status, HbA1c, and CKD progression
16
Changes from BL to each study visit (when measured) in Serum hepcidin, Serum ferritin, TSAT, 
HbA1c level, Fasting blood glucose, eGFR, Urine albumin/creatinine ratio, Time to (and proportion 
of subjects) Serum Creatinine having doubled during the study and Proportion of subjects with
ESRD.
6.1.3.1
Hb level averaged over weeks 28 to 36, 44 to 52, and 96 to 104 without use of 
rescue therapy within 6 weeks prior to and during this evaluation period.
All scheduled and unscheduled hemoglobin values that belong to each period will be taken 
into account for calculating the average using the analysis windows (defined in Table 31, 
Section 7.11.4).
In addition, the averages over weeks 28-36, 44-52 and 96-104 will be categorized into the 
following categories: 
●
<10.0 g/dL,
●
10.0-12.0 g/dL,
●
>12.0 g/dL,
●
≥ 10.0 g/dL.
In case a subject does not have any available Hb value within this evaluation period, or in 
case a subject requires rescue therapy within 6 weeks prior to and during this 8-week 
evaluation period, refer to Section 7.11.1 for imputation rules
6.1.3.2
Time to achieve the first Hb response as defined by primary endpoint.
6.1.3.2.1
Time (weeks) to achieve the first Hb response, without rescue therapy, as 
defined by the primary endpoint
Hb response is defined in Section 6.1.1.1
For a subject without rescue therapy before Hb response, the time to achieve Hb response 
will be calculated (in weeks) as:
(First event date – Analysis date of first dose intake + 1) / 7
where ‘First event date’ is defined as ‘First date of both values that meet the criteria for 
response’ and ‘Analysis date of first dose intake’ is defined in Section 6.5.4
For a subject without Hb response or with rescue therapy before Hb response, the time to 
censoring will be calculated (in weeks) as: 
(Min[Date of End of Efficacy Emergent Period, Date of initiation of rescue therapy, Analysis 
date of Week 24 visit] – Analysis date of first dose intake+ 1) / 7


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6.1.3.3
Hb change from BL to each post-dosing time point
All scheduled and unscheduled hemoglobin values that belong to each window will be taken 
into account using one value per analysis window, as defined in Table 31 and Section 7.11.4
Baseline Hb is defined in Section 6.1.1.1
At each visit, Hb will also be categorized into the following categories: <10 g/dL, 10-12 g/dL 
and >12 g/dL. 
6.1.3.4
Hb change from BL to the average Hb value of weeks 28 to 36, 44 to 52, and 96 
to 104 regardless of the use of rescue therapy
The same rules as defined in Section 6.1.2.1, but regardless use of rescue therapy. 
6.1.3.5
Categorical analysis of Hb values
The following endpoints will be analyzed : proportion of Hb values within 10.0-12.0 g/dL 
and ≥10.0 g/dL, by time intervals, the percentage of time with Hb values falling in each Hb 
interval  (< 10.0 g/dL, within 10.0-12.0 g/dL, ≥10.0 g/dL, > 12.0 g/dL, > 13.0 g/dL and 
> 14.0 g/dL) during the Efficacy Emergent Period and the potential Excessive Hematopoiesis 
(EH).
Proportion of Hb values : 
The following proportion in percentage for each subject will be defined: 
●
Number of Hb values within 10.0-12.0 g/dL / Total number of Hb values*100 and 
(≥10.0 g/dL)/Total number of Hb values*100
in weeks 28 to 36, 44 to 52 and 96 to 104 without use of rescue therapy within 6 weeks prior 
to and during this 8 week evaluation period. All scheduled and unscheduled hemoglobin 
values that belong to each period will be taken into account using the analysis windows 
defined in Table 31, Section 7.11.4.
Percentage of time :
The percentage of time each patient has a Hb value <10.0 g/dL, within 10.0-12.0 g/dL, 
≥10.0 g/dL, > 12.0 g/dL, > 13.0 g/dL  or > 14.0 g/dL
will be calculated (as a percentage of the total of the length of time between the first and last 
Hb assessment during the evaluated period). The percentage of time will be calculated via 
linear interpolation. That is, if the change in Hb category (for instance from within 
10.0-12.0 g/dL to > 12.0 g/dL) occurs between two visits V0 and V1, the day of change will 
be calculated by:
Where x1 and x0 are the dates when Hb was measured at V0 and V1 respectively,
y0 and y1 are the Hb value at the respective visits V0 and V1 and y is the level of the Hb


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boundary (i.e 12.0, 13.0 or 14.0 g/dL). Percentage of time each subject has Hb value 
≥10.0 g/dL will be derived as 100% - percentage time for Hb values < 10 g/dL.
Figure 1 shows visually how the linear interpolation will calculate the total number of days 
that a subject is in each Hb category for an example subject:
Figure 1
Example of Linear Extrapolation
In case that several Hb values are on the same day the average of these values will be used to 
represent the Hb of that day in the above formula. This calculation will provide the day that 
the change in Hb value occurs. The number of days that the Hb value has been in each 
category will be determined and the percentage calculated based on the length of time 
between the first and last Hb assessment during the evaluated period, i.e.:
Date of Last Hb assessment during the evaluated period – Date of first assessment during the 
evaluated period.
No imputation will be performed if no Hb value is available in relevant time windows.
In case a subject requires rescue therapy within 6 weeks prior to and during these 8-week 
evaluation periods, refer to Section 7.11.1 for imputation rules.
Potential Excessive Hematopoiesis (EH), regardless use of rescue therapy, based on Hb 
central lab will be defined as:
o
Hb increase by >2.0 g/dL between any two visits within 4 weeks of treatment 
during the Efficacy Emergent Period.
Time to first occurrence of potential EH regardless the use of rescue therapy during the 
Efficacy Emergent Period will be defined in weeks as :
(First event date – Analysis date of first dose intake + 1) / 7


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where ‘First event date’ is defined as first date of occurence of the criterion met during the 
Efficacy Emergent Period.
For a subject without potential EH, the time to censoring will be calculated (in weeks) as: 
(Date of last hemoglobin assessment during the Efficacy Emergent Period – Analysis date of 
first dose intake + 1) / 7
Refer to Section 6.1 and 7.11.6 for the definition of the Efficacy Emergent Period. 
6.1.3.6
Occurrence (number) of hospitalizations, number of days of hospitalization
per patient- exposure -year and time to first hospitalization
The occurrence and the number of hospitalizations per subject during the Efficacy Emergent 
Period will be calculated.
The number of days of hospitalization per patient- exposure-year (PEY) will be calculated 
as : 
[Sum of the durations of all hospitalizations in days (Minimum ((Date of discharge, End of 
Efficacy Emergent Period) – Date of admission + 1)] / [(Duration of Efficacy Emergent 
Period in days / 365.25)].
When hospitalization is ongoing, the date of end of the Efficacy Emergen Period will be used 
for the derivation of the hospitalization duration. In case of missing dates the hospitalization 
duration will be imputed by the average duration per stay derived from the subjects with non-
missing duration within the same treatment group . Duration of treatment exposure is defined 
in Section 6.5.4
If the date of admission of a hospitalization record is the same as the date of discharge of the 
previous record, for example because two records are created to illustrate that the subject is 
moved from one hospital to another hospital or from a standard care to the intensive care unit 
(ICU), then the date of the transfer should not be counted twice and thus the hospitalizations 
duration for the later period is calculated as (Date of discharge – Date of admission). In such 
case hospitalization occurrence will also be counted only once.
Hospitalizations will also be described by reason for admission (admission for anemia or 
other reasons).
Time to first hospitalization in years  will be defined in years as :
(First event date during the Efficacy Emergent Period – Analysis date of first dose intake + 
1)/365.25
With ‘First event date’ defined as ‘Date of first Admission’  and ‘Analysis date of first dose 
intake defined in Section 6.5.4.
For a subject without hospitalization, the time to censoring will be calculated as: 
[Date of End of Efficacy Emergent Period – Analysis date of first dose intake + 1) / 365.25
With date of End of Efficacy Emergent Period is defined in Section 7.11.6


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6.1.3.7
Occurrence and time to first use of rescue therapy [composite of RBC 
transfusions, IV iron supplementation and ESA treatment] during the first 
24 weeks
Rescue medication  is defined in Section 6.1.2.3  Start of rescue medication is only counted 
as event if it was started within the first 24 weeks of treatment. Subjects without event were 
censored at the date of the Week 24 visit.
6.1.3.8
Occurrence and time to first use of RBC transfusions, number of RBC packs 
per month, volume of RBC transfused per month
The blood transfusion form of the eCRF in the cumulative visit will be used to derive the 
number of RBC packs.
Monthly volume of blood transfused and the monthly total number of RBC units/packs (for 
each subject, the sum of blood volume and units transfused during the Efficacy Emergent 
Period / divided total number of days multiplied by 28 days) will be derived.
For RBC transfusions, when the number of units is not given but the volume transfused is 
given, the number of units will be estimated by volume transfused/250 mL (for transfusion of 
packed cell units) or volume transfused/500 mL (for transfusion of full blood).
When transfused volume is not given but the number of RBC units is given, the volume will 
be estimated as number of RBC units times 250 mL (for transfusion of packed cell units) or 
number of units times 500 mL (for transfusion of full blood).'
For subjects with use of RBC transfusion, the time to use of RBC transfusion is calculated as:
(First event date – Analysis date of first dose intake + 1) / 365.25
With ‘First event date’ defined as ‘Date of first RBC transfusion’ during the Efficacy 
Emergent Period and ‘Analysis Date of first dose intake’ defined in Section 6.5.4
For a subject without use of RBC transfusion, the time to censoring is calculated as: 
(Date of End of Efficacy Emergent Period – Analysis date of first dose intake + 1] / 365.25
With date of End of Efficacy Emergent Period defined in Section 7.11.6
6.1.3.9
Occurrence and time to first use of IV iron supplementation. Mean monthly 
IV iron (mg) per subject during day 1 to week 36, weeks 37-52 and weeks 
53-104 (monthly defined as a period of 4 weeks)
The use of IV iron is collected in the Concomitant Medication form of the eCRF. The route 
of administration (Intravenous) is also captured in the eCRF. All medications are coded with 
WHO-DD. Records selected will be those coded as IRON PREPARATIONS, ATC 3rd level 
code: B03A and where route is INTRAVENOUS.
Having received IV Iron is a binary variable (Yes/No), where “Yes” is defined as having at 
least one record selected during the Efficacy Emergent Period. The Efficacy Emergent Period 
will be divided in periods of 28 days and for each of these periods, the monthly mean of IV
iron will be calculated.


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Only use of IV Iron that was ongoing or started during the Efficacy Emergent Period will be 
taken into account. 
The Mean Monthly IV iron use per subject (in mg) during the first 36 weeks is defined by the 
following formula:
 	 
   ()	 Analysis date of first dose intake 
  $(%& ' 	 () 36 ,,   %& . 	  .)
(($(%& ' 	 () 36 ,,   %& . 	  .) −'& 1 ') + 1)/ 28
Monthly is defined as a period of 4 weeks.
Subjects without a relevant concomitant medication record will be assumed that they used no 
IV iron, thus set to 0 mg.
The same method will be used to calculate monthly IV iron use for week 37-52 and 53-104. 
Analysis visits will be used as indicated in Section 7.11.4.
For subjects with use of IV iron, the time to first use of IV iron is calculated as:
(First event date – Analysis date of first dose intake + 1) / 365.25
With ‘First event date’ defined as ‘Date of first IV iron’ during the Efficacy Emergent Period 
and ‘Analysis date of first dose intake’ defined in Section 6.5.4
For a subject without use of IV iron, the time to censoringis calculated as: 
(Date of End of Efficacy Emergent Period – Analysis date of first dose intake + 1] / 365.25
With date of End of Efficacy Emergent Period defined in Section 7.11.6
6.1.3.10 Occurrence and time to first use of ESA. Number of ESA-Weeks per year
The concomitant medication form of the eCRF in the cumulative visit will be used to detect 
rescue medication with ESAs as defined in Section 6.1.2.3
The number of ESA-weeks per year are defined as the duration of ESA exposure divided by 
the total efficacy period in years. Each period when ESA [ATC code = B03XA] was taken 
will be summed by subjects as follows: 
[sum (each period (min(End date of efficacy emergent period, End date of ESA therapy) + X 
days – Start date of ESA therapy +1)/7 )]/total period in years;
X will be defined as the duration of the effect of ESA following the last ESA administration, 
based on the following rules:
If Frequency = 1 PER WEEK then X=7
If Frequency = 2 PER WEEK then X=3
If Frequency = 3 PER WEEK then X=2
If Frequency = 1 PER MONTH then X=28
If Frequency = ONCE then X=0
If Frequency = BIM (Bi-monthly) then X=14
If Frequency = QD (daily) then X=1


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If Frequency = QM (monthly) then X=28
If Frequency =QOD (every other day) then X=2
If Frequency = TID (three times daily) then X=1
If Frequency = 4 TIMES PER WEEK then X=2
If Frequency = EVERY 3 WEEKS then X=21
Additional frequency may be considered depending on the data.
For subjects with use of ESA, the time to first use of ESA is calculated as:
(First event date – Analysis date of first dose intake + 1) / 365.25
With ‘First event date’ defined as ‘Date of first ESA’ and ‘Analysis date of first dose intake’ 
defined in Section 6.5.4
For a subject without use of ESA, the time to censoring is calculated as: 
(Date of End of Efficacy Emergent Period – Analysis date of first dose intake + 1] / 365.25
With date of End of Efficacy Emergent Period defined in Section 7.11.6
6.1.3.11 Change from BL to each post-dosing study visit in Total cholesterol, 
LDL/High-density Lipoprotein (HDL) ratio, Non-HDL cholesterol, 
Apolipoproteins A1 and B, ApoB/ApoA1 ratio
For each sample the following will be calculated:
●
LDL/HDL ratio (LDL Cholesterol divided by HDL Cholesterol)
●
Non-HDL cholesterol (Total Cholesterol minus HDL Cholesterol)
Change from baseline to each post-dosing study visit will be calculated for the following 
lipid parameters:
●
Total cholesterol 
●
LDL cholesterol
●
HDL cholesterol
●
Low-density lipoprotein (LDL) / high-density lipoprotein (HDL) ratio
●
Non-HDL cholesterol
●
Triglyceride
●
Apolipoproteins A1 and B (ApoA1 and ApoB)
●
ApoB/ApoA1 ratio.
All available data will be summarized descriptively for all parameters above, regardless of 
fasting status.
No imputation will be performed in case of a missing value. If several values are available in 
the same window, one value will be used, as defined in Table 33 and Section 7.11.4  
Baseline assessment is the assessment from Day 1 visit. If this value is missing, then the 
latest screening period value will be used as baseline. 


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6.1.3.12 Occurrence of mean LDL cholesterol <100 mg/dL calculated over weeks 12 to 
28
The evaluation period is defined as the average of all available LDL cholesterol values in 
weeks 12-28 (visit at 12, 20 and 28 weeks, as defined in Table 33 and Section 7.11.4). The 
occurrence of mean LDL cholesterol <100 mg/dL over weeks 12 to 28 will then be defined 
as a binary variable (Yes/No), where ”Yes” is defined as mean LDL cholesterol <100 mg/dL 
over weeks 12 to 28.
No imputation will be performed in case of a missing value.
This endpoint will be reported on fasting values and regardless of fasting status.
6.1.3.13 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 to 28
Occurrence of achieved antihypertensive treatment goal (SBP < 130 mmHg and 
DBP < 80 mmHg) based on the mean SBP and mean DBP is calculated over an evaluation 
period defined as the average of all available values in weeks 12 to 28 during the Safety 
Emergent Period, similarly as in Section 6.1.2.6 (analysis windows defined in Table 31, 
Section 7.11.4). Occurrence of achieved antihypertensive treatment goal will then be defined 
as a binary variable (Yes/No), where “Yes” is defined as SBP < 130 mmHg and 
DBP < 80 mmHg.
No imputation will be performed in case of a missing value.
6.1.3.14 Change from BL to the average value of weeks 12 to 28 in Quality of Life 
scores
All study subjects will be required to complete Quality of Life (QoL) questionnaires as 
indicated in the schedule of assessments: 
●
SF-36
●
FACT-An
●
EQ-5D 5L
●
WPAI:ANS
The next sections provide further details on how to derive these instruments, some 
derivations will be provided by an external vendor (QualityMetric).
6.1.3.14.1 Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36)
The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) is a multi-purpose, 
short-form health survey with 36 questions (see Appendix 10.1). It yields an 8-scale profile 
of functional health and well-being scores as well as psychometrically-based physical and 
mental health summary measures. It is a generic measure, as opposed to one that targets a 
specific age, disease, or treatment group. Accordingly, the SF-36 has proven useful in
surveys of general and specific populations, comparing the relative burden of diseases, and in 
differentiating the health benefits produced by a wide range of different treatments.


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The SF-36 contains 36 items that measure eight dimensions or scales: (1) physical 
functioning (PF); (2) role limitations due to physical health problems (RP); (3) bodily pain 
(BP); (4) social functioning (SF); (5) general health perceptions (GH); (6) role limitations 
due to emotional problems (RE); (7) vitality, energy or fatigue (VT); and (8) mental health 
(MH) (see Appendix 10.1). In addition, two summary measures, defined as the Physical 
Component Score (SF-36 PCS) and Mental Component Score (SF-36 MCS) will be 
provided.
Scoring of each dimension and the summary measure will be performed by QualyMetric 
using QualityMetric Health Outcomes(tm) Scoring Software 4.5.
Change from baseline to the average value in weeks 12-28 will be calculated for the Physical 
Component Scores of SF-36 (SF-36 PCS), following the same rules as defined in 
Section 6.1.2.5
For missing SF-36 PCS values, refer to Section 7.11.1 imputation rules. Baseline always 
refers to the assessment at day 1 to be performed prior to first study drug administration.
The number and percent of subjects with an increase from baseline of <3 / >=3 points and of 
<5 / >=5 points will be calculated for each visit for the following: Vitality Score (SF-36 VT), 
Physical Functioning score (SF-36 PF) and Physical Component score (SF-36 PCS).
In addition, the eight dimensions and the two summary measures and their associated change 
from baseline will be reported by visit.
6.1.3.14.2 Functional Assessment of Cancer Therapy –Anemia (FACT-An)
The Functional Assessment of Cancer Therapy – General (FACT-G; version 4) contains 
27 items that cover four dimensions of well-being: physical (PWB) – 7 items, functional 
(FWB) – 7 items, social/family (SWB) – 7 items, and emotional (EWB) – 6 items. 
The ‘additional concerns’ section contains 20 items: 13 fatigue specific items 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 seven additional items related to anemia comprise 
the Anemia Subscale (AnS). Administration of the FACT-G plus the Anemia Subscale (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. A final higher score indicates better QoL (see Appendix 10.2).
Each individual item is scored from 0 (Not at all) to 4 (Very much), and then the total score 
is obtained by summation of the resulted scores.


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If there are missing items, subscale scores can be standardized. This is done by multiplying 
the sum of the subscale by the number of items in the subscale, then dividing by the number 
of items actually answered. This can be done on the scoring guide or by using the formula 
below:
Prorated subscale score = [Sum of item scores] x [N of items in subscale] / [N of items 
answered]
When there are missing data, standardizing by subscale in this way is acceptable
(Webster 2003) as long as more than 50% of the items were answered (e.g., a minimum of 
4 of 7 items, 4 of 6 items, etc). The total score is then calculated as the sum of the 
un-weighted subscale scores.  The FACT scale is considered to be an acceptable indicator of 
a subject’s quality of life as long as overall item response rate is greater than 80% (e.g., at 
least 22 of 27 FACT-G items completed). This is not to be confused with individual subscale 
item response rate, which allows a subscale score to be prorated for missing items if greater 
than 50% of items are answered. In addition, a total score should only be calculated if ALL 
of the component subscales have available scores.
The FACT-An instrument will be scored according to Appendix 10.2. The following 9 scores 
will be calculated:
●
PWB subscale score
●
SWB subscale score
●
EWB subscale score
●
FWB subscale score
●
AnS subscale score
●
FACT-An TOI score
●
FACT-G total score
●
FACT-An total score
●
Fatigue subscale score
Change from baseline to the average value in weeks 12-28 will be reported for the two scores 
(Anemia subscale ‘Additional concerns’ of FACT-An score and Total FACT-AN score). In 
addition, the score and change from baseline will be reported for each visit for all six scores.
Change from baseline to the average value in weeks 12-28 will be calculated for the 
FACT-An subscore, following the same rules as defined in Section 6.1.2.4
No imputation will be performed in case of a missing value.
Baseline always refers to the assessment at day 1 to be performed prior to first study drug 
administration.
6.1.3.14.3 EQ-5D 5L 
The EQ-5D 5L is an international standardized non-disease specific (i.e., generic) instrument 
for describing and valuing health status, and a multi-dimensional measure of health-related 
QoL (see Appendix 10.3).


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It includes two main components: (1) a VAS scale rating perception of overall health and (2) 
5 qualitative domains: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and 
Anxiety/Depression. For more details and description of the questionnaire, refer to 
Appendix 10.3
Change from baseline to the average value in weeks 12-28 will be calculated for the EQ 5D 
5L VAS, following the same rules as defined in Section 6.1.2.4
Frequency distributions will be described for each visit for:
●
EQ-5D 5L Mobility Score
●
EQ-5D 5L Self-Care Score
●
EQ-5D 5L Usual Activities Score
●
EQ-5D 5L Pain/Discomfort Score
●
EQ-5D 5L Anxiety/Depression Score
The evaluation period for the VAS score is defined as the average of available EQ-5D 5L 
VAS scores of weeks 12-28 (visit at W12 and W28).
No imputation will be performed in case of a missing item. Baseline always refers to the 
assessment at day 1 to be performed prior to first study drug administration.
6.1.3.14.4 Work Productivity and Activity Impairment (WPAI: ANS)
The objective of the Work Productivity and Activity Impairment questionnaire: Anemic 
Symptoms v2 (WPAI: ANS) is to measure work and activity impairment during the past 
seven days due to anemia. It is self-assessed. 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 (see Appendix 10.4).
For subjects who are currently employed, the following four items will be calculated:
●
Percent work time missed due to anaemic symptoms: 100 x Q2/(Q2+Q4)
●
Percent impairment while working due to anaemic symptoms: 100 x Q5/10
●
Percent overall work impairment due to anaemic symptoms: 100 x Q2/(Q2+Q4)+[(1-
Q2/(Q2+Q4))x(Q5/10)]
●
Percent activity impairment due to anaemic symptoms: 100 x  Q6/10
Change from baseline to the average value in weeks 12-28 and in weeks 36-52 will be 
calculated for these items, following the same rules as defined in Section 6.1.2.4 The 
evaluation period score is defined as the average of available WPAI: ANS subscore of weeks 
12-28 (visit at W12 and W28) and weeks 36-52 (visit at W36 and W52).
No imputation will be performed in case of a missing item. Baseline always refers to the 
assessment at day 1 to be performed prior to first study drug administration.


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6.1.3.15 Patients’ Global Impression of Change (PGIC)
The Patients’ Global Impression of Change (PGIC) is a subject-rated instrument that 
measures change in subjects’ overall status since the start of the study on a 7-point qualitative 
scale ranging from 1 (very much improved) to 7 (very much worse) (see Appendix 10.5).
Data will be reported qualitatively by assessment as follows:
●
Reported subject status,
●
Combined Categories as binary:
o
Very Much Improved + Much Improved (yes/no)
o
Very Much Improved + Much Improved + Minimally Improved (yes/no)
No imputations will be performed in case of a missing item. 
6.1.3.16 Hepcidin and Iron, HbA1c and CKD progression parameters
Changes from baseline to each study visit (see analysis windows in Table 31, Section 7.11.4) 
will be calculated for these parameters:
1.
Serum hepcidin 
2.
Serum ferritin
3.
Serum Iron
4.
TSAT
5.
HbA1c level
6.
Fasting blood glucose
7.
Serum creatinine (log transformed)
8.
Albumin/creatinine ratio in urine (log transformed)
Serum creatinine and albumin/creatinine ratio in urine will be log transformed and any 
assessment occurring after the initiation of  any dialysis (acute or chronic) will be excluded 
for the summaries. 
For all variables above, baseline assessment is the assessment from Day 1 visit. If this value 
is missing, then the screening period value, if collected for that parameter, will be used.
CKD Progression variables:
●
Time to CKD progression (composite of doubling serum creatinine, chronic dialysis or 
renal transplant, and Death)
First occurrence of serum creatinine being doubled compared with baseline  during the Safety 
Emergent Period (see Section 6.2) will be calculated.
Occurrence of chronic dialysis or renal transplant (whichever occurring first) during the 
Safety Emergent Period (see Section 6.2) will be calculated.
Time to occurrence for a subject who died during the Safety Emergent Period (see 
Section 6.2) will be calculated.


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For a subject, the time to CKD progression will be calculated (in years) as:
(First event date – Analysis date of first dose intake + 1) / 365.25
With ‘First event date’ defined as ‘First occurrence of serum creatinine being doubled 
compared with baseline, first occurrence of chronic dialysis or renal transplant, occurrence of  
subject who died (whichever occurring first)’ and ‘Analysis date of first dose intake’ defined 
in Section 6.5.4
For a subject without event, the time to censoring will be calculated (in years) as: 
(End of Safety Emergent Period – Analysis date of first dose intake + 1) / 365.25
With ‘Analysis date of first dose intake’ defined in Section 6.5.4
●
Time to chronic dialysis or renal transplant or occurrence for a subject who died
Occurrence of chronic dialysis or renal transplant (whichever occurring first) during the 
Safety Emergent Period (see Section 6.2) will be calculated.
Time to occurrence for a subject who died during the Safety Emergent Period (see 
Section 6.2) will be calculated.
For a subject, the time to chronic dialysis or renal transplant or occurrence for a subject who 
died will be calculated (in years) as:
(First event date – Analysis date of first dose intake + 1) / 365.25
With ‘First event date’ defined as ‘first occurrence of chronic dialysis or renal transplant, 
occurrence of  subject who died (whichever occurring first)’ and ‘Analysis date of first dose 
intake’ defined in Section 6.5.4.
For a subject without event, the time to censoring will be calculated (in years) as: 
(End of Safety Emergent Period – Analysis date of first dose intake + 1) / 365.25
With ‘Analysis date of first dose intake’ defined in Section 6.5.4
●
Time to doubling of serum creatinine
First occurrence of serum creatinine being doubled compared with baseline  during the 
Safety Emergent Period (see Section 6.2) will be calculated: 
(First event date – Analysis date of first dose intake + 1) / 365.25
For a subject without event, the time to censoring will be calculated (in years) as: 
(End of Safety Emergent Period – Analysis date of first dose intake + 1) / 365.25
With ‘Analysis date of first dose intake’ defined in Section 6.5.4
●
Time to doubling of serum creatinine or chronic dialysis or renal transplant:
First occurrence of serum creatinine being doubled compared with baseline  during the 
Safety Emergent Period (see Section 6.2) will be calculated. In addition, first occurrence 
of chronic dialysis or renal transplant during the Safety Emergent Period will be derived. 


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The endpoint is defined as time to doubling serum creatinine or chronic dialysis or renal 
transplant what ever comes first: 
(First event date – Analysis date of first dose intake + 1) / 365.25
For a subject without event, the time to censoring will be calculated (in years) as: 
(End of Safety Emergent Period – Analysis date of first dose intake + 1) / 365.25
With ‘Analysis date of first dose intake’ defined in Section 6.5.4
●
Time to chronic dialysis or renal transplant:
Occurrence of chronic dialysis or renal transplant (whichever occurring first) during the 
Safety Emergent Period (see Section 6.2) will be calculated and time to event in years 
will be defined as :
(First event date – Analysis date of first dose intake) /365.25
With ‘First event date’ defined as ‘Date of dialysis or Date of renal transplant (whichever 
occurring first) and ‘Analysis date of first dose intake’ defined in Section 6.5.4.
For a subject without dialysis or transplant, the time to censoring will be calculated as: 
(Date of End of Safety Emergent Period – Analysis date of first dose intake + 1) / 365.25
With Date of End of Safety Emergent Period defined in Section 7.11.5
●
Occurrence of End Stage Renal Disease is taken directly from the eCRF with the 
following categories: f the following:
○
Underwent >30 days of dialysis therapy
○
Received kidney transplant
○
Planned kidney transplant 
○
Physician recommended renal replacement therapy and subject refused 
therapy
○
Began dialysis and died < 30 days later
●
ESRD-free survival is defined as time form first dose alive and not progressed to ESRD. 
The time to event will be derived where event is death or ESRD whatever is first.
The time to event will be derived (in years) as:
(Date of event – Analysis date of first dose intake + 1) / 365.25
where ‘date of event’ is defined as date of occurrence of End Stage Renal Disease 
(recorded End Stage Renal Disease as AE) or date of death, whichever comes first, 
during the Safety Emergent Period.
For a subject wthout event, the time to censoring will be calculated (in years) as:
(End of Safety Emergent Period – Analysis date of first dose intake + 1) / 365.25
●
Proportion and Time to at least a 40%  eGFR decrease from baseline, based on all eGFR 
values before start of acute or chronic dialysis


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Time to at least 40% decrease in eGFR from baseline, chronic dialysis or renal 
transplant:
First occurrence of at least 40% decrease in eGFR from baseline  during the Safety Emergent 
Period (see Section 6.2) will be calculated.
Occurrence of chronic dialysis or renal transplant (whichever occurring first) during the 
Safety Emergent Period (see Section 6.2) will be calculated.
For a subject, the time to at least 40% decrease in eGFR from baseline, chronic dialysis or 
renal transplant will be calculated (in years) as:
(First event date – Analysis date of first dose intake + 1) / 365.25
With ‘First event date’ defined as ‘First occurrence of 40% decrease in eGFR from baseline, 
first occurrence of chronic dialysis or renal transplant (whichever occurring first) and 
‘Analysis date of first dose intake’ defined in Section 6.5.4
For a subject without event, the time to censoring will be calculated (in years) as: 
(End of Safety Emergent Period – Analysis date of first dose intake + 1) / 365.25
With ‘Analysis date of first dose intake’ defined in Section 6.5.4
●
Time to at least 40% decrease in eGFR from baseline
First occurrence of at least 40% decrease in eGFR from baseline  during the Safety Emergent 
Period (see Section 6.2) will be calculated.
For a subject, the time to at least 40% decrease in eGFR from baseline will be calculated (in 
years) as:
(First event date – Analysis date of first dose intake + 1) / 365.25
With ‘First event date’ defined as ‘First occurrence of 40% decrease in eGFR from baseline, 
and ‘Analysis date of first dose intake’ defined in Section 6.5.4
For a subject without event, the time to censoring will be calculated (in years) as: 
(min[End of Safety Emergent Period, first occurrenct of chronic dialysis date] – Analysis 
date of first dose intake + 1) / 365.25
With ‘Analysis date of first dose intake’ defined in Section 6.5.4
6.1.4
Other exploratory variables: hs-CRP (High Sensitivity C-Reactive Protein) 
and sTFR (Soluble Transferrin Receptor)
The variables hs-CRP and sTFR will be collected from the central laboratory on the 
following visits: Day 1, weeks 4, 12, 20, 36, 52, EOT and EOS. Absolute values and changes
from baseline to each study visit will be calculated. Baseline assessment is the assessment 
from Day 1 visit. If Day 1 assessment is missing, change from baseline will not be reported. 
Analysis windows are defined in Table 31, Section 7.11.4.


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6.2
Safety Variables
Safety will be assessed by evaluation of the following variables:
●
Treatment-emergent adverse events (TEAEs; frequency, severity, seriousness, and 
relationship to study drug),
●
Vital signs (systolic and diastolic blood pressure, pulse, respiratory rate and weight),
●
Clinical laboratory variables (hematology, biochemistry including liver enzymes and 
total Bilirubin, and urinalysis),
●
Physical examination,
●
12-lead electrocardiogram (ECG).
●
Vascular Access Thrombosis
The Safety Emergent Period will be defined as the evaluation period from the Analysis date 
of first drug intake up to 28 days after the Analysis Last Dose date (defined in Section 6.5.4).
Refer to Section 7.11.5 for more details on the derivation of the date of End of the Safety 
Emergent Period. This period will also be used to identify the minimum or maximum values 
collected on-treatment, defined as values collected from Day 2 up to the end of the Safety 
Emergent Period.
6.2.1
Adverse Events
6.2.1.1
Treatment emergent adverse event (TEAE)
TEAE is defined as an adverse event observed after starting administration of the test 
drug/comparative drug. If the adverse event occurs on Day 1 and the onset check box is 
marked “Onset after first dose of study drug” or the onset check box is left blank, then the 
adverse event will be considered treatment emergent. If the adverse event occurs on Day 1 
and the onset check box is marked “Onset before first dose of study drug”, then the adverse 
event will not be considered treatment emergent. If a subject experiences an event both 
during the pre-investigational period and during the investigational period, the event will be 
considered as TEAE only if it has worsened in severity (i.e., it is reported with a new start 
date). Only adverse events starting during the Safety Emergent Period will be counted as 
TEAE .
A drug-related TEAE is defined as any TEAE with at least possible relationship to study 
treatment as assessed by the investigator or with missing assessment of the causal 
relationship. 
Severity of AEs will be graded according to National Cancer Institute - Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.0.
For AE onset date imputation rules, refer to Section 7.11.2
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 20.0.
6.2.1.2
Standardized MedDRA Queries
No standardized MedDRA Queries (SMQs) will be performed.


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6.2.1.3
Time to occurrence of a TEAE (by type of AE group)
TEAEs are also classified into a number of groups depending on the following factors: 
●
Serious TEAEs
●
Death during the Safety Emergent Period
●
Any deaths (during the 24-month period)
●
Related Serious TEAEs
●
TEAEs Leading to permanent Discontinuation of the study drug
●
TEAEs NCI CTC Grade 3 or Higher
●
MedDRA System Organ Class (SOC)
The time to occurrence for a subject with a TEAE for a given type (except any deaths) will 
be calculated (in years) as:
(First TEAE date of the given type during the Safety Emergent Period – Analysis date 
of first dose intake + 1) / 365.25
With ‘Analysis date of first dose intake’ defined in Section 6.5.4 All adverse events 
collected during the Safety Emergent Period will be counted as TEAE, irrespective of use of 
rescue therapy.
Subjects who have not experienced a TEAE for that given type will be censored; the subject
will be censored and the time to censoring for these subjects will be calculated (in years) as:
(Date of End of Safety Emergent Period – Analysis date of first dose intake +1) / 365.25
With date of end of Safety Emergent Period defined in Section 7.11.5
For any deaths during the 24-month period (including those occuring during the Post-Study 
Follow Up Period), time to occurrence for a subject who died during study / post study 
follow up) will be calculated (in years) as:
[End date for corresponding Fatal AE – Analysis date of first dose intake + 1] / 365.25
With ‘End date for corresponding Fatal AE’ which cover both study and post-study FU
occurring up to Day 760 (i.e., month 24 + one month follow up + 3 days window as per 
protocol).
Subjects who have not died; the subject will be censored and the time to censoring for these 
subjects will be calculated (in years) as:
Minimum between [Day 760 and Max (Date of last known date when subject alive 
(End of Post-study FU), Date of lastcontact (Post study FU visit/call), Date of last 
Study evaluation (EOS form)) – Analysis date of first dose intake +1) / 365.25


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Additional analyses censoring  data post dialysis:
Time to occurrence with censoring all data at the initiation of permanent dialysis will be 
calculated as above where events occurring after initiation of dialysis will not be considered. 
Subjects who initiated dialysis and who have not experienced an event prior to the dialysis 
will be censored and the time to censoring for these subjects will be calculated (in years) as:
(Date of first dialysis – Analysis date of first dose intake +1) / 365.25
Subjects who have not experienced an event and did not initiate dialysis during the Safety 
Emergent Period, the time to censoring will be calculated (in years) as
(Date of End of Safety Emergent Period – Analysis date of first dose intake +1) / 365.25.
6.2.1.4
AE within 7 days
Additional analyses restricted to AEs that observed after starting administration of the test 
drug/comparative drug and up to Analysis Date of Last Dose + 7 days wil be defined. If the 
AE occurs on Day 1 and the onset check box is marked “Onset before first dose of study 
drug”, then the adverse event will not be considered. 
Time to occurrence of event will be calculated (in years) as:
(First event date of the given type occurring from Day 1 (post dose) up to Analysis 
date of minimum of (Last Dose + 7 days,  end of safety period)) – Analysis date of 
first dose intake + 1) / 365.25
With ‘Analysis date of first dose intake’ defined in Section 6.5.4 and Analysis Date of Last 
Dose defined in Section 6.5.3
Subjects who have not experienced an AE for that given type will be censored; the subject
will be censored and the time to censoring for these subjects will be calculated (in years) as:
Minimum [Analysis Date of Last Dose + 7 days, Max (EOS, Date of Death)] – Analysis date 
of first dose intake +1) / 365.25
6.2.1.5
Definition of incidence rate
The incidence rate (per 100 subject years at risk) will be calculated as follows:
100
(years)
risk 
at 
 time
cumulative
Total
event
 with 
subjects
of
Number 

Where Total cumulative time at risk is the sum of individual time at risk defined as either 
time to occurrence of the event or time to censoring for subjects with no event. Time to 
occurrence of the event and time to censoring are defined in Section 6.2.1.3
Number of subjects at risk is defined as the number of subjects with (censored or non-
censored) times to the event of interest greater or equal to t.


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6.2.1.6
Definitions of event rate
The event rate (per 100 patient year) during the Safety Emergent Period will be calculated as 
either:
100
Years
Exposure
Patient 
events
of
Number 

Or 
100
Years
Exposure
Patient 
event
an 
ng
experienci
subjects
of
Number 

Where Patient Exposure Years is defined as [Sum of individual exposure in days (Analysis 
date of last dose – Analysis date of first dose + 1)] / [(Duration of Safety Emergent Period in 
days / 365.25)].
The definition used will be indicated in the description of the corresponding analysis in 
Section 7
6.2.2
Vital Signs
The following endpoints will be assessed:
●
Systolic blood pressure (SBP)
●
Diastolic blood pressure (DBP)
●
Pulse 
In addition, the following assessments will be done:
●
Respiratory rate
●
Weight
Single measurements for blood pressure (BP) will be taken at three visits during the 
screening period. Measurements will be taken in triplicate with 2-minute intervals for all 
other visits. An average will be calculated from the three readings, the average in the eCRF 
system will not be used.
In case of missing values within a visit, the available readings will be used.
The position and date for the assessment will also be recorded. Change from baseline will be 
calculated as the measurement taken at the specific visit minus the measurement at baseline 
visit. 
For all vital parameters, the minimum and the maximum post-baseline value during the 
Safety Emergent Period will be defined. For this calculation, only values from day 2 up to the 
date of End of the Safety Emergent Period (see Section 7.11.5).
Baseline assessment is the assessment from day 1 visit. If day 1 assessment is missing, 
screening period assessment will be used in the analysis. For missing visits, the last 
observation will be carried forward.


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From the assessments collected in the ‘Vital Signs - HD/HDF Subjects Only’ form, only the 
pre-dialysis ones will be used for the classification of analysis visit (see Table 31, 
Section 7.11.4) and the definition of potentially clinical vital signs criteria. 
Vital signs values are potentially clinically significant (PCS) if they meet both the observed 
value criteria and the change from baseline criteria listed in Table 6 (10 combined criteria). 
Table 6
Potentially Clinically Significant (PCS) Vital signs Criteria
Vital Sign Parameter
Flag
Criteria
Observed Values
Change from Baseline
Respiratory Rate
(breaths per min)
High
≥ 20
Increase of  ≥ 5
Low
≤ 10
Decrease of ≥ 5
Systolic Blood Pressure 
(mmHg)
High
≥ 170
Increase of ≥ 20
Low
≤ 90
Decrease of ≥ 20
Diastolic Blood Pressure 
(mmHg)
High
≥ 110
Increase of ≥ 15
Low
≤ 45
Decrease of ≥ 15
Pulse 
(beats per min)
High
≥ 120
Increase of ≥ 20
Low
≤ 50
Decrease of ≥ 20
Weight (kg)
High
-
Increase of ≥ 10%
Low
-
Decrease of ≥ 10%
Potentially Clinically Significant Vital Signs Criteria will be calculated at each study visit 
and on-treatment (at any moment during the Safety Emergent Period) using the worst value 
among all available measurements. 
Time to occurrence of PCS Vital signs:
For each potentially clinically significant vital signs criteria (i.e., 10 combined criteria), the 
time to occurrence of a PCS at any moment during the Safety Emergent Period (see 
Section 6.2) will be calculated (in years) as:
(First occurrence date – Analysis date of first dose intake + 1) / 365.25
With ‘First occurrence date‘ defined as the first date when both criteria (i.e on observed and 
change from baseline) are met and Analysis date of first dose intake’ defined in 
Section 6.5.4
Subjects without abnormality will be censored and time to censoring for these subjects will 
be calculated (in years) as:
(Date of last vital signs assessment where the parameter analyzed is non-missing during the 
Safety Emergent Period – Analysis date of first dose intake +1) / 365.25
Post-dialysis Vital Signs data will be listed and PCS criteria (observed value) only will be
evaluated for them and flagged in the listing. No summary tables or Time to Event will be 
performed for them due to insufficient data.


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6.2.3
Clinical laboratory variables
6.2.3.1
Potentially Clinically Significant (PCS) Laboratory Criteria
Laboratory test values are potentially clinically significant (PCS) if they meet either the low 
or high PCS criteria listed in Table 7 below.
Table 7
Potentially Clinically Significant (PCS) Laboratory Criteria
Potentially Clinically Significant Laboratory Criteria
Laboratory Parameter
Unit
Low PCS Criteria
High PCS Criteria
Alanine Aminotransferase (ALT)
U/L
no lower limit
> 3X ULN
> 5X ULN#
> 8X ULN#
> 10X ULN#
> 20X ULN#
Aspartate Aminotransferase 
(AST)
U/L
no lower limit
> 3X ULN
> 5X ULN#
> 8X ULN#
> 10X ULN#
> 20X ULN#
Alkaline Phosphatase (ALP)
U/L
no lower limit
> 1.5 X ULN#
> 3 X ULN
ALT or AST
U/L for ALT or AST
no lower limit
ALT or AST > 8X ULN 
Total Bilirubin
µmol/L
no lower limit
> 1.5 X ULN 
> 2 X ULN#
Moderate Liver Abnormality**
U/L for ALT and AST,
µmol/L for Total 
Bilirubin
no lower limit
ALT and/or AST > 3X 
ULN or Total Bilirubin > 
2X ULN
Severe Liver Abnormality**
U/L for ALT and AST,
µmol/L for Total 
Bilirubin
no lower limit
ALT and/or AST > 3X 
ULN and Total Bilirubin 
> 2X ULN
Gamma Glutamine Transaminase 
(GGT)
U/L
no lower limit
> 3X ULN
Calcium
mmo1/L
< 0.8 X LLN
>1.2 X ULN
Creatinine
µmo1/L
>1.5 X Baseline
Potassium
mmo1/L
< 0.75 X LLN
>1.2 X ULN
Sodium
mmo1/L
< 0.9 X LNL
>1.1 X ULN
Total Protein
g/L
< 0.9 X LNL
>1.1 X ULN
Blood Urea Nitrogen (BUN)
mmo1/L
>1.5 X Baseline
Neutrophils
106/L
≤1000
Platelet Count
107/L
≤100
≥700
White Blood Cell Count
107/L
≤2.5
≥15
Triacylglycerol/Lipase
U/L
no lower limit
> 3X ULN or > 2 X  
Baseline
LLN: Lower limit of normal, value provided by the laboratory
ULN: Upper limit of normal, value provided by the laboratory
*Hemoglobin in SI unit (for conventional unit g/dL, divide by 10)
** a subject’s ALT and Total Bilirubin laboratory draw date or AST and Total Bilirubin laboratory draw date 
must occur on the same blood sample in order to be counted. 
# Additional criteria required for summary of Liver Function Tests only (see Section 7.5.2.1)
Potentially Clinically Significant Laboratory Criteria will be calculated at each study visitand 
on-treatment (see Section 6.2) using the worst value among all available measurements, 


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except for Moderate and Severe Liver Abnormalities which will be calculated on-treatment 
only.
Time to occurrence of an abnormality (for selected criteria)
Time to occurrence of an abnormality, will be derived only for the following PCS criteria:
●
Hemoglobin <6 g/dL
●
Hemoglobin >14 g/dL
●
Alanine Aminotransferase (ALT) > 3X ULN
●
Aspartate Aminotransferase (AST) > 3X ULN
●
Total Bilirubin > 1.5 X ULN 
For each potentially clinically significant laboratory criteria, the time to occurrence of an 
abnormality for a subject with an abnormality at any moment during the Safety Emergent 
Period (see Section 6.2) will be calculated (in years) as defined in Section 6.2.2  
Time to censoring will be defined (in years) as :
(Date of last laboratory assessment where parameter analyzed is non-missing during the 
Safety Emergent Period – Analysis date of first dose intake +1) / 365.25
6.2.3.2
Laboratory assessments
For all laboratory parameters, the minimum and the maximum values on treatment (see 
Section 6.2) will be defined.
In addition, each laboratory result will be classified as low (L), normal (N), or high (H) at 
each visit according to the laboratory supplied reference ranges.
Change from baseline will be calculated as the measurement taken at the specific visit minus 
the measurement at baseline visit. 
Baseline assessment is the assessment from the day 1 visit, except for Hb (see Section 6.1.1). 
If Day 1 is missing, the screening or unscheduled assessment that is closest prior to Day 1 
will be used.
Screening is defined as the screening or unscheduled assessment that  is closest to Day 1. 
For the lipid panel and glucose parameter, two baseline values will be defined based on 
fasting status: regardless of fasting and fasted.
6.2.4
Physical Examination
A comprehensive physical examination will be conducted during the screening period and at 
the 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 
(HEENT), lungs, heart, chest and back, abdomen, genitourinary, extremities, skin and any 
other, if deemed necessary.


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A targeted examination (e.g., respiratory and cardiovascular) will be conducted and recorded 
in the source documents.
Only the date of the physical examination will be recorded in the eCRF. There will be no 
table or listing for the physical examination. Any clinically relevant adverse change will be 
recorded as an AE in the eCRF.
6.2.5
12-lead Electrocardiogram (ECG)
The 12-lead ECG measurements will be performed on all subjects at specific times. A single 
ECG measurement will be taken with the subject in the supine position, after the subject has 
been lying quietly for 5 minutes. Clinically significant abnormalities will be reported as an 
AE.
The visit, ECG date, Pulse, RR Interval, PR interval, QRS Interval, QT Interval, overall 
interpretation and relevant comments will be recorded in the eCRF.
Baseline assessment is the assessment from day 1 visit. If day 1 assessment is missing, 
screening period assessment will be used in the analysis.
QTc interval will be calculated using both 
●
Bazett (QTcB = QT/(RR Interval);/<) and 
●
Fridericia (QTcF = QT/(RR Interval);/=) corrections, 
where QT is in msec and RR Interval in seconds; and if RR Interval is not available, it will be 
replaced with 60/HR.
For all ECG parameters, the maximum post-baseline value on treatment will be defined (see 
Section 6.2).
ECG values are potentially clinically significant (PCS) if they meet or exceed the upper limit 
values listed in Table 8 below. 
Table 8
ECG Parameters classification
ECG Parameter
Classsification
QTc interval (msec)
> 450 msec, > 480 msec,  > 500 msec;
QTc interval change (msec)
> 30 msec and  > 60 msec
(increase from baseline)
QRS (msec)
≥ 150 msec
PR (msec)
≥ 250 msec
Time to occurrence of PCS ECG :
For the two QTc criteria (QTc > 500 msec ; change from baseline in QTc > 60 msec), the 
time to occurrence (in years) for a subject with occurrence of the PCS at any moment during 
Safety Emergent Period (defined in Section 6.2) will be calculated (in years) as defined in 
Section 6.2.2  


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Time to censoring will be defined as :
(Date of last ECG assessment where parameter analyzed is non-missing during the Safety 
Emergent Period – Analysis date of first dose intake +1) / 365.25
6.2.6
Vascular Access Thrombosis (VAT)
For each AE listed as VAT, additional information regarding the event will be recorded.
6.3
Pharmacokinetic Variables
All details of the population PK analysis will be described in a separate analysis plan.
6.4
Pharmacodynamic Variables
Not applicable.
6.5
Other Variables
6.5.1
Eligibility criteria
Eligibility at screening will be recorded as a yes/no variable for each criterion. The date of 
the informed consent for the subjects will also be documented.
6.5.2
Demographic and Baseline Characteristic Variables
Demographic characteristics will be recorded at screening (sex, the day, month and year of 
birth, age, race, height and weight). 
Collection of date of birth depends on local regulations. Day of birth will be recorded in the 
eCRF as the first of the month when the day is not allowed to be collected. In cases where 
only year of birth is allowed to be collected, day and month will be recorded in the eCRF as 
the first of January. Age will be recalculated in SDTM and ADAM datasets. 
If DB is the Date of Birth and DFirst is the Date of First Dose intake, Age is 
Age= (DFirst-DB+1)/365.25.  If the Date of First Dose intake is not available, Date of 
Informed Consent will be used.
Based on recalculated age, three categories will be defined:
●
< 65 years
●
65 - 74 years,
●
≥75 years
Each subject’s body mass index (BMI) will be calculated as:
BMI (Kg/m²) = Weight (Kg)/ [Height (m)]²,
in which the height will be converted from cm. into m. by dividing by 100.
Tobacco history and use will be recorded at screening.  


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The average maximum quantity of tobacco per week will be calculated using the average 
maximum quantity and frequency filled in the CRF. If the frequency is “Day”, the average 
maximum quantity of tobacco per week will be determined as follows:
average maximum quantity per day x 7
If the frequency is “/Month”, the average maximum quantity of tobacco per week will be 
determined as follows:
average maximum quantity per month / 4.3482
Screening Hb will be defined as the mean of the three latest central laboratory Hb values 
prior to the day of randomization.
Baseline Hb is defined in Section 6.1.1
Based on the mean screening Hb value, two categories will be defined: 
●
≤8.0 g/dL
●
> 8.0 g/dL
History of cardiovascular, cerebrovascular or thromboembolic diseases at baseline will be 
determined by performing a medical review of preferred terms recorded on any of the 
medical history forms. . History will be categorized as:
●
Yes
●
No
Countries and Regions
Subjects will be enrolled from the following countries: 
Region A (Western Europe) 
●
Spain
●
UK
●
Italy
●
Belgium
Region B (Rest of the World)
●
Bulgaria
●
Hungary
●
Russia
●
Romania
●
Poland
●
Turkey
●
South Africa
●
Serbia
●
Ukraine
●
Georgia


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●
Estonia
●
Greece
●
Panama
●
Peru
●
Guatemala
●
Columbia
●
Dominican Republic
●
Belarus
Region B includes additional countries which were not part of the initial list of countries 
from Central and Eastern Europe as per IRT due to extended recruitment in Central and 
South Americas as well as Africa. 
Randomization will be stratified by region using two categories: 
●
Region A: Western Europe
●
Region B: Rest of the World
A limited amount of subjects is expected to be recruited out of Europe and will be 
randomized under the Central and Eastern Europe level of the Interactive Response 
Technology . 
Time to Treatment Discontinuation
Time to Treatment Discontinuation in years is defined as:
Time to Treatment Discontinuation (years) = (‘Date of Treatment Discontinuation -
(‘Analysis date of first dose intake +1)/365.25
In case a subject completed the treatment period, time to censoring will be calculated as :
(Analysis date of last dose – Analysis date of first dose intake + 1) / 365.25
With Analysis data of last dose defined in Section 6.5.4
Time in years from Diagnosis of Anemia
Time from diagnosis of anemia in years is defined as:
Time from Diagnosis of Anemia (years) = (‘Analysis date of first dose intake ‘-‘Date of 
Diagnosis’)/365.25
In case of partial dates, imputation rules apply and are detailed in Section 7.11.2
Time in years from Diagnosis of CKD
Time from diagnosis of CKD in years is defined as:
Time from Diagnosis of CKD (years) = (‘Analysis date of First Dose intake ‘-‘Date of 
Diagnosis of CKD’)/365.25
In case of partial dates, imputation rules apply and are detailed in Section 7.11.2


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Time from Diagnosis of Targeted Medical History
Onset date and the start date of analysis for the study drug are collected and the time from 
diagnosis of targeted medical history in years is defined as
Time from Diagnosis of Targeted Medical History (years) =
(‘Analysis date of first dose intake’– ‘Onset Date’)/365.25
In case of partial dates, imputation rules apply and are detailed in Section 7.11.2
This will be calculated for each patient who was diagnosed with the targeted medical history: 
hypertension, diabetes mellitus type 1, type2 and combined, dyslipidemia and vascular 
access.
eGFR
eGFR will be provided by the central laboratory only for the selected visits as described in 
the schedule of assessments. It will be calculated by the central lab using the following 4-
variable Modification of Diet in Renal Disease (MDRD) equation:
eGFR (in mL/min per 1.73m2) = 175 x (SCr in mg/dL)-1.154 x (Age in years)-0.203
x (0.742 if female) x (1.21 if African American)
where SCr = serum creatinine concentration.
Since SCr will be collected for all the selected visits above plus additional ones, eGFR will 
be derived using the same formula and the derived eGFR will be used for the analysis. 
Checks will be performed by programming in order to ensure that derived eGFR values will 
match with eGFR provided by ICON for the selected visits.
Screening eGFR will be classified in the following categories : < 30 mL/min/1.73 m< versus 
≥30 mL/min/1.73m<, and <10,10-<15 15-<30, 30-<45, 45-<60, and >=60 mL/min/1.73m2
Iron Repletion at Screening
Subjects will be classified in one of the following four groups according to the TSAT and 
ferritin levels collected at Screening (prior to first drug intake):
●
ferritin < 30 ng/mL or TSAT < 5%
●
30 < ferritin < 100 ng/mL and 5% < TSAT < 20%
●
30 < ferritin < 100 ng/mL and TSAT > 20%  
●
ferritin > 100 ng/mL  and 5% < TSAT < 20%
●
ferritin > 100 ng/mL  and TSAT > 20%  
Regarding Iron Repletion at screening, both TSAT and Ferritin should be coming from the 
same blood sample in cases that we have more than one record.


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Iron Repletion at Baseline
Subjects will be classified in one of the following four groups according to the TSAT and 
ferritin levels collected on Day 1:
●
ferritin < 30 ng/mL or TSAT < 5%
●
30 < ferritin < 100 ng/mL and 5% < TSAT < 20%
●
30 < ferritin < 100 ng/mL and TSAT > 20%  
●
ferritin > 100 ng/mL  and 5% < TSAT < 20%
●
ferritin > 100 ng/mL  and TSAT > 20%  
Regarding Iron Repletion at baseline, both TSAT and Ferritin should be coming from the 
same blood sample in cases that we have more than one record on Day 1. If no Day 1 
assessment is available, Iron Repletion at Screening will be used.
Use of ESAs during the last year prior to start of study treatment
Subjects will be classified as either having used or not ESAs during the last year. Previous 
use of ESAs is collected in the Treatment History for Anemia Form.
6.5.3
Previous and concomitant medication
Previous medication is defined as a medication with at least one dose taken before the date of 
first dose of study drug. 
Concomitant medication is defined as a medication with at least one dose taken between the 
date of first dose (inclusive) and the date of the End of the Safety Emergent Period.
Previous and concomitant drug use will be recorded, including non-prescription medication, 
complementary and alternative medications. Handling of missing date information for prior 
or concomitant medications is given in Section 7.11.2
If the medication start date and end date are both missing, the medication will be counted as 
both previous and concomitant.
If the medication start date is missing and the end date is prior the date of first drug 
administration, the medication will be counted as previous medication.
If the medication start date is missing and the end date is after the date of first drug 
administration, the medication will be counted as concomitant medication.
6.5.4
Variables related to study drugs
Randomization/Treatment Arms
Table 9 below presents the groups to which subjects are randomized under the initial protocol 
version 1.0.


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Table 9
Randomization arms under Protocol version 1.0
Randomization
Arm Code 
(OARMCD)
Correction Period
Maintenance period
Randomization Arm 
(OARM)
1A
TIW
QW
Roxadustat TIW/QW
1P
TIW
QW
Placebo TIW/QW
2A
TIW
BIW
Roxadustat TIW/BIW
2P
TIW
BIW
Placebo TIW/BIW
3A
TIW
TIW
Roxadustat TIW/TIW
3P
TIW
TIW
Placebo TIW/TIW
Table 10 below presents the groups to which subjects are randomized under protocol 
version 2.0 and later. 
Table 10
Treatment arms under protocol version 2.0
Randomization Arm Code (ARMCD)
Randomization Arm (ARM)
A
Roxadustat 
B
Placebo
For the statistical analysis, treatments will be pooled across placebo and roxadustat under 
both protocol versions.
Analysis date of First Dose Intake 
Date of first study drug dose intake is collected in the Day 1 visit in the Randomization 
eCRF. In case of a missing/partial date, the earliest available date will be used. It will be on 
the same day than the randomization date and before the next dose date.
Analysis Date of Last Dose
Date of Last Study Drug Dose is collected at the End of Extended Treatment visit in the End 
of Extended Treatment eCRF. When this date is not known, all efforts should be made to 
obtain the date from the investigator. If it is still missing after all efforts have been made, 
then the visit date of the End of Extended Treatment Visit will be used as the Analysis Date 
of Last Dose. If subject is lost to follow-up and none of these dates are available then the date 
of the last available assessment during the study will be used.
If analysis date of last dose is missing due to fact that date of last dose is a partial date with 
day unknown (month and year populated), then minimum between the date of death and end 
of month for the partial date will be used.
Duration of exposure in days (overall)
For each subject, the Length of Time on treatment will be calculated in days, using the 
following formula:
(‘Analysis Date of Last Dose’ - ‘Analysis Date first dose intake’) + 1


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Amount of Prescribed (planned) Medication
The number of milligrams prescribed at each visit (including unscheduled visits) is captured 
in the Changes in Dosing eCRF. The investigator reported dose and frequency will be used 
when available. When the investigator reported dose and frequency are not available, the IRS 
reported dose and frequency will be used. 
The prescribed daily and weekly dose at each visit (including unscheduled visits) will be 
calculated as follows:
Daily Prescribed dose in mg is Prescribed weekly Dose divided by 7
Prescribed weekly dose is defined as prescribed dose x 3 as the prescribed frequency is TIW 
for study drug for patients randomized following protocol amendment 2.0. For patients 
randomized prior protocol amendment 2.0, other prescribed frequencies may be entered in 
the eCRF and should be used for the calculation of the prescribed weekly dose.
Each visit will have an associated start and end date as follows:
●
Each visit (including unscheduled) has an associated date. This is the start date.
●
Each visit (including unscheduled) will have an associated end date. This date will 
be the date of the next consecutive visit [including unscheduled visits and EOT] 
minus 1 day. This is the end date.
Time periods of interest are defined below (monthly is defined as a period of 4 weeks or 
28 days) as follows:
Table 11
Time periods of interest 
Time Period
Analysis Start Day
Analysis End Day*
Week 4 (Month 1)
Day 1
Day 28
Week 8 (Month 2)
Day 29
Day 56
Week 12 (Month 3)
Day 57
Day 84
Week 16 (Month 4)
Day 85
Day 112
Week 20 (Month 5)
Day 113
Day 140
Etc….
Week 104 (Month 26)
Day 701
Day 728
Overall Treatment Period
Day 1
End Day of Extended Treatment Period
Day 1 - Week 24
Day 1
End Day of Month 6 (day 168)
Day 1 – Week 36
Day 1
End Day of Month 9 (day 252)
Day 1 – Week 52
Day 1
End Day of Month 12 (day 364)
*or EOT whichever is first
**Extended treatment period only applies for subjects who do not discontinue prior to week 52.
This will allow us to calculate the amount of prescribed medication in a time period as the 
sum of the daily prescribed amount within the time windows defined above.
In addition, amount of prescribed medication in mg/kg will be calculated. To convert a dose 
given in mg into a dose in mg/kg, the body weight recorded at day 1 will be used.


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Amount of Consumed Medication
The consumed Investigational Product Medication is captured in the Study Drug 
Accountability eCRF which includes the following kit information:
●
Kit strength, kit treatment, kit dispensed, date of kit dispensed, kit strength total number 
of tablets dispensed
●
Kit returned, returned date, total number of tablets returned
For each kit, the following will be calculated:
●
Start Day of Exposure for each kit: study day kit dispensed 
●
End Day of Exposure for each kit: study day kit returned – 1 Day
●
Amount dispensed for each kit: kit strength x number of tablets dispensed
●
Amount returned for each kit: kit strength x number of tablets returned
●
Amount consumed for each kit: amount dispensed – amount returned
●
Daily consumed dose for each kit : amount consumed/(end day of exposure-start day of 
exposure +1)
The same methodology as described for Amount Prescribed (planned) Medication will apply 
to calculate amount of consumed medication for each time period by summing up the 
different daily consumed amount of the different kits on a given day (subjects will be 
dispensed more than one kit on a given visit).
In addition, amount of consumed medication in mg/kg will be calculated. 
Compliance 
Compliance will be calculated for the time periods defined in Amount of Prescribed 
(planned) Medication. Compliance in % will be calculated for each time period (not reported 
cumulatively) as:
Amount consumed during time period
Amount prescribed during time period ×  100
The following compliance categories will be defined:
●
less than 50% (significant drug noncompliance)
●
at least 50%, less than 75% (moderate drug noncompliance)
●
at least 75%, less than 125% (acceptable compliance)
●
greater or equal 125% (drug over compliance)
●
unknown
Dose Changes 
Dosing changes are collected in the Study Drug - Dosing Decisions eCRF. 
●
A dose change is the change in the number of milligrams on the dose per intake (for 
example from 200 mg to 250 mg). 
For example a change from 200 TIW to 250 TIW is a change of 600 mg to 750 mg per week 
which is regarded as a change in intake dose.


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For each subject the total number of dose changes will be calculated.
7
STATISTICAL METHODOLOGY
7.1
General Considerations
●
All statistical comparisons will be made using two sided tests at the =0.05 significance 
level unless specifically stated otherwise. Null hypotheses for superiority testing will be 
of no treatment difference and corresponding alternative hypothesis will be two-sided. 
Null hypotheses for non-inferiority testing will be of inferiority of roxadustat treatment 
and will be one-sided at the =0.025.
●
All data processing, summarization, and analyses will be performed using SAS® 
Version 9.3 (SAS Enterprise Guide 4.3) or higher. Specifications for tables, data listings 
and figures (TLFs) formats can be found in the TLF Specifications for this study.
●
All data will be summarized by treatment arm (roxadustat and placebo) and for the total, 
unless specified otherwise.
●
For continuous variables that are recorded as “< X” or “> X”, the value of “X” will be 
used in the calculation of summary statistics. The original values will be used for the 
listings.
●
All percentages will be rounded to one decimal place and lined up by the decimal place. 
The percentage will be suppressed when the count is zero.
●
Any p-values will be rounded to four decimal places and will be presented as ‘< 0.0001’ 
if they are less than 0.0001 after rounding.
●
For continuous variables, descriptive statistics will include the number of subjects (n), 
mean, standard deviation, median, minimum and maximum. Frequencies and 
percentages will be displayed for categorical data. Percentages by categories will be 
based on the number of subjects with no missing data, i.e., will add up to 100%. Number 
of missing values will be shown in the frequencies tables
●
All data included in summary tables, inferential analyses or figures will also be listed.
●
Listings will be done on all randomized subjects and all assessments (all collected data 
in the eCRF will be listed except the physical examination data).
●
Model checking will be performed using graphical outputs provided by the SAS 
procedures.
For the definition of subgroups of interest please refer to Section 7.8.
7.2
Study Population
For this section, unless specified otherwise, PPS refers to the analysis set which excludes 
from the FAS all the subjects criteria listed in Table 3  See Section 5.3 for more details.
7.2.1
Disposition of Subjects
The following subject data will be summarized and presented:
●
Number and percentage of subjects with informed consent, who discontinued before 
randomization and randomized (overall only);


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●
Number and percentage of subjects randomized in each analysis set, by treatment arm 
and overall;
●
Number and percentage of subjects who completed and discontinued treatment in each 
period (primary treatment period and extended treatment period), by primary reason for 
treatment discontinuation and by treatment arm for All Randomized, SAF, FAS and 
PPS; 
●
Number and percentage of subjects who completed and discontinued the study, by 
primary reason for study discontinuation and by treatment arm for All Randomized and 
SAF; 
●
Number and percentage of subjects who completed and discontinued the post study 
follow-up period for All Randomized and SAF, and
●
Number and percentage of subjects excluded from PPS  by reason for exclusion defined 
in Section 5.3, by treatment arm for the FAS.
The following data will be presented graphically by treatment arm for the FAS and the SAF: 
●
Treatment discontinuation by reason using bar chart;
●
Treatment discontinuation by time interval and reason using bar chart; and
●
Time to treatment discontinuation using a Kaplan-Meier plot. 
In addition, the following graphs will be done by treatment arm, for the FAS and PPS:
●
Treatment discontinuation for lack of efficacy using a cumulative incidence plot; 
●
Treatment discontinuation for adverse event using a cumulative incidence plot.
●
Treatment discontinuation for withdrawal by subject using a cumulative incidence plot.
Time intervals will be analyzed using the following categories:
●
Less than 2 weeks 
●
At least 2 weeks, less than 4 weeks
●
At least 4 daweeks, less than 12 weeks
●
At least 12 weeks, less than 24 weeks
●
At least 24 weeks, less than 36 weeks
●
At least 36 weeks, less than 52 weeks
●
At least 52 weeks, less than 78 weeks
●
78 weeks or more
●
Unknown.
In addition, the randomization stratification strata from both sources (CRF and IRT) will be 
reported by treatment arm. Discrepancy between stratification from CRF and IRT will be 
summarized and the total number of patients with discrepancy overall and for each 
stratification factor will be provided
Subjects who screened failure will also be listed.
All data collected during the Post-Study Follow up period will be listed by visit (i.e type of 
contact, subject status and occurrence of overnight hospitalizations).


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7.2.2
Protocol Deviations
Protocol deviations, as defined in the study protocol (Section 8.1.6: Protocol Deviations) will 
be assessed for all randomized subjects. The number and percentage of subjects meeting any 
criteria will be summarized for each criterion and overall, by treatment arm, as well as by 
study site. Subjects deviating from a criterion more than once will be counted once for the 
corresponding criterion. Subjects who have more than one protocol deviation will be counted 
once in the overall summary. 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 withdrawal criteria during the study and was not withdrawn,
●
PD3 - Received wrong treatment or incorrect dose
○
PD3_1- Received wrong treatment kit
○
PD3_2- Received incorrect dose
●
PD4 - Received excluded concomitant treatment
7.2.3
Demographic and Other Baseline Characteristics
Demographic and other baseline/screening characteristics will be summarized by descriptive 
statistics and frequency tabulations.
Number and percentage of subjects randomized in each country and site will be presented for 
the All Randomized and SAF. Descriptive statistics for age, weight, body mass index (BMI) 
and height at baseline will be presented. Frequency tabulations for sex and race will be 
presented. Descriptive statistics and frequency tabulations will also be presented for the 
subgroup variables presented in Section 7.8  Additionally, demographic and other baseline 
characteristics will be presented for the following variables: 
●
Baseline and Screening Hb value as continuous and categorical (≤ 8.0 g/dL versus 
>8.0 g/dL),
●
Baseline and Screening eGFR value as continuous and categorical 
(< 30 mL/min/1.73 m< versus ≥ 30 mL/min/1.73m<, and <10, 10-<15, 15-<30, 30-<45, 
45-<60, and >=60 mL/min/1.73m2
●
History of previous treatment with ESA: Yes vs. No.
Demographic and baseline characteristics summaries above will be done for the All 
Randomized, SAF, FAS and PPS. This table will be repeated for subjects randomized after 
Amendment 2.0 is implemented.
Selected demographics collected at screening will be done on Screen Failure subjects.
All Medical History will be analyzed using the SAF, as described below:
Medical History other than anemia, CKD, cardiovascular disease and targeted medical 
history are coded in MedDRA, they will be summarized by System Organ Class and 
Preferred Term.


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Anemia history, CKD history, targeted medical history, cardiovascular history, tobacco 
history and family history of cardiovascular disease will be summarized. 
The number and proportion of subjects with each typical symptom for CKD will be 
described, as well as the number and proportion of subjects with each typical symptom for 
anemia.
Demographic and baseline data will also be listed. 
7.2.4
Previous and Concomitant Medications
Previous and concomitant medications are coded with WHO-DD, and will be summarized by 
therapeutic subgroup (ATC 2nd level), chemical subgroup (ATC 4th level) and preferred 
WHO name for the SAF. 
Subjects taking the same medication multiple times will be counted once per medication. 
Treatment history for anemia will be summarized separately.
Missing dates' imputation rules are detailed in Section 7.11.2
7.3
Study Drugs
Roxadustat (=Investigational Product Medicine) is for oral administration and supplied as red 
coated oval tablets of 20, 50 and 100 mg. Roxadustat and placebo tablets are identical in size, 
shape and color to preserve the blinding method.
7.3.1
Exposure
The following information on drug exposure will be presented by treatment arm and overall, 
for the SAF. 
Exposure related variables are defined in Section 6.5.4
Descriptive statistics will be produced for:
●
The amount of drug (roxadustat and placebo) the subject was exposed to during the 
treatment period (in mg and in mg/kg), by month, during the first 24, 36, 52 weeks and 
overall;
●
Number and percentage of subjects with dose increases, decreases or interruptions 
during the treatment period.
Duration of exposure will be summarized in two ways:
●
Descriptive statistics will be presented overall, during the first 24 weeks, 36 weeks and 
52 weeks; 
●
Exposure time will be categorized overall, and by treatment  period, according to the 
following categories (and frequency tabulations):
o
Less than 2 weeks
o
At least 2 weeks, less than 4 weeks
o
At least 4 weeks, less than 12 weeks
o
At least 12 weeks, less than 24 weeks


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o
At least 24 weeks, less than 36 weeks
o
At least 36 weeks, less than 52 weeks
o
At least 52 weeks, less than 78 weeks
o
78 weeks or more
o
Unknown.
Box-plots of monthly dose and monthly dose/kg by month will be produced by treatment arm 
(roxadustat and placebo). 
Study drug medication will also be listed showing for each subject and each visit the 
dispensed kit numbers and the actual medication in each kit. For instance, if a subject 
randomized to placebo, at one visit was mistakenly dispensed a kit containing roxadustat then 
the listing will show that roxadustat was given to the subject on the intended visit. 
7.3.2
Treatment Compliance
Overall compliance with the dosing schedule will be examined for subjects in the SAF whose 
total study drug count and first and last days of treatment are known.
Percent overall compliance will be summarized in two ways, by month, by treatment period, 
during the first 24 weeks, 36 weeks, 52 weeks and overall:
●
Descriptive statistics will be presented, 
●
Percent compliance categories will be categorized according to the categories defined in 
Section 6.5.4
Counts and percentages of subjects in each of these categories will be summarized.
Results will be displayed by treatment arm and overall.
7.4
Analysis of Efficacy 
For all continuous efficacy variables, in addition to inferential analyses, descriptive statistics 
will be produced for the actual values and for the changes from baseline (BL) by visit.
Similarly, for all categorical efficacy variables, frequencies and proportions will be produced 
by analysis visit.
Quantitative  endpoints with repeated measures over time will be analyzed using MMRM and 
ANCOVA with Multiple Imputations (MI) as the preferred methods for imputation of 
missing data, as per FDA recommendation at the time of SPA assessment of FGCL-4592-
060.
For this section, PPS refers to the analysis set which excludes from the FAS all the subjects 
criteria listed in Table 3. See Section 5.3 and and Classification specifications for more 
details.
Analysis visits windows are detailed in Section 7.11.4.
Missing data imputation rules are detailed in Section 7.11.1


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7.4.1
Analysis of Primary Endpoint(s)
There are two 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.
7.4.1.1
EU (EMA) Primary Endpoint
7.4.1.1.1
Primary Analysis of the EU (EMA) Primary Endpoint
The EU (EMA) primary efficacy endpoint will be analyzed using the FAS. See 
Section 7.11.1 for imputation rules, in case of missing values in the evaluation period or in 
case of rescue therapy prior to Hb response.
The proportion of responders in the primary efficacy variable will be compared using a 
Cochran–Mantel–Haenszel (CMH) test adjusting for the region, history of CV, baseline Hb 
and baseline eGFR, comparing roxadustat to 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 Placebo group
versus
●
H1:  Hb responder rate in the roxadustat group ≠Hb responder rate in Placebo 
The CMH adjusted odds ratio (roxadustat versus placebo) and its 95% confidence interval
will be provided. Superiority of roxadustat versus placebo will be declared if the lower bound 
of the two-sided 95% confidence interval of the CMH odds ratio is higher than 1.
The SAS procedure will be similar to the following:
proc freq;
tables covariates*Treatment*Response / cmh;
run;
The covariates will be: 
●
Region [West Europe, Rest of the World))
●
Baseline Hb values ( ≤8 g/dL vs. >8 g/dL)
●
History of  cardiovascular, cerebrovascular or thromboembolic diseases (Yes vs. No)
●
Baseline eGFR (<30 mL/min/1.73 m2 vs. ≥30 mL/min/1.73 m2 )
The analysis will use the collected eCRF data to derive these covariates. Note that the choice 
was made to use Baseline Hb and eGFR as covariates rather than Screening Hb and eGFR 
which were stratification factors since Baseline values are the latest pre-dose assessements 
(and no difference between Screening and Baseline is expected).
In addition, a 95% confidence interval for the proportion of each roxadustat and Placebo 
based on the exact method of Clopper-Pearson will be calculated and presented.


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The SAS procedure will be similar to the following:
proc freq;
tables Treatment / binomial(exact) alpha=0.05;
run;
Model checking 
The assumption that the odds ratios are homogeneous across strata will be tested using the 
Breslow-Day test for stratified 2x2 tables. The model will be checked using covariates above 
defined by raw data.
In addition, this test will be repeated replacing the covariates by country. For this analysis, 
countries with less than 20 subjects in the FAS will be pooled in a grouped level per region.
This model checking information will be provided as part of the raw SAS outputs.
7.4.1.1.2
Secondary Analyses (sensitivity) of the EU (EMA) Primary Endpoint
Table 12 summarizes all sensitivity analyses to be performed with the EU (EMA) primary 
endpoint.
Table 12
Primary and sensitivity analyses for the EU (EMA) primary endpoint
Code
Set 
Rescue 
Therapy 
Endpoint
Method
Covariates
Primary
FAS
Without 
rescue therapy 
Response
CMH
Region, history of CV, Baseline Hb and 
Baseline eGFR
S1
All 
Randomized
Without 
rescue therapy 
Response
CMH
Region, history of CV, Baseline Hb and 
Baseline eGFR
S2
PPS
Without 
rescue therapy 
Response
CMH
Region, history of CV, Baseline Hb and 
Baseline eGFR
S3
FAS
Regardless 
rescue therapy
Response
CMH
Region, history of CV, Baseline Hb and 
Baseline eGFR
S4
FAS 
Without 
rescue therapy 
Response
Logistic
Region, history of CV, Baseline Hb and 
Baseline eGFR as continuous covariates
S5
FAS*
Without 
rescue therapy 
Response
CMH
Region, history of CV, Baseline Hb and 
Baseline eGFR
*patients who were randomized after the implementation of protocol v2.0
For the logistic regressions, the odds ratio (roxadustat vs. placebo) and their 95% confidence 
intervals will be produced, if convergence achieved. 
The SAS procedure will be similar to the following:
proc logistic;
   class treatment region CV_history;
   model response = treatment region cv_history baseline_Hb 
baseline_eGFR;
run;
For all sensitivity analyses, no hypothesis testing will be done, only confidence intervals 
presented and graphically represented in a forest plot. 


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If a relevant baseline variable is identified for which a clinically important imbalance exists 
at baseline between treatment groups, additional sensitivity analysis on the primary endpoint 
may be performed using a logistic model adjusting for this baseline variable. This will allow
the assessment of the impact of these imbalances on the treatment comparisons.
7.4.1.1.3
Additional Analyses of the EU (EMA) Primary Endpoint
The analysis of the EU (EMA) primary endpoint will be repeated by subgroup of interest. For 
definitions of subgroups of interest, see Section 7.8
For the EU (EMA) primary endpoint, subgroup analyses will be performed using the primary 
analysis in Table 12  If one of the subgroups is the same as a stratification factor, the factor 
will be omitted from the model.
Table 13
Additional Analyses of the EU (EMA) Primary Endpoint
Code
Set 
Rescue Therapy 
Endpoint*
Method
Covariates
A1
FAS
Without rescue 
therapy 
Response by 
Subgroup
CMH
Region, history of CV, Baseline 
Hb and Baseline eGFR
* Subgroup: (1) age, (2) sex, , (3) region, (4) baseline hemoglobin category, (5) history of CV, (6) Baseline 
eGFR category (7) Baseline CRP category and (8) Baseline Iron Repletion Status category 
Subgroup analysis will be done by producing separate summaries similar to those produced 
for the primary analysis. In addition, forest plots will be generated per each subgroup 
showing subgroup factors on the y-axis and CMH adjusted odds ratios and their 95% 
confidence interval on the x-axis.
The potential existence of subgroup by treatment interaction will be visually inspected.
7.4.1.2
US (FDA) Primary Endpoint
7.4.1.2.1
Primary Analysis of the US (FDA) Primary Endpoint
The US (FDA) primary efficacy endpoint will be analyzed using the All Randomized Set
The change from baseline to the average Hb of weeks 28 to 52 will be computed from an 
analysis of covariance (ANCOVA) model with multiple imputations (MI), adjusting for 
covariates (covariates defined below), comparing roxadustat to placebo. 
The primary hypothesis to be tested for the US (FDA) primary efficacy analysis is:
H0: Hb mean change from baseline to the average level from Week 28 to Week 52 in 
the roxadustat group = Hb mean change from baseline in the placebo group 
versus:
H1: Hb mean change from baseline to the average level of Week 28 to Week 52 in the 
roxadustat group ≠Hb mean change from baseline in the placebo group. 
Difference of least square means (roxadustat minus placebo) and its 100x(1-α/2)% 
confidence interval will be estimated for the change from baseline to the average of weeks 28 
to 52. Superiority of roxadustat versus placebo  will be considered successful if the lower 
bound of the two-sided 95% confidence interval of the difference between treatment arms 
(roxadustat minus placebo) is higher than 0.


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The covariates will be: 
●
Region (West Europe, Ex-Central East Europe)
●
Baseline Hb values ( continuous)
●
History of  cardiovascular, cerebrovascular or thromboembolic diseases (Yes vs. No)
●
Baseline eGFR (continous)
The analysis will not use the randomization strata as stratification errors during the 
randomization process may occur. The analysis will use the collected eCRF data to derive 
these covariates. 
ANCOVA with MI model:
The MI ANCOVA model will be used to compare the roxadustat and placebo groups in a 
fixed sequence procedure: 
The following steps will be used to conduct the primary analysis. 
1.
Generate 1000 datasets, using seed 654289, where intermittent missing hemoglobin data 
will be imputed for each treatment relying on non-missing data from all subjects within 
each treatment group using the Monte Carlo Markov Chain MCMC imputation model 
with treatment, baseline hemoglobin, baseline eGFR, region, history of  cardiovascular, 
cerebrovascular or thromboembolic diseases and the available non missing hemoglobin 
for each scheduled Week. 
The MCMC statement in the SAS PROC MI procedure with monotone option will be 
used. As a result, each dataset will only have missing ending data, or a monotone 
missing data pattern. 
2.
For each dataset from step 1, missing ending data (hemoglobin up through end of 
evaluation period) will be imputed using seed 472794. As a result, 1000 imputed 
complete datasets will be generated.
●
Missing data at Week 1 will be imputed using the regression imputation model with 
baseline stratification factor, baseline and hemoglobin from Week 1, using the SAS 
PROC MI procedure with the REGRESSION option in the MONOTONE statement. 
●
The SAS PROC MI procedure will use data separately from each treatment subjects 
to impute the missing data for a specific Week (i.e. only those that need the
imputation for the Week). Since subjects from the different treatment groups for that 
Week are excluded from the step, they will not contribute to the imputation for the 
Week.
●
Repeat for all other scheduled Weeks sequentially (Week 2 to the end of evaluation 
period). Subjects whose missing data were imputed for previous Weeks will 
contribute to the imputation for the current Week. 
The regression imputation model includes an intercept and the slopes of the hemoglobin 
from previous Weeks and the stratification factors. 
3.
Analyze each imputed dataset using the ANCOVA using the mean of all observed or 
imputed Hb values within the evaluation period. The model will contain terms for 
baseline Hb measurement as a covariate and treatment arm and the other randomization 
stratification factors except screening Hb (≤8 vs >8) as fixed effects.


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4.
Combine estimates from the results of each of the 1000 ANCOVA runs using SAS 
PROC MIANALYZE. 
Report the results of the least-squares mean estimates of the change from baseline in 
hemoglobin during the evaluation period, the estimates of treatment effect (e.g., least-squares 
mean change form baseline in hemoglobin for the treatment group minus the least-squares 
mean change from baseline in hemoglobin for the placebo group) and the corresponding 
p-values and 95% CIs during the evaluation period.
All available Hb values will be used for the calculation of the average in weeks 28 to 52, as 
defined in analysis windows in Section 7.11.4.
Hb imputation rules using MI are detailed in Section 7.11.1.
A forest plot will be generated showing strata on the y-axis and differences in mean changes 
from BL to the average in week 28-52 and their 95% confidence interval on the x-axis.
Model checking:
Residual plots will be produced showing the following: 
●
Model residuals in the y-axis and model predictions in the x-axis,
●
Model residuals in the y-axis and baseline Hb in the x-axis.
Different dot styles will be used for the two treatment arms. Solid black symbols (square)
will be used for roxadustat and non-solid red symbols (X) will be used for placebo.
Residual plots will be done for the ANCOVA with MI analyses (Primary, S1 and S2 in 
Table 14). 
In addition, an empirical cumulative distribution function of the residuals will be plotted for 
the same ANCOVA analysis.
If a relevant baseline variable is identified for which a clinically important imbalance exists 
at baseline between treatment groups, additional sensitivity analyses of the primary endpoint 
may be performed using a logistic model adjusting for this baseline variable. This will allow 
us to assess the impact of these imbalances on the treatment comparisons.
Descriptive analyses
In addition to the inferential analysis, central laboratory and HemoCue hemoglobin Hb 
values and their associated change from baseline, will be reported descriptively by visit. For 
central lab Hb values, the average of weeks 28-52 will also be reported.
The following data will be presented graphically, by treatment arm: 
●
Hb results using mean values (+/- 95% CI) plot
●
Hb change from baseline results using mean values (+/- 95% CI) plot.
A plot  will be generated showing the change between the central laboratory and HemoCue 
hemoglobin values by visit (+/- 95% CI) during the Efficacy Emergent Period.
7.4.1.2.2
Sensitivity Analyses  of the US (FDA) Primary Endpoint
Table 14 summarizes all sensitivity analyses to be performed with the US (FDA) primary
endpoint.


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Table 14
Primary and sensitivity analysis for the US (FDA) primary endpoint
Code
Set 
Rescue 
Therapy 
Endpoint
Method
Covariates
Primary
All 
Randomized
Regardless 
rescue 
therapy
Change to the 
Average Hb in 
weeks 28-52
ANCOVA 
with MI
Region, History of CV, BL 
Hb, BL eGFR as 
continuous covariates
S1
FAS
Regardless 
rescue 
therapy
Change to the 
Average Hb in 
weeks 28-52
ANCOVA 
with MI
Region, History of CV, BL 
Hb, BL eGFR as 
continuous covariates
S2
PPS
Regardless 
rescue 
therapy
Change to the 
Average Hb in 
weeks 28-52
ANCOVA 
with MI
Region, History of CV, BL 
Hb, BL eGFR as 
continuous covariates
S3
All 
Randomized
Regardless 
rescue 
therapy
Change to the 
Average Hb in 
weeks 28-52
MMRM
Region, History of CV, 
visits and visits by 
treatment as categorical 
variables. BL Hb and BL 
eGFR as continuous 
covariates.
S4
All 
Randomized
Regardless 
rescue 
therapy
Change to the 
Average Hb in 
weeks 28-52
PMM (Last 
Mean Carried 
Forward)
Region, History of CV, BL 
Hb, BL eGFR as 
continuous covariates
S5
All 
Randomized
Regardless 
rescue 
therapy
Change to the 
Average Hb in 
weeks 28-52
PMM 
(Baseline 
Carried 
Forward, 
Roxadustat 
only)
Region, History of CV, BL 
Hb, BL eGFR as 
continuous covariates
S6
All 
Randomized
Regardless 
rescue 
therapy
Change to the 
Average Hb in 
weeks 28-52
PMM 
(Baseline 
Carried 
Forward, both 
groups)
Region, History of CV, BL 
Hb, BL eGFR as 
continuous covariates
S7
All 
Randomized
Regardless 
rescue 
therapy
Change to the 
Average Hb in 
weeks 28-52
PMM (Jump 
to control)
Region, History of CV, BL 
Hb, BL eGFR as 
continuous covariates
S8
All 
Randomized
Without 
rescue 
therapy
Change to the 
Average Hb in 
weeks 28-52
ANCOVA 
with MI
Region, History of CV, BL 
Hb, BL eGFR as 
continuous covariates
S9
All 
Randomized
Without 
rescue 
therapy
Change to the 
Average Hb in 
weeks 28-52
MMRM
Region, History of CV, 
visits and visits by 
treatment as categorical 
variables. BL Hb and BL 
eGFR as continuous 
covariates.
For all sensitivity analyses, no hypothesis testing will be done, only confidence intervals will 
be presented and graphically represented in a forest plot.
MMRM model:
An MMRM model will be run for the purpose of implicit imputation of missing data by using 
all the available information from the observed data up to Week 52 via the within-patient 
correlation structure. The analysis will be based on the estimated difference between the two 


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treatment arms overall mean effects throughout the evaluation period (weeks 28 to 52) based 
on this MMRM model.
The model will contain treatment arm, region, CV History, visits and visit by treatment as 
categorical variables and baseline Hb, baseline eGFR and baseline Hb by visit as continuous 
variables.
The unstructured covariance pattern model will be applied first. If the algorithm for 
unstructured covariance pattern does not converge then heterogeneous Toeplitz structure will 
be used instead. If this second model also does not converge, then the (homogeneous) 
Toeplitz structure will be tried. Finally, if none of them converge, first order autoregressive 
(AR (1)) as a covariance structure will be used to achieve convergence.
A similar model as the general example below will be used:
cikjn = intercept + ßn Mbaseline,ikjn + τi + αn+ (ατ)in + γk + εikjn
where
●
cikjn is each analysis visit change from baseline of subject j in treatment arm i, and
stratum k at time n,
●
ßn is the slope of cikjn at visit n as a function of the baseline Hb, 
●
Mbaseline,ikjn is the baseline measurement of subject j in treatment arm i and stratum k at 
time n,
●
τi , is the mean effect of treatment arm i,
●
αn is the mean effect at time n,
●
(ατ)in is the interaction term between treatment arm i and time n,
●
γk is the mean effect of stratum k,
●
εikjn is the residual at time n for subject j in treatment arm i and stratum k.
The SAS procedure will be similar to the following:
proc mixed;
class subject_id treatment region cv_history visit;
model change = treatment region cv_history  baseline_Hb 
baseline_eGFR visit treatment*visit baseline_Hb*visit;
repeated visit /subject = subject_id type=un;
lsmeans visit*treatment / cl alpha = 0.05;
estimate ‘Roxadustat v.s. Placebo at weeks 28-52’ 
treatment 1 -1
treatment*visit 0 0 0 0 .. 0.2 0.2 0.2 0.2 0.2 -0.2 -0.2 -0.2 
-0.2  / cl;
where visit in 
(‘Day1’,’Week1’,’Week2’,...,’Week8’,’Week10’,...,’Week52’);
run;
One analysis Hb value for each visit will be used, as defined in analysis windows in 
Section 7.11.4 and Table 31.
A forest plot will be generated showing strata on the y-axis and differences in mean changes 
from BL to the average in weeks 28-52 and their 95% confidence interval on the x-axis.


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In addition, MMRM least square means and 95% confidence intervals will be calculated for 
each visit for the difference in treatment arms. MMRM least square means and their 95% 
confidence intervals will be plotted versus time.
Model checking:
Residual plots will be produced showing the following: 
●
Model residuals in the y-axis and model predictions in the x-axis,
●
Model residuals in the y-axis and baseline Hb in the x-axis.
Different dot styles will be used for the two treatment arms. Solid black symbols (square) 
will be used for roxadustat and non-solid red symbols (X) will be used for placebo.
Residual plots will be done for the MMRM analysis. The plot will be repeated by visit at 
Weeks 28, 32, 36, 40, 44, 48 and 52.
In addition, an empirical cumulative distribution function of the residuals will be plotted for 
the MMRM analysis.
The model will also be checked using the stratification factors used for the randomization 
[IRS].
Pattern Mixture Model (PMM)
PMMs provide a general and flexible framework for sensitivity analyses that allows 
formulating assumptions regarding missing data in a transparent and clinically interpretable 
manner. This is expected to address the possibility of the data being missing not at random 
(MNAR).
The following aspects of data missingness, may affect the estimates.
●
Timing and extent of missingness 
●
Assumed underlying mechanism for data missingness
A. Timing and Extent of Missing Data
To assess the potential effect of data missingness on the estimate of treatment effect, subjects 
will be classified as full data or missing data cases. Patterns of missingness will be based on 
non-missing hemoglobin before the end of the evaluation period.
●
Full data cases are defined as subjects with non-missing hemoglobin for all scheduled 
weeks of the Treatment period. 
●
Missing data cases are defined as subjects with a missing hemoglobin on at least one 
scheduled Week of the treatment period. The missing data cases are further grouped into 
intermittent missing and monotone missing cases.
○
Intermittent missing hemoglobin cases are defined as subjects with a missing 
hemoglobin for at least one scheduled week of but not on consecutive 
scheduled weeks up to end of the evaluation period.
○
Monotone missing hemoglobin cases are defined as subjects who have 
consecutive scheduled Weeks with missing hemoglobin up to the end of 


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evaluation period. A subject who is a Monotone missing case could have 
intermittent missing hemoglobin prior to the ending Week. 
Subjects will be grouped as follows:
●
Full data cases 
●
Intermittent missing data cases 
●
Monotone missing data cases 
Should the incidence of Monotone missing data cases and intermittent missing data cases be 
relatively small, then those cases will be combined so that the groups are full data cases and 
missing data cases. The summary of missing pattern in first 52 scheduled visits will be 
presented in a table/graph.
B. Assumptions on Missing Data Mechanism 
In addition to the extent of data missingness, the mechanism under which missing data occur 
may affect the estimate of the parameter of interest. 
The potential impact of missing efficacy endpoints on the estimates of treatment effects will 
be assessed using alternative statistical models with different underlying assumptions on the 
missing data mechanism (missing not at random(MNAR)) (Little and Rubin, 1987).
C. Last Mean Carried Forward
A pattern-mixture model using a last mean carried forward multiple imputation method will 
be used as another sensitivity analysis to explore the robustness of the ANCOVA results for 
the primary efficacy variables. Using this method, missing data after ending week will be 
imputed based on the last non-missing mean from its own treatment group.
D. PMM –Baseline Carried Forward (Roxadustat only and both groups)
The analysis is similar to “PMM – Last Mean Carried Forward”. The imputation data will be 
generated similarly as last mean carried forward method described above but instead of using 
post-baseline observed data, only baseline data will be used. The similar analyses will be 
conduct in two scenarios.
●
The baseline carried forward imputation will be performed for the roxadustat treatment 
group only, while for active control group, the imputation data will be generated using 
the last mean carried forward described above. 
●
The baseline carried forward imputation will be performed for the both treatment groups
E. PMM – Jump to Control 
A pattern-mixture model using a Prior Visit Mean carried forward jump to control multiple 
imputation method (Carpenter et al, 2013) will also be used as another sensitivity analysis 
similar to the PMM- Prior Visit Mean carried forward except for step 3, where the joint 
distribution of the patient’s observed and missing data are considered to be multivariate 
normal with mean and covariance matrix from the control (placebo) treatment arm.


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7.4.1.2.3
Additional Analyses of the US (FDA) Primary Endpoint
The analysis of the US (FDA) primary endpoint will be repeated by subgroup of interest. For 
definitions of subgroups of interest, see Section 7.8
For the US (FDA) primary endpoint, subgroup analyses will be performed using the primary 
and the third sensitivity analysis (S3 in Table 14) on the All Randomized Set. If one of the 
subgroups is the same as a stratification factor, the factor will be omitted from the model.
In addition, a sensitivity analysis will be performed by adding to the MMRM model all Hb 
values that will be collected even after the end of efficacy emergent period up to EOT (EOT 
+ 2 weeks assessments should not be included), See analysis A3 in Table 15 below.
Table 15
Additional Analyses of the US (FDA) Primary Endpoint
Code
Set 
Rescue 
Therapy 
Endpoint*
Method
Covariates
A1
All 
Randomized
Regardless 
rescue 
therapy
Change to the 
Average Hb in 
weeks 28-52 by 
Subgroup
ANCOVA 
with MI
Region, History of CV, BL Hb, 
BL eGFR as continuous covariates
A2
All 
Randomized
Regardless 
rescue 
therapy
Change to the 
Average Hb in 
weeks 28-52 by 
Subgroup
MMRM
Region, History of CV, visits and 
visits by treatment as categorical 
variables. BL Hb and BL eGFR as 
continuous covariates.
A3
All 
Randomized
Regardless 
rescue 
therapy
Change to the 
Average Hb in 
weeks 28-52 
including all Hb 
values
MMRM
Region, History of CV, visits and 
visits by treatment as categorical 
variables. BL Hb and BL eGFR as 
continuous covariates.
* Subgroup: (1) age, (2) sex,  (3) region, (4) baseline hemoglobin category, (5) history of CV, (6) Baseline 
eGFR category, (7) Baseline CRP category [only for A1] and (8) Baseline Iron Repletion Status category [only 
for A1]
Subgroup analyses will be done by producing separate summaries similar to those produced 
for the primary analysis. In addition, forest plots will be generated per each subgroup 
showing subgroup factors on the y-axis and change from baseline and their 95% confidence 
interval on the x-axis.
The potential existence of subgroup by treatment interaction will be visually inspected. 
7.4.2
Analysis of Key Secondary Endpoints 
The primary analysis set for the analysis of the key secondary endpoints will be the PPS for 
the non-inferiority tests and the FAS for the superiority tests.
All inferential analyses will evaluate the difference between the treatment arms: roxadustat 
versus placebo.
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 depicted in
Table 16 in order to maintain the overall two-sided type I error rate at 0.05. If the null 
hypothesis is rejected for a test, the claim of superiority (or non-inferiority) will be 


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considered successful and the test will progress to the next comparison in sequence as 
follows: 
Table 16
Key Secondary Endpoints fixed sequence testing procedure
Test
Analysis set 
Endpoint
Comparison
1
FAS
Hb change from BL 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 roxadustat versus 
placebo
2
FAS
Change from BL in Low Density Lipoprotein 
(LDL) cholesterol to the average LDL 
cholesterol of weeks 12 to 28.
Superiority of roxadustat versus 
placebo
3
FAS
Use and time to first use of rescue therapy 
during the treatment period
Superiority of roxadustat versus 
placebo
4
FAS
Change from BL in SF-36 Vitality (VT) sub-
score to the average VT sub-score of weeks 
12 to 28 for all subjects 
Superiority of roxadustat versus 
placebo
5
FAS
Change from BL in SF-36 Physical 
Functioning (PF) sub-score to the average PF 
sub-score of weeks 12 to 28 for all subjects
Superiority of roxadustat versus 
placebo
6 *
PPS
Change from BL in mean arterial pressure 
(MAP) to the average MAP value of weeks 
20 to 28.
*: Non-inferiority of roxadustat 
versus placebo (the non-inferiority 
margin for the difference between 
groups is fixed as 2 mmHg)
7 *
PPS
Time to first occurrence of hypertension 
(defined as an increase from BL of 
≥20 mmHg systolic blood pressure (SBP) 
and SBP ≥ 170 mmHg or an increase from 
baseline of ≥15 mmHg diastolic blood 
pressure (DBP) and DBP  ≥ 110 mmHg 
*: Non-inferiority of roxadustat 
versus placebo (the non-inferiority 
margin for the difference between 
groups is fixed as a hazard ratio of 
1.3)
8 *
FAS
Rate of progression of CKD measured by 
annualized eGFR slope over time
*: Superiority of roxadustat versus 
placebo
*: These key secondary endpoints will not be included in the hierarchical testing procedure.
No multiplicity adjustment will be done for the last three endpoints. Details of the analysis 
for each of these secondary endpoints are given below.
7.4.2.1
Hb change from baseline 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
Hb change from baseline to the average Hb value in weeks 28-36 will be compared by 
treatment arms using a MMRM model as in Section 7.4.1.2
The analysis will be similar to the analysis provided in Section 7.4.1.2, except that evaluation 
period will be from baseline to weeks 28-36, without having received rescue therapy within 6 
weeks prior to and during this 8-week evaluation period.
The analysis will be done on the FAS. 


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This superiority test will be considered successful if the lower bound of the two-sided 95% 
confidence interval of the difference between treatment arms (roxadustat minus placebo) is 
higher than 0.
An additional analysis (not part of the sequence) will be done for this endpoint  on the FAS 
regardless the use of rescue therapy,as detailed in Table 17:
Table 17
Primary and sensitivity analysis for the Hb change form BL to the 
average Hb in weeks 28-36
Code
Set 
Rescue 
Therapy 
Endpoint
Method
Covariates
Primary
FAS
Without 
rescue therapy
Change to the 
Average Hb in 
weeks 28-36
MMRM
Region, History of CV, visits and 
visits by treatment as categorical 
variables. BL Hb and BL eGFR as 
continuous covariates.
S1
FAS
Regardless 
rescue therapy
Change to the 
Average Hb in 
weeks 28-36
MMRM
Region, History of CV, visits and 
visits by treatment as categorical 
variables. BL Hb and BL eGFR as 
continuous covariates.
7.4.2.2
Change from BL in Low Density Lipoprotein (LDL) cholesterol to the average 
LDL cholesterol of weeks 12 to 28
LDL change from baseline to the average LDL value in weeks 12-28 will be compared by 
treatment arms using a MMRM model as in Section 7.4.1.2 (with the addition of LDL at 
baseline as continuous covariate). The analysis will be done on the FAS. 
The analysis will be similar to the analysis provided in Section 7.4.1.2 This superiority test 
will be considered successful if the upper bound of the two-sided 95% confidence interval of 
the difference between treatment arms (roxadustat minus placebo) is below 0.
An additional analysis (not part of the sequence) will be done on the All Randomized Set, as 
detailed in Table 18.
Table 18
Primary and sensitivity analysis for the LDL change from BL to the 
average LDL in weeks 12-28
Code
Set 
Endpoint
Method
Covariates
Primary
FAS
Change from 
baseline to the 
Average LDL in 
weeks 12-28
MMRM
Region, History of CV, visits and 
visits by treatment as categorical 
variables. BL LDL, BL Hb and BL 
eGFR as continuous covariates.
S1
All 
Randomized
Change from 
baseline to the 
Average LDL in 
weeks 12-28
MMRM
Region, History of CV, visits and 
visits by treatment as categorical 
variables. BL LDL, BL Hb and BL 
eGFR as continuous covariates.
For missing LDL imputation rules for MMRM refer to Section 7.11.1.
Theses analyses will be done on all values (regardless the fasting status).


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In addition to the inferential analysis, LDL cholesterol and LDL cholesterol change from 
baseline will be reported descriptively by visit for fasted values. The average of weeks 12-28 
will also be reported.
Residual plots will be produced showing the following:
●
Model residuals in the y-axis and model predictions in the x-axis,
●
Model residuals in the y-axis and baseline LDL-cholesterol in the x-axis. 
7.4.2.3
Use and time to first use rescue therapy during the treatment period 
[composite of RBC transfusions, IV iron supplementation and rescue ESA]
Time to first use of rescue therapy will also be analyzed similarly as in Section 7.4.2.7 except 
that only superiority will be tested and will be declared if the upper bound of the two-sided 
95% confidence interval of the hazard ratio of the two treatment arms is below 1.
In addition, the number and percentage of subjects with rescue therapy during the Efficacy 
Emergent Period will be reported by treatment group. 
Table 19
Primary and sensitivity analysis for use and time to first use rescue 
therapy 
Code
Set 
Endpoint
Method
Covariates
Primary
FAS
Time to first use 
rescue therapy 
Cox regression +  
Kaplan Meier
Stratified on Region, History of 
CV and adjusted on BL Hb, BL 
eGFR as continuous covariates
S1
All Randomized
Time to first use 
rescue therapy 
Cox regression +  
Kaplan Meier
Stratified on Region, History of 
CV and adjusted on BL Hb, BL 
eGFR as continuous covariates
S2
FAS
time to first use 
rescue therapy 
Cox regression +  
survival curve 
(Breslow 
estimator) using 
IPCW method 
Stratified on Region, History of 
CV and adjusted on BL Hb, BL 
eGFR as continuous covariates
For the IPCW method, refer to Appendix 10.7 for details. If the conclusions of the analysis 
using stratified cox model and IPCW method are not concordant, additional analysis using 
IPCW method will performed for each of the endpoints separately. 
●
Time to first use of RBC transfusion
●
Time to first use of IV iron supplementation
●
Time to first use of ESA
Details of these endpoints are provided in Sections 7.4.3.8, 7.4.3.9 and 7.4.3.10
7.4.2.4
Change from baseline in SF-36 VT subscore to the average in weeks 12–28
Change from baseline in VT subscore of SF-36 to the average of weeks 12–28 will be 
compared by treatment arm for all subjects (primary analysis) and in the subsets of subjects 
with baseline vitality subscore below 50 and equal or above to 50. It will be done using a 
MMRM method adjusting for the region, history of CV, baseline SF-36 VT subscore, 


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baseline Hb and baseline eGFR as covariates. Baseline SF-36 VT subscore, baseline Hb and 
baseline eGFR will be included as continuous variables.
The analysis will be similar to the analysis provided in Section 7.4.1.2  Superiority will be 
declared if the lower bound of the two-sided 95% confidence interval of the difference 
between roxadustat and placebo is above 0.
The analysis will be done on the FAS.
Table 20
Primary and sensitivity analysis for change from BL in SF-36 VT sub-
score to the average in weeks 12 to 28
Code
Set 
Endpoint
Method
Covariates
Primary
FAS
SF36-VT Change from 
Baseline at Weeks 12-28 
for all subjects
MMRM
Region, History of CV, visits and 
visits by treatment as categorical 
variables. BL Hb , BL SF-36 VT 
subscore and BL eGFR as continuous 
covariates.
S1
FAS
SF36-VT Change from 
Baseline at Weeks 12-28 
for subjects  with BL 
VT subscore below 50
MMRM
Region, History of CV, visits and 
visits by treatment as categorical 
variables. BL Hb , BL SF-36 VT 
subscore and BL eGFR as continuous 
covariates.
S2
FAS
SF36-VT Change from 
Baseline at Weeks 12-28 
for subjects  with BL 
VT subscore equal or 
above 50
MMRM
Region, History of CV, visits and 
visits by treatment as categorical 
variables. BL Hb , BL SF-36 VT 
subscore and BL eGFR as continuous 
covariates.
Residual plots will be produced showing the following:
●
Model residuals in the y-axis and model predictions in the x-axis,
●
Model residuals in the y-axis and baseline SF-36 VT subscore in the x-axis.
In addition to the inferential analyses, SF-36 VT and SF-36 VT change from baseline will be 
reported descriptively by visit, using all available data. The average of weeks 12-28 will also 
be reported.
7.4.2.5
Change from BL in SF-36 Physical Functioning (PF) sub-score to the average 
PF sub-score of weeks 12 to 28 
Change from baseline in PF subscore of SF-36 to the average of weeks 12–28 will be 
compared by treatment arm for all subjects (primary analysis) and in the subsets of subjects 
with baseline PF subscore below 35 and equal or above 35. It will be done using a MMRM 
method adjusting for the region, history of CV, baseline SF-36 PF subscore, baseline Hb and 
baseline eGFR as covariates. Baseline SF-36 PF subscore, baseline Hb and baseline eGFR 
will be included as continuous variables.


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The analysis will be similar to the analysis provided in Section 7.4.1.2  Superiority will be 
declared if the lower bound of the two-sided 95% confidence interval of the difference 
between roxadustat and placebo is above 0.
The analysis will be done on the FAS.
Table 21
Primary and sensitivity analysis for change from BL in SF-36 Physical 
Functioning (PF) sub-score to the average PF sub-score of weeks 12 to 28 
for all subjects 
Code
Set 
Endpoint
Method
Covariates
Primary
FAS
SF36-PF Change from 
Baseline at Weeks 12-
28 for all subjects
MMRM
Region, History of CV, visits and 
visits by treatment as categorical 
variables. BL Hb , BL SF-36 PF 
subscore and BL eGFR as continuous 
covariates.
S1
FAS
SF36-PF Change from 
Baseline at Weeks 12-
28 for subjects  with BL 
PF subscore below 35
MMRM
Region, History of CV, visits and 
visits by treatment as categorical 
variables. BL Hb , BL SF-36 PF 
subscore and and BL eGFR as 
continuous covariates.
S2
FAS
SF36-PF Change from 
Baseline at Weeks 12-
28 for subjects  with BL 
PF subscore equal or 
above 35
MMRM
Region, History of CV, visits and 
visits by treatment as categorical 
variables. BL Hb , BL SF-36 PF 
subscore and BL eGFR as continuous 
covariates.
Residual plots will be produced showing the following:
●
Model residuals in the y-axis and model predictions in the x-axis,
●
Model residuals in the y-axis and baseline SF-36 PF subscore in the x-axis.
In addition to the inferential analyses, SF-36 PF and SF-36 PF change from baseline will be 
reported descriptively by visit, using all available data. The average of weeks 12-28 will also 
be reported.
7.4.2.6
Change from BL in mean arterial pressure (MAP) to the average MAP value 
of weeks 20 to 28
The blood pressure effect is shown by use of the change from baseline in MAP. 
MAP change from baseline to the average MAP value in weeks 20-28 will be analyzed using 
a MMRM model as in Section 7.4.1.2.1 (with the addition of MAP at baseline as continous 
covariate) . The analysis will be done on the PPS.
For missing MAP imputation rules, refer to Section 7.11.1
Non-inferiority can be concluded if the upper bound of the two-sided 95% CI of the 
difference between roxadustat and placebo (roxadustat minus placebo), calculated on the PPS
is below 2 mm Hg.
An additional analysis (not part of the sequence) will be done on the All Randomized. 


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Table 22
Primary and sensitivity analysis for the MAP change from BL to the 
average MAP in weeks 20-28
Code
Set 
Endpoint
Method
Covariates
Primary
PPS
Change from 
baseline to the 
Average MAP in 
weeks 20-28
MMRM
Region, History of CV, visits and 
visits by treatment as categorical 
variables. BL MAP, BL Hb and BL 
eGFR as continuous covariates.
S1
All 
Randomized
Change from 
baseline to the 
Average MAP in 
weeks 20-28
MMRM
Region, History of CV, visits and 
visits by treatment as categorical 
variables. BL MAP, BL Hb and BL 
eGFR as continuous covariates.
In addition to the inferential analyses, MAP and MAP change from baseline will be reported 
descriptively by visit, using all available data. The average of weeks 20-28 will also be 
reported.
Residual plots will be produced showing the following:
●
Model residuals in the y-axis and model predictions in the x-axis,
●
Model residuals in the y-axis and baseline MAP in the x-axis. 
7.4.2.7
Time to first 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)
Time to first occurrence of an increase in blood pressure, including time to censoring, 
defined in Section 6.1.2.7, will be used in a Cox Proportional Hazards regression analysis, to 
compare treatment arms, stratified for region and history of CV and adjusted for baseline 
eGFR and baseline Hb (both continuous), and provide hazard ratio and their 95% confidence 
intervals.
Non-inferiority will be declared if the upper bound of the 2-sided 95% confidence interval of 
the hazard ratio (roxadustat as relative to placebo), calculated on the PPS, is below 1.3. As 
per Table 16, once the null hypothesis is rejected, superiority will be checked for this variable 
on the FAS, as part of the fixed sequence testing procedure. Superiority will be concluded if 
the upper bound of the two-sided 95% CI of the hazard ratio of the two treatment arms 
(roxadustat as relative to placebo) is below 1. 
The stratified Cox Model can be written: 



)
z
exp(
t
x
;t
j
0
j




where
j - indicator for stratum 
z – treatment indicator – which is either roxadustat or placebo


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The SAS procedure for the Cox regression will be similar to the following:
proc phreg;
   model time_to_event*cens_var(1) = treatment Hb_Bas eGFR_bas / rl;
   strata CVHist Region;
run;
The SAS procedure for the Cox regression using IPCW method uses above similar code with 
weight statement. Refer to Appendix 10.7 for details.
Table 23
Primary and sensitivity analysis for the time to first occurrence of 
hypertension
Code
Set 
Endpoint
Method
Stratas/Covariates
Primary
PPS
time to first 
occurrence of 
hypertension
Cox regression 
+ Kaplan 
Meier
Stratified on Region and  History of 
CV, and adjusted on BL Hb, BL eGFR 
as continuous covariates
S1
All 
Randomized
time to first 
occurrence of 
hypertension
Cox regression 
+ Kaplan 
Meier
Stratified on Region, History of CV 
and adjusted on BL Hb, BL eGFR as 
continuous covariates
S2
FAS
time to first 
occurrence of 
hypertension
Cox regression 
+ Kaplan 
Meier
Stratified on Region, History of CV 
and adjusted on BL Hb, BL eGFR as 
continuous covariates
In addition, the cumulative incidence curve of subjects with an increase in blood pressure 
from baseline will be plotted by treatment arm. 
The cumulative incidence will be calculated as one minus the Kaplan-Meier estimate of the 
survival function. Two types of analyses can be performed: modeling the cause specific 
hazard or modeling the hazard of the sub-distribution. The first approach has been chosen in 
this SAP, because competing risks are assumed not to exist, since the main interest is to study 
the treatments effect and this method provides results to be generalized across datasets with 
different competing risks. One minus the Kaplan-Meier estimate can be interpreted as the 
probability that an event of interest occurs to a subject by time t, in the absence of any 
competing risk. 
In addition to the cumulative incidence plot, the cumulative incidence at 3, 6 and 9 months 
with the 95% confidence interval will be reported using Greenwood’s formula.
Model checking
The proportional hazards assumption will be checked graphically using a log-cumulative 
hazard plot against log-survival time. This plot will give approximately parallel lines if the 
proportional hazards assumption between treatment arms subgroups holds. This plot will be 
provided as part of the raw SAS outputs.
In addition, the number and percentage of subjects with an increase from baseline in blood 
pressure during the Safety Emergen Period will be reported by treatment arm (roxadustat and 
placebo) on the PPS. For subjects who have experienced more than one increase in blood 
pressure, only their first event following study treatment will be used in the analysis.


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In addition, the incidence rate (per 100 subject years at risk) will be calculated as follows:
100
(years)
risk 
at 
 time
cumulative
Total
event
 with 
subjects
of
Number 

Where Total cumulative time at risk is the sum of individual time at risk defined as either 
time to occurrence of the event or time to censoring for subjects with no event.
Number of subjects at risk is defined as the number of subjects with (censored or non-
censored) times to the event of interest greater or equal to t.
7.4.2.8
Rate of progression of CKD measured by annualized eGFR slope over time
Geometric Mean (GM) and coefficient of variation (CV) will be displayed for eGFR. In 
addition, change from baseline and 95% CI will be presented. 
The annualized eGFR slope over time (expressed in ml/min per 1.73 m² or % per year) will 
be determined using the SAS code below:
proc mixed data=egfr2;
class usubjid strata_except_egfr_hb TRTPN TRTP;
model aval= strata_except_egfr_hb HGBBL atptn 
HGBBL*atptn
egfrbl*atptn atptn*TRTPN*TRTP 
atptn*strata_except_egfr_Hb
/ solution ddfm=kr 
outpredm=pred cl;
random intercept atptn / subject=usubjid type=un ;
estimate 'Annnualized slope Roxadustat'
intercept 0
strata except_egfr_hb 0 0 0 0
HGBBL 0
atptn 1
HGBBL*atptn &meanHbBase 
egfrbl*atptn &mean egfrbl
atptn*TRTPN*TRTP 1 0
atptn*strata_except_egfr_Hb &prop_strata 
/cl; 
estimate 'Annnualized slope Placebo'
intercept 0
strata_except_egfr_hb 0 0 0 0
HGBBL 0
atptn 1
HGBBL*atptn &meanHbBase 
egfrbl*atptn &mean egfrbl
atptn*TRTPN*TRTP 0 1
atptn*strata_except_egfr_Hb &prop_strata
/cl; 
ods output lsmeans=lsmeans_un
estimates=est_un;
ods output FitStatistics=FitStatistics SolutionF=SolutionF;
run;
Annualized eGFR slope over time is estimated by a random slopes and intercepts model 
using all available eGFR values (one baseline and all post-treatment values up to End of 
Treatment Period or start of dialysis) adjusted on Baseline Hb, Region, CV history at 


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Baseline and the interaction terms (Baseline eGFR by timepoint and Baseline Hb by 
timepoint). All assessments collected after initiation of acute or chronic dialysis will be 
excluded from the analysis.
Superiority will be declared if the lower bound of the two-sided 95% confidence interval of 
the difference in Least Square Means between roxadustat and placebo is above 0.
Model checking:
Residual plots will be produced showing the following: 
●
Model residuals in the y-axis and model predictions in the x-axis,
●
Model residuals in the y-axis and baseline Hb in the x-axis.
Different dot styles will be used for the two treatment arms. Solid black symbols (square) 
will be used for roxadustat and non-solid red symbols (X) will be used for placebo.
If the residual diagnostics show heteroscedasticity, additional analysis will be performed 
where annualized eGFR slope over time (% per year) is estimated by a random slopes and 
intercepts model using all available (log-transformed) eGFR values (one baseline and all 
post-treatment values up to End of Treatment Period or start of dialysis) adjusted on Baseline 
Hb, Region, CV history at Baseline and the interaction terms (Baseline log(eGFR) by 
timepoint and Baseline Hb by timepoint).  
Least Square Means will be transformed back to the original scale and expressed as annual 
percent changes.
7.4.2.9
Additional Analyses of the Key Secondary Endpoints
Each of these key secondary endpoints will also be analyzed by the subgroups of interest 
defined in Section 7.8, using only the primary analysis method, descriptively (no hypothesis 
testing). 
Table 24
Additional Analyses of the Key Secondary Endpoints
Code
Set 
Endpoint
Method
Covariates
A1
FAS
Change to the Average 
Hb in weeks 28-36 
(without rescue therapy) 
by Subgroup
MMRM
Region, History of CV, visits and 
visits by treatment as categorical 
variables. BL Hb and BL eGFR as 
continuous covariates.
A2
FAS
Change from baseline to 
the Average LDL in 
weeks 12-28 by 
Subgroup
MMRM
Region, History of CV, visits and 
visits by treatment as categorical 
variables. BL LDL, BL Hb and BL 
eGFR as continuous covariates.
A3
FAS
SF36-PF Change from 
Baseline at Weeks 12-
28 for all subjects by 
Subgroup
MMRM
Region, History of CV, visits and 
visits by treatment as categorical 
variables. BL Hb, BL SF-36-PF 
subscore and BL eGFR as continuous 
covariates.
Table continued on next page


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Code
Set 
Endpoint
Method
Covariates
A4
FAS
SF36-VT Change from 
Baseline at Week 28 for 
all subjects by Subgroup
MMRM
Region, History of CV, visits and 
visits by treatment as categorical 
variables. BL Hb , BL SF-36-VT 
subscore and BL eGFR as continuous 
covariates.
A5
PPS
Change from baseline to 
the Average MAP in 
weeks 20-28 by 
Subgroup
MMRM
Region, History of CV, visits and 
visits by treatment as categorical 
variables. BL MAP, BL Hb and BL 
eGFR as continuous covariates.
A6
PPS 
time to first occurrence 
of hypertension by 
Subgroup
Cox regression 
+ Kaplan 
Meier
Stratified on Region, History of CV 
and adjusted on BL Hb, BL eGFR as 
continuous covariates
* Subgroup: (1) age, (2) sex,  (3) region, (4) baseline hemoglobin category, (5) history of CV (6) Baseline eGFR 
category (7) Baseline CRP category [only for A1] and (8) Baseline Iron Repletion Status category [only for A1]
Forest plots will be produced where all subgroup factors will appear in the y-axis and the 
appropriate statistic comparing roxadustat to placebo and the 95% confidence interval will 
appear in the x-axis.
7.4.3
Analysis of Additional Secondary Efficacy Endpoints 
All the analyses below will be superiority tests. These inferential analyses will be performed 
on the FAS and presented treatment effect as Roxadustat versus placebo. 
Descriptive statistics will be presented by treatment arm. 
7.4.3.1
Hb level averaged over weeks 28 to 36, 44 to 52, and 96 to 104 without use of 
rescue therapy within 6 weeks prior to and during these 8-week evaluation 
periods
Averaged Hb over weeks 28-36, 44 to 52 and 96 to 104 will be described by treatment arm 
on the FAS. 
The SAS procedure will be similar to the one provided in Section 7.4.2.1  
In addition, the number and proportion of subjects with average Hb over weeks 28-36 and 
over weeks 44-52 and 96-104 and by visit within the <10 g/dL, 10-12 g/dL and >12 g/dL 
categories will be reported. 
7.4.3.2
Time to achieve the first Hb response as defined by primary endpoint for EU 
(EMA)
Time to achieve the first Hb response, without rescue therapy, will be analyzed using the 
same methods described in Section 7.4.2.7, on the FAS.
Superiority will be declared if the lower bound of the two-sided 95% confidence interval of 
the hazard ratio is above 1.
Cumulative incidence will be provided at 4, 8, 16, and 24 weeks with their associated 95% 
confidence interval reported using Greenwood’s formula.


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7.4.3.3
Hb change from BL to each post-dosing time point
Hb value and change from BL Hb to each post dosing time point will be described by 
treatment arm on the FAS.
The analysis and SAS procedure will be the same as in Section 7.4.2.1  
7.4.3.4
Hb change from BL to the average Hb value of weeks 28 to 36, 44 to 52, and 96 
to 104 regardless of the use of rescue therapy
The analysis will be done similarly as in Section 7.4.2.1, on the FAS except that it will be for 
weeks 28-36, 44-52 and 96-104.
7.4.3.5
Categorical analysis for Hb values
Proportion of Hb values :
The proportion of Hb values within 10-12 g/dL or ≥10 g/dL is a quantitative variable in the 
0 – 100 range for each subject. Descriptive statistics for this variable will be presented by 
treatment arm. This variable will be presented in weeks 28-36, in weeks 44-52 and in weeks 
96 -104, on the FAS. 
Percentage of time during the Efficacy Emergent Period: 
Descriptive statistics for the percentage of time with Hb values falling in each interval 
interval  (<10.0 g/dL, within 10.0-12.0 g/dL, > 12.0 g/dL, ≥10.0 g/dL, > 13.0 g/dL and 
> 14.0 g/dL) between the first and last Hb assessement during the Efficacy Emergent Period 
will be presented by treatment arm.
The number and percentage of subjects, and the number of events, will be reported based on 
Hb values from the central lab with Hb increase by >2.0 g/dL between any two visits within 
4 weeks of treatment.
Time to first occurrence of potential EH will also be analyzed similarly as in Section 7.4.2.7
(except that all data during the Efficacy Emergent Period will be taken into account for the 
analysis). The results will be presented by period (First 6 weeks, Week 7 - Week 27, 
Week 28 - Week 52 and > Week 52)
7.4.3.6
Occurrence (number) of hospitalizations,number of days of hospitalization per 
PEY and time to first hospitalization
The number and percentage of subjects with hospitalization will be reported. Descriptive 
statistics and frequency tabulations by treatment arm of the total duration of hospitalization 
(days), the average duration of each hospitalization (days), the number of hospitalizations, 
number of days of hospitalization per PEY and reason for hospitalization will also be 
reported.
Time to first hospitalization will also be analyzed similarly as in Section 7.4.2.7 (except that 
all data during the Efficacy Emergent Period will be taken into account for the analysis).


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Superiority will be declared if the upper bound of the two-sided 95% confidence interval of 
the hazard ratio of the two treatment arms is below 1. Both descriptive summary and time to 
first hospitalization will be reported by eGFR category (<15 vs ≥15).
As a sensitivity analysis, the above analysis will be repeated using IPCW method 
(Appendix 10.7).
The analysis will be done on the FAS.
7.4.3.7
Occurrence and time to first use of rescue therapy during the First 24 Weeks
[composite of RBC transfusions, IV iron supplementation and rescue ESA]
The number and percentage of subjects with rescue therapy during the first 24 weeks will be 
reported by treatment arm.
Time to first use of rescue therapy will also be analyzed similarly as in Section 7.4.2.7
(except that all data during the Efficacy Emergent Period will be taken into account for the 
analysis).
The analysis will be done on the FAS. 
Superiority will be declared if the upper bound of the two-sided 95% confidence interval of 
the hazard ratio of the two treatment arms is below 1.
7.4.3.8
Occurrence and time to first use of RBC transfusions, number of RBC packs 
per subject, volume of RBC transfused per subject
The number and percentage of subjects with RBC transfusion will be reported. Descriptive 
statistics by treatment arm for number of RBC packs and volume of blood transfused will be 
reported. Time to first use of RBC transfusion will be analyzed during the Efficacy Emergent 
Period similarly as in Section 7.4.2.7
Mean monthly number of RBC packs and volume of RBC transfused during the Efficacy 
Emergent Period will be compared by treatment arm using a ANCOVA model as in 
Section 7.4.1.2.1 (except that no multiple imputation will be performed). Subjects with no 
medication record of RBC will be assumed that they received no RBC and therefore number 
of packs and volume will be set to 0. The number and percentage of subjects with number of 
RBC Packs/Volume >0 will be presented.The analysis will be done on the FAS.
Superiority will be declared if the upper bound of the two-sided 95% confidence interval of 
the hazard ratio of the two treatment arms is below 1.
7.4.3.9
Occurrence and time to first use of IV iron supplementation. Mean monthly 
IV iron (mg) per subject during day 1 to week 36, weeks 37-52 and weeks 
53-104 (monthly defined as a period of 4 weeks)
The number and percentage of subjects who received IV Iron and the total amount of IV Iron 
used during the Efficacy Emergent Period will be reported descriptively by treatment arm.
The incidence and cumulative incidence of subjects receiving IV Iron will be calculated 
similarly as in Section 7.4.2.7


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Mean monthly IV iron (mg) per subject during day 1 to week 36, weeks 37-52 and 
weeks 53-104 will be summarized by treatment arm. Subjects with no medication record of 
IV Iron will be assumed that they received no IV Iron (for patients under treatment during 
that month). 
The analysis will be done on the FAS.
Furthermore, the total amount of IV Iron used during the efficacy emergent period as well as  
for Day 1 to week 36, weeks 37 to 52 and weeks 53 to 104.
Time to first use of IV iron will also be analyzed similarly as in Section 7.4.2.7
Superiority will be declared if the upper bound of the two-sided 95% confidence interval of 
the hazard ratio of the two treatment arms is below 1.
7.4.3.10 Occurrence and time to first use of ESA. Number of ESA-Week per year
The number and percentage of subjects with ESA use as rescue therapy, and the number of 
ESA-weeks/year will be reported descriptively by treatment arm. 
Time to first use of ESA will also be analyzed similarly as in Section 7.4.2.7 (except that all 
data during the Efficacy Emergent Period will be taken into account for the analysis).
The analysis will be done on the FAS.
Superiority will be declared if the upper bound of the two-sided 95% confidence interval of 
the hazard ratio of the two treatment arms is below 1.
7.4.3.11 Change from BL to each post-dosing study visit in Total cholesterol, 
LDL/High-density Lipoprotein (HDL) ratio, Non-HDL cholesterol, 
Apolipoproteins A1 and B, ApoB/ApoA1 ratio
Descriptive statistics (value, change from baseline) by visit and treatment arm. Descriptive 
statistics will also be reported regardless of fasting status.
7.4.3.12 Occurrence of mean LDL cholesterol <100 mg/dL calculated over weeks 12 to 
28 
The number and percentage of subjects with mean LDL cholesterol less than 100 mg/dL 
(fasting values and regardless fasting status) on average in weeks 12-28 will be reported by 
treatment arm and by baseline value. 
7.4.3.13 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 to 28.
The number and percentage of subjects with achieved antihypertensive treatment goal over 
an evaluation period defined as the average of available values in weeks 12-28 will be 
reported by treatment arm.


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7.4.3.14 Health related Quality of Life Questionnaires Change from BL to the average 
value of weeks 12 to 28
The following questionnaires will be analyzed:
●
SF-36 (Physical Component Score (PCS));
●
FACT-An (Anemia Subscale (“Additional Concerns”), Total FACT-An Score);
●
EQ-5D 5L (VAS Score);
●
Work Productivity and Activity Impairment Questionnaire: Anemic Symptoms 
(WPAI:ANS).
SF-36 and FACT-An
Descriptive statistics (value, change from baseline) will be presented for SF-36 (subscale and 
component scores) and FACT-An (total and subscale scores) by visit and treatment arm. 
Mean values will also be plotted over time and by treatment arm.
In addition, for the average value in weeks 12-28, an inferential analysis, similar to the one 
defined in Section 7.4.2.1 will be performed for the following endpoints:
●
Physical Component Scores of SF-36 (SF-36 PCS)
●
Anemia Subscale (“Additional Concerns”) of  FACT-An Scores
●
Total FACT-An Scores
For SF-36, at each visit, the frequency and proportion of subjects with a change from 
baseline <3/>= 3 points and <5/>=5 points will be reported for Physical Functioning, Vitality 
and Physical Component scores.
EQ-5D 5L
For the EQ-5D 5L VAS score, change from baseline to each visit and to the average of 
weeks 12-28 will be described by treatment arm.
For the 5 EQ-5D 5L qualitative domains, the number and percentage of subjects in each 
response level value will be reported by visit and treatment arm.
Work Productivity and Activity Impairment (WPAI)
The number and proportion of employed subjects will be reported by visit and treatment arm.
WPAI calculated variables will be summarized descriptively by visit and treatment arm.
Furthermore, change from baseline to each visit and to the average of weeks 12-28 and 36-52 
will be described by treatment arm.
7.4.3.15 Patients’ Global Impression of Change (PGIC)
Patients’ Global Impression of Change will be summarized descriptively by visit and 
treatment arm. 


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7.4.3.16 Hepcidin and Iron, HbA1c and CKD progression parameters
Changes from baseline to each study visit will be calculated for these parameters:
●
Serum hepcidin 
●
Serum ferritin
●
TSAT
●
HbA1c level
●
Fasting blood glucose
●
Serum creatinine (log transformed)
●
Albumin/creatinine ratio in urine (log-transformed)
Descriptive statistics and frequency tabulations will be presented for these parameters and for 
the change from baseline by visit and treatment arm. Mean values will also be plotted versus 
visit by treatment arm.
Geometric Mean (GM) and coefficient of variation (CV) will be displayed for serum 
creatinine and albumin/creatinine ratio in urine . In addition, GM Ratio from baseline and 
95% CI will be presented these parameters by transforming the change from baseline of the 
log-transformed data back to the original scale. 
All time to event endpoints as defined in Section 6.1.3.16  will be  will be analyzed using the 
same methods described in Section 7.4.2.7, on the FAS. Superiority will be declared if the 
lower bound of the two-sided 95% confidence interval of the hazard ratio is above 1. 
As a sensitivity analysis, the above stratified cox model will be repeated using IPCW method 
(Appendix 10.7) for the following endpoints:
●
Time to CKD progression (composite of doubling serum creatinine, chronic dialysis or 
renal transplant, and Death)
If the conclusions of the analysis using stratified cox model and IPCW method are not 
concordant, additional analysis using IPCW method will performed for each of the 
following endpoints separately.
○
Time to doubling of serum creatinine 
○
Time to chronic dialysis or renal transplant
○
Time to occurrence for a subject who died or chronic dialysis or renal transplant
●
Time to at least 40% decrease in eGFR from baseline, chronic dialysis or renal transplant
If the conclusions of the analysis using stratified cox model and IPCW method are not 
concordant, additional analysis using IPCW method will performed for each of the 
following endpoint separately.
○
Time to at least 40% decrease in eGFR from baseline 
A listing of dialysis data will also be provided.


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7.4.4
Analysis of Exploratory Variables: hs-CRP (High Sensitivity C-Reactive 
Protein) and sTFR (Soluble Transferrin Receptor)
For each visit, descriptive statistics with the absolute values and change from baseline for hs-
CRP and sTFR will be displayed by treatment arm.
Genotyping will be shipped to a delegated CRO and analyzed under the responsibility of 
Bioanalysis-Europe of Astellas Pharma Europe B.V. A separate report will be provided.
7.5
Analysis of Safety
Safety analyses will be performed using the Safety Analysis Set (SAF). 
Missing dates' imputation rules for AE onset date and stop date are detailed in Section 7.11.2
For each safety parameter, the last non-missing assessment prior to the first dose of study 
drug will be used as the baseline for all analyses, unless specified otherwise.
7.5.1
Adverse Events
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 20.0. They will be summarized by System Organ Class (SOC) and 
Preferred Term (PT).
7.5.1.1
Overview
An overview table will include the following details, by treatment arm:
●
Number and percentage of subjects with TEAEs,
●
Number and percentage of subjects with causally drug related TEAEs,
●
Number and percentage of subjects with serious TEAEs,
●
Number and percentage of subjects with serious drug related TEAEs,
●
Number and percentage of subjects with TEAEs leading to permanent discontinuation of 
study drug, 
●
Number and percentage of subjects with causally drug related TEAEs leading to 
permanent discontinuation of study drug, 
●
Number and percentage of subjects with NCI CTC Grade 3 or higher TEAEs,
●
Number and percentage of subjects with TEAEs leading to death 
●
Number and percentage of subjects with drug related TEAEs leading to death and 
●
Number of deaths occurring during the Safety Emergent Period and overall.
7.5.1.2
Proportion of subjects with TEAEs by SOC/PT
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized by treatment arm. Summaries will be provided for:
●
TEAEs
●
TEAEs (by PT only)
●
Drug related TEAEs, 
●
TEAEs with NCI CTC Grade 3 or higher 
●
TEAEs by severity


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●
Drug related TEAEs by severity
●
Serious TEAEs, 
●
Drug related serious TEAEs,
●
TEAEs leading to permanent discontinuation of study drug, 
●
Drug related TEAEs leading to permanent discontinuation of study drug, 
●
TEAEs excluding serious adverse events that equal to or exceed a threshold of 5.0% in 
any treatment arm (roxadustat or placebo),
●
TEAEs leading to death,
●
Drug-related TEAEs leading to death,
●
Common TEAEs that equal to or exceed a threshold of 5.0% in any treatment arm 
(roxadustat or placebo)
●
TEAEs by relationship to the study drug,
●
AEs occurring during the post study follow up period
●
Serious AEs during the post-stiudy follow up period 
●
Onset of common (>=5% in Any treatment arm(roxadustat or placebo)) TEAEs by 
treatment duration: <3 months, ≥3 to ≤6 months, >6 to ≤12 months, >12 months
For the summaries by severity or relationship to the study drug,in the subject count, if a 
subject has multiple TEAEs with the same SOC or PT, but with different severity or 
relationship, then the subject will be counted only once with the worst severity and highest 
degree of relationship, however, if any of the severity or relationship values are missing then 
the subject will be counted only once with missing severity or relationship. In the adverse 
event count, the adverse events will be presented in each category they were classified to. 
Drug related TEAEs will be presented in a similar way by severity only.
Maximum severity or relationship will be defined as the worst severity and highest degree of 
relationship on-treatment (see Section 6.2).
No queries will be done for SMQs.
7.5.1.3
Event-rates per 100 patient-years
The number of events and event rate (per 100 patient years) during the Safety Emergent 
Period with TEAEs, as classified by SOC and PT will be calculated by treatment arm. 
Summaries will be provided for:
●
TEAEs
●
TEAEs censored at start of chronic dialysis
●
TEAE NCI CTC Grades 3 or higher
●
Serious TEAEs, 
●
TEAEs leading to death.
7.5.1.4
Incidence rates and cumulative incidence
Since the percentage of adverse events might be different between treatment arms due to the 
difference in the discontinuation rates, in addition to the frequency tables above, the 
incidence rate (per 100 subject years at risk) and the cumulative incidence at 6 months, 12, 


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18 months & 24 months with the 95% confidence interval, using Greenwood’s formula, will 
be reported by treatment arm.
It will be done for each of the following event types of special interest: 
●
Serious TEAEs, 
●
TEAE for each SOC (>10% for a SOC in total SAF)
●
Deaths occurring during the Safety Emergent Period, 
●
Any death (including post-study follow up period),
●
Related serious TEAEs, 
●
AEs leading to discontinuation of study drug, and
●
TEAE NCI CTC Grades 3 or higher.
Hazard ratios of each of the TEAE categories of special interest above will be computed by 
using Cox Proportional Hazards regression stratified on region and history of CV and 
adjusted on baseline Hb and baseline eGFR as continuous covariates. Hazard ratios 
(roxadustat as relative to placebo) and their 95% CI will be calculated for each TEAE 
category.
As a sensitivity analysis, the above analysis will be repeated using IPCW method 
(Appendix 10.7) for the following event types of special interest:
●
Serious TEAEs, 
●
TEAE for each SOC (>10% for a SOC in total SAF)
●
Deaths occurring during the Safety Emergent Period, and
●
TEAE NCI CTC Grades 3 or higher.
A dot-and-forest plot will be produced showing each of the above TEAE categories on the y-
axis. The incidence rates by treatment arm, the stratified Cox hazard ratios (roxadustat as 
relative to placebo) and their 95% CI will be shown on the x-axis.
In addition, cumulative incidence plots for subjects experiencing each of the TEAE 
categories above will be produced by treatment arm.
Incidence rate (per 100 subject years at risk) in each treatment arm by SOC and PT and the 
cumulative incidences by SOC will also be produced for the most common TEAEs (>=5% in 
total SAF). In addition, cumulative incidence plots of subjects experiencing at least one most 
common TEAEs in a SOC will be produced. A dot-and-forest plot will be produced showing 
each SOC in the y-axis and the incidence rates, the Cox hazard ratio and its 95% CI in the x-
axis. The SOC will be sorted by the hazard ratio. 
7.5.1.5
Sensitivity/Subgroup analyses
-
Subgroups of interest :
The number and percentage of subjects reporting TEAEs in each treatment arm will be 
tabulated by SOC and PT for the subgroups of interest defined in Section 7.8


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-
Baseline eGFR category (< 15 vs ≥ 15) only :
The following summaries will be provided by comparing Baseline eGFR categories ( < 15 vs 
≥ 15) :
●
Event rate per 100 patient-years for TEAEs by SOC and PT
●
Incidence rate and cumulative incidence for serious TEAEs
●
Incidence rate and cumulative incidence for deaths during the safety emergent period
●
Incidence rate and cumulative incidence for drug-related serious TEAEs
●
Incidence rate and cumulative incidence for AEs leading to discontinuation of study drug
●
Incidence rate and cumulative incidence for TEAE NCI CTC Grades 3 or higher
-
Incidence rate and cumulative incidence censoring events occurring on or after the 
start of chronic dialysis :
The same analysis in incidence as described in Section 7.5.1.4 will be performed (i.e.,
incidence rate, hazard ratios, dot-and-forest plots and cumulative incidence plots) by 
censoring all data occurring at initiation of chronic dialysis (see Section 6.2.1.3 for more 
details regarding the definition of time to event and time to censoring) :
It will be done for :
●
Serious TEAEs
●
Serious TEAEs by baseline eGFR category (< 15 vs ≥ 15)
●
Deaths occurring during the Safety Emergent Period, 
●
Deaths occurring during the Safety Emergent Period by eGFR category (< 15 vs ≥ 15)
●
Drug-related serious TEAEs, 
●
Drug-related serious TEAEs by eGFR category (< 15 vs ≥ 15)
●
AEs leading to discontinuation of study drug,
●
AEs leading to discontinuation of study drug by eGFR category (< 15 vs ≥ 15)
●
TEAE NCI CTC Grades 3 or higher
●
TEAE NCI CTC Grades 3 or higher by eGFR category (< 15 vs ≥ 15)
●
Incidence rate for TEAE by SOC and most common PTs
●
Cumulative incidence by SOC for most common PTs.
7.5.1.6
AEs within 7 days
Additional summaries or analyses with events to be considered restricted to any adverse 
event starting up to Analysis Date of Last Dose + 7 days:
●
Overview summary table of subjects with AEs
●
Number and percentage of subjects with AEs, as classified by SOC and PT
●
Number and percentage of subjects with AEs leading to death, as classified by PT
●
Incidence rate for serious AEs (i.e., incidence rate, hazard ratios, dot-and-forest plots and 
cumulative incidence plots as described in Section 7.5.1.4 will be provided)
●
Incidence rate for AEs NCI CTC Grades 3 or higher (i.e., incidence rate, hazard ratios, 
dot-and-forest plots and cumulative incidence plots as described in Section 7.5.1.4 will 
be provided)


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Pre-specified adjudicated cardiovascular and thrombo-embolic events will be analyzed in
meta-analyses across multiple phase 3 studies and compared between treatment groups 
(roxadustat versus control). The statistical method for this analysis pooling studies will be 
detailed in a Pooled Statistical Analysis Plan (pSAP). The results will be presented in a 
separate report.
All data will also be listed. All Adverse Events collected from site 70051 will be listed 
separately.
7.5.2
Clinical Laboratory Evaluation
Descriptive statistics for laboratory values (in SI units) and changes from baseline at each 
assessment time point and for the maximum and minimum on-treatment (i.e., during Safety 
Emergent Period) value will be presented by treatment arm and treatment for the quantitative 
laboratory parameters. 
Maximum and minimum on-treatment values will be determined using all the original values 
and not the derived windows.
Shift tables and number and percentage of subjects with shift to low and shift to high will be 
reported by treatment arm for the quantitative laboratory parameters. 
Box plots of quantitative laboratory values (in SI units) versus visit will be produced by 
treatment arm (two arms in one page). 
A plot for each parameter of mean (+/- 95% CI) versus visit will be produced by treatment 
arm (two arms in one page). 
Summary by visit for qualitative laboratory parameters will be provided by treatment arm.
All clinical laboratory data will also be listed. 
Potentially clinically significant (PCS) laboratory abnormalities
For each potentially clinically significant (PCS) criterion defined in Section 6.2.3.1, the 
percentage of subjects with abnormalities by visit and at any moment during the Safety 
Emergent Period and who did not meet the criteria at baseline will be reported by treatment 
arm.
Incidence rate (per 100 subject years at risk) and the cumulative incidence at 6 months, 12, 
18 months & 24 months with the 95% confidence interval using Greenwood’s formula of 
PCS abnormalities will also be reported, using only subjects who did not meet the criteria at 
baseline, by treatment arm. Risk of PCS abnormalities will be compared using the same Cox 
model as used in Section 7.5.1  Hazard ratio and its 95% will be calculated for the frequency 
of roxadustat as relative to placebo. A dot-and-forest plot will be produced showing the PCS 
abnormalities above in the y-axis and the incidence rates, the Cox hazard ratio and their 95% 
CI in the x-axis. 
In addition, cumulative incidence plots for subjects experiencing each PCS abnormality will 
be produced by treatment arm (two arms in one page).


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7.5.2.1
Liver function tests
Descriptive summary of PCS values in Liver Enzymes and Total Bilirubin will be provided 
as per Astellas standard TLB_005 and FFG_008.
In addition, a matrix scatter plot of Liver Enzymes and Bilirubin (as in Astellas standard 
FFG_009) will be plotted showing the maximum ALT, AST, ALP and total bilirubin during
the Safety Emergent Period crossed against each other. Different dots will be used for 
roxadustat and placebo.
Individual displays of Liver Enzymes and Bilirubin parameters, listed in Section 6.2.3.1, will 
be reported for all subjects with ALT and / or AST > 3 x ULN or total bilirubin > 2 x ULN 
during Safety Emergent Period.
For subjects who require further liver function investigations, additional information will be 
collected and listed.
7.5.3
Vital Signs
Descriptive and changes from baseline for vital signs (systolic blood pressure, diastolic blood 
pressure, respiratory rate, weight and pulse) at each assessment time point and for the 
maximum and minimum on-treatment (i.e during Safety Emergent Period) value will be 
presented by treatment arm.
Maximum on-treatment value will be determined using all the original values and not the 
derived windows.
A plot for each parameter of mean (+/- 95% CI) versus visit will be produced by treatment 
arm (two arms in one page). 
PCS Vital signs criteria (10 Combined) will be analyzed in the same way as explained in 
Section 7.5.2 for PCS laboratory abnormalities. 
All vital signs data will also be listed. 
7.5.4
Electrocardiograms (ECGs)
Descriptive and changes from baseline for ECG parameters (Pulse, PR Interval, RR Interval, 
QRS interval, QT interval, and QTc interval) at each assessment time point and for the 
maximum on-treatment (i.e during Safety Emergent Period) value will be presented by 
treatment arm. 
Maximum on-treatment value will be determined using all the original values and not the 
derived windows.
The number and percentage of subjects with post-baseline PCS values (see Table 8) will be 
tabulated by treatment group. The percentages are to be calculated relative to the number of 
subjects with available baseline and at least one post-baseline assessment. The numerator will 
be  total number of subjects with at least one post-baseline PCS ECG value. Shift tables may 
be presented.


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The following PCS QTc Criteria (both QTcB and QTcF) :
-
QTc > 500 msec 
-
Change from baseline in QTc > 60 msec
will be analyzed separately in the same way as explained in Section 7.5.2 for PCS laboratory 
abnormalities.
A plot for each parameter of mean (+/- 95% CI) versus visit will be produced by treatment 
arm (two arms in one page).  
In addition, ECG parameters will be reported according to Astellas standards TEG_003 and 
TEG_004.
All ECG data will also be listed. 
7.5.5
Pregnancies
A listing of pregnancy test results will be provided.
7.6
Analysis of PK
The statistical methods for PK data will be described in a separate analysis plan. Results of 
the population PK analysis will not be reported in the Clinical Study Report but in a separate 
population PK report. 
Plasma concentration data of roxadustat will be listed. 
7.7
Analysis of PD
Not Applicable.
7.8
Subgroups of Interest
Selected efficacy and safety endpoints will be summarized for the subgroups defined on the 
basis of the categorized variables listed below in Table 25
Table 25
Subgroups of interest
Grouping variables
Subgroups
Age group
< 65 years
65 - 74 years
≥ 75 years
Sex
Female
Male
Region
Western Europe
Rest of the World 
Baseline Hb
≤ 8 g/dL
> 8 g/dL
History of cardiovascular, cerebrovascular or 
thromboembolic diseases
Yes
No
Table continued on next page


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Grouping variables
Subgroups
Baseline eGFR
< 30 mL/min/1.73m<
≥ 30 mL/min/1.73m<
Baseline eGFR1
< 15 mL/min/1.73m<
≥ 15 mL/min/1.73m<
Baseline CRP 2
≤ ULN
> ULN
Baseline Iron Repletion Status 2
(TSAT >= 20% and ferritin >= 100 ng/mL)  vs (TSAT < 20% 
or ferritin < 100 ng/mL)
1 : only for the two primary efficacy endpoints and also for selected AE summaries.
2 : only for the two primary efficacy endpoints and the key secondary endpoint on Hb (week 28- week 36)
7.9
Other Analyses
The current analysis plan is based on version 2.0 of the protocol. An exploratory analysis on 
Hb maintenance will be conducted in the sub-set of  patients treated for at least 24 weeks 
under protocol version 1.0.  The sub-set includes patients that discontinued treatment prior to 
Week 24 under protocol version 1.0. The pooled roxadustat arm will be seperated into 
3 groups according to their randomized treatment: (TIW, BIW, QW). Tables with summary 
statistics by visit up to Week 24 will be derived for the Hb values and the average weekly 
prescribed dose by the 4 treatment groups (placebo, roxadustat TIW, roxadustat BIW, 
roxadustat QW). In addition, the change from baseline to the Hb value average over Weeks 
12-24 (excluding rescue medication) will be analysed using the MMRM model using Hb and 
eGFR at baseline as co-variates. In addition, average weekly dose will be summarized by 
treatment arm by 4-weekly period until subject switched to protocol version 2.0.
7.10
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 Data and Safety Monitoring Board (DSMB).
7.11
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
7.11.1
Missing Data
For relevant analyses without rescue therapy, for subjects who used rescue therapy, the 
reported Hb values after the initiation of rescue therapy will be set to missing (instead of the 
reported values) for 6 weeks from the start date of rescue therapy (or the end in case the 
duration of rescue therapy > 1 day).
The following imputations will be performed for the continuous endpoints, unless specified 
otherwise :
●
An MMRM model will be run for the purpose of implicit imputation of missing data by 
using all the available information from the observed data via the within-patient 
correlation structure for continuous endpoints with inferential analysis.


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●
An ANCOVA model with multiple imputations  (MI) will also be run.
No imputations will be done for endpoints with no inferential analysis.
7.11.2
Missing Dates
As a general rule, the worst case scenario imputation rule is usually used. A start date is 
generally imputed to the first possible day, unless the available information in the partly 
missing date is equal to the one in the reference date. In this case, the substituted date is set to 
the reference date. An end date is generally imputed to the last possible day.
Completely missing dates will not be imputed.
Diagnosis of anemia, CKD and Targeted Medical History
The following rules will be applied to impute partially missing dates of diagnosis of Anemia, 
CKD and targeted medical history, as defined in Table 26 below.
Table 26
Definitions of the Analysis Date of Diagnosis of Anemia, CKD and 
Targeted Medical History
Reported Date (from the eCRF)
Analysis Date (Derived)
--/MM/YYYY
01/MM/YYYY
--/--/YYYY 
01/01/YYYY
DD/--/----, or
--/MM/----, or
--/--/----
No imputation 
Previous or Concomitant medication: 
For previous or concomitant medications, including rescue medications and chornic dialysis, 
partially missing start dates and/or stop dates will be imputed as defined in Table 27 and 
Table 28 below:
Table 27
Definitions of the Previous or Concomitant Medication Analysis Start 
Date
Reported Date (from the eCRF)
Analysis Date (Derived)
--/MM/YYYY
01/MM/YYYY
--/--/YYYY 
01/01/YYYY
DD/--/----, or
--/MM/----, or
--/--/----
No imputation 
If the imputed start date is after the stop date, then the imputed start date will be one day 
prior to the stop date.


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Table 28
Definitions of the Previous or Concomitant Medication Analysis Stop 
Date
Reported Date (from the eCRF)
Analysis Date (Derived)
--/MM/YYYY
31/MM/YYYY, or
30/MM/YYYY, or
29/MM/YYYY, or
28/MM/YYYY
--/--/YYYY 
31/12/YYYY
DD/--/----, or
--/MM/----, or
--/--/----
No imputation 
AE Onset date
For adverse events, partially missing start dates and/or stop dates will be imputed as defined 
in Table 29 and Table 30 below:
Table 29
Definitions of the Analysis Adverse Event Onset Date
Reported Date
Date of First Drug Intake
Analysis Date (Derived)
--/MM/YYYY
--/02/2008
--/02/2008
--/02/2008
DD/MM/YYYY
14/02/2008
14/02/2007
14/02/2009
14/02/2008*
01/02/2008
01/02/2008
--/--/YYYY
--/--/2008
--/--/2008
--/--/2008
DD/MM/YYYY
14/02/2008
14/02/2007
14/02/2009
14/02/2008
01/01/2008
01/01/2008
DD/--/----
--/MM/----
--/--/----
No imputation 
* If the month and year is the same as the month and year of first drug intake, use date of the first drug intake.
Table 30
Definitions of the Analysis Adverse Event End Date
Reported Date
Analysis Date (Derived) *
--/MM/YYYY
31/MM/YYYY or
30/MM/YYYY or
29/MM/YYYY or
28/MM/YYYY
--/--/YYYY
31/12/YYYY
DD/--/----, or
--/MM/----, or
--/--/----
No imputation 
*Death has to be taken into consideration when calculating this.


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7.11.3
Outliers
As a general rule, all values, including outliers will be analyzed.
7.11.4
Visits Windows
The study protocol gives the overall study schedule and the permissible intervals for visits 
expressed as the number of days relative to the first study medication date (Day 1).
For all study assessments reported by visit, the value which assessment day is the latest 
collected within the corresponding analysis visit window  will be used. If more than one
value is collected that day, then the latest value will be used in the analysis. 
Analysis Visit windows, as depicted in Table 31 below, will be used for the following study 
assessments reported by visit:
●
Central laboratory parameters (except Lipid Panel),
●
Vital Signs,
●
ECG parameters,
●
Exposure.
Table 31
Analysis Visit Windows
CRF Visit
Target EFGF
Analysis Visit Windows Actual 
Assessment Day
Analysis Visit
Screening
Day -42 to Day -1 
Screening
Day 1
Day 1
Day 1
Baseline
Week 1
Day 7 * (Week #) + 1
Day 2 to Day 11
Week 1
Week 2
Day 7 * (Week #) + 1
Day 12 to Day 21
Week 2
Week 4 – 22
Day 7 * (Week #) + 1
[Target Day – 7, Target Day +6]
Week 4 - 22
Week 24
Day 7 * (Week #) + 1
[Target Day – 7, Target Day + 13]
Week 24
Week 28 – 100
Day 7 * (Week #) + 1
[Target Day – 14, Target Day + 13]
Week 28 - 100
Week 104/EOT 
(for completers)
Day 7 * (Week #) + 1
[Target Day – 14, Target Day + 28]
Week 104
EOT Visit (for 
premature 
discontinuations) 
or unscheduled 
(on-tretament)
NA
NA
Analysis Visit 
corresponding to the 
actual visit window
EOT + 2 Weeks 
Visit
14 Days after EOT 
visit day
NA
EOT + 2 weeks
EOS Visit
28 Days after EOT 
visit day
NA
EOS
Unscheduled
NA
Day of EOT+1, Day of EOT+20
EOT+2 weeks
Unscheduled
NA
Day of EOT+21, Day of EOT+31
EOS
a:  Relative to Day 1 (first dose date of study medication) 
Analysis Visit windows, as depicted in Table 32 below, will be used for the quality of life 
efficacy study assessments: 


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Table 32
Analysis Visit Windows for QoL
CRF Visit
Target Daya
Analysis Visit Windows Actual 
Assessment Day
Analysis Visit
Day 1
Day 1
Day 1
Baseline
Week 8
Day 7 * (Week #) + 1
[Target Day – 14, Target Day + 13]
Week 8
Week 12
Day 7 * (Week #) + 1
[Target Day – 14, Target Day + 27]
Week 12
Week 28
Day 7 * (Week #) + 1
[Target Day – 28, Target Day + 27]
Week 28
Week 36
Day 7 * (Week #) + 1
[Target Day – 28, Target Day +27
Week 36
Week 52
Day 7 * (Week #) + 1
[Target Day – 56, Target Day + 83]
Week 52
Week 76
Day 7 * (Week #) + 1
[Target Day – 84, Target Day + 97]
Week 76
Week 104/EOT (for 
completers)
Day 7 * (Week #) + 1
[Target Day – 98, Target Day + 28]
Week 104
EOT Visit (for 
premature 
discontinuations)
NA
NA
Analysis Visit 
corresponding to 
the actual visit 
window
Unscheduled
NA
NA
Analysis Visit 
corresponding to 
the actual visit 
window
a:  Relative to Day 1 (first dose date of study medication) 
Analysis Visit windows, as depicted in Table 33 below, will be used for the Lipid Panel, 
including LDL cholesterol efficacy study assessment:
Table 33
Analysis Visit Windows for Lipid Panel
CRF Visit
Target Daya
Analysis Visit Windows Actual 
Assessment Day
Analysis Visit
Day 1
Day 1
Day 1
Baseline
Week 4
Day 7 * (Week #) + 1
Day 2 to Day 42
Week 4
Week 8
Day 7 * (Week #) + 1
[Target Day – 14, Target Day + 13]
Week 8
Week 12
Day 7 * (Week #) + 1
[Target Day – 14, Target Day + 27]
Week 12
Week 20
Day 7 * (Week #) + 1
[Target Day – 28, Target Day + 27]
Week 20
Week 28
Day 7 * (Week #) + 1
[Target Day – 28, Target Day + 27]
Week 28
Week 36
Day 7 * (Week #) + 1
[Target Day – 28, Target Day + 27]
Week 36
Week 44
Day 7 * (Week #) + 1
[Target Day – 28, Target Day + 27]
Week 44
Week 52
Day 7 * (Week #) + 1
[Target Day – 28, Target Day + 55]
Week 52
Week 68
Day 7 * (Week #) + 1
[Target Day – 56, Target Day + 55]
Week 68
Week 84
Day 7 * (Week #) + 1
[Target Day – 56, Target Day + 69]
Week 84
Week 104/EOT (for 
completers)
Day 7 * (Week #) + 1
[Target Day – 70, Target Day + 28]
Week 104
Table continued on next page


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CRF Visit
Target Daya
Analysis Visit Windows Actual 
Assessment Day
Analysis Visit
EOT Visit (for 
premature 
discontinuations)
NA
NA
Analysis Visit 
corresponding to 
the actual visit 
window
EOS Visit
NA
Last assessment between Day 2 and 
study termination day
EOS
Unscheduled
NA
NA
Analysis Visit 
corresponding to 
the actual visit 
window
a:  Relative to Day 1 (first dose date of study medication) 
For the MMRM analyses, which requires one value per visit, one analysis Hb value for each 
planned visit will be used.
For the ANCOVA analyses, which use the average, all available values in the analysis 
windows will be used for the calculation.
7.11.5
End of Safety Emergent Period
The end of Safety Emergent Period will be defined as :
-
Minimum [Analysis date of Last Dose + 28 days , max(EOS Visit, Date of death)) in 
case Analysis date of Last Dose = Date of Last Dose 
-
Minimum [(Analysis date of Last Dose + 28 days , max(EOS Visit, Date of death))
in case Analysis date of Last Dose = Date of the End of Extended Treatment Visit 
(due to missing date of Last Dose) and the subject is treatment completer or 
discontinued due to any reason apart from Lost to follow up.
-
Analysis date of Last dose in case Analysis date of Last Dose = Date of the End of 
Extended Treatment Visit (due to missing date of Last Dose) and the subject 
discontinued due to Lost to follow up.
-
Analysis date of Last dose in case Analysis date of Last Dose = Date of last available 
assessment (due to missing date of last dose and date of the End of Extended 
Treatment Visit). In case a subject died, then Minimum [Date of last available 
assessment + 28 days , Date of death)].
With Analysis Date of Last Dose defined in Section 6.5.4
7.11.6
End of Efficacy Emergent Period
For all subjects, the end of Efficacy Emergent Period will be defined as :
-
Minimum (Analysis date of Last Dose + 7 days , EOT Visit)


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8
DOCUMENT REVISION HISTORY 
Version
Date
Changes
Comment/rationale for change
1.0
28-May-
2014
NA
Document finalized
2.0
21-January-
2016
1) Reduction of the number of 
sensitivity analyses for the 
secondary endpoints.
2) New ordering for the key 
secondary endpoints.
3) Implementation of the Time to 
event approach for the PPS and 
adjustment of the relevant 
sections.
4) Change from ITT to All 
Randomized as per Astellas 
standard. Definition remains 
unchanged.
5) Use of the Safety Emergent 
Period (i.e last dose + 28 days) 
as evaluation period by default 
for the safety endpoints.
6) Use of the Efficacy Emergent 
Period (i.e last dose + 7 days) as 
evaluation period by default for 
most of the efficacy time to 
event endpoints.
7) Use of “Time to censoring” 
instead of”time at risk” for 
patient with no event for more 
clarity.
8) Clarification of time to 
censoring for events evaluated 
during the Safety Emergent 
Period/Efficacy Emergent
1) Due to harmonization 
with Fibrogen 060 study 
SAP and to limit the 
additional analyses .
2) Due to the importance of 
the QoL endpoints and 
the  harmonization with 
Fibrogen 060 study SAP.
3) PPS definition has been 
revised in order to limit 
the exclusion of data by 
using a time to event 
approach rather than 
creating one PPS set for 
each period of interest.
4) Astellas standards 
requirement.
5) Decision agreed by the 
study team to use a 
consistent approach for 
all the safety endpoints 
by extending the 
evaluated period up to 28 
days after last dose, 
which matched the AE 
analyses.
6) Decision agreed with the 
study team to use a 
consistent approach for 
time to event efficacy 
endpoints by extending 
the evaluated period up 
to 7 days after last dose.
7) Clarification of the 
wording. Time to 
censoring is more 
appropriate.
8) Based on the new 
definitions of 
Efficacy/Safety 
Emergent period, time to 
censoring for all time to 


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Version
Date
Changes
Comment/rationale for change
Period.
9) Time to PCS vital signs added.
10) Time to PCS ECG focused to 
QTc instead of all ECG 
assessments.
11) Additional censoring rules for 
the post-dialysis data (used for 
some time to event related to 
AEs).
12) Update regarding derivation of 
MAP values : average of the 3 
measurements instead of 2 (now 
in line with FG SAP).
13) Implementation of primary 
efficacy endpoint for FDA 
(change in Hb from baseline to 
the average level between week 
28 and week 52) and 
description of statistical 
analyses including sensitivity 
analyses for missing data
14) Implementation of time to first 
hospitalization, time to first 
occurrence of serum creatinine 
doubled, time to first potential 
EH (2 different criteria 
separately), time to dialysis.
15) Reduction in the number of
analyses of subgroup of 
interests.
events have been 
updated accordingly.
9) Time to PCS were 
already planned for lab 
and ECG but not for 
Vital signs. Decision was 
taken to provide them as 
well.
10) Time to event for PCS 
ECG other than QTcF 
was considered not of 
interest.
11) In order to assess the 
impact of dialysis on 
incidence rates of AEs, 
sensitivity analyses will 
be conducted by  
censoring patients at the 
date of dialysis.
12) Using the average of all 
3 measurments is more 
efficient and is consistent  
with Fibrogen 060 study 
SAP.
13) This additional endpoint 
has been added in 
protocol amendment 
1.0.Sensitivity analyses 
for missing data were 
added following FDA 
feedback on Fibrogen 
060 study. Both Fiborgen 
and Astellas now in line 
regarding this endpoint.
14) Due to harmonization 
with Fibrogen 060 study 
SAP and the expected 
difference in treatment 
durations
15) Due to harmonization 
with Fibrogen 060 study 
SAP.


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Version
Date
Changes
Comment/rationale for change
16) Addition of the analysis of 
percentage of time when Hb > 
12, 13 or 14.
17) MMRM model added for 
number of RBC and volume of 
RBC during the treatment 
period.
18) Removal of descriptive analysis 
on the categorical change form
baseline in Total FACT-An 
Score.
19) Removal of the descriptive 
analysis on change from day of 
first dialysis to week 4 and 
week 12 of dialysis for SF-36, 
FACT-AN scores, EQ-5D, 
WPAI. 
20) Updated rule for complete 
missing start date and end date 
for concomitant medications. In 
that case, the medication will be 
considered as both previous and 
concomitant instead of only 
concomitant.For the analysis of 
monthly IV Iron use, MMRM 
has been replaced by 
ANCOVA.
21) Additional tables run on group 
of subjects enrolled after 
protocol amendment 
implementation
16) Due to harmonization 
with Fibrogen 060 study 
SAP.
17) The concept of 
percentage of time with 
high Hb values was 
implemented in order to 
account for differences 
in individual treatment 
durations.
18) Inferential analysis for 
RBC was missing in the 
v1.0.
19) Descriptive statistics for 
categorical change not 
necessary since analysis 
on absolute change 
already planned and 
considered sufficient.
20) Exploratory summary 
statistics of SF-36, 
FACT-AN scores, EQ-
5D, WPAI for patients 
on dialysis not required 
since this is a small 
subset of patients and not 
based on the randomized 
population. 
21) Previous rule considered 
too conservative since a 
missing year of start is 
usually for previous 
medications than 
concomitant. Decision 
was taken to consider 
such medications as both 
previous and 
concomitant.
22) MMRM model for 
monthly IV Iron was not 
adapted due the data 
distribution. Since 
montly average will be 


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Version
Date
Changes
Comment/rationale for change
calculated, ANCOVA is 
more appropriate.
23) Added in order to assess 
the impact of protocol 
amendment 1.0.
3.0
06-
November-
2017
1) Removal of the reporting for 
date informed consent for 
genotyping and genotyping 
sample.
2) Number and percentage of 
subjects with drug related 
TEAEs leading to death added.
3) Use of SBP ≥170 mmHg AND 
an increase from BL 
≥20 mmHg or as DBP ≥110 
mmHg, AND an increase from 
BL ≥15 mmHg for the 
definition of hypertension.
4) Use of the Safety Emergent 
Period as evaluation period to 
be considered a concomitant 
medication.
5) ATC codes for Iron-chelating 
agents were updated.
6) Belarus was added in the list of 
countries for Region B.
7) Use of the Efficacy Emergent 
Period as evaluation period to 
be considered for the definition 
of rescue therapy.
8) Removal of the criterion "at 
least one Hb value >13 g/dL 
during the Efficacy Emergent 
Period" for the definition of 
Potential Excessive 
Hematopoiesis (EH).
1) Decision agreed by the 
study team.
2) Astellas standards 
requirement
3) Due to harmonization 
with Fibrogen 060 study 
SAP.
4) Decision agreed by the 
study team.
5) The ATC codes in 
previous version were 
not correct as they 
actually did not cover the 
Iron supplementation 
agents
6) Protocol requirement.
7) Decision agreed with the 
study team to use a 
consistent approach for 
rescue therapy by 
extending the evaluated 
period up to 7 days after 
last dose.
8) Due to harmonization 
with Fibrogen 060 study 
SAP.


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Version
Date
Changes
Comment/rationale for change
9) For the analysis of number of 
RBC packs and volume, 
MMRM has been replaced by 
ANCOVA
10) Removal of the calculation of 
the amount of IV iron in 
monthly intervals during the 
Efficacy Emergent Period.
11) Removal of the supplementary 
analysis for each post-dosing 
timepoint for subjects with 
mean LDL cholesterol less than 
100 mg/dL. Average W12-W28 
should be done for both 
regardless and fasting.
12) Implementation of the 
derivation of the hospitalization 
duration.  When hospitalization 
is ongoing, the date of end of 
the Efficacy Emergent Period 
will be used.
13) Removal of other baseline 
factors including: Diabetes 
mellitus, age, gender, BMI, 
baseline eGFR, baseline CRP, 
ferritin, TSAT, CHr, 
Hypertension from ANCOVA 
with MI.
14) Update the calculation of the 
number of days of 
hospitalization per PEY as: 
Minimum ((Date of discharge, 
End of Efficacy Emergent 
Period) – Date of admission + 
1)] / [(Duration of Efficacy 
Emergent Period. 
15) No comparison for IV Iron 
between treatment arms.
9) MMRM model for RBC 
packs and volume was 
not adapted due the data 
distribution. Since 
monthly average will be 
calculated, ANCOVA is 
more appropriate.
10) Decision agreed by the 
study team not to report 
Mean IV Iron for each 
month but only for the 
period of interest.
11) Decision agreed by the 
study team.
12) Decision agreed by the 
study team to be more 
accurate.
13) Due to harmonization 
with Fibrogen 060 study 
SAP.
14) Decision agreed by the 
study team to be 
consistent with the 
definition.
15) Due to the very small 
number of subjects with 
IV Iron.


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Version
Date
Changes
Comment/rationale for change
16) Figure added with the 
comparison between central 
laboratory hemoglobin 
(g/dL) and HemoCue 
hemoglobin (g/dL). 
17) Removal of the analysis for 
subjects who have reached Hb 
>= 11.0 g/dL prior to week 28.
18) For time to first occurrence of
serum creatinine doubled 
compared with baseline, a 
subject will be counted with an 
event either for doubled serum 
creatinine or ESRD, whichever 
comes first. Otherwise, we 
censor at date of last non-
missing serum creatinine 
assessment during the Safety 
Emergent Period.
19) For WPAI scale, the number 
and proportion of employed 
subjects was summarized by 
visit and treatment arm.
20) Fatigue subscale score added 
for FACT-An questionnaire.
21) Time to All Deaths including 
Post study FU added.
22) Time to AEs by eGFR 
categories (<15 vs
≥15 mL/min/1.73m<) added.
23) Number of events and event 
rate (per 100 patient years) 
during the Safety Emergent 
Period with TEAEs added.
24) New sensitivity analysis 
(MMRM) for change to the 
16) Decision agreed by the 
study team to check the 
differences between the 
two methods.
17) Decision agreed by the 
study team
18) Decision agreed by the 
study team to be 
consistent with the 
definition for time to first 
occurrence of serum 
creatinine doubled 
compared with baseline.
19) Decision agreed by the 
study team to check the 
number of employed 
subjects by visit and 
treatment arm. 
20) Descriptive statistics 
fatigue were added due 
to a request from Health 
Economics and 
Outputs Research 
Department.
21) Decision agreed by the 
study team.
22) Decision agreed by the 
study team.
23) Decision agreed by the 
study team to compare 
treatments in a fair way 
due to potential 
difference in exposure 
between the two arms.
24) Decision agreed by the 
study team.


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Version
Date
Changes
Comment/rationale for change
average Hb in weeks 28-52 
including all Hb values up to  
end of treatment visit.
25) Interaction term baseline*visit 
added to the main MMRM 
model for Hb analysis
25) Based on internal 
statistical guidance and 
check on model fit.
4.0
08-March-
2018
1) Two additional subgroup 
analyses [Baseline CRP 
category (≤ULN vs. > ULN)] 
and Baseline Iron Repletion 
Status category [(TSAT >= 
20% and ferritin >= 100 ng/mL)  
vs. others] added for the 
primary efficacy endpoints and
the key secondary efficacy 
endpoint in Hb (week 28 –
week 36)
1) Baseline CRP group 
(CRP ≤ULN vs. CRP > 
ULN) is considered as a 
marker for inflammation 
which may affect 
treatment response. A 
subgroup analysis is 
added to explore the 
consistency of the effect 
of roxadustat on the Hb 
related primary efficacy 
parameters. Iron 
repletion status may 
affect treatment response 
and is added for 
consistency with 
Fibrogen 060 study SAP.
5.0
11-Jul-
2018
1) Time to Rescue Therapy during 
the first 24 weeks was replaced 
by Time to Rescue Therapy 
during the treatment period as 
Key Secondary Efficacy 
endpoint. Endpoint at 24 weeks 
was therefore considered as 
Other Secondary endpoint
2) VT and PF SF-36 scores have 
been switched in the 
hierarchical order of the key 
secondary endpoints
3) eGFR slope over time was 
added at the bottom of the list 
of key secondary endpoint
4) Details were added in All 
Randomized section regarding 
exclusion of subjects from site 
70051
5) Additional analyses on adverse 
1) Due to harmonization 
with Fibrogen 060 study 
SAP.
2) Due to harmonization 
with Fibrogen 060 study 
SAP.
3) Due to harmonization 
with Fibrogen 060 study 
SAP.
4) Site 70051 was 
terminated due to GCP 
violations and it is now 
clearly mentioned in the 
population section that 
those subjects are 
excluded from all 
analysis set.
5) Due to harmonization 


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Version
Date
Changes
Comment/rationale for change
event were added considering 
events ococuring up to last dose 
+_7 days (i.e OT-7)
6) Details regarding derivation of 
CV history were added in 
relevant section
7) Time to first dialysis was 
changed to Time to chronic 
dialysis or renal transplant
with Fibrogen 060 study 
SAP.
6) To provide additional 
details about derivation.
7) Due to harmonization 
with Fibrogen 060 study 
SAP.
5.0
18-Jul-
2018
Time to event endpoints: 
For the following endpoints (new or 
existing), IPCW analysis is added.
Additional endpoints of interest are 
added as indicated by new. 
a. Rescue therapy:
Time to first use of rescue therapy 
[composite of RBC transfusions, IV 
iron supplementation and rescue ESA]
Time to first use of RBC transfusion 
Time to first use of IV iron 
supplementation 
Time to first use of ESA
b. Hospitalization:
  Time to first hospitalization
c. CKD progression:
Time to CKD progression (composite 
of doubling serum creatinine, chronic 
dialysis or renal transplant, and Death) 
(new)
Time to doubling serum creatinine 
(new)
Time to chronic dialysis or renal 
transplant
Time to chronic dialysis or renal 
transplant or occurrence for a subject 
who died (new)
Time to at least 40% decrease in eGFR 
from baseline, chronic dialysis or renal
transplant (new)
Time to at least 40% decrease in 
eGFR from baseline (new)
d. Adverse Events:
Time to serious TEAE
Time to death
Time to TEAE with grade 3 or higher
Time to TEAE by SOC (>10% for a 
SOC in total SAF)
Due to harmonization with 
Fibrogen 060 study SAP.
5.0
18-Jul-
2018
Appendix 8 is added about inverse 
probability censoring weighted model
To provide details about inverse 
probability censoring weighted 


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Version
Date
Changes
Comment/rationale for change
model
5.0
18-Jul-
2018
Rate of progression of CKD measured 
by annualized eGFR slope over time:
Analysis is updated to use non-log 
transformed eGFR values. 
To perform log transformed 
analysis only if residual analysis 
indicates heteroscedasticity
5.0
18-Jul-
2018
A summary is added for onset of 
common (>=5% in Any Treatment 
Group) TEAEs by Treatment Duration: 
<3 months, ≥3 to ≤6 months, >6 to ≤12 
months, >12 months
To provide summary of common 
TEAEs by treatment duration.
5.0
02-Aug-
2018
End point time to doubling of serum 
creatinine or ESRD is updated as 
Time to doubling of serum creatinine or 
chronic dialysis or renal transplant
To be consistent with Time to 
CKD progression Endpoint.


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9
REFERENCES
Cella D. The functional assessment of Cancer Therapy-Anemia (FACT-An) Scale: A new tool for the 
assessment of outcome in cancer anemia and fatigue. Hematology Seminars 1997; 34: 13-19 
Gart J, Nam J. Approximate Interval Estimation of the Difference in Binomial Parameters: Correction 
for Skewness and Extension to Multiple Tables. Biometrics. 
1990, 46: 637-643
Ge M, Durham LK, Meyer RD, Xie W, Thomas N. Covariate-Adjusted Difference in Proportions 
from Clinical Trials Using Logistic Regression and Weighted Risk Differences. Drug 
Information Journal 2011; 45: 481
Hedeker D, Gibbons R. Application of Random-Effectes Pattern-Mixture Models for Missing Data in 
Longitudinal Studies. Psychological Methods 1997, Vol 2, No 1 64-78.
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics)
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics)
Ratitch B, O’Kelly M. Implementation of Pattern-Mixture Models Using Standard SAS/STAT 
Procedures, PharmaSUG2011.
Spiessens B, Debois M. Adjusted significance levels for subgroup analyses in clinical trials. 
Contemporary Clinical Trials, Volume 31, Issue 6; November 2010.
Webster K, Cella D and Yost K. The Functional Assessment of Chronic Illness Therapy (FACIT) 
Measurement System: properties, applications, and interpretation. Heath and Quality of Life 
Outcomes 2003; 1: 79. 


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10
APPENDICES
10.1
Appendix 1:
SF-36 v2


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SF-36 v2


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SF-36 v2


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SF-36 v2


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SF-36 v2


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SF-36 v2


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SF-36 Model


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10.2
Appendix 2:
FACT-An (Version 4)
10.2.1
FACT-An Questionnaire


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FACT-An (Version 4)


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FACT-An (Version 4)


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10.2.2
FACT-An Scoring Guidelines
Instructions:* 1. Record answers in "item response" column. If missing, mark with an X
2. Perform reversals as indicated, and sum individual items to obtain a score.
3. Multiply the sum of the item scores by the number of items in the subscale, 
then divide by the number of items answered. This produces the subscale 
score.
4. Add subscale scores to derive total scores (TOI, FACT-G & FACT-An). 
5. The higher the score, the better the QOL.
Subscale
  Item Code    Reverse item?       Item response        
Item Score
PHYSICAL
GP1
4
-
________
=________
WELL-BEING
GP2
4
-
________
=________
   (PWB)
GP3
4
-
________
=________
      
GP4
4
-
________
=________
      
GP5
4
-
________
=________
      
GP6
4
-
________
=________
      
GP7
4
-
________
=________
              Sum individual item scores: ________  
                      Multiply by 7: ________
             Divide by number of items answered: ________
=PWB subscale score
SOCIAL/FAMILY
GS1
0
+
________
=________
WELL-BEING
GS2
0
+
________
=________
    (SWB)
GS3
0
+
________
=________
      
GS4
0
+
________
=________
      
GS5
0
+
________
=________
   
GS6
0
+
________
=________
      
GS7
0
+
________
=________
             Sum individual item scores: ________  
                     Multiply by 7: ________
            Divide by number of items answered: ________
=SWB subscale score
EMOTIONAL
GE1
4
-
________
=________
WELL-BEING
GE2
0
+
________
=________
    (EWB)
GE3
4
-
________
=________
      
GE4
4
-
________
=________
     
GE5
4
-
________
=________
GE6
4
-
________
=________
             Sum individual item scores: ________  
                     Multiply by 6: ________
            Divide by number of items answered: ________
=EWB subscale score
Score range: 0-28
Score range: 0-28
Score range: 0-24


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FUNCTIONAL  
GF1
0
+
________
=________
WELL-BEING 
GF2
0
+
________
=________
     (FWB)
GF3
0
+
________
=________
      
GF4
0
+
________
=________
      
GF5
0
+
________
=________
      
GF6
0
+
________
=________
      
GF7
0
+
________
=________
             Sum individual item scores: ________  
                     Multiply by 7: ________
            Divide by number of items answered: ________
=FWB subscale score
Subscale
         Item Code       Reverse item?            Item response        
Item Score
ANEMIA
HI7
     
4
-
________
=________
SUBSCALE
HI12
4
-
________
=________
(AnS)
An1
4
-
________
=________
An2
4
-
________
=________
An3
4
-
________
=________
An4
4
-
________
=________
An5
0
+
________
=________
An6
4
-
________
=________
An7
0
+
________
=________
An8
4
-
________
=________
An9
4
-
________
=________
An10
4
-
________
=________
B1
4
-
________
=________
An11
4
-
________
=________
An12
4
-
________
=________
BL4
0
+
________
=________
An13
0
+
________
=________
An14
4
-
________
=________
An15
4
-
________
=________
An16
4
-
________
=________
              Sum individual item scores:________  
                   Multiply by 20: ________
            Divide by number of items answered: ________
=An Subscale score
To derive a FACT-An Trial Outcome Index (TOI):
  __________ + __________ + __________ =________=FACT-An TOI
  (PWB score)   (FWB score)   (AnS score)  
To Derive a FACT-G total score:
        __________ + __________ + __________ + __________=________=FACT-G Total score
        (PWB score)    (SWB score)   (EWB score)  (FWB score)
Score range: 0-28
Score range: 0-136
Score range: 0-108
Score range: 0-80


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To Derive a FACT-An total score:
              _________ + __________ + __________ + __________ + __________ =________=FACT-An Total score
                            (PWB score)  (SWB score)   (EWB score)  (FWB score)   (AnS score)
*For guidelines on handling missing data and scoring options, please refer to the Administration and Scoring 
Guidelines in the manual or on-line at www.facit.org.
FACIT-Fatigue Subscale Scoring Guidelines
Instructions:*  1. Record answers in "item response" column. If missing, mark with an X
2. Perform reversals as indicated, and sum individual items to obtain a score.
3. Multiply the sum of the item scores by the number of items in the
subscale, then divide by the number of items answered.  This produces the 
subscale score.
4. The higher the score, the better the QOL.
Subscale
Item Code
Reverse item?
Item response
Item
Score
FATIGUE
HI7
4
-
=
SUBSCALE
HI12
4
-
=
An1
4
-
=
An2
4
-
=
Score range: 0-52
An3
4
-
=
An4
4
-
=
An5
0
+
=
An7
0
+
=
An8
4
-
=
An12
4
-
=
An14
4
-
=
An15
4
-
=
An16
4
-
=
              Sum individual item scores:________  
                   Multiply by 13: ________
            Divide by number of items answered: ________
=Fatigue Subscale score
Score range: 0-188


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10.3
Appendix 3:
EQ-5D 5L v2


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EQ-5D 5L v2


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10.4
Appendix 4:
WPAI:ANS V2.0
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. 


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WPAI:ANS
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
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


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10.5
Appendix 5:
Patient Overall Impression of Change
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


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10.6
Appendix 6:
Medication  WHO Drug Dictionary Codes
Name
Code
ESA except darbepoetin alfa 
ATC level 4 = B03XA [WHODD drug code = 
'00909301001', '00928301001', '07973701001', 
‘01703101001’]
Darbepoetin alfa
ATC level 4 = B03XA [WHODD drug code = 
'02198701001']
IV Iron
ATC level 4 = B03AC [WHODD drug code =
'00023501001', '90135401001']
RBC transfusion
ATC level 4 = B05AX [WHODD drug code =
'01186901001']
Any investigational drug
WHODD drug code = '99999701001'
Hypoxia-inducible factor HIF-PHI
ATC level 4 = B03XA
Iron-chelating agents
ATC code = V03AC01, V03AC02 and V03AC03
Androgens
ATC level 3 = G03B and G03E
Dapsone 
ATC level 4 =  J04BA
Acetaminophen/paracetamol
ATC level 4 = N02BE, N02AA, R05X


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10.7
Appendix 7:
Inverse probability censoring weighted model
Background
The possible presence of differential SDD rates between the roxadustat arm and the placebo 
arm, which may indicate informative censoring, will have a strong impact on the use of 
conventional survival methodology using Cox regression or other non-parametric survival 
analysis methods, which may lead to heavy bias in the estimation of the hazard ratio (HR). 
Patients who dropped out may have dependent or nonrandom censoring. The IPCW approach 
presented below is often used under these situations.
Step 1:  Model the censoring mechanism.
In the censoring model, the event of interest is censoring, hence the subjects who are lost to 
follow-up have an 'event'. Subjects that are not censored, i.e. those who experience the 
original event of interest, are now considered censored' since their censoring time is not 
observed. The probability of being censored will be estimated. 
Step 2: Estimate the Product-Limit estimator and Cox proportional hazards estimator
Estimate the P-L estimator and Cox regression estimators using time to censoring for each 
subject j at each time point t, K 0
j (t) and KZ
j (t). The Cox Model will include e GFR 
categories (e GFR < =10, 10<= e GFR < 15, 15<= e GFR < 30, and e GFR >= 30), and 
Dialysis initiation (Yes, No) as time varying covariates. Stratification factors including 
baseline Hemoglobin values, Study and other common stratification factors will also be 
included in the model.  
Step 3:  Calculate the unstablized and stabilized IPCW weights for each of the subjects, j, 
Wunstabj (t) =)1/ Kz
j (t), Wstabj (t) = K 0
j (t)/ Kz
j (t).
Step 4:  Estimate the survival and/or Cox model for time to event in the absence of censoring 
with the IPCW weights, SIPCW.


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10.8
Appendix 8:
Signatures
List of Key Contributors and Approvers
Key Contributors
The following contributed to or reviewed this Statistical Analysis Plan as relevant to their 
indicated discipline or role.
Primary author 
Contributors and Reviewers




 
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 
08/03/2018 07:23:46
Statistical Analysis Plan
Scientific Lead Approval
Study Statistician Approval
Version 5.0
08/02/2018 20:58:05
Statistics Lead
N/A
08/02/2018 20:35:49
N/A
mgc1400722
1517-CL-0608
6.0
N/A