Clinical trial NCT02021318
Conditions: Anemia in Chronic Kidney Disease in Non-dialysis Patients
Keywords: Non-dialysis Roxadustat ASP1517 Chronic Kidney Disease (CKD) Anemia Hemoglobin
Sponsor: Astellas Pharma Europe B.V.
Start date: 2014-03-12; Completion date: 2019-11-06
Enrollment: 616 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study was to evaluate the efficacy of roxadustat compared to darbepoetin alfa in the treatment of anemia in nondialysis-dependent chronic kidney disease (NDD CKD) participants.

Detailed description:
This was a phase 3, multicenter, randomized, open-label, active-controlled study. The study was planned to provide key efficacy and safety data for the approval of roxadustat in the treatment of anemia associated with CKD. Participants assigned to roxadustat treatment were administered roxadustat orally as a combination of tablets of different strengths. Participants assigned to darbepoetin alfa treatment were administered darbepoetin alfa subcutaneously or intravenously.

The study consisted of 3 study periods:

* Screening period: up to 6 weeks
* Treatment period: 104 weeks
* Follow-up period: 4 weeks until planned study end (end of year 2)

Arms: arm 1: Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg (milligram) given thrice weekly (TIW) to participants weighing up to 70 kg (kilogram) 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 (gram per deciliter) and Hb increase from baseline 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 up to a maximum of 104 weeks. arm 2: Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 μg/kg (microgram per kilogram), as a single subcutaneous or intravenous (IV) injection once weekly or 0.75 μg/kg, as a single subcutaneous injection once every 2 weeks) as per European Summary of Product Characteristics (EU SmPC) along with IV iron supplementation according to the standard of care. Dose-adjustment 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 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 darbepoetin alfa 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 darbepoetin alfa for up to a maximum of 104 weeks.
Interventions: intervention 1: Roxadustat intervention 2: Darbepoetin alfa
Intervention descriptions: intervention 1: Oral tablet. intervention 2: Subcutaneous or intravenous injection.

Protocol documents:
Prot_002.pdf: 
A Phase 3, Randomized, Open-Label, Active-Controlled Study
to Evaluate the Efficacy and Safety of Roxadustat in
the Treatment of Anemia in Chronic Kidney Disease
Patients Not on Dialysis
ISN/Protocol 1517-CL-0610
ClinicalTrials.gov Identifier: NCT02021318
Date of Protocol Version 3.0: 31 Mar 2016
Sponsor: Astellas Pharma Europe B.V.
Sylviusweg 62
2333 BE Leiden
The Netherlands


Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 1 of 160
Version 3.0, Incorporating Substantial Amendment 2
A Phase 3, Randomized, Open-Label, Active-Controlled Study 
to Evaluate the Efficacy and Safety of Roxadustat in 
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-0610
Version 3.0
Incorporating Substantial Amendment 2 [See Attachment 1]
31 March 2016
EudraCT number 2013-000951-42
Sponsor:
Astellas Pharma Europe B.V.
Sylviusweg 62, 2333 BE Leiden
The Netherlands
Protocol History:
Version 1.0 [14 Aug 2013]
Version 2.0 [18 May 2015]
                                                
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-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 2 of 160
Version 3.0, Incorporating Substantial Amendment 2
Table of Contents
I.
SIGNATURES ······················································································ 9
II.
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL····························12
III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ··················13
IV.
SYNOPSIS··························································································19
V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS·································33
1
INTRODUCTION·················································································37
1.1
Background ····················································································37
1.1.1
Epidemiology of Chronic Kidney Disease and End Stage Renal Disease········37
1.1.2
Anemia Associated with CKD·························································37
1.1.3
Treatment of Anemia ···································································38
1.2
Non-clinical and Clinical Data ······························································39
1.2.1
Mechanism of Action of Roxadustat··················································39
1.2.2
Clinical Experience with Roxadustat ·················································41
1.2.2.1
Pharmacokinetics and Pharmacodynamics ·····································41
1.2.2.2
Efficacy ·············································································42
1.2.2.3
Summary············································································44
1.2.3
Clinical Experience with Darbepoetin alfa···········································44
1.3
Summary of Key Safety Information for Study Drugs ···································45
1.3.1
Roxadustat················································································45
1.3.2
Darbepoetin alfa ·········································································46
1.4
Risk-Benefit Assessment·····································································47
2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ··································49
2.1
Study Objectives ··············································································49
2.1.1
Primary Objective ·······································································49
2.1.2
Secondary Objectives ···································································49
2.2
Study Design and Dose Rationale···························································49
2.2.1
Study Design·············································································49
2.2.1.1
General··············································································49
2.2.1.2
Study Population···································································49
2.2.1.3
Description of Study·······························································49
2.2.1.4
Randomization and Open-Label ·················································52
2.2.1.5
Comparator ·········································································52
2.2.2
Roxadustat Dose Rationale·····························································52
2.3
Endpoints·······················································································53


Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 3 of 160
Version 3.0, Incorporating Substantial Amendment 2
2.3.1
Primary Endpoints·······································································53
2.3.2
Key Secondary Endpoints ······························································53
2.3.3
Additional Secondary Endpoints ······················································54
2.3.3.1
Efficacy Endpoints ································································54
2.3.3.2
Safety Endpoints···································································55
3
STUDY POPULATION··········································································56
3.1
Selection of Study Population ·······························································56
3.2
Inclusion Criteria··············································································56
3.3
Exclusion Criteria ·············································································57
4
TREATMENT(S)··················································································59
4.1
Identification of Investigational Product(s) ················································59
4.1.1
Test Drug·················································································59
4.1.2
Comparative Drug·······································································60
4.2
Packaging and Labeling ······································································60
4.3
Study Drug Handling ·········································································60
4.4
Blinding ························································································61
4.5
Assignment and Allocation ··································································61
5
TREATMENTS AND EVALUATION························································62
5.1
Dosing and Administration of Study Drugs and Other Medication·····················62
5.1.1
Dose/Dose Regimen and Administration Period ····································62
5.1.2
Changes in Study Drug Dose ··························································63
5.1.2.1
Dose Adjustment Rules for Subjects Receiving Roxadustat ·················63
5.1.2.2
Dose Adjustment Rules for Subjects Receiving Darbepoetin Alfa ··········65
5.1.3
Previous and Concomitant Treatment·················································65
5.1.3.1
Previous Medication·······························································65
5.1.3.2
Concomitant Medication··························································66
5.1.3.3
Prohibited Medication·····························································68
5.1.3.4
Procedure and Non-drug Therapy Recording ··································68
5.1.4
Treatment Compliance··································································68
5.1.5
Rescue Therapy Guidelines ····························································69
5.1.6
Emergency Procedures··································································70
5.1.7
Restrictions During the Study··························································70
5.2
Demographics and Baseline Characteristics ···············································70
5.2.1
Demographics············································································70


Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 4 of 160
Version 3.0, Incorporating Substantial Amendment 2
5.2.2
Medical History··········································································70
5.2.3
Renal Ultrasound ········································································71
5.2.4
Diagnosis of the Target Disease, Severity, and Duration of Disease··············71
5.2.5
Further Laboratory Testing Prior to Randomization ································72
5.3
Efficacy Assessment··········································································72
5.3.1
Primary Efficacy Assessment··························································72
5.3.2
Additional Efficacy Assessments······················································72
5.3.2.1
Blood Pressure ·····································································72
5.3.2.2
Serum Lipid Panel ·································································72
5.3.3
Additional Assessments ································································72
5.3.3.1
Health Related Quality of Life Questionnaires·································72
5.3.3.2
Hospitalizations····································································74
5.3.3.3
Iron Status, HbA1c, CKD Progression and UACR····························74
5.3.3.4
Additional Assessments···························································74
5.4
Safety Assessment ············································································74
5.4.1
Vital Signs················································································74
5.4.1.1
Blood Pressure ·····································································74
5.4.1.2
Heart Rate ··········································································75
5.4.1.3
Respiratory Rate ···································································75
5.4.2
Adverse Events ··········································································75
5.4.2.1
Adverse Events of Possible Hepatic Origin ····································75
5.4.3
Laboratory Assessments································································76
5.4.3.1
HemoCue ···········································································76
5.4.3.2
Urinalysis ···········································································76
5.4.3.3
Central Laboratory·································································76
5.4.4
Physical Examination···································································78
5.4.5
Electrocardiogram (ECG) ······························································78
5.5
Adverse Events and Other Safety Aspects ·················································79
5.5.1
Definition of Adverse Events (AEs) ··················································79
5.5.2
Definition of Serious Adverse Events (SAEs) ·······································80
5.5.3
Criteria for Causal Relationship to the Study Drug ·································82
5.5.4
Criteria for Defining the Severity of an Adverse Event ····························82
5.5.5
Reporting of Serious Adverse Events (SAEs) ·······································82
5.5.6
Follow-up of Adverse Events··························································84
5.5.7
Procedure in Case of Pregnancy·······················································84


Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 5 of 160
Version 3.0, Incorporating Substantial Amendment 2
5.5.8
Emergency Procedures and Management of Overdose ·····························85
5.5.9
Supply of New Information Affecting the Conduct of the Study··················85
5.6
Test Drug Concentration ·····································································85
5.6.1
Blood Samples for Roxadustat PK Analysis ·········································86
5.7
Other Measurements, Assessments or Methods ···········································86
5.7.1
α1-AGP and Albumin in Serum ·······················································86
5.7.2
Archival of Serum Samples for Biomarker Analysis ·······························86
5.7.3
Archival of Urine Samples for Biomarker Analysis ································87
5.7.4
Optional Genotyping Sample ··························································87
5.8
Total Amount of Blood·······································································87
6
DISCONTINUATION············································································87
6.1
Discontinuation of Individual Subject(s)···················································87
6.2
Discontinuation of the Site···································································89
6.3
Discontinuation of the Study·································································89
7
STATISTICAL METHODOLOGY ···························································89
7.1
Sample Size····················································································89
7.2
Analysis Set····················································································90
7.2.1
Intent-to-Treat Set (ITT)································································90
7.2.2
Full Analysis Set (FAS) ································································90
7.2.3
Per Protocol Set (PPS) ··································································90
7.2.4
Safety Analysis Set (SAF)······························································91
7.2.5
Pharmacokinetic Analysis Set (PKAS) ···············································91
7.3
Demographics and Other Baseline Characteristics········································91
7.4
Analysis of Efficacy ··········································································91
7.4.1
Analysis of Primary Endpoint ·························································91
7.4.1.1
Primary Analysis···································································91
7.4.1.2
Secondary Analysis································································93
7.4.1.3
Subgroup Analysis·································································93
7.4.2
Analysis of Secondary Endpoints ·····················································93
7.4.2.1
Primary Analysis···································································93
7.4.2.2
Secondary Analysis································································95
7.4.2.3
Subgroup Analysis·································································95
7.4.3
Analysis of Additional Endpoints ·····················································95
7.5
Analysis of Safety·············································································96


Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 6 of 160
Version 3.0, Incorporating Substantial Amendment 2
7.5.1
Adverse Events ··········································································96
7.5.2
Laboratory Assessments································································97
7.5.3
Vital Signs················································································97
7.5.4
ECGs······················································································97
7.6
Analysis of Pharmacokinetics ·······························································97
7.7
Analysis of Pharmacodynamics ·····························································97
7.8
Protocol Deviations and Other Analyses···················································97
7.9
Interim Analysis···············································································98
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········98
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ····················99
8.1
Procedure for Clinical Study Quality Control ·············································99
8.1.1
Data Collection ··········································································99
8.1.2
Specification of Source Documents···················································99
8.1.3
Clinical Study Monitoring···························································· 100
8.1.4
Direct Access to Source Data/Documents·········································· 100
8.1.5
Data Management ····································································· 100
8.1.6
Protocol Deviations ··································································· 100
8.1.7
End of Trial in All Participating Countries········································· 101
8.2
Ethics and Protection of Subject Confidentiality········································ 101
8.2.1
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) / 
Competent Authorities (CA) ························································· 101
8.2.2
Ethical Conduct of the Study························································· 102
8.2.3
Informed Consent of Subjects ······················································· 102
8.2.3.1
Subject Information and Consent·············································· 102
8.2.3.2
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ··························· 102
8.2.4
Subject Confidentiality ······························································· 103
8.3
Administrative Matters ····································································· 103
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study ··· 103
8.3.2
Documents and Records Related to the Clinical Study ··························· 104
8.3.3
Protocol Amendment and/or Revision·············································· 105
8.3.4
Insurance of Subjects and Others···················································· 105
8.3.5
Signatory Investigator for Clinical Study Report·································· 105
9
QUALITY ASSURANCE······································································ 106
10
STUDY ORGANIZATION···································································· 106


Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
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10.1
Independent Data and Safety Monitoring Board (DSMB) ····························· 106
10.2
Independent Event Review Committee (IERC) ········································· 106
10.3
Other Study Organization ·································································· 106
11
REFERENCES ·················································································· 107
12
APPENDICES ··················································································· 110
12.1
List of Prohibited Concomitant Medication·············································· 110
12.2
Liver Safety Monitoring and Assessment ················································ 111
12.3
Instructions for Subjects Moving from Protocol v1.0 to Protocol v2.0··············· 114
12.3.1
Visit Schedule·········································································· 114
12.3.2
Dosing Instructions for Subjects Moving from Protocol v1.0 to Protocol 
v2.0······················································································ 114
12.3.3
ESA Rescue Therapy ································································· 115
12.4
Instructions for Subjects Requiring Dialysis············································· 116
12.4.1
Dosing ·················································································· 116
12.4.2
Dose Adjustment ······································································ 116
12.4.3
ESA Rescue Therapy ································································· 116
12.4.4
Supplemental Iron Use································································ 116
12.4.5
Health Related Quality of Life······················································· 116
12.4.6
Timing of Study Assessments ······················································· 116
12.5
Short Form-36 Health Survey (SF-36) ··················································· 117
12.6
Functional Assessment of Cancer Therapy- Anemia (FACT-AN)···················· 123
12.7
EuroQol Questionnaire (EQ-5D-5L)······················································ 126
12.8
Subjects’ Global Impression of Change (PGIC) Scale ································· 129
12.9
Work Productivity and Activity Impairment Questionnaire: Anemic Symptoms 
(WPAI:ANS) ················································································ 130
13
ATTACHMENT 1:   SUBSTANTIAL AMENDMENT 2 ······························· 132
14
SPONSOR’S SIGNATURES·································································· 160
List of In-Text Tables
Table 1
Schedule of Assessments·····································································34
Table 2
Treatment Arms and Dosing Frequency····················································50
Table 3
Expected Number of Subjects Randomized················································51
Table 4
Initial Dosing of Roxadustat (TIW)·························································63
Table 5
Dose Adjustment Rules for Roxadustat ····················································64
Table 6
Proposed Maximum Daily Dose of Statins Not to Be Exceeded························67


Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
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31 Mar 2016
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Table 7
Laboratory Tests ··············································································77
Table 8
Examples of Sampling Schedules for Population PK·····································86
Table 9
Sample Size Calculations per Treatment Arm·············································89
Table 10
Secondary Endpoints Fixed Sequence Testing Procedure································93
List of In-Text Figures
Figure 1
HIF-PHI Mechanism of Action······························································40


Sponsor: APEB
ISN/Protocol 1517-CL-0610
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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-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
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31 Mar 2016
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2.
COORDINATING INVESTIGATOR’S SIGNATURE
A Phase 3, Randomized, Open-Label, Active-Controlled Study to Evaluate the 
Efficacy and Safety of Roxadustat in the Treatment of Anemia in Chronic 
Kidney Disease Patients Not on Dialysis
ISN/Protocol 1517-CL-0610
Version 3.0 / Incorporating Substantial Amendment 2
31 March 2016
I have read all pages of this clinical study protocol for which Astellas is the Sponsor. I agree that it 
contains all the information required to conduct this study.
Coordinating Investigator:
Signature:
<Insert name, department/affiliation, name of institution>
Date (DD Mmm YYYY)
Printed Name:
Address:


Sponsor: APEB
ISN/Protocol 1517-CL-0610
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3.
INVESTIGATOR’S SIGNATURE
A Phase 3, Randomized, Open-Label, Active-Controlled Study to Evaluate the 
Efficacy and Safety of Roxadustat in the Treatment of Anemia in Chronic 
Kidney Disease Patients Not on Dialysis
ISN/Protocol 1517-CL-0610
Version 3.0 / Incorporating Substantial Amendment 2
31 March 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-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
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III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AE
Adverse Event
α1-AGP
Alpha 1-Acid Glycoprotein
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
AnS
Anemia Subscale
anti-HCV Ab
Anti-hepatitis C Virus 
APEB
Astellas Pharma Europe BV
ASP1517
= FG-4592 (codename of investigational product) or roxadustat (international 
nonproprietary name)
AST
Aspartate Aminotransferase
AT
Aminotransferases
AUC
Area under the plasma concentration – time curve
BIW
twice weekly
BL
Baseline
BL Hb
Baseline Hemoglobin (please refer to key definitions for information)
BP
Blood Pressure
CA
Competent Authority 
CBC
Complete Blood Count
CHMP
Committee for Medicinal Products for Human Use
CHOIR
Correction of Hemoglobin and Outcomes in Renal Insufficiency
CHr
Hemoglobin content of reticulocytes
CKD
Chronic Kidney Disease
CL/F
Apparent total body clearance
Cmax
Maximum concentration
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
ELISA
Enzyme-Linked ImmunoSorbent Assay
EOS
End of Study
EOT
End of Treatment
EPAR
European Public Assessment Report
EPO
Erythropoietin
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
EWB
Emotional Well being


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Abbreviations
Description of abbreviations
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) 
FWB
Functional Well-being
GCP
Good Clinical Practice
GDS
Global Data Science
GGT
Gamma Glutamyl Transferase
GMP
Good Manufacturing Practice
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
HIF-PH
Hypoxia-inducible factor prolyl hydroxylase
HIF-PHI
Hypoxia-inducible factor 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 Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IERC
Independent Event Review Committee
IMP
Investigational Medicinal Product
IMPD
Investigational Medicinal Product Dossier
IND
Investigational New Drug (Application)
INN
International Nonproprietary Name
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intra Uterine Device 
IUS
Intra Uterine System
ISN
International Study Number
IV
Intravenous(ly)
ka
First order absorption rate constant
KDIGO
Kidney Disease Improving Global Outcomes
KDOQI
Kidney Disease Outcomes Quality Initiative
kg
Kilogram
LDL
Low-density Lipoprotein
LA-CRF
Liver Abnormality Case Report Form
LFT
Liver Function Tests


Sponsor: APEB
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Abbreviations
Description of abbreviations
LOCF
Last Observation Carried Forward
LLN
Lower Limit of Normal 
LSO
Last Subject Out
MAP
Mean Arterial Pressure
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram 
MI
Myocardial Infarction
mL
Milliliters 
MMRM
Mixed Model of Repeated Measures
MTD
Maximum Tolerated Dose
NASH
Non-alcoholic steatohepatitis
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria for Adverse Events
NDD-CKD
Nondialysis-dependent chronic kidney disease
NONMEM
Non-linear Mixed Effects Modeling
OATP1B1
Organic anion transporting polypeptide 1B1
PCS
Physical Component Scores
PD
Pharmacodynamic
PF
Physical Functioning
PGIC
Patients’ Global Impression of Change
PHI
Protected Health Information
PK
Pharmacokinetic
PKAS
Pharmacokinetic Analysis Set
PL
Package Leaflet
PPK
Population Pharmacokinetics
PPKPD
Population Pharmacokinetic/Pharmacodynamic
PPS
Per Protocol Set
PR
Partial Response
PWB
Physical Well-being
QoL
Quality of Life
QRS 
QRS interval 
QTc
QT Interval corrected for heart rate
QW
Once weekly
RBC
Red Blood Cell
r-HuEPO
Recombinant Human Erythropoietin
RRT
Renal Replacement Therapy
SAE
Serious AE
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SC
Subcutaneous(ly)
SI
International System of Units 
SF-36
Short Form 36
SmPC
Summary of Product Characteristics
SOC
System Organ Class
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SWB
Social Well-being
t½
Apparent Terminal Elimination Half-life


Sponsor: APEB
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Abbreviations
Description of abbreviations
TBL
Total Bilirubin 
TEAE
Treatment-Emergent Adverse Event
TESAE
Treatment-Emergent Serious Adverse Event
TIBC
Total Iron-Binding Capacity
TIW
Three times weekly
tmax
Time to Attain Cmax
TREAT
Trial to Reduce Cardiovascular Events with Aranesp Therapy
TSAT
Transferrin Saturation (also known as FeSAT, iron saturation) 
UACR
Urine albumin/creatinine ratio
ULN
Upper Limit of Normal
USRDS
United States Renal Data System
VAS
Visual Analogue Scale
V/F
Apparent volume of distribution
VT
Vitality
WBC
White Blood Cell
Wk(s)
Week(s)
WPAI:ANS
Work Productivity and Activity Impairment questionnaire: Anemic Symptoms


Sponsor: APEB
ISN/Protocol 1517-CL-0610
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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 roxadustat or darbepoetin alfa, 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 where a 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 three Hb values: the last two Hb values during screening and the Hb 
value at the day of randomization (day 1), all assessed by the central 
laboratory. 
Discontinuation
A discontinuation is a subject who enrolled into the study and for whom study 
treatment is permanently discontinued prematurely for any reason. 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 randomization.
Hb Correction
Hemoglobin level ≥11.0 g/dL and a Hb increase from baseline 
BL Hb ≥1.0 g/dL as assessed by the central laboratory at two consecutive 
study visits separated by at least 5 days in the correction period.
Hb Response
Hemoglobin level ≥11.0 g/dL and a Hb increase from baseline 
BL Hb ≥1.0 g/dL in case BL Hb was > 8.0 g/dL, or an increase in Hb from 
BL Hb by ≥2.0 g/dL in case BL Hb was ≤8.0 g/dL, as assessed by the central 
laboratory at two consecutive study visits separated by at least 5 days.
Post study 
follow-up
Period of time from EOS visit to projected week 108 or until consent 
withdrawn. This period is only applicable to subjects who prematurely 
discontinued treatment. These subjects will be followed up every 6 months for 
vital status, serious adverse events (SAEs), cardiovascular and thromboembolic 
adverse events (AEs). 
Randomization
The process of assigning trial subjects to treatment or control groups using an 
element of chance to determine assignments in order to reduce bias.
(After randomization subjects receive either roxadustat or darbepoetin alfa 
from day 1 until End Of Treatment [EOT].) 
Rescreening
Process of repeating screening. If subject fails screening they may be re-
screened once if deemed appropriate; all screening procedures will be repeated. 
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, 


Sponsor: APEB
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Terms
Definition of terms
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.”
Screen failure
Potential subject who did not meet one or more inclusion and/or exclusion
criteria required for participation in a trial. See also screening of subjects.
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
TEAE
A treatment-emergent adverse event (TEAE) is an AE that started during the 
treatment period and was not present prior to the first dose of study drug, or the 
AE was present prior to the first dose of study drug but increased in severity 
during the treatment period. An AE that occurs more than 28 days after the last 
dose of study medication will not be counted as a TEAE.
Treatment period
It is the period of time - between first dose of the test drug and EOT visit -
where major interests of protocol objectives are observed, and where 
roxadustat (study drug) or darbepoetin alfa (comparative drug) is given to a 
subject. The treatment period consists of the correction and maintenance 
periods.
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values


Sponsor: APEB
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IV.
SYNOPSIS
Date and Version # of Protocol Synopsis:
31 March 2016 / Version 3.0
Sponsor:
Astellas Pharma Europe B.V. (APEB)
Protocol Number:
1517-CL-0610
Name of Study Drug:
Roxadustat (ASP1517/FG-4592)
Phase of Development:
Phase 3
Title of Study:
A Phase 3, Randomized, Open-Label, Active-Controlled Study to Evaluate the Efficacy and Safety of 
Roxadustat in the Treatment of Anemia in Chronic Kidney Disease Patients Not on Dialysis
Planned Study Period:
From 1Q2014 to 2Q2021
Study Objectives:
The primary objective of this study is to evaluate the efficacy of roxadustat compared to darbepoetin 
alfa in the treatment of anemia in nondialysis-dependent Chronic Kidney Disease (NDD-CKD) 
subjects.
The secondary objectives of this study are to:
Evaluate the safety of roxadustat compared to darbepoetin alfa in the treatment of anemia in 
NDD-CKD subjects.
Evaluate the health-related quality of life (HRQoL) benefit of roxadustat compared to darbepoetin 
alfa in the treatment of anemia in NDD-CKD subjects.
Planned Total Number of Study Centers and Locations:
Approximately 200 study centers globally.
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 on dialysis. 
Number of Subjects to be Randomized:
Approximately 570 subjects will be randomized; this will lead to approximately 450 subjects in the 
Per Protocol Analysis Set (PPS).
Study Design Overview:
This is a multicenter, randomized, open-label, active-controlled study.
The study will consist of three study periods:
Screening period: up to 6 weeks
Treatment period: 104 weeks
Follow-up period: 4 weeks
Subjects that have discontinued treatment prior to their projected week 104 will continue to be 
followed for vital status, serious adverse events (SAEs), cardiovascular and thromboembolic adverse 
events (AEs) in a post study follow-up period.
During the course of the study, visits and assessments will be performed as defined in the Schedule of 
Assessments. 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 (EOT).
Subjects will receive study treatment - roxadustat or darbepoetin alfa - for 104 weeks.


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Screening Period
During the screening period (up to 42 days duration), hemoglobin (Hb) levels will be assessed in a 
central laboratory for matching the inclusion criterion (mean of two Hb values must be ≤10.5 g/dL, 
see inclusion criterion 4 below). Subjects meeting all of the inclusion criteria and none of the 
exclusion criteria will be randomized at day 1, which marks the end of screening period and start of 
the treatment period. If a subject fails screening, the subject may be rescreened once (immediately or 
later) if deemed appropriate by the investigator. The subject must be re-consented. A new 
rescreening period will start and all screening procedures must be repeated.
Treatment Period (Correction Period and Maintenance Period)
The treatment period consists of a correction period and a maintenance period. Subjects are 
randomized to 1 of 2 treatment arms in a 1:1 ratio: one treatment arm will receive roxadustat 
administered orally and one treatment arm will receive darbepoetin alfa administered subcutaneously 
(SC) or intravenously (IV). Study treatment administration is implemented in an open-label manner.
Table 1: Treatment Arms and Dosing Frequency
Treatment Arm
Study Treatment
Dosing Frequency in Treatment Period
Correction Period
Maintenance Period
1
Roxadustat
TIW
TIW
2
Darbepoetin alfa
Dosing per European (EU) SmPC
SmPC = Summary of Product Characteristics; TIW = three times weekly
Correction Period
The aim of the correction period is to correct Hb levels to ≥11.0 g/dL and a Hb increase from 
BL Hb ≥1.0 g/dL as measured at two consecutive study visits separated by at least 5 days (as 
assessed by central laboratory).
Dosing and dose adjustments of roxadustat will follow prespecified dose adjustment rules. Dosing 
and dose adjustments of darbepoetin alfa will be per EU approved Summary of Product 
Characteristics (SmPC).
Once Hb is corrected (Hb ≥11.0 g/dL or higher, and a Hb increase from BL Hb ≥1.0 g/dL) the 
subjects 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 
level between 10.0 g/dL and 12.0 g/dL.
Dose adjustments of roxadustat will follow prespecified dose adjustment rules.
Dose adjustments of darbepoetin alfa will be per EU approved Summary of Product Characteristics 
(SmPC).
Follow-up Period
After the treatment period, subjects proceed to the 4-week follow-up period.
Post Study Follow-up (for premature treatment discontinued subjects only)
Subjects that have prematurely discontinued study treatment will complete the EOT visits (EOT visit 
and EOT + 2 weeks visit) and end of study (EOS) visit. Thereafter, these subjects (only if they have 
taken at least one dose of study drug) will continue to be followed up every 6 months for vital status, 
SAEs, cardiovascular and thromboembolic AEs until their projected date of completion of the follow-
up period (i.e., projected week 108 date) or until consent withdrawn.
Data Safety Monitoring Board
A Data Safety Monitoring Board (DSMB) will review prespecified safety data periodically in 
collaboration with the Sponsor to ensure subject safety. Details will be specified in a DSMB charter.


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Independent Event Review Committee
An Independent Event Review Committee (IERC) will adjudicate all prespecified cardiovascular and 
cerebrovascular events in a blinded manner to ensure a consistent safety assessment. Details will be 
specified in an IERC charter.
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 has been 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 CKD, with Kidney Disease Outcomes Quality Initiative (KDOQI) 
Stage 3, 4 or 5, not on 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 two most recent (prior to randomization) Hb values during the 
screening period, obtained at least 4 days apart, must be ≤10.5 g/dL, with a difference of 
≤1.0 g/dL. The last Hb value must be within 10 days prior to randomization.
5.
Subject is deemed suitable by the investigator for treatment with erythropoiesis stimulating agents 
(ESA) using the criteria specified in the Kidney Disease Improving Global Outcomes (KDIGO)
2012 recommendation considering the rate of fall of Hb concentration, prior response to iron 
therapy, the risk of needing a transfusion, the risks related to ESA therapy and the presence of 
symptoms attributable to anemia.
6.
This criterion has been removed.
7.
This criterion has been removed.
8.
Subject has a serum folate level ≥ lower limit of normal (LLN) at screening.
9.
Subject has a serum vitamin B12 level ≥LLN at screening.
10. Subject’s alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are ≤3 x upper 
limit of normal (ULN), and total bilirubin (TBL) is ≤1.5 x ULN.
11. Subject’s body weight is 45.0 kg to a maximum of 160.0 kg.
12. Female subject is either:
Of non-childbearing potential:
post-menopausal (defined as at least 1 year without any menses) prior to screening,
or
documented surgically sterile
Or if of childbearing 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 continue to do so for 28 days after 
final study treatment administration. If required by local law, 2 highly effective methods of 
birth control must be used, 1 of which must be a barrier method.
13. Female subject must not be breastfeeding at screening or throughout the study period, and for 
28 days after the final study treatment administration.


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14. Female subject must not donate ova starting at screening and throughout the study period and for 
28 days after final study drug administration.
15. Male subject and their female spouse/partner(s) who are of childbearing potential must be using a 
highly effective form of birth control* starting at screening and continue to do so throughout the 
study period and for 12 weeks after final study treatment administration. If required by local law, 
2 highly effective methods of birth control must be used, 1 of which must be a barrier method.
16. Male subject must not donate sperm starting from screening, throughout the study period and up 
to 12 weeks after final study drug administration.
17. Subject agrees not to participate in another interventional study from the time of signing informed 
consent until the End of Study visit (EOS).
*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.
Waivers to the inclusion criteria will NOT be allowed.
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 received any dose of IV iron within 6 weeks prior to randomization.
3.
Subject has received a Red Blood Cell (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 a known 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 undergo elective surgery that is expected to lead to significant blood loss 
during the study period 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 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., deep vein thrombosis or pulmonary embolism) within 
12 weeks prior to randomization.


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15. Subject has one or more contraindications for treatment with darbepoetin alfa:
Uncontrolled hypertension in the opinion of the investigator, or two or more blood pressure 
values of systolic blood pressure (SBP) ≥160 mmHg or diastolic blood pressure (DBP) 
≥95 mmHg (within 2 weeks prior to randomization).
Known hypersensitivity to darbepoetin alfa, recombinant human erythropoietin, or any of the 
excipients.
16. Subject has a diagnosis or suspicion (e.g., complex kidney cyst of Bosniak Category 2F or higher) 
of renal cell carcinoma as shown on renal ultrasound within 12 weeks prior to randomization.
17. Subject has a history of malignancy, except for the following: cancers determined to be cured or 
in remission for ≥5 years, curatively resected basal cell or squamous cell skin cancers, cervical 
cancer in situ, or resected colonic polyps.
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 that is 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 or retinal vein occlusion.
21. Subject has had any prior organ transplant (that has not been explanted),  subject is scheduled for 
organ transplantation, or subject is likely to initiate renal replacement therapy including dialysis 
within the first year of the study in the opinion of the investigator.
22. Subject will be excluded from participation if any of the following apply:
a. subject has received investigational therapy within 30 days or 5 half lives or limit set by 
national law, whichever is longer, prior to initiation of screening, or
b. any condition which, in the investigator’s opinion, makes the subject unsuitable for study 
participation.
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. Subject has 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.
Waivers to the exclusion criteria will NOT be allowed.
Investigational Product:
Roxadustat (ASP1517/FG-4592)

Tablets

Strengths of 20 mg, 50 mg and 100 mg
Mode of Administration:

Oral
Doses:
The initial study drug (roxadustat) dose (per dose amount) is based on the tiered, weight-based dosing 
scheme shown in the table below:




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
Next dose adjustment review is 4 weeks after dose resumption and in 4-weekly intervals 
thereafter.
Dose Adjustment for Excessive Hematopoiesis
If at any time during the treatment period Hb increases by > 2.0 g/dL within 4 weeks:

The dose should be reduced by one dose step

Only one dose reduction for excessive hematopoiesis is recommended within a period of 4 weeks.
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.
Comparative Drug:

Darbepoetin alfa (Aranesp®) solution for injection in a pre-filled syringe.

Range of strengths: 20, 30, 40, 60 and 100 μg.
Mode of Administration:

Subcutaneous (SC) or intravenous (IV) as judged appropriate by the investigator.
Dose:
Darbepoetin alfa dosing is to follow the EU SmPC. All administrations will be performed by the 
investigator or a qualified member of the site staff or, after 36 weeks of treatment, by the subject 
themselves or caregiver, e.g., relative, if well trained and willing to self-administer.

Initial dose:
0.45 μg/kg body weight as a single SC or IV injection once weekly; alternatively 0.75 μg/kg 
body weight SC once every two weeks.

Dose adjustment:
If the increase in Hb is inadequate (less than 1.0 g/dL within 4 weeks) increase the dose by 
approximately 25%. During the correction period, dose increases must not be made more 
frequently than once every four weeks; during the maintenance period, dose changes should not 
be made more frequently than every two weeks.
If the rise in Hb is greater than 2.0 g/dL in 4 weeks, reduce the dose by approximately 25%.
Once the target Hb level has been achieved with once every 2-week dosing, darbepoetin alfa 
may be administered SC once monthly using an initial dose equal to twice the previous once 
every 2-week dose.
All dose adjustments are made based on Hb values assessed using the HemoCue® device.
Target of treatment is achieving Hb response (defined as Hb values of ≥11.0 g/dL and Hb increase 
from BL Hb ≥1.0 g/dL at 2 consecutive study visits separated by at least 5 days [as assessed by the 
central laboratory]) and thereafter maintaining Hb in the target range of 10.0 to 12.0 g/dL.
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.
1.
RBC Transfusion (for all subjects)
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 


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investigator is of the opinion that the blood transfusion is a medical necessity. Study treatment may be 
continued even if a blood transfusion has been administered.
2.
ESA (only for subjects treated with roxadustat)
If the investigator considers administration of ESA as a medical necessity, darbepoetin alfa may be 
initiated if the following criteria are met:

the subject’s Hb level is < 9.0 g/dL (HemoCue) as confirmed at two consecutive visits,
and

the subject’s Hb level has not responded adequately despite 2 or more roxadustat dose 
increases in the previous 8 weeks, or the roxadustat dose reached the maximum dose limit,
and

reducing the risk of alloimmunization in transplant eligible subjects and/or reduction of other 
RBC transfusion-related risks is a goal.
Prior to the initiation of darbepoetin alfa, the subject’s Hb response, as well as factors influencing the 
Hb response, such as iron status, inflammatory status, hemolysis, blood loss or other potential reasons 
for Hb decrease should be considered and, where applicable, be addressed by the investigator.
The subject may continue in the study while on rescue treatment with darbepoetin alfa, however, it is 
not allowed to administer roxadustat during the same time period.
The course of darbepoetin alfa (i.e., the amount that may be administered) will be limited by duration 
of therapy and effect on Hb. The course of darbepoetin alfa rescue treatment will not exceed 4 weeks 
in duration, and darbepoetin alfa rescue will be stopped as soon as Hb ≥9.0 g/dL. To continue study 
participation, treatment with roxadustat study drug should be resumed within one week after the last 
administration of darbepoetin alfa at the dose level the subject was on prior to initiating darbepoetin 
alfa rescue therapy.
If a subject requires a second course of rescue darbepoetin alfa, the subject must be discontinued from 
treatment.
Doses:
The doses of rescue therapies are per investigator’s discretion.
Emergency Procedure:
Therapeutic Phlebotomy
If there are clinical concerns for a subject’s high Hb levels, the investigator may decide to perform a 
therapeutic phlebotomy instead of, or in addition to, a study treatment dose hold (stop dosing). The 
therapeutic phlebotomy should be documented in the eCRF and source documentation, and discussed 
with the Medical Monitor.
Concomitant Medication Restrictions and/or Requirements:
Supplemental Iron Use
For subjects receiving roxadustat
i.
Oral iron
For subjects receiving roxadustat, oral iron is recommended for supplementation to support 
erythropoiesis and as the first-line treatment for iron deficiency, unless the subject is 
intolerant to this treatment. The recommended daily dose is 200 mg of elemental iron.
Administration of roxadustat between -1 hour and +1 hour of intake of oral iron is not 
recommended.
ii.
Intravenous iron
For subjects receiving roxadustat, IV iron supplementation is only allowed if all of the 
following criteria are met:


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
The subject has not responded adequately to 2 or more dose increases of roxadustat or has 
reached the maximum dose limit, and

The subject has iron deficiency (either ferritin < 100 ng/mL [< 220 pmol/L] or 
TSAT < 20%) or the subject does not tolerate oral iron therapy.
Treatment with roxadustat may continue during IV iron administration. Discontinuation of 
IV iron administration is recommended once ferritin levels are ≥100 ng/mL (≥220 pmol/L)
and TSAT ≥20%.
For subjects receiving darbepoetin alfa
For subjects treated with darbepoetin alfa, oral or IV iron supplementation is required to maintain iron 
repletion. IV iron should only be administered if ferritin is < 100 ng/mL (< 220 pmol/L) or TSAT is 
< 20%. IV iron may be administered per local practice. Discontinuation of IV iron therapy is 
recommended once ferritin levels are ≥100 ng/mL (≥220 pmol/L) and TSAT ≥20%.
Anti-hypertensive Medication
To avoid confounding effects on study endpoints, changes to anti-hypertensive medications should be 
minimized, and made only if deemed medically necessary by the investigator or if pre-specified 
changes in blood pressure are met.
Prohibited Medication
The following medications are prohibited during the period identified:

Any ESA: within 12 weeks prior to randomization until EOT.

IV iron: within 6 weeks prior to randomization.

RBC transfusion: within 8 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 screening until EOS.

Roxadustat or another HIF-PHI: at any time prior to randomization. After randomization any 
HIF-PHI other than roxadustat, as allocated by randomization, until EOS.

Iron-chelating agents (e.g., deferoxamine, deferiprone, or deferasirox therapy): from 4 weeks 
prior to randomization until EOS.

Androgens from day of randomization until EOS.

Dapsone in any dose amount or chronic use of acetaminophen/paracetamol >2.0 g/day from the 
day of randomization until EOS.
Duration of Treatment:
104 weeks
Formal Stopping Rules:
Subjects should be prematurely discontinued from 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 study 
treatment.

Significant noncompliance with study procedures, as determined by principal investigator and/or 
Sponsor.

Pregnancy in a study subject.

Subjects randomized to roxadustat: requirement of a second course of rescue therapy with 
darbepoetin alfa deemed necessary by the investigator based upon the criteria for use of rescue 
treatment.


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
Subject receives an organ transplant.
Subjects that have prematurely discontinued study treatment will complete the EOT visits (EOT visit 
and EOT + 2 weeks visit) and EOS visit. Thereafter, these subjects who have taken at least one dose 
of study drug will continue to be followed up every 6 months for vital status, SAEs, cardiovascular 
and thromboembolic AEs until their projected date of completion of follow-up period (i.e., projected 
week 108 date) or until consent is 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 a study subject.

The Sponsor may decide to prematurely stop the study, e.g., for safety considerations.
Endpoints for Evaluation
Primary:
The primary efficacy variable is:

Hb response defined as: Hb ≥11.0 g/dL and a Hb increase from BL Hb by ≥1.0 g/dL in any 
subject with BL Hb > 8.0 g/dL, OR an increase from BL Hb by ≥2.0 g/dL in any subject with 
BL Hb ≤8.0 g/dL as measured at 2 consecutive visits separated by at least 5 days during the first 
24 weeks of treatment without administration of rescue therapy prior to Hb response.
Key Secondary:

Hb change from BL to the average Hb of weeks 28 to 36, without having received rescue therapy 
within 6 weeks prior to and during this 8-week evaluation period.

Change from BL in Low-Density Lipoprotein (LDL) cholesterol to the average LDL cholesterol 
of weeks 12 to 28.

Mean monthly IV iron use (mg) per subject during weeks 1 to 36 (monthly defined as a period of 
4 weeks). 

Change from BL in SF-36 Physical Functioning (PF) sub-score to the average PF sub-score of 
weeks 12 to 28.

Change from BL in SF-36 Vitality (VT) sub-score to the average VT sub-score of weeks 12 
to 28.

Blood pressure effect: 
o Change from BL in mean arterial pressure (MAP) to the average MAP value of 
weeks 20 to 28.
o Occurrence and time to occurrence of hypertension (defined as either systolic blood pressure 
[SBP] > 170 mmHg AND an increase from BL of ≥20 mmHg SBP or diastolic blood 
pressure [DBP] >110 mmHg AND an increase from BL of ≥15 mmHg DBP on 
2 consecutive visits) during weeks 1 to 36.
Additional Secondary:
Hb correction and maintenance:

Hb change from BL to the average Hb value of weeks 28 to 52 regardless of the use of rescue 
therapy.

Time (weeks) to achieve the first Hb response as defined by primary endpoint.

Hb response defined as: Hb ≥11.0 g/dL and a Hb increase from BL Hb by ≥1.0 g/dL in any 
subject with BL Hb > 8.0 g/dL, OR an increase from BL Hb by ≥2.0 g/dL in any subject with 
BL Hb ≤8.0 g/dL as measured at 2 consecutive visits separated by at least 5 days during the first 
24 weeks of treatment regardless of administration of rescue therapy prior to Hb response.


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
Hb averaged over weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104, without use of rescue therapy 
within 6 weeks prior to and during this evaluation period.

Hb value and Hb change from BL at each post-dosing time point.

Hb change from BL to the average Hb value of weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104, 
regardless of the use of rescue therapy.

Proportion of Hb values within 10.0 to 12.0 g/dL in weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104, 
without use of rescue therapy within 6 weeks prior to and during this 8-week evaluation period.
Hospitalizations

Occurrence (number) of hospitalization(s).

Number of days of hospitalization.
Rescue therapy use

Having received rescue therapy (either RBC transfusions [for all subjects] or darbepoetin alfa use 
[for roxadustat treated subjects only])

Having received RBC transfusions.

Number of RBC packs per subject.

Volume of RBC transfused per subject.
Changes in cholesterol levels

Change from BL to each post-dosing scheduled measurement 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 to 28, 
and weeks 36 to 52 of treatment).
Blood pressure effect

Occurrence of achieved antihypertensive treatment goal (SBP < 130 mmHg systolic and 
DBP < 80 mmHg) based on the mean SBP and mean DBP calculated over weeks 12 to 28 and 
36 to 52 of treatment with study drug.
HRQoL and EQ5D 5L benefits

Change from BL to the average value of weeks 12 to 28 and 36 to 52 in:
o Physical Component Score (PCS) 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 VAS Score
o WPAI:ANS Score

PGIC (qualitatively by assessment)
Iron, HbA1c, and CKD progression

Changes from BL to each scheduled measurement in:
o Serum ferritin
o TSAT
o HbA1c level
o Fasting blood glucose
o eGFR (including eGFR slope over time)
o Urine albumin/creatinine ratio

Serum creatinine having doubled during the study in comparison with baseline


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
Occurrence of End Stage Renal Disease (ESRD)
Safety:
Safety will be assessed by evaluating the following:

Occurrence of AEs, SAEs, treatment emergent adverse events (TEAEs), treatment emergent 
serious adverse events (TESAEs), and clinically significant changes in laboratory values from BL.

Changes from BL in vital signs, electrocardiogram (ECG) findings, and clinical laboratory values.

Occurrence of prespecified adjudicated cardiovascular and cerebrovascular events.
Statistical Methods
Sample Size Justification:
Approximately 570 subjects will be randomized to receive roxadustat or darbepoetin alfa as follows:
Table 4: Sample Size Calculations per Treatment Arm 
Treatment Group
Protocol version 1.0
Protocol versions 2 and 3
Total
Randomized
PPS
Randomized†
PPS
Randomized
PPS
Roxadustat
100
80
210
168
310
248
Darbepoetin alfa
50
40
210
168
260
208
Total
150
120
420
336
570
456
† The number of subjects under protocol v2 and v3 will depend on the number of subjects randomized under 
protocol v1.
Randomization will be stratified by the following four factors:

Region: region A versus region B*
* Assignment to region will be determined based on health care 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).
Assuming that the PPS analysis will consist of 80% of subjects in the Full Analysis Set (FAS), 
570 randomized subjects in the FAS will lead to 456 subjects in the PPS. Two hundred and forty 
eight (248) subjects for the roxadustat treatment group and 208 subjects for the darbepoetin alfa 
treatment group will provide at least 98% test power to demonstrate statistically non-inferiority of 
roxadustat versus darbepoetin alfa in the primary endpoint assuming that the proportion of subjects 
with response in both groups is the same and at least 80% and a non-inferiority margin for the 
difference of proportions of 15%. The power for the sensitivity analysis of post-amendment data 
(336 subjects) will be at least 93%.
Analysis Sets
The following analysis sets are defined and will be used for the statistical analysis:

Intent-to-Treat (ITT)

Full Analysis Set (FAS)

Per-Protocol Set (PPS)

Safety Analysis Set (SAF)

Pharmacokinetic Analysis Set (PKAS)
Efficacy:
Analysis of Primary Endpoint 
The difference in the proportion of responders in the primary efficacy endpoint between pooled 
roxadustat and darbepoetin alfa will be calculated using Mattinen & Nurminen approach adjusting for 


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the stratification factors. The primary hypothesis to be tested for the primary efficacy analysis is:
H0: Hb responder rate in the pooled roxadustat group < Hb responder rate in the darbepoetin alfa 
group minus 15%
versus
H1: Hb responder rate in the pooled roxadustat group ≥Hb responder rate in the darbepoetin alfa 
group minus 15%
This null hypothesis will be rejected if the two-sided 95% confidence interval for the difference of 
proportions lies entirely above -15%.
In addition, a 95% CI will be calculated for the proportion of responders on roxadustat and
darbepoetin alfa based on the exact method of Clopper-Pearson. Sensitivity analyses will be 
conducted to assess the consistency of the results before and after protocol amendments 1 and 2.
Efficacy:
Analysis of Key Secondary Endpoints
Once the primary hypothesis has been rejected for the primary endpoint, the key secondary variables 
will be tested using a fixed sequence testing procedure as follows:
1.
Hb change from BL to the average Hb of weeks 28 to 36 (non-inferiority of pooled roxadustat 
versus darbepoetin alfa) without having received rescue therapy within 6 weeks prior to and 
during this 8-week evaluation period. The non-inferiority margin for the difference between 
groups is 0.75 g/dL.
2.
LDL cholesterol change from BL to the average of weeks 12 to 28 (superiority of pooled 
roxadustat versus darbepoetin alfa).
3.
Mean monthly IV iron (mg) use per subject during weeks 1 to 36 (superiority of pooled 
roxadustat versus darbepoetin alfa).
4.
SF-36 PF sub-score change from BL to the average of weeks 12 to 28 (non-inferiority of pooled 
roxadustat versus darbepoetin alfa). The non-inferiority margin is fixed as a difference of 3 points.
5.
SF-36 VT sub-score change from BL to the average of weeks 12 to 28 (non-inferiority of pooled 
roxadustat versus darbepoetin alfa). The non-inferiority margin is fixed as a difference of 3 points.
6.
MAP change from BL to the average MAP of weeks 20 to 28 (non-inferiority of pooled 
roxadustat versus darbepoetin alfa). The non-inferiority margin for the difference between groups 
is 1 mmHg.
7.
Incidence of hypertension (non-inferiority of pooled roxadustat versus darbepoetin alfa). The non-
inferiority margin is fixed as a hazard ratio of 1.3.
8.
MAP change from BL to the average MAP of weeks 20 to 28 (superiority of pooled roxadustat 
versus darbepoetin alfa).
9.
Incidence of hypertension (superiority of pooled roxadustat versus darbepoetin alfa).
The primary analysis set will be PPS for the non-inferiority tests and FAS for the superiority tests.
Pharmacokinetics:
Population PK data will be generated for roxadustat from a timed blood sampling scheme. All details 
of the population PK (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 or population 
pharmacokinetic/pharmacodynamic (PPKPD) modeling. When deemed necessary, data from this 
study may be combined with data from other studies. Results will be reported in a separate PPKPD 
modeling report.


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Safety:
Safety analyses will be performed using the Safety Analysis Set (SAF). Safety parameters include 
AEs, SAEs, laboratory parameters (with special emphasis on excessive Hb response and liver 
function tests [LFTs]), vital signs, and ECG parameters.
The number and percentage of subjects reporting TEAEs and TESAEs in each treatment group will be 
tabulated. Descriptive statistics will be presented for laboratory parameters, vital signs values and 
ECG parameters by visit and for the changes from BL to each visit.
The statistical method for analysis of adjudicated safety data will be detailed in a pooled
cardiovascular safety Statistical Analysis Plan (SAP).
Safety data and dosing decisions will be monitored on an ongoing basis. Ongoing review of safety 
data will be conducted by an independent DSMB.
Interim Analyses:
An interim analysis will be performed when all subjects have completed 36 weeks of treatment;
efficacy and safety data will be analyzed and reported, excluding the endpoints measured after 
36 weeks. Since all primary and secondary analyses have been defined over this period of time, no 
multiplicity adjustment is required as the information fraction at the interim analysis is 100%.
In addition, a descriptive analysis on both safety and efficacy will be performed to provide 
information from this study for regulatory filings of roxadustat in case the planned interim analysis 
has not been reached. This will include only descriptive statistics by arm (i.e., without formal 
hypothesis testing).
Once the study is completed, efficacy and safety will be analyzed again and reported including the 
complete study treatment of 104 weeks.


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V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS
Flow Chart
STUDY DESIGN 3.0


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Table 1
Schedule of Assessments
Assessments
Screening 
Period
Treatment Period
(Correction Period and Maintenance Period)
Follow-up Period
Unscheduled 
Visits
Post study 
Follow-up c
Visit / Week
Up to6 
weeks a
Day 1b
Weekly
(wks 1 - 2)
± 2 days
Every 2 Weeks 
(wks 4 - 24)
± 2 days
Every 4 Weeks 
(wks 28 - 100)
± 3 days
EOT c
(wk 104)
± 3 days
EOTc + 2 wks
± 3 days
EOS c
(EOT + 4 wks)
± 3 days
Every 6 months 
until projected 
wk 108
S1
S2
Written informed consent
X
Randomization
X
Eligibility criteria
X
X
Demographics
X
Medical history
X
Physical examination  
X
X
wks 12d, 24d 
wks 36d, 52d, 76d
X
Xd
Od
Heighte, weight
X
X
wks 12, 24
wks 36, 52, 76
X
X
O
Blood pressuref, heart ratef, respiratory rateg
X
X
X
X
X
X
X
X
O
CBC with WBC diff, red cell indices and 
platelets
X
X
X
wks 4, 8, 12, 20
wks 28, 36, 44, 52, 
60, 68, 76, 84, 92, 
100
X
X
O
Hemoglobinh
Xi
X
X
X
Oi1
HemoCue assessmentj
X
X
X
X
O
Reticulocyte count and Hb in reticulocytes 
(CHr)
X
X
X
wks 4, 6, 8, 12, 16, 
20
wks 28, 36, 44, 52, 
60, 68, 76, 84, 92, 
100
X
X
O
12-lead ECG 
X
X
wks 12, 24
wks 36, 52, 76
X
O
Serum chemistry
X
X
wks 4, 8, 12, 20
wks 28, 36, 44, 52, 
60, 68, 76, 84, 92, 
100
X
X
X
O
LFTsk
wk 2
wks 6, 16
O
Renal ultrasoundl
X
O
Serum lipid panelm
X
X
wks 4, 8, 12, 20 wks 28, 36, 44, 52, 
68, 84
X
X
O
Serum iron, ferritin, TIBC, TSAT
X
X
wks 4, 8, 12, 20
wks 28, 36, 44, 52, 
60, 68, 76, 84, 92, 
100
X
X
O
HbA1c
X
X
wk 12
wks 28, 36, 44, 60, 
84
X
X
O
Vitamin B12, folate
X
HIV immunoassay, HBsAg, 
anti-HCV antibody
X
Serum pregnancy testn
X
wks 12, 24
wks 36, 48, 60, 72, 
84, 96
X
O
Table continued on next page


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Assessments
Screening 
Period
Treatment Period
(Correction Period and Maintenance Period)
Follow-up Period
Unscheduled 
Visits
Post study 
Follow-up c
Visit / Week
Up to6 
weeks a
Day 1b
Weekly
(wks 1 - 2)
± 2 days
Every 2 Weeks 
(wks 4 - 24)
± 2 days
Every 4 Weeks 
(wks 28 - 100)
± 3 days
EOT c
(wk 104)
± 3 days
EOTc + 2 wks
± 3 days
EOS c
(EOT + 4 wks)
± 3 days
Every 6 months 
until projected 
wk 108
S1
S2
eGFRo
X
X
wk 20
wks 36, 52, 68, 84
X
X
O
hs-CRP
X
wks 4, 12, 20
wks 36, 52
X
X
Archival serum samples for biomarkersp
X
wks 4, 12, 20
wks 52, 76
Blood sample for PKq
wks 2 to 8
Genotypingr
O
QoL questionnairess
X
wks 8, 12 
wks 28, 36, 52, 76
X
O
Urinary testingt
X
wks 12, 24
wks 36, 52, 64, 76, 
88
X
O
Archival urine samples for biomarkers
X
wk 24
wks 52, 76
Study drug dispensingu
├────────────────────────────┤
O
Dose adjustment reviewv
X
X
X
O
Hospitalization recordingw
X
X
◄─────────────────────────────────────────────────────────────►
X
AE recording
X
X
◄─────────────────────────────────────────────────────────────►
Concomitant medication, procedure and non-
drug therapy recording
X
X
◄─────────────────────────────────────────────────────────────►
Vital status, SAEs, cardiovascular and 
thromboembolic AEsw
X
S1/S2 = Screening visit 1and 2; EOT = End of Treatment; EOS = End of Study; Wk(s) = Week(s); X = mandatory test/assessment; O = optional test/assessment.
Note: see Appendix 12.4 Instructions for Subjects Requiring Dialysis.
a The requirement of a 4-day separation between the screening Hb values defines the minimum duration of the screening period. The maximum duration of the screening period is 6 
weeks. Sites are recommended to schedule the two screening visits in the shortest time span possible.
b All study assessments are to be performed prior to first study drug administration.
c In case of premature treatment discontinuation or withdrawal during the treatment period, subjects will complete the EOT visits (EOT visit and EOT + 2 weeks visit) and EOS 
visit. Thereafter, subjects who have taken at least one dose of study drug will continue to be followed up at a 6-monthly frequency for vital status, SAEs, cardiovascular and 
thromboembolic AEs until their projected date of completion of the follow-up period (i.e., projected week 108 date) or until consent withdrawn.
d Targeted physical examination only (e.g., respiratory and cardiovascular).
e Height measurement only required at first screening visit.
Footnotes continued on next page


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f Blood pressure and heart rate measured singly during the screening period, and in triplicate at all other visits. It is recommended during the treatment period that measurements 
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 and heart rate will be recorded prior to and after dialysis (hemodialysis [HD]/hemodiafiltration [HDF] subjects only).
g Respiratory rate measured singly during screening period and all other visits. It is recommended during the treatment period that 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 Separate Hb should be collected at all the visits where Complete Blood Count (CBC) is not collected (i.e., Hb at weeks 6, 10 until the end of the study).
i An additional (third) Hb value may be collected if necessary. Only for subjects who are switched from protocol version 2.0 to 3.0 during (re) screening can a fourth Hb value be 
collected, as was applicable under protocol version 2.0.
i1 If during an unscheduled visit, Hb needs to be assessed, this should always be done with the HemoCue AND a central laboratory Hb assessment.
j If during an unscheduled visit Hb needs to be assessed, this should always be done with the HemoCue AND a central laboratory Hb assessment. This HemoCue assessment should 
be done on the blood sample that is collected for Hb analysis for the central laboratory.
k In addition to LFTs collected as part of Serum Chemistry, LFTs will separately be collected at the indicated weeks.
l Renal ultrasound examination within 12 weeks prior to randomization. Not required if results of a previous renal ultrasound (or other renal imaging modality such as CT scan or 
MRI) within 12 weeks prior to randomization is available and ruling out renal cell carcinoma. If other imaging modality, a conclusive report on the kidney should be available.
m Fasting whenever possible.
n Collect from female subjects of childbearing potential only.
o Using Modification of Diet in Renal Disease (MDRD) formula; calculated by the central laboratory.
p At day 1, week 20, 52, and 76, two equal volume samples should be collected.
q Sampling roxadustat will be done at 6 time points over 1 to 3 visits between weeks 2 and 8. See Section 5.6. At each pharmacokinetic visit, one additional sample will be collected 
for determination of Alpha 1-Acid Glycoprotein (α1-AGP) and albumin concentration.
r Optional assessment for subjects treated with roxadustat. A separate informed consent form must be signed before genotyping sample is collected. Sample collection can be done 
at any timepoint throughout the treatment period of the study.
s Including SF-36, FACT-An, EQ-5D 5L, PGIC and WPAI:ANS. PGIC will not be performed on day 1. Questionnaires to be completed by the subject preferably prior to any study 
assessments. When subjects need dialysis therapy, Quality of Life (QoL) questionnaires will be completed on the day of first dialysis (preferably before the dialysis is started), 4 
weeks later and 12 weeks later.
t 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.
u Dosing of darbepoetin alfa per EU SmPC.
v Subjects randomized to roxadustat: dose adjustment review from week 4 onward, and every 4 weeks thereafter until EOT (wks 4, 8, 12 etc), 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.
w Telephone or in-person follow-up call with subject.


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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 (kidney transplant or dialysis). In 2007, CKD affected 13% of 
the US adult population (approximately 29 million US adults) and its prevalence is growing 
rapidly [Coresh 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 CKD patients suffering from End Stage Renal Disease (ESRD) also continues 
to increase worldwide. The US has one of the highest prevalence rates of ESRD in the 
world: in 2010, the US had over 1700 ESRD patients per million population, a 23% increase 
compared to 10 years prior (United States Renal Data System [USRDS, 2011]. In 2009, 
there were approximately 570,000 ESRD patients in the US, of whom 370,000 were 
receiving hemodialysis, 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 renal replacement therapy (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 five-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 may first present 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: 50.1% of the dialysis patients 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 1999 Jungers prospectively studied 403 consecutive ambulatory pre-dialysis 


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patients and found that 60% of patients with a creatinine clearance of < 20 mL/min/1.73 m2
were anemic (Hb <11 g/dL) [Jungers et al, 2002]. Between 2003 and 2005 Thilly studied 
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 
(CHOIR) studies in the Food and Drug Administration (FDA) briefing document for the 
October 2007 Cardiovascular and Renal Drugs 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 the need for 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 intravenously). 
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 erythropoietin (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 & Adamson, 1989; Winearls et al, 1986; US Recombinant Human Erythropoietin 
Predialysis Study Group, 1991], despite the documented safety risks such as hypertension 
and thrombosis.
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 


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studies in ESRD and nondialysis-dependent chronic kidney disease (NDD-CKD) 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; 
Drüeke 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 hemodialysis usually 
requires concomitant intravenous (IV) iron supplementation.
There is currently an unmet medical need for an oral treatment that will correct anemia in 
NDD-CKD and dialysis-dependent chronic kidney disease (DD-CKD) patients to a target Hb 
level that is safe and well tolerated.
Roxadustatb 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 1). 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 three 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; Büchler 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].
                                                
b 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 INN roxadustat.


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Figure 1
HIF-PHI Mechanism of Action
Source: Epstein, et al. Cell, 2001.
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 hypoxia-inducible 
factor 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 hypoxia-inducible factor prolyl hydroxylase inhibitor 
(HIF-PHI) that transiently induces HIF stabilization and leads to a functional HIF 
transcriptional response that mimics the erythropoietic response associated with exposure of 
humans to intermittent hypoxia. HIF induces expression of not only EPO, but also the EPO 
receptor and proteins that promote iron absorption and recycling [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 
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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-PHIs such as roxadustat alter expression not only of the EPO gene 
but also of genes regulating iron metabolism, it is postulated that roxadustat may be effective 
in treating these anemias as well [Langsetmo et al, 2005].
Chronic hypoxia and intermittent hypoxia induce different sets of genes associated with HIF 
transcriptional activity, presumably because intermittent stimulation allows the restoration of 
HIF degradation, turnover, and inactivation. Transient activation of HIF thereby precludes 
sustained gene expression and the induction of genes that are expressed late after HIF 
activation, as well as expression of additional genes that are secondary to activation of 
HIF-dependent genes. Both 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 DD-CKD and NDD-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 
07 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 NDD-CKD and 431 subjects with 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 three 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 (PK) and pharmacodynamics (PD) of roxadustat were characterized in 
studies in healthy subjects and in DD-CKD and NDD-CKD subjects. Roxadustat showed 
generally dose proportional PK (except at the lowest dose of 0.3 mg/kg); t1/2 was 12 to 
14 hours in healthy subjects, and 15 to 19 hours in dialysis subjects (after single doses of 
1 and 2 mg/kg). The exposure was higher in dialysis subjects compared to healthy subjects.


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A relative bioavailability study was conducted in 24 healthy subjects comparing the capsule 
formulation, which was used in phase 1 and phase 2, with the tablet formulation which was 
developed for phase 3. PK parameters were comparable between the two formulations.
With an intermittent dose regimen of once weekly (QW), twice weekly (BIW) or three times 
weekly (TIW), no or limited accumulation in mean area under the plasma concentration (AUC) 
or maximum concentration (Cmax) was observed. Furthermore no evidence was found for time-
dependent PK (no auto-induction or inhibition). Roxadustat is highly protein bound and the PK 
of roxadustat is not affected by dialysis. Metabolites found in urine suggested phase 2 
metabolism as the major metabolic pathway. In plasma, parent roxadustat is the main 
component. The inhibitory potential of roxadustat on cytochrome P450 (CYP) enzymes, based 
on in vitro studies is limited, and the lowest inhibition constant (Ki) value was observed for 
CYP 2C8 (16 μM). In a clinical drug-drug interaction study with rosiglitazone, a probe drug 
for CYP 2C8, roxadustat did not show any inhibitory potential on CYP 2C8 in vivo.
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 volunteers (Study FGCL-SM4592-016), roxadustat administered orally 
as a single dose up to 4.0 mg/kg, and QW, BIW, or TIW for 4 weeks at doses up to 
3.75 mg/kg, was pharmacodynamically active as evidenced by dose-dependent transient 
increases in endogenous EPO (starting from single doses of 0.3 mg/kg), increases in 
reticulocytes (starting from doses of 2 mg/kg), and Hb responses (starting at 3 mg/kg). The 
mean peak level of plasma EPO following the day 26 dose of 2.0 mg/kg TIW (the high 
therapeutic dose studied) was 326.3 ± 197.0 mIU/mL.
In PD studies conducted with roxadustat in CKD subjects not on dialysis 
(Study FGCL-4592-017), the mean maximum EPO increase from BL ranged from 82-443 
and 492-554 mIU/mL after a single 1 and 2 mg/kg dose, respectively. In dialysis subjects
(Study FGCL-4592-039), 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 subjects, the reported 
mean administered individual ESA dose was 8,000 IU, which would correspond to plasma 
EPO Cmax levels exceeding 3,000 mIU/mL [Fishbane & 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 subjects not on dialysis 
(Study FGCL-SM4592-017) showed that roxadustat promoted erythropoiesis at lower doses 
in CKD subjects than in healthy volunteers. In contrast to the classical paradigm suggesting 


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that anemia in CKD subjects is caused by the inability of these subjects 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 subjects who completed 4 weeks 
of dosing; more robust mean Hb increases of 2.0 to 2.3 g/dL occurred at roxadustat doses of 
1.5 and 2.0 mg/kg TIW, respectively. Hemoglobin responder (Hb increase of ≥1.0 g/dL) 
rates were 62%, 60%, 91%, and 100% in the roxadustat 0.7, 1.0, 1.5, and 2.0 mg/kg TIW 
cohorts, respectively. The Hb responses were also robust at the higher roxadustat doses (1.5 
to 2.0 mg/kg) in the BIW dosing groups. With the additional criterion that Hb achieves a 
level of ≥11.0 g/dL as well as increasing by ≥1.0 g/dL, the Hb responder rate with 
roxadustat 2.0 mg/kg was 89% and 91% in BIW and TIW dosing, respectively. The rapid 
rates of rise in Hb with roxadustat treatment were not accompanied by elevations in blood 
pressure, as has been reported with ESA treatment [Eschbach et al, 1989].
Data from a completed 16- to 24-week treatment study in CKD subjects 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 subjects. Corrected Hb levels were 
maintained within target range for the 16- or 24-week treatment period at TIW and BIW 
dosing and were generally maintained even with conversion to once weekly dosing. 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. Treatment with roxadustat in these anemic CKD patients led to positive changes 
or trends for positive changes from baseline in subscales of the SF-36 QoL questionnaire 
(Vitality, Mental Component, and Social Functioning). 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 NDD-CKD subjects. 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 subjects on dialysis showed the feasibility 
of converting subjects 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; no restriction was made in the study protocol for the use 
of oral iron. 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.
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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 DD-CKD and NDD-CKD subjects with anemia who have been 
enrolled and treated in completed and ongoing clinical studies. Roxadustat leads to a robust 
dose-related erythropoietic response in subjects 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.
1.2.3
Clinical Experience with Darbepoetin alfa
The comparative drug darbepoetin alfa (Aranesp®) is approved since 2001 in the European 
Union (EU) for the treatment of anemia associated with chronic renal failure in adults and 
pediatric subjects. It is a commonly used ESA in Europe for the treatment of anemic 
NDD-CKD subjects and has demonstrated its ability to correct and maintain Hb in subjects in 
several controlled randomized trials.
Two exploratory dose- and schedule-finding studies (NESP-960245 and NESP-960246) 
investigated the effects of darbepoetin alfa for correction of anemia in hemodialysis (HD) and 
peritoneal dialysis subjects by IV and subcutaneous (SC) injection respectively. The results of 
both studies showed a clear dose-related effect of darbepoetin alfa by IV as well as by SC route 
and independent of the schedule (once or three times weekly). At two of the selected dose 
levels, 60% to 70% of subjects produced an optimal rate of rise in Hb, which was the primary 
endpoint, within the first 4 weeks (1g/dL). Based on the results of these studies it was 
concluded that 0.45 to 0.75 μg/kg of darbepoetin alfa administered once weekly IV or SC is the 
most appropriate starting dose for treatment of anemia in CKD subjects [Macdougall et al, 
2003].
The pharmacokinetic PK studies showed that darbepoetin alfa has a slower clearance and a 
significantly longer terminal half-life in CKD subjects when compared to recombinant 
human erythropoietin (r-HuEPO). There was no evidence of accumulation of darbepoetin 
alfa over time. There are no special precautions for use based on the pharmacokinetic PK 
data, although darbepoetin alfa should be used with caution in subjects with acute hepatic 
failure, as the liver is a likely route for drug elimination.
The two multi-center randomized open-label trials explored the correction of anemia in 
subjects on dialysis (NESP-980211) or pre-dialysis (NESP-980202). The aim of the studies 
was to correct anemia and maintain Hb concentration within a predefined target range for up to 
20 and 24 weeks, respectively. Subjects were randomized to receive darbepoetin alfa or 
r-HuEPO. The primary endpoint for both studies was defined as the proportion of subjects that 
achieved a Hb response (Hb increase of ≥1.0 g/dL from baseline and a Hb concentration of 
≥11.0 g/dL during the initial 24 weeks of treatment). The selected starting dose was 


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0.45 μg/kg once weekly for darbepoetin alfa as suggested by the exploratory dose finding 
studies. The starting dose for r-HuEPO was approximately equivalent to this dose in 
study NESP-980202 (50 U/kg twice weekly), and 40% higher than this dose in NESP-980211 
(50 U/kg three times weekly) [Locatelli et al, 2001; EMEA, EPAR Aranesp, 2004].
In the first pivotal correction study (NESP-980202) r-HuEPO-naive subjects were not yet on 
dialysis and study drugs were administered by SC injection. A total of 129 subjects received 
darbepoetin alfa, 37 received r-HuEPO. A Hb response was achieved in 93% of subjects in the 
darbepoetin alfa group and 92% in the rHuEPO group. Subjects from this study had the option 
to extend dosing up to 104 weeks and were so eligible for long-term efficacy and safety.
In the second pivotal correction of anemia study (NESP-980211, US trial) subjects were on 
dialysis (mainly hemodialysis) and received study drugs by SC or IV injection route. A total 
of 122 subjects were randomized (darbepoetin alfa: 91; r-HuEPO: 31). A Hb response was 
achieved in 72% of subjects in the darbepoetin alfa group and 84% in the r-HuEPO group. 
This reflects the 40% higher starting dose for r-HuEPO in this trial.
Two pivotal phase 3 studies (NESP-970200 conducted in Europe and Australia with a study 
duration of 52 weeks, and NESP-980117 conducted in United states and Canada with a study
duration of 28 weeks) evaluated the ability of darbepoetin alfa to maintain hemoglobin in the 
predefined target range, when CKD subjects on dialysis and stable on r-HuEPO therapy, 
were converted to darbepoetin alfa therapy. Both studies indicate that darbepoetin alfa was 
not inferior to r-HuEPO. The lower boundary of the 95% CI for the difference in mean 
change in hemoglobin (darbepoetin alfa minus r-HuEPO) was far above the prespecified 
clinical acceptable difference of –1.0 g/dL for NESP-980117 as well as above the more 
rigorous criteria of –0.5 g/dL for the NESP-970200. This applied equally to per protocol and 
intention to treat analysis sets and demonstrates that darbepoetin alfa is not inferior to 
r-HuEPO for maintaining subjects Hb concentration within the predefined target range.
Data from one uncontrolled long-term safety study demonstrated that darbepoetin alfa once 
weekly/once every two weeks by the IV or SC route is safe and effective in maintaining Hb 
in subjects with CKD undergoing dialysis. Data from a long-term safety of darbepoetin alfa 
in subjects who had completed one year of treatment on a previous darbepoetin alfa clinical 
trial show that for subjects who have already received 52 weeks of darbepoetin alfa 
treatment, the Hb concentration can be safely maintained at a stable level without changes in 
the average weekly darbepoetin alfa dose [EMEA, 2004; EMEA, 2003].
1.3
Summary of Key Safety Information for Study Drugs
1.3.1
Roxadustat
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 subjects. The most commonly reported AEs 
in healthy subjects were headache, pharyngolaryngeal pain, and nasal congestion. The most 
commonly reported AEs (> 5%) in CKD subjects not on dialysis were diarrhea, nausea, 
urinary tract infection, nasopharyngitis, peripheral edema, hyperkalemia, headache and 


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hypertension. The most commonly reported adverse events (AEs) (> 3%) in CKD subjects 
on dialysis were diarrhea, nausea, hypertension and upper respiratory tract infection. The 
only expected non-serious adverse drug reaction was 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 AE 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 FGCL-SM4592-017, and 6.9% in Study FGCL-4592-041) and 
thrombosis (overall incidence < 1%). No increased cancer risk has been noted with 
roxadustat treatment, though it should be noted that the study program was not powered to 
detect absence of cancer risk.
Liver enzymes were monitored closely throughout the 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.
Five pancreatitis events were noted during the roxadustat phase 2 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 one of the pancreatitis cases was considered as possibly related by the 
investigator. Amylase levels were routinely measured in the FGCL-4592-040 study and 
mean levels were not found to be elevated during the course of the study. A higher incidence 
of pancreatitis in subjects with type 2 diabetes mellitus, and CKD, has been well defined in 
the literature.
For further information please refer to the most recent version of the Investigator Brochure.
1.3.2
Darbepoetin alfa
The safety profile of darbepoetin alfa was assessed in 1578 CKD subjects treated with 
darbepoetin alfa and 591 treated with r-HuEPO. Out of the 1578 subjects 847 (54%) 
received SC darbepoetin alfa. AEs were consistent across all studies and were similar in the 
two treatment groups – darbepoetin alfa and r-HuEPO. The majority of AE were due to 
underlying disease. Only hypertension, vascular access thrombosis and injection site pain 
(SC route) were consistently reported as related to study drug. As hypertension is the most 
common AE with both darbepoetin alfa and r-HuEPO, and as most deaths were due to 
cardiac events, control of blood pressure is an important consideration in all CKD subjects.
There were no overall changes in blood pressure or HR in the study although there was 
considerable variability in individual blood pressure measurements.
The clinical results showed that the safety profile of darbepoetin alfa is similar to that of 
r-HuEPO when administered by the IV or SC route. The odds-ratio (95% CI) between 
darbepoetin alfa and r-HuEPO for the incidence of AEs showed that there is no evidence that 
AEs occurred more frequently with IV darbepoetin alfa compared to r-HuEPO therapy. 


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When administered by the SC route, the only event that occurred more frequently during 
darbepoetin alfa treatment was injection site pain.
The AEs observed during post marketing experience with darbepoetin alfa were: aggravated 
hypertension, cerebrovascular disorders, myocardial infarction, angina pectoris and skin 
reactions. A warning on possible cross reactivity of epoetin antibodies with different 
epoetins and to a number of adverse drug reactions was also added in the Summary of 
Product Characteristics (SmPC). Furthermore a warning was included in section 4.4 of the 
SmPC to specify that cases of severe hypertension, including hypertensive crisis, 
hypertensive encephalopathy, and seizures, have been observed in CKD subjects treated with 
darbepoetin alfa. Further to the request of the Committee for Medicinal Products for Human 
Use (CHMP) regarding the assessment of outcome of Study 20010184 "Trial to Reduce 
Cardiovascular Events with Aranesp® Therapy" (TREAT) in March 2010, additional 
warnings and the results of the TREAT study were included into the current product 
information for darbepoetin alfa. Also, the specific section of the Aranesp Package Leaflet 
(PL), section 2 "Before you use Aranesp®" was updated to align it with the SmPC, reflecting 
the concern that elevated hemoglobin concentrations could increase the risk of myocardial 
infarction, stroke and death [EMEA, 2004].
1.4
Risk-Benefit Assessment
Based upon the results of the studies described above, the expected benefit of roxadustat is 
the correction of anemia and relief of signs and symptoms of anemia resulting in an increased 
quality of life, 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.
An established dose adjustment algorithm, similar to the one used in phase 2 studies with 
roxadustat, will be used during the current study to titrate roxadustat doses to enable subjects 
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 roxadustat rules for the use of supplemental IV iron and 
rescue treatments such as darbepoetin alfa (for roxadustat treated subjects) or RBC 
transfusion are in place in order to assure safety of the affected study subjects.
In PK studies with roxadustat there was no evidence of drug accumulation with the proposed 
clinical regimen of up to three 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 DD-CKD and NDD-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. Also, the protocol includes a 
recommendation for the investigator to consider the posology of other concomitantly 


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administered drugs that are substrates of the organic anion transporting polypeptide 1B1
(OATP1B1) and to refer to the SmPCs of these drugs.
Furthermore, there is a drug interaction with phosphate binders: concomitant intake of 
phosphate binders and roxadustat reduces the absorption of roxadustat. Subjects should take 
roxadustat in a consistent manner relative to their phosphate binder intake, and discuss with 
the investigator before changing their phosphate binder dose or dosing time. As a further risk 
mitigation this study protocol includes a recommendation that roxadustat be taken separately 
from phosphate binders. 
As it is anticipated that other multivalent cation-containing drugs and mineral supplements 
(e.g., iron, calcium, magnesium, aluminium), sucralfate or magnesium- or aluminium-
containing antacids would produce a similar interaction, the study protocol includes the 
advice that roxadustat be taken separately from these drugs.
Darbepoetin alfa 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. It is a commonly used ESA in Europe for the treatment of anemic NDD-CKD 
subjects and has demonstrated its ability to correct and maintain Hb in subjects in several 
controlled randomized trials.
The rules for dose adjustment and for events of excessive hematopoiesis in the present study 
will follow the approved posology of darbepoetin alfa. In case of insufficient response to 
darbepoetin alfa, rules for RBC transfusions are in place in order to assure safety of the 
affected study subjects.
The safety of treatment with roxadustat and darbepoetin alfa in this study will be carefully 
monitored to include AEs and SAEs, laboratory parameters such as electrolytes, liver 
enzymes, serum lipase and iron indices. Emphasis will be placed on cardiovascular, 
cerebrovascular, and thrombo-embolic events, which are not uncommon in the study 
population; an independent event review committee (IERC) will assess and adjudicate all 
significant occurrences of such events. In addition, an independent Data and 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 of the orally administered 
roxadustat to date, it is anticipated that roxadustat will be comparable in safety and efficacy 
to the marketed, parenterally administered darbepoetin alfa 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 subject can be avoided. The benefit-risk profile for the participation 
of subjects in this study is therefore considered to be acceptable.


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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 compared to 
darbepoetin alfa in the treatment of anemia in NDD-CKD subjects.
2.1.2
Secondary Objectives
The secondary objectives of this study are to:

Evaluate the safety of roxadustat compared to darbepoetin alfa in the treatment of anemia 
in NDD-CKD subjects.

Evaluate the HRQoL benefit of roxadustat compared to darbepoetin alfa in the treatment 
of anemia in NDD-CKD subjects.
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, open-label, active-controlled study. This study 
is planned to recruit approximately 570 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.
2.2.1.2 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 
≤10.5 g/dL upon repeated screening measurements. Anemia of non-renal origin is to be 
excluded. Washout periods of at least 12 weeks for any prior ESA, at least 6 weeks for any 
IV iron treatment, and 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 assigned to roxadustat treatment will be administered roxadustat orally as a 
combination of tablets of different strengths. Subjects assigned to darbepoetin alfa treatment 
will be administered darbepoetin alfa subcutaneously (SC) or intravenously (IV) by the 
investigator or a qualified member of the site staff or, after 36 weeks of treatment, by the 
subject themselves or caregiver, e.g., relative, if well trained and willing to self-administer.
Study treatment administration is implemented in an open-label manner.


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The study will consist of three study periods as follows:

Screening period: up to 6 weeks

Treatment period: 104 weeks

Follow-up period: 4 weeks
Subjects that have discontinued treatment prior to their projected week 104 will continue to 
be followed for vital status, SAEs, cardiovascular and thromboembolic AEs in a post study 
follow-up period.
During the course of the study, visits and assessments will be performed as defined in the 
Schedule of Assessments.
Screening Period
During the screening period (up to 42 days duration), Hb levels will be assessed in a central 
laboratory for matching the inclusion criterion (mean of two Hb values must be ≤10.5 g/dL, 
see inclusion criterion 4). Subjects meeting all of the inclusion criteria and none of the 
exclusion criteria will be randomized at day 1, which marks the end of screening period and 
start of the treatment period. If a subject fails screening, the subject may be rescreened once 
(immediately or later) if deemed appropriate by the investigator. The subject must be 
re-consented. A new rescreening period will start and all screening procedures must be 
repeated.
Treatment Period (Correction and Maintenance Period)
After subjects have been confirmed eligible for study participation, subjects are randomized 
to 1 of 2 treatment arms (1:1 ratio) as illustrated in Table 2 The randomization will occur 
through Interactive Response Technology (IRT). The randomization will result in a 1:1 ratio 
of subjects receiving roxadustat administered orally or darbepoetin alfa administered by SC
or IV injection.
Table 2
Treatment Arms and Dosing Frequency
Treatment 
Arms
Study Treatment
Dosing Frequency in Treatment 
Period
Correction 
Period
Maintenance Period
1
Roxadustat
TIW
TIW
2
Darbepoetin alfa
Dosing per EU SmPC
SmPC: Summary of Product Characteristics; TIW: three times weekly
In protocol version 1 subjects were randomized in a ratio of 2:1 receiving roxadustat versus 
darbepoetin alfa. The expected number of subjects randomized on protocol version 1, 
protocol versions 2 and 3 and the total number of randomized subjects per treatment arm are 
represented in the following table.


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Table 3
Expected Number of Subjects Randomized 
Treatment 
Arms
Study Treatment
Expected Number of 
Protocol v1 Subjects 
Randomized (Ratio 
2:1)
Expected Number of 
Protocol v2 and 3
Subjects Randomized
(Ratio 1:1)†
Total Expected 
Number of 
Subjects 
Randomized per 
Treatment Arm
1
Roxadustat
100
210
310
2
Darbepoetin alfa
50
210
260
Total
150
420
570
† The number of subjects under protocol v2 and v3 will depend on the number of subjects randomized under 
protocol v1.
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. From week 24 onwards, visits 
will occur every four weeks until the end of treatment (EOT).
Subjects will receive study treatment (roxadustat or darbepoetin alfa) for 104 weeks.
Correction Period
The aim of the correction period is to correct Hb levels to ≥11.0 g/dL and a Hb increase 
from BL Hb ≥1.0 g/dL as measured at two consecutive study visits separated by at least 
5 days (as assessed by central laboratory). Dosing and dose adjustments of roxadustat will 
follow prespecified dose adjustment rules. Dosing and dose adjustments of darbepoetin alfa 
will be per EU approved Summary of Product Characteristics (SmPC).
Once Hb is corrected the subjects 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 10.0 g/dL and 12.0 g/dL. Dose adjustments of roxadustat will follow 
prespecified dose adjustment rules. Dose adjustments of darbepoetin alfa will be per EU 
approved Summary of Product Characteristics (SmPC).
Follow-up Period
After the end of the treatment period, subjects proceed to the 4-week follow-up period.
Post study Follow-up (for premature treatment discontinued subjects only)
Subjects that have prematurely discontinued study treatment will complete the EOT visits 
(EOT visit and EOT +2 weeks visit) and EOS visit. Thereafter, these subjects who have 
taken at least one dose of study drug will continue to be followed up every 6 months for vital 
status, SAEs, cardiovascular and thromboembolic AEs until their projected date of 
completion of the follow-up period (i.e., projected week 108 date) or until consent 
withdrawn.


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2.2.1.4 Randomization and Open-Label
A randomized 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.
An open label design was chosen since the investigational and comparator drug are provided 
via different routes of administration and have a different requirement for iron 
supplementation.
2.2.1.5 Comparator
Darbepoetin alfa supplied as a solution for injection in a pre-filled syringe, and is 
administered by SC or IV injection. Once the route of administration is chosen (IV or SC), it 
is recommended to keep the same administration route for a subject throughout the study. It 
is administered in combination with IV or oral iron to maintain iron repletion. 
2.2.2
Roxadustat Dose Rationale
Starting doses of roxadustat were studied in three ways in phase 2:

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)

using an absolute starting dose regardless of body weight
The tiered weight-based approach has been chosen for the development of roxadustat in the 
phase 3 program to provide the best opportunity for managing subjects’ controlled correction 
to target Hb values.
Based upon simulations derived from a kinetic-pharmacodynamic model built from 
phase 2 data a tiered weight-based approach with starting doses of 70 mg given TIW for 
subjects weighing up to 70 kg and 100 mg given TIW for subjects 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 is expected to provide 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 is 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 prespecified 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 


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were successful in Hb correction and Hb maintenance and will be adopted in this study with 
minor modifications.
The maximum allowed roxadustat dose in this study is set at 3.0 mg/kg or 300 mg per 
administration, 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 volunteers 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 (MTD) was reached in the 
clinical development of roxadustat based on the observed pharmacodynamic response (plasma 
EPO levels) and the predicted relation between EPO levels and Hb response; therefore, 
exploration of higher doses was not conducted. Plasma EPO levels increased in a supra-linear 
fashion with increasing roxadustat doses. It is 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 104 weeks will provide sufficient data on the efficacy and safety of 
long term treatment of anemic CKD subjects with roxadustat.
2.3
Endpoints
2.3.1
Primary Endpoints
The primary efficacy endpoint is Hb response. Hb response is defined as:

Hb ≥11.0 g/dL and a Hb increase from BL Hb by ≥1.0 g/dL in any subject with 
BL Hb >8.0 g/dL, OR

An increase from BL Hb by ≥2.0 g/dL in any subject with BL Hb ≤8.0 g/dL
as measured at 2 consecutive visits separated by at least 5 days during the first 24 weeks of 
treatment without administration of rescue therapy prior to Hb response.
2.3.2
Key Secondary Endpoints
The secondary efficacy endpoints in this study are:

Hb change from BL to the average Hb of weeks 28 to 36, without having received rescue 
therapy within 6 weeks prior to and during this 8-week evaluation period

Change from BL in Low Density Lipoprotein (LDL) cholesterol to the average LDL 
cholesterol of weeks 12 to 28

Mean monthly IV iron (mg) use per subject during weeks 1 to 36 (monthly defined as a 
period of 4 weeks)

Change from BL in SF-36 Physical Functioning (PF) sub-score to the average PF 
sub-score of weeks 12 to 28

Change from BL in SF-36 Vitality (VT) sub-score to the average VT sub-score of 
weeks 12 to 28 


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
Blood pressure effect:
o
Change from BL in mean arterial pressure (MAP) to the average MAP value of
weeks 20 to 28
o
Occurrence and time to occurrence of hypertension (defined as either SBP 
> 170 mmHg AND an increase from BL of ≥20 mmHg SBP or DBP > 110 mmHg 
AND an increase from BL of ≥15 mmHg DBP on 2 consecutive visits) during 
weeks 1 to 36
2.3.3
Additional Secondary Endpoints
2.3.3.1 Efficacy Endpoints
Hb correction and maintenance:

Hb change from BL to the average Hb value of weeks 28 to 52 regardless of rescue 
therapy

Time (weeks) to achieve the first Hb response as defined by primary endpoint.

Hb response defined as: Hb ≥11.0 g/dL and a Hb increase from BL Hb by ≥1.0 g/dL in 
any subject with BL Hb > 8.0 g/dL, OR an increase from BL Hb by ≥2.0 g/dL in any 
subject with BL Hb ≤8.0 g/dL as measured at 2 consecutive visits separated by at least 
5 days, during the first 24 weeks of treatment regardless of administration of rescue 
therapy prior to Hb response.

Hb averaged over weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104, without use of rescue 
therapy within 6 weeks prior to and during this evaluation period.

Hb value and Hb change from BL to each post-dosing time point.

Hb change from BL to the average Hb value of weeks 28 to 36, 44 to 52, 72 to 80, 96 to 
104 regardless of the use of rescue therapy 

Proportion of Hb values within 10.0 to 12.0 g/dL in weeks 28 to 36, 44 to 52, 72 to 80, 
96 to 104 without use of rescue therapy within 6 weeks prior to and during this 8-week 
evaluation period.
Hospitalizations

Occurrence (number) of hospitalization(s)

Number of days of hospitalization
Rescue therapy use

Having received rescue therapy (composite of RBC transfusions [all subjects] and 
darbepoetin alfa use [roxadustat treated subjects only])

Having received RBC transfusions

Number of RBC packs per subject

Volume of RBC transfused per subject
Changes in cholesterol levels

Change from BL to each scheduled measurement in:
o
Total cholesterol
o
LDL/High-density Lipoprotein (HDL) ratio


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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 
to 28, and weeks 36 to 52 of treatment).
Blood pressure effect

Occurrence of achieved anti-hypertensive treatment goal (SBP < 130 mmHg and DBP 
< 80 mmHg) based on the mean SBP and mean DBP calculated over weeks 12 to 28 and 
36 to 52 of treatment with study drug.
HRQoL and EQ5D 5L benefits

Change from BL to the average value of weeks 12 to 28 and 36 to 52 in:
o
Physical Component Score (PCS) 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 VAS Score
o
WPAI:ANS Score (Work Productivity and Activity Impairment Questionnaire)

PGIC (qualitatively by assessment)
Iron, HbA1c, and CKD progression

Change from BL to each scheduled measurement in:
o
Serum ferritin
o
TSAT
o
HbA1c level
o
Fasting blood glucose
o
eGFR (including eGFR slope over time)
o
Urine albumin/creatinine ratio (UACR)

Serum creatinine having doubled during the study in comparison with baseline

Occurrence of ESRD
2.3.3.2 Safety Endpoints
Safety will be assessed by evaluating the following:

Occurrence of Treatment Emergent AEs (TEAEs), and clinically significant changes in 
laboratory values from BL

Changes from BL in vital signs, electrocardiogram (ECG) findings, and clinical 
laboratory values

Occurrence of prespecified adjudicated cardiovascular and cerebrovascular events.


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3
STUDY POPULATION
3.1
Selection of 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 in need of dialysis.
3.2
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 has been
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 CKD, with Kidney Disease Outcomes Quality Initiative 
(KDOQI) Stage 3, 4 or 5, not on 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 two most recent (prior to randomization) Hb values during the 
screening period, obtained at least 4 days apart, must be ≤10.5 g/dL, with a difference of 
≤1.0 g/dL. The last Hb value must be within 10 days prior to randomization.
5.
Subject is deemed suitable by the investigator for treatment with ESA using the criteria 
specified in the KDIGO 2012 recommendation considering the rate of fall of Hb 
concentration, prior response to iron therapy, the risk of needing a transfusion, the risks 
related to ESA therapy and the presence of symptoms attributable to anemia.
6.
This criterion has been removed.
7.
This criterion has been removed.
8.
Subject has a serum folate level ≥ lower limit of normal (LLN) at screening.
9.
Subject has a serum vitamin B12 level ≥LLN at screening.
10. Subject’s alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are 
≤3 x upper limit of normal (ULN), and total bilirubin (TBL) is ≤1.5 x ULN. 
11. Subject’s body weight is 45.0 kg to a maximum of 160.0 kg.
12. Female subject is either:
Of non-childbearing potential:

post-menopausal (defined as at least 1 year without any menses) prior to screening,
or

documented surgically sterile 


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Or if of childbearing 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 continue to do so 
for 28 days after final study treatment administration. If required by local law, 
2 highly effective methods of birth control must be used, 1 of which must be a 
barrier method.
13. Female subject must not be breastfeeding at screening or throughout the study period, 
and for 28 days after the final study treatment administration.
14. Female subject must not donate ova starting at screening and throughout the study 
period and for 28 days after final study drug administration. 
15. Male subject and their female spouse/partner(s) who are of childbearing potential must 
be using a highly effective form of birth control* starting at screening and continue to 
do so throughout the study period and for 12 weeks after final study treatment 
administration. If required by local law, 2 highly effective methods of birth control 
must be used, 1 of which must be a barrier method.
16. Male subject must not donate sperm starting from screening, throughout the study 
period and up to 12 weeks after final study drug administration.
17. Subject agrees not to participate in another interventional study from the time of signing 
informed consent until the end of study visit (EOS).
* 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
Waivers to the inclusion criteria will NOT be allowed.
3.3
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 received any dose of IV iron within 6 weeks prior to randomization.


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3.
Subject has received a Red Blood Cell (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 a known 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 undergo elective surgery that is expected to lead to significant 
blood loss during the study period or anticipated elective coronary revascularization.
9.
Subject has active or chronic gastrointestinal bleeding.
10. Subject has received any prior treatment with roxadustat or a 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 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., deep vein thrombosis or pulmonary embolism) 
within 12 weeks prior to randomization.
15. Subject has one or more contraindications for treatment with darbepoetin alfa:
Uncontrolled hypertension in the opinion of the investigator, or two or more blood 
pressure values of SBP ≥160 mmHg or DBP ≥95 mmHg (within 2 weeks prior to 
randomization).
Known hypersensitivity to darbepoetin alfa, recombinant human erythropoietin, or any 
of the excipients.
16. Subject has a diagnosis or suspicion (e.g., complex kidney cyst of Bosniak Category 2F
or higher) of renal cell carcinoma as shown on renal ultrasound within 12 weeks prior to 
randomization.
17. Subject has a history of malignancy, except for the following: cancers determined to be 
cured or in remission for ≥5 years, curatively resected basal cell or squamous cell skin 
cancers, cervical cancer in situ, or resected colonic polyps.


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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 that is 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 or retinal vein occlusion.
21. Subject has had any prior organ transplant (that has not been explanted),  subject is 
scheduled for organ transplantation, or subject is likely to initiate renal replacement 
therapy including dialysis within the first year of the study in the opinion of the 
investigator.
22. Subject will be excluded from participation if any of the following apply:
a. subject has received investigational therapy within 30 days or 5 half lives or limit 
set by national law, whichever is longer, prior to initiation of screening, or 
b. any condition which, in the investigator’s opinion, makes the subject unsuitable for 
study participation. 
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. Subject has 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.
Waivers to the exclusion criteria will NOT be allowed.
4
TREATMENT(S)
4.1
Identification of Investigational Product(s)
4.1.1
Test Drug
Roxadustat is supplied as red, film-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).


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The excipients include lactose monohydrate, microcrystalline cellulose, povidone, 
croscarmellose sodium, magnesium stearate, and colorant Red Opadry II.
4.1.2
Comparative Drug
Darbepoetin alfa is supplied as a solution for SC or IV injection in a pre-filled syringe. It is 
centrally provided in the following strengths 20, 30, 40, 60 and 100 µg and needs to be 
administered in combination with IV or oral iron to maintain iron repletion. All administrations 
will be performed by the investigator or a qualified member of the site staff or, after 36 weeks 
of treatment, by the subject themselves or caregiver, e.g., relative, if well trained and willing to 
self-administer. Darbepoetin alfa (Aranesp®) should be administered IV or SC according to 
the Package Insert or SmPC (EU SmPC for Aranesp®). Copies of this SmPC will be 
distributed as part of the study materials.
4.2
Packaging and Labeling
All supplied medication used in this study will be prepared, packaged, and labeled under the 
responsibility of qualified staff at Astellas Pharma Europe B.V. (APEB) or Sponsor’s 
designee in accordance with APEB or Sponsor’s designee Standard Operating Procedures 
(SOPs), Good Manufacturing Practice (GMP) guidelines, ICH GCP guidelines, and 
applicable local laws/regulations.
The medication will bear a label conforming to regulatory guidelines, Good Manufacturing 
Practice and local laws and regulations that identifies the contents as investigational drug.
A Qualified Person of Astellas Pharma Europe B.V. (APEB) or Sponsor’s designee will 
perform the final release of the medication according to Directive 2003/94/EC annex 13.
Roxadustat 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.
Darbepoetin alfa will be provided as a solution for injection in pre-filled syringes. Each 
pre-filled syringe will be packaged in a single box.
For storage and administration purposes, please refer to the EU SmPC to warrant correct use.
4.3
Study Drug Handling
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries
from the Sponsor are received by the investigator/or designee and that:

such deliveries are recorded

study drug is handled and stored according to labeled storage conditions

study drug with appropriate expiry/retest and is only dispensed to study subjects in 
accordance with the protocol, and

any unused study drug is returned to the Sponsor


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Drug inventory and accountability records for the study drugs will be kept by the 
investigator/or designee. Study drug accountability throughout the study must be 
documented and reconciled. The following guidelines are therefore pertinent:

The investigator agrees not to supply study drugs to any persons except the eligible 
subjects in this study in accordance with the protocol.

The investigator or designee will keep the study drugs in a pharmacy or other locked and 
secure storage facility under controlled storage conditions, accessible only to those 
authorized by the investigator to dispense the study drugs.

A study drug inventory will be maintained by the investigator or designee. 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 the study, the investigator or designee 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/or returned medication. Any discrepancies must be accounted for and 
documented. Appropriate forms of deliveries and returns must be signed by the site staff 
delegated this responsibility.

The site must return study drug 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.
4.4
Blinding
This section is not applicable as this is an open-label study.
4.5
Assignment and Allocation
Randomization and treatment assignments will be performed via IRT prepared on behalf of 
the Sponsor (under the responsibility of the Global Data Science [GDS] Department of 
APEB). Specific procedures for randomization through the IRT are contained in the study 
procedures manual.
Approximately 570 subjects will be randomized to receive roxadustat TIW or darbepoetin 
alfa as shown in Table 9 assuming 150 subjects will be randomized pre-amendment.
Randomization will be stratified by the following four factors:

Region: region A versus region B*
* Assignment to region will be determined based on health care comparability.

Screening Hb values (Hb ≤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)


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5
TREATMENTS AND EVALUATION
Subjects must be consented and registered in IRT before any screening tests or assessments 
are performed. Participating study sites are required to document all screened candidates 
initially considered for inclusion in this study. If a subject is 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. After obtaining consent, and prior to 
the start of screening assessments, the investigator will register the subject in IRT, which 
starts the screening period, and a subject identification number will be assigned.  No 
screening tests or assessments should be performed prior to registration and 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 results do not meet the inclusion criteria or meet the exclusion 
criteria at screening, any laboratory assessment may be repeated once within the 42-day 
screening period. This includes an additional (third) Hb value that may be collected if 
necessary. The mean of 2 most recent Hb values during the 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 rescreening period starts and all screening procedures must be 
repeated. Subject must also be registered in IRT as re-screened under the same subject 
identification number as first screening.
Subjects confirmed not eligible after re-screening, should be registered in IRT as a re-screen 
failure.
5.1
Dosing and Administration of Study Drugs and Other Medication
5.1.1
Dose/Dose Regimen and Administration Period
Following the screening period, eligible subjects will enter the treatment period upon 
randomization (day 1).
Subjects will be randomized via IRT to receive roxadustat or darbepoetin alfa. The first 
study treatment should be on the day of randomization, i.e., day 1, after all study assessments 
have been completed.
All subjects will be treated for 104 weeks.
Subjects receiving roxadustat
Roxadustat tablets will be dispensed to subjects at each study visit during the treatment 
period with instructions for self-administration, according to the dosing schedule. The study 
drug tablets are to be swallowed whole with room-temperature drinking water. 


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The initial roxadustat dose (per dose amount) is based on the tiered, weight-based dosing 
scheme shown in the table below.
Table 4
Initial Dosing of Roxadustat (TIW)
Study Drug
(Dose Frequency)
Weight
(≥45.0 to ≤70.0 kg)
Weight
(> 70.0 to ≤160.0 kg)
Roxadustat (TIW)
70 mg
100 mg
All subjects will administer study drug doses TIW. The period between two roxadustat 
administrations should be at least 36 hrs 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. 
The roxadustat treated subjects that had entered the study under protocol v1.0, upon signing 
the informed consent for the amendment 1, had their dose frequency (on QW and BIW under 
protocol v1.0) and dose amount adjusted according to the instructions in Appendix 12.3
Section 5.1.2 describes the dose adjustment rules within this protocol to enable investigators 
to adjust the dose for their subjects to achieve Hb correction and to maintain their Hb levels 
within the predefined target range in this study.
Subjects receiving darbepoetin alfa
Darbepoetin alfa dosing is to follow the EU SmPC. The initial dosing is weight based. 
Darbepoetin alfa will be administered by SC or IV injection by the investigator or a qualified 
member of the site staff or, after 36 weeks of treatment, by the subject themselves or 
caregiver, e.g., relative, if well trained and willing to self-administer.
Similar to roxadustat treatment, the target of treatment is achieving Hb correction (defined as 
Hb values of ≥11.0 g/dL and Hb increase from BL Hb ≥1.0 g/dL at 2 consecutive study 
visits separated by at least 5 days [as assessed by the central laboratory]) and thereafter 
maintaining Hb in the target range of 10.0 to 12.0 g/dL.
5.1.2
Changes in Study Drug Dose
5.1.2.1 Dose Adjustment Rules for Subjects Receiving Roxadustat
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.
Dose adjustments will follow unique dose adjustment rules [Table 5].




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Dose Adjustment for Excessive Hematopoiesis
If at any time during the treatment period Hb increases by > 2.0 g/dL at any time within 
4 weeks, the dose should be reduced by one dose step.
Note: Only one 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.
5.1.2.2 Dose Adjustment Rules for Subjects Receiving Darbepoetin Alfa
The initial dose is weight-based according to the EU SmPC and either 0.45 μg/kg body 
weight, as a single SC or IV injection once weekly or 0.75 μg/kg body weight, as a single SC 
injection once every two weeks, as judged appropriate by the investigator. Dose adjustment 
should be made according to the EU SmPC.
If the rise in Hb is greater than 2.0 g/dL in 4 weeks, the dose is to be reduced by 
approximately 25%. Once the target Hb level has been achieved with once every 2-week 
dosing, darbepoetin alfa may be administered SC once monthly using an initial dose equal to 
twice the previous once every 2-week dose.
All these dose adjustments are made based on Hb values using HemoCue in both the 
correction and the maintenance period.
Target of treatment is achieving Hb correction (defined as Hb values of ≥11.0 g/dL and Hb 
increase from BL Hb ≥1.0 g/dL at 2 consecutive study visits separated by at least 5 days [as 
assessed by the central laboratory]) and thereafter maintaining Hb in the target range of 
10.0 to 12.0 g/dL.
5.1.3
Previous and Concomitant Treatment
5.1.3.1 Previous Medication
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 medication within four months prior to 
randomization should be documented in the eCRF. The medication name, start and stop date, 
route, dose and 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, 
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Certain previous medications are prohibited for a specified time frame prior and/or during the 
study treatment period and/or until EOS. These medications and restrictions are described in 
Section 5.1.3.3
5.1.3.2 Concomitant Medication
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), total daily dose 
(if applicable) 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.
5.1.3.2.1
Supplemental Iron Use
Subjects receiving roxadustat
i. Oral iron
For subjects receiving roxadustat, 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 treatment. The recommended daily dose is 200 mg of 
elemental iron. Subjects should be advised to take roxadustat at least one hour before or one 
hour after oral iron.
ii. IV iron
For subjects receiving roxadustat, IV iron supplementation is allowed if all of the following 
criteria are met:

The subject has not responded adequately in terms of hemoglobin response to 2 or more 
consecutive dose increases of roxadustat or reached the maximum dose limit, and

The subject has iron deficiency (either ferritin < 100 ng/mL [< 220 pmol/L] or 
TSAT < 20%) or the subject is intolerant of oral iron therapy.
Treatment with roxadustat may continue during IV iron administration. Discontinuation of 
IV iron administration is recommended once ferritin levels are ≥100 ng/mL (≥220 pmol/L) 
and TSAT ≥20%.
Subjects receiving darbepoetin alfa
For subjects treated with darbepoetin alfa, oral or IV iron supplementation is required to 
maintain iron repletion. IV iron should only be administered if ferritin < 100 ng/mL
(< 220 pmol/L) or TSAT < 20%. IV iron may be administered per local practice. 
Discontinuation of IV iron therapy is recommended once ferritin levels are ≥100 ng/mL 
(≥220 pmol/L) and TSAT ≥20%. 


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5.1.3.2.2
Statins and Other Substrates for OATP1B1
For subjects receiving roxadustat
There is a risk that roxadustat will increase the plasma levels of statins and other drugs that 
are substrates of OATP1B1, 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 6].
The investigator is also advised to consider this potential interaction between roxadustat and 
other drugs that are substrates for OATP1B1 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 SmPCs of these drugs for further details and guidance.
Table 6
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
* The rosuvastatin SmPC defines severe renal impairment as GFR < 30 mL/min.
5.1.3.2.3
Phosphate Binders and Other Multivalent Cation-containing Drugs and 
Mineral Supplements
For subjects receiving roxadustat
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 
intake, 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 take roxadustat at least one hour before or one hour after their phosphate binder.


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It is anticipated that other multivalent cation-containing drugs and mineral supplements (e.g.,
iron, calcium, magnesium, aluminium), sucralfate or magnesium- or aluminium-containing 
antacids would produce a similar interaction; therefore, subjects should take roxadustat at 
least one hour before or one hour after intake of these preparations.
5.1.3.2.4
Anti-hypertensive Medications
To avoid confounding effects on study endpoints, changes to anti-hypertensive medications 
should be minimized, and made only if deemed medically necessary by the investigator or if 
prespecified changes in blood pressure are met.
5.1.3.3 Prohibited Medication
The following medications are prohibited during the period identified (see also 
Appendix 12.1):

Any ESA: within 12 weeks prior to randomization until EOT

IV iron: within 6 weeks prior to randomization. 

RBC transfusion: within 8 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 screening until EOS

Roxadustat or another HIF-PHI: at any time prior to randomization. After randomization 
any HIF-PHI other than roxadustat, as allocated by randomization, until EOS

Androgens from day of randomization until EOS

Iron-chelating agents (e.g., deferoxamine, deferiprone, or deferasirox therapy): from 
4 weeks prior to randomization until EOS

Dapsone in any dose amount or chronic use of acetaminophen/paracetamol > 2.0 g/day 
from the day of randomization until EOS
Use of herbal medicine is not prohibited but strongly discouraged during the course of the 
study.
5.1.3.4 Procedure and Non-drug Therapy Recording
Any other procedures or non-drug therapies need to be recorded from informed consent until 
EOT. This also includes the recording of hospitalizations until the projected date of week 108.
5.1.4
Treatment Compliance
For subjects randomized to roxadustat, 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. All roxadustat bottles dispensed to the subject should be returned by the 
subject to the site, including empty bottles for reconciliation by the study monitor.


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For subjects randomized to darbepoetin alfa the administration of each dose at site will be 
recorded in the eCRF with information on dose and route and reasons for each dose change.
All administrations will be performed by the investigator or a qualified member of the site 
staff or, after 36 weeks of treatment, by the subject themselves or caregiver, e.g., relative, if 
well trained and willing to self-administer.
The quantity and dose of syringes dispensed to and taken by the subject will be counted and 
recorded in the eCRF. The empty packages of darbepoetin alfa should be stored at site for 
reconciliation by the study monitor. In case of self-administration after 36 weeks of treatment, 
the empty packages of darbepoetin alfa should be returned by the subject to the site.
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.
1) RBC Transfusion (for all subjects)
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 treatment may be continued even if a blood transfusion has been 
administered.
2) ESA (only for subjects treated with roxadustat)
If the investigator considers administration of ESA as a medical necessity, darbepoetin alfa 
may be initiated if the following criteria are met:

the subject’s Hb level is < 9.0 g/dL (HemoCue) as confirmed at two consecutive 
visits,
AND

the subject’s Hb level has not responded adequately despite 2 or more roxadustat dose 
increases in the previous 8 weeks, or the roxadustat dose reached the maximum dose 
limit,
AND

reducing the risk of alloimmunization in transplant eligible subjects and/or reduction 
of other RBC transfusion-related risks is a goal.
Prior to the initiation of darbepoetin alfa, the subject’s Hb response, as well as factors 
influencing the Hb response, such as iron status, inflammatory status, hemolysis, blood loss 
or other potential reasons for Hb decrease should be considered and, where applicable, be 
addressed by the investigator.
The subject may continue in the study while on rescue treatment with darbepoetin alfa, 
however, it is not allowed to administer roxadustat during the same time period.


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The course of darbepoetin alfa (i.e., the amount that may be administered) will be limited by 
duration of therapy and effect on Hb. The course of darbepoetin alfa rescue treatment will 
not exceed 4 weeks in duration, and darbepoetin alfa rescue will be stopped as soon as 
Hb ≥9.0 g/dL. To continue study participation, treatment with roxadustat study drug should 
be resumed within one week after the last administration of darbepoetin alfa at the dose level 
the subject was on prior to initiating darbepoetin alfa rescue therapy.
If a subject requires a second course of rescue darbepoetin alfa, the subject must be 
discontinued from treatment.
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 study treatment dose hold. 
This should be documented in the eCRF and source documentation, and discussed with the
Medical Monitor.
5.1.7
Restrictions During the Study
Subjects are not permitted to consume more than three 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 
serum pregnancy test at screening AND, if heterosexually active, must agree to use a highly 
effective form of birth control as stated in the inclusion criteria. If required by local law, 
2 highly effective methods of birth control must be used, 1 of which must be a barrier method.
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 treatment. If a subject discontinues prematurely, contraception must be 
practiced for 12 weeks (male subjects) and 28 days (female subjects) following final 
administration of study treatment.
Pregnancy, spontaneous or therapeutic abortion, or events related to pregnancy must be 
reported (see Section 5.5.7).
5.2
Demographics and Baseline Characteristics
5.2.1
Demographics
Demographic data recorded during screening, including date of birth (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, will be obtained at 
screening. All relevant past and present conditions as well as prior surgical procedures, and 


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previous and current tobacco use will be recorded in the subject’s eCRF. Relevant conditions 
include conditions that have been treated with medication within four months prior to 
randomization. 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 should be performed within 12 weeks prior to randomization. 
This is not required if results of a previous renal ultrasound (or other renal imaging modality 
such as CT scan or MRI) within 12 weeks prior to randomization are available and it 
conclusively excludes the presence of renal cell carcinoma. Renal ultrasound findings are 
required prior to randomization to exclude subjects with a presence or suspicion of renal cell 
carcinoma (exclusion criterion 16). Sites are reminded to schedule the renal ultrasound, 
following the first screening visit and prior to randomization, only for those subjects that 
have not had a renal ultrasound, or other renal imaging modality, in the specified period. The 
date of the renal ultrasound examination and the assessment of the presence or 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 of anemia, the date of 
diagnosis of CKD, CKD stage and etiology. Also the non-drug therapy history and 
medication history for anemia in the last 12 months prior to randomization will be obtained.
CKD 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. Documentation of reduced eGFR should be available in the 
subject’s source documentation. In addition, calculation of eGFR to confirm the degree of 
CKD will be performed by the central laboratory at screening for eligibility and on day 1.
eGFR will be calculated using the following MDRD equation: GFR (mL/min per 1.73 m2) = 
175 × Serum Cr –1.154 × age–0.203 × (0.742, if female) × (1.212, if black).
Anemia will be measured by repeated Hb measurements (central laboratory assessment) 
during screening; the mean of the 2 most recent Hb values during the screening period, 
obtained at least 4 days apart, must be ≤10.5 g/dL with a difference of ≤1.0 g/dL. 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, RBC indices, WBC 
count and differential, platelet count and reticulocyte count

Iron status

Serum vitamin B12 and folate levels.
For more details on the laboratory tests, please see Section 5.4.3


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5.2.5
Further Laboratory Testing Prior to Randomization
Other laboratory tests mandatory prior to randomization of a subject include immunoassay
for HIV, Hepatitis B (HBsAg) and hepatitis C antibody (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 5.4.3.3
5.3
Efficacy Assessment
5.3.1
Primary Efficacy Assessment
Efficacy assessment of treatment with study treatment will be based primarily upon Hb as 
assessed by central laboratory from IV blood sampling.
For the exact timing of Hb assessments refer to the Schedule of Assessments, [Table 1].
The use of rescue medication (as recorded in the eCRF) will be taken into account for the 
evaluation of the primary efficacy assessment.
5.3.2
Additional Efficacy Assessments
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 blood pressure refer to 
Section 5.4.1.1
5.3.2.2 Serum Lipid Panel
Blood sampling for serum lipids should be done in a fasting condition, wherever possible. 
The following parameters will be assessed: total cholesterol, LDL-cholesterol, 
HDL-cholesterol, triglycerides, apolipoproteins A1 and B.
5.3.3
Additional Assessments
5.3.3.1 Health Related Quality of Life Questionnaires
All study subjects will be required to complete Quality of Life (QoL) questionnaires as 
indicated in the Schedule of Assessments (Table 1): SF-36, FACT-An, EQ-5D 5L, PGIC and 
WPAI:ANS (see Appendices 12.4-12.9). The QoL questionnaires are to be completed by the 
subject prior to any other study assessments on the study visits.
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. The SF-36 consists of eight 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’.


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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 four dimensions of physical well being (PWB)—7 items, functional 
(FWB)—7 items, social/family (SWB)—7 items each, and emotional (EWB)—6 items. A 
subscale of 13 fatigue specific items (the Fatigue Subscale) plus seven 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 AnS is referred to as the FACT-An
(see Appendix 12.6). 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 EuroQol Questionnaire - 5 Dimensions -5 Levels (EQ-5D-5L) is a self-reported 
questionnaire. The EQ-5D is being used as a measure of respondents' Health Related Quality 
of Life (HRQoL) and utility values. The EQ-5D consists of the EQ-5D descriptive system 
and the EQ visual analogue scale (VAS). The EQ-5D descriptive system comprises 
5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate 
problems, severe problems, extreme problems. The 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). The EQ-5D-5L is 
shown in Appendix 12.7
5.3.3.1.4
Patient Global Impression of Change Scale (PGIC)
The PGIC (Appendix 12.8) 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), when compared to the start of the study treatment.
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 seven days due to anemia [Reilly et al, 1993].  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. The 
WPAI:ANS is shown in Appendix 12.9


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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 one dose of study 
drug), until the projected date of the EOS visit (week 108).
5.3.3.3 Iron Status, HbA1c, CKD Progression and UACR
Serum iron, TSAT, ferritin, HbA1c, fasting blood glucose, eGFR and UACR will be assessed 
(central laboratory) according to the Schedule of Assessments, Table 1
5.3.3.4 Additional Assessments
Exploratory assessments in this study include the following parameters:

High Sensitivity C-reactive protein (hs-CRP)

Relevant selected biomarkers may be assessed from archived serum/plasma samples and 
urine samples

PGIC Score

WPAI:ANS Score
5.4
Safety Assessment
5.4.1
Vital Signs
The vital signs blood pressure, HR and respiratory rate will be assessed at the visits as 
described in the Schedule of Assessments, [Table 1].
See additional information in Appendix 12.4.
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 the 2 visits during the 
screening period, and in triplicate with a least two minute intervals for all other visits. The 
same arm should be used consistently for measurements throughout the study.


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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 blood pressure measurement (see 
Section 5.4.1.1), by using any other suitable device or manually (wrist HR within 
one 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 the 2 visits during the screening period, and in triplicate with 
at least two 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 
one 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 
provided to each site and a dedicated staff member (and one 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 12.2 Liver Safety Monitoring and Assessment for detailed information on liver 
abnormalities, monitoring and assessment, if the AE for a subject enrolled in a study and 
receiving study drug is accompanied by increases in liver function testing (LFT, e.g.: AST, 
ALT, bilirubin, etc.) or is suspected to be due to hepatic dysfunction.
In the event of a confirmed, severe hepatic abnormality as defined in Appendix 12.2 it is the 
investigator’s responsibility to ensure contact with the Sponsor/delegated CRO (Contract 
Research Organization) by telephone or fax immediately (i.e., within 24 hours of awareness).


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5.4.3
Laboratory Assessments
5.4.3.1 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.
5.4.3.2 Urinalysis
Dipstick analysis will be performed for protein, pH and glucose. A quantitative assessment 
of albuminuria (UACR) will be performed by the central laboratory. Ideally, the sample 
should be from the first morning void.
5.4.3.3 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 
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.
In Table 7, the laboratory tests that will be performed during the conduct of the study are listed. 
The exact timing of all assessments can be found in [Table 1] Schedule of Assessments.


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Table 7
Laboratory Tests
Lab assessment type
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 and Hb in reticulocytes (CHr)
Serum Chemistry
Sodium
Potassium
Calcium
Chloride
Glucose (fasting condition wherever possible)
Creatinine
Magnesium
Bicarbonate
Phosphorus
Uric Acid
Albumin
Total protein
Lactate dehydrogenase
Blood urea nitrogen
Lipase
Liver Function Tests:

AST

ALT

Bilirubin (Total and direct)

GGT

ALP
Lipid Panel (in fasting condition wherever possible):

Total Cholesterol

LDL

HDL

Triglycerides

Apolipoproteins A1, B and ApoB/ApoA1 ratio
Serum iron
Ferritin 
TIBC
TSAT (= measured as FESAT)
Pregnancy test (for female subjects of child bearing potential only)
HbA1c
Vitamin B12
Folate
Table continued on next page


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Lab assessment type
Parameters to be analyzed
Serology (Immunology):

HIV Immunoassay

HBsAg 

Anti-HCV antibody 
Special Laboratory Analytes
hs-CRP
Serum Biomarkers
Archival of serum samples for biomarkers
PK analysis
Level of roxadustat
Covariates for PK

Albumin 

α1-AGP 
Whole Blood
Genotyping
Urinalysis
Qualitative

Protein

pH

Glucose
Quantitative

Creatinine

Albumin

UACR
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 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.
A targeted physical 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).
Height is measured only at screening. Weight is measured at screening, day 1, weeks 24, 36, 
52, 76, EOT and EOS.
5.4.5
Electrocardiogram (ECG)
Local 12-lead ECGs will be performed on all subjects at specific time points as described in
Table 1, 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 
using the HR in the eCRF. ECG recording will be kept as source documents.


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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 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 one 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 treatment will be considered as ‘non-treatment emergent’.
Baseline conditions that worsen during the study will be recorded as AEs. AEs with a start 
date after subjects have completed EOS procedures will not be captured.
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 and 
documented in source documents only.


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Data to be recorded in the eCRF include a description of the event, date of onset, onset status 
(onset before/after first dose of study medication), end of the event, severity, SAE, 
seriousness criteria, action with respect to study medication, treatment required, relationship 
to study treatment 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 treatment or through to EOS, 
except for pregnancy reporting (see Section 5.5.7). 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).
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 treatment
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 AE 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 AE 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 AE 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

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 


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or may require intervention to prevent one 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 12.2 (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 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 the SAE and/or Special 
Situation worksheet and within the timelines of reporting SAEs, thus within 24 hours of 
becoming aware of this event, regardless whether or not a (S)AE occurred. 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 a 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.
The Sponsor has a list of events that they classify as “always serious” events. If an AE 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.
If a subject becomes pregnant during treatment, this should be reported as if it were a SAE. 
Refer to Section 5.5.7


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5.5.3
Criteria for Causal Relationship to the Study Drug
AEs that fall under either "Possible" or "Probable" should be defined as "AEs whose 
relationship to the study drugs could not be ruled out".
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
AEs, including abnormal clinical laboratory values, will be graded using the National Cancer 
Institute-Common Terminology Criteria for AE (NCI-CTCAE) guidelines (Version 4.03). 
The items that are not stipulated in the NCI-CTCAE Version 4.03 will be assessed according 
to the criteria below and entered into the eCRF:
Grade
Assessment Standard
1-Mild
Asymptomatic, or mild symptoms, clinical or diagnostic observations 
noted; intervention not indicated.
2-Moderate
Local or noninvasive intervention indicated.
3-Severe
Medically significant but not immediately life threatening, 
hospitalization or prolonged hospitalization.
4-Life Threatening
Life threatening consequences, urgent intervention indicated
5-Death
Death related to AE
5.5.5
Reporting of Serious Adverse Events (SAEs)
In the case of a serious adverse event (SAE), the investigator must contact his/her respective
delegated CRO (INC Drug Safety or other CRO as specified in the Investigator Site File) by 
telephone or fax immediately (within 24 hours of awareness).
The investigator should complete and submit an SAE worksheet containing all information that 
is required by the Regulatory Authorities to the delegated CRO by fax or email immediately 
(within 24 hours of awareness).  If the faxing or e-mailing of an SAE Worksheet is not 


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possible or is not possible within 24 hours, the local drug safety contact should be informed by 
phone.
The SAE worksheet should be sent to the delegated CRO that is responsible for the 
investigator’s country:
INC Drug Safety or other CRO as specified in the Investigator Site File:
Email: INCDrugSafety@INCResearch.com
Fax: toll-free numbers will be provided for each country; the specific fax number can be 
found on the SAE form fax cover sheet
Tel: +49 89 99 39 13 198
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. 
If there are questions, or if clarification is needed regarding the SAE, please contact the 
Sponsor’s Medical Monitor or his/her designee or the delegated CRO that is responsible for 
the investigator’s country (for contact details, see Section II of the protocol and as specified 
on the contact list in the Investigator Site File).
Follow-up information for the event should be sent promptly (within 7 days of the initial 
notification).
Full details of the SAE should also be recorded on the medical records and on the eCRF.  
The following minimum information is required to be completed on the SAE Worksheet:

The ISN/Study number 1517-CL-0610

Subject number, sex and age

The date of report

A description of the SAE (event, seriousness of the event), and

Causal relationship to the study drug
All SAEs, including death, should be reported, when occurring up to EOS visit or up to 
28 days after the last intake of study medication, whichever is last. In addition, any event 
leading to hospitalization 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 to the regulatory 
agencies as necessary, and will inform the investigators of such regulatory reports. 
Investigators must submit safety reports as required by their Institutional Review Board 
(IRB)/Independent Ethics Committee (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 CRO will notify all investigators responsible for ongoing clinical studies with the study 
drug of all SAEs which require submission per local requirements IEC.
The investigators should provide written documentation of IRB/IEC notification for each 
report to the Sponsor.


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Please contact the Sponsor's Medical Monitor for any other problem related to the safety, 
welfare, or rights of the subject.
5.5.6
Follow-up of Adverse Events
All AEs 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 AE follow-up, the AE 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 12.2 for detailed instructions on Drug Induced Liver Injury.
5.5.7
Procedure in Case of Pregnancy
If a female subject or female partner of a male subject becomes pregnant during the study 
dosing 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 miscarriage, 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

Unless a congenital anomaly are identified prior to spontaneous abortion or miscarriage, 
the embryo or fetus should be assessed for congenital defects by visual examination
If during the conduct of a clinical trial, a male subject makes his partner pregnant, the subject 
should report the pregnancy to the investigator. The investigator will report the pregnancy to 
the delegated CRO as an SAE.


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5.5.8
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 may be performed. The Medical Monitor 
should be contacted as applicable.
In the event of suspected darbepoetin alfa overdose, refer to the approved EU SmPC.
The therapeutic margin of darbepoetin alfa is very wide. Even at very high serum levels, no 
symptoms of overdose have been observed. In the event of polycythemia, darbepoetin alfa 
should be temporarily withheld. If clinically indicated, phlebotomy may be performed.
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. Investigators should inform the IRB/IEC of such information when 
needed.
5.6
Test Drug Concentration
For the purpose of evaluation of the population PK, blood samples will be obtained from the 
subjects that are treated with roxadustat. The intention is to collect 6 blood samples per 
roxadustat-treated subject at the following time points:
A: 2 to 0 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 at one visit, or over 2 to 3 visits. These visits should take 
place 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 PK visit (last assessment 
of the visit).
The investigator is free to choose at which study visits, between week 2 and 8 of treatment, to 
draw the samples and in which order. The study site will agree with the subjects on timing 
and process of the sampling. Based on preference of the study site and the subject, there is a 
choice of three sampling schedules to perform the PK samples collection, see [Table 8].
During weeks 1 to 8, subjects treated with roxadustat will be instructed to record the date and 
time of study drug intake in the study medication diary. The information will be used to record 
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of PK sampling in the eCRF. The date and time of PK sampling and the actual study drug dose 
taken on the day of sampling will be recorded in the eCRF.
During the PK visits one additional sample will be collected for determination of alpha 
1-Acid Glycoprotein (α1-AGP) and albumin concentration.
Table 8
Examples of Sampling Schedules for Population PK
Schedule#
PK Visit 1
PK Visit 2
PK Visit 3
1
Collect pre-dose sample A.
Take study drug in clinic.
Collect samples B to F.
None
None
2
Collect pre-dose sample A.
Take study drug in clinic.
Collect samples B and C.
Take study drug.
Collect samples D to F.
None
3
Collect pre-dose sample A.
Take study drug in clinic.
Collect samples B and C.
Take study drug.
Collect sample D and E.
Take study drug.
Collect sample F.
# The order of the PK visits for schedule 2 and 3 is a decision for the investigator.
5.6.1
Blood Samples for Roxadustat PK Analysis
Samples of venous blood for bioanalysis of roxadustat, related metabolites of roxadustat and 
exploratory biomarkers will be collected into appropriately labeled tubes containing sodium-
heparin as anticoagulant.
All further details on the processing of the samples, storage and shipment conditions will be 
provided in the laboratory manual.
5.7
Other Measurements, Assessments or Methods
5.7.1
α1-AGP and Albumin in Serum
Serum levels of albumin and α1-AGP will be included as covariate in the PK 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 PK 
sampling is performed (1-3 visits). If 1 or more PK samples are taken at a visit, one α1-AGP 
sample should be taken at that visit as well.
All details on the processing of the samples, storage and shipment conditions will be 
provided in the laboratory manual.
5.7.2
Archival of Serum Samples for Biomarker Analysis
Serum 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, 
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 central laboratory manual.


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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.
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 central 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 for subjects randomized to the roxadustat arm.
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 EDTA 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 
in accordance with relevant guidelines and procedures, maximally 5 years after the last 
subject completed the study.
5.8
Total Amount of Blood
The total amount of blood to be collected per subject during the study, based on the subject’s 
screening period, the 104 weeks’ treatment period and the follow-up period and allowing full 
re-screening and unscheduled visits is estimated to be approximately 460 mL.
6
DISCONTINUATION
6.1
Discontinuation of Individual Subject(s)
A discontinuation is a subject who enrolled into the study and for whom study treatment is 
permanently discontinued prematurely for any reason.
The subject is free to discontinue from study treatment or withdraw from the 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.


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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.
Discontinued subjects will complete the EOT visits (EOT visit and EOT + 2 weeks visit) and 
EOS visit procedures. The appropriate documentation must be entered on the eCRF.
Premature treatment discontinuation
Subjects should be prematurely discontinued from 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

Subjects randomized to roxadustat: requirement of a second course of rescue therapy with 
darbepoetin alfa deemed necessary by the investigator based upon the criteria for use of 
rescue treatment

Subject receives an organ transplant
Subjects that have prematurely discontinued study treatment will complete the EOT visits 
(EOT visit and EOT + 2 weeks visit) and EOS visit. Thereafter, these subjects who have 
taken at least one dose of study drug will continue to be followed up every 6 months for vital 
status, SAEs, cardiovascular and thromboembolic AEs until their projected date of 
completion of the follow-up period (i.e., projected week 108 date) or until consent is
withdrawn.
Study withdrawal
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 a study subject

The Sponsor may decide to prematurely stop the study, e.g., for safety considerations
Women of childbearing potential who discontinue from treatment and/or 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.


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6.2
Discontinuation of the Site
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the Sponsor.
6.3
Discontinuation of the Study
The Sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination. Advance notice is not required if the study is stopped due to safety concerns. If 
the Sponsor terminates the study for safety reasons, the Sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination.
7
STATISTICAL METHODOLOGY
The statistical analysis will be coordinated by the responsible biostatistician of APEB. A 
Statistical Analysis Plan (SAP) will be written to provide details of the analysis, along with 
specifications for tables, listings and figures to be produced. The SAP will be finalized 
before the database soft lock at the latest. Any changes from the analyses planned in SAP 
will be justified in the Clinical Study Report (CSR).
Prior to Database Lock, a Final Review of Data and Table Listings Figures 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 lock
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
standard deviation, minimum, median and maximum) for continuous endpoints, and 
frequency and percentage for categorical endpoints.
7.1
Sample Size
Approximately 570 subjects will be randomized to receive roxadustat or darbepoetin alfa as 
follows:
Table 9
Sample Size Calculations per Treatment Arm 
Treatment 
Group
Protocol version 1
Protocol versions 2 and 3
Total
Randomized
PPS
Randomized†
PPS
Randomized
PPS
Roxadustat
100
80
210
168
310
248
Darbepoetin alfa
50
40
210
168
260
208
Total
150
120
420
336
570
456
† The number of subjects under protocol v20 and v3 will depend on the number of subjects randomized under 
protocol v1.


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Randomization will be stratified by the following four factors:

Region: region A versus region B*
* Assignment to region will be determined based on health care 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)
Assuming that the PPS analysis will consist of 80% of subjects in the Full Analysis Set (FAS), 
570 randomized subjects in the FAS will lead to 456 subjects in the PPS. Two hundred and 
forty eight (248) subjects for the roxadustat treatment group and 208 subjects for the 
darbepoetin alfa treatment group will provide at least 98% test power to demonstrate 
statistically non-inferiority of roxadustat versus darbepoetin alfa in the primary endpoint 
assuming that the proportion of subjects with response in both groups is the same and at least 
80% and a non-inferiority margin for the difference of proportions of 15%. The power for the 
sensitivity analysis of post-amendment data (336 subjects) will be at least 93%.
7.2
Analysis Set
Detailed criteria for analysis sets will be laid out in Classification Specifications and the 
allocation of subjects to analysis sets will be determined prior to database hard-lock
The following analysis sets are defined and will be used for the statistical analysis:

Intent-to-Treat Set (ITT)

Full Analysis Set (FAS)

Per-Protocol Set (PPS)

Safety Analysis Set (SAF)

Pharmacokinetic Analysis Set (PKAS)
7.2.1
Intent-to-Treat Set (ITT)
All randomized subjects will be included in the ITT.
The primary and secondary efficacy endpoints will be analyzed using the ITT as a sensitivity 
analysis.
7.2.2
Full Analysis Set (FAS)
All randomized subjects who received at least one dose of study drug and have at least 
one post-dose Hb assessment will be included in the FAS. 
The primary and secondary efficacy endpoints will be analyzed using the FAS.
7.2.3
Per Protocol Set (PPS)
All FAS subjects who received at least 2 weeks of study treatment with valid corresponding 
Hb measurements and without any criteria for PPS exclusion will be included in the PPS.  


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Criteria for PPS exclusion will be defined in the SAP. The primary and secondary efficacy 
endpoints will also be analyzed using the PPS. Additional PPS sub-populations (e.g., PPS-
36) will be described in the SAP.
7.2.4
Safety Analysis Set (SAF)
All subjects that received at least one dose of study drug will be included in the SAF. All 
safety data will be analyzed using the SAF.
7.2.5
Pharmacokinetic Analysis Set (PKAS)
The PKAS consists of all randomized subjects who meet the following criteria:

Received at least one dose of study drug, and

At least one quantifiable plasma concentration of roxadustat was obtained and dosing and 
sampling history has been recorded.
The PKAS will be used for all tables and graphical summaries of the PK data.
7.3
Demographics and Other Baseline Characteristics
Demographic (age, race, sex) and other baseline characteristics, including stratification 
factors, and subject disease characteristics will be summarized for the SAF, ITT, FAS and 
PPS populations.
Descriptive statistics will be calculated for continuous variables (e.g., age, weight, baseline 
Hb, body mass index and baseline eGFR) and frequency counts and percentages will be 
tabulated for categorical variables (e.g., sex, race, baseline Hb category, region, baseline 
eGFR category and history of cardiovascular disease or cerebrovascular disease) by study 
treatment arm, roxadustat group and overall.
7.4
Analysis of Efficacy
7.4.1
Analysis of Primary Endpoint 
The primary efficacy endpoint is:
Hb response defined as: Hb ≥11.0 g/dL and a Hb increase from BL Hb by ≥1.0 g/dL in any 
subject with BL Hb > 8.0 g/dL, or an increase from BL Hb by ≥2.0 g/dL in any subject with 
BL Hb ≤8.0 g/dL as measured at 2 consecutive visits separated by at least 5 days during the 
first 24 weeks of treatment without administration of rescue therapy prior to Hb response.
7.4.1.1 Primary Analysis
The primary analysis will be performed on the PPS.
The difference in the proportion of responders in the primary efficacy variable between 
pooled roxadustat and darbepoetin alfa will be calculated using Mattinen & Nurminen 
approach adjusting for the following stratification factors:

Region: region A versus region B*
* Assignment to region will be determined based on health care comparability.


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
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)
The primary hypothesis to be tested for the primary efficacy analysis is:
H0: Hb responder rate in the pooled roxadustat group < Hb responder rate in the 
darbepoetin alfa group minus 15%
versus
H1: Hb responder rate in the pooled roxadustat group ≥Hb responder rate in the 
darbepoetin alfa group minus 15%
This null hypothesis will be rejected if the two-sided 95% CI for the difference of proportions 
lies entirely above -15%.
In addition, a 95% CI will be calculated for the proportion of responders on roxadustat and 
darbepoetin alfa based on the exact method of Clopper-Pearson. Sensitivity analyses will be 
conducted to assess the consistency of the results before and after protocol amendments 1 
and 2 (e.g., protocol versions 2.0 and 3.0 respectively).
Justification of the non-inferiority margin.
In general an appropriate choice of margin should provide both:
a) Assurance that the test drug has a clinically relevant effect greater than zero (placebo). 
This aspect of the choice of margin is discussed in EMEA Guideline on the choice of the 
non-inferiority margin, section III [EMEA, 2005].
b) Assurance that the test product is not substantially inferior to the reference in EMA 
guideline. This aspect of the choice of margin is discussed in EMEA Guideline on the 
choice of the non-inferiority margin, section IV [EMEA, 2005].
Two randomized pivotal placebo controlled studies are planned in this population 
(FGCL-4592-060 and 1517-CL-0608) that will directly prove superiority over placebo. 
Since direct comparisons provide always a higher level of evidence than indirect tests, the 
main criterion to fix the NI-margin in the 1517-CL-0610 study is bullet b above, i.e., to prove 
that the difference between roxadustat and darbepoetin alfa is unimportant.
From a clinical point of view, a true response rate for roxadustat of 15% lower than the true 
response rate for darbepoetin alfa is regarded an unimportant loss in efficacy since roxadustat
is anticipated to have a number of advantages that have been shown during the phase 2
program: no need for IV iron supplementation, no increase of blood pressure and no increase 
of platelet counts. 
No regulatory guideline exists in this therapeutic indication recommending a non-inferiority 
margin. However, the selected non-inferiority margin of 15% is in line with the FDA 
guideline in the urinary tract infections indication, where a high responder rate was also 
expected and a non-inferiority margin of 15% was recommended [FDA, 1998].


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7.4.1.2 Secondary Analysis
The same analysis of the primary endpoint as described in [Section 7.4.1.1] will be repeated
using the FAS and ITT. A sensitivity analysis on the primary efficacy endpoint will be 
performed on the subgroup of subjects being randomized after the implementation of 
protocol v2.0 and v3.0.
7.4.1.3 Subgroup Analysis
The analysis of the primary variable will be repeated separately by gender, age group, region, 
BL Hb categories, iron repletion at BL, diabetes and eGFR categories. Other subgroup 
analyses might be added to the SAP.
7.4.2
Analysis of Secondary Endpoints
7.4.2.1 Primary Analysis
The primary analysis set will be PPS for the non-inferiority tests and FAS for the superiority 
tests.
Once the primary hypothesis has been rejected for the primary endpoint, the key secondary 
endpoints below (Table 10) will be tested using a fixed sequence testing procedure, as depicted 
in Table 10 in order to maintain the overall one-sided type I error rate at 0.025. If the one-
sided p-value from a test is < 0.025, the claim of superiority (or non-inferiority) will be 
considered successful and the test will progress to the next comparison in sequence as follows:
Table 10
Secondary Endpoints Fixed Sequence Testing Procedure
Test
Endpoint
Comparison*
1
Hb change from BL to the average Hb of weeks 28 to 36 
without having received rescue therapy within 6 weeks 
prior to and during this 8-week evaluation period (the 
non-inferiority margin for the difference between groups 
is 0.75 g/dL).
Non-inferiority of pooled 
roxadustat versus darbepoetin alfa
2
LDL cholesterol change from BL to the average of 
weeks 12 to 28
Superiority of pooled roxadustat 
versus darbepoetin alfa
3
Mean monthly IV iron (mg) use per subject during 
weeks 1 to 36
Superiority of pooled roxadustat 
versus darbepoetin alfa
4
SF-36 PF sub-score change from BL to the average of 
weeks 12 to 28
(the non-inferiority margin is fixed as a difference of 3
points)
Non-inferiority of pooled 
roxadustat versus darbepoetin alfa
5
SF-36 vitality sub-score change from BL to the average 
of weeks 12 to 28 (the non-inferiority margin is fixed as 
a difference of 3 points)
Non-inferiority of pooled 
roxadustat versus darbepoetin alfa
6
MAP change from BL to the average MAP of weeks 20 
to 28
(the non-inferiority margin for the difference between 
groups is 1 mmHg)
Non-inferiority of pooled 
roxadustat versus darbepoetin alfa
Table continued on next page


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Test
Endpoint
Comparison*
7
Incidence of hypertension (the non-inferiority margin is 
fixed as a hazard ratio of 1.3)
Non-inferiority of pooled 
roxadustat versus darbepoetin alfa 
8
MAP change from BL to the average MAP of weeks 20 
to 28
Superiority of pooled roxadustat 
versus darbepoetin alfa 
9
Incidence of hypertension 
Superiority of pooled roxadustat 
versus pooled darbepoetin alfa 
*Subjects randomized to roxadustat QW, BIW and TIW under protocol v1 will be pooled together.
1.
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 (non-inferiority) 
will be analyzed using a Mixed Model of Repeated Measures (MMRM) with unstructured 
covariance matrix model (pooled roxadustat versus darbepoetin alfa). The model will 
contain terms for treatment arm, baseline measurement, visit, visit x treatment interaction 
and other stratification factors. The non-inferiority margin for the difference between 
groups is 0.75 g/dL. Non-inferiority can be concluded if the lower limit of the two-sided 
95% CI of the difference between the two treatment arms is above -0.75 g/dL.
2.
Change from BL in LDL cholesterol to the average value of LDL cholesterol of 
weeks 12-28 (superiority) will be compared (pooled roxadustat versus darbepoetin alfa) 
using an MMRM with unstructured covariance matrix model. The model will contain 
terms for treatment arm, baseline measurement, visit, visit x treatment interaction and 
other stratification factors.
3.
Monthly IV iron use (mg) during weeks 1 to 36 (superiority) will be compared (pooled 
roxadustat versus darbepoetin alfa) using a MMRM with unstructured covariance matrix 
model. The model will contain terms for treatment arm, baseline measurement, visit, visit 
x treatment interaction and other stratification factors.
4.
Change from BL in PF subscore of SF-36 to the average of weeks 12–28 (non-inferiority) 
will be compared (pooled roxadustat versus darbepoetin alfa) for all subjects, using an 
MMRM with unstructured covariance matrix model. The model will contain terms for 
treatment arm, baseline measurement, visit, visit x treatment interaction and other 
stratification factors. Non-inferiority can be concluded if the lower limit of the 2-sided 
95% CI of the difference between the 2 treatment arms is above -3 points.
5.
Change from BL in Vitality subscore of SF-36 to the average of weeks 12–28 will be 
compared (pooled roxadustat versus darbepoetin alfa) for all subjects, using an MMRM 
with unstructured covariance matrix model. The model will contain terms for treatment 
arm, baseline measurement, visit, visit x treatment interaction and other stratification 
factors. Non-inferiority can be concluded if the lower limit of the 2-sided 95% CI of the 
difference between the 2 treatment arms is above -3 points.
6.
Change from BL in MAP to the average of weeks 20–28 (non-inferiority) will be 
compared (pooled roxadustat versus darbepoetin alfa) using a MMRM with unstructured 
covariance matrix model. The model will contain terms for treatment arm, baseline 
measurement, visit, visit x treatment interaction and other stratification factors. 


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Non-inferiority can be concluded if the lower limit of the two-sided 95% CI of the 
difference between the two treatment arms is below 1 mm Hg.
7.
Incidence rate (per 100 subject years at risk) and cumulative risk curve of subjects with 
hypertension from BL will be reported and compared (pooled roxadustat versus 
darbepoetin alfa) using stratified Cox Proportional Hazards regression adjusting for 
stratification factors. Hazard ratio and the two-sided 95% CI will be calculated for the 
frequency of pooled roxadustat as relative to darbepoetin alfa. Non-inferiority will be 
declared if the upper bound of the 2-sided 95% CI is below 1.3. 
8.
Change from BL in MAP to the average of weeks 20–28 (superiority) will be compared 
(pooled roxadustat versus darbepoetin alfa) using an MMRM with unstructured 
covariance matrix model (pooled roxadustat versus darbepoetin alfa). The model will 
contain terms for treatment arm, baseline measurement, visit, visit x treatment interaction 
and other stratification factors.
9.
Incidence rate (per 100 subject years at risk) and cumulative risk curve of subjects with 
hypertension from BL will be reported and compared (pooled roxadustat versus 
darbepoetin alfa) using stratified Cox Proportional Hazards regression adjusting for 
stratification factors. Hazard ratio and the two-sided 95% CI will be calculated for the 
frequency of pooled roxadustat as relative to darbepoetin alfa. 
7.4.2.2 Secondary Analysis
The analysis of the secondary endpoints as described in 7.4.2.1 will be repeated using (a) the 
FAS and ITT and (b) the PPS for both non-inferiority tests and superiority tests.
For all secondary variables analyzed using MMRM, an additional sensitivity analysis will be 
performed using an Analysis of Covariance (ANCOVA) model with Last Observation 
Carried Forward (LOCF) method using BL value and the stratification factors as covariates.
As an additional sensitivity analysis, the mean Hb change from BL, first secondary variable, 
will also be calculated using all Hb values regardless of rescue therapy (this is included 
among the additional endpoints). This will be analyzed using an MMRM model similar to 
the one described in Section 7.4.2.1
Additional sensitivity analyses will be defined in the SAP.
7.4.2.3 Subgroup Analysis
The analysis of selected secondary variables 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.
7.4.3
Analysis of Additional Endpoints 
The Hb change from BL to the average Hb of weeks 28 to 52 regardless of the use of rescue 
therapy will be analyzed on the ITT population using an 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. Non-inferiority can 


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be concluded if the lower limit of the two-sided 95% CI of the difference between the 
two treatment arms (roxadustat minus darbepoetin) is above -0.75 g/dL.
Statistical analysis for the other additional endpoints will be detailed in the SAP.
7.5
Analysis of Safety
Safety analyses will be performed using the SAF. Safety parameters include AEs, SAEs
laboratory parameters (with special emphasis on excessive Hb response and liver function 
tests [LFTs]), vital signs, 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 baseline assessment for all analyses.
All safety analyses will be presented both by treatment group (pooled roxadustat and 
darbepoetin alfa) and by all 4 study arms, and by visit (if relevant).
The number and percentage of subjects reporting TEAEs and TESAEs in each treatment 
group will be tabulated. Descriptive statistics will be presented for laboratory, vital signs 
values and ECG parameters by visit and for the changes from BL to each visit. Further 
details will be described in the SAP. The statistical method for analysis of adjudicated safety 
data will be detailed in a pooled cardiovascular safety SAP.
Safety data and dosing decisions will be monitored on an ongoing basis. Ongoing review of 
safety data will be conducted by an independent DSMB.
7.5.1
Adverse Events
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA).
An AE (classified by preferred term) started during the treatment period will be considered a 
Treatment Emergent AE (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 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 system organ class (SOC) and preferred term; by SOC, preferred term, and 
severity; and by SOC, preferred term, and relationship to study medication. If more than one 
event occurs with the same preferred term for the same subject, the subject will be counted 
only once for that preferred term using the most severe and most related occurrence for the 
summarization by severity and by relationship to the study medication.
The overall distribution of TEAEs by severity and relationship to study medication will be 
summarized by treatment group.
The proportion of subjects with TESAE, fatal SAEs (i.e., events that caused death), and AEs 
leading to discontinuation of study drug will be summarized by SOC, preferred term and 
treatment group.


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TEAEs will also be reported in terms of cumulative incidence versus time and as an incidence 
rate per subject-exposure-year.
Listings will be presented of subjects with SAEs, subjects with AEs leading to 
discontinuation and subjects who died.
7.5.2
Laboratory Assessments
For quantitative laboratory measurements, descriptive statistics will be used to summarize 
results (in International System of Units [SI]) and change from baseline by treatment group and 
time point. Shifts relative to normal ranges from baseline to each time point during treatment 
period in lab tests will also be tabulated. Laboratory data will be displayed in listings.
7.5.3
Vital Signs
Descriptive statistics for vital signs (e.g., systolic and diastolic blood pressure, 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
ECGs
Descriptive statistics for ECG parameters (HR, PR interval, QRS interval, QT interval and QTc 
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. Presence of potentially clinically significant ECG values will be reported using 
similar statistics as mentioned for TEAEs.
7.6
Analysis of Pharmacokinetics
Plasma concentration data of roxadustat will be subjected to population PK analysis. The 
aim of this analysis is to describe the PK behavior of roxadustat in the target population and 
to evaluate the effects of selected covariates on the PK of roxadustat. The results of the 
population PK analysis will not be reported in the Clinical Study Report but in a separate 
population PK modeling report.
7.7
Analysis of Pharmacodynamics
Pharmacodynamic data may be submitted to population pharmacodynamic or population 
pharmacokinetic/pharmacodynamic (PPKPD) modeling. When deemed necessary, data from 
this study may be combined with data from other studies. Results will be reported in a 
separate PPKPD report.
7.8
Protocol Deviations and Other Analyses
Protocol deviations as defined in Section 8.1.6 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.


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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
An interim analysis will be performed when all subjects have completed 36 weeks of
treatment; efficacy and safety data will be analyzed and reported, excluding the endpoints 
measured after 36 weeks. Since all primary and secondary analyses have been defined over 
this period of time, no multiplicity adjustment is required as the information fraction at the 
interim analysis is 100%. Once the study is completed, efficacy and safety will be analyzed 
again and reported including the complete study treatment of 104 weeks.
In addition, a descriptive analysis on both safety and efficacy will be performed to provide 
information from this study for regulatory filings of roxadustat in case the planned interim 
analysis has not been reached. This will include only descriptive statistics by arm (i.e.,
without formal hypothesis testing).
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)
(Section 10.1).
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
For the primary endpoint, subjects without at least two Hb values as measured at 2 consecutive 
visits separated by at least 5 days during the first 24 weeks of treatment will be classified as 
non-responders.
Main analysis of the efficacy endpoints with repeated measures over time will follow the
MMRM methodology. In addition, as a sensitivity analysis, an LOCF method will be fitted.
Visit time windows will be detailed in the SAP.


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8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS
8.1
Procedure for Clinical Study Quality Control
8.1.1
Data Collection
The investigator or site designee will enter data collected 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 (including laboratory values, if applicable) in the eCRF as 
soon as possible after the subject visit.
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. Subject diaries and 
questionnaires will be completed by the subject on paper. The investigator or site designee 
should review the diaries and questionnaire data for correct completion while the subject is at 
the site. The investigator or site designee will enter only the relevant information from the 
medication diary (i.e., roxadustat intake data related to PK sampling) and all questionnaire 
data directly into the EDC system. eCRFs, 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 a central laboratory. Laboratory results will be provided to 
the investigator who will print, sign and retain the laboratory results. In addition all 
abnormalities will be checked and documented as clinically relevant or not clinically 
relevant. Laboratory data will be transferred electronically to the Sponsor or designee at 
predefined intervals during the study. The laboratory will provide the Sponsor or designee 
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 to 
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.
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

The identification of the participation in study 

Original signed and dated informed consent forms 

Visit dates

Medical history and physical examination details

Key efficacy and safety data 

Results of HemoCue Hb assessments on all visits 


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
Decision on study drug dosing on all visits.

AEs and concomitant medication 

Results of relevant examinations such as ECG charts, renal ultrasound outcome.

Central laboratory printouts

Medication diaries (for roxadustat subjects only)

Paper questionnaires

Dispensing and return of study drug details

Reason for premature discontinuation from study treatment (if applicable)

Subject number

Method(s) 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) 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 (WHO) Drug Dictionary respectively.
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 


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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 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 (TMF).
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)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, 
the Investigator’s Brochure, the informed consent and all other forms of subject information 
related to the study (e.g., advertisements used to recruit subjects) and any other necessary 
documents be reviewed by an IEC/IRB. The IEC/IRB will review the ethical, scientific and 
medical appropriateness of the study before it is conducted. IEC/IRB approval of the 
protocol, informed consent and subject information and/or advertising, as relevant, will be 
obtained prior to the authorization of drug shipment to a study site.


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Any substantial amendments to the protocol will require IEC/IRB approval prior to 
implementation of the changes made to the study design at the site. The investigator will be 
required to submit, maintain and archive study essential documents according to ICH GCP.
Any serious AEs that meet reporting criteria, as dictated by local regulations, will be reported 
to both responsible Ethics Committees and Regulatory Agencies, as required. During the 
conduct of the study, the investigator should promptly provide written reports (e.g., ICH 
Expedited Reports, and any additional reports required by local regulations) to the IEC/IRB 
of any changes that affect the conduct of the study and/or increase the risk to subjects. 
Written documentation of the submission to the IEC/IRB should also be provided to Sponsor.
If required by local regulations, the investigator shall make accurate and adequate written 
progress reports to the IEC/IRB at appropriate intervals, not exceeding one year. The 
Sponsor shall submit a summary of the final clinical study report to the IRB/IEC and the 
Regulatory Agency within one year after last subject out (LSO) or termination of the study.
8.2.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki.
8.2.3
Informed Consent of Subjects
8.2.3.1 Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the subject or 
his/her guardian or legal representative, and answer all questions regarding this study. Prior to 
any study-related screening procedures being performed on the subject, the informed consent 
statement will be reviewed and signed and dated by the subject or his/her guardian or legal 
representative, the person who administered the informed consent and any other signatories 
according to local requirements. A copy of the signed informed consent form will be given to 
the subject and the original will be placed in the subject’s medical record. An entry must also 
be made in the subject’s dated source documents to confirm that informed consent was 
obtained prior to any study-related procedures and that the subject received a signed copy.
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor regulatory authorities and other applicable individuals 
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 or his/her representative 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 to participate in the study 
(e.g., report of serious drug adverse drug reaction). The communication must be 
documented in the subject’s medical records and must document whether the subject is 
willing to remain in the study or not.


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2.
The investigator must update their ICF and submit it for approval to the IRB/IEC. The 
investigator or his/her representative must obtain written informed consent from the 
subject on all updated ICFs throughout their participation in the study. The investigator 
or his/her designee must re-consent subjects with the updated ICF even if relevant 
information was provided orally. The investigator or his/her representative who 
obtained the written informed consent and the subject should sign and date the informed 
consent form. A copy of the signed informed consent form will be given to the subject 
and the original will be placed in the subject’s medical record. An entry must be made 
in the subject’s records documenting the re-consent process.
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 shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons.
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 regional legislation related to the privacy and 
protection of personal information.
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 described in the Clinical Study Agreement.


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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 (IMPD) 

Questionnaires and SAE Report Worksheet

Investigator’s File

Study drugs with all necessary documentation

Clinical Trial Agreement

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:
For EU:

Financial disclosure in compliance with federal regulation 21CFR Part 54

Signed and dated FDA form 1572, if conducted under a US IND

If the investigator submits to the IRB/IEC: Submission letter to the IRB/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.)

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, CRFs, and Investigator's File) and relevant correspondence. These documents are to be 
kept on file for the appropriate term determined by local regulation: until at least 15 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 15 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product.
The Sponsor will notify the site/investigator if the MAA is approved or if the IMPD is 
discontinued.


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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 local regulations.
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 the CRFs supplied 
for each subject.
The documents of the Efficacy and Safety Evaluation Committee (minutes and standard 
operating procedures and others) and the judgment committee outside the study sites 
(minutes and standard operating procedures and others) shall be retained by the Sponsor.
8.3.3
Protocol Amendment and/or Revision
Any changes to the study that arise after approval of the protocol must be documented as
protocol amendments: substantial amendments and/or non-substantial amendments.
Depending on the nature of the amendment, either IRB/IEC, Competent Authority approval 
or notification may be required. The changes will become effective only after the approval 
of the Sponsor, the investigator, 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 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
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 the representative for 
the Coordinating Investigator(s) or the Principal Investigator(s). The representative for the 
Coordinating Investigator (s) or the Principal Investigator(s) 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. The representative for Coordinating Investigator(s) or the
Principal Investigator(s) will be selected from the participating investigators by the Sponsor
prior to database lock.


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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, 
recorded, and reported in compliance with the protocol, GCP, and applicable regulatory 
requirement(s).
The Sponsor or Sponsor's designee may arrange to audit the clinical study at any or all 
investigational sites and facilities. 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 prespecified safety data periodically in collaboration with the Sponsor
to ensure subject safety. A separate DSMB charter will establish the process, meeting 
frequency and scope of responsibilities.
10.2
Independent Event Review Committee (IERC)
An Independent Event Review Committee (IERC) will adjudicate all prespecified 
cardiovascular and cerebrovascular events in a blinded manner to ensure a consistent safety 
assessment.
Details of event identification and process of adjudication will be described in an IERC 
charter.
10.3
Other Study Organization
Not applicable.


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11
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_Procedural_steps_taken_and_scientific_information_after_authorisation/human/000332/WC5
00026145.pdf.
EMEA. Aranesp European Public Assessment Report [EPAR]. 2004.
EMEA, Guideline on the choice of the non-inferiority margin,
Doc.Ref. EMEA/CPMP/EWP/2158/99, London, 27 July 2005.
Epstein ACR, Gleadle JM, McNeill LA, Hewitson KS, O’Rourke J, Mole DR, et al. Cell.
2001;107(1):43-54.
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 
subjects with endstage renal disease. Results of a phase III multi-center 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):1274-1282.


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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.
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):3110-3119.
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):9361-9374.
Jungers PY, Robino C, Choukroun G, Nguyen-Khoa T, Massy ZA. Incidence of anaemia, and use of 
epoetin therapy in pre-dialysis subjects: a prospective study in 403 subjects. Nephrol Dial 
Transplant 2002;17(9):1621-1627.
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.
Locatelli F, Olivares J, Walker R, Wilkie M, Jenkins B, Dewey C, Gray SJ; European/Australian 
NESP 980202 Study Group. Novel erythropoiesis stimulating protein for treatment of anemia 
in chronic renal insufficiency. Kidney Int. 2001 Aug;60(2):741-7
Macdougall IC, Matcham J, Gray SJ, NESP-960245/246 Study Group. Correction of anaemia with 
darbepoetin alfa in subjects with chronic kidney disease receiving dialysis. Nephrol Dial 
Transplant 2003 Mar;18(3):576-581.
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 )
Peyssonnaux C, Nizet V, Johnson RS. Role of the hypoxia inducible factors HIF in iron metabolism. 
Cell Cycle 2008;7(1): 28-32.
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and 
activity impairment instrument. PharmacoEconomics 1993; 4(5): 353-365.
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):3133-3140.
Semenza GL. Hypoxia-inducible factor 1: master regulator of O2 homeostasis. Curr.Opin.Genet.Dev. 
1998;8(5):588-594.
Semenza, GL. HIF-1: mediator of physiological and pathophysiological responses to hypoxia. 
J.Appl.Physiol 2000;88(4):1474-1480.
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):241-243.


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The US Recombinant Human Erythropoietin Predialysis Study Group. Double-blind, placebo-
controlled study of the therapeutic use of recombinant human erythropoietin for anemia 
associated with chronic renal failure in predialysis subjects. Am J Kidney Dis. 1991 
Jul;18(1):50-59.
Thilly N, Stengel B, Boini S, Villar E, Couchoud C Frimat L. Evaluation and determinants of 
underprescription of erythropoiesis stimulating agents in pre-dialysis subjects with anaemia. 
Nephron Clin Pract. 2008;108(1):67-74.
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.
United States Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER), Guidance for Industry: Complicated Urinary Tract 
Infections and Pyelonephritis – Developing Antimicrobial Drugs for Treatment, July 1998
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)
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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-
5514.
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):1462-1464.
Winearls CG, Oliver DO, Pippard MJ, Reid C, Downing MR, Cotes PM. Effect of human 
erythropoietin derived from recombinant DNA on the anaemia of subjects maintained by 
chronic haemodialysis. Lancet 1986;2(8517):1175-1178.
Zhang Y, Thamer M, Stefanik K, Kaufman J, Cotter DJ. Epoetin Requirements Predict Mortality in 
Hemodialysis Subjects. 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):213-224.


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12
APPENDICES
12.1
List of Prohibited Concomitant Medication
The following medications are prohibited during the period identified:

Any ESA: within 12 weeks prior to randomization until EOT

IV iron: within 6 weeks prior to randomization 

RBC transfusion: within 8 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 screening until EOS

Roxadustat or another HIF-PHI: at any time prior to randomization. After randomization 
any HIF-PHI other than roxadustat, as allocated by randomization, until EOS

Iron-chelating agents (e.g., deferoxamine, deferiprone, or deferasirox therapy): from 
4 weeks prior to randomization until EOS

Androgens from day of randomization until EOS

Dapsone in any dose amount from the day of randomization until EOS 

Chronic use of acetaminophen/paracetamol > 2.0 g/day from the day of randomization 
until EOS


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12.2
Liver Safety Monitoring and Assessment
Any subject enrolled in a clinical study with active drug therapy and reveals an increase of 
serum aminotransferases (AT) to > 3 × ULN, or bilirubin > 2 × ULN, should undergo 
detailed testing for liver enzymes (including at least ALT, AST, ALP, and TBL). Testing
should be repeated within 48-72 hours of notification of the test results. 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 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) that has been developed globally and can be activated for any 
study 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 may be reported as a Serious AE
(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 ‘AEs’ on the AE page of the (e)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 (NASH) 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 
the (e)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 LFT’s, 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%).
In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, drug should be discontinued.
*) 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 


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(or transplant). The two “requirements” for Hy’s Law are: 1) Evidence that a drug can cause 
hepatocellular-type injury, generally shown by an increase in transaminase elevations higher 
3 times the upper limit of normal (“2 x ULN elevations are too common in treated and 
untreated subjects to be discriminating”); 2) Cases of increased bilirubin (at least 2 x ULN) 
with concurrent transaminase elevations at least 3x ULN and no evidence of intra- or extra-
hepatic bilirubin obstruction (elevated alkaline phosphatase) or Gilbert’s syndrome. [Temple 
R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf 2006 
Apr;15(4):241-3.]
Reference
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” 
issued by FDA on July 2009.


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12.3
Instructions for Subjects Moving from Protocol v1.0 to Protocol v2.0
12.3.1
Visit Schedule
Subjects that have entered the study under protocol v1.0, upon signing the informed consent
for the amendment 1, will have their visit frequency adjusted according to Table 1, Schedule of 
Assessments. For example, if subject signs 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.
12.3.2
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 that have entered the study under protocol version 1.0, upon signing the informed 
consent for the amendment 1, will have their dose frequency (on QW and BIW under 
protocol v1.0) and dose amount adjusted. Subjects randomized to roxadustat QW or BIW 
who do not agree to change to TIW, should be discontinued from the study treatment and 
continue in the post study follow-up period.
At this visit, it is first determined if the subject would need a dose titration according to the 
dose adjustment rules as per Section 5.1.2.1  Once that is established subjects 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 
hemodialysis 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 conversion table below, at the visit when the informed consent for the 
amendment 1 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 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 reduction have been met.
#  Contact the medical monitor if down titration is needed.
12.3.3
ESA Rescue Therapy
If, upon implementation of protocol v2.0, a subject on roxadustat has already received 1 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 after implementation of protocol v2.0.


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12.4
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., hemodialysis (HD), hemodiafiltration (HDF) and peritoneal 
dialysis (PD) 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.

For subjects treated with darbepoetin, the route of administration of darbepoetin is 
according to local standard of care for dialysis patients.
12.4.2
Dose Adjustment

The dose adjustment rules remain unchanged (see Section 5.1.2.1). 

The maximum allowed dose in subjects on permanent dialysis is 3.0 mg/kg (based on 
post-dialysis weight in HD subjects and weight minus abdominal fluid based on last
filling in PD subjects) or 400 mg per administration, whichever is lower.
12.4.3
ESA Rescue Therapy
If roxadustat subjects meet the criteria for ESA rescue therapy while on dialysis, darbepoetin 
alfa will be administered IV or SC according to its Package Insert or SmPC for dialysis 
subjects. The subject must be discontinued from study treatment if the subject requires a 
second course of rescue darbepoetin alfa.
12.4.4
Supplemental Iron Use
Iron supplementation rules are unchanged in subjects starting dialysis who are randomized to  
roxadustat (see Section 5.1.3.2.1). In subjects randomized to darbepoetin, IV iron 
supplementation will be given according to standard of care.
12.4.5
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.
12.4.6
Timing of Study Assessments

If a study visit occurs on a dialysis day, all study assessments should be performed before 
start of dialysis. 

Blood pressure and HR should be measured in triplicate prior to and after end of dialysis 
(HD/HDF subjects only). 


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12.5
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!
1.
In general, would you say your health is:
Excellent
Very good
Good
Fair
Poor





1
2
3
4
5
2.
Compared to one year ago, how would you rate your health in 
general now?
Much better
now than one
year ago
Somewhat
better
now than one
year ago
About the
same as
one year ago
Somewhat
worse
now than one
year ago
Much worse
now than one
year ago





1
2
3
4
5


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


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


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


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9.
These questions are about how you feel and how things have been 
with you during the past 4 weeks. For each question, please give the 
one answer that comes closest to the way you have been feeling. How 
much of the time during the past 4 weeks…
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
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


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


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12.6
Functional Assessment of Cancer Therapy- Anemia (FACT-AN)


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12.7
EuroQol Questionnaire (EQ-5D-5L)


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12.8
Subjects’ Global Impression of Change (PGIC) Scale


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12.9
Work Productivity and Activity Impairment Questionnaire: 
Anemic Symptoms (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


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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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13
ATTACHMENT 1:  SUBSTANTIAL AMENDMENT 2
I.  The purpose of this amendment is:
Substantial Changes
1. Change in hemoglobin (Hb) eligibility criteria.
DESCRIPTION OF CHANGE:
The number of Hb values assessed during the screening period is reduced from three to two 
and the mean Hb entry threshold is increased from ≤10.0 g/dL to ≤10.5 g/dL. This results 
in a change in inclusion criterion 4 and texts throughout the protocol that refer to the mean 
Hb entry threshold.
RATIONALE:
Reducing the number of Hb screening values required to be assessed during the screening 
period from three to two reduces the number of screening visits, and is likely to shorten the 
screening period and accelerate the decision on patient eligibility concerning the Hb 
inclusion criterion. The Hb stability criterion defined by a maximum allowed difference 
between screening values of 1.0 g/dL remains unchanged to avoid unduly unstable Hb levels 
at baseline. 
The current Hb entry criterion (mean Hb ≤10.0 g/dL at screening) is reconsidered.  The 
current Hb value of ≤10.0 g/dL is considered too low and incongruent with contemporary 
clinical practice, especially in countries with high standard of care. Feedback from sites and 
investigators raise this criterion as the principal cause of screen failure, or alternatively, as a 
reason for not screening patients at all. This change will not bias or impact Hb-related 
endpoint assessments, nor does it affect other key elements of the trial design including the 
roxadustat dosing algorithm and principles for dose adjustments. The updated European 
Renal Best Practice (ERBP) position statement from a 2013 publication by Locatelli and 
colleagues provides valid support to increase the Hb threshold for inclusion: according to this 
statement the Hb levels should not routinely fall below 10 g/dL in all patients prior to 
initiation of erythropoiesis stimulating agent (ESA) therapy.  Consequently, the mean Hb 
entry threshold is increased to ≤10.5 g/dL. 
2. Update of the iron criteria: ferritin level ≥100 ng/mL and transferrin saturation 
(TSAT) level ≥20% at screening are removed.
DESCRIPTION OF CHANGE:
The iron criteria are updated to better reflect clinical practice, and as a result inclusion 
criteria 6 and 7 are removed.
RATIONALE:
The current iron repletion criteria do not always mimic clinical practice and are based on a
paradigm which dictates the requirement of full iron repletion prior to commencing ESA 
therapy. The proposed changes aim to better reflect clinical practice and allow for inclusion 
of patients with iron indices indicative of relative or functional iron deficiency, under the 
condition that they are deemed eligible in the opinion of the investigator as per the 2012 


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Kidney Disease Improving Global Outcomes (KDIGO) anemia guidelines. These guidelines
recommend to check and correct iron deficiency prior to initiation of ESA therapy, but 
arguably without absolute requirement to achieve the thresholds of ferritin ≥100 ng/mL and 
TSAT ≥20%. The KDIGO anemia guidelines further advocate individualized assessments 
in the clinical decision to initiate ESA therapy, and it may not always be feasible to ensure 
full iron repletion in individual patients. Finally, the 6 week washout period of IV iron may 
also limit investigators to administer sufficient iron to achieve the key ferritin and TSAT 
thresholds.
3. Exclusion Criterion 21 extended to exclude patients who are close to initiating 
renal replacement therapy including dialysis.
DESCRIPTION OF CHANGE:
Exclusion criterion 21 is extended to exclude patients that are close to initiating renal 
replacement therapy including dialysis (within the first year of the study).
RATIONALE:
The primary objective of this study is to assess the efficacy and safety of roxadustat in non-
dialysis chronic kidney disease (CKD) patients. Currently there are no specific criteria that 
prevent randomization of patients who are close to initiating renal replacement therapy, 
including dialysis. Randomization of these patients leads to reduced exposure and less 
patients available for primary and key secondary endpoint assessments in the intended target 
population of this study. The revised exclusion criterion aims to increase awareness amongst 
investigators that patients predicted to undergo dialysis treatment, or be discontinued from 
the treatment phase due to renal transplantation during the first year of the study should not 
be randomized.
Non-Substantial Changes
1. Contact details of key sponsor personnel
DESCRIPTION OF CHANGE:
Medical Monitor is changed to 
.
RATIONALE:
 has taken over medical monitor responsibilities from 
.
2. Extension of the planned study period
DESCRIPTION OF CHANGE:
The planned study period is extended from 3Q2018 until 2Q2021.
RATIONALE:
Enrollment was slower than expected at the start of the study; therefore, the study duration
has been increased.  This increase in the duration of the trial is considered non-substantial as 
PPD
PPD
PPD


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exposure to the treatment with Investigational Medicinal Product (IMP) is not extended.  The 
definition of the end of the trial for the study subjects is unchanged and the monitoring 
arrangements are not changed.
3. Post-study follow-up visits
DESCRIPTION OF CHANGE:
In case of premature discontinuation, subjects were to complete the end of treatment (EOT) 
visit and end of study (EOS) visit. This has been reworded to: 2 EOT visits and 1 EOS visit.
RATIONALE:
In the current protocol it is not clear that there are in total 3 follow-up visits for subjects that 
prematurely discontinue study treatment.  The 3 follow-up visits are: 1. EOT visit, 2. EOT+2 
week visit, 3. EOS visit.  This is clarified throughout the protocol text and in Table 1: 
footnote c and the column EOT + 2 weeks.
4. Inclusion Criterion 5 has been extended
DESCRIPTION OF CHANGE:
Inclusion criterion 5 that addresses the suitability for treatment with ESA using the criteria 
specified in the KDIGO 2012 recommendation, has been further clarified.
RATIONALE:
Criteria of suitability for treatment with ESA are further explained in more detail in order to 
provide more clarity and guidance to the investigator.  These criteria are based upon the 
wording used in the KDIGO 2012 anemia management guidelines.  These guidelines request 
the treating physician to initiate the use of ESAs in non-dialysis CKD patients considering 
the rate of fall of Hb concentration, prior response to iron therapy, the risk of needing a 
transfusion, the risks related to ESA therapy and the presence of symptoms attributable to 
anemia.
5. Concomitant medication: Supplemental iron use 
DESCRIPTION OF CHANGE:
I. Oral iron: Rewording of supplemental iron use guidance for roxadustat-treated subjects in 
case of intolerance to oral iron.
II. Intravenous iron for all treated subjects: upon reaching iron repletion (once ferritin is 
≥100 ng/mL and TSAT ≥20%) it is recommended to discontinue IV iron supplementation.
RATIONALE:
Text updates have been made to align with other phase 3 protocols in the global program for 
consistency throughout the roxadustat development program. 
6. Prohibited medication
DESCRIPTION OF CHANGE:


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The list of prohibited medications is clarified and only to summarize the prohibited 
medication for the identified period.  In protocol version 1.0 for ESA, IV iron and red blood 
cell (RBC) transfusion, it was stated when these medications were prohibited, but also when 
these medications were allowed.  The time when these medications are allowed is removed.
RATIONALE:
ESA rescue therapy, IV iron and RBC transfusion are only prohibited during the screening 
period.  Within the treatment period these medications are restricted in use and follow certain 
criteria. These criteria are described under protocol sections of concomitant medication 
(Section 5.1.3) and rescue therapy guidelines (Section 5.1.5).  Therefore to avoid confusion, 
the references to the treatment period are being removed from the prohibited medication lists.
7. Additional efficacy secondary endpoint
DESCRIPTION OF CHANGE:
Additional secondary endpoint has been deleted : Iron use - Monthly oral iron (mg) use per 
subject during weeks 1 to 36, and weeks 36 to 52 (monthly defined as a period of 4 weeks)
RATIONALE:
Use of oral iron is not considered a clinically meaningful endpoint since the study protocol 
recommends supplementation of oral iron to support erythropoiesis and as the first-line 
treatment for iron deficiency in both treatment arms.
8. Changes in reference to pre- and post-amendment
DESCRIPTION OF CHANGE: 
The current tables (synopsis table 4, protocol table 3 and 10) refer to pre- and post-
amendment.  “Pre-amendment” are changed to “Protocol version 1” and “post-amendment” 
are changed to “Protocol version 2 and 3”.
RATIONALE:
With the current amendment these tables are updated to reflect the situation taking all 
protocol versions into account.
9. Primary Analysis: Sensitivity analyses on the primary analysis of the primary 
endpoint
DESCRIPTION OF CHANGE:
A sensitivity analysis on the results of the primary analysis of the primary endpoint before 
and after protocol amendment 1 and protocol amendment 2 is added.
RATIONALE:
This sensitivity analysis is added to evaluate the impact on the primary endpoint in both 
protocol amendments 1 and 2.  The changes implemented following both amendments could 
have led to inconsistent results between those patients included before amendment 1 versus 
those included after amendment 1, and patients included before amendment 2 versus those 


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included after amendment 2.
10. Synopsis and interim analysis 
DESCRIPTION OF CHANGE: 
A descriptive analysis of both safety and efficacy data is added to support a regulatory 
submission in case the planned interim analysis is not reached. This includes only 
descriptive statistics.
RATIONALE:
Enrollment has been slower than expected at the start of the study.  It was anticipated that at 
the time of submission for marketing authorization, the currently planned interim analysis 
would not have been reached. In order to provide full disclosure of the results, a descriptive
analysis is included. Only summary data and both safety and efficacy (without inferential 
statistics) will be presented without any impact on the ongoing study.
11. Flow Chart
DESCRIPTION OF CHANGE:
The term “Absence of renal carcinoma per renal ultrasound” is deleted from the box 
describing the key selection criteria in the flow chart.
RATIONALE:
The purpose of the box in the flow chart describing key selection criteria is to inform on a 
high level about the most relevant criteria qualifying a subject for inclusion into the study.  In 
this context and keeping in mind that the protocol includes approximately 40 inclusion and 
exclusion criteria, the criterion “Absence of renal carcinoma per renal ultrasound” is not 
regarded as a key selection criterion. CKD stage, Hb entry value and the suitability for 
treatment with ESAs are considered the key selection criteria.
12. Schedule of Assessments
DESCRIPTION OF CHANGE:
Updates to the Schedule of Assessments to reflect changes made in this Amendment and to 
add other clarifications.
RATIONALE:
To provide up to date and accurate information.
13. Summary of key safety information for study design: roxadustat
DESCRIPTION OF CHANGE:
Five pancreatitis events were noted during the roxadustat clinical development program, the 
majority of which have been associated with gallstones or biliary sludge; one was due to a 
pancreatic duct stricture and another case had multiple risk factors for pancreatitis.


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RATIONALE:
‘Phase 2’ is added to make clear that the ‘five pancreatitis events’ refer to data from the 
phase 2 development program.  Meanwhile the phase 3 program has been ongoing for more 
than 2 years
14. Three times weekly (TIW) dosing regimen of roxadustat
DESCRIPTION OF CHANGE:
The protocol described the roxadustat dosing schedule of TIW to be dosed at least 2 days 
apart (e.g., Monday, Wednesday, Friday). This changes into: the period between two 
roxadustat administrations should be at least 36 hrs. 
RATIONALE:
Alignment with phase 3 dialysis protocol and providing logic to dosing regimen TIW. 
15. Dose adjustment rules for subjects receiving darbepoetin alfa
DESCRIPTION OF CHANGE:
Deletion of Table 6: Recommended Dose Adjustment Rules for Darbepoetin Alfa
RATIONALE:
The principal reason for Table deletion is that the table does not fully reflect all elements of 
the Summary of Product Characteristics (SmPC).
16. Return of (un)used medication to site 
DESCRIPTION OF CHANGE:
Clarification on the return of empty medication packages for subjects treated with 
darbepoetin alfa who are self-administering the medication after 36 weeks of treatment.  A 
sentence is added with regard to treatment compliance for subjects randomized to 
darbepoetin:  In case of self-administration after 36 weeks of treatment, the empty packages 
of darbepoetin alfa should be returned by the subject to the site.
RATIONALE:
To clarify that in case subjects self-inject darbepoetin alfa (only following 36 weeks of 
treatment with darbepoetin alfa), they need to return the empty packages to perform the 
check on treatment compliance.
17. Safety Assessments
DESCRIPTION OF CHANGE:
The number of visits on which vital signs are measured is reduced and an average is not 
derived from the 2nd and 3rd readings.


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RATIONALE:
As all three readings for the vital sign parameters will be used in the statistical analysis, an 
average of the 2nd and 3rd readings was no longer relevant and was inconsistent with the 
analysis.
18. Reporting of SAEs
DESCRIPTION OF CHANGE:
Deleted the contact details of MedPace for reporting of SAEs.
RATIONALE:
Contact details of MedPace as currently stated in the protocol are not applicable. 
19. Total blood volume
DESCRIPTION OF CHANGE:
The total volume of 440 mL is changed to 460 mL.
RATIONALE:
The blood volume is adjusted to better depict the total blood volume required by the current 
visit schedule.
20. Secondary analysis: additional sensitivity analysis
DESCRIPTION OF CHANGE:
In addition, this variable will be analyzed using the subset of subjects who have reached Hb 
≥11.0 g/dL prior to week 28.
RATIONALE:
While subgroup analysis based on baseline characteristics are scientifically sound and well 
accepted by regulatory guidelines, post-baseline responses affected by the treatment are not 
appropriate variables to define subgroups for investigation (see graft guideline on the 
investigation of subgroups in confirmatory clinical trials, EMA/CHMP/539146/2013). 
Therefore the subgroup analysis restricted to subjects who have reached 11 g/dL during the 
study has been removed from the protocol.
21. Appendix 12.4 Instructions for subjects requiring dialysis
DESCRIPTION OF CHANGE:
Addition of text to Appendix 12.4 to describe that: 1. The iron supplementation rules are 
unchanged (Section 5.1.3.2.1) in subjects starting dialysis.  2. The route of administration of 
darbepoetin is according to the local standard of care for dialysis patients.
RATIONALE:
Provides alignment with the phase 3 dialysis protocol and guidance in the applicable text 
regarding management of subjects after having initiated dialysis.  This change allows a 


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switch in the application route if deemed required (e.g., from subcutaneous use to 
intravenous use).
22. Appendix 12.10 
DESCRIPTION OF CHANGE:
Appendix 12.10 has been deleted.
RATIONALE:
A general reference was added in the text to the KDIGO 2012 guideline.  Appendix 12.10 
did not add any further information and is therefore deleted.
23. Minor Administrative Changes
DESCRIPTION OF CHANGE: 
Includes minor administrative changes, e.g., typos, format, numbering, consistency 
throughout the protocol following the latest Astellas document consistency guidance.
RATIONALE:
Update the protocol to correct formatting and to provide clarifications to ensure complete 
understanding of study procedures.
II.  Amendment Summary of Changes: Substantial Changes
III List of Abbreviations and Definition of Key Terms, IV Synopsis, Study Design 
Overview and Inclusion Criteria, 2 Study Objective(s), Design, and Endpoints, 3 Study 
Population, and 5 Treatments and Evaluation
List of Key Study Terms, 2.2.1.2 Study Population, 2.2.1.3 Description of Study, 3.2 
Inclusion Criteria #4 and 5.2.4 Diagnosis of the Target Disease, Severity, and Duration of 
Disease
WAS:
The mean of the subject’s three most recent (prior to randomization) 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.
IS AMENDED TO:
The mean of the subject’s three two most recent (prior to randomization) Hb values during 
the screening period, obtained at least 4 days apart, must be ≤10.05 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.


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IV Synopsis, Inclusion Criteria and 3 Study Population
3.2 Inclusion criteria #6 and #7
WAS:
6. Subject has a ferritin level ≥100 ng/mL (≥220 pmol/L) at screening.
7. Subject has a transferrin saturation (TSAT) level ≥20% at screening.
IS AMENDED TO:
6. Subject has a ferritin level ≥100 ng/mL (≥220 pmol/L) at screening. This criterion has 
been removed.
7. Subject has a transferrin saturation (TSAT) level ≥20% at screening. This criterion has 
been removed.
IV Synopsis, Exclusion Criteria and 3 Study Population
3.2 Exclusion criterion #21
WAS:
Subject has had any prior organ transplant (that has not been explanted), or subject is 
scheduled for organ transplantation.
IS AMENDED TO:
Subject has had any prior organ transplant (that has not been explanted), or subject is 
scheduled for organ transplantation, or subject is likely to initiate renal replacement 
therapy including dialysis within the first year of the study in the opinion of the 
investigator.
V Flow Chart and Schedule of Assessments
Table 1: Schedule of Assessments
ADDED:
i An additional (third) Hb value may be collected if necessary. Only for subjects who 
are switched from protocol version 2.0 to 3.0 during (re) screening can a fourth Hb 
value be collected, as was applicable under protocol version 2.0.
2 Study Objective(s), Design, And Endpoints
2.2.1.2 Study Population
DELETED:
Subjects are iron replete; inclusion is permitted if ferritin ≥ 100 ng/mL (≥220 pmol/L) and 
Transferrin Saturation (TSAT) ≥ 20%.




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WAS:
Subject is deemed suitable by the investigator for treatment with erythropoiesis stimulating 
agents (ESA) using the criteria specified in the KDIGO 2012 recommendation (see 
Appendix 12.10).
IS AMENDED TO:
Subject is deemed suitable by the investigator for treatment with erythropoiesis stimulating 
agents (ESA) using the criteria specified in the KDIGO 2012 recommendation (see 
Appendix 12.10). considering the rate of fall of Hb concentration, prior response to 
iron therapy, the risk of needing a transfusion, the risks related to ESA therapy and 
the presence of symptoms attributable to anemia.
IV Synopsis, Concomitant Medication Restrictions and/or Requirements, 2 Study 
Objective(s), Design, and Endpoints, and 5 Treatments and Evaluation
2.2.1.5 Comparator and 5.1.3.2.1 Supplemental Iron Use
WAS:
Subjects receiving roxadustat
i. Oral iron
For subjects receiving roxadustat, oral iron is recommended for dietary supplementation to 
support erythropoeisis and as the first-line for prevention and treatment of iron deficiency. 
The recommended daily dose is 200 mg of elemental iron; in case of iron intolerance or for 
other reasons a lower dose may be given. Subjects should be advised to take roxadustat at 
least one hour before or one hour after oral iron.
ii. IV iron
For subjects receiving roxadustat, IV iron supplementation is allowed if all of the following 
criteria are met:

The subject has not responded adequately in terms of hemoglobin response to 2 or more 
consecutive dose increases of roxadustat or reached the maximum dose limit, and

The subject has iron deficiency (either ferritin <100 ng/mL [<220 pmol/L] or 
TSAT < 20%) or the subject is intolerant of oral iron therapy.
Treatment with roxadustat may continue during IV iron administration. IV iron 
administration should be stopped once ferritin levels are ≥100 ng/mL (≥220 pmol/L) and 
TSAT ≥20%.
Subjects receiving darbepoetin alfa
For subjects treated with darbepoetin alfa, oral or IV iron supplementation is required to 
maintain iron repletion and will be administered only if ferritin <100 ng/mL (<220 pmol/L) 
or TSAT < 20%. The route of iron administration is up to the investigator’s discretion and 
follows the KDIGO 2012 recommendation for NDD-CKD subjects (see Appendix 12.10). 
Criteria such as the severity of iron deficiency, availability of venous access, response to
prior oral iron therapy, side effects with prior oral or IV iron therapy, and subject 
compliance will be considered.


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IS AMENDED TO:
Subjects receiving roxadustat
i. Oral iron
For subjects receiving roxadustat, oral iron is recommended for dietary supplementation to 
support erythropoiesis and as the first-line for prevention and treatment of iron deficiency 
unless the subject is intolerant to this treatment.  The recommended daily dose is 200 mg 
of elemental iron; in case of iron intolerance or for other reasons a lower dose may be given. 
Subjects should be advised to take roxadustat at least one hour before or one hour after oral 
iron.
ii. IV iron
For subjects receiving roxadustat, IV iron supplementation is allowed if all of the following 
criteria are met:

The subject has not responded adequately in terms of hemoglobin response to 2 or more 
consecutive dose increases of roxadustat or reached the maximum dose limit, and

The subject has iron deficiency (either ferritin <100 ng/mL [<220 pmol/L] or 
TSAT < 20%) or the subject is intolerant of oral iron therapy.
Treatment with roxadustat may continue during IV iron administration.  Discontinuation of
IV iron administration should be stopped is recommended once ferritin levels are 
≥100 ng/mL (≥220 pmol/L) and TSAT ≥20%.
Subjects receiving darbepoetin alfa
For subjects treated with darbepoetin alfa, oral or IV iron supplementation is required to 
maintain iron repletion and will be administered only if ferritin <100 ng/mL (<220 pmol/L) 
or TSAT < 20%. The route of iron administration is up to the investigator’s discretion and 
follows the KDIGO 2012 recommendation for NDD CKD subjects (see Appendix 12.10). 
Criteria such as the severity of iron deficiency, availability of venous access, response to 
prior oral iron therapy, side effects with prior oral or IV iron therapy, and subject 
compliance will be considered.. IV iron should only be administered if ferritin < 100 
ng/mL (< 220 pmol/L) or TSAT < 20%. IV iron may be administered per local 
practice. Discontinuation of IV iron therapy is recommended once ferritin levels are 
≥100 ng/mL (≥220 pmol/L) and TSAT ≥20%.
IV Synopsis, Prohibited Medication, 5 Treatments and Evaluation and 12 Appendices
5.1.3.3 Prohibited Medication and 12.1 List of Prohibited Concomitant Medications
WAS:
The following medications are prohibited during the period identified:

Any ESA: within 12 weeks prior to randomization until EOT, except for darbepoetin 
alfa as part of randomized treatment or as rescue therapy.

IV iron: within 6 weeks prior to randomization. From day of randomization onwards IV 
iron is allowed as part of supplemental iron use, if protocol-specified criteria are met.

RBC transfusion: within 8 weeks prior to randomization. From the day of 


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Version 3.0, Incorporating Substantial Amendment 2
randomization onwards RBC transfusions are allowed as part of the rescue therapy, if 
protocol-specified criteria are met.
IS AMENDED TO:
The following medications are prohibited during the period identified:

Any ESA: within 12 weeks prior to randomization until EOT, except for darbepoetin 
alfa as part of randomized treatment or as rescue therapy.

IV iron: within 6 weeks prior to randomization. From day of randomization onwards IV 
iron is allowed as part of supplemental iron use, if protocol specified criteria are met.

RBC transfusion: within 8 weeks prior to randomization. From the day of 
randomization onwards RBC transfusions are allowed as part of the rescue therapy, if 
protocol specified criteria are met.
IV Synopsis, Additional Secondary and 2 Study Objective(s), Design, and Endpoints
2.3.3.1 Efficacy Endpoints
DELETED:
Iron use

Monthly oral iron (mg) use per subject during weeks 1 to 36, and weeks 36 to 52 
(monthly defined as a period of 4 weeks)
IV Synopsis, Statistical Methods, 2 Study Objective(s), Design, and Endpoints and 7 
Statistical Methodology
2.2.1.3 Description of Study, 7.1 Sample Size
WAS:
In protocol version 1.0 (pre-amendment) subjects were randomized in a ratio of 2:1 
receiving roxadustat versus darbepoetin alfa. The expected number of subjects randomized 
pre-amendment, post-amendment and overall are represented in the following table.
Table 3 Expected Number of Subjects Randomized Pre-amendment and Post-amendment
Treatment 
Arms
Study Treatment
Expected Number of 
Pre-amendment 
Subjects Randomized 
(Ratio 2:1)*†
Expected Number of 
Post-amendment 
Subjects Randomized
(Ratio 1:1)
Total Expected 
Number of 
Subjects 
Randomized per 
Treatment Arm
1
Roxadustat
100
210
310
2
Darbepoetin alfa
50
210
260
Total
150
420
570
* The number of subjects post-amendment will depend on the number of subjects randomized pre-amendment. 
The number of subjects randomized pre-amendment is assumed to be 150.
† Subjects pre-amendment randomized to QW and BIW will be converted to the TIW arm according to the 
schedule as included in Appendix 12.3
IS AMENDED TO:


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Version 3.0, Incorporating Substantial Amendment 2
In protocol version 1.0 (pre amendment) subjects were randomized in a ratio of 2:1 
receiving roxadustat versus darbepoetin alfa. The expected number of subjects randomized 
on protocol version 1, protocol versions 2 and 3 and the total number of randomized 
subjects per treatment arm pre amendment, post amendment and overall are represented 
in the following table.
Table 3 Expected Number of Subjects Randomized Pre amendment and Post amendment
Treatment 
Arms
Study Treatment
Expected Number of 
Pre amendment
Protocol v1
Subjects 
Randomized (Ratio 
2:1)*†
Expected Number of 
Post amendment
Protocol v2 and 3 
Subjects 
Randomized
(Ratio 1:1)†
Total Expected 
Number of 
Subjects 
Randomized per 
Treatment Arm
1
Roxadustat
100
210
310
2
Darbepoetin alfa
50
210
260
Total
150
420
570
* † The number of subjects under protocol v2 and v3 post amendment will depend on the number of subjects 
randomized under protocol v1 pre amendment. The number of subjects randomized pre amendment is 
assumed to be 150.
† Subjects pre amendment randomized to QW and BIW will be converted to the TIW arm according to the 
schedule as included in Appendix 12.3
IV Synopsis, Analysis of Primary Endpoint and 7 Statistical Methodology
7.4.1.1 Primary Analysis
ADDED:
Sensitivity analyses will be conducted to assess the consistency of the results before and 
after protocol amendments 1 and 2 (e.g., protocol versions 2.0 and 3.0 respectively).
IV Synopsis, Interim Analyses and 7 Statistical Methodology
7.9 Interim Analysis
ADDED:
In addition, a descriptive analysis on both safety and efficacy will be performed to 
provide information from this study for regulatory filings for roxadustat in case the 
planned interim analysis has not been reached. This will include only descriptive 
statistics by arm (i.e., without formal hypothesis testing).
V Flow Chart and Schedule of Assessments
Flow Chart
WAS:


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Version 3.0, Incorporating Substantial Amendment 2
IS AMENDED TO:
STUDY DESIGN 3.0


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V Flow Chart and Schedule of Assessments
Table 1: Schedule of Assessments
WAS:
Assessments
Screening 
Period
Treatment Period
(Correction Period and Maintenance Period)
Follow-up Period
Unscheduled 
Visits
Post study 
Follow-up c
Visit / Week
2-6 weeks a
Day 1b
Weekly
(wks 1 - 2)
± 2 days
Every 2 Weeks 
(wks 4 - 24)
± 2 days
Every 4 Weeks 
(wks 28 - 100)
± 3 days
EOT c
(wk 104)
± 3 days
EOT + 2 wks
± 3 days
EOS c
(EOT + 4 wks)
± 3 days
Every 6 months 
until projected 
wk 108
S1
S2 S3
Written informed consent
X
Randomization
X
Eligibility criteria
X
X
Demographics
X
Medical history
X
Physical examination  
X
X
wks 12d, 24d 
wks 36d, 52d, 76d
X
Xd
Od
Heighte, weight
X
X
wks 12, 24
wks 36, 52, 76
X
X
O
Blood pressuref, heart ratef, respiratory rateg
X
X
X
X
X
X
X
X
X
X
CBC with WBC diff, red cell indices and 
platelets
X
X
X
wks 4, 8, 12, 20
wks 28, 36, 44, 
52, 60, 68, 76, 84, 
92, 100
X
X
O
Hemoglobinh
X
X
X
X
X
X
HemoCue assessmenti
X
X
X
X
X
Reticulocyte count and Hb in reticulocytes 
(CHr)
X
X
X
wks 4, 6, 8, 12, 
16, 20
wks 28, 36, 44, 
52, 60, 68, 76, 84, 
92, 100
X
X
O
12-lead ECG 
X
X
wks 12, 24
wks 36, 52, 76
X
O
Serum chemistry
X
X
wks 4, 8, 12, 20
wks 28, 36, 44, 
52, 60, 68, 76, 84, 
92, 100
X
X
X
O
LFTsj
wk 2
wks 6, 16
O
Renal ultrasoundk
X
X
O
Serum lipid panell
X
X
wks 4, 8, 12, 20 
wks 28, 36, 44, 
52, 68, 84
X
X
O
Serum iron, ferritin, TIBC, TSAT
X
X
wks 4, 8, 12, 20
wks 28, 36, 44, 
52, 60, 68, 76, 84, 
92, 100
X
X
O
HbA1c
X
X
wk 12
wks 28, 36, 44, 
60, 84
X
X
O
Vitamin B12, folate
X
HIV immunoassay, HBsAg, 
anti-HCV antibody
X


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Serum pregnancy testm
X
wks 12, 24
wks 36, 48, 60, 
72, 84, 96
X
O
Table continued on next page
eGFRn
X
X
wk 20
wks 36, 52, 68, 84
X
X
O
hs-CRP
X
wks 4, 12, 20
wks 36, 52
X
X
Archival serum samples for biomarkerso
X
wks 4, 12, 20
wks 52, 76
X
X
Blood sample for PKp
wks 2 to 8
Genotypingq
O
QoL questionnairesr
X
wks 8, 12 
wks 28, 36, 52, 76
X
O
Urinary testings
X
wks 12, 24
wks 36, 52, 64, 
76, 88
X
O
Archival urine samples for biomarkers
X
wk 24
wks 52, 76
X
Study drug dispensingt
├────────────────────────────┤
O
Dose adjustment reviewu
X
X
X
O
Hospitalization recordingv
X
X
X
◄─────────────────────────────────────────────────────────────►
X
AE recording
X
X
X
◄─────────────────────────────────────────────────────────────►
Concomitant medication, procedure and non-
drug therapy recording
X
X
X
◄─────────────────────────────────────────────────────────────►
Vital status, SAEs, cardiovascular and 
thromboembolic AEsv
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.
Note:  see Appendix 12.3 Instructions for Subjects Moving from Protocol v1.0 to Protocol v2.0.
Note:  see Appendix 12.4 Instructions for Subjects Requiring Dialysis.
a Due to the requirement of 4-day separation between the screening Hb values, the screening period will last a minimum of 2 weeks but is allowed to be a maximum 6 weeks. Sites 
are recommended to schedule the three screening visits in the shortest time span possible.
b All study assessments are to be performed prior to first study drug administration.
c In case of premature treatment discontinuation or withdrawal during the treatment period, subjects will complete the EOT and EOS visits. Thereafter, subjects who have taken at 
least one dose of study drug will continue to be followed up at a 6-monthly frequency for vital status, SAEs, cardiovascular and thromboembolic AEs until their projected date of 
completion of the follow-up period (i.e., projected week 108 date) or until consent withdrawn.
d Targeted physical examination only (e.g., respiratory and cardiovascular).
e Height measurement only required at first screening visit.
Footnotes continued on next page
f Blood pressure and heart rate measured singly during the screening period, and in triplicate at all other visits. It is recommended during the treatment period that measurements 
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 and heart rate will be recorded prior to and after dialysis (hemodialysis [HD]/hemodiafiltration [HDF] subjects only).


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g Respiratory rate measured singly during screening period and all other visits. It is recommended during the treatment period that 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 Separate Hemoglobin should be collected at all the visits where Complete Blood Count (CBC) is not collected (i.e., Hb at weeks 6, 10 until the end of the study).
i HemoCue assessment is done on the blood sample that is collected for Hb analysis for the central laboratory.
j In addition to LFTs collected as part of Serum Chemistry, LFTs will separately be collected at the indicated weeks.
k Renal ultrasound examination within 12 weeks prior to randomization. Not required if results of a previous renal ultrasound (or other renal imaging modality such as CT scan or 
MRI) within 12 weeks prior to randomization is available and ruling out renal cell carcinoma. If other imaging modality, a conclusive report on the kidney should be available.
l Fasting whenever possible.
m Collect from female subjects of childbearing potential only.
n Using Modification of Diet in Renal Disease (MDRD) formula; calculated by the central laboratory.
o At day 1, week 20, 52, 76, and EOT, two equal volume samples should be collected.
p Sampling roxadustat will be done at 6 time points over 1 to 3 visits between weeks 2 and 8. See Section 5.6. At each pharmacokinetic visit, one additional sample will be collected 
for determination of Alpha 1-Acid Glycoprotein (α1-AGP) and albumin concentration.
q 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.
r Including SF-36, FACT-An, EQ-5D 5L, PGIC and WPAI:ANS. PGIC will not be performed on day 1. Questionnaires to be completed by the subject preferably prior to any study 
assessments. When subjects need dialysis therapy, Quality of Life (QoL) questionnaires will be completed on the day of first dialysis (preferably before the dialysis is started), 4 
weeks later and 12 weeks later.
s 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.
t Dosing of darbepoetin alfa per EU SmPC.
u Subjects randomized to roxadustat: dose adjustment review from week 4 onward, and every 4 weeks thereafter until EOT (wks 4, 8, 12 etc), 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.
v Telephone or in-person follow-up call with subject.
IS AMENDED TO:


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Assessments
Screening 
Period
Treatment Period
(Correction Period and Maintenance Period)
Follow-up Period
Unscheduled 
Visits
Post study 
Follow-up c
Visit / Week
Up to 2- 6 
weeks a
Day 1b
Weekly
(wks 1 - 2)
± 2 days
Every 2 Weeks 
(wks 4 - 24)
± 2 days
Every 4 Weeks 
(wks 28 - 100)
± 3 days
EOT c
(wk 104)
± 3 days
EOTc + 2 wks
± 3 days
EOS c
(EOT + 4 wks)
± 3 days
Every 
6 months until 
projected 
wk 108
S1
S2 S3
Written informed consent
X
Randomization
X
Eligibility criteria
X
X
Demographics
X
Medical history
X
Physical examination  
X
X
wks 12d, 24d 
wks 36d, 52d, 76d
X
Xd
Od
Heighte, weight
X
X
wks 12, 24
wks 36, 52, 76
X
X
O
Blood pressuref, heart ratef, respiratory rateg
X
X
X
X
X
X
X
X
XO
CBC with WBC diff, red cell indices and 
platelets
X
X
X
wks 4, 8, 12, 20
wks 28, 36, 44, 52, 
60, 68, 76, 84, 92, 
100
X
X
O
Hemoglobinh
Xi
X
X
X
X Oi1
HemoCue assessmentji
X
X
X
X
XO
Reticulocyte count and Hb in reticulocytes 
(CHr)
X
X
X
wks 4, 6, 8, 12, 16, 
20
wks 28, 36, 44, 52, 
60, 68, 76, 84, 92, 
100
X
X
O
12-lead ECG 
X
X
wks 12, 24
wks 36, 52, 76
X
O
Serum chemistry
X
X
wks 4, 8, 12, 20
wks 28, 36, 44, 52, 
60, 68, 76, 84, 92, 
100
X
X
X
O
LFTskj
wk 2
wks 6, 16
O
Renal ultrasoundlk
X
X
O
Serum lipid panelml
X
X
wks 4, 8, 12, 20 wks 28, 36, 44, 52, 
68, 84
X
X
O
Serum iron, ferritin, TIBC, TSAT
X
X
wks 4, 8, 12, 20
wks 28, 36, 44, 52, 
60, 68, 76, 84, 92, 
100
X
X
O
HbA1c
X
X
wk 12
wks 28, 36, 44, 60, 
84
X
X
O
Vitamin B12, folate
X
HIV immunoassay, HBsAg, 
anti-HCV antibody
X
Serum pregnancy testnm
X
wks 12, 24
wks 36, 48, 60, 72, 
84, 96
X
O
Table continued on next page


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Assessments
Screening 
Period
Treatment Period
(Correction Period and Maintenance Period)
Follow-up Period
Unscheduled 
Visits
Post study 
Follow-up c
Visit / Week
Up to 2- 6 
weeks a
Day 1b
Weekly
(wks 1 - 2)
± 2 days
Every 2 Weeks 
(wks 4 - 24)
± 2 days
Every 4 Weeks 
(wks 28 - 100)
± 3 days
EOT c
(wk 104)
± 3 days
EOTc + 2 wks
± 3 days
EOS c
(EOT + 4 wks)
± 3 days
Every 
6 months until 
projected 
wk 108
S1
S2 S3
eGFRon
X
X
wk 20
wks 36, 52, 68, 84
X
X
O
hs-CRP
X
wks 4, 12, 20
wks 36, 52
X
X
Archival serum samples for biomarkerspo
X
wks 4, 12, 20
wks 52, 76
X
X
Blood sample for PKqp
wks 2 to 8
Genotypingrq
O
QoL questionnairessr
X
wks 8, 12 
wks 28, 36, 52, 76
X
O
Urinary testingts
X
wks 12, 24
wks 36, 52, 64, 76, 
88
X
O
Archival urine samples for biomarkers
X
wk 24
wks 52, 76
X
Study drug dispensingut
├────────────────────────────┤
O
Dose adjustment reviewvu
X
X
X
O
Hospitalization recordingwv
X
X
◄─────────────────────────────────────────────────────────────►
X
AE recording
X
X
◄─────────────────────────────────────────────────────────────►
Concomitant medication, procedure and non-
drug therapy recording
X
X
◄─────────────────────────────────────────────────────────────►
Vital status, SAEs, cardiovascular and 
thromboembolic AEswv
X
S1/S2/S3 = Screening visit 1,and 2 and 3; EOT = End of Treatment; EOS = End of Study; Wk(s) = Week(s); X = mandatory test/assessment; O = optional test/assessment.
Note:  see Appendix 12.3 Instructions for Subjects Moving from Protocol v1.0 to Protocol v2.0.
Note:  see Appendix 12.4 Instructions for Subjects Requiring Dialysis.
a a
Due to tThe requirement of a 4-day separation between the screening Hb values, defines the minimum duration of the screening period. will last a minimum of 2 weeks 
but is allowed to be a The maximum duration of the screening period is 6 weeks. Sites are recommended to schedule the three two screening visits in the shortest time span 
possible.
bb
All study assessments are to be performed prior to first study drug administration.
c c
In case of premature treatment discontinuation or withdrawal during the treatment period, subjects will complete the EOT visits (EOT visit and EOT + 2 weeks visit) and 
EOS visits. Thereafter, subjects who have taken at least one dose of study drug will continue to be followed up at a 6-monthly frequency for vital status, SAEs, cardiovascular 
and thromboembolic AEs until their projected date of completion of the follow-up period (i.e., projected week 108 date) or until consent withdrawn.
d d
Targeted physical examination only (e.g., respiratory and cardiovascular).
e e
Height measurement only required at first screening visit.
Footnotes continued on next page


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f f       Blood pressure and heart rate measured singly during the screening period, and in triplicate at all other visits. It is recommended during the treatment period that 
measurements 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 and heart rate will be recorded prior to and after dialysis (hemodialysis [HD]/hemodiafiltration 
[HDF] subjects only).
g g
Respiratory rate measured singly during screening period and all other visits. It is recommended during the treatment period that 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 h
Separate Hemoglobin should be collected at all the visits where Complete Blood Count (CBC) is not collected (i.e., Hb at weeks 6, 10 until the end of the study).
i An additional (third) Hb value may be collected if necessary. Only for subjects who are switched from protocol version 2 to 3 during (re) screening can a fourth Hb 
value be collected, as was applicable under protocol version 2.
i1 If during an unscheduled visit, Hb needs to be assessed, this should always be done with the HemoCue AND a central laboratory Hb assessment.
i j If during an unscheduled visit Hb needs to be assessed, this should always be done with the HemoCue AND a central laboratory Hb assessment.  The HemoCue 
assessment should be is done on the blood sample that is collected for Hb analysis for the central laboratory.
jk In addition to LFTs collected as part of Serum Chemistry, LFTs will separately be collected at the indicated weeks.
kl Renal ultrasound examination within 12 weeks prior to randomization. Not required if results of a previous renal ultrasound (or other renal imaging modality such as CT scan or 
MRI) within 12 weeks prior to randomization is available and ruling out renal cell carcinoma. If other imaging modality, a conclusive report on the kidney should be available.
lm
Fasting whenever possible.
m n
Collect from female subjects of childbearing potential only.
n o
Using Modification of Diet in Renal Disease (MDRD) formula; calculated by the central laboratory.
o p
At day 1, week 20, 52, and 76, and EOT, two equal volume samples should be collected.
p q
Sampling roxadustat will be done at 6 time points over 1 to 3 visits between weeks 2 and 8. See Section 5.6. At each pharmacokinetic visit, one additional sample will be 
collected for determination of Alpha 1-Acid Glycoprotein (α1-AGP) and albumin concentration.
qrOptional assessment for subjects treated with roxadustat. A separate informed consent form must be signed before genotyping sample is collected. Sample collection can be 
done at any timepoint throughout the treatment period of the study.
r s
Including SF-36, FACT-An, EQ-5D 5L, PGIC and WPAI:ANS. PGIC will not be performed on day 1. Questionnaires to be completed by the subject preferably prior to any 
study assessments. When subjects need dialysis therapy, Quality of Life (QoL) questionnaires will be completed on the day of first dialysis (preferably before the dialysis is 
started), 4 weeks later and 12 weeks later.
s tIdeally, 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.
t u
Dosing of darbepoetin alfa per EU SmPC.
u v
Subjects randomized to roxadustat: dose adjustment review from week 4 onward, and every 4 weeks thereafter until EOT (wks 4, 8, 12 etc), 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.
v w 
Telephone or in-person follow-up call with subject.


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1 Introduction
1.3.1 Roxadustat
WAS:
Five pancreatitis events were noted during the 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. 
IS AMENDED TO:
Five pancreatitis events were noted during the roxadustat phase 2 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. 
5 Treatments and Evaluation
Section 5.1.1 Dose/Dose Regimen and Administration Period
WAS:
All subjects will administer study drug doses TIW and study drug doses must be at least 2 
days apart (e.g., Monday Wednesday, Friday) 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. 
The roxadustat treated subjects that have entered the study under protocol v1.0, upon 
signing the informed consent for the amendment 1, will have their dose frequency (on QW 
and BIW under protocol v1.0) and dose amount adjusted according to the instructions in 
Appendix 12.3. Subjects randomized to roxadustat QW or BIW who do not agree to change 
to TIW, should be discontinued from the study treatment and continue in the post study 
follow-up period.
IS AMENDED TO:
All subjects will administer study drug doses TIW and study drug doses must be at least 2 
days apart (e.g., Monday Wednesday, Friday).  The period between two roxadustat 
administrations should be at least 36 hrs 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. 
The roxadustat treated subjects that have had entered the study under protocol v1.0, upon 
signing the informed consent for the amendment 1, will have had their dose frequency (on 
QW and BIW under protocol v1.0) and dose amount adjusted according to the instructions 
in Appendix 12.3. Subjects randomized to roxadustat QW or BIW who do not agree to 
change to TIW, should be discontinued from the study treatment and continue in the post 
study follow up period.


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5 Treatments and Evaluation 
5.1.2.2 Dose Adjustment Rules for Subjects receiving Darbepoetin alfa
DELETED: 
Table 6: Dose Adjustment Rules for Darbepoetin Alfa
5 Treatments and Evaluation
5.1.4 Treatment Compliance
ADDED:
In case of self-administration after 36 weeks of treatment, the empty packages of 
darbepoetin alfa should be returned by the subject to the site.
5 Treatments and Evaluation
5.4 1.1 Blood Pressure
WAS:
Blood pressure (systolic and diastolic) will be measured singly on the three visits during the 
screening period, and in triplicate with a least two minute intervals for all other visits. An 
average of the 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 the three 2 visits during 
the screening period, and in triplicate with a least two minute intervals for all other visits. 
An average of the 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.
5 Treatments and Evaluation
5.4 1.2 Heart Rate
WAS:
HR will be measured singly on 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 in the 
eCRF. An average will be calculated from the 2nd and 3rd readings automatically within the 
eCRF.
IS AMENDED TO:
HR will be measured singly on the three 2 visits during the screening period, and in 
triplicate with at least two 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.


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5 Treatments and Evaluation
5.5.2 Definition of Serious Adverse Events (SAEs)
WAS:
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.
IS AMENDED TO:
All of the events of interest noted above should be recorded on a the SAE and/or Special 
Situation worksheet and within the timelines of reporting SAEs, thus within 24 hours of 
becoming aware of this event, regardless whether or not a (S)AE occurred. 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.
5 Treatments and Evaluation
5.5.5 Reporting of Serious Adverse Events (SAEs)
WAS:
In the case of a Serious Adverse Event (SAE), the investigator must contact his/her 
respective delegated CRO (INC Drug Safety or Medpace Clinical Safety) 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 the delegated CRO by fax or email 
immediately (within 24 hours of awareness).
If the faxing of an SAE Worksheet is not possible or is not possible within 24 hours, the 
local drug safety contact should be informed by phone.
The SAE worksheet should be sent to the delegated CRO that is responsible for the 
investigator’s country:
INC Drug Safety and as specified in the Investigator Site File:
Email: INCDrugSafety@INCResearch.com
Fax: toll-free numbers will be provided for each country; the specific fax number can be 
found on the SAE form fax cover sheet
Tel: +49 89 99 39 13 198
Medpace Clinical Safety and as specified in the Investigator Site File:
Medpace SAE hotline – USA:
Telephone: +1-800-730-5779, ext. 2999 or +1-513-579-9911, ext. 2999
Fax:  +1-866-336-5320 or +1-513-579-0444
Email: medpace-safetynotification@medpace.com
Or
Medpace SAE hotline – Europe:
Telephone: +49 89 89 55 718 44
Fax: +49 89 89 55 718 104
Email: medpace-safetynotification@medpace.com


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IS AMENDED TO:
In the case of a Sserious Aadverse Eevent (SAE), the investigator must contact his/her 
respective delegated CRO (INC Drug Safety or Medpace Clinical Safety or other CRO as 
specified in the Investigator Site File) by telephone or fax immediately (within 24 hours of 
awareness).
The investigator should complete and submit an SAE worksheet containing all information 
that is required by the Regulatory Authorities to the delegated CRO by fax or email 
immediately (within 24 hours of awareness).
If the faxing or e-mailing of an SAE Worksheet is not possible or is not possible within 24 
hours, the local drug safety contact should be informed by phone.
The SAE worksheet should be sent to the delegated CRO that is responsible for the 
investigator’s country:
INC Drug Safety and or another CRO as specified in the Investigator Site File:
Email: INCDrugSafety@INCResearch.com
Fax: toll-free numbers will be provided for each country; the specific fax number can be 
found on the SAE form fax cover sheet
Tel: +49 89 99 39 13 198
Medpace Clinical Safety and as specified in the Investigator Site File:
Medpace SAE hotline – USA:
Telephone: +1 800 730 5779, ext. 2999 or +1 513 579 9911, ext. 2999
Fax:  +1 866 336 5320 or +1 513 579 0444
Email: medpace-safetynotification@medpace.com
Or
Medpace SAE hotline – Europe:
Telephone: +49 89 89 55 718 44
Fax: +49 89 89 55 718 104
Email: medpace-safetynotification@medpace.com
5 Treatments and Evaluation
5.8 Total Amount of Blood
WAS:
The total amount of blood to be collected per subject during the study, based on the 
subject’s screening period, the 104 weeks’ treatment period and the follow-up period and 
allowing full re-screening and unscheduled visits is estimated to be approximately 440 mL.
IS AMENDED TO:
The total amount of blood to be collected per subject during the study, based on the 
subject’s screening period, the 104 weeks’ treatment period and the follow-up period and 
allowing full re-screening and unscheduled visits is estimated to be approximately 4460 mL.


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7 Statistical Methodology
7.4.2.2 Secondary Analyses
DELETED:
In addition, this variable will be analyzed using the subset of subjects who have reached Hb 
≥11.0 g/dL prior to week 28.
11 References
WAS:
EMEA. Aranesp – Procedural steps taken and scientific information after the authorization 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Procedural_steps_taken_and_scientific_information_after_authorisation/human/00033
2/WC500026145.pdf 
EMEA. Aranesp European Public Assessment Report [EPAR] 2004; EMEA. Aranesp 
Procedural steps taken and scientific information after the authorisation. Changes made 
after 2003). 
EMEA, EPAR Aranesp 2004
IS AMENDED TO:
EMEA. Aranesp –Procedural steps taken and scientific information after the authorizsation. 
Changes made after 2003. 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Procedural_steps_taken_and_scientific_information_after_authorisation/human/00033
2/WC500026145.pdf.
EMEA. Aranesp European Public Assessment Report [EPAR]. 2004.; EMEA. Aranesp 
Procedural steps taken and scientific information after the authorisation. Changes made 
after 2003).
EMEA, EPAR Aranesp 2004
12 Appendices 
12.4 Instructions for Subjects Requiring Dialysis
WAS:
Subjects who initiate temporary or permanent dialysis treatment are allowed to continue in 
the study. All modes of dialysis, i.e., hemodialysis (HD), hemodiafiltration (HDF) and 
peritoneal dialysis (PD), 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.


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12.4.2 Dose Adjustment

The dose adjustment rules remain unchanged (see Section 5.1.2.1). 

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 PD subjects) or 400 mg per administration, whichever is lower.
12.4.3 ESA Rescue Therapy
If roxadustat subjects meet the criteria for ESA rescue therapy while on dialysis, 
darbepoetin alfa will be administered IV or SC according to its Package Insert or SmPC for 
dialysis subjects. The subject must be discontinued from study treatment if the subject 
requires a second course of rescue darbepoetin alfa.
IS AMENDED TO:
Subjects who initiate temporary or permanent dialysis treatment are allowed to continue in 
the study. All modes of dialysis, i.e., hemodialysis (HD), hemodiafiltration (HDF) and 
peritoneal dialysis (PD), 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.

For subjects treated with darbepoetin, the route of administration of 
darbepoetin is according to local standard of care for dialysis patients.
12.4.2 Dose Adjustment

The dose adjustment rules remain unchanged (see Section 5.1.2.1). 

The maximum allowed dose in subjects on permanent dialysis is 3.0 mg/kg (based 
on dry weight post-dialysis weight in HD subjects and weight minus abdominal 
fluid based on last filling in PD subjects) or 400 mg per administration, whichever is 
lower.
12.4.3 ESA Rescue Therapy
If roxadustat subjects meet the criteria for ESA rescue therapy while on dialysis, 
darbepoetin alfa will be administered IV or SC according to its Package Insert or SmPC for 
dialysis subjects. The subject must be discontinued from study treatment if the subject 
requires a second course of rescue darbepoetin alfa.
12.4.4 Supplemental Iron Use
Iron supplementation rules are unchanged in subjects starting dialysis who are 
randomized to  roxadustat (see Section 5.1.3.2.1). In subjects randomized to 
darbepoetin, IV iron supplementation will be given according to standard of care.


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12 Appendices
12.10 KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease 2012 
(KDIGO 2012)
DELETED:
12.10  KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease 2012 
(KDIGO 2012)
Please refer for the KDIGO 2012 guidelines to:
VOLUME 2 | ISSUE 4 | AUGUST 2 2012
http://www.kidney international.org


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14
SPONSOR’S SIGNATURES

SAP_003.pdf: 
Sponsor: Astellas Pharma Europe B.V.
SAP Final Version 3.0 
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19 Sep 2018
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STATISTICAL ANALYSIS PLAN
Final Version 3.0, dated 19 September 2018
A Phase 3, Randomized, Open-Label, Active-Controlled Study 
to Evaluate the Efficacy and Safety of Roxadustat in the Treatment of Anemia in 
Chronic Kidney Disease Patients Not on Dialysis
ISN: 1517-CL-0610
EudraCT number: 2013-000951-42
Sponsor name
Astellas Pharma Europe B.V. 
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
I.
LIST OF ABBREVIATIONS AND KEY TERMS··········································· 8
1
INTRODUCTION·················································································15
2
FLOW CHART AND VISIT SCHEDULE···················································16
3
STUDY OBJECTIVE(S) AND DESIGN······················································20
3.1
Study Objective(s) ············································································20
3.1.1
Primary Objective ·······································································20
3.1.2
Secondary Objectives···································································20
3.2
Study Design···················································································20
3.2.1
General ···················································································21
3.2.2
Study Population ········································································21
3.2.3
Description of Study ····································································21
3.2.4
Comparator···············································································23
3.2.5
Interim analysis··········································································23
3.3
Randomization·················································································23
4
SAMPLE SIZE ····················································································24
5
ANALYSIS SETS ·················································································25
5.1
All Randomized ···············································································25
5.2
Full Analysis Set (FAS) ······································································25
5.3
Per Protocol Set (PPS)········································································26
5.4
Safety Analysis Set (SAF) ···································································26
5.5
Pharmacokinetics Analysis Set (PKAS)····················································26
6
ANALYSIS VARIABLES ·······································································26
6.1
Efficacy Endpoints············································································26
6.1.1
Primary Efficacy Endpoint·····························································27
6.1.2
Key Secondary Efficacy Endpoints ···················································27
6.1.2.1
Hb change from BL to the average Hb in weeks 28-36·······················28
6.1.2.2
Change from BL in Low–Density Lipoprotein (LDL) to the average 
LDL cholesterol of weeks 12-28·················································29
6.1.2.3
Time to first IV iron use during weeks 1 to 36 and Mean monthly IV 
iron use per subject during weeks 1 to 36 period ······························29
6.1.2.4
Change from BL in SF-36 Physical Functioning (PF) sub-score to the 
average SF-36 PF sub-score value in weeks 12 to 28 ·························30


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6.1.2.5
Change from BL in SF-36 Vitality (VT) sub-score to the average SF-
36 VT sub-score value in weeks 12 to 28·······································30
6.1.2.6
Change from Baseline in Mean Arterial Pressure (MAP) to the 
average MAP value in weeks 20-28·············································30
6.1.2.7
Occurrence and time to first occurrence of hypertension during week 1 
to 36 ·················································································31
6.1.3
Additional Secondary Efficacy Endpoints ···········································31
6.1.3.1
Hb change from BL to the average Hb value of weeks 28 to 52 
regardless of the use of rescue therapy. ·········································33
6.1.3.2
Time (weeks) to achieve the first Hb response as defined by the 
primary endpoint···································································33
6.1.3.3
Hb averaged over weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104, 
without use of rescue therapy within 6 weeks prior to and during the 
evaluation periods ·································································33
6.1.3.4
Hb value and Hb change from BL to each post-dosing time point ··········34
6.1.3.5
Hb change from BL Hb to the average Hb value of weeks 28 to 36, 44 
to 52, 72 to 80, 96 to 104 regardless of the use of rescue therapy ···········34
6.1.3.6
Categorical analysis of Hb values ···············································34
6.1.3.7
Occurrence and time to first potential Excessive Hematopoiesis (EH) ·····36
6.1.3.8
Occurrence (number) of hospitalizations, number of days of 
hospitalization per patient- exposure -year and time to first 
hospitalization······································································36
6.1.3.9
Occurrence and time to first use of  RBC transfusions, number of 
RBC packs per subject, volume of RBC transfused per subject ·············37
6.1.3.10
Occurrence and time to first use of rescue therapy (composite of RBC 
transfusions [all subjects] and darbepoetin alfa use [roxadustat treated 
subjects only])······································································37
6.1.3.11
Occurrence of iron supplementation ············································38
6.1.3.12
Change from BL to each post-dosing assessments in lipid parameters ·····38
6.1.3.13
Occurrence of mean LDL cholesterol <100 mg/dL (2.59 mmol/L), 
calculated over weeks 12 to 28, and weeks 36 to 52 of treatment ···········39
6.1.3.14
Occurrence of achieved antihypertensive treatment goal (SBP <130 
mmHg systolic and DBP<80 mmHg) based on the mean SBP and 
mean DBP calculated over weeks 12 to 28 and 36 to 52 of treatment 
with study···········································································39
6.1.3.15
Change from BL to the average value of weeks 12 to 28 and 36 to 52 
in Quality of Life scores ··························································39
6.1.3.16
Patients’ Global Impression of Change (PGIC)································43
6.1.3.17
Iron, HbA1c and CKD progression parameters································43


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6.1.4
Other exploratory variables: hs-CRP (High Sensitivity C-Reactive Protein) 
and sTFR (Soluble Transferrin Receptor) ············································46
6.2
Safety Variables···············································································47
6.2.1
Adverse Events ··········································································47
6.2.1.1
Treatment emergent adverse event (TEAE) ····································47
6.2.1.2
Standardized MedDRA Queries ·················································47
6.2.1.3
Time to occurrence of any TEAE (by type of AE group)·····················48
6.2.1.4
Definition of incidence rate·······················································49
6.2.1.5
Definitions of event rate ··························································49
6.2.1.6
AE up to plus 7 Days······························································49
6.2.1.7
Adjudicated CV related Events ··················································50
6.2.2
Vital Signs················································································50
6.2.3
Clinical laboratory variables ···························································52
6.2.3.1
Potentially Clinically Significant (PCS) Laboratory Criteria·················52
6.2.3.2
Laboratory assessments···························································53
6.2.4
Physical Examination···································································53
6.2.5
12-lead Electrocardiogram (ECG)·····················································54
6.3
Pharmacokinetic Variables···································································55
6.4
Pharmacodynamic Variables ································································55
6.5
Other Variables················································································55
6.5.1
Eligibility criteria········································································55
6.5.2
Demographic and Baseline Characteristic Variables································55
6.5.3
Previous and concomitant medication ················································59
6.5.4
Variables related to study drug ························································59
7
STATISTICAL METHODOLOGY ···························································63
7.1
General Considerations·······································································63
7.2
Study Population ··············································································64
7.2.1
Disposition of Subjects ·································································64
7.2.2
Protocol Deviations ·····································································65
7.2.3
Demographic and Other Baseline Characteristics ···································66
7.2.4
Previous and Concomitant Medications ··············································67
7.3
Study Drugs····················································································67
7.3.1
Exposure··················································································67
7.3.2
Treatment Compliance··································································68
7.4
Analysis of Efficacy ··········································································68


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7.4.1
Analysis of Primary Endpoint ·························································68
7.4.1.1
Primary Analysis of the Primary Endpoint ·····································68
7.4.1.2
Secondary Analyses (sensitivity) of the Primary Endpoint···················71
7.4.1.3
Additional Analyses of the Primary Endpoint··································73
7.4.2
Analysis of Key Secondary Endpoints················································73
7.4.2.1
Hb change from baseline to the average Hb in weeks 28-36 ·················75
7.4.2.2
Change from baseline in LDL cholesterol to the average value of LDL 
cholesterol in weeks 12-28 ·······················································80
7.4.2.3
Time to first IV iron use during weeks 1 to 36 and Monthly IV iron 
use during Day 1 to Week 36 ····················································80
7.4.2.4
Change from baseline in SF-36 PF subscore to the average in weeks 
12–28················································································81
7.4.2.5
Change from baseline in SF-36 VT subscore to the average in weeks 
12–28················································································82
7.4.2.6
Change from baseline in mean arterial pressure (MAP) to the average 
MAP value of weeks 20–28 ······················································83
7.4.2.7
Time to first occurrence of hypertension during weeks 1 to 36··············84
7.4.2.8
Additional Analyses of the Key Secondary Endpoints························87
7.4.3
Analysis of the Additional Secondary Endpoints····································88
7.4.3.1
Hb change from BL to the average Hb value of weeks 28 to 52 
regardless of the use of rescue therapy··········································88
7.4.3.2
Time to achieve the first Hb response (without rescue therapy and 
regardless of rescue therapy) during the Efficacy Emergent Period·········88
7.4.3.3
Hb averaged over weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104
without having received rescue therapy within 6 weeks prior to and 
during this 8-week period·························································88
7.4.3.4
Hb value and Hb change from BL Hb to each post-dosing time point 
(regardless of rescue therapy) ····················································88
7.4.3.5
Hb change from BL Hb to the average Hb value of weeks 28 to 36, 44 
to 52, 72 to 80, 96 to 104 regardless of the use of rescue therapy ···········89
7.4.3.6
Categorical analysis of Hb values ···············································89
7.4.3.7
Occurrence and time to first potential Excessive Hematopoiesis (EH) ·····89
7.4.3.8
Occurrence (number) of hospitalizations, number of days of 
hospitalization per PEY and time to first hospitalization ·····················89
7.4.3.9
Occurrence and time to first use of RBC transfusions, number of RBC 
packs per subject, volume of RBC transfused per subject ····················89


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7.4.3.10
Occurrence and time to first use of rescue therapy [composite of RBC 
transfusions [all subjects] and darbepoetin alfa use [roxadustat treated 
subjects only])······································································90
7.4.3.11
Occurrence of iron supplementation. Mean monthly IV iron (mg) per 
subject during weeks 37-52 and weeks 53-104 (monthly defined as a 
period of 4 weeks). Time to first IV Iron during the efficacy emergent 
period················································································90
7.4.3.12
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································90
7.4.3.13
Occurrence of mean LDL cholesterol <100 mg/dL (2.59 mmol/L), 
calculated over weeks 12 to 28, and weeks 36 to 52 of treatment ···········90
7.4.3.14
Occurrence of achieved antihypertensive treatment goal (SBP <130 
mmHg systolic and DBP<80 mmHg) based on the mean SBP and 
mean DBP calculated over weeks 12 to 28 and 36 to 52······················91
7.4.3.15
Health related Quality of Life Questionnaires Change from BL to the 
average value of weeks 12 to 28 and 36-52 ····································91
7.4.3.16
Patients’ Global Impression of Change (PGIC)································92
7.4.3.17
Iron, HbA1c, and CKD progression parameters ·······························92
7.4.4
Analysis of Exploratory Variables: hs-CRP (High Sensitivity C-Reactive 
Protein) and sTFR (Soluble Transferrin Receptor)··································93
7.5
Analysis of Safety·············································································93
7.5.1
Adverse Events ··········································································94
7.5.1.1
Overview ···········································································94
7.5.1.2
Proportion of subjects with TEAEs by SOC/PT ·······························94
7.5.1.3
Event-rates per 100 patient-years················································95
7.5.1.4
Incidence rates and cumulative incidence ······································95
7.5.1.5
Sensitivity/Subgroup analyses ···················································96
7.5.1.6
AEs up to 7 days···································································97
7.5.1.7
Adjudicated events ································································97
7.5.2
Clinical Laboratory Evaluation ························································97
7.5.2.1
Liver function tests ································································98
7.5.3
Vital Signs················································································98
7.5.4
Electrocardiograms (ECGs)····························································99
7.5.5
Pregnancies···············································································99
7.6
Analysis of PK··············································································· 100
7.7
Analysis of PD··············································································· 100


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7.8
Subgroups of Interest ······································································· 100
7.9
Other Analyses ·············································································· 100
7.10
Interim Analysis (and Early Discontinuation of the Clinical Study)·················· 100
7.11
Handling of Missing Data, Outliers, Visit Windows, and Other  Information······· 101
7.11.1
Missing Data ··········································································· 101
7.11.2
Missing Dates·········································································· 101
7.11.3
Outliers ················································································· 103
7.11.4
Visits Windows········································································ 103
7.11.5
End of Safety Emergent Period······················································ 106
7.11.6
End of Efficacy Emergent Period ··················································· 106
8
DOCUMENT REVISION HISTORY······················································· 107
9
REFERENCES ·················································································· 113
10
APPENDICES ··················································································· 114
10.1
Appendix 1: SF-36 v2 ······································································ 114
10.2
Appendix 2: FACT-An (Version 4)······················································· 121
10.2.1
FACT-An Questionnaire ····························································· 121
10.2.2
FACT-An Scoring Guidelines ······················································· 124
10.3
Appendix 3: EQ-5D 5L v2································································· 128
10.4
Appendix 4: WPAI:ANS V2.0 ···························································· 130
10.5
Appendix 5: Patient Overall Impression of Change ···································· 132
10.6
Appendix 6: Medication WHO Drug Dictionary Codes································ 133
10.7
Appendix 7: Signatures····································································· 134


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I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AE
Adverse Event
α1-AGP
Alpha 1-Acid Glycoprotein
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase 
ANCOVA
Analysis of Covariance
AnS
Anemia Subscale
anti-HCV Ab
Anti-hepatitis C Virus 
APEB
Astellas Pharma Europe BV
Apo
Apolipoproteins
ASC
Analysis Set Classification 
ASP1517
= FG-4592 (codename of investigational product) or roxadustat (international 
nonproprietary name)
AST
Aspartate Aminotransferase 
ATC
Anatomical Therapeutic Chemical
BIW
Twice weekly
BL
Baseline
BL Hb
Baseline Hemoglobin (please refer to key definitions for information)
BMI
Body Mass Index
BP
Blood Pressure
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CHMP
Committee for Medicinal Products for Human Use
CHOIR
Correction of Hemoglobin and Outcomes in Renal Insufficiency
CHr
Reticulocyte Hemoglobin Content
CI
Confidence Interval
CKD
Chronic Kidney Disease
CL/F
Apparent total body clearance
CMH
Cochran-Mantel-Haenszel
Cmax
Maximum concentration
CRF
Case Report Form
CRO
Contract Research Organization
CRP
C Reactive Protein
CSE
Composite Safety Endpoint
CSR
Clinical Study Report
CV
Cardiovascular
DBP
Diastolic Blood Pressure
DILI
Drug-induced Liver Injury
dL
Deciliter
DS
Data Science
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
eCRF
Electronic CRF
EDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate
EH
Excessive Hematopoiesis


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Abbreviations
Description of abbreviations
EoS
End of Study
EoT
End of Treatment
EPO
Erythropoietin
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)
FWB
Functional Well-being
g
Gram
GGT
Gamma Glutamyl Transferase
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
HIF-PH
HIF Prolyl Hydroxylase
HIV
Human Immunodeficiency Virus
HRQoL
Health-Related Quality of Life
hs-CRP
High Sensitivity C-reactive protein
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
IND
Investigational New Drug (Application)
INN 
International Nonproprietary Name
INR
International Normalized Ratio
IRT
Interactive Response Technology
ISN
International Study Number
IV
Intravenous(ly)
Kg
Kilogram
LDL
Low-density Lipoprotein
LA-CRF
Liver Abnormality Case Report Form
LFT
Liver Function Tests
LLN
Lower Limit of Normal 


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Abbreviations
Description of abbreviations
LOCF
Last Observation Carried Forward
LSO
Last Subject Out
MACE
Major Adjudicated Cardiovascular Event (death, non-fatal myocardial
infarction and/or stroke)
MACE+
MACE including, in addition, hospitalizations for either unstable angina and/or
chronic heart failure
MAP
Mean Arterial Pressure
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram 
MI
Myocardial Infarction
mL
Milliliters 
mmHg
Millimeters of Mercury
Μg
Microgram
MMRM
Mixed Model of Repeated Measures
MSAP
Meta-Analysis Statistical Analysis Plan
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria for Adverse Events
NDD-CKD
Nondialysis-dependent chronic kidney disease
O
Optional 
PCS
Physical Component Score
PD
Protocol Deviation
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
QW
Once weekly
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
SC
Subcutaneous(ly)
SD
Standard Deviation
SI
International System of Units 
SF-36
Short Form 36


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Abbreviations
Description of abbreviations
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
SmPC
Summary of Product Characteristics
SMQ
Standardized MedDRA Query
SOC
System Organ Class
SOP
Standard Operating Procedure
SQ
Subcutaneous
sTfR
Soluble Transferrin Receptor
SWB
Social Well-being
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-DD
World Health Organization Drug Dictionary 
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 is as any untoward medical occurrence in a subject 
administered roxadustat or darbepoetin alfa, and which does not necessarily 
have a causal relationship with this treatment.
Baseline
1) Observed values/findings which are regarded as calibrated zero status in 
the present study; 2) Time when ‘Baseline’ is observed.
Baseline Hb value
Baseline Hb is defined as the mean of all available central laboratory Hb 
values collected before or including the date of first study drug intake (pre-
dose) [i.e. 4 latest values for patients enrolled under protocol version 1.0 and 
2.0, and 3 latest values for those under protocol version 3.0].
Discontinuation
The act of concluding participation, 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.
Efficacy Emergent 
Period
Evaluation period from the Analysis date of first dose intake up to End of 
Treatment visit or last non-missing Hb assessment (for subjects who died 
during the treatment period).
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 randomization.
Hb Correction
Hemoglobin level ≥11.0 g/dL and an Hb increase from baseline BL Hb ≥1.0 
g/dL as assessed by the central laboratory at two consecutive study visits 
separated by at least 5 days in the Correction Period.
Hb Response
Hemoglobin level ≥11.0 g/dL and an Hb increase from baseline BL Hb ≥1.0 
g/dL in case BL Hb was >8.0 g/dL, or an increase in Hb from BL Hb by 
≥2.0 g/dL in case BL Hb was ≤8.0 g/dL, as assessed by the central 
laboratory at two consecutive study visits separated by at least 5 days.
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. 
Investigational period
Period of time where major interests of protocol objectives  are observed, 
and where the test drug or comparative drug (sometimes without 
randomization) is usually given to a subject, and continues until the last 
assessment after completing administration of the test drug or comparative 
drug.


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Terms
Definition of terms
Post study follow-up
Period of time from EOS visit to projected week 108 or until consent 
withdrawn. This period is only applicable to subjects who prematurely 
discontinued treatment. These subjects will be followed up every 6 months 
for vital status, serious adverse events (SAEs), cardiovascular and 
thromboembolic adverse events (AEs).
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 first study drug 
intake.
Randomization
The process of assigning trial subjects to treatment or control groups using 
an element of chance to determine assignments in order to reduce bias (after 
randomization subjects receive either roxadustat or darbepoetin alfa from 
day 1 until End of Treatment (EOT)). 
Roxadustat
International Nonproprietary Name (INN) of ASP1517/FG-4592 
investigational product
Re-screening
Process of repeating screening, See also screening and screen failure
If subject fails screening they may be re-screened once if deemed 
appropriate; all screening procedures will be repeated
Safety Emergent 
Period
Evaluation period from the Analysis date of first drug intake up to the 
minimum between [(Analysis Date of last dose + 28 days + x), EOS visit, 
Date of death], with x corresponding to additional days based on the last 
dosing frequency.
Screening
1) Process for retrieving candidates for the study. 2) Process for checking 
the eligibility of subjects usually done during the “pre-investigational 
period”
Screen failure
Screened subject, but did not fulfil protocol inclusion and/or exclusion 
criteria and failed to receive randomized or open label study treatment, or 
decided not to participate anymore (withdrew consent) prior to completing
pre-investigational period
Screening Hb value
Mean of all available central laboratory Hb values collected during 
screening period [i.e. 3 latest values for patients enrolled under protocol 
version 1.0 and 2.0, and 2 latest values for those under protocol version 3.0]. 
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
Time to event
Time from a defined starting point (analysis date of first dose intake) to the 


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Terms
Definition of terms
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
It is the period of time - between first dose of the test drug and last dose -
where major interests of protocol objectives are observed, and where 
roxadustat (study drug) or darbepoetin alfa (comparative drug) is given to a 
subject. The treatment period consists of the Correction and Maintenance 
period.
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 variables and other data. 
The SAP version 1.0, dated 26 May 2014 was based on protocol version 1.0, dated 14 August 
2013. This SAP is an amended version due to the protocol amendments (Amendment 1, 
dated 18 May 2015 and Amendment 2, dated 31 March 2016) as well as further 
harmonization with the other non-dialysis studies in this clinical program.
The SAP is finalized and signed prior to accumulation of substantial amount of data (open-
label study) to ensure lack of bias. If needed, amendments to the approved SAP may be made 
prior to database hard lock. Amendments will be version controlled.
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 statistical analysis is coordinated by the responsible biostatistician of APGD. Any 
changes from the analyses planned in the SAP will be justified in the Clinical Study Report 
(CSR).
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
Figure 1
Flow Chart


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Table 1
Schedule of Assessments
Assessments
Screening 
Period
Treatment Period
(Correction Period and Maintenance Period)
Follow-up Period
Unscheduled 
Visits
Post study 
Follow-up c
Visit / Week
Up to6 
weeks a
Day 1b
Weekly
(wks 1 - 2)
± 2 days
Every 2 Weeks 
(wks 4 - 24)
± 2 days
Every 4 Weeks 
(wks 28 - 100)
± 3 days
EOT c
(wk 104)
± 3 days
EOTc + 2 wks
± 3 days
EOS c
(EOT + 4 wks)
± 3 days
Every 6 months 
until projected 
wk 108
S1
S2
Written informed consent
X
Randomization
X
Eligibility criteria
X
X
Demographics
X
Medical history
X
Physical examination  
X
X
wks 12d, 24d 
wks 36d, 52d, 76d
X
Xd
Od
Heighte, weight
X
X
wks 12, 24
wks 36, 52, 76
X
X
O
Blood pressuref, heart ratef, respiratory rateg
X
X
X
X
X
X
X
X
O
CBC with WBC diff, red cell indices and 
platelets
X
X
X
wks 4, 8, 12, 20
wks 28, 36, 44, 52, 
60, 68, 76, 84, 92, 
100
X
X
O
Hemoglobinh
Xi
X
X
X
X
Oi1
HemoCue assessmentj
X
X
X
X
O
Reticulocyte count and Hb in reticulocytes 
(CHr)
X
X
X
wks 4, 6, 8, 12, 16, 
20
wks 28, 36, 44, 52, 
60, 68, 76, 84, 92, 
100
X
X
O
12-lead ECG 
X
X
wks 12, 24
wks 36, 52, 76
X
O
Serum chemistry
X
X
wks 4, 8, 12, 20
wks 28, 36, 44, 52, 
60, 68, 76, 84, 92, 
100
X
X
X
O
LFTsk
wk 2
wks 6, 16
O
Renal ultrasoundl
X
O
Serum lipid panelm
X
X
wks 4, 8, 12, 20 wks 28, 36, 44, 52, 
68, 84
X
X
O
Serum iron, ferritin, TIBC, TSAT
X
X
wks 4, 8, 12, 20
wks 28, 36, 44, 52, 
60, 68, 76, 84, 92, 
100
X
X
O
HbA1c
X
X
wk 12
wks 28, 36, 44, 60, 
84
X
X
O
Vitamin B12, folate
X
HIV immunoassay, HBsAg, 
anti-HCV antibody
X
Serum pregnancy testn
X
wks 12, 24
wks 36, 48, 60, 72, 
84, 96
X
O
Table continued on next page


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Assessments
Screening 
Period
Treatment Period
(Correction Period and Maintenance Period)
Follow-up Period
Unscheduled 
Visits
Post study 
Follow-up c
Visit / Week
Up to6 
weeks a
Day 1b
Weekly
(wks 1 - 2)
± 2 days
Every 2 Weeks 
(wks 4 - 24)
± 2 days
Every 4 Weeks 
(wks 28 - 100)
± 3 days
EOT c
(wk 104)
± 3 days
EOTc + 2 wks
± 3 days
EOS c
(EOT + 4 wks)
± 3 days
Every 6 months 
until projected 
wk 108
S1
S2
eGFRo
X
X
wk 20
wks 36, 52, 68, 84
X
X
O
hs-CRP
X
wks 4, 12, 20
wks 36, 52
X
X
Archival serum samples for biomarkersp
X
wks 4, 12, 20
wks 52, 76
Blood sample for PKq
wks 2 to 8
Genotypingr
O
QoL questionnairess
X
wks 8, 12 
wks 28, 36, 52, 76
X
O
Urinary testingt
X
wks 12, 24
wks 36, 52, 64, 76, 
88
X
O
Archival urine samples for biomarkers
X
wk 24
wks 52, 76
Study drug dispensingu
├────────────────────────────┤
O
Dose adjustment reviewv
X
X
X
O
Hospitalization recordingw
X
X
◄─────────────────────────────────────────────────────────────►
X
AE recording
X
X
◄─────────────────────────────────────────────────────────────►
Concomitant medication, procedure and non-
drug therapy recording
X
X
◄─────────────────────────────────────────────────────────────►
Vital status, SAEs, cardiovascular and 
thromboembolic AEsw
X
S1/S2 = Screening visit 1and 2; EOT = End of Treatment; EOS = End of Study; Wk(s) = Week(s); X = mandatory test/assessment; O = optional test/assessment.
a The requirement of a 4-day separation between the screening Hb values defines the minimum duration of the screening period.  The maximum duration of the screening period is 6 
weeks.  Sites are recommended to schedule the two screening visits in the shortest time span possible.
b All study assessments are to be performed prior to first study drug administration.
c In case of premature treatment discontinuation or withdrawal during the treatment period, subjects will complete the EOT visits (EOT visit and EOT + 2 weeks visit) and EOS visit.  
Thereafter, subjects who have taken at least one dose of study drug will continue to be followed up at a 6-monthly frequency for vital status, SAEs, cardiovascular and 
thromboembolic AEs until their projected date of completion of the follow-up period (i.e., projected week 108 date) or until consent withdrawn.
d Targeted physical examination only (e.g., respiratory and cardiovascular).
e Height measurement only required at first screening visit.
Footnotes continued on next page


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f Blood pressure and heart rate measured singly during the screening period, and in triplicate at all other visits.  It is recommended during the treatment period that measurements 
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 and heart rate will be recorded prior to and after dialysis (hemodialysis [HD]/hemodiafiltration [HDF] subjects only).
g Respiratory rate measured singly during screening period and all other visits.  It is recommended during the treatment period that 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 Separate Hb should be collected at all the visits where Complete Blood Count (CBC) is not collected (i.e., Hb at weeks 6, 10 until the end of the study).
i An additional (third) Hb value may be collected if necessary. Only for subjects who are switched from protocol version 2.0 to 3.0 during (re) screening can a fourth Hb value be 
collected, as was applicable under protocol version 2.0.
i1 If during an unscheduled visit, Hb needs to be assessed, this should always be done with the HemoCue AND a central laboratory Hb assessment.
j If during an unscheduled visit Hb needs to be assessed, this should always be done with the HemoCue AND a central laboratory Hb assessment. This HemoCue assessment should 
be done on the blood sample that is collected for Hb analysis for the central laboratory.
k In addition to LFTs collected as part of Serum Chemistry, LFTs will separately be collected at the indicated weeks.
l Renal ultrasound examination within 12 weeks prior to randomization.  Not required if results of a previous renal ultrasound (or other renal imaging modality such as CT scan or 
MRI) within 12 weeks prior to randomization is available and ruling out renal cell carcinoma.  If other imaging modality, a conclusive report on the kidney should be available.
m Fasting whenever possible. 
n Collect from female subjects of childbearing potential only.
o Using Modification of Diet in Renal Disease (MDRD) formula; calculated by the central laboratory.
p At day 1, week 20, 52, and 76, two equal volume samples should be collected.
q Sampling roxadustat will be done at 6 time points over 1 to 3 visits between weeks 2 and 8. See Section 5.6 of the protocol. At each pharmacokinetic visit, one additional sample will 
be collected for determination of Alpha 1-Acid Glycoprotein (α1-AGP) and albumin concentration.
r Optional assessment for subjects treated with roxadustat.  A separate informed consent form must be signed before genotyping sample is collected.  Sample collection can be done at 
any timepoint throughout the treatment period of the study.
s Including SF-36, FACT-An, EQ-5D 5L, PGIC and WPAI:ANS. PGIC will not be performed on day 1.  Questionnaires to be completed by the subject preferably prior to any study 
assessments.  When subjects need dialysis therapy, Quality of Life (QoL) questionnaires will be completed on the day of first dialysis (preferably before the dialysis is started), 4 
weeks later and 12 weeks later.
t 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.
u Dosing of darbepoetin alfa per EU SmPC.
v Subjects randomized to roxadustat: dose adjustment review from week 4 onward, and every 4 weeks thereafter until EOT (wks 4, 8, 12 etc), 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.
w Telephone or in-person follow-up call with subject.


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3
STUDY OBJECTIVE(S) AND DESIGN
3.1
Study Objective(s)
3.1.1
Primary Objective
The primary objective of this study is to evaluate the efficacy of roxadustat compared to 
darbepoetin alfa in the treatment of anemia in NDD-CKD subjects.
3.1.2
Secondary Objectives
The secondary objectives of this study are to:

Evaluate the safety of roxadustat compared to darbepoetin alfa in the treatment of 
anemia in NDD-CKD subjects.

Evaluate the HRQoL benefit of roxadustat compared to darbepoetin alfa in the treatment 
of anemia in NDD-CKD subjects.
3.2
Study Design
There are two protocol substantial amendments (Amendment 1, dated 18 May 2015 and 
Amendment 2, dated 31 March 2016).
The main protocol changes on the Amendment 1 are:
a)
Changes in the study dosing regimen:

Dosing frequency changed from three times weekly (TIW), twice weekly (BIW) 
and once weekly (QW) to TIW only;

Initial study drug dose changed from 70, 100 and 150 mg to 70 and 100 mg only;

Maximum dose reduced from 3.5 mg/kg to 3.0 mg/kg and maximum absolute 
dose reduced from 400 mg to 300 mg;

Dose step of 120 mg was removed.
b)
As a result of a), number of treatment arms were changed from 4 to 2 (roxadustat vs 
darbepoetin) and allocation ratio from 2:1 to 1:1
c)
Reduction in visit schedule by removal of 12 study visits, resulting in total of 39 visits.
The main protocol changes on the Amendment 2 are:
a)
Change in hemoglobin (Hb) eligibility criteria:

The number of Hb values assessed during the screening period is reduced from 
three to two and the mean Hb entry threshold is increased from ≤10.0 g/dL to 
≤10.5 g/dL.  This results in a change in inclusion criterion 4 and texts throughout 
the protocol that refer to the mean Hb entry threshold.
b)
Update of the iron criteria: ferritin level ≥100 ng/mL and transferrin saturation 
(TSAT) level ≥20% at screening are removed.
c)
Exclusion Criterion 21 extended to exclude patients who are likely to initiate renal 
replacement therapy including dialysis within the first year of the study in the opinion 
of the investigator.


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3.2.1
General
This is a phase 3, multi-center, randomized, open-label, active-controlled study. This study is 
planned to recruit approximately 570 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 anaemia associated with CKD.
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 
≤10.5 g/dL upon repeated screening measurements. Anemia of non-renal origin is to be 
excluded. Washout periods of at least 12 weeks for any prior ESA, at least 6 weeks for any 
IV iron treatment, and 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.
3.2.3
Description of Study
Subjects assigned to the roxadustat treatment arms will be administered roxadustat orally as a 
combination of tablets of different strengths. Subjects assigned to the darbepoetin alfa 
treatment will be administered darbepoetin alfa subcutaneously (SC) or intravenously (IV) by 
the investigator or a qualified member of the site staff or, after 36 weeks of treatment, by the 
subjects themselves or caregiver, e.g. relative, if well trained and willing to self-administer. 
Study treatment administration is implemented in an open-label manner. 
The study will consist of three study periods as follows:

Screening Period: up to 6 weeks

Treatment Period: 104 weeks 

Follow-up Period: 4 weeks
Subjects that have discontinued treatment prior to their projected week 104 will continue to 
be followed for vital status, SAEs, cardiovascular and thromboembolic AEs in a post study 
follow-up period.
During the course of the study, visits and assessments will be performed as defined in the 
Schedule of Assessments.
Screening Period
During the Screening Period (up to 42 days duration), Hb levels will be assessed in a central 
laboratory for matching the inclusion criterion (mean of two Hb values must be ≤10.5 g/dL, 
see inclusion criterion 4). Subjects meeting all of the inclusion criteria and none of the 
exclusion criteria will be randomized at day 1, which marks the end of screening period and 
start of the treatment period. If a subject fails screening, the subject may be rescreened once 
(immediately or later) if deemed appropriate by the investigator.  The subject must be 


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re-consented.  A new rescreening period will start and all screening procedures must be 
repeated.
Treatment Period (Correction and Maintenance Period)
After subjects have been confirmed eligible for study participation, subjects are randomized 
to 1 of 2 treatment arms (1:1 ratio) as illustrated in Table 2  The randomization will occur 
through an Interactive Response Technology (IRT). The randomization will result in an 1:1 
ratio of subjects receiving roxadustat administered orally or darbepoetin alfa administered by 
SC or IV injection. 
Table 2
Treatment Arms and Dosing Frequency
Treatment 
Arms
Study Treatment
Dosing Frequency in Treatment 
Period
Correction 
Period
Maintenance Period
1
Roxadustat
TIW
TIW†
2
Darbepoetin alfa
Dosing per EU SmPC
SmPC: Summary of Product Characteristics; TIW: three times weekly
† Subjects who were randomized under protocol v1.0 to QW and BIW will be converted to the TIW.
In protocol version 1 subjects were randomized in a ratio of 2:1 receiving roxadustat versus 
darbepoetin alfa.  The expected number of subjects randomized on protocol version 1, 
protocol versions 2 and 3 and the total number of randomized subjects per treatment arm are 
represented in the following table.
Table 3
Expected Number of Subjects Randomized 
Treatment 
Arms
Study Treatment
Expected Number of 
Protocol v1 Subjects 
Randomized (Ratio 
2:1)
Expected Number of 
Protocol v2 and 3 
Subjects Randomized
(Ratio 1:1)†
Total Expected 
Number of 
Subjects 
Randomized per 
Treatment Arm
1
Roxadustat
100
210
310
2
Darbepoetin alfa
50
210
260
Total
150
420
570
† The number of subjects under protocol v2 and v3 will depend on the number of subjects randomized under 
protocol v1.
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.  From week 24 onwards, visits 
will occur every four weeks until the end of treatment (EOT).
Subjects will receive study treatment (roxadustat or darbepoetin alfa) for 104 weeks.
Correction Period
The aim of the correction period is to correct Hb levels to ≥11.0 g/dL and a Hb increase from 
BL Hb ≥1.0 g/dL as measured at two consecutive study visits separated by at least 5 days (as 
assessed by central laboratory).  Dosing and dose adjustments of roxadustat will follow 


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prespecified dose adjustment rules.  Dosing and dose adjustments of darbepoetin alfa will be 
per EU approved Summary of Product Characteristics (SmPC).
Once Hb is corrected the subjects will enter into the maintenance period.
Maintenance Period
After achieving Hb correction, 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 10.0 g/dL and 12.0 g/dL.  Dose 
adjustments of roxadustat will follow prespecified dose adjustment rules.  Dose adjustments 
of darbepoetin alfa will be per EU approved Summary of Product Characteristics (SmPC).
Follow-up Period
After the end of the treatment period, subjects proceed to the 4-week follow-up period. 
Post study Follow-up (for premature treatment discontinued subjects only)
Subjects that have prematurely discontinued study treatment will complete the EOT visits 
(EOT visit and EOT +2 weeks visit) and EOS visit.  Thereafter, these subjects who have 
taken at least one dose of study drug will continue to be followed up every 6 months for vital 
status, SAEs, cardiovascular and thromboembolic AEs until their projected date of 
completion of the follow-up period (i.e., projected week 108 date) or until consent 
withdrawn.
3.2.4
Comparator
Darbepoetin alfa supplied as a solution for injection in a pre-filled syringe, and is 
administered by SC or IV injection.  Once the route of administration is chosen (IV or SC), it 
is recommended to keep the same administration route for a subject throughout the study.  It 
is administered in combination with IV or oral iron to maintain iron repletion. Darbepoetin 
alfa will be provided in pre-filled syringes of the following strengths: 20, 30, 40, 60 and 
100 g.
3.2.5
Interim analysis
An interim analysis will be performed when all subjects have completed 36 weeks of 
treatment. More details will be included in section 7.10
3.3
Randomization
A randomized 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.
Darbepoetin alfa will be administered by SC or IV injection, whereas roxadustat is 
administered orally. An open label design was chosen since the investigational and 
comparator drug are provided via different routes of administration and have a different 
requirement for iron supplementation. 
Randomization and treatment assignments will be performed via IRT prepared on behalf of 
the Sponsor (under the responsibility of the Data Science (DS) Department of APEB).


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Specific procedures for randomization through the IRT are contained in the study procedures 
manual. In protocol version 1 subjects were randomized in a ratio of 2:1 and in protocol 
versions 2 and 3 in a ratio 1:1 receiving roxadustat versus darbepoetin alfa.  
Approximately 570 subjects will be randomized to receive roxadustat TIW or darbepoetin 
alfa as shown in Table 4 assuming 150 subjects will be randomized under the first version of 
the protocol.
Randomization will be stratified by the following four factors: 
●
Region: region A (Western Europe and Israel) versus region B (Central and Eastern 
Europe) *;
* Assignment to region will be determined based on health care comparability.

Screening Hb values (Hb ≤8.0 g/dL versus >8.0 g/dL);

History of cardiovascular, cerebrovascular or thromboembolic diseases (Yes versus No);

Screening eGFR (<30 mL/min/1.73 m2 versus ≥30 mL/min/1.73 m2). 
4
SAMPLE SIZE
Approximately 570 subjects will be randomized to receive roxadustat or darbepoetin alfa as 
follows:
Table 4
Sample Size Calculations per Treatment Arm 
Treatment 
Group
Protocol version 1
(Ratio 2:1)
Protocol versions 2 and 3
(Ratio 1:1)
Total
Randomized
PPS
Randomized†
PPS
Randomized
PPS
Roxadustat
100
80
210
168
310
248
Darbepoetin alfa
50
40
210
168
260
208
Total
150
120
420
336
570
456
† The number of subjects under protocol v2.0 and v3.0 will depend on the number of subjects randomized under 
protocol v1.
The sample size calculation is based on the primary endpoint: Percentage of Hb responders 
during the first 24 weeks of treatment without rescue therapy. Assuming that the Per Protocol 
Analysis Set (PPS) will consist of 80% of subjects in the Full Analysis Set (FAS), a number 
of 570 randomized subjects in the FAS will lead to approximately 456 subjects in the PPS. 
Two hundred and forty eight (248) subjects for the roxadustat treatment group and
208 subjects for the darbepoetin alfa treatment group will provide at least 98% test power to 
demonstrate statistically non-inferiority of roxadustat versus darbepoetin alfa in the primary 
endpoint assuming that the proportion of subjects with response in both groups is the same 
and at least 80% and a non-inferiority margin for the difference of proportions of 15% (see 
justification below).  The power for the sensitivity analysis of post-amendment 1 data 
(336 subjects) will be at least 93%.
Note that the actual number of patients randomized under protocol v2.0 and v3.0 will lead a 
slight increase in power (according to the actual recruitment at the time of the SAP 
amendment).


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Justification of the non-inferiority margin
In general an appropriate choice of margin should provide both:
a)
Assurance that the test drug has a clinically relevant effect greater than zero (placebo). 
This aspect of the choice of margin is discussed in EMEA Guideline on the choice of the 
non-inferiority margin; section III [EMEA, 2005].
b)
Assurance that the test product is not substantially inferior to the reference in EMA 
guideline. This aspect of the choice of margin is discussed in EMEA Guideline on the 
choice of the non-inferiority margin; section IV [EMEA, 2005].
Two randomized pivotal placebo controlled studies are planned in this population 
(FGCL-4592-060 and 1517-CL-0608) that will directly prove superiority over placebo.  
Since direct comparisons provide always a higher level of evidence than indirect tests, the 
main criterion to fix the NI-margin in the 1517-CL-0610 study is bullet b above, i.e., to prove 
that the difference between roxadustat and darbepoetin alfa is unimportant.
From a clinical point of view, a true response rate for roxadustat of 15% lower than the true 
response rate for darbepoetin alfa is regarded an unimportant loss in efficacy since roxadustat 
is anticipated to have a number of advantages over ESAs that have been shown during the 
phase II program:  less need for IV iron supplementation and no increase of blood pressure. 
No regulatory guideline exists in this therapeutic indication recommending a non-inferiority 
margin. However, the selected non-inferiority margin of 15% is in line with the FDA 
guideline in the urinary tract infections indication, where a high responder rate was also 
expected and a non-inferiority margin of 15% was recommended [FDA, 1998].
5
ANALYSIS SETS
In accordance with ICH recommendations in guidelines E3 and E9, the following analysis 
sets will be used for the analyses.
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 (as documented in the IRT subjects and 
corresponds to the Intent-To-Treat (ITT) set defined in the protocol.
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 post-dose Hb value. 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.


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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 5. This PPS will be used for the primary 
endpoint analysis, for selected secondary analyses and for all disposition, demography and 
baseline characteristics. 
Table 5
Criteria for excluding a complete 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 first 24 weeks or until EOT, whatever comes first.
5
Administration of wrong randomization study drug for more than one week during the first 24 
weeks or until EOT, whatever comes first.
6
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.
7
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 will be defined 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.
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 EOT Visit. In case a subject died during the treatment period, 
the end will be set to the last non-missing Hb assessment. This period will be used as 
reference period for the time to event analyses related to efficacy endpoints, unless specified 


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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
Primary definition of Hb Response (Yes/No)
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 by at least 5 days, 
during the first 24 weeks of treatment without having received rescue therapy (i.e., RBC 
transfusion for all subjects or darbepoetin alfa for roxadustat treated subjects) prior to Hb 
response.
Alternative definitions of Hb Response (Yes/No) used for sensitivity analyses:

[regardless use of rescue therapy]: similar to the primary definition except that all 
Hb values will be used regardless the use of rescue therapy during the first 24 weeks.

[Modified definition, without use of rescue therapy]: Since the latest protocol 
amendment 2.0 allows subjects with screening Hb between 10.0 and 10.5 to be 
enrolled, this alternative Hb response will be defined as Hb ≥11.0 g/dL only. 
Baseline Hb is defined as the mean of all available central laboratory Hb values collected 
before or including the date first study drug intake (pre-dose) [up to 4 latest available values, 
the number of Hb values considered depends on the protocol version according to subjects 
will be randomized].
All 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 Section 7.11.4).
6.1.2
Key Secondary Efficacy Endpoints
The primary analysis set will be PPS for the non-inferiority tests and FAS for the superiority
tests.
The key secondary efficacy endpoints in this study are listed in Table 6


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Table 6
Key Secondary Efficacy Endpoints
Number
Endpoint
1
Hb change from BL to the average Hb in weeks 28-36, without having received  
rescue therapy (i.e. RBC transfusion for all subjects, or darbepoetin alfa for 
roxadustat treated subjects) 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 12-28
3
Time to first IV iron use during weeks 1 to 36 #
4
Change from BL in SF-36 Physical Functioning (PF) sub-score to the average PF 
sub-score in weeks 12 to 28
5
Change from BL in SF-36 Vitality (VT) sub-score to the average VT sub-score in 
weeks 12 to 28 
6
Change from BL in Mean Arterial Pressure (MAP) to the average MAP value in 
weeks 20-28
7
Occurrence and time to first occurrence of hypertension (defined as [systolic BP 
≥170 mmHg AND systolic BP increase from BL ≥20 mmHg] or [diastolic BP 
≥110 mmHg AND diastolic BP increase from BL ≥15 mmHg]) during weeks 1 to 
36
# The key secondary endpoint, Mean monthly IV iron use (mg) per subject during weeks 1 to 
36 (monthly defined as a period of 4 weeks) is updated as Time to first IV iron use during 
weeks 1 to 36. This is due to the small number of subjects who took IV iron during the first 
36 weeks.
6.1.2.1 Hb change from BL to the average Hb in weeks 28-36
All available Hb values obtained from the central laboratory will be considered (i.e., both 
scheduled and unscheduled Hb values), but only Hb values within analysis visit windows at 
weeks 28, 32 and 36, will be used for the calculation of the average of weeks 28 to 36 (see 
Section 7.11.4 for the analysis windows definition and the differentiation between the 
MMRM and ANCOVA analyses).
Similarly to the primary endpoint, this key secondary endpoint will be derived using different 
rules regarding the use of rescue therapy: 
[without rescue therapy]: in case a subject requires rescue therapy within 6 weeks prior to 
and during this 8-week evaluation period, the reported Hb values collected during weeks 28 
to 36 analysis windows falling within any rescue therapy period will be set to missing. 
Imputation of missing data will be performed using either MMRM or ANCOVA analyses, 
see Section 7.11.4 for more details).
[regardless rescue therapy]: all Hb values will be considered for the analysis, regardless of 
the use of rescue therapy.
Baseline Hb is defined in section 6.1.1


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6.1.2.2 Change from BL in Low–Density Lipoprotein (LDL) to the average LDL 
cholesterol of weeks 12-28
The analysis will be done on all values (fasted and non-fasted) of Day 1 and scheduled visits 
up to analysis Week 28 within Efficacy Emergent Period.
All available scheduled LDL values will be considered (regardless the fasting status), but 
only LDL values in analysis visit windows at weeks 12, 20 and 28, will be selected for the 
calculation of the average LDL cholesterol of weeks 12-28 (see 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 Time to first IV iron use during weeks 1 to 36 and Mean monthly IV iron use 
per subject during weeks 1 to 36 period
The use of IV iron is recorded in the Concomitant Medication form of the eCRF.. All 
medications are coded with WHO-DD. Records selected will be those coded as ATC 3rd level 
=IRON PREPARATIONS and route is INTRAVENOUS.
Only use of IV Iron that was ongoing or started during the Efficacy Emergent Period will be 
taken into account with the note that prior IV iron treatment ending on Day 1 will not be 
counted. Subjects without a relevant concomitant medication record will be assumed that 
they used no IV iron, thus set to 0 mg.
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 -,   ( 
 /0 
 /

11' / 20)
((%(&	' ( 
 )* 36 -,   ( 
 /0 
 /

11' / 20)
−(' 1 () + 1)/ 28
Monthly is defined as a period of 4 weeks or 28 days.
Additional variables for IV iron use consist of:  
-
Received IV Iron as binary variable (Yes/No) during the first 36 weeks, where “Yes” is 
defined as having at least one record selected during Min (Analysis date of Week 36, end 
of efficacy emergent period).
-
Time to first use of IV Iron during the first 36 Weeks will be calculated (in years) as 
(Date of first use of IV Iron  – Analysis Date of first dose intake + 1) / 365.25


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Where ‘Analysis Date of first dose intake’ is defined in section 6.5.4. The date of 
censoring for a subject without the event of interest is defined as the Minimum [Analysis 
date of Week 36 visit, end of Efficacy Emergent Period].
6.1.2.4 Change from BL in SF-36 Physical Functioning (PF) sub-score to the average 
SF-36 PF sub-score value in weeks 12 to 28
For details on the derivation of the SF-36 PF subscore, refer to section 6.1.3.15.1.
All available SF-36 PF sub-scores will be considered i.e., both scheduled and unscheduled 
SF-36 PF values, but only SF-36 PF subscores in the analysis visit windows at weeks 12 and 
28 will be selected for the calculation of the average PF sub-score of weeks 12 to 28 (see 
Section 7.11.4 for the analysis windows definition and the differentiation between the 
MMRM and ANCOVA analyses).
For missing SF-36 PF imputation rules, refer to Section 7.11.1
Baseline subscore is the assessment from Day 1 visit (i.e. the last one before first dose 
intake).
6.1.2.5 Change from BL in SF-36 Vitality (VT) sub-score to the average SF-36 VT 
sub-score value in weeks 12 to 28
For details on the calculation of the SF-36 VT scale subscore, see section 6.1.3.15.1.
Similar rules as for Section 6.1.2.4 will be used for the calculation of the values of the SF-36 
VT scale sub-score.
6.1.2.6 Change from Baseline in Mean Arterial Pressure (MAP) to the average MAP 
value in weeks 20-28
Blood pressure will be measured singly for the two 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 of the 
triplicates will be calculated for each visit. If less than three readings are available, all 
available values 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 will be considered, i.e. both scheduled and unscheduled MAP 
values, but only 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 Section 7.11.4 for the 
analysis windows definition and the differentiation between the MMRM and ANCOVA 
analyses). For subjects who started dialysis, only assessments collected pre-dialysis will be 
used. Post-dialysis ones will only be listed and excluded from this analysis.
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 less than three readings are available, 


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the non-missing readings will be used in the calculation of the average). 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 during week 1 to 36
Occurrence of hypertension (i.e. increased blood pressure) is a binary variable (Yes/No), 
defined as:

systolic BP ≥170 mmHg AND systolic BP increase from BL ≥20 mmHg, or 

diastolic BP ≥110 mmHg AND diastolic BP increase from BL ≥15 mmHg
during the period of week 1 to 36. The date of occurrence of hypertension is defined as the 
first date where SBP criterion or DBP criterion is met, whichever occurs first. All available 
blood pressure values within the Safety Emergent Period up to and including the analysis 
date of Week 36 will be taken into account. 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. For subjects who started dialysis, only assessments collected pre-dialysis will be 
used. Post-dialysis ones will only be listed and excluded from this analysis.
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) / 365.25
Where ‘Analysis Date of first dose intake’ is defined in section 6.5.4, and where ‘First event 
date’ is the first date of the occurrence of hypertension.
The time to censoring for a subject without the event of interest is calculated as:
(Minimum [Analysis date of Week 36 visit, Date of last vital signs assessment during the 
Safety Emergent Period] – Analysis date of first dose intake + 1) / 365.25
Refer to sections 6.2 and 7.11.5 for more details regarding the Safety Emergent Period.
6.1.3
Additional Secondary Efficacy Endpoints
The additional efficacy endpoints are listed in Table 7
Table 7
Additional Secondary Efficacy Endpoints
Number
Endpoint
Hb correction and maintenance
1
Hb change from BL to the average Hb value of weeks 28 to 52 regardless of 
rescue therapy.
2
Time (weeks) to achieve the first Hb response as defined by the primary endpoint.
3
Hb averaged over weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104, without use of
rescue therapy within 6 weeks prior to and during these evaluation periods.
4
Hb value and Hb change from BL Hb to each post-dosing time point.
Table continued on next page


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Number
Endpoint
5
Hb change from BL Hb to the average Hb value of weeks 28 to 36, 44 to 52, 72 to 
80, 96 to 104 regardless of the use of rescue therapy.
6
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, 72 to 80, and 96 to 104 without use of rescue therapy within 6 weeks 
prior to and during this 8-week evaluation period
7
Occurrence and time to first potential Excessive Hematopoiesis (EH) defined as 
Hb increase by >2.0 g/dL between any two visits within 4 weeks of treatment.
Hospitalizations
8
Occurrence (number) of hospitalizations, number of days of hospitalization per 
patient-year exposure and time to first hospitalization.
Rescue Therapy Use
9
Occurrence and time to first use of RBC transfusions, number of RBC packs per 
subject, volume of RBC transfused per subject.
10
Occurrence and time to first use of rescue therapy (composite of RBC 
transfusions [all subjects] and darbepoetin alfa use [roxadustat treated subjects 
only])
Iron supplementation
11
Occurrence of iron supplementation. Mean monthly IV iron (mg) per subject 
during weeks 37-52 and weeks 53-104 (monthly defined as a period of 4 weeks). 
Time to first IV Iron during the efficacy emergent period. Use of oral iron.
Change in Cholesterol Levels, Apolipoproteins
12
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 and ApoB/ApoA1 ratio.
13
Occurrence of average LDL cholesterol <100 mg/dL (2.59 mmol/L), calculated 
over weeks 12 to 28, and weeks 36 to 52 of treatment.
Blood Pressure Effect
14
Occurrence of achieved antihypertensive treatment goal (SBP <130 mmHg 
systolic and DBP<80 mmHg) based on the mean SBP and mean DBP calculated 
over weeks 12 to 28 and 36 to 52 of treatment with study drug.
HRQoL
15
Change from BL to the average value of weeks 12 to 28 and 36 to 52 (SF-36 
Physical Component Score (PCS), Anemia Subscale (“Additional Concerns”) of 
Functional Assessment of Cancer Therapy (FACT-An) Score, Total FACT-An 
and Trial Outcome Index (TOI) Scores, EQ-5D 5L VAS Score and Work 
Productivity and Activity Impairment (WPAI:ANS).
16
Patient Global Impression of Change (PGIC) at last assessment.
Iron status, HbA1c, and CKD progression
17
Changes from BL to each study visit (when measured) in Serum ferritin, TSAT, 
iron, HbA1c level, fasting blood glucose, eGFR (including eGFR slope over 
time), Urine albumin/creatinine ratio. Time to (and proportion of subjects) with 
serum creatinine having doubled during the study and Proportions of subjects 
with ESRD. Occurrence and time to chronic dialysis start.


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6.1.3.1 Hb change from BL to the average Hb value of weeks 28 to 52 regardless of the 
use of rescue therapy.
The same rules as defined in Section 6.1.2.1, apply for weeks 28 to 52 and regardless use of 
rescue therapy. 
6.1.3.2 Time (weeks) to achieve the first Hb response as defined by the 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
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 ’Date of the first value that meets the criteria for 
response ’ and ‘Analysis date of first dose intake’ is defined in section 6.5.4
For a subject without 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
With date of End of Efficacy Emergent Period defined in section 7.11.6
6.1.3.2.2
Time (weeks) to achieve the first Hb response, regardless of rescue therapy
This variable is similar to the one defined in section 6.1.3.2.1 but regardless of the use of 
rescue therapy.
Time to censoring will then be calculated (in weeks) as:
(Minimum [Analysis date of Week 24 visit, Date of End of Efficacy Emergent Period ] –
Analysis date of first dose intake + 1) / 7
With date of End of Efficacy Emergent Period defined in section 7.11.6  
6.1.3.3 Hb averaged over weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104, without use of 
rescue therapy within 6 weeks prior to and during the evaluation periods
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, 72-80 and 96-104 will be categorized into 
the following categories: 

<10 g/dL,

10-12 g/dL,

>12 g/dL,


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
≥10.0 g/dL.
In case a subject requires rescue therapy within 6 weeks prior to and during this 8-week 
evaluation period, all Hb assessments collected during that period will be set to missing.
6.1.3.4 Hb value and 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 windows, as defined in Section 7.11.4
Baseline Hb is defined in section 6.1.1
At each planned visit, Hb will also be categorized into the following categories: 

<10 g/dL, 

10-12 g/dL,

>12 g/dL,

≥10 g/dL
6.1.3.5 Hb change from BL Hb to the average Hb value of weeks 28 to 36, 44 to 52, 72 
to 80, 96 to 104 regardless of the use of rescue therapy
This variable is similar to the one defined in section 6.1.2.1, applied for these time points and
regardless of the use of rescue therapy.
Proportion of Hb values within 10.0 to 12.0 g/dL and ≥10 g/dL in weeks 28 to 36, 44 to 52, 
72 to 80, and 96 to 104 is calculated as per section 6.1.3.3
6.1.3.6
Categorical analysis of Hb values
The following endpoints will be analyzed: proportion of Hb values within 10.0-12.0 g/dL and 
≥10 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 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
●
Number of Hb values with ≥10 g/dL / Total number of Hb values*100
in weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104 and overall treatment period 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 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 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 


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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 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 2 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 2
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.


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6.1.3.7 Occurrence and time to first potential Excessive Hematopoiesis (EH)
Potential Excessive Hematopoiesis (EH), regardless use of rescue therapy, based on Hb 
central lab will be defined as 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
where ‘First event date’ is defined as first date of occurrence 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: 
Min[(Date of last Hb assessment during the Efficacy Emergent Period, End of 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. 
6.1.3.8 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 [Min((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 Emergent 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.
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


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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
6.1.3.9 Occurrence and time to first use of RBC transfusions, number of RBC packs 
per subject, volume of RBC transfused per subject
The blood transfusion form of the eCRF in the cumulative visit will be used to derive all 
variables related to the use of RBC transfusions.
Only RBC transfusions that started during the study treatment and up to the End of Efficacy 
Emergent Period will be taken into account. Medication Onset Date is the date of the first use 
of RBC transfusion.
Volume of blood transfused and the total number of RBC packs (for each subject, the sum of 
blood volume and packs transfused during the Efficacy Emergent Period) will be calculated.
For RBC transfusions, when the number of units is not given but the volume transfused is 
given, the number of units will be estimated as volume transfused/250 mL (for transfusion of 
packed cell units) or volume transfused/500 mL (for transfusion of full blood).
For RBC transfusions, when the volume transfused is not given but the number of RBC units 
is given, the volume transfused will be estimated as number of RBC units times 250 mL (for 
transfusion of packed cell units) or as number of RBC 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
6.1.3.10 Occurrence and time to first use of rescue therapy (composite of RBC 
transfusions [all subjects] and darbepoetin alfa use [roxadustat treated subjects 
only])
Rescue therapy is defined as RBC transfusion for all subjects and darbepoetin alfa (SC or IV) 
for roxadustat-treated subjects. The latter information is derived from the Dosing CRF form.
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. 
Medication Onset Date is the date of the first use of rescue medication.


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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
Occurrence of rescue therapy will be defined as binary variable (RBC or ESA for roxadustat 
subjects) in case of any event during the efficacy emergent period.
6.1.3.11 Occurrence of iron supplementation 
The occurrence of IV Iron use and mean monthly IV iron use per subject (in mg) for weeks 
37 to 52 and 53-104 will be calculated similarly as in section 6.1.3.2  Analysis visits will be 
used as indicated in Table 31, section 7.11.4. Records selected will be those coded as ATC 
3rd level = IRON PREPARATIONS and route is INTRAVENOUS.
Time to first IV Iron will be derived similarly to time to first use of rescue therapy, in section 
6.1.3.10, with first event date corresponding to the Date of first dose of IV Iron during the 
efficacy emergent period. Censoring rules will be the same as for use of rescue therapy.
The occurrence of oral iron use will be also derived by the relevant periods (week 1-36, week 
37-52, week 53-104) as a yes or no use of oral iron. Records selected will be those coded as 
ATC 3rd level = IRON PREPARATIONS and route is ORAL. This will be combined with IV 
iron use for these periods.
6.1.3.12Change from BL to each post-dosing assessments in lipid parameters
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:
1.
Total cholesterol 
2.
LDL cholesterol
3.
HDL cholesterol
4.
Low-density lipoprotein (LDL) / high-density lipoprotein (HDL) ratio
5.
Non-HDL cholesterol
6.
Triglycerides
7.
Apolipoproteins A1 and B (ApoA1 and ApoB)
8.
ApoB/ApoA1 ratio.


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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 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.
6.1.3.13 Occurrence of mean LDL cholesterol <100 mg/dL (2.59 mmol/L), calculated 
over weeks 12 to 28, and weeks 36 to 52 of treatment
The evaluation period is defined as the average of all planned LDL cholesterol values in 
weeks 12-28 (visit at 12, 20 and 28 weeks) and weeks 36 to 52 (visit at 36, 44 and 52 weeks), 
as defined in Section 7.11.4  The occurrence of mean LDL cholesterol <100 mg/dL over 
weeks 12 to 28, and weeks 36 to 52 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, and weeks 36 to 
52 respectively.
No imputation will be performed in case of a missing value.
This endpoint will be reported on fasting values and regardless of fasting status.
6.1.3.14 Occurrence of achieved antihypertensive treatment goal (SBP <130 mmHg 
systolic and DBP<80 mmHg) based on the mean SBP and mean DBP 
calculated over weeks 12 to 28 and 36 to 52 of treatment with study 
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 12-28, similarly as in 
Section 6.1.2.6 (analysis windows defined in 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. It is calculated similarly for 
weeks 36 to 52.
No imputation will be performed in case of a missing value.
6.1.3.15 Change from BL to the average value of weeks 12 to 28 and 36 to 52 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 (SF-36 scales) will be provided by an external vendor (QualityMetric).


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6.1.3.15.1 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 1: SF-36 v2). It yields an 8-scale 
profile of functional health and well-being scores as well as psychometrically-based physical 
and mental health summary measures. It is a generic measure, as opposed to one that targets 
a specific age, disease, or treatment group. Accordingly, the SF-36 has proven useful in 
surveys of general and specific populations, comparing the relative burden of diseases, and in 
differentiating the health benefits produced by a wide range of different treatments. The SF-
36 contains 36 items that measure eight dimensions 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 1: SF-36 v2). 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 QualityMetric 
using QualityMetric Health Outcomes(tm) Scoring Software 4.5. 
Change from baseline to the average value in weeks 12-28 and 36-52 will be calculated for
the Physical Component Scores of SF-36 (SF-36 PCS), following the same rules as defined 
in section 6.1.2.4
The evaluation period score is defined as the average of available SF-36 score values of 
weeks 12-28 (visit at week 12 and week 28) and weeks 36-52 (visit at week 36 and week 52).
For imputation rules, refer to section 7.11.1 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 the average of available SF-36 score values of weeks 12-
28 (visit at week 12 and week 28) and weeks 36-52 (visit at week 36 and week 52) 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.
6.1.3.15.2 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) 


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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 (see 
Appendix 2: FACT-An (Version 4)
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. Note that some scores need to be reversed 
for the derivation of the total score (see section 10.2.2).
If there are missing items, subscale scores will be standardized as long as there are more than 
50% of items answered. 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]
The total score is then calculated as the sum of the un-weighted subscale scores, as long as 
overall item response rate is greater than 80%. In addition, 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 2: FACT-An (Version 4)  
The following 9 scores will be calculated:
1.
PWB subscale score
2.
SWB subscale score
3.
EWB subscale score
4.
FWB subscale score
5.
AnS subscale score
6.
FACT-An TOI score
7.
FACT-G total score
8.
FACT-An total score
9.
FACT-An Fatigue Score
Change from baseline to the average value in weeks 12-28 and 36-52 will be reported for the 
two scores (Anemia subscale ‘Additional concerns’ of FACT-An score and FACT-An total 
score). In addition, the score and change from baseline will be reported for each visit for all 
9 scores.
The number and percent of subjects with an increase from baseline of <3 / ≥3 points in the 
Anemia Subscale score and a change from baseline of <7 / ≥7 points in the Total FACT-An 
score will be calculated for periods weeks 12-28 and weeks 36-52. 
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.


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6.1.3.15.3 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 3: EQ-5D 5L v2).
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
3: EQ-5D 5L v2
Change from baseline to the average value in weeks 12-28 and 36-52 will be calculated for 
EQ-5D 5L VAS.
Frequency distributions will be described for each visit for:
1.
EQ-5D 5L Mobility Score
2.
EQ-5D 5L Self-Care Score
3.
EQ-5D 5L Usual Activities Score
4.
EQ-5D 5L Pain/Discomfort Score
5.
EQ-5D 5L Anxiety/Depression Score
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.
6.1.3.15.4 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 4: 
WPAI:ANS V2.0).
For subjects who are currently employed, the following four items and the change from 
baseline 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
For these variables, no imputations will be performed in case one 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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6.1.3.16 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 5: Patient 
Overall Impression of Change).
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, except that the score at the last 
post-baseline assessment will be derived too.
6.1.3.17 Iron, HbA1c and CKD progression parameters
Changes from baseline to each study visit (see analysis windows in Section 7.11.4) will be 
calculated for these exploratory parameters:
1.
Serum ferritin
2.
TSAT
3.
Serum Iron
4.
HbA1c level (including by diabetes in the history)
5.
Fasting blood glucose (including by diabetes in the history)
6.
eGFR (including eGFR slope over time)
7.
Serum Creatinine (log transformed)
8.
Albumin/creatinine ratio in urine
Serum creatinine, eGFR and albumin/creatinine ratio in urine will be log transformed and 
any assessment occurring after the initiation of acute or chronic dialysis will be excluded for 
the summaries.
For all variables listed 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.
‘Analysis date of first dose intake’ is defined in Section 6.5.4 and Date of End of Safety 
Emergent Period is defined in section 7.11.5
CKD Progression exploratory variables
-
Annualized eGFR slope over time:
The annualized eGFR slope over time will be estimated in each treatment arm by the random 
slope and intercept model using all data available from each patient (one baseline and all 
post-treatment values up to start of acute or chronic dialysis).  Change from Baseline to each 
study visit will be calculated.


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-
Doubling serum creatinine: 
Occurrence of serum creatinine being doubled compared with baseline at any moment during 
the Safety Emergent Period (see section 6.2) will be calculated. 
The ratio of the maximum serum creatinine (on-treatment) by baseline value will be 
determined using the formula below:
Maximum on-treatment during Safety Emergent Period serum creatinine value / baseline 
value
Time to first occurrence of serum creatinine doubled compared with baseline will be derived 
as follows:
(First event date – Analysis date of first dose intake + 1) / 365.25
where ‘First event date’ is defined as first date of assessment where serum creatinine value is 
doubled compared to baseline during the Safety Emergent Period.
For a subject without event, 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
-
Time to Doubling serum creatinine or chronic dialysis or kidney 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 kidney transplant during the Safety Emergent Period will be derived. The endpoint 
is defined as time to doubling serum creatinine or chronic dialysis or kidney transplant 
whatever comes first: 
(First event date – Analysis date of first dose intake + 1) / 365.25
where ‘First event date’ is defined as first date of assessment where serum creatinine value is 
doubled compared to baseline or chronic dialysis or kidney transplant whatever comes first.
For a subject without event, 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
-
Occurrence of End Stage Renal Disease (ESRD): 
Defined as at least one of 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


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-
Occurrence and time to chronic dialysis or kidney transplant:
Occurrence of chronic dialysis or kidney transplant during the Safety Emergent Period (see 
section 6.2) will be derived and time to first occurrence (i.e dialysis or kidney transplant, 
whichever occurs first) in years will be defined in years as:
(First event date – Analysis date of first dose intake) /365.25
where ‘First event date’ defined as Date of chronic dialysis or date of kidney transplant, 
whichever comes first.
For a subject without event, the time to censoring will be calculated as: 
(Date of End of Safety Emergent Period – Analysis date of first dose intake + 1) / 365.25
-
Time to chronic dialysis or kidney transplant or Death
Occurrence of chronic dialysis or kidney 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
where ‘First event date’ defined as ‘first occurrence of chronic dialysis or kidney transplant, 
occurrence of  subject who died (whichever occurring first)’.
For a subject without event, 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
-
Time to CKD progression (composite of doubling serum creatinine, chronic dialysis or 
kidney transplant or 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 kidney 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 CKD progression will be calculated (in years) as:
(First event date – Analysis date of first dose intake + 1) / 365.25
where ‘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)’.


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For a subject without event, 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
-
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
Where ‘First event date’ is defined as ‘First occurrence of 40% decrease in eGFR from 
baseline.
For a subject without event, the time to censoring will be calculated (in years) as: 
(min[Date of End of Safety Emergent Period, first occurrence of chronic dialysis date] –
Analysis date of first dose intake + 1) / 365.25
-
Time to at least 40% eGFR decrease from baseline or chronic dialysis or kidney 
transplant
Event is defined as occurrence of at least 40% decrease in eGFR from baseline, or start of 
chronic dialysis or a kidney transplant. 
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, chronic dialysis or 
renal transplant will be calculated (in years) as:
(First event date – Analysis date of first dose intake + 1) / 365.25
Where ‘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).
For a subject without event, 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
6.1.4
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 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 rate, respiratory rate and weight),
●
Clinical laboratory variables (hematology, biochemistry including liver function tests, 
and urinalysis),
●
Local 12-lead electrocardiogram (ECG).
●
Pre-specified adjudicated cardiovascular and cerebrovascular events.
The Safety Emergent Period will be defined as the evaluation period from the Analysis date 
of first drug intake up to the minimum between [(Analysis Date of last dose + 28 days + x), 
EOS visit date, Date of death], with x corresponding to additional days based on the last 
dosing frequency. 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. If an AE is reported with both start and stop dates are completely missing and the 
adverse event occurs on Day 1 check box is missing, then this will be considered as a 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 any 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 Death (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 death) 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 occurring 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 last contact (Post study FU visit/call), Date of last Study evaluation 
(EOS form)) – Analysis date of first dose intake +1) / 365.25.
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. 


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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.
For dialysis date imputation rules, refer to Section 7.11.2.
6.2.1.4 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.
6.2.1.5 Definitions of event rate
The event rate (per 100 patient year) during the Safety Emergent Period will be calculated as 
either:
100
period
Safety 
Years
Total
events
of
Number 

Where Total Years Safety period is defined as [Sum of individual sa in days (Analysis date 
of last dose – Analysis date of first dose + 1)] / [(Duration of Safety Emergent Period in days 
/ 365.25)].
6.2.1.6 AE up to plus 7 Days
Additional analyses restricted to treatment-emergent AEs that observed after starting 
administration of the test drug/comparative drug and up to the minimum between [(Analysis 
Date of last dose +  7 days + x), EOS visit date, Date of death], with x corresponding to 
additional days based on the last dosing frequency will be defined. 
Time to occurrence of event will be calculated (in years) as:
(First event date occurring as defined above – Analysis date of first dose intake + 1) / 365.25
With ‘Analysis date of first dose intake’ defined in Section 6.5.4
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:


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Minimum [(Analysis Date of Last Dose + 7 days + x), EOS visit date, Date of Death)] –
Analysis date of first dose intake +1) / 365.25.
6.2.1.7 Adjudicated CV related Events
The variables are based on treatment-emergent events that have been confirmed using the 
centralized adjudication, regardless of the term reported by the investigator. The adjudication 
will be performed blinded to treatment assignment.
The following composite endpoints will be evaluated:

Major Adjudicated Cardiovascular Event (death, non-fatal myocardial infarction 
and/or stroke) (MACE): time to first occurrence of death, myocardial infarction or 
stroke.

MACE including, in addition, hospitalizations for either unstable angina and/or 
chronic heart failure (MACE+): time to first occurrence of death, myocardial 
infarction, stroke, hospitalization for either unstable angina and/or congestive heart 
failure.

CV-MACE: time to first occurrence of CV death, myocardial infarction or stroke.

Cardiovascular (CV)-MACE+: time to first occurrence of CV death, myocardial 
infarction, stroke, hospitalization for either unstable angina and/or congestive heart 
failure.
The following individual event endpoints will be evaluated:

Death 

Cardiovascular (CV death)

Myocardial infarction

Stroke

Unstable angina that requires hospitalization

Congestive heart failure that requires hospitalization

Deep vein thrombosis and/or pulmonary embolism

Vascular access thrombosis

Hypertensive emergency. 
6.2.2
Vital Signs
The following endpoints will be assessed:

Systolic blood pressure (SBP)

Diastolic blood pressure (DBP)

Pulse rate

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. In case of missing values 


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among the triplicates, the available readings will be used.  Note that the average in the eCRF 
system will not be used.
Change from baseline will be calculated for all data collected during the study as the 
measurement taken at the specific visit minus the measurement at baseline visit. 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 all vital parameters, the minimum and the 
maximum post-baseline value during the Safety Emergent Period will be derived. For this 
calculation, only values from day 2 up to the date of End of the Safety Emergent Period (see 
section 7.11.5) will be considered.
From the assessments collected in the ‘Vital Signs - HD/HDF Subjects Only’ form, only the 
pre-dialysis ones will be used for the by-visit summaries and the definition of potentially 
clinical vital signs criteria. The post-dialysis assessments will be listed only.
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 8
Table 8
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
SBP (mmHg)
High
≥ 170
Increase of ≥ 20
Low
≤ 90
Decrease of ≥ 20
DBP (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 at 
any moment during the Safety Emergent Period using the worst value among all available 
measurements. 
Time to occurrence of a PCS (for each Vital Signs PCS criteria)
For each potentially clinically significant vital sign criteria (i.e. 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’ defined in section 6.5.4


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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
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 9 below.
Table 9
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 LLN
>1.1 X ULN
Total Protein
g/L
< 0.9 X LLN
>1.1 X ULN
Blood Urea Nitrogen (BUN)
mmo1/L
>1.5 X Baseline
Neutrophils
10:/L
≤1000
Platelet Count
10;/L
≤100
≥700
White Blood Cell Count
10;/L
≤2.5
≥15
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
Footnotes appear on next page


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** 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 visit 
and on-treatment (see section 6.2) using the worst value among all available measurements, 
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 (i.e. 
during Safety Emergent Period, 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 day 1 visit, except for Hb. If Day 1 assessment is 
missing, the screening or unscheduled assessment that is closest prior to Day 1 will be used.
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)?/A) corrections, 
where QT is in msec and RR Interval in seconds; and if RR is not available, it will be 
replaced with 60/HR.
For all ECG parameters, the maximum post-baseline value on treatment will be defined (i.e. 
during Safety Emergent Period, see section 6.2).
ECG values are potentially clinically significant (PCS) if they meet or exceed the upper limit 
values listed in Table 10 below. 
Table 10
ECG Parameters classification
ECG Parameter
Classification
QTc interval (msec)
> 450 msec, > 480 msec, > 500 msec;
QTc interval change (msec)
> 30 msec and > 60 msec
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  
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


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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. 
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 follow:
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


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Screening Hb will be defined as the mean of all available central laboratory Hb values 
collected during screening period [i.e. 3 latest values for patients enrolled under protocol 
version 1.0 and 2.0, and 2 latest values for those under protocol version 3.0]. 
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 
defined using selected MedDRA preferred terms based on the recorded medical history on 
the Cardiovascular Disease History and other medical history eCRF. CV History will be 
categorized as:

Yes

No
Countries and Regions
Subjects will be enrolled from the following 29 countries: 
Region A (Western Europe and Israel)

Denmark

Finland

France

Germany

Ireland

Netherlands

Portugal

Spain

Sweden

UK

Austria

Israel
Region B (Central and Eastern Europe)

Croatia

Czech Republic

Latvia

Slovakia

Slovenia

Serbia

Russia

Poland

Romania

Hungary


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
Bulgaria

Ukraine

Georgia

Macedonia

Montenegro

Bosnia

Belarus
Randomization will be stratified by region using two categories: 

Region A: Western Europe and Israel

Region B: Central and Eastern Europe. 
Time to Treatment Discontinuation
Time to Treatment Discontinuation in years is defined as:
Time to Treatment Discontinuation (years) = (Date of EOT Visit – Analysis date of first dose 
intake +1)/365.25
In case a subject completed the treatment period, time to censoring will be calculated as:
(Date of EOT Visit – Analysis date of first dose intake + 1) / 365.25
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
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


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This will be calculated for each patient who was diagnosed with the targeted medical history: 
hypertension, diabetes mellitus type 1, type 2 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. 
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-<30, 30-<45, 45-<60, and ≥60 mL/min/1.73m2
Iron status 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 < 100 ng/mL and TSAT < 20%

ferritin < 100 ng/mL and TSAT > 20%  

ferritin > 100 ng/mL  and 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.
Iron status 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 < 100 ng/mL and TSAT < 20%

ferritin < 100 ng/mL and TSAT > 20%  

ferritin > 100 ng/mL  and 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 ESAs or not during the last year. Previous 
use of ESAs is collected in the Treatment History for Anemia eCRF.


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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 previous and concomitant medication.
6.5.4
Variables related to study drug
Randomization Arms
Table 11 below presents the groups to which subjects are randomized under protocol 
version 1.
Table 11
Randomization arms under protocol version 1
Randomization Arm Code
(ARMCD)
Randomization Arm (ARM)
1A
Roxadustat - TIW correction - QW maintenance
2A
Roxadustat - TIW correction - BIW maintenance
3A
Roxadustat - TIW correction - TIW maintenance
B
Darbepoetin alfa
Table 12 below presents the groups to which subjects are randomized under protocol 
version 2 or 3.
Table 12
Randomization arms under protocol versions 2 and 3
Randomization Arm Code 
(ARMCD)
Randomization Arm (ARM)
A
Roxadustat TIW
B
Darbepoetin alfa
For the statistical analysis, treatments will be pooled across roxadustat under both protocol 
versions.


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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 Treatment visit in the End of 
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 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
Treatment Period
For each subject, the Length of Time on treatment period will be calculated in days, using the 
following formula:
Analysis Date of Last Dose – Analysis Date first dose intake + 1
Safety Emergent Period
For each subject, the Length of Time during the Safety Emergent Period (see section 6.2) will 
be calculated in days, using the following formula:
End Date of Safety Emergent Period – Analysis Date first dose intake + 1
Patient-Exposure Years (PEY)
Treatment Period
For each subject, PEY on treatment period will be calculated in days as the duration of 
exposure divided by 365.25.
Safety Emergent Period
For each subject, PEY during the Safety Emergent Period will be calculated in days as the 
duration of exposure divided by 365.25.
Switch to maintenance (Yes/No)
If a subject has the variable Dose Decision =“Switch to Maintenance” in the roxadustat and 
darbepoetin alfa eCRF forms, Dosing Decision then the subject will be classified as Yes.
Otherwise, the subject will be classified as never switched to maintenance.


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Subjects who achieved maintenance
When a subject achieves Hb ≥11.0 g/dL and an Hb increase from BL Hb ≥1.0 g/dL as 
measured at two consecutive visits [dates] (with available data), separated by at least 5 days, 
the subject will be classified as a subject having achieved maintenance. In addition, subjects 
will be classified as having achieved maintenance using Hb central lab data.
Amount of Prescribed Medication
Roxadustat
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. 
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 or amendment 3.0. 
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 13
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 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
This will allow 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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Darbepoetin alfa
The same methodology will be used for darbepoetin alfa. Note that prescribed frequency for 
darbepoetin alfa are: once weekly, every two weeks and monthly. The unit for darbepoetin 
alfa is microgram (µg). 
In addition, amount of prescribed medication in µg/kg will be calculated. To convert a dose 
given in µg into a dose in µg/kg, the body weight recorded at day 1 will be used.
Amount of Consumed Medication
Roxadustat
The amount of medication taken will be estimated based on the amount of dispensed and 
returned medication. The dispensed and returned Investigational Product Medication is 
captured in the Study Drug FG4592 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)
Note: if nothing has been returned it is assumed that the medication has been taken. 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. To convert a dose 
given in mg into a dose in mg/kg, the body weight recorded at day 1 will be used.
Darbepoetin alfa
The same methodology will be used for darbepoetin alfa. Note that instead of tablets 
dispensed/returned, there will be syringes dispensed/administered. Administration date is not 
captured, therefore the start and end day of exposure will be defined as follows:

Start Day of Exposure for each kit: study day kit dispensed 

End Day of Exposure for each kit: for kits administered, the next consecutive date that 
darbepoetin alfa was dispensed – 1 Day


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In addition, amount of consumed medication in µg/kg will be calculated. To convert a dose 
given in µg into a dose in µg/kg, the body weight recorded at day 1 will be used.
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 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 change, Dose decrease, dose increase and dose hold for roxadustat and 
darbepoetin alfa
Dosing changes (decrease, increase and dose hold) are derived from the study drug 
accountability data recorded in the eCRF for both roxadustat and darbepoetin alfa. 
A dose change is the change in the number of milligrams or micrograms on the dose per 
intake (for example from 200 mg to 250 mg as dose increase). 
For example, for roxadustat, a change from 200 TIW to 250 TIW is a change of 600 mg to 
750 mg per week which is regarded as an increase in intake dose. 
The same applies for darbepoetin alfa, but not weekly as it could be administered weekly, 
bi-weekly or monthly. A monthly-dose change will be calculated instead.
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 will be of no 
treatment difference and corresponding alternative hypothesis will be two-sided. Null 
hypothesis 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 darbepoetin alfa) and for 
the total, unless specified otherwise.


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
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 and will be provided as part of the CSR section 13.1.9 (Raw SAS outputs).
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 5  See Section 5.3 for more details.
7.2.1
Disposition of Subjects
The following subject data will be summarized and presented:
●
Number of subjects with informed consent, who discontinued before randomization and
randomized (overall only);
●
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, by 
primary reason for treatment discontinuation 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 SAF and the FAS: 
●
Treatment discontinuation by reason using bar chart;
●
Treatment discontinuation by time interval and reason using bar chart; and


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●
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:
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
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.
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.
Screening failures 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).
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 and overall, 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 (incorrect active ingredient, that 
excludes rescue therapy (darbepoetin alfa) as per protocol guidelines),
o
PD3_1- Received wrong treatment kit
o
PD3_2- Received incorrect dose

PD4 – Received prohibited concomitant treatment


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7.2.3
Demographic and Other Baseline Characteristics
Demographic and other baseline/screening characteristics as per section 6.5.2 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, SAF, FAS and PPS.
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.
●
LDL Cholesterol : <LLN; LLN-ULN; > ULN
●
CRP : ≤ULN; > ULN
Demographic and baseline characteristics summaries above will be done for All Randomized, 
the SAF, FAS and PPS. This table will be repeated for subjects randomized after Amendment 
1.0 and 2.0 are implemented (separately).
Baseline values of primary and key secondary variables will be presented for the same 
analysis sets and populations mentioned above:

Hb (g/dL)

LDL Cholesterol

SF-36 PF and VT subscores

MAP
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 on the SAF.
Anemia history, chronic kidney disease history, targeted medical history, cardiovascular-
vascular access thrombosis history, tobacco history and family history of cardiovascular 
disease will be summarized on the SAF. 
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 on the SAF.


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Demographic and baseline data will also be listed. 
7.2.4
Previous and Concomitant Medications
Previous 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. 
As with previous medication, concomitant medication will be summarized similarly 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 (=FG-4592 Investigational Medicinal Product) is for oral administration and 
supplied as red coated oval tablets of 20, 50 and 100 mg.
Darbepoetin alfa (=Comparator Medicinal Product) is administered by SC or IV injection, 
and supplied as a solution for injection in a pre-filled syringe of 20, 30, 40, 60 and 100 μg.
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 6.5.4  
Descriptive statistics will be produced for:

The amount of drug (roxadustat or darbepoetin alfa) the subject was exposed to during 
the treatment period (in mg or µg and in mg/kg or µg/kg), at study start, by month, and
during the first 24, 36, 52 weeks and overall treatment period;
Duration of exposure will be summarized in two ways:
●
Descriptive statistics and frequency tabulations will be presented on treatment period and 
on Safety Emergent Period; 
●
Exposure time will be categorized by treatment period and by Safety Emergent 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
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


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o
Unknown.
In addition Patient-Exposure Year (PEY) will be calculated both on treatment period and on 
Safety Emergent Period.
For roxadustat, box-plots of average weekly prescribed dose (mg and mg/kg) by 4-weekly 
periods will be produced. A separate box-plot for darbepoetin alfa in another page will be 
produced, using a different unit (µg instead of mg).
Number and percentage of subjects with dose changes, increases, decreases or hold (any, one, 
two) will be summarized for both correction and the maintenance periods separately.
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 darbepoetin alfa, 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 
amount of dispensed and returned study drug and first and last days of treatment are known.
Percent overall compliance will be summarized in two ways, by month, and during the first 
24, 36, 52 weeks and during the overall treatment period:
●
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 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.
For this section, PPS refers to the analysis set which excludes from the FAS all the subjects 
criteria listed in Table 5. See Section 5.3 and Classification specifications for more details.
Analysis visits are detailed in section 7.11.4
Missing data imputation rules are detailed in section 7.11.1  
7.4.1
Analysis of Primary Endpoint
7.4.1.1 Primary Analysis of the Primary Endpoint
The primary efficacy endpoint will be analyzed using the PPS.  




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collected eCRF data to derive these covariates. Note that log-transformed eGFR might be 
used as covariate in the model instead of eGFR if it is demonstrated that eGFR is not 
normally distributed.
The SAS code will be similar to the one below:
proc freq;
  tables  region*CV_history* Hb_category*eGFR*arm*response/     
riskdiff (cl=MN common); 
run;
The stratified MN method has recently been implemented in SAS version 9.4. The current 
SAP states use of SAS version 9.3 or higher (see section 7.1). Therefore, depending on the 
availability of SAS version 9.4 at the time of analysis, the stratified MN statistics could be 
replaced by the alternative methodology based on the standard normal statistic proposed by 
Gart and Nam (see reference in section 9).
The SAS code will be similar to the one below:
proc genmod;
  class arm region CV_history; 
  model response=eGFR_continuous region CV_history 
Hb_continuous arm /dist=bin link=identity; 
  lsmeans arm / diff cl;
run;
In addition, a 95% confidence interval for the proportion of roxadustat and darbepoetin alfa 
responders based on the exact method of Clopper-Pearson will be calculated and presented.
Sensitivity analyses will be conducted to assess the consistency of the results before and after 
protocol amendments 1 and 2 (e.g., protocol versions 2.0 and 3.0 respectively).
Model checking:
Homogeneity among strata (covariates defined above) will be tested using the Gailsimon test. 
This test will assess the qualitative interaction between treatment effect and subjects’ subsets 
in strata, i.e. assess if the direction of true treatment difference varies among subsets of 
subjects.
The SAS procedure will be similar to the following:
proc freq;
tables covariates*Treatment*response / gailsimon;
run;
A forest plot will be generated showing strata on the y-axis and differences in proportions 
and their 95% confidence interval on the x-axis. Stratas with 5 subjects or less may be 
combined.


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7.4.1.2 Secondary Analyses (sensitivity) of the Primary Endpoint
The following analyses will be done as sensitivity analyses of the primary endpoint:

The primary analysis [without rescue therapy] will be repeated on the FAS (S1);

Sensitivity analysis [regardless of use of rescue therapy] will be performed on the PPS 
(S2);

Sensitivity analysis [regardless of use of rescue therapy] will be performed on the FAS 
(S3);

The primary endpoint will be analyzed using logistic regression including the covariates, 
on both PPS [without rescue therapy] (S4) and FAS [without rescue therapy] (S5). 
Baseline Hb (defined in 6.1.1) and baseline eGFR [or log(eGFR)] (defined in 6.1.3.17),
will be included as continuous variables instead of categorical variables;

Sensitivity analysis [regardless of use of rescue therapy] using logistic regression as 
mentioned above will be performed on the PPS (S6) and on the FAS (S7);

The primary analysis [without rescue therapy] will be performed on the subgroup of 
subjects being randomized after the implementation of protocol v2.0 and v3.0 (S8).
Analysis will be performed separately for each set of subjects.

The primary analysis [without rescue therapy] on PPS will be performed using the 
modified definition of Hb response [i.e using only absolute value ≥11.g/dL] (S9).

The primary analysis [without rescue therapy] on FAS will be performed using the 
modified definition of Hb response [i.e using only absolute value ≥ 11.g/dL] (S10).
For all sensitivity analyses except the primary analysis and primary analysis repeated 
excluding data from the site(s) with potential data quality issues, no hypothesis testing will be 
done, only confidence intervals presented. For the logistic regressions, the odds ratio 
(roxadustat vs. darbepoetin alfa) and their 95% confidence intervals will be produced, if 
convergence achieved. The non-inferiority margin of 15% will be transferred into an odds 
ratio margin as an indication only. Assuming a response rate 65% for roxadustat and 80% for 
darbepoetin with N=248 and N=208 respectively, this odds ratio will be 0.50. 
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;
Table 14 summarizes all sensitivity analyses to be performed with the primary endpoint.
Table 14 also lists the sensitivity analysis to be performed excluding data from the site(s)
with potential data quality issues. Data from this site(s) will not be excluded from the safety 
analyses.


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Table 14
Primary and sensitivity analysis for the primary endpoint
Code
Set 
Response 
Definition 
Model
Covariates
Analysis is 
repeated 
excluding data 
from the site(s)
with potential 
data quality 
issues
Primary
PPS
Without rescue 
therapy
MN CI
Region, History of CV, 
Baseline Hb, Baseline 
eGFR
No
S1
FAS
Without rescue 
therapy 
MN CI
Region, History of CV, 
Baseline Hb, Baseline 
eGFR
Yes
S2
PPS
Regardless of 
rescue therapy, 
MN CI
Region, History of CV, 
Baseline Hb, Baseline 
eGFR
No
S3
FAS
Regardless of 
rescue therapy 
MN CI
Region, History of CV, 
Baseline Hb, Baseline 
eGFR
Yes
S4
PPS
Without rescue 
therapy
Logistic
Region, CV History, 
baseline eGFR, baseline 
Hb as continuous 
covariates
No
S5
FAS
Without rescue 
therapy
Logistic
Region, CV History, 
baseline eGFR, baseline 
Hb as continuous 
covariates
Yes
S6
PPS
Regardless of 
rescue therapy
Logistic
Region, CV History, 
baseline eGFR, baseline 
Hb as continuous 
covariates
No
S7
FAS
Regardless of 
rescue therapy
Logistic
Region, CV History, 
baseline eGFR, baseline 
Hb as continuous 
covariates
Yes
S8
PPS*
Without rescue 
therapy
MN CI
Region, History of CV, 
Baseline Hb, Baseline 
eGFR
No
S9
PPS
Modified definition, 
without use of 
rescue therapy
MN CI
Region, History of CV, 
Baseline Hb, Baseline 
eGFR
No
S10
FAS
Modified definition, 
without use of 
rescue therapy
MN CI
Region, History of CV, 
Baseline Hb, Baseline 
eGFR
Yes
*patients who were randomized after the implementation of protocol v2.0 and v3.0 (analysis will be performed 
separately for each set of subjects).
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


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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.
7.4.1.3 Additional Analyses of the Primary Endpoint
The analysis of the primary endpoint will be repeated by subgroup of interest. For definitions
of subgroups of interest, see section 7.8
For the primary endpoint, subgroup analyses will be performed using the primary analysis on 
the PPS and the third sensitivity analyses (S3 in Table 14) on the FAS. If one of the 
subgroups is the same as a stratification factor, the factor will be omitted from the model. 
Table 15
Additional Analyses of the Primary Endpoint
Code
Set 
Response 
Definition
Endpoint*
Method
Covariates
A1
PPS
Without rescue 
therapy 
Response by 
Subgroup
MN CI
Region, history of CV, 
Baseline Hb and 
Baseline eGFR§
A2
FAS
Regardless of 
rescue therapy
Response by 
Subgroup
MN CI
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 group (8) Iron repletion status.
§ In case model does not converge for some subgroups, no adjustment on covariates will be done.
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 differences in proportions 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 treatment groups: roxadustat vs. darbepoetin alfa, unless 
specified otherwise.
Once the primary hypothesis has been rejected (section 7.4.1.1), the secondary variables 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. 
For non-inferiority at tests 1, 4, 5, 6 and 7, the test will be considered successful if:

the lower bound of the two-sided 95% CI of the difference between two treatment arms 
is above a set margin for tests 1, 4, and 5,


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
the upper bound of the two-sided 95% CI of the hazard ratio of treatment arms is below a 
set margin for tests 6 and 7. 
For superiority at tests 2, 3, 8 and 9, the test will be considered successful if:

the upper bound of the two-sided 95% confidence interval of the difference between 
treatment arms is below 0 for tests 2 and 8, 

the upper bound of the two-sided 95% confidence interval of the hazard ratio of the two 
treatment arms is below 1 for test 3,

the upper bound of the two-sided 95% confidence interval of the hazard ratio of 
treatment arms is below 1 for test 9.
For each success, the test will be performed for the next comparison and so on. In case of test 
failure, the procedure will be stopped. Only the primary analysis of each secondary endpoint 
will be used to claim the significance.
Table 16
Key Secondary Endpoints fixed sequence testing procedure
Test
Analysis set
Endpoint
Comparison*
1
PPS
Hb change from BL to the average Hb 
of weeks 28 to 36 without having 
received rescue therapy (i.e. RBC 
transfusion for all subjects, or 
darbepoetin alfa for roxadustat 
subjects) within 6 weeks prior to and 
during this 8-week evaluation period 
Non-inferiority of 
roxadustat versus 
darbepoetin alfa (the non-
inferiority margin for the 
difference between groups 
is 0.75 g/dL).
2
FAS
LDL change from BL to the average of 
weeks 12 to 28
Superiority of roxadustat 
versus darbepoetin alfa
3
FAS
Time to first IV iron use during weeks 
1 to 36
Superiority of roxadustat 
versus darbepoetin alfa
4
PPS
SF-36 PF sub-score change from BL to 
the average of weeks 12 to 28
Non-inferiority of 
roxadustat versus 
darbepoetin alfa (the non-
inferiority margin is fixed 
as a difference of three 
points)
5
PPS
SF-36 vitality sub-score change from 
BL to the average of weeks 12 to 28 
Non-inferiority of 
roxadustat versus 
darbepoetin alfa (the non-
inferiority margin is fixed 
as a difference of three 
points)
Table continued on next page


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Test
Analysis set
Endpoint
Comparison*
6
PPS
MAP change from BL to the average 
MAP of weeks 20 to 28
Non-inferiority of 
roxadustat versus 
darbepoetin alfa (the non-
inferiority margin for the 
difference between groups 
is 1 mmHg)
7
PPS
Time to first occurrence of 
hypertension during weeks 1 to 36, 
defined as:
-
systolic BP >170 mmHg AND 
systolic BP increase from BL ≥20 
mmHg, or 
-
diastolic BP >110 mmHg AND 
diastolic BP increase from BL ≥15 
mmHg
Non-inferiority of 
roxadustat versus 
darbepoetin alfa (the non-
inferiority margin is fixed 
as a hazard ratio of 1.3)
8
FAS
MAP change from BL to the average 
MAP of weeks 20 to 28
Superiority of roxadustat 
versus darbepoetin alfa 
9
FAS
Time to first occurrence of 
hypertension during weeks 1 to 36, 
defined as :
-
systolic BP >170 mmHg AND 
systolic BP increase from BL ≥20 
mmHg, or 
-
diastolic BP >110 mmHg AND 
diastolic BP increase from BL ≥15 
mmHg
Superiority of roxadustat 
versus darbepoetin alfa 
*Subjects randomized to roxadustat QW, BIW and TIW under protocol v1 will be pooled together.
Details of the analysis for each of these secondary endpoints are given below.
Descriptive statistics and frequency tabulations will be reported using all available data and 
imputed data, as defined in section 7.11.1.
7.4.2.1 Hb change from baseline to the average Hb in weeks 28-36
The primary analysis will be performed on the PPS [without rescue therapy see section 
6.1.2.1]. Hb change from baseline to the average Hb value in weeks 28-36 will be analyzed 
using a Mixed Model of Repeated Measures (MMRM) with unstructured covariance matrix 
model (roxadustat versus darbepoetin alfa). The model will contain treatment arm, region, 
CV History, visits and visit by treatment as categorical variables and baseline Hb, baseline 
eGFR as continuous variables.
The non-inferiority margin for the difference between groups is 0.75 g/dL. Non Inferiority 
can be concluded if the lower bound of the two-sided 95% CI of the difference between the 
two treatments arms is above -0.75 g/dL. See figure 3 below:




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●
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 at Weeks 28-36’
int X covariates X / divisor=x;
estimate ‘Roxadustat v.s. Darbepoetin alfa at weeks 28-36’ 
treatment 1 -1
treatment*visit 0 0 0 0 .. 0.3 0.3 0.3 -0.3 -0.3 -0.3/ cl;
where visit in 
(,’Week1’,’Week2’,...,’Week8’,’Week10’,...,’Week36’);
run;
One analysis Hb value for each visit will be used, as defined in analysis windows in
Section 7.11.4
A forest plot will be generated showing strata on the y-axis and differences in estimated 
mean changes from BL to the average in weeks 28-36 (obtained from MMRM model) and 
their 95% confidence interval on the x-axis.
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.
Sensitivity analyses
Sensitivity analyses to be performed for this endpoint (Hb change from BL to the average Hb 
of weeks 28-36) are summarized below and detailed in Table 17.

The primary analysis (MMRM, without rescue therapy) will be repeated on the FAS 
(S1);

Sensitivity analyses will be performed (MMRM, regardless rescue therapy) on the PPS 
(S2) and on the FAS (MMRM, regardless recue therapy,) (S3); 

An Analysis of Covariance (ANCOVA) model with Last Observation Carried Forward 
(LOCF) will be fitted including region, history of CV, baseline Hb and baseline eGFR 
[or log(eGFR)] as continuous covariates, for the PPS (without rescue therapy) (S4) and 
the FAS (without rescue therapy) (S5); 

Another ANCOVA model with LOCF will be repeated on FAS population (regardless 
rescue therapy) (S6).


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Table 17
Primary and sensitivity analyses for the Hb change from baseline
Code
Set 
Sensitivity 
analysis
Endpoint
Method
Covariates
Primary
PPS
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
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.
S2
PPS
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.
S3
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.
S4
PPS
Without rescue 
therapy
Change to the 
Average Hb in 
weeks 28-36 
ANCOVA
with LOCF
Region, history of 
CV, baseline Hb 
and baseline eGFR 
as continuous 
covariates. 
S5
FAS
Without rescue 
therapy
Change to the 
Average Hb in 
weeks 28-36 
ANCOVA
with LOCF 
Region, history of 
CV, baseline Hb 
and baseline eGFR 
as continuous 
covariates. 
Table continued on next page


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Code
Set 
Sensitivity 
analysis
Endpoint
Method
Covariates
S6
FAS
Regardless 
rescue therapy
Change to the 
Average Hb in 
weeks 28-36 
ANCOVA
with LOCF
Region, history of 
CV, baseline Hb 
and baseline eGFR 
as continuous 
covariates. 
ANCOVA model
The following model will be used:
cikj = intercept + ß · Mbaseline,ikj + τi + γk + εikj
where
●
cikj is the change from baseline to the average Hb values in weeks 28-36 of subject j in 
arm i and stratum k
●
ß is the slope of cikj as a linear function of the baseline Hb 
●
Mbaseline,ikj is the baseline Hb of subject j in treatment arm i and stratum k
●
τi is the mean effect of treatment arm i
●
γk, is the mean effect of stratum k
●
εikj is the residual for subject j in treatment arm i and stratum k.
The SAS procedure will be similar to the following:
proc mixed;
class region history_CV treatment;
model change = treatment baseline_Hb baseline_eGFR region 
history_CV;
run;
For the sensitivity analyses S4, S5 and S6, an additional covariate “Completer at Week 36” 
(Yes/No) will be added to the model above to account for LOCF. 
For missing data imputation rules using an ANCOVA model with LOCF, refer to section 
7.11.1
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 28-36 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.


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7.4.2.2 Change from baseline in LDL cholesterol to the average value of LDL 
cholesterol in weeks 12-28
Change from baseline in LDL cholesterol to the average value of LDL cholesterol in weeks 
12-28 will be compared by treatment arms using a MMRM model as in Section 7.4.2.1 (with 
the addition of LDL at baseline as continuous covariate).
The analysis will be similar to the primary analysis provided in section 7.4.2.1, except that it 
will be a superiority test instead of a non-inferiority test. This superiority test will be 
considered successful if the upper bound of the two-sided 95% confidence interval of the 
difference between treatment arms is below 0.
The analysis will be done on the FAS. An additional analysis (not part of the sequence) will 
be done on the PPS, 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
PPS
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.
This analysis will be done on all values (regardless the fasting status).
In addition to the inferential analysis, LDL cholesterol and LDL cholesterol change from 
baseline will be reported descriptively by visit. The average of weeks 12-28 will also be 
reported.
7.4.2.3 Time to first IV iron use during weeks 1 to 36 and Monthly IV iron use during 
Day 1 to Week 36
The average monthly IV iron use (mg) during Day 1 to Week 36 will be compared by 
treatment groups using an analysis of covariance (ANCOVA) model using region, history of 
CV, baseline Hb and baseline eGFR as covariates. Subjects with no medication record of IV 
Iron will be assumed that they received no IV Iron. For those subjects, monthly IV iron use 
will be set to zero mg. Subjects who received Intramuscular Iron are counted under IV Iron in 
the analyses.


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The analysis will be done on the FAS. This superiority test will be considered successful if 
the upper bound of the two-sided 95% confidence interval of the difference between 
treatment arms is below 0. An additional analysis will be performed on the PPS.
Time to first use of IV Iron during the first 36 weeks will be analyzed similarly to time to 
hypertension (see section 7.4.2.7).
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.
Table 19
Primary and sensitivity for Mean monthly IV iron use (mg) during Day 1 
to Week 36 and Time to first IV iron use during weeks 1 to 36
Code
Set 
Endpoint
Method
Covariates
Primary
FAS
Mean monthly IV iron use 
(mg) during Day 1 to 
Week 36
ANCOVA
Region, History of CV, 
Baseline Hb and Baseline 
eGFR
S1
PPS
Mean monthly IV iron use 
(mg) during Day 1 to 
Week 36
ANCOVA
Region, History of CV, 
Baseline Hb and Baseline 
eGFR
Primary
FAS
time to first IV iron use 
during weeks 1 to 36
Cox 
regression + 
Kaplan 
Meier
Stratified on Region and  
History of CV, and adjusted 
on BL Hb, BL eGFR as 
continuous covariates
S1
PPS
Time to first IV iron use 
during weeks 1 to 36
Cox 
regression + 
Kaplan 
Meier
Stratified on Region and  
History of CV, and adjusted 
on BL Hb, BL eGFR as 
continuous covariates
7.4.2.4 Change from baseline in SF-36 PF subscore to the average in weeks 12–28
Change from baseline in PF subscore of SF-36 to the average of weeks 12–28 will be 
compared by treatment arm, for the PPS 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. Non-inferiority can be concluded if the lower bound of the two-sided 
95% CI of the difference between the two treatment groups is above -3 points (see figure 6 
below).
The analysis for this variable will be similar to the one provided in section 7.4.2.1 (all the 
available information from the observed data up to analysis date of Week 28 will be used).
In addition, this model will be repeated for the FAS.




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In addition, this model will be repeated for the FAS.
Table 21
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
PPS
SF36-VT Change 
from Baseline at 
Weeks 12-28 
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 
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.
In addition to the inferential analysis, SF-36 VT and SF-36 VT change from baseline will be 
reported descriptively by visit. The average of weeks 12-28 will also be reported.
7.4.2.6 Change from baseline in mean arterial pressure (MAP) to the average MAP 
value of weeks 20–28
The blood pressure effect is assessed by the change from baseline in MAP. 
Change from baseline in MAP to the average in weeks 20–28 will be compared by treatment 
arm using a MMRM model as in Section 7.4.2.1 (all the available information from the 
observed data up to Week 28 will be used)
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 the two treatment arms is below 1 mm Hg (see Figure 4 below). This will 
be calculated on the PPS.
As per Table 16, once the non-inferiority is concluded, superiority will be checked for this 
variable on the FAS. Superiority can be concluded if the upper bound of the two-sided 95% 
CI of the difference between the two treatment arms is below 0 mm Hg.






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Table 23
Primary and sensitivity analysis for the time to first occurrence of 
hypertension during weeks 1 to 36
Code
Set 
Endpoint
Method
Stratas/Covariates
Primary
PPS
time to first occurrence 
of hypertension in 
week 1 to 36
Cox 
regression + 
Kaplan 
Meier
Stratified on Region and  
History of CV, and adjusted on 
BL Hb, BL eGFR as continuous 
covariates
Primary
FAS
time to first occurrence 
of hypertension during 
weeks 1 to 36
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 during weeks 1 to 36 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 risks. 
In addition to the cumulative incidence plot, the cumulative incidence at Week 6, Week 12, 
Week 18, Week 24, Week 30 and Week 36 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 occurrence of hypertension during 
weeks 1 to 36 will be reported by treatment arm on the PPS. For subjects who have 
experienced more than one hypertension, only their first event following study treatment will 
be used in the analysis.
In addition, the incidence rate (per 100 subject years at risk) will also 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.


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7.4.2.8 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
PPS
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
Mean monthly IV iron use 
(mg) during Day 1 to 
Week 36 by Subgroup
ANCOVA
Region, History of CV, visits and 
visits by treatment as categorical 
variables. BL Hb and BL eGFR as 
continuous covariates.
A4
PPS
SF36-PF Change from 
Baseline at Weeks 12-28 
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.
A5
PPS
SF36-VT Change from 
Baseline at Week 28 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.
A6
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.
A7
FAS
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.
A8
PPS
time to first occurrence of 
hypertension in week 1 to 
36 by Subgroup
Cox 
regression + 
Kaplan 
Meier
Stratified on Region and  History of 
CV, and adjusted on BL Hb, BL 
eGFR as continuous covariates
A9
FAS
time to first occurrence of 
hypertension in week 1 to 
36 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 group (8) Iron repletion status.


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Forest plots will be produced where all subgroup factors will appear on the y-axis and the 
appropriate statistic comparing roxadustat versus darbepoetin alfa and the 95% confidence 
interval will appear on the x-axis.
7.4.3
Analysis of the Additional Secondary 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 Darbepoetin alfa using 95% 
confidence intervals.
Descriptive statistics will be presented by treatment arm.
7.4.3.1 Hb change from BL to the average Hb value of weeks 28 to 52 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 28-52 and regardless the use of rescue therapy.  
7.4.3.2 Time to achieve the first Hb response (without rescue therapy and regardless of 
rescue therapy) during the Efficacy Emergent Period
Time to achieve the first Hb response, without rescue therapy, will be analyzed using the 
same methods described in section 7.4.2.7. In addition, the analysis will be repeated
regardless of rescue therapy.
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, 24, 52, 72 and 96 weeks with their 
associated 95% confidence interval reported using Greenwood’s formula.
7.4.3.3 Hb averaged over weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104 without having 
received rescue therapy within 6 weeks prior to and during this 8-week period
Averaged Hb over weeks 28-36, 44 to 52, 72 to 80 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, 72-80 and 96-104 and by visit within the <10 g/dL, 10-12 g/dL, ≥10 g/dL
and >12 g/dL categories will be shown. 
7.4.3.4 Hb value and Hb change from BL Hb to each post-dosing time point 
(regardless of rescue therapy)
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, except that it is 
regardless of rescue therapy.


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7.4.3.5 Hb change from BL Hb to the average Hb value of weeks 28 to 36, 44 to 52, 72 
to 80, 96 to 104 regardless of the use of rescue therapy
This 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, 72-80 and 96-104 regardless use of rescue therapy.
7.4.3.6
Categorical analysis of 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, in weeks 72-
80 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, ≥10 g/dL, > 12.0 g/dL, > 13.0 g/dL and 
> 14.0 g/dL) between the first and last Hb assessment during the Efficacy Emergent Period 
will be presented by treatment arm.
7.4.3.7 Occurrence and time to first potential Excessive Hematopoiesis (EH)
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)
7.4.3.8 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 on the FAS 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).
7.4.3.9 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 for any reason will be reported. 
Descriptive statistics by treatment arm for number of RBC packs and volume of blood 


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transfused will be reported as well as number of RBC packs and volume per PEY. Time to 
first use of RBC transfusion will be analyzed during the Efficacy Emergent Period similarly 
as in Section 7.4.2.7 using the FAS.
7.4.3.10 Occurrence and time to first use of rescue therapy [composite of RBC 
transfusions [all subjects] and darbepoetin alfa use [roxadustat treated subjects 
only])
The number and percentage of subjects with rescue therapy during the treatment period 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.
7.4.3.11 Occurrence of iron supplementation. Mean monthly IV iron (mg) per subject 
during weeks 37-52 and weeks 53-104 (monthly defined as a period of 4 weeks). 
Time to first IV Iron during the efficacy emergent period
Occurrence of Iron use will be summarized by time period (during the efficacy emergent 
period, during the first 36 weeks, during week 37 – 52 and week 53- 104) and by type of Iron 
(IV Iron only, Oral Iron only, IV and Oral iron and No iron).
Mean monthly IV Iron use during weeks 37-52 and weeks 53-104 will be analyzed same way 
as for the first 36 weeks (see section 7.4.2.3).
Time to first use of IV Iron will be analyzed similarly to use of rescue therapy (see section 
7.4.3.10).
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.
7.4.3.12 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, treatment arm will be presented 
regardless of fasting status. Descriptive statistics will also be reported with fasted values.
7.4.3.13 Occurrence of mean LDL cholesterol <100 mg/dL (2.59 mmol/L), calculated 
over weeks 12 to 28, and weeks 36 to 52 of treatment
The number and percentage of subjects with mean LDL cholesterol less than 100 mg/dL
(2.59 mmol/L)(regardless fasting status) on average in weeks 12-28 and 36-52 will be 
reported by treatment arm and baseline category (< 2.59 mmol/L , ≥ 2.59 mmol/L and 


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overall). Descriptive statistics and frequency tabulations will also be reported regardless of 
fasting status.
7.4.3.14Occurrence of achieved antihypertensive treatment goal (SBP <130 mmHg 
systolic and DBP<80 mmHg) based on the mean SBP and mean DBP 
calculated over weeks 12 to 28 and 36 to 52 
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 and 36-52 will 
be reported by treatment arm.
7.4.3.15 Health related Quality of Life Questionnaires Change from BL to the average 
value of weeks 12 to 28 and 36-52
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 and frequency tabulations (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 and 36-52, an inferential analysis, similar to 
the one defined in section 7.4.2.1 will be performed for the following endpoints:
1.
Physical Component Scores of SF-36 (SF-36 PCS)
2.
Anemia Subscale (“Additional Concerns”) of  FACT-An Scores
3.
Total FACT-An Scores
For SF-36, at each visit, the frequency and proportion of subjects with an increase from 
baseline <3/≥3 points and <5/≥5 points will be reported for Physical Functioning, Vitality
and Physical Component scores. 
For FACT-An, at each visit, the frequency and proportion of subjects with a increase from 
baseline <3/≥3 points in the FACT-An Anemia and a change from baseline <7/≥7 points in 
the Total FACT-An score will be reported. 
EQ-5D 5L
For the EQ-5D 5L VAS score, change from baseline to each visit and to the average of weeks 
12-28 and 36-52 will be described by treatment arm. Mean values will be plotted over time 
and by treatment arm. For the VAS score average value in weeks 12-28, an inferential 
analysis, similar to the one defined in section 7.4.2.1 will be performed.


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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 by descriptive statistics and frequency 
tabulations, by visit and treatment arm.
Furthermore, change from baseline to each visit and to the average value in weeks 12-28 and 
36-52 will be described by treatment arm.
7.4.3.16 Patients’ Global Impression of Change (PGIC)
Patients’ Global Impression of Change will be summarized descriptively by visit and 
treatment arm. 
7.4.3.17 Iron, HbA1c, and CKD progression parameters
Changes from baseline to each study visit will be calculated for these parameters:

Serum ferritin

TSAT

Serum Iron

HbA1c level

Fasting blood glucose

eGFR (including slope over time)

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.
For HbA1c and Fasting blood glucose, summaries will be presented by Baseline Diabetes 
Mellitus status (regardless of type). 
Geometric Mean (GM) and coefficient of variation (CV) will be displayed for serum 
creatinine, eGFR and albumin/creatinine ration in urine. In addition, GM Ratio from baseline 
and 95% CI will be presented for these parameters by transforming the change from baseline 
of the log-transformed back to the original scale. This will be presented by treatment arm.
CKD Progression parameters:
-
Annualized eGFR slope over time: 
The annualized eGFR (expressed in ml/min per 1.73 m² per year) will be determined using 
the SAS code below:
proc mixed data=egfr2;
class usubjid strata_except_egfr_hb TRTPN TRTP;


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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 &meanegfrbl
atptn*TRTPN*TRTP 1 0
atptn*strata_except_egfr_Hb &prop_strata 
/cl; 
estimate 'Annnualized slope Darbepoetin'
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 
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.
All time to event endpoints as defined in Section 6.1.3.17 will be analyzed using the same 
methods described in Section 7.4.2.7 on the FAS. 
The number and percentage of subjects who have initiated dialysis or kidney transplant at 
any moment during the safety emergent period will be reported. A listing of dialysis data will 
also be provided.
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.
7.5
Analysis of Safety
Safety analyses will be performed using the Safety Analysis Set (SAF). 


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Missing dates' imputation rules for AE onset 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 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 drug related TEAEs leading to permanent 
discontinuation of study drug, 
●
Number and percentage of subjects with drug related TEAEs leading to death 
●
Number and percentage of subjects with NCI CTC Grade 3 or higher TEAEs, 
●
Number and percentage of subjects with 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 (PT only)
●
Drug related TEAEs, 
●
Serious TEAEs, 
●
Drug related serious TEAEs, 
●
TEAEs with NCI CTC Grade 3 or higher
●
TEAEs by relationship
●
TEAEs by severity
●
Drug related TEAEs by severity
●
TEAEs leading to permanent discontinuation of study drug, 
●
Drug related TEAEs leading to permanent discontinuation of study drug,
●
TEAEs leading to death,
●
Drug-related TEAEs leading to death,
●
TEAEs excluding serious adverse events, that equal to or exceed a threshold of 5.0% in 
any treatment arm, 


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●
Common TEAEs that equal to or exceed a threshold of 5.0% in any treatment arm 
●
TEAEs by relationship to the study drug,
●
AEs occurring during the post study follow up period (i.e after Analysis date of Last 
Dose + 28 days) and
●
Serious AEs occurring during the post study follow up period
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.
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
●
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 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, 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: 

Serious TEAEs, 

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 cardiovascular, 


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cerebrovascular or thromboembolic diseases and adjusted on baseline Hb and baseline eGFR 
as continuous covariates. Hazard ratios (roxadustat as relative to darbepoetin alfa) and their 
95% CI will be calculated for each TEAE category.
A dot-and-forest plot will be produced showing each of the above TEAE categories in the 
y-axis. The incidence rates by treatment arm, the stratified Cox hazard ratio (roxadustat as 
relative to darbepoetin alfa) and its 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
-
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)


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●
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 up to 7 days
Additional summaries or analyses with a subset of the treatment–emergent events irestricted 
up to Analysis Date of Last Dose adjusted for dosing frequency + 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, 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, 
and cumulative incidence plots as described in section 7.5.1.4 will be provided)
7.5.1.7 Adjudicated events
The pre-specified adjudicated cardiovascular and thrombo-embolic events will be 
descriptively presented by treatment group.  Time to the different type of events will be 
presented using Kaplan-Meier estimates. Comparison between roxadustat and darbepoetin 
will be presented using hazard ratios and 95% confidence intervals from the Cox regression 
model used for all other time to event endpoints. If appropriate, censoring at start of dialysis 
can be applied. 
All data will also be listed.
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 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. 


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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 Table 9, 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.
For the selected PCS criteria (Hb <6 g/dL, Hb >14 g/dL, ALT > 3X ULN, AST > 3X ULN, 
Total Bilirubin > 1.5X ULN), 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 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 darbepoetin alfa. A dot-and-forest 
plot will be produced showing the PCS abnormalities above on the y-axis and the incidence 
rates, the Cox hazard ratio and their 95% CI on 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).
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 darbepoetin alfa.
Individual displays of Liver Enzymes and Bilirubin parameters, listed in 6.2.3.1, will be 
reported for all subjects with either ALT or AST > 3 x ULN or total bilirubin > 2 x ULN 
during Safety Emergent Period (as in Astellas standard FFG_011) .
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 during the study 


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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). 
Potentially Clinically Significant (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 and minimum on-treatment (i.e during Safety Emergent Period) value will be 
presented 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 10) will be 
tabulated by treatment arm. 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.
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.


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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 and Israel
Central and Eastern Europe
Baseline Hb
≤8 g/dL
>8 g/dL
History of cardiovascular, cerebrovascular or 
thromboembolic diseases
Yes
No
Baseline eGFR
<30 mL/min/1.73 m@
≥ 30 mL/min/1.73m@
Baseline eGFR
<15 mL/min/1.73 m@
≥ 15 mL/min/1.73m@
Baseline CRP group 
CRP ≤ULN vs. CRP > ULN
Baseline Iron repletion status 
Baseline TSAT ≥20% and Baseline ferritin 
≥100 ng/mL Yes vs. No
For a group variable, subgroup analysis will not be done in case the size of a at least one of 
the subgroup is too small (i.e. less than 5% of the patient population). 
7.9
Other Analyses
No other analyses are planned.
7.10
Interim Analysis (and Early Discontinuation of the Clinical Study)
An interim analysis will be performed when all subjects have completed 36 weeks of 
treatment. Since all primary and key secondary analyses have been defined over this period 
of time, no multiplicity adjustment is required as the information fraction at the interim 
analysis is 100%. Results of the endpoints measured over a period longer than 36 weeks will 


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be mainly described to provide full disclosure, but no interferential analyses will be done. For 
safety, the interim analysis will include all available data at the time of the last subject 
reaching Week 36. Adjudicated data will not be part of the interim analysis. Once the study is 
completed, efficacy and safety will be analyzed again and reported including the complete 
study treatment of 104 weeks. More details about the data cut-off process can be found in the 
Data Cut-Off Specifications document.
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 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.
For all secondary variables analyzed using MMRM, an additional sensitivity analysis will be 
performed using an ANCOVA model with LOCF method using BL value and the 
stratification factors as covariates:
●
Hb (continuous): Available data in time period under evaluation will be used. If no 
Hb is available during the time period under evaluation, the average of the previous 
four post-baseline Hb values will be carried forward. For analyses without rescue 
therapy, for subjects who used rescue therapy, the last Hb value prior to the initiation 
of rescue therapy will be carried forward for imputation for 6 weeks from the end date 
of rescue therapy (in place of the collected values). If at least one non-missing Hb 
assessment is available during the period of evaluation, then no imputation will be 
performed. When the start date is different than the end date of rescue therapy, the 
last observation will be carried forward during the period as well.
No imputation 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.


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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 as well as for chronic 
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.
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 


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Adverse Event
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.
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,


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●
ECG parameters.
●
Exposure listings
Table 31
Analysis Visit Windows
CRF Visit
Target HIJI
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)
and unscheduled 
(on-treatment)
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: 
Table 32
Analysis Visit Windows for QoL
CRF Visit
Target HIJI
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
Table continued on next page


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CRF Visit
Target HIJI
Analysis Visit Windows Actual 
Assessment Day
Analysis Visit
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
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
Any
NA
All the assessments not falling 
within any of the analysis visit 
windows defined above
Not Windowed
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 HIJI
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
Table continued on next page


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CRF Visit
Target HIJI
Analysis Visit Windows Actual 
Assessment Day
Analysis Visit
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
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 + x +28 days), EOS visit date, date of death] with x the number of days calculated from 
the last frequency corresponding to the last non missing dosing record collected by the site 
(i.e dose holds will therefore not be considered) .
X will be derived as follows (standardized on 3 times per week, the standard frequency for 
roxadustat) :
if frequency = “3 TIMES PER WEEK” then x=0 
if frequency = “2 TIMES PER WEEK” then x=1 
if frequency = “1 TIME PER WEEK” then x=5 
if frequency = “EVERY 2 WEEKS” then x=12 
if frequency = “QM” then x =26 
Additional frequencies might be recorded. For those cases, X will be derived using the same 
rule as above.
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 EOT visit. In case a 
subject died during the treatment period, the end of Efficacy Emergent Period will be set to 
the last non-missing Hb assessment.


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8
DOCUMENT REVISION HISTORY 
Version
Date
Changes
Comment/rationale for change
1.0
26 May 
2014
NA
Document finalized
2.0
22 August 
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) An additional analysis set has been 
defined ’All Randomized’ as per 
Astellas standard. 
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 
Period.
9) Time to PCS ECG focused to QTc 
instead of all ECG assessments.
10) Update regarding derivation of 
MAP values: average of the 3 
measurements instead of 2 (now in 
line with FG SAP).
11) Implementation of additional 
secondary endpoint: Hb change 
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) This additional analysis set has 
been added in protocol 
amendment 1.0.
5) Use of the Safety Emergent 
Period (i.e last dose + 28 days) 
as evaluation period by default 
for the safety endpoints.
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 events have been 
updated accordingly.
9) Time to event for PCS ECG 
other than QTcF was 
considered not of interest.
10) Using the average of all 3 
measurements is more efficient 
and is consistent with Fibrogen 
060 study SAP.
11) This additional endpoint has 
been added in protocol 


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from BL to the average Hb value of 
weeks 28-52 regardless of the use of 
rescue therapy for alignment with 
global program.
12) Analysis for key secondary 
endpoints has been updated: Mixed 
Model of Repeated Measures 
(MMRM) replacing Analysis of 
Covariance (ANCOVA) with Last 
Observation Carried Forward 
(LOCF) and Removal of Dunnett’s 
multiple comparison procedure.
13) Additional secondary endpoint has 
been deleted: Iron use - Monthly 
oral iron (mg) use per subject during 
weeks 1 to 36, and weeks 36 to 52 
(monthly defined as a period of 4 
weeks).
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) Update regarding the analysis on 
cholesterol data: use of all data as 
main analysis and fasted only as 
additional instead of fasted only as 
main.
16) Reduction in the number of analyses 
of subgroup of interests.
17) Addition of the analysis of 
percentage of time when Hb > 12, 
13 or 14.
18) MMRM model added for number of 
RBC and volume of RBC during the 
treatment period.
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) Additional tables run on group of 
subjects enrolled after protocol 
amendment implementation.
21) Definition of hypertension updated 
amendment 1.0.
12) This has been added in 
protocol amendment 1.0.
13) This additional endpoint has 
been deleted in protocol 
amendment 2.0.
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.
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) 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.  
20) Added in order to assess the 
impact of protocol amendment 
1.0 and 2.0.
21) Due to harmonization with 


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using ≥ instead of > for the SBP and 
DBP thresholds
22) Addition of subgroup analyses on 
Baseline VT and PF subscores for 
SF-36 
23) Change in the choice of covariance 
structure for MMRM models.
24) Implementation of de facto 
sensitivity analyses on the FAS for 
the primary endpoint and secondary 
endpoints related to Hb 
Fibrogen 060 SAP.
22) Due to harmonization with 608 
SAP for HEOR purpose.
23) Due to harmonization with 
Fibrogen 060 SAP.
24) Added to perform sensitivity 
analyses accounting for all Hb 
assessments collected during 
the study (real practice analysis 
on ITT)
2.0
07 
December 
2016
NA
Document finalized
3.0
19 
September 
2018
1) The alternative definitions of the 
Primary Efficacy Endpoint Hb 
response have been clarified by:  
a) Removing ‘without 
discontinuation’ and ‘regardless 
of discontinuation’.
b) Including an additional 
definition dropping the criterion 
of at least 1.0 g/dL increase. 
2) For the key secondary endpoint 
Hb change from BL to the 
average Hb in weeks 28-36 have 
been clarified by removing 
‘without discontinuation’ and 
‘regardless of discontinuation’ 
and created one definition for 
regardless rescue therapy.
3) The key secondary endpoint Mean 
monthly IV iron use (mg) per 
subject during weeks 1 to 36 
(monthly defined as a period of 4 
weeks) has been revised as Time 
to first IV iron use during weeks 
1 to 36.
1a), 2) All Hb values up to the 
End of Treatment assessment 
will be considered independent 
if subject discontinued yes/no. 
1b) Since the latest protocol 
amendment 2.0 allows subjects 
with screening Hb between 10.0 
and 10.5 to be enrolled, this 
additional definition of Hb 
response has been added (i.e. Hb 
≥11.0 g/dL only).
3) Small number of subjects 
were treated with IV iron and 
therefore the mean monthly IV 
iron dose could not be 
considered as a continuous 
endpoint. Instead we will look at 
it as a binary endpoint with a 
time to event analysis. Results 
for both endpoints will be 
described. 
3.0
19 
September 
2018
4) Derivation details has been added 
or further clarifications have 
been included where needed: 
a. Occurrence and time to first 
potential EH: 
b. Iron Use: Derivation of iron 
based on the ATC 3th class has 
been clarified. 
4) Details added to support the 
statistical programming of the 
derived variables. 


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c. Number of days of 
hospitalization per patient-
exposure-year (PEY).
d. Concomitant medication 
definition.
e. FACT-An total score.
f. Time to Treatment 
Discontinuation: time to 
censoring derivation.
g. Time to occurrence of any 
TEAE (by type of AE group): 
Bullet point ‘TEAEs leading to 
Death’ is updated as ‘Death 
during the Safety Emergent 
Period’.
h. For HRQoL endpoint PGIC, 
only the last assessment will be 
used.
i. For FACT-An, the missing 
score ‘FACT-An Fatigue Score’ 
is added.
j. TEAE definition for AE both 
start and stop dates are 
completely missing and the 
adverse event occurs on Day 1 
check box is missing is added.
k. PCS Laboratory Criteria: 
Hemoglobin >120 g/L is updated 
as Hemoglobin >14 g/dL.
l. For the statistical analysis, 
treatments will be pooled across 
roxadustat under both protocol 
versions.
m. Demographic and Other 
Baseline Characteristics: eGFR 
categories 60-<90 and ≥90 
mL/min/1.73m2 is combined into 
one category.
n. Volume transfused when the 
number of RBC units is given 
o. Occurrence of rescue therapy 
as a binary variable.
3.0
19 
September 
2018
5) More extensive analyses of 
adverse events are included: 
a. For adverse events incidence 
rate, number of subjects at risk.
b. Time to occurrence of any 
death (during the 24-month 
Period including follow-up)
c, Definitions of event rate
d. AE up to plus 7 Days
5) Additional AE analysis have 
been included to harmonize with 
the other placebo-controlled 
Phase 3 studies with roxadustat. 
The adjudicated events for this 
study will not be part of the 
pooled CV analysis as this study
is still ongoing. In addition, this 


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e. Adjudicated CV related Events 
study is the only active-controlled 
study in non-dialysis patients.
3.0
19 
September 
2018
6) Iron, HbA1c and CKD 
progression parameters:
a. clarified that these are 
exploratory variables.
b. Clarified that any assessment 
for creatinine and eGFR 
occurring after the initiation of 
acute or chronic dialysis will be 
excluded for the summaries and 
further analysis. 
c. Updated the list of exploratory 
endpoints related to CKD 
progression. The composite 
endpoint as well as the 
components will be included. 
6) Clarification added and to 
harmonize the CKD progression 
endpoints in line with the other 
placebo-controlled Phase 3 
studies. 
3.0
19 
September 
2018
7) For the primary aanalysis of the 
primary endpoint, SAS code 
using version 9.3 is added
8) Section 7.4.1.2 Secondary 
Analyses (sensitivity) of the 
Primary Endpoint
In the Table a column is added 
for the analyses repeated 
excluding data from the site(s) 
with potential data quality issues.
7) Details of the SAS code has 
been added knowing that SAS 9.4 
is not implemented.
8) As a sensitivity analysis of 
efficacy data.
3.0
19 
September 
2018
9) Section 7.4.1.3 Additional 
Analyses of the Primary 
Endpoint and section 7.4.2.8 
Additional Analyses of the Key 
Secondary Endpoints
a) analysis for subgroups 
Baseline CRP group and Iron 
repletion status are added. 
b) The following footnote is 
added for the table in section 
7.4.1.3 Additional Analyses of 
the Primary Endpoint:
In case model does not converge 
for some subgroups, no 
adjustment on covariates will be 
done.
c) . ≥10.0 g/dL is added for all 
categorical endpoints using the 
Hb values.
9 a) To provide analysis for these 
subgroups of interest.
b) To clarify about the model 
convergence issue.
c) to harmonize across the 
development program
3.0
19 
September 
2018
10) Interpretation of fixed 
sequencing test is updated for 
tests 3, 6, 8 and 9.
10) For test 3, this is due to the 
change in endpoint as mentioned 
in Section 


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11) for EQ-5D 5L, an inferential 
analysis for the VAS score 
average value in weeks 12-28 is 
added.
12) Additional subgroups are added 
for Baseline eGFR (< 15 vs ≥ 
15), Baseline CRP group (≤ULN 
vs > ULN) and Baseline Iron 
repletion status (TSAT ≥20% 
and ferritin ≥100 ng/mL Yes vs 
No).
6.1.2 Key Secondary Efficacy 
Endpoints.
For tests 2, 6 and 8, 
typographical error.
11) To provide inferential 
analysis for EQ-5D VAS score.
12) Additional clinically 
important subgroups have been 
identified and included in the 
analysis.
3.0
19 
September 
2018
13) Section 7.10 Interim Analysis 
(and Early Discontinuation of the 
Clinical Study)
Clarified that results of the 
endpoints measured over a period 
longer than 36 weeks will be 
mainly described to provide full 
disclosure, but no interferential 
analyses will be done. Also 
clarified that Adjudicated data 
will not be part of the interim 
analysis.
14) Section 7.11.1 Missing Data
For other endpoints, paragraph 
related to LOCF method 
imputation is removed.
15) End of Safety Emergent Period 
and End of Efficacy Period are 
revised to take into account the 
different dosing frequency of 
darbepoetin treatment.
13) More details on the interim 
analysis is provided, as there is no 
separate interim analysis plan 
compiled.
14) LOCF method will not be 
applied due to comments from the 
FDA.
15) Darbepoetin is administered 
in a different (less frequent) 
dosing regimen compared to 
roxadustat. The definition of the 
periods have been revised to align 
both treatment regimens with 
respect to the end date.


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9
REFERENCES
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)
Cella D. The functional assessment of Cancer Therapy-Anemia (FACT-An) Scale: A new tool for the 
assessment of outcome in cancer anemia and fatigue. Hematology Seminars 1997;34:13-19 
Ge M, Durham LK, Meyer RD, Xie W and Thomas N. Covariate-Adjusted Difference in Proportions 
from Clinical Trials Using Logistic Regression and Weighted Risk Differences. Drug 
Information Journal 2011;45:481
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. 
Miettinen, O. and Nurminen, M., Comparative Analysis of Two Rates, Statistics in Medicine, 
1985;4:213-226,
Gail, M. and R. Simon. Testing for Qualitative Interactions between Treatment Effects and Patient 
Subsets. Biometrics. Vol. 41 No. 2 (June 1985):361-372.


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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.
Score range: 0-188


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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


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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
CM3ATCL=”IRON Preparations” AND route = 
intravenous
Oral Iron
CM3ATCL=”IRON Preparations” AND route = 
oral
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: 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 
 
IQVIA
Contributors and Reviewers
Data Science
Data Science
Clinical Science
IQVIA
Medical Science, Chiltern
PPD
PPD
PPD
PPD
PPD
PPD