Conditions: Anemia End Stage Renal Disease (ESRD)
Keywords: ASP1517 FG-4592 Anemia End Stage Renal Disease (ESRD) Erythropoetin Stimulating Agents (ESAs) Chronic Kidney Disease Hematopoetic Agents HIF-PH inhibitor Hemoglobin Dialysis roxadustat
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 838
Healthy volunteers: no

Brief summary:
This study was conducted to explore a new therapy for anemia in participants with end stage renal disease (ESRD) on dialysis. Anemia is a reduced number of red blood cells or hemoglobin. Hemoglobin (which contains iron) is important for the transport of oxygen in your blood. The purpose of this study was to evaluate if roxadustat is effective and safe in the maintenance treatment of anemia in ESRD participants on stable dialysis. Roxadustat was compared to epoetin alfa and darbepoetin alfa, commercially available medicines for treatment of anemia.

Detailed description:
This study consisted of three study periods as follows:

* Screening Period: up to 6 weeks
* Treatment Period: a minimum of 52 weeks up to a maximum of 104 weeks
* Follow-up Period: 4 weeks

Arms:
arm 1: Participants received roxadustat three times a week (TIW) for at least 52 weeks up to a maximum of 104 weeks. Participants received initial dose of roxadustat in doses of 100 mg, 150 mg or 200 mg, according to the average weekly dose of epoetin or darbepoetin alfa prior to randomization. Participants' roxadustat dosage was adjusted every 4 weeks to maintain Hb level within the target range 10.0 to 12.0 g/dL. Dose adjustment steps were as follows: 20, 40, 50, 70, 100, 150, 200, 250, 300, and 400 mg. Oral iron treatment of 200 mg was allowed for supplementation to support erythropoiesis. Treatment with intravenous iron was allowed only if certain protocol criteria were met. arm 2: Participants received epoetin alfa once weekly, twice weekly or TIW and darbepoetin alfa once a week or once every other week. Participants were treated for at least 52 weeks up to a maximum of 104 weeks. Treatment dosage was adjusted according to the pre-specified rule of keeping the participant's Hb levels between 10.0 to 12.0 g/dL. Participants were not allowed to switch from the epoetin alfa to darbepoetin alfa or vice versa.

Interventions: intervention 1: Roxadustat intervention 2: Epoetin alfa intervention 3: Darbepoetin alfa intervention 4: Iron
Intervention descriptions: intervention 1: Participants received initial dose of roxadustat orally as a tablet in doses of 100 mg, 150 mg or 200 mg, according to the average weekly dose of epoetin or darbepoetin alfa prior to randomization. Participants' roxadustat dosage was adjusted every 4 weeks to maintain Hb level within the target range 10.0 to 12.0 g/dL. Dose adjustment steps were as follows: 20, 40, 50, 70, 100, 150, 200, 250, 300, and 400 mg. Oral iron treatment of 200 mg was allowed for supplementation to support erythropoiesis. Treatment with intravenous iron was allowed only if certain protocol criteria were met. intervention 2: Participants received epoetin alfa via intravenous or subcutaneous injection, once a week, twice a week, or three times a week (TIW). Epoetin alfa dosage was adjusted to maintain Hb level within the target range. Dosing of epoetin alfa was per UK SmPC of Eprex®. Participants received IV iron supplementation according to the standard of care. intervention 3: Participants received darbepoetin alfa via intravenous or subcutaneous injection, once a week or once every other week. Darbepoetin alfa dosage was adjusted to maintain Hb level within the target range. Dosing of darbepoetin alfa was per EU SmPC of Aranesp®. Participants received IV iron supplementation according to the standard of care. intervention 4: Oral iron treatment was recommended for supplementation to support erythropoiesis and as first-line treatment for iron deficiency, unless participant was intolerant to this treatment. For participants receiving roxadustat the recommended daily dose was 200 mg of elemental iron. Participants were advised to take roxadustat at least 1 hour before or 1 hour after oral iron. Intravenous iron supplementation for participants receiving roxadustat was allowed if all of the following criteria were met: The participant's Hb level had not responded adequately to roxadustat following two consecutive dose increases or reached the maximum dose limit, and participant's ferritin was \< 100 ng/mL (\< 220 pmol/L) or TSAT \< 20%, or the participant was intolerant of oral iron therapy. For participants treated with epoetin alfa or darbepoetin alfa, IV iron supplementation was given according to standard of care.

Protocol document:
Prot_000.pdf: 
A Phase 3, Randomized, Open-Label, Active-Controlled Study to 
Evaluate the Efficacy and Safety of Roxadustat in the 
Maintenance Treatment of Anemia in End Stage Renal Disease 
Subjects on Stable Dialysis
ISN/Protocol 1517-CL-0613
ClinicalTrials.gov Identifier: NCT02278341
Date of Protocol v3 Incorporating Substantial 
Amendment 2 Reissue: 30 May2017
Sponsor: Astellas Pharma Europe B.V. (APEB)
Sylviusweg 62,
2333 BE Leiden
The Netherlands


Sponsor: APEB
ISN/Protocol 1517-CL-0613
EudraCT number 2013-001497-16
- CONFIDENTIAL -
30 May 2017
Astellas
Page 1 of 141
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 
Maintenance Treatment of Anemia in End Stage Renal 
Disease Subjects on Stable Dialysis
Protocol for Phase 3 Study of Roxadustat (ASP1517/FG-4592)a
ISN/Protocol 1517-CL-0613
Version 3.0 
Incorporating Substantial Amendment 2 [See Attachment 1]
30 May 2017
EudraCT number 2013-001497-16
Sponsor:
Astellas Pharma Europe B.V.
Sylviusweg 62, 2333 BE Leiden
The Netherlands
Protocol History:
Version 1.0 [30Jun2014]
Version 1.1 [25Feb2015-DE]
Version 2.0 [13May 2015]
Version 2.1 [09Jun2015-DE]
Version 2.2 [15Apr 2016]
Version 2.2 [15Apr2016-DE] 
Investigator: Investigator information is on file at Astellas
--------------------------------------------------------------------------------------------------------------------------------------
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.
a The INN of the compound is roxadustat. FG-4592 is the code name used by FibroGen Inc. to describe the 
investigational product. The development partner Astellas uses the code ASP1517. Both codes refer to the same 
product as the INN.


Sponsor: APEB
ISN/Protocol 1517-CL-0613
EudraCT number 2013-001497-16
- CONFIDENTIAL -
30 May 2017
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Page 2 of 141
Version 3.0 Incorporating Substantial Amendment 2
Table of Contents
I.
SIGNATURES ······················································································ 7
II.
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL····························10
III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ··················11
IV.
SYNOPSIS··························································································16
V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS·································31
1
INTRODUCTION·················································································36
1.1
Background ····················································································36
1.1.1
Epidemiology of Chronic Kidney Disease and End Stage Renal Disease········36
1.1.2
Anemia Associated with CKD·························································36
1.1.3
Treatment of Anemia ···································································37
1.2
Nonclinical and Clinical Data ·······························································38
1.2.1
Mechanism of Action of Roxadustat··················································38
1.2.2
Clinical Experience with Roxadustat ·················································40
1.2.3
Clinical Experience with Epoetin alfa ················································44
1.2.4
Clinical Experience with Darbepoetin alfa···········································45
1.3
Summary of Key Safety Information for Study Drugs ···································47
1.3.1
Roxadustat (Test Drug)·································································47
1.3.2
Epoetin alfa (Comparative Drug)······················································48
1.3.3
Darbepoetin alfa (Comparative Drug) ················································49
1.4
Risk-Benefit Assessment·····································································50
2
STUDY OBJECTIVES, DESIGN, AND ENDPOINTS ····································51
2.1
Study Objectives ··············································································51
2.1.1
Primary Objective ·······································································51
2.1.2
Secondary Objectives ···································································51
2.2
Study Design and Dose Rationale···························································52
2.2.1
Study Design·············································································52
2.2.2
Roxadustat Dose Rationale·····························································55
2.3
Endpoints·······················································································56
2.3.1
Primary Endpoint········································································56
2.3.2
Key Secondary Endpoints ······························································56
2.3.3
Additional Secondary Endpoints ······················································57
3
STUDY POPULATION··········································································59


Sponsor: APEB
ISN/Protocol 1517-CL-0613
EudraCT number 2013-001497-16
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Version 3.0 Incorporating Substantial Amendment 2
3.1
Selection of Study Population ·······························································59
3.2
Inclusion Criteria··············································································59
3.3
Exclusion Criteria ·············································································61
4
TREATMENTS····················································································62
4.1
Identification of Investigational Product(s) ················································62
4.1.1
Test Drug·················································································62
4.1.2
Comparative Drugs······································································62
4.2
Packaging and Labeling ······································································63
4.3
Study Drug Handling ·········································································63
4.4
Blinding ························································································64
4.5
Assignment and Allocation ··································································64
5
TREATMENTS AND EVALUATION························································65
5.1
Dosing and Administration of Study Drugs and Other Medication·····················66
5.1.1
Dose/Dose Regimen and Administration Period ····································66
5.1.2
Increase or Reduction in Dose of Study Drug ·······································67
5.1.3
Previous and Concomitant Treatment·················································69
5.1.4
Treatment Compliance··································································72
5.1.5
Rescue Therapy Guidelines ····························································72
5.1.6
Restrictions During the Study··························································73
5.2
Demographics and Baseline Characteristics ···············································74
5.2.1
Demographics············································································74
5.2.2
Medical History··········································································74
5.2.3
Renal Ultrasound ········································································74
5.2.4
Diagnosis of the Target Disease, Severity, and Duration of Disease··············74
5.2.5
Further Laboratory Testing Prior to Randomization ································75
5.3
Efficacy Assessment··········································································75
5.3.1
Primary Efficacy Assessment··························································75
5.3.2
Secondary Efficacy Assessments······················································75
5.3.3
Additional Assessments ································································75
5.4
Safety Assessment ············································································77
5.4.1
Vital Signs················································································77
5.4.2
Adverse Events ··········································································78
5.4.3
Laboratory Assessments································································78


Sponsor: APEB
ISN/Protocol 1517-CL-0613
EudraCT number 2013-001497-16
- CONFIDENTIAL -
30 May 2017
Astellas
Page 4 of 141
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5.4.4
Physical Examination···································································80
5.4.5
ECG·······················································································80
5.5
Adverse Events and Other Safety Aspects ·················································81
5.5.1
Definition of Adverse Events ··························································81
5.5.2
Definition of Serious Adverse Events (SAEs) ·······································82
5.5.3
Criteria for Causal Relationship to the Study Drug ·································84
5.5.4
Criteria for Defining the Severity of an Adverse Event ····························84
5.5.5
Reporting of Serious Adverse Events·················································84
5.5.6
Follow-up of Adverse Events··························································86
5.5.7
Monitoring of Common Serious Adverse Events ···································86
5.5.8
Procedure in Case of Pregnancy·······················································86
5.5.9
Emergency Procedures and Management of Overdose ·····························87
5.5.10
Supply of New Information Affecting the Conduct of the Study··················87
5.6
Test Drug Concentration ·····································································87
5.6.1
Blood Samples for roxadustat PK Analysis ··········································90
5.7
Other Measurements, Assessments or Methods ···········································90
5.7.1
α1-AGP and Albumin in Serum ·······················································90
5.7.2
Hepcidin in Serum·······································································90
5.7.3
Archival of Serum Samples for Biomarker Analysis ·······························90
5.7.4
Optional Genotyping Sample ··························································91
5.8
Total Amount of Blood·······································································91
6
DISCONTINUATION············································································91
6.1
Discontinuation of Individual Subject(s)···················································91
6.2
Discontinuation of the Site···································································92
6.3
Discontinuation of the Study·································································92
7
STATISTICAL METHODOLOGY ···························································92
7.1
Sample Size····················································································93
7.2
Analysis Set····················································································94
7.2.1
ITT ························································································94
7.2.2
FAS ·······················································································94
7.2.3
PPS························································································94
7.2.4
SAF ·······················································································94
7.2.5
PKAS ·····················································································94
7.3
Demographics and Other Baseline Characteristics········································95


Sponsor: APEB
ISN/Protocol 1517-CL-0613
EudraCT number 2013-001497-16
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30 May 2017
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Version 3.0 Incorporating Substantial Amendment 2
7.4
Analysis of Efficacy ··········································································95
7.4.1
Analysis of Primary Endpoint ·························································95
7.4.2
Analysis of Key Secondary Endpoints················································98
7.4.3
Analyses of Additional Secondary Endpoints ····································· 100
7.5
Analysis of Safety··········································································· 100
7.5.1
Adverse Events ········································································ 101
7.5.2
Laboratory Assessments······························································ 101
7.5.3
Vital Signs·············································································· 102
7.5.4
ECGs···················································································· 102
7.6
Analysis of Pharmacokinetics ····························································· 102
7.7
Analysis of Pharmacodynamics ··························································· 102
7.8
Protocol Deviations and Other Analyses················································· 102
7.9
Interim Analysis············································································· 102
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other Information ······· 103
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ·················· 103
8.1
Procedure for Clinical Study Quality Control ··········································· 103
8.1.1
Data Collection ········································································ 103
8.1.2
Specification of Source Documents················································· 103
8.1.3
Clinical Study Monitoring···························································· 104
8.1.4
Direct Access to Source Data/Documents·········································· 104
8.1.5
Data Management ····································································· 104
8.1.6
Protocol Deviations ··································································· 105
8.1.7
End of Study in All Participating Countries········································ 105
8.2
Ethics and Protection of Subject Confidentiality········································ 105
8.2.1
IRB / IEC / Competent Authorities·················································· 105
8.2.2
Ethical Conduct of the Study························································· 106
8.2.3
Informed Consent of Subjects ······················································· 106
8.2.4
Subject Confidentiality ······························································· 107
8.3
Administrative Matters ····································································· 107
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study ··· 107
8.3.2
Documents and Records Related to the Clinical Study ··························· 108
8.3.3
Protocol Amendment and/or Revision·············································· 109
8.3.4
Insurance of Subjects and Others···················································· 109
8.3.5
Signatory Investigator for Clinical Study Report·································· 109


Sponsor: APEB
ISN/Protocol 1517-CL-0613
EudraCT number 2013-001497-16
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30 May 2017
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9
QUALITY ASSURANCE······································································ 109
10
STUDY ORGANIZATION···································································· 110
10.1
DSMB and Other Evaluation Committee(s) ············································· 110
10.2
Other Study Organization ·································································· 110
11
REFERENCES ·················································································· 111
12
APPENDICES ··················································································· 114
12.1
List of Excluded Concomitant Medications·············································· 114
12.2
Liver Safety Monitoring and Assessment ················································ 115
12.3
Instructions for Roxadustat-treated Subjects Moving from Protocol v1.0 to 
Protocol v2.0················································································· 118
12.4
Short Form-36 Health Survey (SF-36 v2)················································ 119
12.5
Functional Assessment of Cancer Therapy- Anemia (FACT-AN)···················· 125
12.6
EuroQol Questionnaire (EQ-5D-5L)······················································ 128
12.7
Subject’s Global Impression of Change (PGIC) Scale ································· 131
13
ATTACHMENT 1:  SUBSTANTIAL AMENDMENT 2 ································ 132
14
SPONSOR’S SIGNATURES·································································· 141
List of In-Text Tables
Table 1
Schedule of Assessments·····································································32
Table 2
Treatment Arms, Dosing Frequencies and Patient Numbers·····························53
Table 3
Initial Dose of Roxadustat ···································································55
Table 4
Dose Adjustment Rules for Roxadustat ····················································67
Table 5
Proposed Maximum Daily Dose of Statins Not to be Exceeded in Patients on 
Dialysis·························································································71
Table 6
Laboratory Tests ··············································································79
Table 7
Examples of Sampling Schedules for Population PK for Subjects on 
Hemodialysis/Hemodiafiltration ····························································89
Table 8
Example of Preferred Sampling Schedule for Population PK for Subjects on 
APD·····························································································89
Table 9
Example of Sampling Schedule for Population PK for Subjects on CAPD············90
Table 10
Key Secondary Endpoints Fixed Sequence Testing Procedure··························98
List of In-Text Figures
Figure 1
HIF-PHI Mechanism of Action······························································39


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I.
SIGNATURES
1.
SPONSOR’S SIGNATURES
Required signatures (e.g. Protocol authors, sponsor’s reviewers and contributors, etc.) are 
located in Section 14, Sponsor’s Signatures; e-signatures (when applicable) are located at the 
end of this document.


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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 Maintenance Treatment of Anemia in 
End Stage Renal Disease Subjects on Stable Dialysis 
ISN/Protocol 1517-CL-0613
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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:
Date (DD Mmm YYYY)
Printed Name:
Address:


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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 Maintenance Treatment of Anemia in 
End Stage Renal Disease Subjects on Stable Dialysis 
ISN/Protocol 1517-CL-0613
Version 3.0 / Incorporating Substantial Amendment 2
30 May 2017
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:
Printed Name:
Date (DD Mmm YYYY)
Address:




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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
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
anti-HCV Ab
Anti-hepatitis C Virus antibody
APD
Automated peritoneal dialysis
APEB
Astellas Pharma Europe BV
ASP1517
=FG-4592; codename of investigational product roxadustat
AST
Aspartate Aminotransferase
BIW
twice weekly
BL
Baseline
BL Hb
Baseline Hemoglobin (please refer to key definitions for information)
CAPD
Continuous ambulatory peritoneal dialysis
CHMP
Committee for Medicinal Products for Human Use
CHOIR
Correction of Hemoglobin and Outcomes in Renal Insufficiency
CI
Confidence interval
CKD
Chronic Kidney Disease
Cmax
Maximum concentration
CRO
Contract Research Organization
CYP
Cytochrome P450
DBP
Diastolic Blood Pressure
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EMA
European Medicines Agency
EOS
End of Study
EOT
End of Treatment
EPO
Erythropoietin
EQ-5D 5L
European Quality of Life 5 Domain 5 Level
ESA
Erythropoiesis Stimulating Agent
ESRD
End Stage Renal Disease
EU
European Union
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 roxadustat
GCP
Good Clinical Practice
Hb
Hemoglobin
HbA1c
Hemoglobin A1c; Glycated hemoglobin
HBsAG
Hepatitis B Surface Antigen
HD
Hemodialysis
HDF
Hemodiafiltration
HDL
High-density Lipoprotein
HIF
Hypoxia-inducible Factor


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Abbreviations
Description of abbreviations
HIF-PH
HIF Prolyl Hydroxylase
HIV
Human Immunodeficiency Virus
HRQoL
Health-Related Quality of Life
hs-CRP
High Sensitivity C-reactive protein
ICF
Informed Consent Form
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
INN
International Nonproprietary Name
INR
International Normalized Ratio
IRB
Institutional Review Board
IRS
Interactive Response System
IUD
Intra Uterine Device
IUS
Intra Uterine System
ISN
International Study Number
ITT
Intention to Treat Set
IV
Intravenous(ly)
ka
First order absorption rate constant
KDOQI
Kidney Disease Outcomes Quality Initiative
kg
Kilogram
LDL
Low-density Lipoprotein
LA-CRF
Liver Abnormality Case Report Form
LFT
Liver Function Tests
LOCF
Last Observation Carried Forward
MACE
Major cardiovascular adverse events: myocardial infarction, stroke, death from 
all causes
MACE+
Myocardial infarction, stroke, death from all causes, chronic heart failure 
requiring hospitalization, unstable angina requiring hospitalization
MAP
Mean Arterial Pressure
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
mL
Milliliters
MMRM
Mixed Model of Repeated Measures
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria for Adverse Events
OATP1B1
Organic anion transporting polypeptide 1B1
PD
Peritoneal Dialysis
PF
Physical Functioning
PGIC
Patients’ Global Impression of Change
PK
Pharmacokinetic
PKAS
Pharmacokinetic Analysis Set
PPS
Per Protocol Set
QoL
Quality of Life
QTc
QT Interval corrected for heart rate
QW
Once weekly
RBC
Red Blood Cell
r-HuEPO
Recombinant Human Erythropoietin
SAE
Serious Adverse Event
SAF
Safety Analysis Set


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Abbreviations
Description of abbreviations
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
TBL
Total Bilirubin 
TEAE
Treatment-Emergent Adverse Event
TESAE
Treatment-Emergent Serious Adverse Event
TIBC
Total Iron Binding Capacity
TIW
Three times weekly
TREAT
Trial to Reduce Cardiovascular Events with Aranesp Therapy
TSAT
Transferrin Saturation
UK
United Kingdom
ULN
Upper Limit of Normal
US
United States
USRDS
United States Renal Data System
VAS
Visual Analogue Scale
VT
Vitality
WBC
White Blood Cell Count
Wk(s)
Week(s)


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List of Key Study Terms
Terms
Definition of terms
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a subject 
administered study drug or has undergone study procedures and which does 
not necessarily have a causal relationship with this treatment.  AE collection 
starts after obtaining signed informed consent and continues until the End of 
Study (EOS) visit.  Serious adverse events (SAEs) and cardiovascular and 
thromboembolic AEs will be collected during the poststudy follow-up period.  
AEs will not be collected during the period between first screen where subject 
has failed screening and first rescreening visit.
Baseline
1) Observed values/findings, which are regarded, as calibrated zero status in 
the present study; 2) Time when ‘Baseline’ is observed. 
Baseline 
Hemoglobin (Hb) 
value
Mean of 4 Hb values: the 3 Screening Hb values and the Hb value at the day of 
randomization, all assessed by the central laboratory. 
Discontinuation
The act of concluding participation in either the study treatment or the study, 
prior to completion of all protocol-required elements, in a study by an enrolled 
subject. Four categories of discontinuation are distinguished: a) dropout: 
active discontinuation by a subject (also a noun referring to such a 
discontinued subject); b) investigator-initiated discontinuation (e.g., for cause); 
c) loss to follow-up: cessation of participation without notice or action by the 
subject; d) sponsor-initiated discontinuation.  Note that subject discontinuation 
does not necessarily imply exclusion of subject data from analysis. 
“Termination” has a history of synonymous use, but is now considered non-
standard.
Enroll
To register or enter into a clinical study; transitive and intransitive.  Informed 
consent precedes enrollment, which precedes randomization.
Hb Response
Mean Hb during weeks 28 to 36 within the target range of 10.0 to 12.0 g/dL.
Post study 
follow-up
Period of time from the actual EOS visit to the projected EOS visit or until 
consent withdrawn.  This period is only applicable to subjects who prematurely 
discontinued treatment.  These subjects will be followed up at a 6-monthly 
frequency for vital status, SAEs and cardiovascular and thromboembolic AEs. 
Randomization
The process of assigning study 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 ESA [epoetin alfa or 
darbepoetin alfa] from day 1 until End Of Treatment [EOT]).
Re-screening
Process of repeating screening. If subject fails screening they may be 
re-screened once if deemed appropriate; all screening procedures will be 
repeated.  Renal ultrasound only to be repeated if not within 12 weeks prior to 
randomization.
Screening
A process of active consideration of potential subjects for enrollment in a 
study.


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Terms
Definition of terms
Screening Hb value
Mean of subject’s 3 most recent screening Hb values, as measured by central 
laboratory, during the screening period, obtained at least 4 days apart. The last 
Hb value must be within 10 days prior to the randomization visit (day 1). 
Screen / Re-screen 
failure
Potential subject who did not meet one or more criteria required for 
participation in a study during screening or re-screening.
Serious Adverse 
Event
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, 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 study.
Treatment period
It is the period of time - between first dose of the study drug and EOT visit 
where major interests of protocol objectives are observed, and where 
roxadustat (test drug), epoetin alfa or darbepoetin alfa (comparative drugs) is 
given to a subject.
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.


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IV.
SYNOPSIS
Date and Version # of Protocol Synopsis:
30 May 2017, Version 3.0
Sponsor:
Astellas Pharma Europe BV (APEB)
Protocol Number:
1517-CL-0613
Name of Study Drug:
Roxadustat
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 Maintenance Treatment of Anemia in End Stage Renal Disease Subjects on Stable 
Dialysis 
Planned Study Period:
From 4Q2014 to 3Q2018
Study Objective(s):
The primary objective of this study is to evaluate the efficacy of roxadustat compared to epoetin alfa 
and darbepoetin alfa in the maintenance treatment of anemia in End Stage Renal Disease (ESRD) 
subjects on stable dialysis.
The secondary objectives of this study are to:
●
Evaluate the safety of roxadustat compared to epoetin alfa and darbepoetin alfa in the 
maintenance treatment of anemia in ESRD subjects on stable dialysis.
●
Evaluate the effects on health-related quality of life of roxadustat compared to epoetin alfa and 
darbepoetin alfa in the maintenance treatment of anemia in ESRD subjects on stable dialysis.
Planned Total Number of Study Centers and Locations:
Approximately 150 centers
Global
Study Population:
The study population consists of adult subjects with ESRD who are on stable hemodialysis (HD) or 
peritoneal dialysis (PD) and on stable treatment with epoetin (i.e. epoetin alfa, beta, theta, zeta, delta 
or omega) or darbepoetin alfa for anemia.  Subjects on polyethylene glycol-epoetin beta (Mircera®) 
are not to be included.  Subjects on hemodiafiltration are also allowed to participate in the study and 
will follow the same study procedures and requirements as HD subjects.
Number of Subjects to be Randomized:
●
750
●
Approximately 400 subjects pretreated with epoetin and approximately 350 subjects pretreated 
with darbepoetin alfa.
Study Design Overview:
This is a phase 3, multicenter, randomized, open-label, active-controlled study.  The study will consist 
of 3 study periods:
●
Screening Period: up to 6 weeks
●
Treatment Period: For all subjects in the study the minimum treatment duration will be 52 weeks 
and the maximum treatment duration will be 104 weeks.  The study end date will be declared 
when the targeted number of MACE* and MACE+** events have been reported across the 
roxadustat phase 3 development program and consequently the treatment will end for all subjects 
who have completed 52 weeks at that point. Subjects who have not completed 52 weeks when 


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the target has been declared will continue until they reach 52 weeks and at that point their 
treatment will end.
●
Follow-up Period: 4 weeks
* MACE: Major cardiovascular adverse events: myocardial infarction, stroke, death from all causes
** MACE+: Myocardial infarction, stroke, death from all causes, chronic heart failure requiring 
hospitalization, unstable angina requiring hospitalization
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 of up to 42 days eligibility assessments will be performed.  Subjects in 
screening will continue treatment with epoetin or darbepoetin alfa per local standard of care.
Treatment Period
Subjects are randomized to 1 of 2 treatment arms as illustrated in Table 1 below.
●
Treatment arm 1: subjects will be switched from epoetin or darbepoetin alfa treatment to 
roxadustat treatment (see Table 2 for doses).
●
Treatment arm 2: subjects will continue erythropoiesis stimulating agent (ESA) treatment, i.e. 
epoetin alfa if pretreated with any epoetin (i.e. epoetin alfa, beta, theta, zeta, delta or omega) and 
darbepoetin alfa if pretreated with darbepoetin alfa, at approximately the same average weekly 
dose the subject was on prior to randomization.  It is not allowed to switch from epoetin alfa to 
darbepoetin alfa or vice versa, during the treatment period.  Subjects on polyethylene 
glycol-epoetin beta (Mircera®) are not to be included.
The randomization will result in an overall 1:1 ratio of subjects receiving roxadustat administered 
orally, or epoetin alfa or darbepoetin alfa administered as subcutaneous (SC) or intravenous (IV) 
injection.  Study treatment administration is implemented in an open-label manner. 
Randomization to treatment arms will occur through an Interactive Response System.
Table 1:  Treatment Arms, Dosing Frequency and Subject Numbers
Treatment Arms
Study Treatment
Dosing Frequency
N
1
roxadustat
TIW
375
2
ESA 
Dosing per SmPC
375
TIW = 3 times weekly; ESA = Erythropoiesis Stimulating Agent (epoetin alfa or darbepoetin alfa)
SmPC = Summary of Product Characteristics
During the treatment period, subjects will attend weekly study visits from day 1 to week 8, followed 
by every other week study visits from week 10 to 36.  Following week 36, study visits will occur 
every 4 weeks until the End of Treatment (EOT).
Randomization and administration of the first dose of study treatment (roxadustat or ESA) is to occur 
on day 1, which should correspond to a day when their next dose of epoetin or darbepoetin alfa would 
have been administered.
On day 1, all study procedures and assessments will be completed prior to the first study treatment 
administration.
During the treatment period, the aim is to maintain the hemoglobin (Hb) levels between 10.0 g/dL and 
12.0 g/dL.  All subjects receiving roxadustat will initiate and continue roxadustat dosing at a dosing 
frequency of 3 times weekly (TIW) throughout the entire period and dose adjustment is to follow 
prespecified dose adjustment rules (see Table 3).  Intake should occur at approximately the same time 
of day and, if possible, dosing days should remain consistent throughout the study.  For HD subjects it 
is recommended that roxadustat is administered any time after completion of dialysis if dosing is 


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scheduled on a dialysis day to avoid potential bias on certain study assessments. Specific rules apply 
on the dialysis day(s) at which pharmacokinetic (PK) sampling is scheduled.
During the treatment period, the active comparator drugs epoetin alfa (Eprex®) and darbepoetin alfa 
(Aranesp®) will be provided by the sponsor.  Dosing, dosing frequencies and dose adjustments should 
be in accordance with the UK Summary of Product Characteristics (SmPC) for Eprex® and EU SmPC 
for Aranesp®.  The protocol-specified frequencies are once weekly, twice weekly or TIW for epoetin 
alfa; and once weekly or once every other week for darbepoetin alfa.  In addition, the protocol allows 
for administration of epoetin alfa once every other week and darbepoetin alfa once every 4 weeks.  
These frequencies are only to be used in subjects on low ESA doses that do not fit into the normal 
frequencies of administration and if deemed clinically appropriate.  For PD subjects, darbepoetin 
dosing every 4 weeks is allowed.
For both treatment arms dose adjustments are to be made based on Hb values using HemoCue®, a 
point-of-care device.
Subjects will receive study treatment (roxadustat or ESA) for a minimum of 52 weeks and a 
maximum of 104 weeks.
Follow-up Period
After EOT period subjects will proceed to the 4-week follow-up period.  The choice of anemia 
treatment during the follow-up period is at the discretion of the investigator.
Poststudy 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 1 dose of study drug) will continue to be followed up at a 6-monthly frequency for vital 
status, serious adverse events (SAEs) and cardiovascular and thromboembolic adverse events (AEs) 
until their projected date of completion of the follow-up period (i.e. projected EOS visit) or until 
consent withdrawn.
Data Safety Monitoring Board/Independent Event Review Committee
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.
An Independent Event Review Committee will adjudicate all relevant cardiovascular and 
cerebrovascular events in a blinded manner to ensure consistent safety assessment.  Details will be 
specified in an Independent Event Review Committee charter.
Optional Genotyping Sample
Optional genotyping sampling for subjects randomized to the roxadustat arm will be included in this 
study.  If a separate (optional) informed consent is signed by the subject, a 5 mL whole blood sample 
for genotyping will be collected after randomization, preferably on day 1.
Selection Criteria:
Inclusion
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.


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3.
Subject is on stable HD, HDF or PD treatment with the same mode of dialysis for ≥4 months 
prior to randomization.
4.
For subject receiving HD or HDF, the vascular access must be via native arteriovenous (AV) 
fistula or graft, or permanent, tunneled catheter.
5.
Subject is on IV or SC epoetin (i.e. epoetin alfa, beta, theta, zeta, delta or omega) or IV or SC 
darbepoetin alfa treatment for ≥8 weeks prior to randomization with stable weekly doses (≤30% 
change from the maximum prescribed average weekly dose, i.e. ([max-min]/max≤ 0.3) during 
4 weeks prior to randomization.  Subjects on polyethylene glycol-epoetin beta (Mircera®) are 
not to be included.
6.
Mean of the subject’s 3 most recent Hb values, as measured by central laboratory, during the 
screening period, obtained at least 4 days apart, must be ≥9.5 g/dL and ≤12.0 g/dL with an 
absolute difference ≤1.3 g/dL between the highest and the lowest value.  The last Hb value must 
be within 10 days prior to the randomization visit (Day 1).
7.
Subject has a ferritin level ≥100 ng/mL (≥220 pmol/L) at screening.
8.
Subject has a transferrin saturation (TSAT) level ≥20% at screening.
9.
Subject has a serum folate level ≥ lower limit of normal (LLN) at screening.
10. Subject has a serum vitamin B12 level ≥ LLN at screening.
11. Subject’s alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are ≤3 x upper 
limit of normal (ULN), and total bilirubin (TBL) is ≤1.5 x ULN.
12. Subject’s body weight (postdialysis weight) is 45.0 kg to a maximum of 160.0 kg.
13. Female subject is either:
Of non-childbearing potential:
●postmenopausal (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 the last 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.
14. Female subject must agree not to breastfeed starting at screening or during the study period, and 
continue to do so for 28 days after the final study treatment administration.
15. Female subject must not donate ova starting at screening and throughout the study period and 
continue to do so for 28 days after final study treatment administration.
16. 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.
17. Male subject must not donate sperm starting from screening, throughout the study period and up 
to 12 weeks after final study drug administration.


Sponsor: APEB
ISN/Protocol 1517-CL-0613
EudraCT number 2013-001497-16
- CONFIDENTIAL -
30 May 2017
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18. Subject agrees not to participate in another interventional study from the time of signing 
informed consent until the EOS visit.
* 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:
Subject will be excluded from participation if any of the following apply:
1.
Subject has received a Red Blood Cell (RBC) transfusion within 8 weeks prior to randomization.
2.
Subject has a known history of myelodysplastic syndrome or multiple myeloma.
3.
Subject has a known hereditary hematologic disease such as thalassemia or sickle cell anemia, 
pure red cell aplasia, or other known causes for anemia other than Chronic Kidney Disease 
(CKD).
4.
Subject has a known hemosiderosis, hemochromatosis, coagulation disorder, or hyper-coagulable 
condition.
5.
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.
6.
Subject is anticipated to undergo elective surgery that is expected to lead to significant blood loss 
during the study period or anticipated elective coronary revascularization.
7.
Subject has active or chronic gastrointestinal bleeding.
8.
Subject has received any prior treatment with roxadustat or a hypoxia-inducible factor prolyl 
hydroxylase inhibitor. 
9.
Subject has been treated with iron-chelating agents within 4 weeks prior to randomization.
10. Subject has a history of chronic liver disease (e.g. cirrhosis or fibrosis of the liver).
11. Subject has known New York Heart Association Class III or IV congestive heart failure.
12. Subject has had a myocardial infarction, acute coronary syndrome, stroke, seizure, or a 
thrombotic/thrombo-embolic event (e.g., deep vein thrombosis or pulmonary embolism) within 
12 weeks prior to randomization.
13. Subject has had uncontrolled hypertension, in the opinion of the investigator, within two weeks 
prior to randomization
14. Subject has known hypersensitivity to epoetin alfa (Eprex®), darbepoetin alfa (Aranesp®) or any 
of their excipients.
15. 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, or another appropriate imaging 
method, within 12 weeks prior to randomization.
16. Subject has a history of malignancy, except for the following: cancers determined to be cured or 
in remission for ≥5 years, curatively resected basal cell or squamous cell skin cancers, cervical 
cancer in situ, or resected colonic polyps.


Sponsor: APEB
ISN/Protocol 1517-CL-0613
EudraCT number 2013-001497-16
- CONFIDENTIAL -
30 May 2017
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17. Subject is positive for any of the following: 
human immunodeficiency virus (HIV)
hepatitis B surface antigen (HBsAg), or
anti-hepatitis C virus antibodies (anti-HCV Ab)
18. Subject has an active clinically significant infection manifested by White Blood Count (WBC) 
> ULN, and/or fever, in conjunction with clinical signs or symptoms of infection within 1 week 
prior to randomization. 
19. Subject has a known untreated proliferative diabetic retinopathy, diabetic macular edema, 
macular degeneration or retinal vein occlusion.
20. Subject has had any prior organ transplant (that has not been explanted), or subject is scheduled 
for organ transplantation. 
21. Subject has participated in any interventional clinical study or has been treated with any 
investigational drugs within 30 days or 5 half lives or limit set by national law, whichever is 
longer, prior to the initiation of screening.
22. Subject has an anticipated use of dapsone in any dose amount or anticipated chronic use of 
acetaminophen/paracetamol >2.0 g/day during the treatment or follow-up period of the study.
23. Subject has a history of alcohol or drug abuse within 2 years prior to randomization.
24. 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 Products:
Roxadustat
●
Tablets
●
Strengths of 20 mg, 50 mg and 100 mg
Mode of Administration:
Oral
Doses:
The initial study drug (roxadustat) dose is based on the dosing scheme shown in Table 2 and is 
determined by the subject’s average prescribed weekly dose of epoetin or darbepoetin alfa within 4 
weeks prior to randomization.
Table 2:  Initial Dose of Roxadustat
epoetin† 
(IU/week)
darbepoetin alfa†
(µg/week)
roxadustat
(mg/dose) TIW
<8,000
<40
100
8,000 to 16,000
40-80
150‡
>16,000
>80
200§
TIW: 3 times weekly
† Average prescribed weekly dose in the last 4 weeks prior to randomization.
‡ If the initial dose of 150 mg exceeds the maximum dose of 3.0 mg/kg, then 100 mg is to be used as the 
starting dose.
§ If the initial dose of 200 mg exceeds the maximum dose of 3.0 mg/kg, then 150 mg is to be used as the 
starting dose.


Sponsor: APEB
ISN/Protocol 1517-CL-0613
EudraCT number 2013-001497-16
- CONFIDENTIAL -
30 May 2017
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After randomization, roxadustat will be dosed TIW for the entire duration of the treatment period. The 
dose of roxadustat will remain constant during the first 4 weeks of the treatment period.  After week 4, 
dose adjustments are permitted on a 4-weekly interval and will be aimed at keeping subjects’ Hb 
levels between 10.0 to 12.0 g/dL.  Dose adjustments will be based upon current Hb and change in Hb 
over the preceding 4 weeks as illustrated in Table 3 (deviation from the 4-week period is allowed 
anytime during the study in case of excessive hematopoiesis or Hb ≥13.0 g/dL).
Table 3:  Dose Adjustment Rules for Roxadustat
Change in Hb Over Past 4 
Weeks (g/dL)a
Hb (g/dL)
<10.5
10.5 to <12.0
12.0 to <13.0
< -1.0
↑
↑
No change
-1.0 to 1.0
↑
No change
↓
> 1.0
No change
↓
↓
Hb: hemoglobin
a Subtract first Hb value from last value Hb to calculate the change
All dose adjustments are made based on Hb values using HemoCue®, a point-of-care device.
Dose increases by 1 dose step (↑) and reductions by 1 dose step (↓) are pre-set
If the dose adjustment is ‘No change’ per the above table, the dose remains unchanged and the 
next dose adjustment review is 4 weeks after that visit.
The dose steps for roxadustat are as follows: 20, 40, 50, 70, 100, 150, 200, 250, 300, and 400 mg.
The maximum dose is the dose step corresponding to 3.0 mg/kg (based on postdialysis weight in 
HD subjects and in PD subjects weight minus abdominal fluid based on last filling) per 
administration or 400 mg, whichever is lower.  At study visits where weight is collected the 
default weight and maximum allowed dose step for a subject will be adjusted if the weight change 
is ≥ 5% compared to the previous default weight collected in the study.  Initial default weight is 
weight at randomization visit.
If there is a safety concern, investigators may deviate from the dose adjustment rules for 
roxadustat.  This should be discussed with the medical monitor and documented in the source 
documentation.
Contact the medical monitor if dose adjustments would lead to doses outside the limits of the dose 
step range; i.e. lower than 20 mg or higher than 400 mg.
In the following cases dose adjustment may be made at any time outside the 4-weekly interval:
Dose reduction in case of excessive hematopoiesis
Dose increase by 1 step in case subject Hb < 9.0 g/dL (HemoCue®) and no dose adjustment 
occurred in the preceding 4 weeks.
At any time when Hb ≥13.0 g/dL
Stop dosing.
Resume dosing when Hb <12.0 g/dL at a dose that is reduced by 2 steps.
Next dose adjustment review is 4 weeks after dose resumption and in 4-weekly intervals 
thereafter.
Dose Adjustment for Excessive Hematopoiesis
At any time during the Treatment Period:
If Hb increases by >2.0 g/dL within 4 weeks, the dose should be reduced by 1 dose step
Note: Only 1 dose reduction for excessive hematopoiesis is recommended within a period of 
4 weeks.  If a blood transfusion has been performed or a course of ESA rescue therapy has been 
administered within 2 weeks of meeting the criteria for excessive hematopoiesis, it is recommended 
not to perform a dose reduction for excessive hematopoiesis.


Sponsor: APEB
ISN/Protocol 1517-CL-0613
EudraCT number 2013-001497-16
- CONFIDENTIAL -
30 May 2017
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After a dose adjustment due to excessive hematopoiesis, the subject’s next dose adjustment review 
will occur 4 weeks later, and in 4-weekly intervals thereafter.
If the dose adjustment interval falls on a non-visit study week, the dose adjustment review should be 
performed at the next scheduled study visit.
Comparative Drug:
ESA: epoetin alfa or darbepoetin alfa
Subjects pretreated with epoetin:
Subjects pretreated with darbepoetin alfa:
Epoetin alfa (Eprex®)
Darbepoetin alfa (Aranesp®)
Mode of Administration:
IV or SC injection (both ESAs).
All administrations will be performed by the investigator or a qualified member of the site staff, by 
the subject themselves or caregiver, e.g. relative, if well trained and willing to self-administer.
Dose(s):
Subjects that are randomized to the ESA arm will receive their ESA at approximately the same 
average weekly dose the subject was on prior to randomization using the same mode of application 
(intravenous [IV] or subcutaneous [SC] injection).
During the treatment period, the active comparator drugs epoetin alfa (Eprex®) and darbepoetin alfa 
(Aranesp®) will be provided by the sponsor.  Dosing, dosing frequencies and dose adjustments should 
be in accordance with the UK SmPC for Eprex® and EU SmPC for Aranesp®.  The protocol-specified 
frequencies are once weekly, twice weekly or TIW for epoetin alfa; and once weekly or once every 
other week for darbepoetin alfa.  In addition, the protocol allows for administration of epoetin alfa 
once every other week and darbepoetin alfa once every 4 weeks.  These frequencies are only to be 
used in subjects on low ESA doses that do not fit into the normal frequencies of administration and if 
deemed clinically appropriate.  For PD subjects, darbepoetin dosing every 4 weeks is allowed.  For 
both ESAs the target of treatment is maintaining Hb in the range of 10.0 to 12.0 g/dL.  Contact the 
medical monitor if dose adjustments would lead to doses lower than 1000 IU epoetin once every other 
week or 10 µg darbepoetin once every 4 weeks.
Initial dose:
The initial ESA dose and frequency of administration are at the investigator's discretion provided the 
average weekly dose remains approximately the same as prior to randomization.  All subjects 
randomized to the ESA arm must receive their ESA dose according to the protocol-specified 
frequencies irrespective of their frequency of administration prior to randomization.
All dose adjustments are made based on Hb values using HemoCue®, a point-of-care device.
Rescue Therapy:
Rescue therapy guidelines are provided to optimize standardization of rescue therapy by investigators 
and to ensure safety of the individual study subjects.
1.
RBC Transfusion (for all subjects)
RBC transfusion is allowed if rapid correction of anemia is required to stabilize the patient’s 
condition or the investigator is of the opinion that the blood transfusion is a medical necessity.  Study 
treatment may continue during or after transfusion administration.
2.
ESA (only for subjects treated with roxadustat)
One course of rescue ESA is allowed.  If the investigator considers administration of ESA as a 
medical necessity, 1 course of rescue ESA may be initiated if the following criteria are met:

the Hb level has not responded adequately despite two or more roxadustat dose increases in the 
previous 8 weeks or the roxadustat dose has reached the maximum dose limit, and


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
the subject’s Hb level is < 9.0 g/dL (HemoCue®) as confirmed at 2 consecutive study visits, 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 rescue ESA (epoetin alfa for subjects treated with any epoetin prior to 
randomization; and darbepoetin alfa for subjects treated with darbepoetin alfa prior to randomization), 
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.  Prior to initiating ESA rescue 
therapy iron deficiency should be corrected (i.e. 100 ng/mL [220 pmol/L] ferritin and 20% TSAT). 
The subject may continue on study, however, the subject is not allowed to be administered both 
rescue ESA and roxadustat during the same time period.  The course of rescue ESA (i.e. the amount 
that may be administered) will be limited by duration of therapy and effect on Hb, including that 1 
course of treatment with rescue ESA will not exceed 4 weeks in duration, and that ESA rescue will be 
stopped as soon as Hb ≥9.0 g/dL as measured by HemoCue.  Treatment with roxadustat may be 
resumed as soon as possible after the following intervals:

At least 2 days after stop of epoetin alfa

At least 1 week after stop of darbepoetin alfa
If a subject requires a second course of rescue with ESAs, the subject must be discontinued from 
study treatment.  The subject will complete the EOT visits (EOT visit and EOT + 2 weeks visit) and 
EOS visit, and will continue to be followed up at a 6-monthly frequency for vital status, SAEs and 
cardiovascular and thromboembolic AEs until their projected date of completion or until consent 
withdrawn.
Doses:
The doses of rescue therapies are at investigator’s discretion.
Emergency Procedure:
Therapeutic Phlebotomy
If there are clinical concerns for a subject’s high Hb level, 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 electronic Case Report Form and source documents, and discussed with the study 
medical monitor.
Concomitant Medication Restrictions and/or Requirements:
Supplemental Iron
1.
Subjects receiving roxadustat
a.
Oral iron
For subjects receiving roxadustat, oral iron is recommended for supplementation to support 
erythropoiesis and as first-line treatment  for  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 1 h before or 1 h after oral iron.
b.
Intravenous iron
For subjects receiving roxadustat, IV iron supplementation is allowed if all of the following criteria 
are met:

The subject’s Hb level has not responded adequately to roxadustat following two consecutive 
dose increases or reached the maximum dose limit, and

The subject’s ferritin is <100 ng/mL (<220 pmol/L) or TSAT < 20%, or the subject is intolerant 
of oral iron therapy.


Sponsor: APEB
ISN/Protocol 1517-CL-0613
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- CONFIDENTIAL -
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Treatment with roxadustat should 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%. 
Serum ferritin and TSAT can be measured at any time after IV iron delivery at the discretion of the 
investigator.
2.
Subjects receiving epoetin alfa or darbepoetin alfa
For subjects treated with epoetin alfa or darbepoetin alfa, IV iron supplementation will be 
given according to standard of care.
Antihypertensive and Lipid-lowering Medication
To avoid confounding effects on study endpoints, changes to antihypertensive and lipid lowering 
medications should be minimized as much as possible, and made only if deemed medically necessary 
by the investigator.
Prohibited Medication
The following medications are prohibited during the period identified:
●
Any investigational drug: within 30 days or 5 half lives or limit set by national law (whichever is 
longer), prior to the initiation of screening until EOS.
●
Roxadustat or another hypoxia-inducible factor prolyl hydroxylase inhibitor: at any time prior to 
randomization.  After randomization any hypoxia-inducible factor prolyl hydroxylase inhibitor 
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 randomization onwards until EOS.
●
Dapsone in any dose amount, or chronic doses of acetaminophen/paracetamol >2.0 g/day, from 
randomization until EOS.
Use of herbal medicines is discouraged during the course of the study.
Duration of Treatment:
52 weeks to 104 weeks
Formal Stopping Rules
Subjects should be prematurely discontinued from study treatment for any of the following 
reasons:
●
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.
●
Subject no longer consents to participate in treatment phase of the study.
●
Subject receives an organ transplant
●
Subject randomized to roxadustat who requires a second course of ESA rescue therapy
If subjects have prematurely discontinued study treatment (and have taken at least 1 dose of study 
drug), they will continue to be followed up at a 6-monthly frequency for the subject’s vital status, 
SAEs and cardiovascular and thromboembolic AEs until their projected date of completion of 
follow-up period (i.e. projected EOS visit) or until consent withdrawn.
Subjects should be withdrawn from the study for any of the following reasons:
●
Subject no longer consents to participate in the study.
●
Subject is lost to follow-up despite reasonable efforts by the investigator to contact the subject.


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The sponsor may decide to prematurely stop the entire study, e.g. for safety considerations.
Endpoints for Evaluation:
Primary
There are 2 separate regionally based primary efficacy endpoints in this study, depending upon 
whether the data are being filed to support submission to the US FDA or to Ex-US health authorities, 
such as the EMA.
●
The EU (EMA) primary efficacy endpoint is change in Hb from baseline (BL) to the average 
level during the evaluation period (defined as week 28 until week 36), without having received 
rescue therapy (i.e. RBC transfusion for all subjects or ESA for subjects treated with roxadustat) 
within 6 weeks prior to and during this 8-week evaluation period.
●
The US (FDA) primary efficacy endpoint is change in Hb from BL to the average level during 
the evaluation period (defined as week 28 until week 52), regardless of rescue therapy.
Key Secondary
●
Hb response defined as mean Hb during weeks 28 to 36 within the target range of 10.0 to 
12.0 g/dL without having received rescue therapy within 6 weeks prior to and during this 8-week 
evaluation period.  
●
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) during day 1 to week 36 (monthly defined as a period of 
4 weeks).
●
Change from BL in Short Form 36 (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
Time to an increase in blood pressure: An increase from BL of ≥ 20 mm Hg systolic blood 
pressure (SBP) and SBP ≥ 170 mmHg or an increase from baseline of ≥15 mmHg diastolic 
blood pressure (DBP) and DBP ≥ 100 mmHg during weeks 1 to 36. 
Additional Secondary
Hb maintenance:
●
Hb response during weeks 28 and 36 regardless of use of rescue therapy.  Hb response defined as 
mean Hb during weeks 28 to 36 within the target range of 10.0 to 12.0 g/dL.
●
Hb change from BL to each postdosing time point. 
●
Hb level averaged over weeks 28 to 36, 44 to 52, and 96 to 104 without use of rescue therapy 
within 6 weeks prior to and during these 8-week evaluation periods.
●
Hb change from BL to the average Hb value of weeks 28 to 36, 44 to 52, and 96 to 104 
regardless of the use of rescue therapy.
●
Proportion of Hb values within 10.0 to 12.0 g/dL in weeks 28 to 36, 44 to 52, and 96 to 104 
without use of rescue therapy within 6 weeks prior to and during these 8-week evaluation 
periods.
Hospitalizations:
●
Occurrence (number) of hospitalizations (HD days - including overnight - are not counted as 
hospitalizations)
●
Number of days of hospitalization


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Rescue therapy use: 
●
Having received rescue therapy (composite of RBC transfusions (all subjects) and rescue ESA 
(roxadustat treated subjects only])
●
Having received RBC transfusions
●
Number of RBC packs per subject
●
Volume of RBC transfused per subject
Iron use: 
●
Having required IV 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)
●
Having required oral iron supplementation
●
Mean monthly oral iron (mg) use per subject during day 1 to week 36, weeks 37 to 52, and 
weeks 53-104 (monthly defined as a period of 4 weeks)
Changes in cholesterol levels, apolipoproteins:
●
Change from BL to each postdosing study visit in 
o
Total cholesterol
o
LDL/High-density Lipoprotein (HDL) ratio
o
Non-HDL cholesterol
o
Apolipoproteins A1 and B
o
ApoB/ApoA1 ratio
●
Occurrence of mean LDL cholesterol <100 mg/dL calculated over weeks 12 to 28
Blood pressure effect:
●
Occurrence of achieved antihypertensive treatment goal in CKD subjects (SBP <140 mmHg and 
DBP <90 mmHg) based on the mean SBP and mean DBP calculated over weeks 12 to 28
Health-related Quality of Life and European Quality of Life 5 Domain 5 Level:
●
Change from BL to the average value of weeks 12 to 28 in
o
SF-36 Physical Component Score
o
Anemia Subscale (“Additional Concerns”) of Functional Assessment of Cancer Therapy-
Anemia Score
o
Total Functional Assessment of Cancer Therapy-Anemia Score
o
European Quality of Life 5 Domain 5 Level visual analogue scale Score
●
Patients’ Global Impression of Change (qualitative assessment)
Hepcidin, Iron status, glycated hemoglobin:
●
Changes from BL to each study visit (when measured) in:
o
Serum hepcidin
o
Serum ferritin
o
TSAT
o
Glycated hemoglobin (HbA1c) level
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, and time to occurrence, of prespecified adjudicated cardiovascular and 
cerebrovascular events (will be reported separately). Various region-specific pooled analyses of 


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prespecified adjudicated cardiovascular and cerebrovascular events (such as major 
cardiovascular AEs [MACE, MACE+] and other events) will be conducted; these analyses will 
be detailed in region-specific pooled safety analysis plans.
Statistical Methods:
Sample Size Justification:
The study is sufficiently powered for both regionally-based primary efficacy endpoints.  
Approximately 750 subjects will be randomized to receive roxadustat or ESA in an open-label fashion 
in a 1:1 ratio.  Randomization will be stratified by the following five factors:

Previous ESA treatment (epoetin versus darbepoetin alfa)

Region (region A versus region B*)

History of cardiovascular, cerebrovascular or thromboembolic diseases (Yes versus No)

Average prescribed weekly ESA dose in last 4 weeks prior to randomization (≤200 IU/kg epoetin 
or ≤ 1 μg/kg darbepoetin alfa versus >200 IU/kg epoetin or > 1 μg/kg darbepoetin alfa)

Screening Hb value (≤11.0 g/dL versus >11.0 g/dL)
* Country assignment to region A and B will be determined based on health care system comparability.
EU (EMA)
Results from simulations of the EU primary efficacy endpoint in stable dialysis subjects suggest that 
dosing levels of ESA prior to randomization may impact Hb response.  Therefore, the EU primary 
analysis of this study will be tested both in the overall population and in the subgroup of patients 
defined as subjects with an average prescribed weekly epoetin or darbepoetin dose within the last 4 
weeks prior to randomization ≤ 200 IU/kg or ≤ 1 μg/kg respectively, following a parametric chain 
procedure (Millen et al., 2011; Spiessens et al, 2010).  The information fraction will be calculated at 
the time of database hard lock; it is defined as the number of subjects in the subgroup with respect to 
the number of subjects in the total study population.
Assuming that the Per Protocol Set (PPS) analysis will consist of 80% of the randomized subjects, 
750 randomized subjects will yield approximately 600 subjects in the PPS.  The overall 1-sided 
significance level (alpha) is fixed at 0.025 and the non-inferiority margin for the EU primary endpoint 
is set to 0.75 g/dL.  The overall alpha will be equally allocated to each of the 2 test populations.  If we 
assume an information fraction of 0.80, this rule will lead to a significance level of 0.0174. 
In this setting, 300 subjects for the roxadustat treatment group and 300 subjects for the ESA treatment 
group will provide 97% power to statistically demonstrate noninferiority of roxadustat versus ESA in 
the EU primary endpoint in both the total study population and the planned subgroup analysis, 
assuming a difference (roxadustat minus ESA) of -0.25 g/dL in the Hb change from BL and a 
standard deviation of 1.5 g/dL.  In the case that these assumptions do not hold across the overall 
population, the planned procedure can still allow for a successful conclusion for the subgroup.
US (FDA)
With 750 randomized subjects (Intention To Treat Set [ITT]), the study will provide at least 
99% power to demonstrate statistical noninferiority of roxadustat vs ESA in the primary endpoint for 
US submission.
Analysis Sets:
The following analysis sets are defined and will be used for the statistical analysis:

ITT: randomized subjects

Full Analysis Set (FAS): randomized subjects who received at least 1 dose of study drug and have 
at least 1 postdose Hb assessment

PPS: FAS subjects who received at least 12 weeks of study treatment with at least 1 postdose Hb 
assessment and without any criteria for PPS exclusion

Safety Analysis Set (SAF): subjects that received at least 1 dose of study drug


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Pharmacokinetic Analysis Set: SAF subjects with at least 1 quantifiable plasma concentration of 
roxadustat with dosing and sampling history recorded
Efficacy:
EU (EMA)
Primary Hypothesis
The Hb change from BL to the average Hb of weeks 28 to 36, without having received rescue therapy 
within 6 weeks prior to and during this 8-week evaluation period will be analyzed using a Mixed 
Model of Repeated Measurements (MMRM) with an unstructured covariance matrix.  The model will 
contain terms for treatment arm, baseline measurement, visit, visit x treatment arm and other 
stratification factors.  For subjects who require rescue therapy, the reported values after the initiation 
of rescue therapy will be set to missing for 6 weeks; the MMRM model will implicitly impute missing 
data via the within-patient correlation structure.
The primary analysis of this EU primary efficacy endpoint will be tested both in the overall 
population and in the subgroup of patients defined as subjects with an average prescribed weekly 
epoetin or darbepoetin alfa dose within the last 4 weeks prior to randomization ≤ 200 IU/kg or 
≤1 μg/kg, respectively, following a parametric chain procedure.
The 2 null hypotheses to be tested are:

HA0: Hb change from baseline in the roxadustat arm ≤ Hb change from baseline in the ESA arm 
minus 0.75 g/dL in the overall study population

HB0: Hb change from baseline in the roxadustat arm ≤ Hb change from baseline in the ESA arm 
minus 0.75 g/dL in the subgroup
The alternative hypotheses HA1 and HB1 are defined as the negation of the null hypotheses HA0 and 
HB0 respectively.  The information fraction will be calculated at the time of database hardlock as the 
number of subjects in the subgroup with respect to the number of subjects in the total study 
population.  The overall 1-sided significance level (alpha) is fixed as 0.025.  The overall alpha will be 
equally allocated to each of the 2 null hypotheses defined above.  In case of an information fraction of 
0.80, this rule will lead to significance level of 0.0174.  Following the parametric chain procedure, if 
at least 1 of both hypotheses is rejected at the significance level of 0.0174, the other 1 can be tested at 
a significance level of 0.025 while still strongly controlling the overall type I error.  The study will be 
successful for the EU primary efficacy endpoint if either of the null hypotheses is rejected.
The EU primary analysis will be tested on the PPS.  The analysis will be repeated on the FAS and ITT 
as secondary analyses.
US (FDA)
The Hb change from BL to the average Hb of weeks 28 to 52, regardless of rescue therapy, will be 
analyzed using a MMRM model with an unstructured covariance matrix.  The model will contain 
terms for treatment arm, baseline measurement, visit, visit x treatment arm, and other stratification 
factors. 
The null hypothesis to be tested for the US primary efficacy analysis is:

H0: Hb change from baseline in the roxadustat arm ≤ Hb change from baseline in the ESA arm 
minus 0.75 g/dL
The alternative hypothesis H1 is defined as the negation of the null hypothesis H0.  The overall 
1-sided significance level (alpha) is fixed as 0.025.  The study will be successful for the US primary 
endpoint if the null hypothesis is rejected.
The US primary analysis will be tested on the ITT.  The analysis will be repeated on the FAS and PPS 
as secondary analyses.
Secondary Hypotheses
Once a primary hypothesis has been rejected for the EU primary efficacy endpoint, the secondary 
endpoints will be tested as described below using a fixed sequence testing procedure.  These tests will 


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be performed only for the overall population in the case that the primary hypothesis was rejected for 
the overall study population.  If the EU primary analysis was not successful for the overall population, 
but only for the subgroup, then the tests will be performed only for the subgroup.
1.
Proportion of Hb responders in the average of weeks 28 to 36 (noninferiority of roxadustat 
versus ESA) without having received rescue therapy.  The non-inferiority margin for the 
difference between groups is 15%. 
2.
LDL cholesterol change from BL to the average of weeks 12 to 28 (superiority of roxadustat 
versus ESA)
3.
Monthly IV iron (mg) use per subject during weeks 1 to 36 (superiority of roxadustat vs ESA).
4.
SF-36 PF sub-score change from BL to the average of weeks 12 to 28 (noninferiority of 
roxadustat versus ESA).  The noninferiority 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 (noninferiority of 
roxadustat versus ESA).  The noninferiority 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 roxadustat 
versus ESA).  The noninferiority margin for the difference between groups is 1 mmHg.
7.
Time to an increase in blood pressure during weeks 1 to 36 (non-inferiority of roxadustat versus 
ESA).  The noninferiority 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 roxadustat versus 
ESA).
9.
Time to an increase in blood pressure during weeks 1 to 36 (superiority of roxadustat versus 
ESA). 
The EU primary analysis will be tested on the PPS for the noninferiority tests and the FAS for the 
superiority tests.
The analysis will be repeated using (a) the FAS and ITT for noninferiority tests and (b) the PPS and 
ITT for superiority tests as secondary analyses
Pharmacokinetics:
PK assessments will only be performed in subjects treated with roxadustat.
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 modeling.  When deemed necessary, data from this study may be 
combined with data from other studies.  Results will be reported in a separate population 
pharmacokinetic/pharmacodynamic modeling report.
Safety:

Safety analyses will be performed using the SAF.  Safety parameters include AEs, SAEs, 
laboratory parameters, vital signs, and ECG parameters. 

The number and percentage of subjects reporting (treatment-emergent) AEs and (treatment-
emergent) SAEs in each treatment group will be tabulated.  Descriptive statistics will be presented 
for laboratory, vital signs values and ECG parameters by visit and for the changes from BL to 
each visit. 

The statistical methods for analysis of adjudicated safety data will be detailed in a separate 
Statistical Analysis Plan.  The analysis of adjudicated safety data will be provided in a separate 
report.

Safety data and dosing decisions will be monitored on an ongoing basis. Ongoing review of safety 
data will be conducted by an independent DSMB.


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V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS
Flow Chart


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Table 1
Schedule of Assessments
Study Period:
Screening 
Period
Treatment Period
Follow-up Period
Unscheduled 
Visits
Poststudy 
Follow-upc
Visit/Week:
2-6 Weeksa
Day 
1b
Weekly
(Wks 1 to 8)
± 2 days
Every 2 Weeks 
(Wks 10 to 36)
± 2 days
Every 4 Weeks 
(Wks 40 to 100)
± 3 days
EOTc
(Week 
104)
± 3 days
EOT 
+ 2 wks
± 3 days
EOSc
(EOT + 4 
wks)
± 3 days
Every 6 
months until 
projected 
EOS
S1
S2
S3
Dialysis procedure
◄───────────────────────────────────────────────────────────────────────►
ESA pretreatment
◄─────┤
Written informed consent
X
Randomization
X
Eligibility Criteria
X
X
Demographics
X
Height, weight d
X
X
X
X
Wks 12, 24, 36
Wks 52, 76
X
X
O
Medical History
X
Physical Examination
X
X
Wks 12e, 24e, 36e
Wks, 52e, 76e
X
Xe
O
Blood pressuref, heart 
ratef, respiratory rateg
X
X
X
X
X
X
X
X
X
O
CBC with WBC diff, red 
cell indices and platelets
X
X
Wks 1, 2, 3, 
4, 8
Wks 12, 20, 28, 
36
Wk 44 
+ every other
8 wks
X
X
O
Hemoglobinh,i
X
X
X
X
X
X
O
HemoCue Assessmenti
X
X
X
X
O
Reticulocyte count and Hb 
in reticulocytes (CHr)
X
X
Wks 1, 2, 4,
6, 8
Wks 12, 16, 20, 
28, 36
Wk 44 
+ every other 
8 wks
X
X
O
12-lead ECG 
X
X
Wks 12, 24, 36
52, 76
X
O
Serum Chemistryj
X
X
Wks 4, 8
Wks 12, 20,
28, 36
Wk 44  
+ every other 
8 wks
X
X
X
O
Renal Ultrasound k
X
O
Liver Function Tests 
(LFTs) l
Wks 2, 6
Wk 16
O
Table continued on next page


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Study Period:
Screening 
Period
Treatment Period
Follow-up Period
Unscheduled 
Visits
Poststudy 
Follow-upc
Visit/Week:
2-6 Weeksa
Day 
1b
Weekly
(Wks 1 to 8)
± 2 days
Every 2 Weeks 
(Wks 10 to 36)
± 2 days
Every 4 Weeks 
(Wks 40 to 100)
± 3 days
EOTc
(Week 
104)
± 3 days
EOT 
+ 2 wks
± 3 days
EOSc
(EOT + 4 
wks)
± 3 days
Every 6 
months until 
projected 
EOS
S1
S2
S3
Serum Lipid Panelm
X
X
Wks 4, 8
Wks 12, 20, 28, 
36
Wks 44, 52, 68, 
84
X
X
O
Serum iron, ferritin, TIBC, 
TSATn
X
X
Wks 4, 8
Wks 12, 20, 28, 
36
Wk 44 
+ every other 
8 wks
X
X
O
HbA1c
X
X
Wk 12, 28, 36
Wks 44, 52, 60, 
84
X
X
O
Vitamin B12, folate
X
O
HIV, HBsAg, 
anti-HCV Antibody
X
O
Serum Pregnancy Test 
(HCG)o
X
Wks 12, 24, 36
Wks 48, 60, 72, 
84, 96
X
O
high sensitivity C-reactive 
protein (hs-CRP), hepcidin
X
Wk 4
Wks 12, 20, 36
Wk 52
X
X
Archival Serum Samples 
for Biomarkers
X
Wk 4
Wks 12, 20
Wks 52, 76
X
X
Blood Sample for PKp
Wks 2 to 8
QoL Questionnairesq
X
Wk 8
Wks 12, 28, 36
Wks 52, 76
X
Dialysater
Wks 2 to 8
Optional genotypings
O
Study Treatment: 
roxadustat dispensing OR 
ESA administrationt
├──────────────────────────────┤
O
Dose Adjustment Reviewu
X
X
X
O
AE and Concomitant 
Medication Recording
◄────────────────────────────────────────────────────────────────────────►
Procedure and non-drug 
Therapy Recording
◄────────────────────────────────────────────────────────────────────────►
Table continued on next page


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Study Period:
Screening 
Period
Treatment Period
Follow-up Period
Unscheduled 
Visits
Poststudy 
Follow-upc
Visit/Week:
2-6 Weeksa
Day 
1b
Weekly
(Wks 1 to 8)
± 2 days
Every 2 Weeks 
(Wks 10 to 36)
± 2 days
Every 4 Weeks 
(Wks 40 to 100)
± 3 days
EOTc
(Week 
104)
± 3 days
EOT 
+ 2 wks
± 3 days
EOSc
(EOT + 4 
wks)
± 3 days
Every 6 
months until 
projected 
EOS
S1
S2
S3
Vital status, SAEs, 
cardiovascular and 
thromboembolic AEs
X
S1/S2/S3=Screening visit 1, 2 and 3; EOT = End of Treatment; EOS = End of Study; Wk(s) = Week(s); X = mandatory test/assessment; O = optional test/assessment. In HD subjects 
all lab sampling is to be performed prior to or at initiation of the dialysis session.
Note: Instructions for roxadustat-treated subjects moving from Protocol v1.0 to Protocol v2.0 in terms of dosing are provided in Appendix 12.3
a 
Due to the requirement of 4-day separation between the screening Hb values, the screening period will last a minimum of 2 weeks approximately, but is allowed to be a maximum 
of 6 weeks.  Sites are recommended to schedule the 3 screening visits in the shortest time span possible.
b
Randomization and administration of the first dose of study drug (roxadustat or ESA) are to occur on day 1, which should correspond to a day when the subjects’ next dose of 
epoetin or darbepoetin alfa would have been administered.  In HD subjects only, postdialysis weight and postdialysis vital signs do not have to be completed prior to 
randomization and first study drug administration.
c 
In case of premature treatment discontinuation, the subject will complete the EOT visits (EOT visit and EOT + 2 weeks visit) and EOS visit.  Thereafter subjects who have taken 
at least 1 dose of study drug will continue to be followed up at a 6-monthly frequency for vital status, SAEs and cardiovascular and thromboembolic AEs until their projected date 
of completion of the follow-up period (i.e. projected EOS date) or until consent withdrawn.  No additional study visits will be required during the poststudy follow-up.
d
Height at first screening visit only; Weight is postdialysis weight in HD subjects.  For day 1 visit the postdialysis weight on the third screening visit is to be recorded in the 
Interactive Response System (IRS) for HD subjects.  Weight for PD subjects is the weight measured at site minus the abdominal fluid based on last filling.  For drug dispensing 
purposes (at visits after randomization), weight from the previous dialysis session may be used.
e
Targeted physical examination (e.g., respiratory and cardiovascular).
f
Blood pressure and heart rate measured singly during the screening period, and in triplicate at all other visits; in HD subjects both pre- and postdialysis.
g
Respiratory rate measured singly during screening period and all other visits; in HD subjects both pre- and postdialysis.
h
Separate Hb should be collected at all the visits where Complete Blood Count (CBC) is not collected; i.e. Hb at weeks 5, 6, 7, 10 until the end of the study.  It is recommended 
that the Hb assessments be performed on the same day of the patient’s dialysis schedule throughout the study.
i
If during an unscheduled visit hemoglobin needs to be assessed, this should always be done with the HemoCue AND a central laboratory hemoglobin assessment.
j
Serum chemistry includes LFTs.
k
Renal ultrasound examination can be performed at any time during the screening period.  Not required if results of a previous renal ultrasound (or other renal imaging modality 
such as CT scan or MRI providing a conclusive report on the kidney) within 12 weeks prior to randomization is available and ruling out renal cell carcinoma.
Footnotes continued on next page


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l
LFTs to be collected at further visits where serum chemistry is not collected.
m Fasting, whenever possible.
n
TSAT = [FeSat (Ferro Saturation = % Iron Saturation) measured by central lab and derived from iron and TIBC].
o Human chorionic gonadotropin (HCG); to be collected from female subjects of childbearing potential only.
p Only for subjects randomized to roxadustat at 6 time points over 1 to 3 visits.  At each PK visit, an additional sample will be collected for albumin and alpha-acidglycoprotein 
determination.
q Includes Short Form 36 (SF-36), Functional Assessment of Cancer Therapy-Anemia (FACT-An), European Quality of Life 5 Domain 5 Level (EQ-5D 5L) and Patients’ 
Global Impression of Change (PGIC).  PGIC will not be performed on day 1.  In HD subjects, the quality of life questionnaires are to be completed by the subject prior to any 
other assessment or at the latest at the start of dialysis session.  It is important that the physician does not discuss the status of the subject prior to completion of the 
questionnaires. In PD subjects the questionnaires are to be completed prior to any study assessment.
r
Only for continuous ambulatory peritoneal dialysis (CAPD) subjects randomized to roxadustat.  Sample to be withdrawn from the drainage bag after draining complete volume 
at the site and at the same visit as the PK blood samples (see footnote o).
s
Optional assessment and only for subjects randomized to roxadustat. If a separate (optional) informed consent form is signed by the subject, a sample can be collected after 
randomization, preferably on day 1.
t 
Dosing of epoetin alfa and darbepoetin alfa according to approved SmPC (Eprex® United Kingdom SmPC; Aranesp® European Union SmPC).  It is recommended that 
roxadustat is administered any time after completion of dialysis (if dosing is scheduled on a dialysis day).
u Subjects randomized to roxadustat: dose adjustment review from week 4 onward, and every 4 weeks thereafter until EOT (deviation from the 4-week period is allowed 
anytime during the study in case 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 study visit.  ESA dose adjustments should follow the SmPC.


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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 condition characterized by progressive loss of kidney 
function that is associated with increased risk for severe complications such as cardiovascular 
disease and premature death.  Importantly, all-cause mortality increases exponentially as CKD 
stages advance [Tonelli et al, 2006].  The average expected remaining lifetime of a dialysis 
patient in the US is 5.9 years, compared to 16.4 years for a patient who received a kidney 
transplant, and 25.2 years for aged-matched controls in the general population [USRDS, 2009].
The number of patients worldwide affected by CKD is growing continuously. Approximately 
13% of the US adult population, or 29 million individuals, are affected by CKD [Coresh et al, 
2007].  The unadjusted CKD prevalence in Europe is estimated to 5-11% [Zoccali et al, 2010].
Epidemiological surveys corroborate that the number of CKD patients who develop end-stage 
renal disease (ESRD) and warrant renal replacement therapy (kidney transplantation or 
dialysis) is increasing as well.  The US has 1 of the highest ESRD rates in the world with a 
reported ESRD prevalence that exceeded 1700 subjects per million in 2010, corresponding to a 
23% increase during the last ten-year period [USRDS, 2011].  In Europe, prevalence of renal 
replacement therapy increased from 480 to 807 patients per million during 1992–2005, 
[Zoccali et al, 2010].
The most frequent causes of ESRD are diabetic kidney disease, hypertension, 
glomerulo-nephritis and polycystic kidney disease. Age and ethnicity are other, non-modifiable, 
risk factors for ESRD.  Notably, individuals older than 75 years represent the most common age 
group in ESRD (1735 per million in the US in 2007).  The influence of ethnicity and risk for 
ESRD is illustrated by substantial differences in ESRD incidence rates across ethnical origins: 
998 per million for African Americans, whereas substantially lower for Asians/Pacific Islanders 
and Whites (396 and 273 per million, respectively) [USRDS, 2009].  The increased prevalence 
of type 2 diabetes combined with a steady rise in the expected average life span predict that the 
number of ESRD patients in the US will increase to 774,000 [USRDS, 2009] in 2020.
Treatment of ESRD varies widely across geographical regions and depends on available 
medical resources.  In the US there are approximately 570,000 ESRD patients, of whom 
370,000 are treated with hemodialysis (HD), 27,000 with peritoneal dialysis (PD), and 173,000 
had a functioning kidney transplant [USRDS, 2011].  Of note, more than 50% of the global 
dialysis patient population is treated in only five countries – the US, Japan, China, Brazil and 
Germany.  The large variability in ESRD prevalence in these countries, ranging from as little 
as 150 patients per million in China to 2370 patients per million in Japan, exemplifies a
marked geographical difference in terms of dialysis practice pattern.
1.1.2
Anemia Associated with CKD
Anemia is a frequently occurring complication in CKD with multiple etiologies.  The 
principal cause of renal anemia is insufficient production of erythropoietin (EPO), a hormone 


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mainly produced in the kidneys that stimulates the synthesis of red blood cells.  In addition, 
CKD-related anemia develops due to impaired ability to absorb iron from the gastrointestinal 
tract as well as to utilize existing iron pools to generate new red blood cells.
Anemia may arise at an early stage 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 
dialysis [Coresh et al, 2007; Go et al, 2004]. Over 90% of patients undergoing dialysis are 
anemic.  Quantitatively, 50.1% of incident dialysis patients had hemoglobin (Hb) levels 
below 10 g/dL and approximately 28% had Hb levels below 9 g/dL [USRDS, 2003].
European surveys on anemia prevalence in CKD corroborate with USRDS data.  A 
prospective study of 403 predialysis patients indicated 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].  In 
another large retrospective anemia care study of 6271 incident dialysis patients, the average 
predialysis Hb level was 10.3 g/dL whereas 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 consequence of anemia on organ function is reduced tissue delivery of 
oxygen, it affects almost every organ system.
Anemia contributes to the excess morbidity and mortality in CKD, and the severity of anemia 
correlates directly with the risk of hospitalization and cardiovascular disease in this population 
[Collins et al, 1998].  Patients with the lowest Hb levels have the poorest outcomes, as was 
emphasized in the post-hoc analysis of mortality by Hb quintiles for the Normal Hematocrit 
and Correction of Hemoglobin (NHCH) and Outcomes in Renal Insufficiency (CHOIR) 
studies in the Food and Drug Administration (FDA) briefing document for the October 2007 
Cardiovascular and Renal Advisory Committee [Unger, 2007]. These results are consistent 
with USRDS registry data which demonstrated that all-cause mortality between 1993-1996 
stratified by Hb level showed significantly higher first-year death rates in patients with Hb 
levels <9 g/dL and 9 to <10 g/dL, compared to 11 to <12 g/dL.  The relative risk for patients 
with Hb <9 g/dL compared to with Hb >12 g/dL are more than 2-fold for all-cause mortality 
[USRDS, 2002] and 1.26 for cardiovascular hospitalization [USRDS, 2001].
Multiple studies have shown that treatment of anemia reduces the need for blood transfusions 
and improves health-related quality of life (HRQoL) [National Kidney Foundation KDOQI, 
2007].
1.1.3
Treatment of Anemia
Erythropoiesis-stimulating agents (ESAs) in combination with iron supplementation is a 
widely accepted approach for treatment of anemia in CKD patients who are not resistant to 
ESAs and in whom iron monotherapy is insufficient to maintain Hb levels within the 
recommended target range. For this purpose, parenteral administration of exogenous 
recombinant human EPO (epoetin alfa or beta) or pegylated analogues is an established 
practice pattern [Eschbach et al, 1987; Winearls et al, 1986; US Recombinant Human 


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Erythropoietin Predialysis Study Group, 1991], despite the documented safety risks such as 
hypertension, thrombosis and cerebrovascular events.  These risks have been partially linked 
to supraphysiologic plasma EPO levels resulting from recombinant ESA therapy.
Anemia treatment in CKD and ESRD improves quality of life (QoL), functional well-being 
and physical performance, yet several studies in these populations 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. 866-76) of ESRD patients who received higher ESA 
doses.  Additionally, ESA therapy for anemia in ESRD patients on HD usually requires 
concomitant intravenous (IV) iron supplementation, while IV iron use is not free of risk in 
such patients.
There is currently an unmet medical need for an oral treatment that will correct anemia in 
CKD nondialysis and dialysis patients to a target Hb level that is safe and well tolerated 
without a supraphysiological rise in serum EPO concentrations.  Roxadustat is an oral 
medication with a new mechanism of action distinct from ESA that could potentially address 
all these requirements and which may translate into an improved safety profile.
1.2
Nonclinical 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 3 oxygen-sensitive isoforms (HIF-1, HIF-2and 
HIF-3), and a constitutively expressed HIF-1subunit, with each heterodimeric isoform 
responsible for the induction of specific sets of genes [Greijer et al, 2005; Hu et al, 2003].  
For example, HIF-1has been shown to regulate vascular endothelial growth factor 
expression [Gray et al, 2005; 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].


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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 motif found within all HIF target genes, termed the hypoxia response 
element, and in cooperation with other co-activators initiates de novo transcription.  One of 
the most sensitive and well-studied HIF-responsive genes is the EPO gene. Increased 
transcription of the EPO gene leads to increased circulating levels of EPO, which acts at sites 
of erythropoiesis to enhance the differentiation and proliferation of red blood cell (RBC) 
precursors.
Although HIF-isoforms are constitutively produced, their accumulation under normoxic 
conditions is prevented by recruitment and binding by the Von Hippel-Lindau protein, which 
targets HIF-isoforms for degradation through the ubiquitin-proteasome pathway.  The 
molecular mechanism for oxygen-dependent degradation of HIF-is based on the 
hydroxylation of specific proline residues, as catalyzed by a family of HIF prolyl 
hydroxylases (HIF-PH) that utilize molecular oxygen as the substrate for hydroxylation.  
Thus, HIF-PH constitutes the body’s main oxygen sensor by regulating the prevalence and 
activity of nuclear HIF protein.  Under hypoxic conditions, HIF-PHs are inactive and lead to 
initiation of the HIF-responsive transcriptional cascade [Wang et al, 1995; Semenza, 1998].
Roxadustat (code names FG4592 or ASP1517) is a potent and reversible HIF-PH inhibitor 
that transiently induces HIF stabilization and leads to a functional HIF transcriptional 
response that mimics the erythropoietic response associated with exposure to intermittent 
hypoxia.  HIF induces expression of EPO, as well as the EPO receptor and proteins that 
promote iron absorption and recycling [Peyssonnaux et al, 2008].  Thus, roxadustat 
pharmacologically stimulates erythropoiesis via the HIF pathway and in a manner consistent 
with the body’s normal homeostatic response to anemia, but under normoxic conditions.
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 


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mediators.  Because HIF-PH inhibitors such as roxadustat alter expression not only of the EPO 
gene but also of genes regulating iron metabolism, it is postulated that roxadustat may be
effective in treating these anemias as well [Langsetmo et al, 2005].
Chronic hypoxia and intermittent hypoxia induce different sets of genes associated with HIF 
transcriptional activity, presumably because intermittent stimulation allows the restoration of 
HIF degradation, turnover, and inactivation.  Transient activation of HIF thereby precludes 
sustained gene expression and the induction of genes that are expressed late after HIF 
activation, as well as expression of additional genes that are secondary to activation of 
HIF-dependent genes.  Both nonclinical and clinical studies of roxadustat have successfully 
used the intermittent dosing paradigm to induce selective erythropoiesis and to optimize the 
Hb dose response.  Furthermore, roxadustat was selected for development over other 
HIF-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.
These characteristics result in several potential advantages over ESAs beyond the convenience 
of oral therapy. These potential advantages include:
●
Increase in the number of EPO receptors in the bone marrow
●
Improved iron metabolism and bioavailability
●
Effective erythropoiesis at non-supraphysiologic plasma EPO levels (10- to 20-fold 
lower than with parenteral ESA therapy)
●
Absence of hypertensive effect
●
Effective erythropoiesis in the presence of inflammation
●
Mitigation of thromboembolic risk 
●
Improvement in lipid profile
1.2.2
Clinical Experience with Roxadustat
Roxadustat is currently being studied in dialysis and nondialysis CKD subjects with anemia.  
Numerous Phase 1 and 2 clinical studies have been completed, in the US, Europe and Asia.  
Information from these studies is provided in the most recent version of the Investigator’s 
Brochure (IB). As of 07 Sep 2014, an estimated total of 1485 subjects have been exposed to 
roxadustat in the clinical development program, comprising 571 healthy subjects and an 
estimated 483 subjects with nondialysis CKD and 431 subjects with dialysis CKD.  In 
completed studies, subjects with CKD have received up to 24 weeks of roxadustat, in doses 
of up to 3.0 mg/kg.  In completed Phase 1 studies, healthy subjects received single doses of 
roxadustat up to 4.0 mg/kg and repeat doses up to 3.75 mg/kg 3 times a week for 4 weeks.  In 
a completed thorough QT study in healthy subjects, single doses up to 5 mg/kg were 
administered, without evidence of QT prolongation.


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The clinical data collected thus far suggest that roxadustat is generally safe and well tolerated 
in healthy adult subjects, and in dialysis and nondialysis CKD subjects with anemia who 
have been treated in the completed and ongoing studies.
1.2.2.1 Pharmacokinetics and Pharmacodynamics
The pharmacokinetics (PK) and pharmacodynamics of roxadustat were characterized in studies 
in healthy subjects and in dialysis and nondialysis CKD subjects.  Roxadustat showed 
generally dose proportional PK (except at the lowest dose of 0.3 mg/kg); t1/2 was 12 to 14 h in 
healthy subjects, and 15 to 19 h in dialysis subjects (after single doses of 1 and 2 mg/kg).  The 
exposure was higher in dialysis subjects compared to healthy subjects. Roxadustat can be 
administered before or after dialysis, since the PK of roxadustat was not significantly altered 
when administered prior to the start of dialysis compared with after dialysis 
[Study FGCL-4592-039].
A relative bioavailability study was conducted in 24 healthy 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 2 formulations.
With an intermittent dose regimen of once weekly (QW), twice weekly (BIW) or 3 times 
weekly (TIW), no or limited accumulation in mean area under the plasma concentration curve 
(AUC) or maximum concentration (Cmax) was observed.  Furthermore no evidence was found 
for time-dependent PK (no auto-induction or inhibition).  Roxadustat is highly protein bound 
and the PK of roxadustat is not affected by dialysis.  Metabolites found in urine suggested 
phase 2 metabolism as the major metabolic pathway.  In plasma, parent roxadustat is the main 
component.  The inhibitory potential of roxadustat on cytochrome P450 (CYP) enzymes, based 
on in vitro studies is limited, and the lowest inhibition constant value was observed for CYP 
2C8 (16 μM). In a clinical drug-drug interaction study with rosiglitazone, a probe drug for 
CYP 2C8, roxadustat did not show any inhibitory potential on CYP 2C8 in vivo.
Additional drug-drug interaction studies were performed with statins and phosphate binders.  
Roxadustat increases the AUCinf of simvastatin 1.9-fold; of rosuvastatin 2.9-fold; and of 
atorvastatin 2.0-fold.  The AUCinf of roxadustat is decreased 2.9-fold and 1.8-fold, 
respectively, by simultaneous administration with the phosphate-binders sevelamer carbonate 
and calcium acetate.  Administration of roxadustat at least 1 h before or 1 h after the 
phosphate binder minimized the interactions.
In healthy adult male subjects (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 level (starting from single doses of 0.3 mg/kg), increases in reticulocytes 
(starting from doses of 2 mg/kg), and Hb responses (starting at 3 mg/kg).  The mean peak 
level of plasma EPO following the day 26 dose of 2.0 mg/kg TIW (the high therapeutic dose 
studied) was 326.3 ± 197.0 mIU/mL.
In pharmacodynamic studies conducted with roxadustat in CKD subjects not on dialysis 
(Study FGCL-4592-017), the mean maximum EPO increase from baseline (BL) ranged from 


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82-443 mIU/mL 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 predialysis and postdialysis.  These increases in endogenous EPO 
were transient and the effect disappeared within approximately 48 h.
In contrast, EPO levels associated with therapeutic ESA dosing range from 1,500 to over 
10000 mIU/mL [Besarab et al, 2009].  In a clinical study with dialysis subjects, the reported 
mean administered individual ESA dose was 8000 IU, which would correspond to plasma EPO 
Cmax levels exceeding 3000 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 subjects.  In contrast to the classical paradigm suggesting 
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 from baseline, 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 Short 
Form 36 (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 nondialysis CKD 
subjects.  Dosing frequency reduction, once Hb correction is achieved, appears to be feasible 
to maintain Hb in the target range.


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A total of 197 ESRD patients undergoing dialysis have received either single or multiple 
roxadustat doses for up to 19 weeks.  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). I n 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 resulted in 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 in roxadustat treatment arms (combined) over a 19-week period.  The 
roxadustat dose requirement for Hb maintenance was mostly between 0.7 mg/kg to 2.0 mg/kg 
in normoresponder subjects, with occasional subjects requiring doses up to 3.0 mg/kg TIW.  
In contrast, the Hb levels in the epoetin alfa control group appeared to decline gradually over 
time despite steady epoetin alfa doses, as IV iron supplementation was not permitted.  In the 
present study, in which IV iron supplementation is prohibited, roxadustat treatment resulted 
in increased levels of serum iron at the end of treatment compared with baseline in the 
6-week treatment arms, whereas serum iron levels decreased from BL in subjects treated with 
epoetin alfa reticulocyte Hb content was better maintained in the pooled roxadustat treatment 
arm than in the pooled epoetin alfa arm, suggesting that functional iron deficiency does not 
occur when treating with roxadustat unaccompanied by IV iron.  This finding is consistent 
with the different mechanism(s) of action of roxadustat and epoetin alfa.
For subjects treated for 19 weeks, the mean corpuscular volume (MCV) level with roxadustat 
treatment was slightly elevated at 2 weeks and was maintained during the study, whereas 
MCV levels for epoetin alfa-treated subjects decreased from BL during study treatment.  This 
suggests roxadustat may also treat iron deficiency anemia by increasing iron availability 
within the subject.
Serum hepcidin, a master regulating hormone of iron metabolism that is generally increased 
with inflammation and is a major contributor to lack of availability of iron for erythropoiesis, 
was reversibly suppressed during roxadustat treatment, thus facilitating oral absorption of 
iron and mobilization of iron for erythropoiesis.
Sixty incident dialysis patients (HD and PD) without ESA treatment have been enrolled in 
the FGCL-4592-053 study assessing the impact of different iron supplementation regimens 
on the efficacy of roxadustat.  All patients received tiered, weight-based roxadustat doses 
TIW, for a duration of 12 weeks: 12 each with no-iron, oral iron, and IV iron and 12 in the 
PD treatment arm, and 12 in a confirmatory arm with no iron supplementation.  There was an 
overall mean maximum Hb increase from baseline of 3.2 g/dL over the 12-week treatment. 


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After the first 4 weeks of treatment (Weeks 2-5), over 50% of subjects achieved an overall 
mean Hb change from BL of at least 1 g/dL.  This proportion increased to almost 80% after 
8 weeks of treatment (Weeks 6-9) and this percentage increased to over 90% by 12 weeks of 
treatment.  Furthermore, it was noted that subjects with lower BL Hb levels were more 
responsive to roxadustat and able to achieve a higher maximum Hb increase than those with 
higher BL Hb values.  The magnitude of maximum Hb increase is greater when the treatment 
of roxadustat is accompanied by iron than without iron.  However, in contrast to ESA where 
IV iron is essential and that ferritin ≥100 ng/mL (≥220 pmol/L) and transferrin saturation 
(TSAT) ≥20% are required for ESA treatment (Macdougall 1996, EU Summary of Product 
Characteristics [SmPC] Eprex®), oral iron supplementation is as effective as IV iron 
supplementation with roxadustat which is effective when ferritin ≥50 ng/mL (≥110 pmol/L) 
and TSAT ≥10% when correcting anemia in dialysis patients.  However, baseline TSAT 
does not seem to influence the maximal achievable rise in Hb level.
Summary
In summary, roxadustat is an orally active HIF-PH inhibitor with potent erythropoietic 
effects.  Roxadustat administration in anemic CKD patients results in intermittent activation 
of HIF, a rise in endogenous serum EPO level (although of lower concentrations relative to 
ESA therapy), and a dose-dependent stimulation of erythropoiesis.  Overall, this suggests that 
roxadustat promotes a coordinated erythropoiesis via mechanisms distinct from ESA therapy.  
Available clinical data support that roxadustat is generally safe and well tolerated in healthy 
adult subjects, and in dialysis and nondialysis CKD subjects with anemia.
1.2.3
Clinical Experience with Epoetin alfa
The comparative drug epoetin alfa Eprex® (Janssen-Cilag) is approved since 1995.  One of 
the treatment approved indications is treatment of anemia associated with chronic renal 
failure in pediatric and adult patients on HD and adult patients on PD.
The pharmacodynamics of erythropoietin is well known and described in the literature.
After IV administration of epoetin, the typical pharmacodynamics profile shows an increase 
in reticulocytes count within the first 2 weeks followed by an increase in the red blood cell 
level as manifested by haematocrit or Hb determinations within 2 to 6 weeks.  After single 
subcutaneous (SC) application an increase in reticulocyte count within 3-4 days with a peak 
around day 8-11 and a return to BL by day 22 has been described [Ramakrishan et al. 2004; 
Cheung et al 1998].  A linear relationship between reticulocyte area under the plasma 
concentration curve and epoetin exposure has been described for single doses up to 
1800 IU/kg [Cheung et al, 1998].  There is high interindividual variability in the reticulocyte 
response to epoetin.
Thirteen clinical studies were conducted with epoetin alfa, involving IV administration to a 
total of 1010 adult anemic patients on dialysis for 986 patient-years.  In the 3 largest of these 
clinical studies, the median maintenance dose necessary to maintain the hematocrit between 
30% to 36% was approximately 75 Units/kg TIW.  In the U.S. multicenter phase 3 study,
approximately 65% of the patients required doses of 100 Units/kg TIW, or less, to maintain 


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their hematocrit at approximately 35%.  Almost 10% of patients required a dose of 
25 Units/kg, or less, and approximately 10% required a dose of more than 200 Units/kg TIW 
to maintain their hematocrit at this level.  In a 26 week, double-blind, placebo-controlled 
study, 118 anemic dialysis patients with an average Hb of approximately 7 g/dL were 
randomized to either PROCRIT® or placebo.  By the end of the study, average Hb increased 
to approximately 11 g/dL in the PROCRIT®-treated patients and remained unchanged in 
patients receiving placebo.  PROCRIT®-treated patients experienced improvements in 
exercise tolerance and patient-reported physical functioning at month 2 that was maintained 
throughout the study.
A multicenter unit dose study was also conducted in 119 patients receiving PD who 
self-administered epoetin alfa subcutaneously for approximately 109 patient-years of 
experience.  Patients responded to epoetin alfa administered SC in a manner similar to 
patients receiving IV administration [Procrit® Prescribing Information].
1.2.4
Clinical Experience with Darbepoetin alfa
The comparative drug darbepoetin alfa Aranesp® is approved since 2001 in the EU for the 
treatment of anemia associated with CKD in adults and pediatric patients.  It is a commonly 
used ESA in Europe to treat anemic nondialysis CKD patients and has demonstrated its 
ability to correct and maintain Hb in several controlled randomized studies.
Two exploratory dose- and schedule-finding studies (NESP-960245 and NESP-960246) 
investigated the effects of darbepoetin alfa for correction of anemia in HD and PD subjects 
by IV and 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 independent of the schedule (once or 3 
times weekly).  At 2 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 (1 g/dL).  Based 
on the results of these studies it was concluded that 0.45 to 0.75μg/kg of darbepoetin alfa 
administered once weekly IV or SC is the most appropriate starting dose for treatment of 
anemia in CKD [Macdougall et al, 2003].
The PK studies showed that darbepoetin alfa has a slower clearance and a significantly longer 
terminal half-life in CKD subjects compared to recombinant human EPO (r-HuEPO).  There 
was no evidence of accumulation of darbepoetin alfa over time.  There are no special 
precautions for use based on the PK data, although darbepoetin alfa should be used with 
caution in patients with acute hepatic failure, as the liver is a likely a route for drug 
elimination.
The 2 multi-center randomized open-label studies explored the correction of anemia in 
subjects on dialysis (NESP-980211) or predialysis (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 BL and a Hb concentration of 
≥11.0 g/dL during the initial 24 weeks of treatment).  The selected starting dose was 
0.45μg/kg once weekly for darbepoetin alfa as suggested by the exploratory dose finding 


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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 3 times weekly) [Locatelli et al, 2001; EMEA, 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 as such eligible for long-term efficacy and 
safety.
In the second pivotal correction of anemia study (NESP-980211, US trial) subjects were on 
dialysis (mainly HD) 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 study.
Two pivotal phase 3 studies (NESP-970200 conducted in Europe and Australia, study 
duration 52 weeks; and NESP-980117 conducted in US and Canada, study duration 
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% confidence interval (CI) for the difference in 
mean change in Hb (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 1 uncontrolled long-term safety study demonstrated that darbepoetin alfa once 
weekly/once every 2 weeks by IV or SC route, is safe and effective in maintaining Hb in 
subjects with CKD undergoing dialysis.  Data from a long-term safety study of darbepoetin 
alfa in subjects who had completed 1 year of treatment on a previous darbepoetin alfa study 
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, Aranesp 2004].
Data from Study 20010184 "Trial to Reduce Cardiovascular Events with Aranesp® Therapy" 
(TREAT) demonstrated that cardiovascular or death events occurred in 632 subjects assigned 
to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. 
placebo, 1.05; 95% CI, 0.94 to 1.17; p = 0.41). Death or ESRD occurred in 652 subjects 
assigned to darbepoetin alfa and 618 subjects assigned to placebo (hazard ratio, 1.06; 95% CI, 
0.95 to 1.19; p = 0.29).  Fatal or nonfatal stroke occurred in 101 subjects assigned to 
darbepoetin alfa and 53 subjects assigned to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 
2.68; p<0.001).  Red-cell transfusions were administered to 297 patients assigned to 
darbepoetin alfa and 496 subjects assigned to placebo (p<0.001).


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Death or ESRD occurred in 652 subjects in the darbepoetin alfa group (32.4%) and in 
618 subjects in the placebo group (30.5%) (hazard ratio for darbepoetin alfa vs. placebo, 
1.06; 95% CI, 0.95 to 1.19; P = 0.29).  ESRD occurred in 338 subjects in the darbepoetin alfa 
group (16.8%) and in 330 subjects assigned to placebo (16.3%) (hazard ratio,1.02; 95% CI, 
0.87 to 1.18; P = 0.83).
1.3
Summary of Key Safety Information for Study Drugs
1.3.1
Roxadustat (Test Drug)
The overall frequency and type of treatment-emergent adverse events (TEAEs) and serious 
TEAEs observed in the clinical studies thus far generally reflect events that would be 
expected to occur in the dialysis and nondialysis CKD subject populations, and have not 
revealed any particular safety concern.  The most commonly reported TEAEs (≥4% and ≥1% 
above placebo rate) in healthy subjects were headache and dizziness.  In the pooled data for 
dialysis and nondialysis CKD, there were no TEAEs reported for 10% or more subjects 
treated with roxadustat.  TEAEs (≥5% and ≥1% above placebo rate) in CKD subjects not on 
dialysis were diarrhea, nausea, nasopharyngitis, peripheral edema, hyperkalemia, headache 
and hypertension.  TEAEs reported for ≥3%) of CKD subjects on dialysis were diarrhea, 
nausea, hypertension and upper respiratory tract infection.  The only expected nonserious 
adverse drug reaction is heart rate increase.
Safety analyses did not reveal any association between the rates of occurrence of 
cardiovascular events with roxadustat, or any effect on adverse event (AE) rates related to 
either increasing Hb levels or on the rate of change of Hb levels.
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.  However, 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 clinical phase 2 development 
program, the majority of which have been associated with gallstones or biliary sludge; 1 of 
which was due to a pancreatic duct stricture and another case had multiple risk factors for 
pancreatitis.  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, is well defined in the 
literature.
For further information please refer to the most recent version of the IB.


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1.3.2
Epoetin alfa (Comparative Drug)
In the studies conducted for the U.S. approval of epoetin alfa in adult patients on dialysis 
(more than 567 patients), the incidence (number of events per patient-year) of the most 
frequently reported AEs were: hypertension (0.75), headache (0.40), tachycardia (0.31), 
nausea/vomiting (0.26), clotted vascular access (0.25), shortness of breath (0.14), 
hyperkalemia (0.11), and diarrhea (0.11).  Other reported events occurred at a rate of less 
than 0.10 events per patient per year [Procrit Prescribing Information].
Events reported to have occurred within several hours of administration of epoetin alfa were 
rare, mild, and transient, and included injection site stinging in dialysis patients and flu-like 
symptoms such as arthralgias and myalgias.
AEs observed during post marketing experience included an increased incidence of 
thrombotic vascular events (TVEs) in patients receiving ESAs including epoetin alfa.  These 
include venous and arterial thrombosis and embolism (including some with fatal outcomes), 
such as deep venous thrombosis, pulmonary emboli, retinal thrombosis and myocardial 
infarction.  Additionally, cerebrovascular events (including cerebral infarction, cerebral 
haemorrhage and transient ischaemic attacks) have been reported.
A warning on possible cross reactivity of epoetin antibodies with different epoetins and to a 
number of adverse drug reactions was added in the SmPC.  There are no known clinically 
significant drug interactions but the effect of epoetin alfa may be potentiated by the 
simultaneous therapeutic administration of a haematinic agent such as ferrous sulphate when 
a deficiency state exists.  Drugs that decrease erythropoiesis may decrease the response to 
epoetin alfa.  For more details please refer to the Eprex® SmPC.
More recently 2 large prospective randomized controlled studies have raised questions about 
the appropriate management of anemia with epoetin in CKD and ESRD patients.  The 
Normal Hematocrit Study (NHS), a randomized, open-label study of 1265 patients with CKD 
on dialysis with documented evidence of congestive heart failure or ischemic heart disease, 
was designed to test the hypothesis that a higher target hematocrit would result in improved 
outcomes compared with a lower target hematocrit.  In this study, subjects were randomized 
to epoetin alfa treatment targeted to a maintenance Hb of either 14 ± 1 g/dL or 10 ± 1 g/dL.  
The study was terminated early with adverse safety findings of higher mortality in the high 
hematocrit target group.  Higher mortality (35% vs. 29%) was observed for the subjects 
randomized to target Hb of 14 g/dL compared to the subjects randomized to target Hb of 
10 g/dL.  For all-cause mortality, the HR was 1.27; (95% CI 1.04, 1.54; p = 0.018).  The 
incidence of nonfatal myocardial infarction, vascular access thrombosis, and other thrombotic 
events was also higher in the group randomized to a target Hb of 14 g/dL.
Similar safety findings were noted in the CHOIR study, a randomized, prospective study 
conducted in 1432 patients with anemia due to CKD who were not undergoing dialysis and 
who had not previously received epoetin alfa therapy.  Patients randomized to epoetin alfa 
treatment targeting a maintenance Hb concentration of either 13.5 g/dL or 11.3 g/dL.  The 
study was terminated early with adverse safety findings.  A major cardiovascular event (death, 
myocardial infarction, stroke, or hospitalization for congestive heart failure) occurred in 125 


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of the 715 subjects (18%) in the higher Hb group compared to 97 of the 717 subjects (14%) 
in the lower Hb group [hazard ratio (HR) 1.34, 95% CI: 1.03, 1.74; p = 0.03].
Finally, the outcome of the CREATE study [Drüeke, 2006] which assessed the efficacy and 
safety of treatment of anemic nondialysis patients using epoetin beta at two different Hb 
target ranges led to similar conclusions.
The EMEA’s Committee for Medicinal Products for Human Use (CHMP) and its 
Pharmacovigilance Working Party concluded that the benefits of the ESAs including epoetin 
alfa continue to outweigh their risks in the approved indications.  However, the CHMP 
recommended changes to the product information, and in February 2008 the European 
Commission made the final decision to amend the SmPCs of all ESAs.  The reported risk of 
TVEs should be carefully weighed against the benefits to be derived from treatment with 
epoetin alfa, particularly in patients with pre-existing risk factors.  In all patients, Hb 
concentrations should be closely monitored due to a potentially increased risk of 
thromboembolic events and fatal outcomes when patients are exposed to Hb concentrations 
above the range for the indication of use (10-12 g/dL in patients with chronic renal failure).  
For more details please refer to the Eprex® SmPC.
1.3.3
Darbepoetin alfa (Comparative Drug)
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 2 
treatment groups – darbepoetin alfa and r-HuEPO. The majority of AEs were due to the 
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 heart rate 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 IV or SC.  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.  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 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 CHMP regarding the assessment of outcome of the TREAT study in March 2010, 


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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, section 2, "Before you use Aranesp®" was updated to align it with the SmPC, 
reflecting the concern that elevated Hb concentrations could increase the risk of myocardial 
infarction, stroke and death [EMEA, Aranesp 2004].  For more details please refer to the 
Aranesp® SmPC.
1.4
Risk-Benefit Assessment
The primary expected benefit of roxadustat is maintenance of Hb level within the 
recommended target range in subjects converted from ESA-based anemia treatment.  Further, 
roxadustat may reduce anemia-related symptoms and signs, increase QoL, and reduce the 
need for IV iron therapy.  Additional benefits include absence of a rise in blood pressure that 
is associated with ESA therapy, and a reduction in serum cholesterol level.  Roxadustat is 
expected to be at least as safe as ESAs, and current data on surrogate outcomes suggest that 
cardiovascular risk may be lower than with ESAs.
An established dose adjustment algorithm, similar to the 1 used in phase 2 studies, will be 
applied for optimal roxadustat dose titration strategies.  This allows correction and 
maintenance of Hb levels to the appropriate target range and facilitates close monitoring of 
Hb fluctuations over time.
Roxadustat doses may be held and the use of therapeutic phlebotomy is allowed in the event 
of clinical concerns for a subject’s high Hb level.  Per protocol, rules for the use of 
supplemental iron (oral or IV) and rescue treatments with epoetin alfa or darbepoetin alfa 
(roxadustat treated subjects only) and red blood cell transfusions are in place to assure subject 
safety in case of insufficient response to roxadustat treatment and/or acute need for correction 
of anemia.
In PK studies with roxadustat there was no evidence of drug accumulation with the proposed 
clinical regimen of 3 times weekly dosing.  The overall frequency and nature of AEs and 
serious AEs (SAEs) observed in clinical studies generally reflect events what would be 
expected to occur in the CKD population (dialysis and nondialysis), 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 
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.


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As it is anticipated that other multivalent cation-containing drugs and mineral supplements 
(e.g., iron, calcium, magnesium, aluminum), sucralfate or magnesium- or aluminum-
containing antacids would produce a similar interaction, the study protocol includes the 
advice that roxadustat be taken separately from these drugs.
Epoetin alfa and darbepoetin alfa have been chosen as comparators to adequately assess the 
efficacy, safety and benefit of achieving Hb response and maintenance in anemic subjects 
treated with roxadustat.  These are commonly used ESAs in Europe for the treatment of 
anemia of ESRD, and have demonstrated their ability to correct and maintain Hb levels in 
this target population in several randomized controlled studies.  The rules for dose adjustment 
and for events of excessive hematopoiesis in the present study will follow their approved 
posology.  In case of insufficient response to epoetin alfa and/or darbepoetin alfa, rules for 
RBC transfusions are in place in order to assure safety of the affected study subjects.
The safety of treatment with ESA comparators in this study will be carefully monitored to 
include AEs, SAEs and laboratory parameters.  Emphasis will be placed on cardiovascular 
and cerebrovascular events, which are not uncommon in the study population; an 
independent expert panel will assess and adjudicate all significant occurrences of such 
events.  In addition, an independent Data Safety Monitoring Board (DSMB) will perform 
regular, periodic assessments of blinded and unblinded data to detect any potential safety 
signals that may arise during the study and advise the sponsor accordingly.
Based on the clinical and nonclinical study results to date, it is anticipated that orally 
administered roxadustat will be comparable in efficacy to marketed parenteral ESA products 
in the treatment of anemia of CKD, with an acceptable safety profile.  Roxadustat may offer a 
valuable alternative to the current treatment options in the management of anemia of CKD.
2
STUDY OBJECTIVES, 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 
epoetin alfa and darbepoetin alfa in the maintenance treatment of anemia in ESRD subjects 
on stable dialysis.
2.1.2
Secondary Objectives
The secondary objectives of this study are to:
●
Evaluate the safety of roxadustat compared to epoetin alfa and darbepoetin alfa in the 
maintenance treatment of anemia in ESRD subjects on stable dialysis.
●
Evaluate the effects on health-related quality of life (HRQoL) of roxadustat compared to 
epoetin alfa and darbepoetin alfa in the maintenance treatment of anemia in ESRD 
subjects on stable dialysis


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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 750 subjects from approximately 150 study centers, mainly 
located in Europe.
The study is planned to provide key efficacy and safety data for the approval of roxadustat in 
the treatment of anemia associated with ESRD on stable dialysis.
2.2.1.2 Study Population
The study population consists of adult subjects with ESRD who are on stable HD or PD and on 
stable treatment with epoetin (i.e. epoetin alfa, beta, theta, zeta, delta or omega) or darbepoetin 
alfa for anemia.  Subjects on polyethylene glycol-epoetin beta (Mircera®) are not to be 
included.  Subjects on hemodiafiltration (HDF) are also allowed to participate in the study and 
will follow the same study procedures and requirements as HD subjects.  Prior to
randomization a subject must be on the same mode of dialysis for ≥4 months and on epoetin or 
darbepoetin alfa treatment for ≥ 8 weeks with stable average weekly doses (defined as ≤30% 
change) during the last 4 weeks prior to randomization.  Anemia is defined as the mean Hb of 
the 3 most recent screening measurements ≥ 9.5 g/dL and ≤ 12.0 g/dL with an absolute 
difference ≤1.3 g/ dL between the highest and the lowest value.  Subjects must be iron replete 
at baseline; inclusion is permitted if ferritin ≥ 100 ng/mL (≥220 pmol/L) and TSAT ≥ 20%. 
Anemia of nonrenal origin is to be excluded.  Washout periods of at least 4 weeks for any iron-
chelating agents, and at least 8 weeks for any RBC transfusion prior to randomization have 
been mandated in order to exclude a potential impact of these recent anemia treatments on the 
assessment of efficacy.
2.2.1.3 Description of Study
Subjects assigned to the roxadustat treatment arm will receive roxadustat orally as a 
combination of tablets of different strengths.  Subjects assigned to the ESA treatment arm will 
be administered epoetin alfa if they were on epoetin (i.e. epoetin alfa, beta, theta, zeta, delta or 
omega) prior to randomization or darbepoetin alfa in case they were on darbepoetin alfa prior 
to randomization.  Study treatment administration is implemented in an open-label manner. 
Subjects on polyethylene glycol-epoetin beta (Mircera®) are not to be included.
The study will consist of 3 study periods:
●
Screening Period: up to 6 weeks
●
Treatment Period: For all subjects in the study the minimum treatment duration will be 
52 weeks and the maximum treatment duration will be 104 weeks.  The study end date 
will be declared when the targeted number of MACE* and MACE+** events have been 
reported across the roxadustat phase 3 development program and consequently the 
treatment will end for all subjects who have completed 52 weeks at that point.  Subjects 


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who have not completed 52 weeks when the target has been declared will continue until 
they reach 52 weeks and at that point their treatment will end.
●
Follow-up Period: 4 weeks
* MACE: Major cardiovascular adverse events: myocardial infarction, stroke, death from all causes
** MACE+: Myocardial infarction, stroke, death from all causes, chronic heart failure requiring 
hospitalization, unstable angina requiring hospitalization
During the course of the study, visits and assessments will be performed as defined in the 
Schedule of Assessments [Table 1].
Screening Period
During the screening period of up to 42 days, eligibility assessments will be performed.  
Subjects will continue epoetin or darbepoetin alfa treatment per local standard of care.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will be 
randomized at Day 1 (baseline), which marks the end of screening period and start of the 
treatment period.
Treatment Period
Subjects are randomized to 1 of 2 treatment arms as illustrated in [Table 2].
●
Treatment arm 1: subjects will be switched from epoetin or darbepoetin alfa treatment to 
roxadustat treatment (see Table 3 for doses).
●
Treatment arm 2: subjects will continue ESA treatment, i.e. epoetin alfa if pretreated 
with any epoetin (i.e. epoetin alfa, beta, theta, zeta, delta or omega) and darbepoetin alfa 
if pretreated with darbepoetin alfa, at approximately the same average weekly dose the 
subject was on prior to randomization.  It is not allowed to switch from epoetin alfa to 
darbepoetin alfa or vice versa, during the treatment period.
In case of randomization to epoetin alfa, all pretreatment used epoetin derivatives are 
considered dose equivalent and should be switched in a 1:1 fashion to epoetin alfa.
The randomization will result in an overall 1:1 ratio of subjects receiving roxadustat 
administered orally, or epoetin alfa or darbepoetin alfa administered by SC or IV injection. 
Randomization to treatment arms will occur through an Interactive Response System (IRS).
Table 2
Treatment Arms, Dosing Frequencies and Patient Numbers
Treatment Arms
Study Treatment
Dosing Frequency
N
1
Roxadustat
TIW
375
2
ESA 
Dosing per SmPC
375
TIW = 3 times weekly; ESA = epoetin alfa or darbepoetin alfa; SmPC = Summary of Product Characteristics
During the treatment period, subjects will attend weekly study visits from day 1 to week 8, 
followed by every other week study visits from week 10 to 36.  Following week 36, study 
visits will occur every 4 weeks until the End of Treatment (EOT).
Randomization and administration of the first dose of study treatment (roxadustat or ESA) is 
to occur on day 1 which should correspond to a day when their next dose of epoetin or 
darbepoetin alfa would have been administered.


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On day 1 all study procedures and assessments will be completed prior to the first study 
treatment administration.
During the treatment period, the aim is to maintain the Hb levels between 10.0 g/dL and 
12.0 g/dL.  All subjects receiving roxadustat will initiate and continue roxadustat dosing at a 
dosing frequency of TIW throughout the entire period and dose adjustment is to follow 
prespecified dose adjustment rules [Table 4].  Intake should occur at approximately the same 
time of day and, if possible, dosing days should remain consistent throughout the study.  For HD 
subjects it is recommended that roxadustat is administered any time after completion of dialysis 
if dosing is scheduled on a dialysis day to avoid potential bias on certain study assessments. 
Specific rules apply on the dialysis day(s) at which PK sampling is scheduled [Section 5.6].
Epoetin alfa (Eprex®) or darbepoetin alfa (Aranesp®) should be administered IV or SC 
according to the Package Insert or SmPC (UK SmPC for Eprex® and EU SmPC for 
Aranesp®).  Copies of these SmPCs will be distributed as part of the study materials.  During 
the treatment period, epoetin alfa and darbepoetin alfa will be provided by the sponsor.  
Dosing, dosing frequencies and dose adjustments should be in accordance with the UK 
SmPC for Eprex® and EU SmPC for Aranesp®.  The protocol-specified frequencies are once 
weekly, twice weekly or TIW for epoetin alfa; and once weekly or once every other week for 
darbepoetin alfa.  In addition, the protocol allows for administration of epoetin alfa once 
every other week and darbepoetin alfa once every 4 weeks.  These frequencies are only to be 
used in subjects on low ESA doses that do not fit into the normal frequencies of 
administration and if deemed clinically appropriate.  For PD subjects, darbepoetin dosing 
every 4 weeks is allowed.
For both treatment arms dose adjustments are to be made based on Hb values using HemoCue®, 
a point-of-care device. 
Subjects will receive study treatment (roxadustat or ESA) for a minimum of 52 weeks and a 
maximum of 104 weeks.
Follow-up Period
After the end of the treatment period subjects will proceed to the 4-week follow-up period. 
The choice of anemia treatment during the follow-up period is at the discretion of the 
investigator and according to local standards.
Post Study Follow-up (only for subjects prematurely discontinued from treatment)
Subjects who 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 1 dose of study treatment, will continue to be followed up at a 6-monthly frequency for 
vital status, SAEs and cardiovascular and thromboembolic AEs until their projected date of 
completion of the follow-up period (i.e. projected EOS visit) or until consent withdrawn.  Data 
collection during this poststudy follow-up occur through phone calls or information collected 
from source data of subjects’ regular, non-study, visits to the clinic.  No additional study visits 
will be required from these subjects during the poststudy follow-up.  The last poststudy 
follow-up data collection should occur around the projected EOS visit.


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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 assessment of 
outcomes.
An open-label design was chosen for several reasons.  A blinded design warrants a double-blind, 
double-dummy design to match the active comparator, and this is in principle not feasible given 
the anticipated need for frequent dose adjustments during the study.  In addition ESA study drugs 
(i.e. epoetin alfa or darbapoetin alfa) are supplied by different manufacturers and differ by SmPC 
and dosing specifications further hampering the possibility of a blinded design.  Another aspect 
is that a double-blind, double-dummy design may elicit inadvertent unblinding due to differences 
in the need for iron supplementation between roxadustat and ESA treated subjects.  Finally, the 
primary endpoint of the study is based on Hb level, which is an objective measurement with low 
risk for introducing bias.  Overall an open label study design is therefore considered the most 
reasonable option.
2.2.1.5 Comparative drug
For subjects randomized to ESA epoetin alfa or darbepoetin alfa, the starting dose, frequency 
and mode of application (IV or SC) are at the investigator's discretion provided the average 
weekly dose remains approximately the same as prior to randomization.
2.2.2
Roxadustat Dose Rationale
Initial dose of roxadustat
The initial study drug (roxadustat) dose is based on the dosing scheme shown in [Table 3]
and is determined by the subject’s average prescribed weekly dose of epoetin or darbepoetin 
alfa within 4 weeks prior to randomization.
Based on dose data and Hb data from an earlier study in dialysis subjects, a simplified dosing 
guide for conversion from 3 different dose ranges of epoetin alfa at baseline for Hb 
maintenance has been developed (see Section 1.2.2.2).  Three methods of modeling of dose 
relationship between roxadustat and baseline stable epoetin dose requirement (change in Hb 
levels versus Ln dose ratio, doses–Hb change modeling over 19 weeks, dose ratio in the last 
4 weeks of treatment), taking into account change in Hb, yield a dose ratio of 17 to 37, 
epoetin (IU/week) : roxadustat (mg TIW).
Table 3
Initial Dose of Roxadustat
epoetin†
(IU/week)
darbepoetin alfa†
(µg/week)
roxadustat
(mg/dose) TIW
<8,000
<40
100
8,000 to 16,000
40-80
150‡
>16,000
>80
200§
† Average prescribed weekly dose in the last 4 weeks prior to randomization.
‡ If the initial dose of 150 mg exceeds the maximum dose of 3.0 mg/kg, then 100 mg is to be used as the 
starting dose.
§ If the initial dose of 200 mg exceeds the maximum dose of 3.0 mg/kg, then 150 mg is to be used as the 
starting dose.


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Dose adjustments for roxadustat
Dose adjustment of roxadustat will be aimed at keeping subjects’ Hb levels between 10.0 to 
12.0 g/dL and will be based upon current Hb (assessed with the HemoCue® point-of-care 
device at the investigational site) and change in Hb over the preceding 4 weeks.
More details on dose adjustments are described in Section 5.1.2.1.
Maximum dose for roxadustat
The maximum allowed roxadustat dose in this study is set at 3.0 mg/kg (based on postdialysis
weight in HD subjects and weight minus abdominal fluid based on last filling in PD subjects) 
or 400 mg per administration, whichever is lower.  The highest dose tested in healthy subjects 
is 5 mg/kg single dose and 3.75 mg/kg TIW.  The doses were safe and well tolerated with 
transient dose dependent heart rate increases observed.  No maximum tolerated dose was 
reached in the clinical development of roxadustat based on the observed pharmaco-dynamic 
response (plasma EPO levels) and the predicted relation between EPO levels and Hb response; 
therefore exploration of higher doses was not deemed necessary.  Plasma EPO levels increased 
in a supra-linear manner with increasing roxadustat doses.  It is expected that the majority of 
the subjects will show adequate Hb response at substantially lower doses than the maximum 
allowed dose.
The treatment period of 104 weeks will provide sufficient data on the efficacy and safety of 
long term treatment of anemia with roxadustat in ESRD subjects on stable dialysis.
2.3
Endpoints
All statistical analyses are performed using the Central Laboratory data.
2.3.1
Primary Endpoint
There are 2 separate regionally based primary efficacy endpoints in this study, depending 
upon whether the data are being filed to support submission to the US FDA or to Ex-US 
health authorities, such as the EMA.
●
The EU (EMA) primary efficacy endpoint is change in Hb from BL to the average level 
during the evaluation period (defined as week 28 until week 36), without having received 
rescue therapy (i.e. RBC transfusion for all subjects or ESA for subjects treated with 
roxadustat) within 6 weeks prior to and during this 8-week evaluation period.
●
The US (FDA) primary efficacy endpoint is change in Hb from BL to the average level 
during the evaluation period (defined as week 28 until week 52), regardless of rescue 
therapy.
2.3.2
Key Secondary Endpoints
The secondary efficacy endpoints in this study are:
●
Hb response, defined as mean Hb during weeks 28 to 36 within the target range of 10.0 
to 12.0 g/dL without having received rescue therapy within 6 weeks prior to and during 
this 8-week evaluation period.


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●
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) during day 1 to week 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 Time to an increase in blood pressure: An increase from BL of ≥20 mm Hg systolic 
blood pressure (SBP) and SBP ≥ 170 mmHg or an increase from baseline of 
≥15 mmHg diastolic blood pressure (DBP) and DBP ≥ 100 mmHg during weeks 1 to 
36.
2.3.3
Additional Secondary Endpoints
2.3.3.1 Efficacy Endpoints
Hb maintenance:
●
Hb response during weeks 28 and 36 regardless of use of rescue therapy.  Hb response 
defined as mean Hb during weeks 28 to 36 within the target range of 10.0 to 12.0 g/dL.
●
Hb change from BL to each postdosing time point.
●
Hb level averaged over weeks 28 to 36, 44 to 52, and 96 to 104 without use of rescue 
therapy within 6 weeks prior to and during these 8-week evaluation periods.
●
Hb change from BL to the average Hb value of weeks 28 to 36, 44 to 52, and 96 to 104 
regardless of the use of rescue therapy.
●
Proportion of Hb values within 10.0 to 12.0 g/dL in weeks 28 to 36, 44 to 52, and 96 to 
104 without use of rescue therapy within 6 weeks prior to and during these 8-week 
evaluation periods.
Hospitalizations:
●
Occurrence (number) of hospitalizations (HD days are not counted as hospitalizations, 
even when performed overnight).
●
Number of days of hospitalization.
Rescue therapy use:
●
Having received rescue therapy [composite of RBC transfusions (all patients) and rescue 
ESA (roxadustat treated subjects only).
●
Having received RBC transfusions.
●
Number of RBC packs per subject.
●
Volume of RBC transfused per subject.


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Iron use:
●
Having required IV 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).
●
Having required oral iron supplementation.
●
Mean monthly oral iron (mg) use per subject during day 1 to week 36, weeks 37 to 52, 
and weeks 53-104 (monthly defined as a period of 4 weeks).
Changes in cholesterol levels, apolipoproteins
●
Change from BL to each postdosing study visit in 
o Total cholesterol. 
o LDL/High-density Lipoprotein (HDL) ratio.
o Non-HDL cholesterol.
o Apolipoproteins A1 and B.
o ApoB/ApoA1 ratio.
●
Occurrence of mean LDL cholesterol <100 mg/dL calculated over weeks 12 to 28.
Blood pressure effect:
●
Occurrence of achieved antihypertensive treatment goal in CKD subjects (SBP 
< 140 mmHg and DBP < 90 mmHg) based on the mean SBP and mean DBP calculated 
over weeks 12 to 28. 
HRQoL and European Quality of Life 5 Domain 5 Level (EQ-5D 5L):
●
Change from BL to the average value of weeks 12 to 28 in
o SF-36 Physical Component Score.
o Anemia Subscale (“Additional Concerns”) of Functional Assessment of Cancer 
Therapy-Anemia (FACT-An) Score.
o Total FACT-An Score.
o EQ-5D 5L visual analogue scale (VAS) Score
●
Patients’ Global Impression of Change (PGIC) (qualitative assessment)
Hepcidin, Iron status, Glycated hemoglobin (HbA1c):
●
Changes from BL to each study visit (when measured) in:
o Serum hepcidin
o Serum ferritin
o TSAT
o Glycated hemoglobin (HbA1c) level
2.3.3.2 Safety endpoints
Safety will be assessed by evaluating the following:
●
Occurrence of AEs, SAEs, 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.


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●
Occurrence, and time to occurrence, of prespecified adjudicated cardiovascular and 
cerebrovascular events (will be reported separately).  Various region-specific pooled 
analyses of prespecified adjudicated cardiovascular and cerebrovascular events (such as 
major cardiovascular adverse events [MACE, MACE+] and other events) will be 
conducted; these analyses will be detailed in region-specific pooled safety analysis plans.
3
STUDY POPULATION
3.1
Selection of Study Population
The study population consists of adult subjects with ESRD who are on stable dialysis (HD, 
HDF or PD) and on stable treatment with epoetin (i.e. epoetin alfa, beta, theta, zeta, delta or 
omega) or darbepoetin alfa for anemia.  Subjects on polyethylene glycol-epoetin beta 
(Mircera®) are not to be included.
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 is on stable HD, HDF or PD treatment with the same mode of dialysis for 
≥4 months prior to randomization.
4.
For subject receiving hemodialysis, the vascular access must be via native arteriovenous 
(AV) fistula or graft, or permanent, tunneled catheter.
5.
Subject is on IV or SC epoetin (i.e. epoetin alfa, beta, theta, zeta, delta or omega) or IV or 
SC darbepoetin alfa treatment for ≥8 weeks prior to randomization with stable weekly 
doses (≤ 30% change from the maximum prescribed average weekly dose, i.e. 
([max-min]/max ≤0.3) during 4 weeks prior to randomization.  Subjects on polyethylene 
glycol-epoetin beta (Mircera®) are not to be included.
6.
Mean of the subject’s 3 most recent Hb values, as measured by central laboratory, during 
the screening period, obtained at least 4 days apart, must be ≥9.5 g/dL and ≤12.0 g/dL 
with an absolute difference ≤1.3 g/dL between the highest and the lowest value. The last 
Hb value must be within 10 days prior to the randomization visit (day 1).
7.
Subject has a ferritin level ≥100 ng/mL (≥220 pmol/L) at screening.
8.
Subject has a transferrin saturation (TSAT) level ≥20% at screening.
9.
Subject has a serum folate level ≥ lower limit of normal (LLN) at screening.
10. Subject has a serum vitamin B12 level ≥ LLN at screening.


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11. Subject’s alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are 
≤3 x upper limit of normal (ULN), and total bilirubin (TBL) is ≤1.5 x ULN.
12. Subject’s body weight (postdialysis weight) is 45.0 kg to a maximum of 160.0 kg.
13. Female subject is either:
Of non-childbearing potential:
●
postmenopausal (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 the last 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.
14. Female subject must agree not to breastfeed starting at screening or during the study 
period, and continue to do so for 28 days after the final study treatment administration.
15. Female subject must not donate ova starting at screening and throughout the study period 
and continue to do so for 28 days after final study treatment administration.
16. 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.
17. Male subject must not donate sperm starting from screening, throughout the study period 
and up to 12 weeks after final study drug administration.
18. 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.


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3.3
Exclusion Criteria
Subject will be excluded from participation if any of the following apply:
1.
Subject has received a Red Blood Cell (RBC) transfusion within 8 weeks prior to 
randomization.
2.
Subject has a known history of myelodysplastic syndrome or multiple myeloma.
3.
Subject has a known hereditary hematologic disease such as thalassemia or sickle cell 
anemia, pure red cell aplasia, or other known causes for anemia other than CKD.
4.
Subject has a known hemosiderosis, hemochromatosis, coagulation disorder, or hyper-
coagulable condition.
5.
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.
6.
Subject is anticipated to undergo elective surgery that is expected to lead to significant 
blood loss during the study period or anticipated elective coronary revascularization.
7.
Subject has active or chronic gastrointestinal bleeding.
8.
Subject has received any prior treatment with roxadustat or a hypoxia-inducible factor 
prolyl hydroxylase inhibitor.
9.
Subject has been treated with iron-chelating agents within 4 weeks prior to 
randomization.
10. Subject has a history of chronic liver disease (e.g. cirrhosis or fibrosis of the liver).
11. Subject has known New York Heart Association Class III or IV congestive heart failure.
12. Subject has had a myocardial infarction, acute coronary syndrome, stroke, seizure, or a 
thrombotic/thrombo-embolic event (e.g., deep vein thrombosis or pulmonary embolism) 
within 12 weeks prior to randomization.
13. Subject has had uncontrolled hypertension, in the opinion of the investigator, within 2 
weeks prior to randomization
14. Subject has known hypersensitivity to epoetin alfa (Eprex®), darbepoetin alfa 
(Aranesp®) or any of their excipients.
15. 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, or another appropriate 
imaging method, within 12 weeks prior to randomization.
16. Subject has a history of malignancy, except for the following: cancers determined to be 
cured or in remission for ≥ 5 years, curatively resected basal cell or squamous cell skin
cancers, cervical cancer in situ, or resected colonic polyps.


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17. 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)
18. Subject has an active clinically significant infection manifested by White Blood Count 
(WBC) >ULN, and/or fever, in conjunction with clinical signs or symptoms of infection 
within 1 week prior to randomization.
19. Subject has a known untreated proliferative diabetic retinopathy, diabetic macular 
edema, macular degeneration or retinal vein occlusion.
20. Subject has had any prior organ transplant (that has not been explanted), or subject is 
scheduled for organ transplantation.
21. Subject has participated in any interventional clinical study or has been treated with any 
investigational drugs within 30 days or 5 half lives or limit set by national law, 
whichever is longer, prior to the initiation of screening.
22. Subject has an anticipated use of dapsone in any dose amount or anticipated chronic use
of acetaminophen/paracetamol > 2.0 g/day during the treatment or follow-up period of 
the study.
23. Subject has a history of alcohol or drug abuse within 2 years prior to randomization.
24. 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
TREATMENTS
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).
The excipients include lactose monohydrate, microcrystalline cellulose, povidone, 
croscarmellose sodium, magnesium stearate, and colorant Red Opadry II.
4.1.2
Comparative Drugs
Epoetin alfa (Eprex®) is supplied as a solution for SC or IV injection in a pre-filled syringe.  It 
will be centrally provided by a Contract Research Organization (CRO) in the following 
strengths: 1000, 2000, 3000, 4000, 6000 and 8000 IU, and needs to be administered according 
to the UK SmPC of Eprex® (see investigator site file).


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Darbepoetin alfa (Aranesp®) is supplied as a solution for SC or IV injection in a pre-filled 
syringe.  It is centrally provided by a CRO in the following strengths: 10, 20, 30, 40, 60 and 
100 µg, and needs to be administered according the EU SmPC of Aranesp (see investigator 
site file).
All administrations will be performed by the investigator or a qualified member of the site 
staff, by the subject themselves or caregiver, e.g. relative, if well trained and willing to self-
administer.
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 the sponsor 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 guidelines, International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) Good Clinical Practice (GCP) guidelines, and applicable local laws/regulations.
The test drug and comparative drugs will bear a label conforming to regulatory guidelines, 
Good Manufacturing Practice and local laws and regulations which identifies the contents as 
investigational drug.
A Qualified Person of APEB or sponsor’s designee will perform the final release of the 
medication according to Directive 2003/94/EC annex 13.
Roxadustat 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. The tablets are packed 
in bottles per six tablets.  Each bottle will have an unique Kit number.
Epoetin alfa and 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.  Each box will have a 
unique kit number.
For storage and administration purposes, please refer to the UK SmPC of Eprex® and EU 
SmPC of Aranesp® 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 at the site’s 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, standard procedures for the alternative 
disposition of the unused study drug can 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.
●
ESA treatment to be given from randomization to EOT will be provided by the sponsor, 
the ESA medication needed in the screening period or after EOT visit will not be 
provided by the sponsor.
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 occur through an IRS system prepared on 
behalf of the sponsor (under the responsibility of the Global Data Science Department of 
APEB).  Specific procedures for randomization through the IRS are contained in the study 
procedures manual.
A total of approximately 750 subjects will be randomized to 1 of the 2 treatment arms in a 
1:1 ratio as follows:
●
Treatment Arm 1: roxadustat
●
Treatment Arm 2: ESA (epoetin alfa or darbepoetin alfa)
See also Table 2 [Section 2.2.1.3] for the treatment arms.
Randomization will be stratified by the following 5 factors:


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●
Previous ESA treatment (epoetin versus darbepoetin alfa)
●
Region (region A versus region B*)
●
History of cardiovascular, cerebrovascular or thromboembolic diseases (Yes versus No)
●
Average prescribed weekly ESA dose in last 4 weeks prior to randomization 
(≤200 IU/kg epoetin or ≤ 1 μg/kg darbepoetin alfa versus >200 IU/kg epoetin or 
> 1 μg/kg darbepoetin alfa)
●
Screening Hb value (≤11.0 g/dL versus >11.0 g/dL)
* Country assignment to region A and B will be determined based on health care system 
comparability.
5
TREATMENTS AND EVALUATION
Subjects must provide a signed Informed Consent Form (ICF) and be registered in IRS before 
any screening assessments are performed.  Participating study sites are required to document 
all screened candidates who provided informed consent.  If a subject is excluded from the 
study, the reasons for exclusion will be documented in the subject’s source documents and in 
the electronic case report form (eCRF).
Registration of subjects into the study, assignment of subject identification numbers, and 
randomization will take place using a centralized IRS system.  Following informed consent 
and prior to the start of the first screening assessments the investigator will register the 
subject in IRS, starting the 42-day screening period, and a subject identification number will 
be assigned.  Any subject identification numbers that are assigned will not be reused even if 
the subject does not receive treatment.
If any of the subject’s laboratory parameter results does not meet the inclusion criteria or meets 
an exclusion criteria this laboratory assessment may be repeated once within the 42 day 
screening period.  This includes assessment of an additional (4th) Hb value, bearing in mind 
that the mean of 3 last Hb values during the 42 day screening period, obtained at least 4 days 
apart, will be used to calculate the subject’s eligibility.
If a subject fails screening, they will be registered in IRS as a screen failure and considered 
out of the study.  However 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 and a new 42-day screening period starts and all screening procedures must be 
repeated. Subject must also be registered in IRS again as re-screened under the same number 
as first screening.
After all screening assessments have been completed to determine study eligibility, the 
subject may be randomized.  Subjects confirmed not eligible after screening or, if applicable, 
after re-screening, should be registered in IRS as a screen/re-screen failure.


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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 who are randomized will enter the treatment 
period (day 1).  Treatment will be given in an open label manner.
●
Subjects will be randomized via IRS to receive roxadustat or ESA (epoetin alfa or 
darbepoetin alfa).  Randomization and administration of the first dose of study treatment 
(roxadustat or ESA) are to occur on day 1, which should correspond to a day when the 
subjects’ next dose of epoetin or darbepoetin alfa would have been administered.  The 
first dose of study treatment should be taken after all study assessments have been 
completed; in HD subjects only, study assessments should also be performed prior to or 
at initiation of dialysis (except for postdialysis weight and postdialysis vital signs, which 
should be measured post dialysis).
●
All subjects will be treated for a minimum of 52 and a maximum of 104 weeks.
Subjects receiving roxadustat
Roxadustat tablets will be dispensed at each study visit during the treatment period with 
defined dosing schedule and instructions for self-administration.  The tablets are to be 
swallowed whole with room-temperature drinking water. 
The initial roxadustat dose is based on the conversion table shown in Table 3 and is 
determined by the subject’s average weekly dose of epoetin or darbepoetin alfa within 4 
weeks prior to randomization.
All HD and PD subjects receiving roxadustat will initiate and continue roxadustat dosing at a 
dosing frequency of TIW throughout the entire study period.  The period between 2 
roxadustat administrations should be at least 36 hrs. Dosing days should remain consistent 
throughout the study.  For HD subjects it is recommended that roxadustat is administered any 
time after completion of dialysis if dosing is scheduled on a dialysis day to avoid potential 
bias on certain study assessments.
An exception is made for the visit(s) where blood samples are drawn for PK analysis as 
described in Section 5.6
Dose adjustments of roxadustat are to follow prespecified dose adjustment rules [Table 4] and 
will be aimed at keeping subject’s Hb levels between 10.0 to 12.0 g/dL.  Dose adjustments will 
be based upon current Hb and change in Hb over the preceding 4 weeks as described in 
Section 5.1.2.1
Subjects receiving ESA
Epoetin alfa (Eprex®) or darbepoetin alfa (Aranesp®) should be administered IV or SC 
according to the Package Insert or SmPC (UK SmPC for Eprex® and EU SmPC for 
Aranesp®).  The initial dose and frequency of administration are at the investigator's 
discretion provided that the average weekly dose remains approximately the same as prior to 
randomization.


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During the treatment period, epoetin alfa and darbepoetin alfa will be provided by the 
sponsor.  Dosing, dosing frequencies and dose adjustments should be in accordance with the 
UK SmPC for Eprex® and EU SmPC for Aranesp®.  The protocol-specified frequencies are 
once weekly, twice weekly or TIW for epoetin alfa; and once weekly or once every other 
week for darbepoetin alfa irrespective of the frequency of administration prior to 
randomization.  In addition, the protocol allows for administration of epoetin alfa once every 
other week and darbepoetin alfa once every 4 weeks.  These frequencies are only to be used 
in subjects on low ESA doses that do not fit into the normal frequencies of administration and 
if deemed clinically appropriate.  For PD subjects, darbepoetin dosing every 4 weeks is 
allowed.
All administrations will be performed by the investigator or a qualified member of the site staff 
or by the subject themselves or caregiver, e.g. relative, if well trained and willing to self-
administer.
For both ESAs the target of treatment is maintaining Hb in the range of 10.0 to 12.0 g/dL.
Investigators and subjects should make every effort to keep dosing days and dosing times 
consistent throughout the study.
5.1.2
Increase or Reduction in Dose of Study Drug
5.1.2.1 Dose Adjustment Rules
All doses, dose decisions and reasons will be documented in the eCRF for both roxadustat 
and ESAs.
Subjects receiving roxadustat
Dose adjustments are permitted on a 4-weekly interval from week 4 onwards and will be 
aimed at keeping subjects’ Hb levels between 10.0 to 12.0 g/dL and will be based upon 
current Hb levels and change in Hb over the preceding 4 weeks as illustrated in [Table 4] 
(deviation from the 4-week period is allowed anytime during the study in case of excessive 
hematopoiesis or Hb ≥13.0 g/dL).
Table 4
Dose Adjustment Rules for Roxadustat
Change in Hb Over 
Past 4 Weeks (g/dL)a
Hb (g/dL)
<10.5
10.5 to <12.0
12.0 to <13.0
< -1.0
↑
↑
No change
-1.0 to 1.0
↑
No change
↓
> 1.0
No change
↓
↓
Hb: hemoglobin
a Subtract first Hb value from last value Hb to calculate the change
●
All dose adjustments are made based on Hb values using HemoCue®, a point-of-care 
device.
●
Dose increases by 1 dose step (↑) and reductions by 1 dose step (↓) are pre-set


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●
If the dose adjustment is ‘No change’ per the above table, the dose remains unchanged 
and the next dose adjustment review is 4 weeks after that visit.
●
The dose steps for roxadustat are as follows: 20, 40, 50, 70, 100, 150, 200, 250, 300, and 
400 mg.
●
The maximum dose is the dose step corresponding to 3.0 mg/kg (based on postdialysis
weight in HD subjects and in PD subjects weight minus abdominal fluid based on last 
filling) per administration or 400 mg, whichever is lower.  At study visits where weight 
is collected the default weight and maximum allowed dose step for a subject will be 
adjusted if the weight change is ≥ 5% compared to the previous default weight collected 
in the study.  Initial default weight is weight at randomization visit.
●
If there is a safety concern, investigators may deviate from the dose adjustment rules for 
roxadustat.  This should be discussed with the medical monitor and documented in the 
source documentation.
●
Contact the medical monitor if dose adjustments would lead to doses outside the limits of 
the dose step range; i.e. lower than 20 mg or higher than 400 mg.
In the following cases dose adjustment may be made at any time outside the 4-weekly interval:
●
Dose reduction in case of excessive hematopoiesis
●
Dose increase by 1 step in case subject Hb < 9.0 g/dL (HemoCue®) and no dose 
adjustment occurred in the preceding 4 weeks.
At any time when Hb ≥13.0 g/dL
●
Stop dosing
●
Resume dosing when Hb <12.0 g/dL at a dose that is reduced by 2 steps
●
Next dose adjustment review is 4 weeks after dose resumption and in 4-weekly intervals 
thereafter.
Dose Adjustment for Excessive Hematopoiesis
At any time during the Treatment Period:
●
If Hb increases by >2.0 g/dL at any time within 4 weeks, the dose should be reduced by 
1 dose step
Note: Only 1 dose reduction for excessive hematopoiesis is recommended within a period of 
4 weeks.  If a blood transfusion has been performed or a course of ESA rescue therapy has 
been administered within 2 weeks of meeting the criteria for excessive hematopoiesis, it is 
recommended not to perform a dose reduction for excessive hematopoiesis.
After a dose adjustment due to excessive hematopoiesis, the subject’s next dose adjustment 
review will occur 4 weeks later, and in 4-weekly intervals thereafter.
If the dose adjustment interval falls on a non-visit study week, the dose adjustment review 
should be performed at the next scheduled study visit.
All dose decisions should be documented in the subject source data.


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Subjects receiving ESA (epoetin alfa or darbepoetin alfa)
All dose adjustments are made based on Hb values using HemoCue®, a point-of-care device.  
Dose adjustments will aim at keeping subjects’ Hb level between 10.0 to 12.0 g/dL.
During the treatment period, the active comparator drugs epoetin alfa (Eprex®) and 
darbepoetin alfa (Aranesp®) will be provided by the sponsor.  Dosing, dosing frequencies and 
dose adjustments should be in accordance with the UK SmPC for Eprex® and EU SmPC for 
Aranesp®.  The protocol-specified frequencies are once weekly, twice weekly or TIW for 
epoetin alfa; and once weekly or once every other week for darbepoetin alfa.  In addition, the 
protocol allows for administration of epoetin alfa once every other week and darbepoetin alfa 
once every 4 weeks.  These frequencies are only to be used in subjects on low ESA doses that 
do not fit into the normal frequencies of administration and if deemed clinically appropriate.  
Contact the medical monitor if dose adjustments would lead to doses lower than 1000 IU 
epoetin once every other week or 10 µg darbepoetin once every 4 weeks.  For PD subjects, 
darbepoetin dosing every 4 weeks is allowed.
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 4 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 prior treatment received for anemia (medication or 
procedures such as ESAs, oral or IV iron, and RBC transfusions) within 12 months prior to 
randomization will be documented in the eCRF.
Certain prior 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 time of informed consent to 
EOS visit.  The medication name, start and stop date, route, dose and frequency and 
indication for each medication will be entered in the eCRF.
For all concomitant medications, from informed consent 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 recorded in the 
subject’s clinical study records as source documentation.


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Supplemental Iron Use
Subjects receiving roxadustat
a. Oral iron
Oral iron treatment is recommended for supplementation to support erythropoiesis and as 
first-line treatment for 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 1 h before or 1 h after oral iron.
b. Intravenous (IV) iron
IV iron supplementation is allowed if all of the following criteria are met:
●
The subject’s Hb level has not responded adequately to roxadustat following 2 
consecutive dose increases or reached the maximum dose limit, and
●
The subject’s ferritin is <100 ng/mL (<220 pmol/L) or TSAT < 20%, or the subject is 
intolerant of oral iron therapy.
Treatment with roxadustat should continue during IV iron administration.  Discontinuation of 
IV iron administration is recommended once ferritin level ≥100 ng/mL (≥220 pmol/L) and 
TSAT ≥20%. Serum ferritin and TSAT can be measured at any time after IV iron delivery at 
the discretion of the investigator.
Subjects receiving ESA
For subjects treated with epoetin alfa or darbepoetin alfa, IV iron supplementation will be 
given according to standard of care.
Statins and Other Substrates for OATP1B1
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 5
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.


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Table 5
Proposed Maximum Daily Dose of Statins Not to be Exceeded in Patients 
on Dialysis
Statin
Proposed maximum dose (mg/day)
Simvastatin
5
Atorvastatin
40
Rosuvastatin
Contraindicated
Fluvastatin
20
Pravastatin
40
Pitavastatin
1
Phosphate Binders and Other Multivalent Cation-containing Drugs and Mineral 
Supplements
Results from a drug-drug interaction study demonstrated a significant reduction in roxadustat 
plasma exposure when a single dose of roxadustat was administered simultaneously with the 
phosphate binders sevelamer carbonate or calcium acetate.
Subjects should take roxadustat in a consistent manner relative to their phosphate binder 
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 1 h before or 1 h after their phosphate binder. 
It is anticipated that other multivalent cation-containing drugs and mineral supplements (e.g., 
iron, calcium, magnesium, aluminum), sucralfate or magnesium- or aluminum-containing 
antacids would produce a similar interaction; therefore, administration of roxadustat between 
-1 h and +1 h of intake of these preparations is not recommended.
Anti-hypertensive and lipid-lowering medication
To avoid confounding effects on study endpoints, changes to anti-hypertensive and lipid 
lowering medications should be minimized as much as possible, and made only if deemed 
medically necessary by the investigator.
5.1.3.3 Prohibited Medication
The following medications are prohibited during the period identified:
●
Any investigational drug: Within 30 days or 5 half lives or limit set by national law 
(whichever is longer), prior to the initiation of screening until EOS.
●
Roxadustat or another hypoxia-inducible factor prolyl hydroxylase inhibitor: at any time 
prior to randomization.  After randomization any hypoxia-inducible factor prolyl 
hydroxylase inhibitor 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 randomization onwards until EOS.
●
Dapsone in any dose amount, or chronic doses of acetaminophen/paracetamol >2.0 g/day, 
from randomization until EOS.
Use of herbal medicines is discouraged during the course of the study.


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5.1.3.4 Procedure and non-drug therapy recording
Any other procedures or non-drug therapies need to be entered in subject’s source 
documentation from informed consent until EOS and will also be recorded in the eCRF.
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 [Section 5.1.1].  If the subject is 
non-compliant with study drug intake, the investigator should discuss this with the subject. 
Deviations should be entered into the eCRF.  All roxadustat bottles dispensed to the subject 
should be returned by the subject to the site (including empty bottles) at each study visit for 
reconciliation of returned tablet count by the study monitor.
For subjects randomized to ESA, the quantity of study drug dispensed and confirmation of 
administration will be recorded in the eCRF.  All administrations will be performed by the 
investigator or a qualified member of the site staff or 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 the subject and confirmation that all doses 
have been taken will be recorded in the eCRF.  The empty outer packages of ESA with the 
unique kit number should be returned by the subjects and stored at site for reconciliation by 
the study monitor.  Empty syringes need to be handled and destroyed according to local 
requirements.
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.  Details of the 
rescue therapy will be recorded in the eCRF.
1. RBC Transfusion (for all subjects)
RBC transfusion is allowed if rapid correction of anemia is required to stabilize the patient’s 
condition or the investigator is of the opinion that the RBC transfusion is a medical necessity.  
Study treatment may continue during or after transfusion administration.  Hb needs to be 
measured pre- and posttransfusion (HemoCue®).
2. ESA (only for subjects treated with roxadustat)
One course of rescue ESA is allowed. If the investigator considers administration of ESA as a 
medical necessity, 1 course of rescue ESA may be initiated if the following criteria are met:
●
the Hb level has not responded adequately despite 2 or more roxadustat dose increases in 
the previous 8 weeks, or the roxadustat dose has reached the maximum dose limit, and
●
the subject’s Hb level is < 9.0 g/dL (HemoCue®) as confirmed at 2 consecutive study 
visits, and 
●
reducing the risk of alloimmunization in transplant eligible subjects and/or reduction of 
other RBC transfusion-related risks is a goal.


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Prior to the initiation of rescue ESA (epoetin alfa for subjects treated with any epoetin prior 
to randomization; and darbepoetin alfa for subjects treated with darbepoetin alfa prior to 
randomization), 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, addressed by the investigator.  Prior 
to initiating ESA rescue therapy, iron deficiency should be corrected (i.e. 100 ng/mL 
[220 pmol/L] ferritin and 20% TSAT).
The subject may continue on study, however, the subject is not allowed to be administered 
both rescue ESA and roxadustat during the same time period.  The course of rescue ESA (i.e. 
the amount that may be administered) will be limited by duration of therapy and effect on 
Hb, including that 1 course of treatment with rescue ESA will not exceed 4 weeks in 
duration, and that ESA rescue will be stopped as soon as Hb ≥9.0 g/dL as measured by 
HemoCue.  Treatment with roxadustat may be resumed as soon as possible after the 
following intervals:
●
At least 2 days after stop of epoetin alfa
●
At least 1 week after stop of darbepoetin alfa
If a subject requires a second course of rescue with ESA, the subject must be discontinued 
from study treatment.  The subject will complete the EOT visits (EOT visit and EOT + 2 
weeks visit) and EOS visit, and will continue to be followed up at a 6-monthly frequency for 
vital status, SAEs and cardiovascular and thromboembolic AEs until their projected date of 
completion or until consent withdrawn.
Doses: The doses of rescue therapies are at 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.  
This should be documented in the eCRF and source documentation, and discussed with the 
study medical monitor.
5.1.6
Restrictions During the Study
●
Subjects are not permitted to consume more than 3 alcohol-containing drinks per day 
during the treatment or follow-up periods.
●
If heterosexually active, female subjects of childbearing potential will be required to use a 
highly effective form of birth control.  If required by local law, 2 highly effective methods 
of birth control must be used, 1 of which must be a barrier method.
●
Heterosexually active male subjects with female partners of childbearing potential 
should also use a highly effective form of birth control.  If required by local law, 2 
highly effective methods of birth control must be used, 1 of which must be a barrier 
method.


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●
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 5.5.8).
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 
and race will be recorded in the eCRF.
5.2.2
Medical History
A detailed medical history, including detailed cardiovascular history and family cardio-
vascular history, will be obtained at screening.  All relevant past and present conditions as 
well as previous and current tobacco use will be recorded in the subject’s eCRF. Relevant 
conditions include conditions that have been treated with medication within 4 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 can be performed at any time during the screening period.  
This can be replaced by a pre-existing examination (or other renal imaging modality such as 
CT or MRI scan if it was conducted within 12 weeks prior to randomization and it 
conclusively excludes the presence of renal cell carcinoma).  Examination results must be 
available prior to randomization (see exclusion criterion 15).  The date and assessment for the 
absence, 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, etiology, vascular access history, date of initiation of current and first 
dialysis and mode of current and first dialysis.  Also the nondrug therapy history and 
medication history for anemia (last 12 months) and the nondrug therapy history for CKD (last 
4 months) prior to randomization will be obtained.
Anemia will be measured by repeated Hb measurements (central laboratory assessment) 
during screening; the mean of the 3 most recent Hb values during the screening period, 
obtained at least 4 days apart, must be ≥ 9.5 g/dL and ≤ 12.0 g/dL, with an absolute 
difference of ≤ 1.3 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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Exclusion of other causes of anemia should be based on an integrated assessment of clinical 
and laboratory signs and symptoms as well as medical history.
5.2.5
Further Laboratory Testing Prior to Randomization
Other laboratory tests mandatory prior to randomization of a subject, for eligibility or baseline 
purposes, include enzyme-linked immunosorbent assay for human immunodeficiency virus, 
Hepatitis B surface antigen and anti-hepatitis C antibody 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. 
5.3
Efficacy Assessment
5.3.1
Primary Efficacy Assessment
The assessment of the efficacy of the study treatments 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 concomitant medication (as recorded in the eCRF) will be taken into account for 
the evaluation of the primary efficacy assessment.
5.3.2
Secondary 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.  Blood pressure will be measured before and after 
dialysis in HD patients.  In PD patients, blood pressure will only be measured at 1 time point 
on the examination day, irrespective of current dialysis cycle.  For details on the 
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 the following 4 QoL questionnaires: SF-36, 
FACT-An, EQ-5D 5L and PGIC (see Appendices).  The timing of the questionnaires is 
indicated in the Schedule of Assessments [Table 1].
In HD subjects the QoL questionnaires are to be completed by the subject prior to or at the 
latest at the start of the dialysis session.  It is important that the investigator does not discuss 
the status of the subject prior to completion of the questionnaires.
In PD subjects, the QoL questionnaires are to be completed prior to any other study 
assessment.


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5.3.3.1.1
Short Form-36 Health Survey (SF-36)
The SF-36 is a QoL instrument designed to assess generic health concepts relevant across age, 
disease, and treatment groups.  It is aimed at both adults and adolescents aged 18 years and 
older.  The SF-36 consists of 8 domains of health status:  Physical functioning (10 items), 
Role-physical (4 items), Bodily pain (2 items), General health (5 items), Vitality (4 items), 
Social functioning (2 items), Role emotional (3 items) and Mental health (5 items).  Two 
component scores, the Physical Component Summary and the Mental Component Summary 
can also be calculated.  For both the SF-36 domain scores and summary scores, higher scores 
indicate better health status.  The SF-36 has a recall period of the ‘past 4 weeks’.
5.3.3.1.2
Functional Assessment of Cancer Therapy –Anemia (FACT-An)
The Functional Assessment of Cancer Therapy- General (FACT-G) Version 4 contains 
27 items that cover 4 dimensions of 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 7 additional items related to anemia comprise the Anemia Subscale (AnS).  
Administration of the FACT-G plus the AnS is referred to as the FACT-An (Appendix 12.5).  
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.  The EQ-5D-5L 
is shown in Appendix 12.6
5.3.3.1.4
Patient Global Impression of Change Scale (PGIC)
The PGIC (Appendix 12.7) 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.
5.3.3.2 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 


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will be recorded in the eCRF. Details of hospitalizations will also be collected at poststudy 
follow-up visits in subjects who prematurely discontinued treatment (only if they have taken 
at least 1 dose of study drug), until the projected date of the EOS visit.
HD within the hospital is not considered to be a hospitalization, even when occurring 
overnight.
5.3.3.3 Iron Status, HbA1c and glucose
Serum iron, TSAT, ferritin, HbA1c and fasting blood glucose will be assessed (central 
laboratory) according to the Schedule of Assessments.
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 for the further characterization of the mode of action or adverse 
effects of roxadustat or for determination of their prognostic value in dialysis patients, may 
be assessed from archived serum/plasma samples.
5.4
Safety Assessment
5.4.1
Vital Signs
The vital signs blood pressure, heart rate, and respiratory rate will be assessed at the visits as 
described in the Schedule of Assessments.
5.4.1.1 Blood Pressure
Blood pressure measurement is recommended to be done with the subject comfortably seated 
in the dialysis bed or 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.  Also the same arm should be used 
consistently for readings throughout the study.
Blood pressure is recommended to be measured singly on each of the 3 visits during the 
screening period, and in triplicate with at least 2 minute intervals for all other study visits.  
All values will be reported in the eCRF. 
In HD subjects both pre- and postdialysis measurements will be collected.
5.4.1.2 Heart Rate
Measurement of heart rate is recommended to be done at rest in a sitting position wherever 
possible.  It can be performed with an oscillometric device as used for blood pressure 
measurement [Section 5.4.1.1], by using any other suitable device or manually (wrist heart 
rate within 1 minute).  The same methodology and device should preferably be used for the 


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subject throughout the study, timing as indicated in the Schedule of Assessments.  Heart rate 
will be measured singly on each of the 3 visits during the screening period and in triplicate 
with at least 2 minute intervals at day 1 and on all other visits.  All values will be reported in 
the eCRF. 
In HD subjects heart rate will be measured pre- and postdialysis.
5.4.1.3 Respiratory Rate
Measurement of respiratory rate will be done at rest in a sitting position wherever possible.  It 
can be performed with any suitable device or manually (number of breathing cycles within 1
minute).  The same methodology and device should preferably be used for the subject 
throughout the study, timing as indicated in the Schedule of Assessments.  Respiratory rate 
will be measured singly during all visits.
In HD subjects a pre- and postdialysis respiratory measurement should be performed.
5.4.2
Adverse Events
AEs will be collected at all study visits. 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. See Section 5.5 for detailed information regarding AE collection and 
data handling. The collection and adjudication of prespecified cardiovascular and 
cerebrovascular events will be detailed in a separate adjudication charter.
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 for detailed information on liver abnormalities, monitoring and 
assessment, if the AE for a subject enrolled in the study and receiving study drug is 
accompanied by increases in LFTs (e.g., AST, ALT, bilirubin, 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 medical monitor of the 
sponsor/delegated CRO by telephone or fax immediately (i.e. within 24 hours of awareness) 
for further follow-up.
5.4.3
Laboratory Assessments
In Table 6, the laboratory tests that will be performed during the conduct of the study are 
listed.  The study visit collection time points are also described in the Schedule of 
Assessments [Table 1].  In HD subjects, laboratory assessments should be performed prior to 
or at the initiation of dialysis.  All details on the processing of the samples, storage and 
shipment conditions will be provided in a separate laboratory manual.


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Table 6
Laboratory Tests
Lab Assessment Type 
Parameters to be Analyzed
Hematology
Complete Blood Count (CBC) with Red Cell indices and WBC differential
Hemoglobin (Hb)
Hematocrit (Hct)
Erythrocytes (RBC)
Mean corpuscular volume (MCV)
Mean corpuscular Hb (MCH)
Mean corpuscular Hb concentration (MCHC)
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 
Creatinine
Magnesium
Bicarbonate
Phosphorus
Uric Acid
Albumin
Total protein
Lactate dehydrogenase
Blood urea nitrogen
Lipase
Liver Function Tests:

AST

ALT

Bilirubin (Total and direct)

Gamma glutamyl transferase (GGT)
Alkaline phosphatase (ALP)
Lipid Panel (in fasting condition wherever possible):

Total Cholesterol

LDL

HDL

Triglycerides

Apolipoproteins A1, B
Iron
Ferritin
TSAT
TIBC
Pregnancy test (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 Ab 

HBsAg 

Anti-hepatitis C virus (HVC) Antibody Tests
Special Laboratory 
Analytes
High sensitivity C-reactive protein (hs-CRP)
Serum Hepcidin
Serum Biomarkers
Archival of serum samples for biomarkers
PK analysis
Plasma – Level of roxadustat
Covariates for PK

Albumin 

α1-AGP 
Dialysate (CAPD subjects)
Level of roxadustat
Genotyping (optional)
DNA isolation
The clinical significance of out-of-range laboratory findings is to be determined and 
documented by the investigator/sub-investigator who is a qualified physician.
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 (in HD subjects 
prior to dialysis) will include general appearance and the following body regions and systems: 
head, eyes, ears, neck and throat, lungs, heart, chest and back, abdomen, genitourinary, 
extremities, skin, and any other, if deemed necessary.
Height is measured only at screening.  Weight is measured according to the Schedule of 
Assessments.  For HD subjects weight is measured after completion of dialysis (postdialysis
weight).  For logistical reasons the weight to be recorded in the IRS for HD subjects is the 
postdialysis weight from last dialysis session before the scheduled study visit.  For day 1 visit 
the postdialysis weight on the third screening visit is to be recorded in the IRS for HD subjects.  
For PD subjects weight is measured at the same time physical examination is done.  For PD 
subjects weight is defined as weight minus weight of abdominal fluid based on last filling.  
One liter PD fluid is to be considered as 1 kg of weight.  In case a subject’s abdominal cavity is 
empty of fluid, the measured weight should be recorded as the true weight.  Height and body 
weight will be recorded in the eCRF.
A targeted physical examination (e.g., respiratory and cardiovascular) will be conducted 
throughout the study as described in Schedule of Assessments [Table 1], and recorded in the 
source documents.
Only the date of the physical examination will be recorded in the eCRF.  Any clinically 
relevant adverse change will be recorded as an AE in the eCRF (see Section 5.5.1).
5.4.5
ECG
12-lead ECGs will be performed at specific time points as described in the Schedule of 
Assessments as to local routines.  A single ECG will be taken after the subject has been lying 
quietly in the supine position for 5 minutes.  Any abnormalities must be evaluated in clinical 
context (based on subject’s medical history and concomitant medication) and the investigator 


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should determine if it is clinically significant.  Clinically significant abnormalities should be 
reported as an AE.
Only the ECG date, Heart Rate, PR interval, QRS Interval, QT Interval, clinical significant 
and relevant comments will be recorded in the eCRF.  The RR interval will be calculated in 
the eCRF using the Heart Rate.  ECG recordings will be kept as source documents.
5.5
Adverse Events and Other Safety Aspects
Safety will be assessed throughout the study.  A complete baseline 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, comprehensive and 
targeted physical examinations, laboratory tests, and ECGs will be performed as described in 
the schedule of assessments.  Any medically significant changes from baseline will be 
monitored throughout the study and appropriate interventions will be taken accordingly.  
Clinical laboratory tests, vital signs or physical examinations etc. may be assessed at 
additional times on unscheduled visits for safety reasons.
AEs, SAEs, and concomitant medication usage will be monitored and recorded throughout 
the study.
5.5.1
Definition of Adverse Events
An AE is defined as any untoward medical occurrence in a subject administered study drug 
or has undergone study procedures and which does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product.
Some countries may have additional local requirements for events that are required to be 
reported as AEs or in an expedited manner similar to an SAE.  In these cases, it is the 
investigator’s responsibility to ensure these AEs or other reporting requirements are followed 
and the information is appropriately recorded in the (e)CRF accordingly.
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG 
data, physical exam) should be defined as an AE only if the abnormality meets 1 of the 
following criteria:
●
Induces clinical signs or symptoms
●
Requires active intervention
●
Requires interruption or discontinuation of study medication
●
The abnormality or investigational value is clinically significant in the opinion of the 
investigator.
AEs present prior to starting study treatment at day 1 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 


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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.
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 date of the event, severity, meeting 
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 [Section 5.5.8].  For subjects that continue into the post study 
follow-up period, SAEs, cardiovascular and thromboembolic AEs will be captured until their 
projected date of completion of the follow-up period (i.e. projected EOS visit).
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 
baseline or previous visit, but shall not be specifically solicited.  There will be no directed 
questioning for any specific AE.  This does not preclude the site from collecting and recording 
any AEs reported by the 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 of an AE.
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


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Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent 1 of the other outcomes listed in the definition 
above.  These events, including those that may result in disability/incapacity, should also 
usually be considered serious.  Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that 
do not result in hospitalization; or development of drug dependency or drug abuse.
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 interaction
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 h 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.
Lack of efficacy (Hb decrease, worsening anemia without significant clinical symptoms) 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 reason these events do not need to be reported.
Off-label use of roxadustat can be excluded for reporting as the product is under development.
If a special situation also induces an AE, 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 AEs.  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 an 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 Adverse Events (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 
In the case of an SAE, the investigator must contact the delegated CRO (INC Research) by 
telephone, e-mail 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 immediately 
(within 24 h of awareness).  Toll free fax number for each country are provided on the fax 
coversheet of the SAE worksheet. In case of fax failure the SAE Worksheet should be 
emailed to the delegated CRO.


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If the faxing of an SAE Worksheet is not possible or is not possible within 24 h, the local 
drug safety contact should be informed by phone.
The contact details of the delegated CRO are:
E-mail: INCDrugSafety@INCResearch.com
Fax (general): +49 89 99 39 13 422
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 any questions, or if clarification is needed regarding the SAE, please contact the 
sponsor’s medical monitor or his/her designee or the delegated CRO (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 after awareness).
Full details of the SAE should be recorded on the medical records and on the eCRF.  The 
investigator must ensure that information on the SAE Worksheet is reconciled with the 
information on the AE pages within the eCRF.
The following minimum information is required to be completed on the SAE Worksheet:
●
The International Study Number (ISN)/Study number 1517-CL-0613, 
●
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 poststudy 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 IRB)/ IEC within timelines set 
by regional regulations (i.e. EU).  Documentation of the submission to and receipt by the 
IRB/IEC of expedited safety reports should be retained by the site.
The delegated CRO will notify all investigators responsible for ongoing clinical studies with 
the study drug of all SAEs, which require submission per local requirements IRB/IEC/head 
of the study site.
The investigators should provide written documentation of IRB/IEC notification for each 
report to the sponsor.
Please contact the sponsor's medical monitor for any other problem related to the safety, 
welfare, or rights of the subject.


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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
Monitoring of Common Serious Adverse Events
Common SAEs are SAEs commonly anticipated to occur in the study population independent 
of drug exposure. SAEs classified as “common” are progression to ESRD.  This does NOT 
change the investigator’s reporting obligations or prevent the need to report an AE meeting 
the definition of an SAE as detailed above.  The purpose of this is to alert the investigator 
that some events reported as SAEs may not require expedited reporting to the regulatory 
authorities based on the classification of “common serious adverse events”.  The sponsor will 
monitor these events throughout the course of the study for any change in frequency.  Any 
changes will be communicated to the participating investigational sites.  Investigators must 
report individual occurrences of these events as stated in Section 5.5.5
5.5.8
Procedure in Case of Pregnancy
If a female subject or 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 in specific forms to the delegated CRO, with timelines 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.  
Additional details should be provided in part C during the pregnancy and/or after the delivery.
The expected date of delivery or expected date of the end of the pregnancy, last menstruation, 
estimated conception date, pregnancy result and neonatal data etc., should be included in this 
information.
The investigator will follow the medical status of the mother, as well as the fetus and will 
report the outcome to the sponsor as if the pregnancy is an SAE.
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


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●
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 this study and up to 12 weeks after the EOT visit, the partner of a 
male subject becomes pregnant, the subject should report the pregnancy to the investigator.  
The investigator will report the pregnancy to the delegated CRO as an SAE.
5.5.9
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 [Section 5.1.5].  The 
sponsor’s medical monitor should be contacted as applicable.
In the event of suspected epoetin alfa or darbepoetin alfa overdose, refer to the SmPCs.
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 (see 
Section 5.1.5).
The therapeutic margin for epoetin alfa is also wide and it has approximately a 3-fold shorter 
half-life than darbepoetin alfa.  Similar to darbepoetin alfa, no specific symptoms of overdose 
have been observed.  In case of polycythemia, same interventions as for darbepoetin alfa 
should be applied, e.g. temporarily withheld dosing and, if clinically indicated, phlebotomy.
5.5.10
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 and will inform the subjects.  Obtaining renewed signature on an adapted ICF may be 
required.
5.6
Test Drug Concentration
For evaluation of PK in subjects on HD/HDF and PD (continuous ambulatory peritoneal 
dialysis [CAPD] and automated peritoneal dialysis [APD]), blood samples will be obtained 
from roxadustat treated subjects only. The intention is to collect 6 blood samples per 
roxadustat treated subject at the following time points:


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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 1 visit, or over 2 to 3 visits for HD/HDF (as illustrated 
in [Table 7]). The preferred schedule and order of PK visits is a joint decision by the 
investigator and study subject. For APD subjects, it is recommended to collect all 6 samples 
in a single visit (as illustrated in [Table 8]). For CAPD subjects, all 6 samples must be 
collected in a single visit (as illustrated in [Table 9]). The PK 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).
During weeks 1 to 8 subjects treated with roxadustat will be instructed to record the date and
time of roxadustat intake in the Study Medication Diary.  The information will be used to 
record the date and time of the roxadustat intake on the occasion prior to PK sampling and 
the day of PK sampling in the eCRF.  The date and time of each PK sample and the actual 
study drug dose taken on the day of sampling will be recorded in the eCRF.
Sample A should be scheduled on a day when previous study drug intake was less than 3 days 
prior to the current visit to ensure quantifiable predose samples.
During each PK visit 1 additional sample will be collected for determination of alpha 1-Acid 
Glycoprotein (α1-AGP) and albumin concentration.
Subjects on HD/HDF:
According to Section 5.1 of the protocol, for HD subjects it is recommended that roxadustat 
is administered any time after completion of dialysis if dosing is scheduled on a dialysis day 
to avoid potential bias on certain study assessments.
However, at all days when PK sampling is scheduled roxadustat must be taken prior to 
dialysis start.  Roxadustat must be taken at the site for PK visit 1 [Table 7].
In addition, at the PK visits, the start and end time of the dialysis should also be recorded in 
the eCRF.


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Table 7
Examples of Sampling Schedules for Population PK for Subjects on 
Hemodialysis/Hemodiafiltration
Schedule
†
PK Visit 1
PK Visit 2
PK Visit 3
1
Collect predose sample A.
Take roxadustat at site.
Start hemodialysis.
Collect samples B to E.
[Stop hemodialysis.]‡
Collect sample F.
None
None
2
Collect predose sample A.
Take roxadustat at site.
Start hemodialysis
Collect samples B and C.
[Stop hemodialysis.]‡
Take roxadustat.
Start hemodialysis.
Collect samples D to E.
[Stop hemodialysis.]‡
Collect sample F.
None
3
Collect predose sample A.
Take roxadustat at site.
Start hemodialysis
Collect samples B and C.
[Stop hemodialysis.]‡
Take roxadustat.
Start hemodialysis.
Collect sample D and E.
[Stop hemodialysis.]‡
Take roxadustat.
Start hemodialysis.
[Stop hemodialysis.]‡
Collect sample F.
† The order of the PK visits for schedule 2 and 3 is a joint decision by the investigator and study subject.
‡ The stop of hemodialysis is independent of blood sample collection. Hemodialysis must not start before 
roxadustat is taken on PK days.
Subjects on APD:
For APD subjects, it is recommended to collect all 6 samples in a single visit. At PK visit 1, 
roxadustat must be taken at the site.  Day-time (manual) PD fluid changes for APD patients 
are not allowed on the day of PK sampling.  In case of subsequent PK visits, roxadustat must 
be taken after draining the last night-time PD fluid prior to the site visit.
Table 8
Example of Preferred Sampling Schedule for Population PK for Subjects 
on APD
Schedule
PK Visit 1
PK Visit 2
PK Visit 3
1
Collect predose sample A.
Take roxadustat at site.
Collect samples B to F.
None
None
Subjects on CAPD:
PK sampling
Subjects on CAPD must complete all PK sampling on a single visit (PK visit 1).  Roxadustat 
must be taken at the site prior to initiation of the first dialysis cycle at the site.
Dialysate
Collection of dialysate is to be performed on the same day as PK sampling (roxadustat treated 
subjects only).  For the evaluation of the roxadustat concentration in dialysate, a dialysate 
sample of 20 mL is collected at the end of the first dialysis cycle at the site.  The sample should 
be withdrawn from the drainage bag after draining the complete volume.  The total infused 


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volume and drained volume of the first dialysis, the start and end time and date of the first 
dialysis cycle at site and the start time of the second dialysis cycle at site must be recorded in 
the eCRF.  The start time of the dialysis cycle is defined as the start of the infusion of a 
solution bag into the abdominal cavity and end time is defined as the time when draining of the 
volume into the drainage bag is completed.  All details on the processing of the sample, storage 
and shipment conditions will be provided in the laboratory manual.
Table 9
Example of Sampling Schedule for Population PK for Subjects on CAPD
Schedule
PK Visit 1
PK Visit 2
PK Visit 3
1
Collect predose sample A.
Take roxadustat at site.
Start first dialysis cycle.
Collect samples B to D.
Collect dialysate. 
Start second dialysis cycle at site.
Collect samples E to F.
None
None
5.6.1
Blood Samples for roxadustat PK Analysis
Samples of venous blood for bioanalysis of roxadustat and related metabolites of roxadustat 
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 evaluated as covariates in the PK analysis, 
since both albumin and α1-AGP are involved in plasma protein binding of roxadustat.  Serum 
albumin and α1-AGP will be analyzed by the central laboratory using a standardized assay.  
All details on the processing of the samples, storage and shipment conditions will be 
provided in the laboratory manual.
5.7.2
Hepcidin in Serum
For the determination of hepcidin, serum samples will be drawn at the visits as indicated in 
Schedule of Assessment.  All details on the processing of the samples, storage and shipment 
conditions will be provided in the laboratory manual.
5.7.3
Archival of Serum Samples for Biomarker Analysis
Serum samples will be drawn at the visits as indicated in the Schedule of Assessments.  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 destructed (if not used in total), maximally 5 years after the 
last subject completed the study.  All details on the processing of the samples, storage and 
shipment conditions will be provided in the laboratory manual.


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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 after randomization, preferably on day 1. The sample will be 
collected into prelabeled polypropylene collection tubes containing EDTA as anticoagulant. 
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 Astellas Pharma Europe B.V.  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 deoxyribonucleic acid) will be managed in 
strictly secured condition and they will be destroyed maximally 5 years after the last subject 
completed the study according to relevant guidances and procedures.
5.8
Total Amount of Blood
The total amount of blood to be collected per subject during the study (screening period, 
treatment period and the follow-up period) is estimated to be approximately 475 mL.
6
DISCONTINUATION
6.1
Discontinuation of Individual Subject(s)
A discontinuation is a subject who was 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.
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:


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●
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.
●
Subject no longer consents to participate in treatment phase of the study.
●
Subject receives an organ transplant
●
Subject randomized to roxadustat who requires a second course of ESA rescue therapy
If subjects have prematurely discontinued study treatment and have taken at least 1 dose of 
study drug), they will continue to be followed up at a 6-monthly frequency for the subject’s 
vital status, SAEs and cardiovascular and thromboembolic AEs until their projected date of 
completion of follow-up period (i.e. projected EOS visit) or until consent 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.
The sponsor may decide to prematurely stop the entire study, e.g. for safety considerations.
6.2
Discontinuation of the Site
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the sponsor.  The sponsor may terminate the study at a study site in 
exceptional circumstances, such as a prolonged period without any enrolments at the site or 
significant non-adherence to the protocol or GCP requirements.
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.  As this is an open-label study, 
the SAP will be finalized prior to accumulation of a substantial amount of data to ensure lack 
of bias. Any changes from the analyses planned in SAP will be justified in the Clinical Study 
Report (CSR).
Prior to database lock, a final review meeting of data and Tables/Listings/Figures will be 
held.  Additionally, a meeting to determine analysis set classifications will also take place 


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prior to database lock.  If required, consequences on the statistical analysis will be discussed 
and documented.
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
The study is sufficiently powered for both regionally-based primary efficacy endpoints. 
Approximately 750 subjects will be randomized to receive roxadustat or ESA in an 
open-label fashion in a 1:1 ratio.  Randomization will be stratified by the following 5 factors:
●
Region (region A versus region B*)
●
Previous ESA treatment (epoetin versus darbepoetin alfa)
●
History of cardiovascular, cerebrovascular or thromboembolic diseases (Yes versus No)
●
Average prescribed weekly ESA dose in last 4 weeks prior to randomization 
(≤200 IU/kg epoetin or ≤ 1 μg/kg darbepoetin alfa versus >200 IU/kg epoetin or 
> 1 μg/kg darbepoetin alfa)
●
Screening Hb value (≤11.0 g/dL versus >11.0 g/dL)
* Country assignment to region A and B will be determined based on health care system comparability.
EU (EMA)
Results from simulations of the EU primary efficacy endpoint in stable dialysis subjects 
suggest that dosing levels of ESA prior to randomization may play a role in Hb response.  
Therefore, the EU primary analysis of this study will be tested both in the overall population 
and in the subgroup of patients defined as subjects with an average prescribed weekly epoetin 
or darbepoetin dose within the last 4 weeks prior to randomization ≤ 200 IU/kg or ≤ 1 μg/kg 
respectively, following a parametric chain procedure [Millen et al, 2011; Spiessens et al, 
2010].  The information fraction will be calculated at the time of database hard lock; it is 
defined as the number of subjects in the subgroup with respect to the number of subjects in the 
total study population. 
Assuming that the Per Protocol Set (PPS) analysis will consist of 80% of the randomized 
subjects, 750 randomized subjects will lead to approximately 600 subjects in the PPS.  The 
overall 1-sided significance level (alpha) is fixed at 0.025 and the non-inferiority margin for 
the EU primary endpoint has been fixed to 0.75 g/dL.  The overall alpha will be equally 
allocated to each of the 2 test populations.  If we assume an information fraction of 0.80, this 
rule will lead to a significance level of 0.0174. 
In this setting, 300 subjects for the roxadustat treatment group and 300 subjects for the ESA 
treatment group will provide 97% power to statistically demonstrate noninferiority of 
roxadustat versus ESA in the EU primary endpoint in both the total study population and the 
planned subgroup analysis assuming a difference (roxadustat minus ESA) of -0.25 g/dL in the 
Hb change from baseline and an SD of 1.5 g/dL.  In the case that these assumptions do not 
hold across the overall population, the planned procedure can still allow for a successful 
conclusion for the subgroup.


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US (FDA)
With 750 randomized subjects (Intention To Treat Set [ITT]), the study will provide at least 
99% power to demonstrate statistical non-inferiority of roxadustat versus ESA in the primary 
endpoint for US submission.
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:
●
Intention To Treat Set (ITT)
●
Full Analysis Set (FAS)
●
PPS
●
Safety Analysis Set (SAF)
●
Pharmacokinetic Analysis Set (PKAS)
7.2.1
ITT
All randomized subjects will be included in the ITT. 
The primary US endpoint will be analyzed using the ITT. The primary EU endpoint and 
selected secondary efficacy endpoints will be analyzed using the ITT in secondary analyses.
7.2.2
FAS
All randomized subjects who received at least 1 dose of study drug and have at least 1
postdose Hb assessment will be included in the FAS.
The primary US and EU endpoints will be analyzed using the FAS in secondary analyses. 
Selected secondary efficacy endpoints will be analyzed using the FAS.
7.2.3
PPS
All FAS subjects who received at least 12 weeks of study treatment with at least 1 postdose Hb 
assessment and without any criteria for PPS exclusion will be included in the PPS.
Criteria for PPS exclusion will be defined in the SAP.  The primary EU endpoint will be 
analyzed using the PPS. Selected secondary efficacy endpoints will be analyzed using the 
PPS.
Additional PPS sub-populations (e.g. PPS-36) will be described in the SAP.
7.2.4
SAF
All subjects that received at least 1 dose of study drug will be included in the SAF. All safety 
data will be analyzed using the SAF.
7.2.5
PKAS
The PKAS consists of all randomized subjects who meet the following criteria:
●
Received at least 1 dose of study drug, and 


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●
At least 1 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 population PK analysis.
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, FAS, ITT and 
PPS populations.
Descriptive statistics will be calculated for continuous variables (e.g., age, weight, baseline Hb, 
body mass index, and average weekly ESA [epoetin and darbepoetin alfa] dose in last 4 weeks 
prior to randomization) by treatment arm.  Frequency counts and percentages will be tabulated 
for categorical variables (e.g., sex, race, previous ESA treatment, average prescribed weekly 
ESA [epoetin and darbepoetin alfa] dose in last 4 weeks prior to randomization [categorical], 
baseline Hb [categorical], region, mode of dialysis, and history of cardiovascular, 
cerebrovascular or thromboembolic disease) by treatment arm.
7.4
Analysis of Efficacy
7.4.1
Analysis of Primary Endpoint
There are 2 separate regionally based primary efficacy endpoints in this study, depending 
upon whether the data are being filed to support submission to the US FDA or to Ex-US 
health authorities, such as the EMA.
●
The EU (EMA) primary efficacy endpoint is change in Hb from BL to the average level 
during the evaluation period (defined as week 28 until week 36), without having received 
rescue therapy (i.e. RBC transfusion for all subjects or ESA for subjects treated with 
roxadustat) within 6 weeks prior to and during this 8-week evaluation period.
●
The US (FDA) primary efficacy endpoint is change in Hb from BL to the average level 
during the evaluation period (defined as week 28 until week 52), regardless of rescue 
therapy.
The central laboratory reported Hb values will be used for this analysis.
7.4.1.1 Primary Analysis
EU (EMA)
The EU primary efficacy endpoint will be analyzed using a Mixed Model Of Repeated 
Measures (MMRM) method with an unstructured covariance matrix.  The model will contain 
terms for treatment arm, baseline Hb measurement, visit, visit x treatment arm and other 
stratification factors.
For subjects who require rescue therapy, the reported values after the initiation of rescue 
therapy will be set to missing for 6 weeks; the MMRM model will implicitly impute missing 
data via the within-patient correlation structure.


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Difference of least square means (roxadustat minus ESA) and its 100x(1-α*2)% CI will be 
estimated for the average of weeks 28 to 36.  The significance level α is fixed by the 
parametric chain procedure explained below.
The primary analysis of the EU primary efficacy endpoint will be tested both in the overall 
population and in the subgroup of patients defined as subjects with an average prescribed 
weekly epoetin or darbepoetin dose within the last 4 weeks prior to randomization 
≤200 IU/kg or ≤ 1 μg/kg, respectively, following a parametric chain procedure [Millen et al., 
2011; Spiessens et al, 2010].
The 2 null hypotheses to be tested are:
●
HA0: Hb change from baseline in the roxadustat arm ≤ Hb change from baseline in the 
ESA arm minus 0.75 g/dL in the total study population 
●
HB0: Hb change from baseline in the roxadustat arm ≤ Hb change from baseline in the 
ESA arm minus 0.75 g/dL in the subgroup population
The alternative hypotheses HA1 and HB1 are defined as the negation of the null hypotheses 
HA0 and HB0 respectively.  The information fraction will be calculated at the time of database 
hardlock as the number of subjects in the subgroup with respect to the number of subjects in 
the total study population. 
The overall 1-sided significance level (alpha) is fixed at 0.025.  The overall alpha will be 
equally allocated to each of the 2 null hypotheses defined above.  In case of an information 
fraction of 0.80, this rule will lead to significance level of 0.0174.  Following the parametric 
chain procedure, if at least 1 of both hypotheses is rejected at the significance level of 0.0174, 
the other 1 can be tested at a significance level of 0.025 while still strongly controlling the 
overall type I error.  The study will be successful for the EU primary efficacy endpoint if 
either of the null hypotheses is rejected, i.e. if the lower limit of the 2-sided 100x(1-α*2)% CI 
for the difference in least square means from the MMRM model is greater than -0.75g/dL.
The EU primary analysis will be tested on the PPS. 
The analysis will be repeated on the FAS and ITT as secondary analyses.  In addition, an 
Analysis of Covariance (ANCOVA) model with Last Observation Carried Forward (LOCF) 
will be used for imputation of missing values (see Section 7.4.1.2 for secondary analyses).
US (FDA)
The US primary efficacy endpoint will be analyzed using an MMRM method with an 
unstructured covariance matrix.  The model will contain terms for treatment arm, baseline Hb 
measurement, visit, visit x treatment arm and other stratification factors.
The null hypothesis to be tested for the US primary efficacy analysis is:
●
H0: Hb change from baseline in the roxadustat arm ≤ Hb change from baseline in the 
ESA arm minus 0.75 g/dL


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The alternative hypothesis H1 is defined as the negation of the null hypothesis H0.  The 
overall 1-sided significance level (alpha) is fixed as 0.025.  The study will be successful for 
the US primary endpoint if the null hypothesis is rejected.
The US primary analysis will be tested on the ITT.
The analysis will be repeated on the FAS and PPS as secondary analyses. In addition, an 
ANCOVA model with LOCF will be used for imputation of missing values (see 
Section 7.4.1.2 for secondary analyses).
Justification of the non-inferiority margin
The clinical importance of a -0.75 g/dL change in Hb has been selected whilst taking into 
consideration the biological variability in Hb, the effect on Hb from transfusing a single unit 
of packed RBCs, and clinical factors that affect Hb measurements.
7.4.1.2 Secondary Analyses
Interpretation of results will be based on the primary analysis sets (PPS for EU primary 
efficacy endpoint and ITT for US primary efficacy endpoint). Sensitivity (secondary) 
analyses with other analysis sets will be conducted to assess the robustness of the results 
from the statistical tests.
The same analysis of the primary endpoint as described in Section 7.4.1.1 will be repeated 
using the following analysis sets:
●
For the EU primary efficacy endpoint, the FAS and the ITT,
●
For the US primary efficacy endpoint, the PPS and the FAS.
Another sensitivity analysis for the EU and US primary efficacy endpoints will be performed 
to handle missing data using an ANCOVA model including baseline Hb and other 
stratification factors as covariates. Missing data will be imputed using the LOCF method.
In addition, a sensitivity analysis on the 2 primary efficacy endpoints (EU and US) will be 
performed on the subgroup of patients being randomized after the implementation of 
protocol v2.0, using the PPS (EU primary efficacy endpoint) and the ITT (US primary 
efficacy endpoint).
Additional sensitivity analyses will be described in the SAP.
7.4.1.3 Subgroup Analysis
The analyses will be repeated separately for the following subgroups:
●
Subjects pretreated with epoetin versus subjects pretreated with darbepoetin alfa.
●
HD (including hemodiafiltration) versus PD.
●
Subjects with an average prescribed weekly epoetin or darbepoetin dose within the last 4
weeks prior to randomization ≤ 200 IU/kg or ≤ 1 μg/kg versus subjects with an average 
> 200 IU/kg or > 1 μg/kg respectively.
Other subgroup analyses will be described in the SAP.


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7.4.2
Analysis of Key Secondary Endpoints
Once a primary hypothesis has been rejected for the EU primary efficacy endpoint, the 
secondary endpoints will be tested as described below using a fixed sequence testing 
procedure.
These tests will be performed only for the overall population in the case that the primary 
hypothesis was rejected for the overall study population.  If the EU primary analysis was not 
successful for the overall population, but only for the subgroup, then the tests will be 
performed only for the subgroup.  The subgroup population is defined as subjects with an 
average prescribed weekly epoetin or darbepoetin dose within the last 4 weeks prior to 
randomization ≤200 IU/kg or ≤ 1 μg/kg. 
The central laboratory reported Hb values will be used for this analysis.
7.4.2.1 Primary Analysis
The EU primary analysis set will be tested on the PPS for the non-inferiority tests and the FAS 
for the superiority tests.
The secondary endpoints will be tested using a fixed sequence testing procedure, as depicted 
below in [Table 10] in order to maintain the overall 1-sided type I error rate for the set of 
secondary endpoints at 0.025.  If the null hypothesis is rejected, 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
Key Secondary Endpoints Fixed Sequence Testing Procedure
Test
Variable
Comparison
1
Proportion of Hb responders in the average of weeks 28 to 36 
without having received rescue therapy. The non-inferiority 
margin for the difference between groups is 0.15.
Non-inferiority of 
roxadustat versus ESA
2
LDL cholesterol change from BL to the average of weeks 12 
to 28.
Superiority of 
roxadustat versus ESA
3
Monthly IV iron (mg) use per subject during weeks 1 to 36.
Superiority of 
roxadustat versus ESA
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 
roxadustat versus ESA
5
SF-36 VT 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 
roxadustat versus ESA
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 
roxadustat versus ESA
7
Time to an increase in blood pressure during weeks 1 to 36. 
The non-inferiority margin is fixed as a hazard ratio of 1.3.
Non-inferiority of 
roxadustat versus ESA
Table continued on next page


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Test
Variable
Comparison
8
MAP change from BL to the average MAP of weeks 20 to 28.
Superiority of 
roxadustat versus ESA
9
Time to an increase in blood pressure during weeks 1 to 36.
Superiority of 
roxadustat versus ESA
1.
The difference in the proportion of Hb responders in the average of weeks 28 to 36 
between roxadustat and ESA will be calculated using the Miettinen & Nurminen 
[Miettinen et al, 1985] approach adjusting for the stratification factors. The null hypothesis 
will be rejected if the lower bound of the 2-sided 100x(1-α*2)% CI for the difference of 
proportions (roxadustat minus ESA) is greater than -0.15.
2.
Change from BL in LDL cholesterol to the average value of LDL cholesterol of weeks 
12-28 will be compared (roxadustat versus ESA) using an MMRM method including BL 
Hb value and other stratification factors as covariates.  Superiority will be declared if the 
upper bound of the 2-sided 100x(1-α*2)% CI of the difference (roxadustat minus ESA) is 
lower than 0 mg/dL.
3.
Monthly IV iron use (mg) during weeks 1 to 36 will be compared (roxadustat versus ESA) 
using an MMRM method including BL Hb and other stratification factors as covariates. 
Superiority will be declared if the upper bound of the 2-sided 100x(1-α*2)% CI of the 
difference (roxadustat minus ESA) is lower than 0 mg.
4.
Change from BL in PF subscore of SF-36 to the average of weeks 12–28 will be compared 
(roxadustat versus ESA) using an MMRM method including BL Hb value and other 
stratification factors as covariates.  Non-inferiority can be concluded if the lower bound of 
the 2-sided 100x(1-α*2)% CI of the difference (roxadustat minus ESA) is greater than 
-3 points.
5.
Change from BL in VT subscore of SF-36 to the average of weeks 12–28 will be 
compared (roxadustat versus ESA) using an MMRM method including BL Hb value and 
other stratification factors as covariates.  Noninferiority can be concluded if the lower 
bound of the 2-sided 100x(1-α*2)% CI of the difference (roxadustat minus ESA) is greater 
than -3 points.
6.
Change from BL in MAP to the average of weeks 20–28 will be compared (roxadustat 
versus ESA) using an MMRM including BL Hb value and other stratification factors as 
covariates.  Noninferiority can be concluded if the upper bound of the 2-sided 
100x(1-α*2)% CI of the difference (roxadustat minus ESA) is lower than 1 mmHg. 
7.
Time to an increase in blood pressure during weeks 1 to 36 will be compared (roxadustat 
relative to ESA) using a Cox Proportional Hazards regression analysis including BL Hb 
value and other stratification factors as covariates. Noninferiority will be declared if the 
upper bound of the 2-sided 100x(1-α*2)% CI of the hazard ratio (roxadustat relative to 
ESA) is lower than 1.3.
8.
Change from BL in MAP to the average of weeks 20–28 will be compared (roxadustat 
versus ESA) using an MMRM method including BL Hb value and other stratification 


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factors as covariates.  Superiority will be declared if the upper bound of the 2-sided 
100x(1-α*2)% CI of the difference (roxadustat minus ESA) is lower than 0 mmHg.
9.
Time to an increase in blood pressure during weeks 1 to 36 will be compared (roxadustat 
relative to ESA) using a Cox Proportional Hazards analysis including BL Hb value and 
other stratification factors.  Superiority will be declared if the upper bound of the 2-sided 
100x(1-α*2)% CI of the hazard ratio (roxadustat relative to ESA) is lower than 1.
7.4.2.2 Secondary Analyses
The analysis of the secondary endpoints as described in Section 7.4.2.1 will be repeated using
the following analysis sets:
●
For non-inferiority tests, the FAS and the ITT
●
For superiority tests, the PPS and the ITT.
For all secondary endpoints analyzed using an MMRM method, an additional sensitivity 
analysis will be performed to handle missing data using an ANCOVA model with the LOCF 
method.
Additional sensitivity analyses will be defined in the SAP.
7.4.2.3 Subgroup Analysis
All secondary endpoints of this study will be analyzed separately using the same subgroups 
as for the primary endpoint (see Section 7.4.1.3).
7.4.3
Analyses of Additional Secondary Endpoints
The statistical analyses of the additional secondary 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 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 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.
Safety data and dosing decisions will be monitored on an ongoing basis.  Ongoing review of 
safety data will be conducted by an independent DSMB.  The statistical method for analysis 
of adjudicated safety data will be detailed in a separate SAP.  Adjudicated safety data will be 
reported in a separate report.


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7.5.1
Adverse Events
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).
An AE (classified by preferred term) occurring during the treatment period will be 
considered a TEAE if it was not present prior to the first dose of study drug, or if 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 1
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 TEAEs, fatal SAEs (i.e. events that caused death), and AEs 
leading to discontinuation of study drug will be summarized by SOC, preferred term and 
treatment group.
TEAEs will also be reported in terms of cumulative incidence versus time and as an incidence 
rate per subject-exposure-year.
For the purpose of EU regulatory filing and other submissions: Adjudicated MACE+ events 
(i.e., myocardial infarction, stroke, death from all causes, hospitalization for chronic heart 
failure, hospitalization for unstable angina) and other pre specified events will be pooled and 
analyzed across multiple studies in the global phase 3 program.  This analysis will be described 
in a separate pooled safety statistical analysis plan.  For the purpose of US FDA regulatory 
filing: Adjudicated major cardiovascular adverse events (MACE; i.e., myocardial infarction, 
stroke, death from all causes) will be pooled across multiple studies in the global phase 3 
program to serve as primary safety endpoint.  The adjudicated MACE events in this study will 
be part of this pooled analysis, but will not be a self-contained endpoint within this individual 
study.  
Adjudicated safety data will be reported in a separate report.
Listings will be presented of subjects with SAEs, subjects with AEs leading to discontinuation 
and subjects who died.
7.5.2
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.


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7.5.3
Vital Signs
Descriptive statistics for vital signs (e.g., systolic and diastolic blood pressure, respiratory 
rate and heart rate) 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 (see Section 5.4.5) 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.  The QT interval corrected for heart rate (QTc) will be 
calculated using both Bazett [QTcB = QT/(RR1/2)] and Fridericia [QTcF = QT/(RR1/3)] 
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 CSR but in a separate population PK 
report.  Plasma concentration listings will be presented only in the CSR.
7.7
Analysis of Pharmacodynamics
Pharmacodynamic data may be submitted to population pharmacodynamic or population 
pharmacokinetic/pharmacodynamic modeling.  When deemed necessary, data from this study 
may be combined with data from other studies.  Results will be reported in a separate 
population pharmacokinetic/pharmacodynamic modeling 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.
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,
PD4 - Received prohibited concomitant treatment.
7.9
Interim Analysis
There will be no interim analysis of the 52 week data.
Safety data and dosing decisions will be monitored on an ongoing basis.  Ongoing review of 
safety data will be completed by an independent DSMB [Section 10.1].


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7.10
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
The primary analysis method to handle missing data of the efficacy primary and secondary 
endpoints with repeated measures over time will be the MMRM.  In addition, as a sensitivity 
analysis to handle missing data, an LOCF method will be performed for these endpoints.
Visit time windows and additional sensitivity analyses will be detailed in the SAP.
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS
8.1
Procedure for Clinical Study Quality Control
8.1.1
Data Collection
The investigator or site designee will enter data into an eCRF using an Electronic Data 
Capture 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 while the subject is at the site.  The investigator or site designee 
will enter the relevant information from the subject diary (i.e. study medication intake data 
related to PK sampling) and all questionnaire data directly into the Electronic Data Capture 
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 site via a site portal.  More details are described in a separate laboratory manual. 
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:
●
Subject identification number
●
Demographic data (date of birth, sex, race, height and body weight)


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●
Inclusion and exclusion criteria details
●
The identification of the participation in study and the study number 1517-CL-0613 
●
Original signed and dated ICFs
●
Visit dates
●
Medical history and physical examination details
●
Key efficacy and safety data
●
AEs and concomitant medication
●
Results of HemoCue® device Hb assessments on all visits
●
Decision on study drug dosage on all visits
●
Results of relevant examinations such as ECG charts, renal ultrasound outcome.
●
Laboratory printouts (such as Central Laboratory assessments, including certification by 
the investigator of abnormal laboratory data being clinically relevant or not)
●
Dispensing and return of study drug details, including study medication Kit numbers and 
tablets returned
●
Reason for premature treatment discontinuation or study withdrawal (if applicable)
●
Method of contraception for subjects or subject’s partner of childbearing potential.
8.1.3
Clinical Study Monitoring
The sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that 
subject's human rights, safety, and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP, and study data reported by the 
investigator/sub-investigator are accurate and complete and that they are verifiable with study-
related records such as source documents.  The sponsor is responsible for assigning study 
monitor(s) to this study for proper monitoring.  They will monitor the study in accordance with 
planned monitoring procedures.
8.1.4
Direct Access to Source Data/Documents
The investigator and the study site must accept monitoring and auditing by the sponsor or 
delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities. 
In these instances, they must provide all study-related records, such as source documents 
(refer to Section 8.1.2) 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 Global Data Science 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 the MedDRA and WHO Drug Dictionary respectively.


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8.1.6
Protocol Deviations
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change.  The investigator is responsible for ensuring 
the study is conducted in accordance with the procedures and evaluations described in this 
protocol and must protect the rights, safety, and welfare of subjects.  The investigator should 
not implement any deviation from, or changes of, the protocol, unless it is necessary to 
eliminate an immediate hazard to trial subjects.
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol.  Protocol waivers are strictly prohibited.
For the purposes of this protocol, deviations requiring notification to sponsor are defined as 
any subject who:
●
Entered into the study even though they did not satisfy entry criteria (PD1).
●
Developed withdrawal criteria during the study and not withdrawn (PD2).
●
Received wrong treatment or incorrect dose (PD3).
●
Received prohibited concomitant treatment (PD4).
When a deviation from the protocol is identified for an individual subject, the local monitor, 
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 Study in All Participating Countries
The end of study is defined as the Last Subject’s Last Visit.
8.2
Ethics and Protection of Subject Confidentiality
8.2.1
IRB / IEC / Competent Authorities
GCP requires that the clinical protocol, any protocol amendments, the IB, 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 


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and/or advertising, as relevant, will be obtained prior to the authorization of drug shipment to 
a study site.
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 1 year.  The sponsor 
shall submit a summary of the final clinical study report to the IRB/IEC and the Regulatory 
Agency within 1 year after last subject out 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. The 
sponsor will develop an ICF containing all relevant information on the study and the 
investigational products.  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
The investigator or his/her representative will immediately inform the subject verbally 
whenever new information becomes available that may be relevant to the subject’s consent or 


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may influence the subject’s willingness to continue to participate in the study (e.g., report of 
serious drug adverse drug reactions).  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.
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 ICF.  A copy of the signed ICF 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 IB 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:
●
Study protocol (and amendments, as applicable)
●
IB (and amendments, as applicable)
●
Investigational Medicinal Product Dossier (IMPD) 
●
Questionnaires and SAE Report Worksheets
●
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:
●
Financial disclosure in compliance with federal regulation 21CFR Part 54
●
Signed and dated FDA form 1572
●
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
●
IRB/IEC 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 and study drug containers of used study drugs
The investigator will archive all study data (e.g., Subject Identification Code List, source data, 
CRFs, Questionnaires 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 granted or if the IMPD is 
discontinued.
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.


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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.
9
QUALITY ASSURANCE
The sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that studies are conducted and data are generated, documented, 
recorded, and reported in compliance with the protocol, GCP, and applicable regulatory 
requirement(s).


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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
DSMB and Other Evaluation Committee(s)
A DSMB will review prespecified safety data of the current study and of other studies 
conducted by the sponsor with roxadustat periodically in collaboration with the Sponsor to 
ensure subject safety.
A DSMB charter will establish the process, meeting frequency and scope of responsibilities.
An Independent Event Review Committee will adjudicate all relevant cardiovascular and 
cerebrovascular events in a blinded manner to ensure consistent safety assessment.  Details of 
event identification and process of adjudication will be described in an Independent Event 
Review Committee charter.
10.2
Other Study Organization
This section is not applicable in the study.


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11
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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, et al.  Chronic Kidney Disease and 
Mortality Risk: A Systematic Review. JASN. 2006;17:(7): 2034-47.
Unger EF.  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 Renal Data System (USRDS). Annual Data Report 2000.
Available from:  http://www.usrds.org/atlas00.aspx
United States Renal Data System (USRDS). Annual Data Report 2001 
Available from:  http://www.usrds.org/atlas01.aspx
United States Renal Data System (USRDS). Annual Data Report 2002 
Available from:  http://www.usrds.org/atlas02.aspx
United States Renal Data System (USRDS). Annual Data Report 2003
Available from: http://www.usrds.org/atlas03.aspx
United States Renal Data System (USRDS). Annual Data Report 2009
Available from: http://www.usrds.org/atlas09.aspx
United States Renal Data System (USRDS). Annual Data Report 2011 
Available from: http://www.usrds.org/atlas11.aspx
Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS 
heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA. 1995;92(12):5510-14.
Warnecke C, Zaborowska Z, Kurreck J, Erdmann VA, Frei U, Wiesener M, et al. Differentiating the 
functional role of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha (EPAS-1) by the use of 
RNA interference: erythropoietin is a HIF-2alpha target gene in Hep3B and Kelly cells. The 
FASEB Journal. 2004;18(12):1462-64.
Winearls CG, Oliver DO, Pippard MJ, Reid C, Downing MR, Cotes PM. Effect of human erythropoietin 
derived from recombinant DNA on the anaemia of subjects maintained by chronic haemodialysis. 
Lancet. 1986;2(8517):1175-78.
Zhang Y, Thamer M, Stefanik K, Kaufman J, Cotter DJ. Epoetin Requirements Predict Mortality in 
Hemodialysis Subjects. Am J Kidney Dis. 2004;44(5):866-76.
Zoccali C, Kramer A, Jager KJ. Chronic kidney disease and end-stage renal disease – a review produced 
to contribute to the report ‘the status of health in the European union: towards a healthier Europe’. 
NDT Plus. 2010;3(3):213-24.


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12
APPENDICES
12.1
List of Excluded Concomitant Medications
Excluded concomitant medications are mentioned in Section 5.1.3.3


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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 International Normalized Ratio (INR) > 1.5 (If INR testing 
is applicable/evaluated).
●
ALT or AST > 3× ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%).
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring 
and follow-up.
Follow-up Procedures
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, 
physical examination and laboratory tests. The site should complete the Liver Abnormality 
Case Report Form (LA-CRF) that can be activated in the eCRF 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 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: 
●
acute viral hepatitis (A,B, C, D, E or other infectious agents)
●
ultrasound or other imaging to assess biliary tract disease
●
other laboratory tests including INR, direct bilirubin
●
Consider gastroenterology or hepatology consultations.
●
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document.
Study Discontinuation
In the absence of an explanation for increased LFTs, such as viral hepatitis, pre-existing or 
acute liver disease or exposure to other agents associated with liver injury, the subject may be 
discontinued from the study. The investigator may determine that it is not in the subject’s 
best interest to continue study enrollment. Discontinuation of treatment should be considered 
if:
●
ALT or AST > 8 × ULN
●
ALT or AST > 5 × ULN for more than 2 weeks 
●
ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5) (If INR testing is 
applicable/evaluated)
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%).
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 
(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 


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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 Roxadustat-treated Subjects Moving from Protocol 
v1.0 to Protocol v2.0
Subjects that have entered the study under protocol version 1.0 will, at the next scheduled 
visit, receive a dose adjustment as needed according to the conversion table below.
Current TIW dose (mg)
120
350
If no dose titration needed
100
300
If up titration needed*
150
400
If down titration needed*
100
300
* Up or down titrations are only applicable when the criteria for dose adjustment have been met.


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12.4
Short Form-36 Health Survey (SF-36 v2)
Your Health and Well-Being
This survey asks for your views about your health. This information will 
help keep track of how you feel and how well you are able to do your usual 
activities. Thank you for completing this survey!
For each of the following questions, please tick the one box that best 
describes your answer.
1.
In general, would you say your health is:
Excellent
Very good
Good
Fair
Poor





1
2
3
4
5
2.
Compared to one year ago, how would you rate your health in 
general now?
Much better
now than one
year ago
Somewhat
better
now than one
year ago
About the
same as
one year ago
Somewhat
worse
now than one
year ago
Much worse
now than one
year ago





1
2
3
4
5


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


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


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


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9.
These questions are about how you feel and how things have been 
with you during the past 4 weeks. For each question, please give the 
one answer that comes closest to the way you have been feeling. How 
much of the time during the past 4 weeks…
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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12.5
Functional Assessment of Cancer Therapy- Anemia (FACT-AN)


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12.6
EuroQol Questionnaire (EQ-5D-5L)


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12.7
Subject’s Global Impression of Change (PGIC) Scale


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13
ATTACHMENT 1:  SUBSTANTIAL AMENDMENT 2
I.  The purpose of this amendment is:
Substantial Changes
1.
Change in Treatment Period
DESCRIPTION OF CHANGE:
The treatment period was 104 weeks and is being changed to a variable treatment period with 
a minimum of 52 weeks and a maximum of 104 weeks.
RATIONALE:
This study is part of a global clinical development program involving several protocols in 
dialysis patients; the other studies are event-driven and the program will be stopped once 
sufficient clinical safety data has been collected in the overall program.  The planned change 
will reduce the treatment exposure of study subjects. 
2.
Deletion of Interim Analysis
DESCRIPTION OF CHANGE:
An interim analysis was to be performed when all subjects had completed 52 weeks of 
treatment; this interim analysis is removed.
RATIONALE:
There are two separate regionally based primary efficacy endpoints in this study. All data for 
these primary efficacy endpoints are collected in 52 weeks of treatment. The interim analysis 
was scheduled to ensure timely reporting of the primary efficacy endpoints for submission of 
the dossier. 
The treatment period is being changed to a variable duration.  This is aligned with the other 
clinical studies in the program for which the safety data will be pooled for analysis across all 
studies in the dialysis population. Therefore, the interim analysis is not necessary to ensure 
timely reporting and is being removed.  
Nonsubstantial Changes
1.
Minor Administrative-type Changes
DESCRIPTION OF CHANGE: 
The medical monitor contact details are updated.
RATIONALE:
There has been a change in medical monitor and therefore the contact details in the protocol 
are updated.
2.
Change in Completion of Follow-up Period


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DESCRIPTION OF CHANGE:
The completion of the poststudy follow-up period was previously designated as the projected 
week 108 visit.  This is changed to the projected end of study (EOS) visit.
RATIONALE:
This minor change is being made to accommodate the variable treatment period of 52 weeks 
to 104 weeks in this study.
II.  Amendment Summary of Changes:
A.  Substantial Changes:
IV Synopsis and 2 Study Objectives, Design and Endpoints
2.2.1.3 Description of Study
WAS:
The study will consist of three study periods:
●
Screening Period: up to 6 weeks
●
Treatment Period: 104 weeks
●
Follow-up Period: 4 weeks
AND
Subjects will receive study treatment (roxadustat or ESA) for 104 weeks.
IS AMENDED TO:
The study will consist of three study periods:
●
Screening Period: up to 6 weeks
●
Treatment Period: 104 weeks For all subjects in the study the minimum treatment 
duration will be 52 weeks and the maximum treatment duration will be 104 weeks.  
The study end date will be declared when the targeted number of MACE* and 
MACE+** events have been reported across the roxadustat phase 3 development 
program and consequently the treatment will end for all subjects who have 
completed 52 weeks at that point. Subjects who have not completed 52 weeks when 
the target has been declared will continue until they reach 52 weeks and at that 
point their treatment will end.
●
Follow-up Period: 4 weeks
* MACE: Major cardiovascular adverse events: myocardial infarction, stroke, death 
from all causes
** MACE+: Myocardial infarction, stroke, death from all causes, chronic heart failure 
requiring hospitalization, unstable angina requiring hospitalization
AND
Subjects will receive study treatment (roxadustat or ESA) for a minimum of 52 weeks and 
a maximum of 104 weeks.




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IV Synopsis, 2 Study Objectives, Design and Endpoints and 6 Discontinuation
2.2.1.3 Description of Study and 6.1 Discontinuation of Individual Subject(s)
WAS:
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 1 dose of study drug) will continue to be followed up 
at a 6-monthly frequency for vital status, serious adverse events (SAEs) and cardiovascular 
and thromboembolic adverse events (AEs) until their projected date of completion of the 
follow-up period (i.e. projected week 108) or until consent withdrawn.
AND
If subjects have prematurely discontinued study treatment (and have taken at least 1 dose of 
study drug), they will continue to be followed up at a 6-monthly frequency for the subject’s 
vital status, SAEs and cardiovascular and thromboembolic AEs until their projected date of 
completion of follow-up period (i.e. projected week 108) or until consent withdrawn.
AND
The last poststudy follow-up data collection should occur around the projected week 108.
IS AMENDED TO:
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 1 dose of study drug) will continue to be followed up 
at a 6-monthly frequency for vital status, serious adverse events (SAEs) and cardiovascular 
and thromboembolic adverse events (AEs) until their projected date of completion of the 
follow-up period (i.e. projected EOS visit week 108) or until consent withdrawn.
AND
If subjects have prematurely discontinued study treatment (and have taken at least 1 dose of 
study drug), they will continue to be followed up at a 6-monthly frequency for the subject’s 
vital status, SAEs and cardiovascular and thromboembolic AEs until their projected date of 
completion of follow-up period (i.e. projected EOS visit week 108) or until consent 
withdrawn.
AND
The last poststudy follow-up data collection should occur around the projected EOS visit
week 108.


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V Flow Chart and Schedule of Assessments
Table 1 Schedule of Assessments
WAS:
Study Period:
Screening 
Period
Treatment Period
Follow-up Period
Unscheduled 
Visits
Poststudy 
Follow-upc
Visit/Week:
2-6 Weeksa
Day 
1b
Weekly
(Wks 1 to 8)
± 2 days
Every 2 Weeks 
(Wks 10 to 36)
± 2 days
Every 4 Weeks 
(Wks 40 to 100)
± 3 days
EOTc
(Week 104)
± 3 days
EOT 
+ 2 wks
± 3 days
EOSc
(EOT + 4 wks)
± 3 days
Every 6 
months until 
projected Wk 
108
S1
S2
S3
Dialysis procedure
◄───────────────────────────────────────────────────────────────────────►
ESA pre-treatment
◄─────┤
Written informed consent
X
Randomization
X
Eligibility Criteria
X
X
Demographics
X
Height, weight d
X
X
X
X
Wks 12, 24, 36
Wks 52, 76
X
X
O
Medical History
X
Physical Examination
X
X
Wks 12e, 24e, 36e
Wks, 52e, 76e
X
Xe
O
Blood pressuref, heart ratef, 
respiratory rateg
X
X
X
X
X
X
X
X
X
O
CBC with WBC diff, red cell 
indices and platelets
X
X
Wks 1, 2, 3, 4, 
8
Wks 12, 20, 28, 
36
Wk 44 
+ every other 
8 wks
X
X
O
Hemoglobinh,i
X
X
X
X
X
X
O
HemoCue Assessmenti
X
X
X
X
O
Reticulocyte count and Hb in 
reticulocytes (CHr)
X
X
Wks 1, 2, 4, 6, 
8
Wks 12, 16, 20, 
28, 36
Wk 44 
+ every other 
8 wks
X
X
O
12-lead ECG 
X
X
Wks 12, 24, 36
52, 76
X
O
Serum Chemistryj
X
X
Wks 4, 8
Wks 12, 20,
28, 36
Wk 44  
+ every other 
8 wks
X
X
X
O
Renal Ultrasound k
X
O
Liver Function Tests (LFTs) l
Wks 2, 6
Wk 16
O
Table continued on next page
Serum Lipid Panelm
X
X
Wks 4, 8
Wks 12, 20, 28, 
36
Wks 44, 52, 68, 
84
X
X
O
Serum iron, ferritin, TIBC, 
TSATn
X
X
Wks 4, 8
Wks 12, 20, 28, 
36
Wk 44 
+ every other 
X
X
O


Sponsor:  APEB
ISN/Protocol 1517-CL-0613
EudraCT number 2013-001497-16
- CONFIDENTIAL -
30 May 2017
Astellas
Page 137 of 141
Version 3.0 Incorporating Substantial Amendment 2
8 wks
HbA1c
X
X
Wk 12, 28, 36
Wks 44, 52, 60, 
84
X
X
O
Vitamin B12, folate
X
O
HIV, HBsAg, 
anti-HCV Antibody
X
O
Serum Pregnancy Test 
(HCG)o
X
Wks 12, 24, 36
Wks 48, 60, 72, 
84, 96
X
O
high sensitivity C-reactive 
protein (hs-CRP), hepcidin
X
Wk 4
Wks 12, 20, 36
Wk 52
X
X
Archival Serum Samples 
for Biomarkers
X
Wk 4
Wks 12, 20
Wks 52, 76
X
X
Blood Sample for PKp
Wks 2 to 8
QoL Questionnairesq
X
Wk 8
Wks 12, 28, 36
Wks 52, 76
X
Dialysater
Wks 2 to 8
Optional genotypings
O
Study Treatment: 
roxadustat dispensing OR 
ESA administrationt
├──────────────────────────────┤
O
Dose Adjustment Reviewu
X
X
X
O
AE and Concomitant 
Medication Recording
◄────────────────────────────────────────────────────────────────────────►
Procedure and non-drug 
Therapy Recording
◄────────────────────────────────────────────────────────────────────────►
Vital status, SAEs, 
cardiovascular and 
thromboembolic AEs
X
c 
In case of premature treatment discontinuation, the subject will complete the EOT visits (EOT visit and EOT + 2 weeks visit) and EOS visit. Thereafter subjects who have taken at least 1 dose of 
study drug will continue to be followed up at a 6-monthly frequency for vital status, SAEs and 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. No additional study visits will be required during the poststudy follow-up.


Sponsor:  APEB
ISN/Protocol 1517-CL-0613
EudraCT number 2013-001497-16
- CONFIDENTIAL -
30 May 2017
Astellas
Page 138 of 141
Version 3.0 Incorporating Substantial Amendment 2
IS AMENDED TO:
Study Period:
Screening 
Period
Treatment Period
Follow-up Period
Unscheduled 
Visits
Poststudy 
Follow-upc
Visit/Week:
2-6 Weeksa
Day 
1b
Weekly
(Wks 1 to 8)
± 2 days
Every 2 Weeks 
(Wks 10 to 36)
± 2 days
Every 4 Weeks 
(Wks 40 to 100)
± 3 days
EOTc
(Week 104)
± 3 days
EOT 
+ 2 wks
± 3 days
EOSc
(EOT + 4 
wks)
± 3 days
Every 6 months 
until projected
EOS Wk 108
S1
S2
S3
Dialysis procedure
◄───────────────────────────────────────────────────────────────────────►
ESA pre-treatment
◄─────┤
Written informed consent
X
Randomization
X
Eligibility Criteria
X
X
Demographics
X
Height, weight d
X
X
X
X
Wks 12, 24, 36
Wks 52, 76
X
X
O
Medical History
X
Physical Examination
X
X
Wks 12e, 24e, 36e
Wks, 52e, 76e
X
Xe
O
Blood pressuref, heart ratef, 
respiratory rateg
X
X
X
X
X
X
X
X
X
O
CBC with WBC diff, red cell 
indices and platelets
X
X
Wks 1, 2, 3, 4, 
8
Wks 12, 20, 28, 
36
Wk 44 
+ every other 
8 wks
X
X
O
Hemoglobinh,i
X
X
X
X
X
X
O
HemoCue Assessmenti
X
X
X
X
O
Reticulocyte count and Hb in 
reticulocytes (CHr)
X
X
Wks 1, 2, 4, 6, 
8
Wks 12, 16, 20, 
28, 36
Wk 44 
+ every other 
8 wks
X
X
O
12-lead ECG 
X
X
Wks 12, 24, 36
52, 76
X
O
Serum Chemistryj
X
X
Wks 4, 8
Wks 12, 20,
28, 36
Wk 44  
+ every other 
8 wks
X
X
X
O
Renal Ultrasound k
X
O
Liver Function Tests (LFTs) l
Wks 2, 6
Wk 16
O
Table continued on next page
Serum Lipid Panelm
X
X
Wks 4, 8
Wks 12, 20, 28, 
36
Wks 44, 52, 68, 
84
X
X
O
Serum iron, ferritin, TIBC, 
TSATn
X
X
Wks 4, 8
Wks 12, 20, 28, 
36
Wk 44 
+ every other 
8 wks
X
X
O
HbA1c
X
X
Wk 12, 28, 36
Wks 44, 52, 60, 
X
X
O


Sponsor:  APEB
ISN/Protocol 1517-CL-0613
EudraCT number 2013-001497-16
- CONFIDENTIAL -
30 May 2017
Astellas
Page 139 of 141
Version 3.0 Incorporating Substantial Amendment 2
84
Vitamin B12, folate
X
O
HIV, HBsAg, 
anti-HCV Antibody
X
O
Serum Pregnancy Test 
(HCG)o
X
Wks 12, 24, 36
Wks 48, 60, 72, 
84, 96
X
O
high sensitivity C-reactive 
protein (hs-CRP), hepcidin
X
Wk 4
Wks 12, 20, 36
Wk 52
X
X
Archival Serum Samples 
for Biomarkers
X
Wk 4
Wks 12, 20
Wks 52, 76
X
X
Blood Sample for PKp
Wks 2 to 8
QoL Questionnairesq
X
Wk 8
Wks 12, 28, 36
Wks 52, 76
X
Dialysater
Wks 2 to 8
Optional genotypings
O
Study Treatment: 
roxadustat dispensing OR 
ESA administrationt
├──────────────────────────────┤
O
Dose Adjustment Reviewu
X
X
X
O
AE and Concomitant 
Medication Recording
◄────────────────────────────────────────────────────────────────────────►
Procedure and non-drug 
Therapy Recording
◄────────────────────────────────────────────────────────────────────────►
Vital status, SAEs, 
cardiovascular and 
thromboembolic AEs
X
c 
In case of premature treatment discontinuation, the subject will complete the EOT visits (EOT visit and EOT + 2 weeks visit) and EOS visit. Thereafter subjects who have taken at least 1 dose of 
study drug will continue to be followed up at a 6-monthly frequency for vital status, SAEs and cardiovascular and thromboembolic AEs until their projected date of completion of the follow-up period 
(i.e. projected EOS week 108 date) or until consent withdrawn. No additional study visits will be required during the poststudy follow-up.


Sponsor: APEB
ISN/Protocol 1517-CL-0613
EudraCT number 2013-001497-16
- CONFIDENTIAL -
30 May 2017
Astellas
Page 140 of 141
Version 3.0 Incorporating Substantial Amendment 2
5 Treatment and Evaluation
5.3.3.2 Hospitalizations and 5.5.1 Definition of Adverse Events
WAS:
5.3.3.2 Hospitalizations:
Details of hospitalizations will also be collected at poststudy 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).
AND
5.5.1 Definition of Adverse Events:
For subjects that continue into the poststudy 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).
IS AMENDED TO:
5.3.3.2 Hospitalizations:
Details of hospitalizations will also be collected at poststudy 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).
AND
5.5.1 Definition of Adverse Events:
For subjects that continue into the poststudy 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 EOS visit week 108).


Sponsor: APEB
ISN/Protocol 1517-CL-0613
EudraCT number 2013-001497-16
- CONFIDENTIAL -
30 May 2017
Astellas
Page 141 of 141
Version 3.0 Incorporating Substantial Amendment 2
14
SPONSOR’S SIGNATURES


 
S-1 
ELECTRONIC SIGNATURE PAGE 
Document Type :  
Document Control Number :  
Amendment Number :  
International Study Number :  
Departmental Study Number :  
Actual Version Number :  
Document Version :  
Nonclinical Initial SD Approved Date (UTC) :  
Date (UTC) 
Signed by 
Sign Off Meaning 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
*UTC: Coordinated Universal Time 
Study Physician Approval
06/16/2017 08:11:11
Clinical Study Protocol
Principal Reviewer Approval
Principal Reviewer Approval
Reissue v3.0, 30May2017
06/16/2017 07:50:08
Study Manager Approval
N/A
05/31/2017 18:44:25
N/A
MGC1700420
06/19/2017 14:05:02
1517-CL-0613
06/20/2017 07:36:24
2.0
Study Statistician Approval
N/A

SAP_001.pdf: 
A Phase 3, Randomized, Open-Label, Active-Controlled Study to 
Evaluate the Efficacy and Safety of Roxadustat in the 
Maintenance Treatment of Anemia in End Stage Renal Disease 
Subjects on Stable Dialysis
ISN/Protocol 1517-CL-0613
ClinicalTrials.gov Identifier: NCT02278341
Date of SAP: 10 Sep 2018
Sponsor: Astellas Pharma Europe B.V. (APEB)
Sylviusweg 62,
2333 BE Leiden
The Netherlands


Sponsor: Astellas Pharma Europe B.V.
SAP Final Version 3.0 10 Sep 2018
ISN/Protocol 1517-CL-0613
Astellas
Page 1 of 125
STATISTICAL ANALYSIS PLAN
Final Version 3.0, dated 10 September 2018
A Phase 3, Randomized, Open-Label, Active-Controlled Study 
to Evaluate the Efficacy and Safety of Roxadustat in the Maintenance Treatment 
of Anemia in End Stage Renal Disease Subjects on Stable Dialysis
ISN: 1517-CL-0613
EudraCT number: 2013-001497-16
Sponsor name
Astellas Pharma Europe B.V. (APEB)
Sylviusweg 62, 
2333 BE Leiden
The Netherlands
This confidential document is the property of the sponsor.  No unpublished information 
contained in this document may be disclosed without prior written approval of the sponsor.


Sponsor: Astellas Pharma Europe B.V.
SAP Final Version 3.0 10 Sep 2018
ISN/Protocol 1517-CL-0613
Astellas
Page 2 of 125
Table of Contents
I.
LIST OF ABBREVIATIONS AND KEY TERMS··········································· 8
1
INTRODUCTION·················································································15
2
FLOW CHART AND VISIT SCHEDULE···················································16
3
STUDY OBJECTIVES AND DESIGN························································21
3.1
Study Objectives ··············································································21
3.1.1
Primary Objective ·······································································21
3.1.2
Secondary Objectives ···································································21
3.2
Study Design···················································································21
3.2.1
General····················································································21
3.2.2
Study Population ········································································21
3.2.3
Description of Study ····································································22
3.2.4
Comparative drugs ······································································24
3.2.5
Interim analysis··········································································24
3.3
Randomization·················································································24
4
SAMPLE SIZE·····················································································25
5
ANALYSIS SETS ·················································································26
5.1
All Randomized ···············································································26
5.2
Full Analysis Set (FAS) ······································································26
5.3
Per Protocol Set (PPS)········································································27
5.4
Safety Analysis Set (SAF) ···································································27
5.5
Pharmacokinetics Analysis Set (PKAS)····················································28
5.6
Pharmacodynamic Analysis Set (PDAS)···················································28
6
ANALYSIS VARIABLES ·······································································28
6.1
Efficacy Endpoints············································································28
6.1.1
Primary Efficacy Endpoint ·····························································28
6.1.1.1
Primary Efficacy Endpoint for EU (EMA) ·····································28
6.1.1.2
Primary Efficacy Endpoint for US (FDA)······································29
6.1.2
Key Secondary Efficacy Endpoints ···················································29
6.1.2.1
Hb response defined as mean Hb during weeks 28 to 36 within the 
target range of 10.0 to 12.0 g/dL without having received rescue 
therapy within 6 weeks prior to and during this 8-week evaluation 
period.···············································································30


Sponsor: Astellas Pharma Europe B.V.
SAP Final Version 3.0 10 Sep 2018
ISN/Protocol 1517-CL-0613
Astellas
Page 3 of 125
6.1.2.2
Change from BL in Low Density Lipoprotein (LDL) cholesterol to the
average LDL cholesterol of weeks 12 to 28. ···································30
6.1.2.3
Mean monthly IV iron use (mg) during day 1 to week 36····················30
6.1.2.4
Change from BL in SF-36 Physical Functioning (PF) sub-score to the 
average PF sub-score of weeks 12 to 28. ·······································31
6.1.2.5
Change from BL in SF-36 Vitality (VT) sub-score to the average VT 
sub-score of weeks 12 to 28. ·····················································31
6.1.2.6
Change from BL in pre-dialysis mean arterial pressure (MAP) to the 
average MAP value of weeks 20 to 28. ·········································31
6.1.2.7
Occurrence and time to first occurrence of an increase in pre-dialysis
blood pressure during weeks 1 to 36.············································32
6.1.3
Additional Secondary Efficacy Endpoints············································33
6.1.3.1
Hb response regardless of use of rescue therapy. ······························34
6.1.3.2
Hb change from BL to each post-dosing time point. ··························34
6.1.3.3
Hb level averaged over weeks 28 to 36, 44 to 52, and 96 to 104 
without use of rescue therapy within 6 weeks prior to and during these 
8-week evaluation periods. ·······················································34
6.1.3.4
Hb change from BL to the average Hb value of weeks 28 to 36, 44 to 
52, and 96 to 104 regardless of the use of rescue therapy.····················34
6.1.3.5
Categorical analysis of Hb values ···············································34
6.1.3.6
Occurrence (number) of hospitalizations, number of days of 
hospitalization per year and time to first hospitalization.·····················37
6.1.3.7
Occurrence and time to first use of rescue therapy, occurrence and 
time to first use of RBC transfusions, number of RBC packs per 
subject, volume of RBC transfused per subject during the treatment 
period.···············································································37
6.1.3.8
Occurrence of iron supplementation.············································39
6.1.3.9
Change from BL to each post-dosing study visit in Total cholesterol, 
LDL/High-density Lipoprotein (HDL) ratio, Non-HDL cholesterol, 
Triglycerides, Apolipoproteins A1 and B, ApoB/ApoA1 ratio.··············39
6.1.3.10
Occurrence of mean LDL cholesterol <100 mg/dL calculated over 
weeks 12 to 28.·····································································40
6.1.3.11
Occurrence of achieved antihypertensive treatment goal in CKD 
subjects (SBP< 140 mmHg and DBP< 90 mmHg) based on the mean 
SBP and mean DBP calculated over weeks 12 to 28. ·························40
6.1.3.12
Change from BL to the average value of weeks 12 to 28 in Quality of 
Life scores. ·········································································41
6.1.3.13
Patients’ Global Impression of Change (PGIC)································44


Sponsor: Astellas Pharma Europe B.V.
SAP Final Version 3.0 10 Sep 2018
ISN/Protocol 1517-CL-0613
Astellas
Page 4 of 125
6.1.3.14
Changes from BL to each study visit (when measured) in Serum 
hepcidin, Serum ferritin, TSAT and HbA1c level. ····························44
6.1.4
Other exploratory variables: hs-CRP (High Sensitivity C-Reactive Protein) 
and Post-dialysis BP ····································································44
6.2
Safety Variables ···············································································44
6.2.1
Adverse Events ··········································································45
6.2.1.1
Treatment emergent adverse event (TEAE) ····································45
6.2.1.2
Standardized MedDRA Queries ·················································45
6.2.1.3
Time to occurrence of a TEAE (by type of AE group)························45
6.2.1.4
Definition of incidence rate·······················································46
6.2.1.5
Definition of event rate ···························································47
6.2.1.6
Adverse events up to 7 days after last dose·····································47
6.2.2
Vital Signs················································································47
6.2.3
Clinical laboratory variables ···························································49
6.2.3.1
Potentially Clinically Significant (PCS) Laboratory Criteria·················49
6.2.3.2
Laboratory assessments ···························································50
6.2.4
Physical Examination···································································50
6.2.5
12-lead Electrocardiogram (ECG)·····················································51
6.2.6
Vascular Access Thrombosis (VAT)··················································52
6.3
Pharmacokinetic Variables···································································52
6.4
Pharmacodynamic Variables·································································52
6.5
Other Variables················································································52
6.5.1
Eligibility criteria········································································52
6.5.2
Demographic and Baseline Characteristic Variables································52
6.5.3
Previous and concomitant medication ················································56
6.5.4
Variables related to study drugs ·······················································56
7
STATISTICAL METHODOLOGY ···························································60
7.1
General Considerations·······································································60
7.2
Study Population ··············································································60
7.2.1
Disposition of Subjects ·································································61
7.2.2
Protocol Deviations ·····································································62
7.2.3
Demographic and Other Baseline Characteristics ···································62
7.2.4
Previous and Concomitant Medications ··············································63
7.3
Study Drugs····················································································63
7.3.1
Exposure··················································································64


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7.3.2
Treatment Compliance··································································65
7.4
Analysis of Efficacy ··········································································65
7.4.1
Analysis of Primary Endpoint(s) ······················································65
7.4.1.1
EU (EMA) Primary Endpoint ····················································66
7.4.1.2
US (FDA) Primary Endpoint·····················································73
7.4.2
Analysis of Key Secondary Endpoints················································77
7.4.2.1
Hb response defined as mean Hb during weeks 28 to 36 within the 
target range of 10.0 to 12.0 g/dL without having received rescue 
therapy within 6 weeks prior to and during this 8-week evaluation 
period.···············································································79
7.4.2.2
Change from BL in Low Density Lipoprotein (LDL) cholesterol to the 
average LDL cholesterol of weeks 12 to 28. ···································80
7.4.2.3
Mean monthly IV iron use (mg) during Day 1 to Week 36 (monthly 
defined as a period of 4 weeks). ·················································81
7.4.2.4
Change from BL in SF-36 Physical Functioning (PF) sub-score to the 
average PF sub-score of weeks 12 to 28. ·······································82
7.4.2.5
Change from BL in SF-36 VT subscore to the average in weeks 12–28····83
7.4.2.6
Change from BL in pre-dialysis mean arterial pressure (MAP) to the 
average MAP value of weeks 20 to 28. ·········································84
7.4.2.7
Time to first occurrence of an increase in pre-dialysis blood pressure: 
An increase from BL of ≥ 20 mm Hg systolic blood pressure (SBP) 
and SBP ≥ 170 mmHg or an increase from baseline of ≥15 mmHg 
diastolic blood pressure (DBP) and DBP ≥ 100 mmHg during weeks 1 
to 36. ················································································85
7.4.2.8
Additional Analyses of the Key Secondary Endpoints························86
7.4.3
Analysis of Additional Secondary Efficacy Endpoints ·····························88
7.4.3.1
Hb response regardless of use of rescue therapy. ······························88
7.4.3.2
Hb change from BL to each post-dosing time point. ··························89
7.4.3.3
Hb level averaged over weeks 28 to 36, 44 to 52, and 96 to 104 
without use of rescue therapy within 6 weeks prior to and during these 
8-week evaluation periods. ·······················································89
7.4.3.4
Hb change from BL to the average Hb value of weeks 28 to 36, 44 to 
52, and 96 to 104 regardless of the use of rescue therapy.····················89
7.4.3.5
Categorical analysis for Hb values ··············································89
7.4.3.6
Occurrence (number) of hospitalizations, number of days of 
hospitalization per year and time to first hospitalization during the 
study. ················································································90


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7.4.3.7
Occurrence and time to first use of rescue therapy, occurrence and 
time to first use of RBC transfusions, number of RBC packs per 
subject, volume of RBC transfused per subject. ·······························90
7.4.3.8
Occurrence of iron supplementation.············································91
7.4.3.9
Change from BL to each post-dosing study visit in Total cholesterol, 
LDL/High-density Lipoprotein (HDL) ratio, Non-HDL cholesterol, 
Triglycerides, Apolipoproteins A1 and B, ApoB/ApoA1 ratio.··············91
7.4.3.10
Occurrence of mean LDL cholesterol <100 mg/dL calculated over 
weeks 12 to 28.·····································································91
7.4.3.11
Occurrence of achieved antihypertensive treatment goal in CKD 
subjects (SBP< 140 mmHg and DBP< 90 mmHg) based on the mean 
SBP and mean DBP calculated over weeks 12 to 28. ·························91
7.4.3.12
Health related Quality of Life Questionnaires Change from BL to the 
average value of weeks 12 to 28 ·················································91
7.4.3.13
Patients’ Global Impression of Change (PGIC)································92
7.4.3.14
Changes from BL to each study visit (when measured) in Serum 
hepcidin, Serum ferritin, TSAT and HbA1c level. ····························92
7.4.4
Analysis of Exploratory Variables: hs-CRP (High Sensitivity C-Reactive 
Protein) and Post-dialysis BP. ·························································93
7.5
Analysis of Safety·············································································93
7.5.1
Adverse Events ··········································································93
7.5.1.1
Overview············································································93
7.5.1.2
Proportion of subjects with TEAEs by SOC/PT ·······························94
7.5.1.3
Number of Events/100 Patient Exposure Year (PEY)·························94
7.5.1.4
Incidence Rates and Cumulative Incidence·····································95
7.5.1.5
Sensitivity/Subgroup Analyses···················································95
7.5.1.6
Adverse events up to 7 days after last dose·····································95
7.5.2
Clinical Laboratory Evaluation ························································96
7.5.2.1
Liver function tests ································································97
7.5.3
Vital Signs················································································97
7.5.4
Electrocardiograms (ECGs)····························································97
7.5.5
Vascular Access Thrombosis (VAT)··················································98
7.5.6
Pregnancies···············································································98
7.6
Analysis of PK·················································································98
7.7
Analysis of PD·················································································98
7.8
Subgroups of Interest ·········································································98
7.9
Other Analyses ················································································99


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7.10
Interim Analysis (and Early Discontinuation of the Clinical Study)····················99
7.11
Handling of Missing Data, Outliers, Visit Windows, and Other  Information·········99
7.11.1
Missing Data ·············································································99
7.11.2
Missing Dates·········································································· 100
7.11.3
Outliers ················································································· 101
7.11.4
Visits Windows········································································ 102
7.11.5
End of Safety Emergent Period······················································ 104
7.11.6
End of Efficacy Emergent Period ··················································· 104
8
DOCUMENT REVISION HISTORY ······················································· 105
9
REFERENCES ·················································································· 108
10
APPENDICES ··················································································· 109
10.1
Appendix 1: SF-36 v2 ······································································ 109
10.2
Appendix 2: FACT-An (Version 4)······················································· 116
10.2.1
FACT-An Questionnaire ····························································· 116
10.2.2
FACT-An Scoring Guidelines ······················································· 119
10.3
Appendix 3: EQ-5D 5L v2································································· 122
10.4
Appendix 4: Patient Overall Impression of Change ···································· 122
10.5
Appendix 5: Medication WHO Drug Dictionary Codes································ 123
10.6
Appendix 6: Signatures····································································· 124


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I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
ADaM
Analysis Data Model
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase 
ANCOVA
Analysis of Covariance
AnS
Anemia Subscale
anti-HCV Ab
Anti-hepatitis C Virus Antibody
APEB
Astellas Pharma Europe B.V.
Apo
Apolipoproteins
ASC
Analysis Set Classifications
ASP1517
=FG-4592(roxadustat); codename(name) of investigational product
AST
Aspartate Aminotransferase 
ATC
Anatomical Therapeutic Chemical
BL
Baseline
BL Hb
Baseline Hemoglobin (please refer to key definitions for information)
BMI
Body Mass Index
BP
Blood Pressure
BUN
Blood Urea Nitrogen
CAPD
Continuous ambulatory peritoneal dialysis
CBC
Complete Blood Count
CHr
Reticulocyte Hemoglobin Content
CKD
Chronic Kidney Disease
CMH
Cochran-Mantel-Haenszel
CRF
Case Report Form
CRO
Contract Research Organization
CRP
C Reactive Protein
CSE
Composite Safety Endpoint
CSR
Clinical Study Report
DBP
Diastolic Blood Pressure
DILI
Drug-induced Liver Injury
dL
Deciliter
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
eCRF
Electronic CRF
EH
Excessive Hematopoiesis
EOS
End of Study
EOT
End of Treatment
EQ-5D 5L
European Quality of Life 5 Domain 5 Level
ESA
Erythropoiesis Stimulating Agent


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Abbreviations
Description of abbreviations
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 (roxadustat)
FWB
Functional Well-being
g
gram
DS
Data Science
GGT
Gamma Glutamyl Transferase
Hb
Hemoglobin
HbA1c
Hemoglobin A1c; Glycated hemoglobin
HBsAG
Hepatitis B Surface Antigen
HCG
Human chorionic gonadotropin
HD
Hemodialysis
HDF
Hemodiafiltration
HDL
High-density Lipoprotein
HEENT
Head, Eyes, Ears, Neck and Throat
HIV
Human Immunodeficiency Virus
HIF
Hypoxia-inducible Factor
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
ICU
Intensive Care Unit
IEC
Independent Ethics Committee
IF
Information Fraction
INR
International Normalized Ratio
IRS
Interactive Response System
ITT
Intention to treat
ISN
International Study Number
IV
Intravenous(ly)
Kg
Kilogram
LA-CRF
Liver Abnormality Case Report Form
LDL
Low-density Lipoprotein
LFT
Liver Function Tests
LLN
Lower Limit of Normal 


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Abbreviations
Description of abbreviations
LSO
Last Subject Out
MAP
Mean Arterial Pressure
MAR
Missing At Random
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram 
MI
Multiple Imputation
mL
Milliliters 
mmHg
Millimeters of Mercury
MMRM
Mixed Model of Repeated Measures
MNAR
Missing Not At Random
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria for Adverse Events
O
Optional 
PCS
Physical Component Score
PD
Protocol Deviation
PD
Peritoneal Dialysis
PEY
Patient-Exposure-Year
PF
Physical Functioning
PGIC
Patients’ Global Impression of Change
PK
Pharmacokinetic
PKAS
Pharmacokinetic Analysis Set
PMM
Pattern Mixture Model
PPS
Per Protocol Set
PT
Preferred Term
PWB
Physical Well-being
QoL
Quality of Life
QRS 
QRS interval 
QTc
QT Interval corrected for heart rate
QTcB
QTc calculated according to Bazett’s formula
QTcF
QTc calculated according to Fridericia’s formula
RBC
Red Blood Cell
RR
Respiratory Rate
RR Interval
Interval between successive Rs of the ECG
SAE
Serious AE
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
SBP
Systolic Blood Pressure
SC
Subcutaneous(ly)
SDTM
Study Data Tabulation Model
SI
International System of Units 
SF-36
Short Form 36
SF-36 PCS
SF-36 Physical Component Score


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Abbreviations
Description of abbreviations
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
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
ULN
Upper Limit of Normal
VAS
Visual Analogue Scale
VT
Vitality
WBC
White Blood Cell
WHO-DRL
World Health Organization Drug Reference List
Wk(s)
Week(s)
µg
Microgram


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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 study drug or has undergone study procedures and which does 
not necessarily have a causal relationship with this treatment. AE collection 
starts after obtaining signed informed consent and continues until the End of 
Study (EOS) visit. SAEs and cardiovascular and thromboembolic AEs will 
be collected during the post study follow-up period. AEs will not be 
collected during the period between first screen where subject has failed 
screening and first rescreening visit.
Baseline
1) Observed values/findings which are regarded as calibrated zero status in 
the present study; 2) Time when ‘Baseline’ is observed.
Baseline Hemoglobin
(Hb) value
Baseline Hb is defined as the mean of four central laboratory Hb values: 
four latest Hb values prior or on the same date as first study drug intake
(pre-dose).
Discontinuation
The act of concluding participation in either the study treatment or the 
study, prior to completion of all protocol-required elements, in a trial by an 
enrolled subject. Four categories of discontinuation are distinguished: a) 
dropout: Active discontinuation by a subject (also a noun referring to such a 
discontinued subject); b) investigator-initiated discontinuation (e.g., for 
cause); c) loss to follow-up: cessation of participation without notice or 
action by the subject; d) Sponsor-initiated discontinuation. Note that subject 
discontinuation does not necessarily imply exclusion of subject data from 
analysis. “Termination” has a history of synonymous use, but is now 
considered non-standard.
Efficacy Emergent 
Period
Defined as the evaluation period from the Analysis date of first dose intake 
up to EOT Visit.
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 Response
Mean Hb during weeks 28 to 36 within the target range of 10.0 to 12.0 g/dL.
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 at a 6-monthly 
frequency for vital status, SAEs and cardiovascular and thromboembolic 
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 test drug or 
comparative drug is given to a subject 
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 ESA (epoetin alfa 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. Renal ultrasound 
only to be repeated if not within 12 weeks prior to randomization.
Safety Emergent 
Period
Defined as the evaluation period from the Analysis date of first drug intake 
up to 28 days after the end of treatment taking into account the different 
dosing frequencies of the study treatments
Screening
A process of active consideration of potential subjects for enrollment in a 
trial.
Screening Hb value
Mean of subject’s three last Hb values collected during the screening period 
and prior to the day of randomization.
Screen /Re-screen 
failure
Potential subject who did not meet one or more criteria required for 
participation in a trial during screening or re-screening.
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 
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. 


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Terms
Definition of terms
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 EOT visit -
where major interests of protocol objectives are observed, and where 
roxadustat (study drug) or ESA (comparative drug) is given to a subject.
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values


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1
INTRODUCTION
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes detailed procedures 
for executing the statistical analysis of the primary and secondary endpoints and other data. 
The SAP is finalized and signed prior to accumulation of a substantial amount of data 
(open-label study) to ensure lack of bias. For operational efficiency an earlier time is usually 
targeted and wherever possible, the SAP should be developed in parallel with protocol 
finalization. If needed, revisions to the approved SAP may be made prior to database hard 
lock. Revisions will be version controlled.
This statistical analysis is coordinated by the responsible biostatistician of APEB. Any 
changes from the analyses planned in the SAP will be justified in the Clinical Study Report 
(CSR).
All details of the Pharmacokinetics Analysis Set (PKAS) will be described in a separate 
analysis plan, and a separate PKAS modeling report will be written.
This SAP is based on protocol version 2.2, dated 15 April 2016 and is an amendment version 
of SAP versions 1.0 and 2.0.
Prior to database hard lock, a final review of data and TLFs meeting will be held to allow a 
review of the clinical trial data and to verify the data that will be used for analysis set 
classification. If required, consequences for the statistical analysis will be discussed and 
documented. A meeting to determine analysis set classifications may also be held prior to 
database hard lock.


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2
FLOW CHART AND VISIT SCHEDULE
Flow Chart


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Table 1
Schedule of Assessments
Study Period:
Screening 
Period
Treatment Period
Follow-up Period
Unscheduled 
Visits
Post study 
Follow upc
Visit/Week:
2-6 Weeksa
Day 
1b
Weekly
(Wks 1 to 8)
± 2 days
Every 2 Weeks 
(Wks 10 to 36)
± 2 days
Every 4 Weeks 
(Wks 40 to 100)
± 3 days
EOTc
(Week 104)
± 3 days
EOT 
+ 2 wks
± 3 days
EOSc
(EOT + 4 
wks)
± 3 days
Every 6 
months until 
projected 
Wk 108
S1
S2
S3
Dialysis procedure
◄───────────────────────────────────────────────────────────────────────►
ESA pre-treatment
◄─────┤
Written informed consent
X
Randomization
X
Eligibility Criteria
X
X
Demographics
X
Height, weightd
X
X
X
X
Wks 12, 24, 36
Wks 52, 76
X
X
O
Medical History
X
Physical Examination
X
X
Wks 12e, 24e, 
36e
Wks, 52e, 76e
X
Xe
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
Wks 1, 2, 3, 
4, 8
Wks 12, 20, 28, 
36
Wk 44 
+ every other 
8 wks
X
X
O
Hemoglobinh
X
X
X
X
X
X
X
HemoCue Assessment
X
X
X
X
X
Reticulocyte count and Hb 
in reticulocytes (CHr)
X
X
Wks 1, 2, 4, 
6, 8
Wks 12, 16, 20, 
28, 36
Wk 44 
+ every other 
8 wks
X
X
O
12-lead ECG 
X
X
Wks 12, 24, 36
52, 76
X
O
Serum Chemistryi
X
X
Wks 4, 8
Wks 12, 20,
28, 36
Wk 44  
+ every other 
8 wks
X
X
X
O
Renal Ultrasound j
X
O
Liver Function Tests (LFTs)k
Wks 2, 6
Wk 16
O
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Study Period:
Screening 
Period
Treatment Period
Follow-up Period
Unscheduled 
Visits
Post study 
Follow upc
Visit/Week:
2-6 Weeksa
Day 
1b
Weekly
(Wks 1 to 8)
± 2 days
Every 2 Weeks 
(Wks 10 to 36)
± 2 days
Every 4 Weeks 
(Wks 40 to 100)
± 3 days
EOTc
(Week 104)
± 3 days
EOT 
+ 2 wks
± 3 days
EOSc
(EOT + 4 
wks)
± 3 days
Every 6 
months until 
projected 
Wk 108
S1
S2
S3
Serum Lipid Panell
X
X
Wks 4, 8
Wks 12, 20, 28, 
36
Wks 44, 52, 68, 
84
X
X
O
Serum iron, ferritin, TIBC, 
TSATm
X
X
Wks 4, 8
Wks 12, 20, 28, 
36
Wk 44 
+ every other 
8 wks
X
X
O
HbA1c
X
X
Wk 12, 28, 36
Wks 44, 52, 60, 
84
X
X
O
Vitamin B12, folate
X
O
HIV, HBsAg, 
anti-HCV Antibody
X
O
Serum Pregnancy Test 
(HCG)n
X
Wks 12, 24, 36
Wks 48, 60, 72, 
84, 96
X
O
high sensitivity C-reactive 
protein (hs-CRP), hepcidin
X
Wk 4
Wks 12, 20, 36
Wk 52
X
X
Archival Serum Samples 
for Biomarkers
X
Wk 4
Wks 12, 20
Wks 52, 76
X
X
Blood Sample for PKo
Wks 2 to 8
QoL Questionnairesp
X
Wk 8
Wks 12, 28, 36
Wks 52, 76
X
Dialysateq
Wks 2 to 8
Optional genotypingr
O
Study Treatment: 
roxadustat dispensing OR 
ESA administrations
├───────────────────────────┤
O
Dose Adjustment Reviewt
X
X
X
O
AE and Concomitant 
Medication Recording
◄────────────────────────────────────────────────────────────────────────►
Procedure and non-drug 
Therapy Recording
◄────────────────────────────────────────────────────────────────────────►
Vital status, SAEs, 
cardiovascular and 
thromboembolic AEs
X
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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. In HD subjects 
all lab sampling is to be performed prior to or at initiation of the dialysis session.
Note: Instructions for roxadustat-treated subjects moving from Protocol v1.0 to Protocol v2.0 in terms of dosing are provided in Protocol Appendix 12.3.
a 
Due to the requirement of 4-day separation between the screening Hb values, the screening period will last a minimum of 2 weeks approximately, but is allowed to be a maximum 
of 6 weeks. Sites are recommended to schedule the three screening visits in the shortest time span possible.
b
Randomization and administration of the first dose of study drug (roxadustat or ESA) are to occur on Day 1, which should correspond to a day when the subjects’ next dose of 
epoetin or darbepoetin alfa would have been administered. In HD subjects only, post-dialysis weight and post-dialysis vital signs do not have to be completed prior to 
randomization and first study drug administration.
c 
In case of premature treatment discontinuation, the subject will complete the EOT 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 and 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. No additional study visits will be required during the Post study Follow-up.
d
Height at first Screening visit only; Weight is post-dialysis weight in HD subjects. For day 1 visit the post-dialysis weight on the third screening visit is to be recorded in the 
Interactive Response System (IRS) for HD subjects. Weight for PD subjects is the weight measured at site minus the abdominal fluid based on last filling. For drug dispensing 
purposes (at visits after randomization), weight from the previous dialysis session may be used.
e
Targeted physical examination (e.g., respiratory and cardiovascular).
f
Blood pressure and heart rate measured singly during the screening period, and in triplicate at all other visits; in HD subjects both pre- and post-dialysis.
g
Respiratory rate measured singly during screening period and all other visits; in HD subjects both pre- and post-dialysis.
h
Separate Hemoglobin should be collected at all the visits where Complete Blood Count (CBC) is not collected; i.e. Hemoglobin at Weeks 5, 6, 7, 10 until the end of the study. It is 
recommended that the Hb assessments be performed on the same day of the patient’s dialysis schedule throughout the study.
i
Serum chemistry includes LFTs.
j 
Renal ultrasound examination can be performed at any time during the screening period. Not required if results of a previous renal ultrasound (or other renal imaging modality such 
as CT scan or MRI providing a conclusive report on the kidney) within 12 weeks prior to randomization is available and ruling out renal cell carcinoma.
k
LFTs to be collected at further visits where Serum Chemistry is not collected.
l
Fasting, whenever possible.
m
TSAT = [FeSat (Ferro Saturation = % Iron Saturation) measured by central lab and derived from iron and TIBC].
n 
Human chorionic gonadotropin (HCG). To be collected from female subjects of childbearing potential only.
o
Only for subjects randomized to roxadustat at 6 time points over 1 to 3 visits. At each PK visit, an additional sample will be collected for albumin and alpha-acidglycoprotein 
determination.
p
Includes Short Form 36 (SF-36), Functional Assessment of Cancer Therapy-Anemia (FACT-An), European Quality of Life 5 Domain 5 Level (EQ-5D 5L) and Patients’ Global 
Impression of Change (PGIC). PGIC will not be performed on Day 1. In HD subjects, the quality of life questionnaires are to be completed by the subject prior to any other 
assessment or at the latest at the start of dialysis session. It is important that the physician does not discuss the status of the subject prior to completion of the questionnaires. In PD 
subjects the questionnaires are to be completed prior to any study assessment.
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q
Only for continuous ambulatory peritoneal dialysis (CAPD) subjects randomized to roxadustat. Sample to be withdrawn from the drainage bag after draining complete volume at 
the site and at the same visit as the PK blood samples (see footnote o).
r
Optional assessment and only for subjects randomized to roxadustat. If a separate (optional) informed consent form is signed by the subject, a sample can be collected after 
randomization, preferably on Day 1.
s
Dosing of epoetin alfa and darbepoetin alfa according to approved SmPC (Eprex® United Kingdom SmPC; Aranesp® European Union SmPC). It is recommended that roxadustat is 
administered any time after completion of dialysis (if dosing is scheduled on a dialysis day).
t
Subjects randomized to roxadustat: dose adjustment review from week 4 onward, and every 4 weeks thereafter until EOT (deviation from the 4-week period is allowed anytime 
during the study in case 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 study visit. ESA dose adjustments should follow the SmPC.


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3
STUDY OBJECTIVES AND DESIGN
3.1
Study Objectives
3.1.1
Primary Objective
The primary objective of this study is to evaluate the efficacy of roxadustat compared to ESA 
(epoetin alfa and darbepoetin alfa) in the maintenance treatment of anemia in End Stage 
Renal Disease (ESRD) subjects on stable dialysis.
3.1.2
Secondary Objectives
The secondary objectives of this study are to:
●
Evaluate the safety of roxadustat compared to ESA (epoetin alfa and darbepoetin alfa) in 
the maintenance treatment of anemia in ESRD subjects on stable dialysis.
●
Evaluate the effects on health-related quality of life (HRQoL) of roxadustat compared to 
ESA (epoetin alfa and darbepoetin alfa) in the maintenance treatment of anemia in 
ESRD subjects on stable dialysis.
3.2
Study Design
3.2.1
General
This is a phase 3, multi-center, randomized, open-label, active-controlled study. This study is 
planned to recruit approximately 750 subjects from approximately 150 study centers, mainly 
located in Europe.
The study is planned to provide key efficacy and safety data for the approval of roxadustat in 
the treatment of anemia associated with ESRD on stable dialysis. Study FGCL-4592-064
with similar design is conducted by FibroGen Inc, in study centers across North America, 
Latin America and Asia Pacific.
3.2.2
Study Population
The study population consists of adult subjects with ESRD who are on stable Hemodialysis 
(HD) or Peritoneal dialysis (PD) and on stable treatment with epoetin (i.e., epoetin alfa, beta, 
theta, zeta, delta or omega) or darbepoetin alfa for anemia. Subjects on polyethylene glycol-
epoetin beta (Mircera®) are not to be included. Subjects on hemodiafiltration (HDF) are also 
allowed to participate in the study and will follow the same study procedures and requirements 
as HD subjects. Prior to randomization a subject must be on the same mode of dialysis for 
≥4 months and on epoetin or darbepoetin alfa treatment for ≥ 8 weeks with stable average 
weekly doses (defined as ≤30% change) during the last 4 weeks prior to randomization. 
Anemia is defined as the mean Hb of the three most recent screening measurements ≥ 9.5 g/dL 
and ≤ 12.0 g/dL with an absolute difference ≤1.3 g/ dL between the highest and the lowest 
value. Subjects must be iron replete at baseline; inclusion is permitted if ferritin ≥ 100 ng/mL 
(≥220 pmol/L) and TSAT ≥ 20%. Anemia of non-renal origin is to be excluded. Washout 
periods of at least 4 weeks for any iron-chelating agents, and at least 8 weeks for any RBC 


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transfusion prior to randomization have been mandated in order to exclude a potential impact 
of these recent anemia treatments on the assessment of efficacy.
3.2.3
Description of Study 
Subjects assigned to the roxadustat treatment arm will receive roxadustat orally as a 
combination of tablets of different strengths. Subjects assigned to the ESA treatment arm will 
be administered epoetin alfa if they were on epoetin (i.e., epoetin alfa, beta, theta, zeta, delta or 
omega) prior to randomization or darbepoetin alfa in case they were on darbepoetin alfa prior 
to randomization. Study treatment administration is implemented in an open-label manner. 
Subjects on polyethylene glycol-epoetin beta (Mircera®) are not to be included.
The study will consist of three study periods:
●
Screening Period: up to 6 weeks
●
Treatment Period: 104 weeks 
●
Follow-up Period: 4 weeks
During the course of the study, visits and assessments will be performed as defined in the 
Schedule of Assessments.
Screening Period
During the Screening Period of up to 42 days, eligibility assessments will be performed. 
Subjects will continue epoetin or darbepoetin alfa treatment per local standard of care.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will be 
randomized at Day 1 (baseline), which marks the end of Screening Period and start of the 
Treatment Period.
Treatment Period
Subjects are randomized to one of two treatment arms as illustrated in Table 2
Table 2
Treatment Arms, Dosing Frequencies and Patient Numbers
Treatment Arms
Study Treatment
Dosing Frequency
N
1
roxadustat
TIW*
375
2
ESA** 
Dosing per SmPC***
375
*TIW = three times weekly; ** ESA = epoetin alfa or darbepoetin alfa
***SmPC = Summary of Product Characteristics
●
Treatment arm 1: subjects will be switched from epoetin or darbepoetin alfa treatment to 
roxadustat treatment (see Table 3 for doses).
●
Treatment arm 2: subjects will continue ESA treatment, i.e. epoetin alfa if pre-treated 
with any epoetin (i.e. epoetin alfa, beta, theta, zeta, delta or omega) and darbepoetin alfa 
if pre-treated with darbepoetin alfa, at approximately the same average weekly dose the 
subject was on prior to randomization. It is not allowed to switch from epoetin alfa to 
darbepoetin alfa or vice versa, during the treatment period.


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The initial study drug (roxadustat) dose is based on the dosing scheme shown in Table 3 and 
is determined by the subject’s average prescribed weekly dose of epoetin or darbepoetin alfa 
within four weeks prior to randomization.
Table 3
Initial Dose of Roxadustat
epoetin* 
(IU/week)
darbepoetin alfa*
(µg/week)
roxadustat
(mg/dose) TIW
<8,000
<40
100
8,000 to 16,000
40-80
150**
>16,000
>80
200***
* Average prescribed weekly dose in the last four weeks prior to randomization.
** If the initial dose of 150 mg exceeds the maximum dose of 3.0 mg/kg, then 100 mg is to be used as the 
starting dose.
*** If the initial dose of 200 mg exceeds the maximum dose of 3.0 mg/kg, then 150 mg is to be used as the 
starting dose.
The randomization will result in an overall 1:1 ratio of subjects receiving roxadustat
administered orally, or epoetin alfa or darbepoetin alfa administered by SC or IV injection. 
Randomization to treatment arms will occur through an Interactive Response System (IRS).
Randomization and administration of the first dose of study treatment (roxadustat or ESA) is 
to occur on Day 1 which should correspond to a day when their next dose of epoetin or 
darbepoetin alfa would have been administered. The first dose of study treatment should be 
taken after all study assessments have been completed; in HD subjects only, study 
assessments should also be performed prior to or at initiation of dialysis (except for post-
dialysis weight and post-dialysis vital signs, which should be measured post dialysis).
During the Treatment Period, subjects will attend weekly study visits from Day 1 to Week 8, 
followed by every other week study visits from Week 10 to 36. Following Week 36, study 
visits will occur every four weeks until the End of Treatment (EOT).
During the Treatment Period, the aim is to maintain the Hb levels between 10.0 g/dL and 
12.0 g/dL. For both treatment arms dose adjustments are to be made based on Hb values 
using HemoCue®, a point-of-care device.
All subjects receiving roxadustat will initiate and continue roxadustat dosing at a dosing 
frequency of TIW throughout the entire period and dose adjustment is to follow pre-specified 
dose adjustment rules (see protocol, Section 5.1.2.1, Table 4). Intake should occur at 
approximately the same time of day and, if possible, dosing days should remain consistent 
throughout the study. For HD subjects it is recommended that roxadustat is administered any
time after completion of dialysis if dosing is scheduled on a dialysis day to avoid potential 
bias on certain study assessments. Specific rules apply on the dialysis day(s) at which PK 
sampling is scheduled (see protocol, Section 5.6).
Subjects will receive study treatment (roxadustat or ESA) for 104 weeks.


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Follow-up Period
After the end of the Treatment Period subjects will proceed to the 4-week Follow-up Period. 
The choice of anemia treatment during the follow-up period is at the discretion of the 
investigator and according to local standards.
Post Study Follow-up (only for subjects prematurely discontinued from treatment)
Subjects who have prematurely discontinued study treatment will complete the EOT and 
EOS visits. Thereafter, these subjects who have taken at least one dose of study treatment, 
will continue to be followed up at a 6-monthly frequency for vital status, SAEs and 
cardiovascular and thromboembolic AEs until their projected date of completion of the 
Follow-up Period (i.e. projected week 108) or until consent withdrawn. Data collection 
during this Post study Follow-up occur through phone calls or information collected from 
source data of subjects’ regular, non-study, visits to the clinic. No additional study visits will 
be required from these subjects during the Post study Follow-up. The last Post study 
Follow-up data collection should occur around the projected week 108.
3.2.4
Comparative drugs
Epoetin alfa (Eprex®) or darbepoetin alfa (Aranesp®) will be administered IV or SC 
according to the Package Insert or Summary of Product Characteristics (United Kingdom 
[UK] SmPC for Eprex® and European Union [EU] SmPC for Aranesp®). Copies of these 
SmPCs will be distributed as part of the study materials.
For subjects randomized to ESA epoetin alfa or darbepoetin alfa, the starting dose, frequency 
and mode of application (IV or SC) are at the investigator's discretion provided the average 
weekly dose remains approximately the same as prior to randomization.
Epoetin alfa and darbepoetin alfa will be provided as a solution for injection in pre-filled 
syringes in the following strengths: 10, 20, 30, 40, 60 and 100 μg for darbepoetin alfa and 
1000, 2000, 3000, 4000, 6000 and 8000 IU for epoetin alfa.
Dose adjustment and administration rules, as per respective SmPCs, are summarized in the 
protocol, Section 5.1.
3.2.5
Interim analysis
No interim analysis will be performed.
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 
assessment of outcomes.
An open-label design was chosen for several reasons. Epoetin alfa and darbepoetin alfa will 
be administered by SC or IV injection, whereas roxadustat is administered orally, and the 
investigational and comparator drugs have a different requirement for iron supplementation.


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Randomization and treatment assignments will be performed via Interactive Response 
System (IRS) prepared on behalf of the Sponsor (under the responsibility of the Data Science 
(DS) Department of APEB). Specific procedures for randomization through the IRS are 
contained in the study procedures manual.
A total of approximately 750 subjects will be randomized to one of the two Treatment Arms 
in a 1:1 ratio as follows:
●
Treatment Arm 1: roxadustat
●
Treatment Arm 2: ESA (epoetin alfa or darbepoetin alfa)
See also Table 2 for the Treatment Arms description.
Randomization will be stratified by the following five factors: 
●
Previous ESA treatment (epoetin versus darbepoetin alfa)
●
Region (region A versus region B)*
●
History of cardiovascular, cerebrovascular or thromboembolic diseases (Yes versus No)
●
Average prescribed weekly ESA dose four weeks prior to randomization (≤200 IU/kg 
epoetin or ≤ 1 μg/kg darbepoetin alfa versus >200 IU/kg epoetin or > 1 μg/kg 
darbepoetin alfa)
●
Screening Hb value (<11.0 g/dL versus >11.0 g/dL)
* The assignment to region (see Section 6.5.2) will be determined based on health care 
system comparability.
4
SAMPLE SIZE
The study is sufficiently powered for both regionally-based primary efficacy endpoints. 
Approximately 750 subjects will be randomized to receive roxadustat or ESA in an 
open-label fashion in a 1:1 ratio.
EU (EMA)
Results from simulations of the EU primary efficacy endpoint in stable dialysis subjects 
suggest that dosing levels of ESA prior to randomization may play a role in Hb response. 
Therefore, the EU primary analysis of this study will be tested both in the overall population 
and in the subset (subgroup) of patients defined as subjects with an average prescribed 
weekly epoetin or darbepoetin dose within the last four weeks prior to randomization 
≤200 IU/kg or ≤ 1 μg/kg respectively, following a parametric chain procedure [Millen et al, 
2011; Spiessens et al, 2010]. The information fraction will be calculated at the time of 
database hard lock; it is defined as the number of subjects in the subset with respect to the 
number of subjects in the total study population. 
Assuming that the Per Protocol Set (PPS) analysis will consist of 80% of the randomized 
subjects, 750 randomized subjects will lead to approximately 600 subjects in the PPS. The 
overall one-sided significance level (alpha) is fixed at 0.025 and the non-inferiority margin 
for the EU primary endpoint has been fixed to -0.75 g/dL. The overall alpha will be equally 


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allocated to each of the two test populations. If we assume an information fraction of 0.80, 
this rule will lead to a significance level of 0.0174. 
In this setting, three hundred (300) subjects for the roxadustat treatment group and 
300 subjects for the ESA treatment group will provide 97% power to statistically demonstrate 
non-inferiority of roxadustat versus ESA in the EU primary endpoint in both the total study 
population and the planned subset population analysis assuming a difference (roxadustat 
minus ESA) of -0.25 g/dL in the Hb change from baseline and an SD of 1.5 g/dL. In the case 
that these assumptions do not hold across the overall population, the planned procedure can 
still allow for a successful conclusion for the subset population.
US (FDA)
With 750 randomized subjects (All Randomized), the study will provide at least 99% power 
to demonstrate statistical non-inferiority of roxadustat versus ESA in the primary endpoint 
for US submission. The overall one-sided significance level (alpha) is fixed at 0.025 and the 
non-inferiority margin for the US primary endpoint has been fixed to -0.75 g/dL.
5
ANALYSIS SETS
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the analysis sets below will be used for the analyses.
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
Criterion for exclusion from All Randomized is defined as follows:
●
Not randomized
The selection of subjects for the All Randomized will be confirmed in the Analysis Set 
Classification (ASC) meeting.
The All Randomized will be used for summaries, selected primary and secondary analyses of 
efficacy endpoints, as well as selected demographic and baseline characteristics.
The All Randomized is regarded as the main analysis set for the US primary endpoint testing 
non-inferiority.
The All Randomized Set will exclude the 2 randomized subjects from site 
, which has 
been terminated prematurely due to GCP violations including data integrity issues. 
Consequently, these subjects will not be included in any of the analyses.
5.2
Full Analysis Set (FAS)
The Full Analysis Set (FAS) consists of all randomized subjects (All Randomized) who 
received at least one dose of study drug and have at least one non-missing post-dose Hb 
assessment. Subjects will be assigned to their planned treatment provided by the IRS.
Criteria for FAS exclusion is defined as follows:


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●
No study drug taken, or
●
No post-dose Hb value 
The selection of subjects for the FAS will be confirmed in the Analysis Set Classification
(ASC) meeting.
The FAS will be used for summaries, selected primary and secondary analyses of efficacy 
endpoints, as well as selected demographic and baseline characteristics.
5.3
Per Protocol Set (PPS)
The Per-Protocol Set (PPS) includes all FAS subjects who do not meet any of the reasons to 
exclude a complete subject from PPS, listed in Table 4. This PPS will be used for the primary 
EU endpoint analysis, for selected secondary analyses and for all disposition, demography 
and baseline characteristics. 
Table 4
Criteria for excluding a subject from PPS
Number
Reasons for exclusion from PPS
1
Subject who receives less than 12 weeks of study treatment.
2
Subject 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 36 weeks
analysis period.
4
Violation of inclusion or exclusion criteria which may affect the assessment of the efficacy 
of the study drug.
5
Administration of wrong randomization study drug for more than one week during the 
reference period (first 36 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 reference period (first 36 weeks) or until EOT, whatever 
comes first.
7
Administration of rescue therapy significantly deviating from the protocol during the 
reference period (first 36 weeks) or until EOT, whatever comes first.
The selection of subjects for the PPS will be confirmed in the ASC meeting. More details 
will be provided in the ASC specifications.
5.4
Safety Analysis Set (SAF)
The safety analysis set consists of all randomized subjects (All Randomized) 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.


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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.
5.6
Pharmacodynamic Analysis Set (PDAS)
Not applicable in this study.
6
ANALYSIS VARIABLES
6.1
Efficacy Endpoints
The Efficacy Emergent Period will be defined as the evaluation period from the Analysis 
date of first dose intake up to EOT Visit. This period will be used as reference period for the 
time to event analyses related to efficacy endpoints, unless specified otherwise. More details 
on the derivation of the date of End of Efficacy Emergent Period are provided in 
Section 7.11.6
6.1.1
Primary Efficacy Endpoint
There are two separate regionally based primary efficacy endpoints in this study, depending 
upon whether the data are being filed to support submission to the EU EMA or to Ex- EU
health authorities, such as the US FDA.
6.1.1.1 Primary Efficacy Endpoint for EU (EMA)
The primary efficacy endpoint for EU is Hb change from baseline (BL) to the average Hb of 
weeks 28 to 36, without having received rescue therapy (i.e., RBC transfusion for all subjects
and ESA for roxadustat subjects) within 6 weeks prior to and during this 8-week evaluation 
period.
For the average in weeks 28-36, all available Hb values obtained from the central laboratory 
will be used (i.e., both scheduled and unscheduled Hb values).
For the analyses that require an Hb value by visit, the last available Hb value in the visit 
window will be kept.
In case a subject does not have any available Hb value during this week 28-36 period
(because they died or withdrew from the study for example), imputation rules will be applied 
(refer to Section 7.11.1 for imputation rules).
In case a subject received rescue therapy within 6 weeks prior to week 28-36 period, i.e., in 
weeks 22-36, Hb value will be set to missing for 6 weeks after they stopped rescue and will 
be imputed similarly.
Baseline Hb is defined as the mean of four central laboratory Hb values: four latest Hb values 
prior or on the same date as first study drug intake (pre-dose).


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6.1.1.2 Primary Efficacy Endpoint for US (FDA)
The primary efficacy endpoint for US is Hb change from BL to the average Hb of weeks 28 
to 52 regardless of rescue therapy.
For the average in weeks 28-52, all available Hb values obtained from the central laboratory 
will be used (i.e., both scheduled and unscheduled Hb values).
For the analyses that require an Hb value by visit, the last available Hb value in the visit 
window will be kept.
In case a subject does not have any available Hb value during this week 28-52 period
(because they died or withdrew from the study for example), imputation rules will be applied 
(refer to Section 7.11.1 for imputation rules).
Baseline Hb is defined as in Section 6.1.1.1
6.1.2
Key Secondary Efficacy Endpoints
The key secondary efficacy endpoints in this study are listed in Table 5
Table 5
Key Secondary Efficacy Endpoints
Number
Endpoint
1
Hb response defined as mean Hb during weeks 28 to 36 within the target range of 10.0 
to 12.0 g/dL without having received rescue therapy within 6 weeks prior to and during 
this 8-week evaluation period.
2
Change from BL in Low Density Lipoprotein (LDL) cholesterol to the average LDL 
cholesterol of weeks 12 to 28.
3
Mean monthly IV iron use (mg) during day 1 to week 36 (monthly defined as a period 
of 4 weeks).
4
Change from BL in SF-36 Physical Functioning (PF) sub-score to the average PF sub-
score of weeks 12 to 28.
5
Change from BL in SF-36 Vitality (VT) sub-score to the average VT sub-score of weeks 
12 to 28.
6
Change from BL in mean arterial pressure (MAP) to the average MAP value of weeks 
20 to 28.
7
Time to first occurrence of increase in blood pressure: An increase from BL of ≥20 mm 
Hg systolic blood pressure (SBP) and SBP ≥ 170 mmHg or an increase from baseline of 
≥15 mmHg diastolic blood pressure (DBP) and DBP ≥ 100 mmHg during weeks 1 to 36.


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6.1.2.1 Hb response defined as mean Hb during weeks 28 to 36 within the target range 
of 10.0 to 12.0 g/dL without having received rescue therapy within 6 weeks 
prior to and during this 8-week evaluation period.
The average Hb value from weeks 28 to 36 weeks will be calculated as defined below. The 
Hb response will then be defined as a binary variable, Hb response (Yes/No), where Hb 
response=”Yes” is defined as:
●
Average Hb ≥10.0 g/dL, and 
●
Average Hb ≤12.0 g/dL.
For this calculation, all available Hb values in weeks 28-36 will be used, i.e. both scheduled 
and unscheduled Hb values from the central laboratory.
In case a subject does not have any available Hb value in weeks 28-36 (if they died or 
withdrew from the study for example), imputation rules will be used (refer to Section 7.11.1
for imputation rules).
In case a subject requires rescue therapy within 6 weeks prior to weeks 28-36, in weeks 22 to 
36, values will be set to missing for 6 weeks after they stopped rescue and will be imputed 
similarly. 
6.1.2.2 Change from BL in Low Density Lipoprotein (LDL) cholesterol to the average 
LDL cholesterol of weeks 12 to 28.
The analysis will be done on all values (fasted and non-fasted) of Day 1 and up to week 28.
All available LDL values will be used (regardless the fasting status), i.e. both scheduled and 
unscheduled LDL values. LDL values in analysis visit windows at weeks 12, 20 and 28 will 
be selected for the calculation of the average LDL cholesterol of weeks 12-28 (see Table 34
and Section 7.11.4 for the analysis windows definition and the differentiation between the 
MMRM and ANCOVA analyses). 
For missing LDL imputation rules, refer to Section 7.11.1. Baseline LDL is defined as the
LDL value on Day 1. If this value is missing, the latest value prior to first study drug 
administration will be used. 
This analysis will also be repeated for fasted values only, as a sensitivity analysis.
6.1.2.3 Mean monthly IV iron use (mg) during day 1 to week 36
The Mean Monthly (defined as a period of 4 weeks or 28 days) IV iron use during day 1 to 
week 36, per subject (in mg) is defined by the following formula:
	 
   ()   	        (	     ,!  !"" ! #)
((	   $   ,!  !"" ! #)%& ' (')  / *+
Analysis visits will be used as indicated in Table 32, Section 7.11.4. 
The use of IV iron is recorded in the Concomitant Medication form of the eCRF, where 
Route is INTRAVENOUS. All medications are coded with WHO-DD. Records selected will 
be those coded as IRON PREPARATIONS.


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Having received IV iron is a binary variable (Yes/No), where “Yes” is defined as having at 
least one record selected during the Efficacy Emergent Period. Subjects using IV iron pre-
treatment with an end date of Day 1 will not be included. Subjects without a relevant 
concomitant medication record will be assumed that they used no IV iron, thus set to 0 mg.
Time to first IV iron during day 1 to week 36 will be derived similarly to time to first 
occurrence of an increase in blood pressure, in Section 6.1.2.7, with first event date 
corresponding to the Date of first dose of IV iron during the day 1 to week 36 period. The 
time to censoring for a subject without the event of interest is calculated as:
(Min (Week 36 analysis date, end of efficacy emergent period) – Analysis date of first dose
intake + 1) / 365.25
6.1.2.4 Change from BL in SF-36 Physical Functioning (PF) sub-score to the average 
PF sub-score of weeks 12 to 28.
For details on the SF-36 PF subscore, refer to Section 6.1.3.12.1
All available SF-36 PF values will be used i.e. both scheduled and unscheduled SF-36 PF 
values. SF-36 PF values in 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 Table 33 and Section 7.11.4
for the analysis windows definition and the differentiation between the MMRM and 
ANCOVA analyses). 
For missing SF-36 PF, refer to Section 7.11.1 for the imputation rules.
Baseline assessment is the assessment from Day 1 visit.
6.1.2.5 Change from BL in SF-36 Vitality (VT) sub-score to the average VT sub-score 
of weeks 12 to 28.
For details on the calculation of the SF-36 VT scale subscore, see Section 6.1.3.12.1.
Similar rules as for Section 6.1.2.4 will be used for the calculation of the SF-36 VT scale 
sub-score.
6.1.2.6 Change from BL in pre-dialysis mean arterial pressure (MAP) to the average 
MAP value of weeks 20 to 28.
Blood pressure will be measured singly for the three visits during the screening period and in 
triplicate with a 2-minute interval for all other visits during the study. During the study, for 
systolic blood pressure (SBP) and diastolic blood pressure (DBP), the average will be 
calculated for each visit using the three readings. If less than three readings are available, all 
non-missing readings will be used in the calculation of the average. 
For this analysis, only pre-dialysis blood pressure values will be considered.
Pre-dialysis MAP will be derived for each visit from the above averaged pre-dialysis SBP 
and the pre-dialysis DBP using the following equation: 
MAP = (2/3) * DBP + (1/3) * SBP


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All available pre-dialysis MAP values will be used, i.e. both scheduled and unscheduled 
MAP values. Pre-dialysis MAP values in analysis visit windows at weeks 20, 22, 24, 26 and 
28 will be selected for the calculation of the average pre-dialysis MAP during weeks 20-28 
(see Table 32 and Section 7.11.4 for the analysis windows definition and the differentiation 
between the MMRM and ANCOVA analyses). 
For missing data imputation rules, refer to Section 7.11.1 Baseline assessment is the 
assessment on Day 1 (average of the three readings). If the baseline assessment is missing, 
then the latest available value prior to first drug administration will be used.
6.1.2.7 Occurrence and time to first occurrence of an increase in pre-dialysis blood 
pressure during weeks 1 to 36.
For this analysis, only pre-dialysis blood pressure values will be considered.
Occurrence of an increase in pre-dialysis blood pressure is a binary variable (Yes/No), 
defined as:
●
Pre-dialysis systolic blood pressure (SBP) increase from BL ≥20 mmHg AND SBP 
>170 mmHg, or 
●
Pre-dialysis diastolic blood pressure (DBP) increase from BL ≥15 mmHg AND DBP 
>100 mmHg.
at any visit from week 1 to week 36. The date of occurrence is defined as the first date where 
SBP criterion or DBP criterion is met, whichever occurs first.
At each visit, pre-dialysis SBP and DBP are calculated as the average from the three
readings, assessed before dialysis. If less than three readings are available, the non-missing 
readings will be used in the calculation of the average.
Baseline assessment is the assessment from Day 1 (pre-dialysis). If this value is missing, then 
the latest available value from the screening period will be used.
Only events starting during the Safety Emergent Period and up to week 36 analysis date will 
be taken into account.
The time to occurrence of an increase in blood pressure 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 occurrence of increase in blood pressure. 
The time to censoring for a subject without the event of interest is calculated as:
(Min (Week 36 analysis date, Date of last vital signs assessment during the week 1-36 
period) – Analysis date of first dose intake + 1) / 365.25
Refer to Section 6.2 and 7.11.5 for more details regarding the Safety Emergent Period. 


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6.1.3
Additional Secondary Efficacy Endpoints
The additional secondary efficacy endpoints are listed in Table 6
Table 6
Additional Secondary Efficacy Endpoints
Number
Endpoint
Hb Maintenance
1
Hb response during weeks 28 and 36 defined as mean Hb – regardless of use of rescue 
therapy within the target range of 10.0 to 12.0 g/dL. Additional definitions to be 
included for sensitivity analyses are mean Hb >=10.0 g/dL during Week 28 and 36, 
during Week 28 and 52 and mean Hb between 10.0 and 12.0 g/dL during Week 28-52.
2
Hb change from BL to each post-dosing time point. 
3
Hb level averaged over weeks 28 to 36, 44 to 52, and 96 to 104 without use of rescue 
therapy within 6 weeks prior to and during these 8-week evaluation periods.
4
Hb change from BL to the average Hb value of weeks 28 to 36, 44 to 52, and 96 to 104 
regardless of the use of rescue therapy.
5
Proportion of Hb values >=10 g/dL and within 10.0 to 12.0 g/dL in weeks 28 to 36, 44 to 
52, and 96 to 104 without use of rescue therapy within 6 weeks prior to and during these 
8-week evaluation periods.
Hospitalizations
6
Occurrence (number) of hospitalizations (HD days are not counted as hospitalizations, 
even when performed overnight), number of days of hospitalization per patient-year 
exposure and time to first hospitalization.
Rescue Therapy Use
7
Occurrence and time to first use of rescue therapy [composite of RBC transfusions (all 
patients) and rescue ESA (roxadustat treated subjects only)], occurrence and time to first 
use of RBC transfusions, number of RBC packs per subject, volume of RBC transfused 
per subject.
Iron Use
8
Occurrence of IV 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). Use of oral 
iron.
Change in Cholesterol Levels, Apolipoproteins
9
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. 
10
Occurrence of mean LDL cholesterol <100 mg/dL calculated over weeks 12 to 28.
Blood Pressure Effect
11
Occurrence of achieved antihypertensive treatment goal in CKD subjects (SBP< 
140 mmHg and DBP< 90 mmHg) based on the mean SBP and mean DBP calculated over 
weeks 12 to 28. 
HRQoL
12
Change from BL to the average value of weeks 12 to 28 (SF-36 Physical Component 
Score (PCS), Anemia Subscale (“Additional Concerns”) of Functional Assessment of 
Cancer Therapy (FACT-An) Score, Total FACT-An Score, EQ-5D 5L VAS Score).
13
Patient Global Impression of Change (PGIC).
Hepcidin, Iron status, HbA1c
14
Changes from BL to each study visit (when measured) in Serum hepcidin, Serum ferritin, 
TSAT and HbA1c level.


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6.1.3.1 Hb response regardless of use of rescue therapy. 
Hb response is defined as the mean Hb during weeks 28 to 36 within the target range of 10.0 
to 12.0 g/dL.The same rules as defined in Section 6.1.2.1 apply for this endpoint, except that 
is defined regardless of use of rescue therapy (values in the rescue period will be used too).
Additional endpoints to be used are mean Hb ≥ 10.0 g/dL over weeks 28 to 36 and Hb 
response (defined as mean Hb values between 10.0 to 12.0 g/dL and also defined as mean Hb 
values >=10.0 g/dL) during weeks 28 to 52. 
6.1.3.2 Hb change from BL to each post-dosing time point. 
All scheduled and unscheduled hemoglobin values that belong to each window will be taken 
into account using one value per analysis window, as defined in Table 32 and Section 7.11.4
Baseline Hb is defined in Section 6.1.1.1
At each visit, Hb will also be categorized into the following categories: <10 g/dL, 10-12 g/dL 
and > 12 g/dL.
6.1.3.3 Hb level averaged over weeks 28 to 36, 44 to 52, and 96 to 104 without use of 
rescue therapy within 6 weeks prior to and during these 8-week evaluation 
periods.
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 32, 
Section 7.11.4).
In addition, the averages over weeks 28-36, 44-52 and 96-104 will be categorized into the 
following categories: 
●
<10 g/dL,
●
>=10 g/dL,
●
10-12 g/dL,
●
>12 g/dL.
In case a subject does not have any available Hb value within this evaluation period, or in 
case a subject requires rescue therapy within 6 weeks prior to and during this 8-week 
evaluation period, refer to Section 7.11.1 for imputation rules.
6.1.3.4 Hb change from BL to the average Hb value of weeks 28 to 36, 44 to 52, and 96 
to 104 regardless of the use of rescue therapy.
The same rules as defined in Section 6.1.1, apply for these periods except that it is regardless 
of rescue therapy.
6.1.3.5 Categorical analysis of Hb values
The following endpoints will be analyzed: 
●
Proportion of Hb values >=10 g/dL and within 10.0-12.0 g/dL by time intervals;


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●
Percentage of time with Hb values falling in each Hb interval (<10.0 g/dL, >=10 g/dL, 
within 10.0-12.0 g/dL, > 12.0 g/dL, > 13.0 g/dL and > 14.0 g/dL) during the Efficacy 
Emergent Period;
●
Potential Excessive Hematopoiesis (EH).
Proportion of Hb values 
The following proportions in percentage for each subject will be defined: 
●
Number of Hb values >= 10.0 g/dL / Total number of Hb values*100
●
Number of Hb values within 10.0-12.0 g/dL / Total number of Hb values*100
in weeks 28 to 36, 44 to 52 and 96 to 104 without use of rescue therapy within 6 weeks prior 
to and during this 8 week evaluation period. All scheduled and unscheduled hemoglobin 
values that belong to each period will be taken into account using the analysis windows
defined in Table 32, Section 7.11.4. The following time periods will be defined in addition: 
56 to 64, 68 to 76 and 80 to 92.
Percentage of time 
The percentage of time each patient has an Hb value <10.0 g/dL, >= 10.0 g/dL, within 10.0-
12.0 g/dL, > 12.0 g/dL, > 13.0 g/dL or > 14.0 g/dL will be calculated (as a percentage of the 
total of the length of time between the first and last Hb assessment during the evaluated 
period). The percentage of time will be calculated via linear interpolation. That is, if the 
change in Hb category (for instance from <= 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 14.0g/dL).
Figure 1 shows visually how the linear interpolation will calculate the total number of days 
that a subject is in each Hb category for an example subject:


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Figure 1
Example of Linear Extrapolation
In case that several Hb values are on the same day the average of these values will be used to 
represent the Hb of that day in the above formula. This calculation will provide the day that 
the change in Hb value occurs. The number of days that the Hb value has been in each 
category will be determined and the percentage calculated based on the length of time 
between the first and last Hb assessment during the evaluated period, i.e.:
Date of Last Hb assessment during the evaluated period – Date of first assessment during the 
evaluated period.
No imputation will be performed if no Hb value is available in relevant time windows.
In case a subject requires rescue therapy within 6 weeks prior to and during these 8-week 
evaluation periods, refer to Section 7.11.1 for imputation rules.
Potential Excessive Hematopoiesis (EH), regardless use of rescue therapy, based on Hb 
central laboratory
The presence of potential EH will be defined as:
- Hb increase by >2.0 g/dL between any 2 visits within 4 weeks of treatment 
Time to first occurrence of potential EH regardless the use of rescue therapy during the 
treatment period will be defined in weeks as:
(First event date – Analysis date of first dose + 1) / 7
where ‘First event date’ is defined as first date of occurrence of the criterion met during the 
treatment period.
For a subject without potential EH, the time to censoring will be calculated (in weeks) as: 


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(Min(Date of last hemoglobin assessment during the Efficacy Emergent Period, End Date of 
the Efficacy Emergent Period) – Analysis date of first dose + 1) / 7
Refer to Section 7.11.6 for the definition of the Efficacy Emergent Period.
6.1.3.6 Occurrence (number) of hospitalizations, number of days of hospitalization per 
year and time to first hospitalization.
The occurrence and the number of non-HD hospitalizations per subject during the Efficacy 
Emergent Period will be calculated. HD days are not counted as hospitalizations, even when 
performed overnight.
The number of days of hospitalization per year treated will be calculated as:
[Sum of the durations of all non-HD hospitalizations in days (Date of discharge – Date of 
admission + 1)] / (duration of efficacy emergent period in days / 365.25). 
In case of missing dates, the hospitalization duration will be imputed by the average duration 
per stay derived from the subjects with non-missing duration within the same treatment group. 
Duration of treatment exposure is defined in Section 6.5.4.
If the date of admission of a hospitalization record is the same as the date of discharge of the 
previous record, for example because two records are created to illustrate that the subject is 
moved from one hospital to another hospital or from a standard care to the intensive care unit 
(ICU), then the two records will be combined in one record. 
Hospitalizations will also be described by reason for admission (admission for anemia or 
other reasons).
Time to first hospitalization in years will be defined in years as:
(First event date during the Efficacy Emergent Period – Analysis date of First dose intake + 
1)/365.25
With ‘First event date’ defined as ‘Date of first Admission and ‘Analysis Date of first dose 
intake’ defined in Section 6.5.4.
For a subject without hospitalization, the time to censoring will be calculated as: 
(Date of End of Efficacy Emergent Period – Analysis Date of first dose intake + 1) / 365.25
With date of End of Efficacy Emergent Period defined in Section 7.11.6
6.1.3.7 Occurrence and time to first use of rescue therapy, occurrence and time to first 
use of RBC transfusions, number of RBC packs per subject, volume of RBC 
transfused per subject during the treatment period.
Rescue therapy is defined as RBC transfusion for all subjects and ESA (SC or IV) for 
roxadustat-treated subjects.
RBC transfusion is collected and coded into the ATC and WHO-DRL dictionaries. The 
following WHO-DRL codes will be classified as RBC transfusion: '01186901001'. ESA 
rescue treatment is recorded on the dosing CRF.


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Only rescue medication that started during the study treatment and up to end of efficacy 
emergent period will be taken into account and considered as use of rescue medication.
For a subject with use of rescue therapy, the time to first 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
The volume of blood transfused and the total number of RBC units/packs (for each subject, 
the sum of blood volume and units/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 by volume transfused/250 mL (for transfusion of 
packed cell units) or volume transfused/500 mL (for transfusion of full blood).
For subjects with use of RBC transfusion, the time to first 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’ is 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
The ESA-weeks are defined as the duration of ESA exposure. Each period when ESA [ATC 
code = B03XA] was taken will be summed by subjects as follows:
sum (each period (min(Analysis Date of last dose, End date of ESA therapy) + X days – Start 
date of ESA therapy +1)/7 );
X will be defined as the duration of the effect of ESA following the last ESA administration
for each ESA therapy use period, based on the following rules:
If Frequency = 1 PER WEEK then X=7
If Frequency = 2 PER WEEK then X=3
If Frequency = 3 PER WEEK then X=2
If Frequency = 1 PER MONTH then X=28


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If Frequency = ONCE then X=0
If Frequency = BIM (Bi-monthly) then X=14
If Frequency = QD (daily) then X=1
If Frequency = QM (monthly) then X=28
If Frequency =QOD (every other day) then X=2
If Frequency = TID (three times daily) then X=1
If Frequency = 4 TIMES PER WEEK then X=2
If Frequency = EVERY 3 WEEKS then X=21
Additional frequency may be considered depending on the data.
6.1.3.8 Occurrence of iron supplementation. 
The use of IV iron is collected in the Concomitant Medication form of the eCRF. All 
medications are coded with WHO-DD. Records selected will be those coded as IRON 
PREPARATIONS, and where route is INTRAVENOUS.
Having received IV Iron is a binary variable (Yes/No), where “Yes” is defined as having at 
least one record selected during the Efficacy Emergent Period. Time to first IV Iron will be 
derived similarly to time to first use of rescue therapy, in Section 6.1.3.7, 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 Efficacy Emergent Period will be divided in periods of 28 days and for each of these 
periods, the monthly mean of IV iron will be calculated. The total amount of IV iron used 
will be calculated for the overall Efficacy Emergent Period. Only use of IV Iron that was 
ongoing or started during the Efficacy Emergent Period will be taken into account.
The Mean Monthly IV iron use per subject (in mg) for weeks 37 to 52 and 53-104 will be 
calculated similarly as in Section 6.1.2.3. The occurrence of oral iron (coded as IRON 
PREPARATIONS and route ORAL) 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. This will be combined with 
IV iron use for these periods.
6.1.3.9 Change from BL to each post-dosing study visit in Total cholesterol, 
LDL/High-density Lipoprotein (HDL) ratio, Non-HDL cholesterol, 
Triglycerides, Apolipoproteins A1 and B, ApoB/ApoA1 ratio. 
For each sample, the following will be calculated:
●
LDL/HDL ratio (LDL Cholesterol divided by HDL Cholesterol)
●
Non-HDL cholesterol (Total Cholesterol minus HDL Cholesterol)


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Change from baseline to each post-dosing study visit will be calculated for the following 
lipid parameters:
●
Total cholesterol 
●
LDL cholesterol
●
HDL cholesterol
●
Low-density lipoprotein (LDL) / high-density lipoprotein (HDL) ratio
●
Non-HDL cholesterol
●
Triglycerides
●
Apolipoproteins A1 and B (ApoA1 and ApoB)
●
ApoB/ApoA1 ratio.
All available data will be summarized descriptively for all parameters above, for fasted 
values and regardless of fasting status.
No imputation will be performed in case of a missing value. If several values are available in 
the same window, one value will be used, as defined in Table 34 and Section 7.11.4  
Baseline assessment is the assessment from Day 1 visit. If this value is missing, then the 
latest screening period value will be used as baseline.
6.1.3.10 Occurrence of mean LDL cholesterol <100 mg/dL calculated over weeks 12 to 
28.
The evaluation period is defined as the average of all available LDL cholesterol values in 
weeks 12-28 (visit at 12, 20 and 28 weeks, as defined in Table 34 and Section 7.11.4). The 
occurrence of mean LDL cholesterol <100mg/dL (2.59 mmol/L) over weeks 12 to 28 will 
then be defined as a binary variable (Yes/No), where ”Yes” is defined as mean LDL 
cholesterol <100mg/dL (2.59 mmol/L) over weeks 12 to 28.
No imputation will be performed in case of a missing value.
This endpoint will be reported on fasting values and regardless of fasting status.
6.1.3.11 Occurrence of achieved antihypertensive treatment goal in CKD subjects 
(SBP< 140 mmHg and DBP< 90 mmHg) based on the mean SBP and mean 
DBP calculated over weeks 12 to 28.
Occurrence of achieved antihypertensive treatment goal (SBP< 140 mmHg and 
DBP< 90 mmHg) based on the mean SBP and mean DBP will be calculated over an 
evaluation period defined as the average of all available values in weeks 12 to 28, similarly 
as in Section 6.1.2.6  The analysis windows is defined in Table 32, 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< 140 mmHg and DBP< 90 mmHg.
No imputation will be performed in case of a missing value.


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6.1.3.12 Change from BL to the average value of weeks 12 to 28 in Quality of Life 
scores.
All study subjects will be required to complete Quality of Life (QoL) questionnaires as 
indicated in the schedule of assessments: 
●
SF-36
●
FACT-An
●
EQ-5D 5L
In HD subjects, questionnaires will be completed by the subject preferably prior to, or at the 
start of dialysis session. In Peritoneal Dialysis subjects, it is done preferably prior to any 
study assessment.
In addition to week 12-28, change from BL to the average value of weeks 36 to 52 will be 
calculated.
The next sections provide further details on how to derive these instruments, some 
derivations will be provided by an external vendor (QualityMetric).
6.1.3.12.1 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). 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). In addition, two summary measures, defined as the Physical 
Component Score (SF-36 PCS) and Mental Component Score (SF-36 MCS) will be 
provided.
Scoring of each dimension and the summary measure will be performed by QualyMetric 
using QualityMetric Health Outcomes(tm) Scoring Software 4.5. 
Change from baseline to the average value in weeks 12-28 will be calculated for the Physical 
Component Scores of SF-36 (SF-36 PCS), following the same rules as defined in 
Section 6.1.2.4
For missing SF-36 PCS values, refer to Section 7.11.1 imputation rules. Baseline always 
refers to the assessment at day 1 to be performed prior to first study drug administration.


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The number and percent of subjects with a change from baseline of <3 / >=3 points and of 
<5 / >=5 points will be calculated for each visit for the following: Vitality Score (SF-36 VT), 
Physical Functioning score (SF-36 PF) and Physical Component score (SF-36 PCS).
In addition, the eight dimensions and the two summary measures and their associated change 
from baseline will be reported by visit.
The normalized values will be used for analysis.
6.1.3.12.2 Functional Assessment of Cancer Therapy –Anemia (FACT-An)
The Functional Assessment of Cancer Therapy – General (FACT-G; version 4) contains 
27 items that cover four dimensions of well-being: physical (PWB) – 7 items, functional 
(FWB) – 7 items, social/family (SWB) – 7 items, and emotional (EWB) – 6 items. 
The ‘additional concerns’ section contains 20 items: 13 fatigue specific items plus 
7 additional items related to anemia were developed for use in conjunction with the FACT-G 
(Cella 1997). The 13 fatigue items plus the seven additional items related to anemia comprise 
the Anemia Subscale (AnS). Administration of the FACT-G plus the Anemia Subscale (AnS) 
is referred to as the FACT-An. The FACT-An has a recall period of the ‘past seven days’. 
Respondents are asked to provide responses, (i.e., ‘Not at all’, ‘A little bit’, ‘Somewhat’, 
‘Quite a bit’ and ‘Very much’), to a list of statements which are either positively or 
negatively phrased. A final higher score indicates better QoL (see Appendix 2).
Each individual item is scored from 0 (Not at all) to 4 (Very much), and then the total score 
is obtained by summation of the resulted scores.
If there are missing items, subscale scores can be standardized. This is done by multiplying 
the sum of the subscale by the number of items in the subscale, then dividing by the number 
of items actually answered. This can be done on the scoring guide or by using the formula 
below:
Prorated subscale score = [Sum of item scores] x [N of items in subscale] / [N of items 
answered]
When there are missing data, standardizing by subscale in this way is acceptable (Webster 
2003) as long as more than 50% of the items were answered (e.g., a minimum of 4 of 7 items, 
4 of 6 items, etc). The total score is then calculated as the sum of the un-weighted subscale 
scores. The FACT scale is considered to be an acceptable indicator of a subject’s quality of 
life as long as overall item response rate is greater than 80% (e.g., at least 22 of 27 FACT-G 
items completed). This is not to be confused with individual subscale item response rate, 
which allows a subscale score to be prorated for missing items if greater than 50% of items 
are answered. In addition, a total score should only be calculated if ALL of the component 
subscales have available scores.  
The FACT-An instrument will be scored according to Appendix 10.2. The following 8 scores 
will be calculated:
●
PWB subscale score
●
SWB subscale score


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●
EWB subscale score
●
FWB subscale score
●
AnS subscale score
●
FACT-An TOI score
●
FACT-G total score
●
FACT-An total score
●
Fatigue subscale score
Change from baseline to the average value in weeks 12-28 will be reported for the two scores 
(Anemia subscale ‘Additional concerns’ of FACT-An score and Total FACT-AN score). In 
addition, the score and change from baseline will be reported for each visit for all six scores.
Change from baseline to the average value in weeks 12-28 will be calculated for the FACT-
An subscore following the same rules as defined in Section 6.1.2.4
No imputation will be performed in case of a missing value.
Baseline always refers to the assessment at day 1 to be performed prior to first study drug 
administration.
6.1.3.12.3 EQ-5D 5L 
The EQ-5D 5L is an international standardized non-disease specific (i.e. generic) instrument 
for describing and valuing health status, and a multi-dimensional measure of health-related 
QoL (see Appendix 10.3).
It includes two main components: (1) a VAS scale rating perception of overall health and (2) 
5 qualitative domains: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and 
Anxiety/Depression. For more details and description of the questionnaire, refer to 
Appendix 10.3
Change from baseline to the average value in weeks 12-28 will be calculated for the EQ 5D 
5L VAS, following the same rules as defined in Section 6.1.2.4
Frequency distributions will be described for each visit for:
●
EQ-5D 5L Mobility Score
●
EQ-5D 5L Self-Care Score
●
EQ-5D 5L Usual Activities Score
●
EQ-5D 5L Pain/Discomfort Score
●
EQ-5D 5L Anxiety/Depression Score
The evaluation period for the VAS score is defined as the average of available EQ-5D 5L 
VAS scores of weeks 12-28 (visit at W12 and W28).
No imputation will be performed in case of a missing item. Baseline always refers to the 
assessment at day 1 to be performed prior to first study drug administration.


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6.1.3.13 Patients’ Global Impression of Change (PGIC)
The Patients’ Global Impression of Change (PGIC) is a subject-rated instrument that 
measures change in subjects’ overall status since the start of the study on a 7-point qualitative 
scale ranging from 1 (very much improved) to 7 (very much worse) (see Appendix 10.4).
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.
6.1.3.14 Changes from BL to each study visit (when measured) in Serum hepcidin, 
Serum ferritin, TSAT and HbA1c level.
Changes from baseline to each study visit (see analysis windows in Table 32) will be 
calculated for these parameters:
●
Serum hepcidin,
●
Serum ferritin,
●
TSAT,
●
Serum Iron,
●
Total Iron Binding Capacity (TIBC).
●
HbA1c level (Subjects with and without diabetes in history, and overall),
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.
6.1.4
Other exploratory variables: hs-CRP (High Sensitivity C-Reactive Protein) and 
Post-dialysis BP
The variable hs-CRP will be collected from the central laboratory on the following visits: 
Day 1, weeks 4, 12, 20, 36, 52, EOT and EOS. Absolute values and changes from baseline to 
each study visit will be calculated. Baseline assessment is the assessment from Day 1 visit. If 
Day 1 assessment is missing, change from baseline will not be reported. Analysis windows 
are defined in Table 32
Post-dialysis BP will be used to perform additional exploratory analyses for BP-related 
endpoints: 1) MAP and 2) Time to first occurrence of increase in blood pressure.  
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), and pre-specified adjudicated cardiovascular and 
cerebrovascular events (will be reported separately),


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


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●
All deaths during study period and post study safety follow up period
●
Related Serious TEAEs
●
TEAEs Leading to permanent Discontinuation of study drug
●
TEAEs NCI CTC(AE) Grade 3 or Higher
●
MedDRA System Organ Class (SOC)
The time to occurrence for a subject with a TEAE for a given type (e.g., serious AE leading 
to discontinuation) 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’ 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
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.


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6.2.1.5 Definition of event rate
The event rate (number of events per 100 subject years) will be calculated as follows:
100
(years)
years
patient 
Total
events
emergent 
-
 treatment
of
Number 

Where Total patient years is the sum of individual time during the safety emerging period 
expressed in years. 
6.2.1.6 Adverse events up to 7 days after last dose
Additional analyses restricted to any treatment-emergent adverse event starting up to 
Analysis Date of Last Dose (adjusted for dosing frequency) + 7 days will be conducted. 
Time to occurrence of event will be calculated (in years) as:
(First event date of the given type occurring from Day 1 (post dose) up to Analysis date of 
Last Dose + X + 7 days) – Analysis date of first dose intake + 1) / 365.25, where X days is 
defined depending on the dosing frequency.
With ‘Analysis date of first dose intake’ Analysis Date of Last Dose defined in Section 6.5.4
and 7.11.5 Subjects who have not experienced an AE for that given type will be censored
and the time to censoring for these subjects will be calculated (in years) as:
Minimum [Analysis Date of Last Dose + X + 7 days, Max (EOS, Date of Death)] – Analysis 
date of first dose intake +1) / 365.25.
6.2.2
Vital Signs
The following endpoints will be assessed, pre and post dialysis:
●
Systolic blood pressure (SBP)
●
Diastolic blood pressure (DBP)
●
Pulse 
In addition, the following assessments will be done:
●
Respiratory rate
●
Weight
Single measurements for blood pressure (BP) will be taken at three visits during the 
screening period. Measurements will be taken in triplicate with 2-minute intervals for all 
other visits. An average will be calculated from the three readings, the average in the eCRF 
system will not be used. If less than three readings are available, the non-missing readings 
will be used in the calculation of the average. 
The position and date for the assessment will also be recorded. Change from baseline will be 
calculated as the measurement taken at the specific visit minus the measurement at baseline 
visit. 


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For all vital parameters, the minimum and the maximum post-baseline value during the 
Safety Emergent Period will be defined. For this calculation, only values from day 2 up to the 
date of End of the Safety Emergent Period (see Section 7.11.5) will be used.
Baseline assessment is the assessment from day 1 visit. If day 1 assessment is missing, 
screening period assessment will be used in the analysis. For missing visits, the last 
observation will be carried forward.
For vital signs, if there are pre-dialysis and post-dialysis assessments, the pre-dialysis
assessment will be used for classification of the analysis visit (see Section 7.11.4) and the 
definition of potentially clinical vital signs criteria will use pre-dialysis and post-dialysis 
assessments separately.
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 7 (10 combined criteria).
Table 7
Potentially Clinically Significant (PCS) Vital signs Criteria
Vital Sign Parameter
Flag
Criteria
Observed Values
Change from Baseline
Respiratory Rate
(breaths per min)
High
≥ 20
Increase of  ≥ 5
Low
≤ 10
Decrease of ≥ 5
Systolic Blood Pressure 
(mmHg)
High
≥ 170
Increase of ≥ 20
Low
≤ 90
Decrease of ≥ 20
Diastolic Blood Pressure 
(mmHg)
High
≥ 110
Increase of ≥ 15
Low
≤ 45
Decrease of ≥ 15
Pulse 
(beats per min)
High
≥ 120
Increase of ≥ 20
Low
≤ 50
Decrease of ≥ 20
Weight (kg)
High
-
Increase of ≥ 10%
Low
-
Decrease of ≥ 10%
Potentially Clinically Significant Vital Signs Criteria will be calculated at each study visit 
and on-treatment (at any moment during the Safety Emergent Period) using the worst value 
among all available measurements. 
Time to occurrence of PCS Vital signs:
For each potentially clinically significant vital signs criterion (i.e 10 combined criteria), the 
time to occurrence of a PCS at any moment during the Safety Emergent Period (see 
Section 6.2) will be calculated (in years) as:
(First occurrence date – Analysis date of first dose intake + 1) / 365.25
With ‘First occurrence date‘ defined as the first date when both criteria (i.e., on observed and 
change from baseline) are met and Analysis date of first dose intake is 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 8 below.
Table 8
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 > 8× ULN
U/L for ALT or AST
no lower limit
ALT or AST > 8X ULN 
Total Bilirubin
µmol/L
no lower limit
> 1.5 X ULN 
> 2 X ULN#
Moderate Liver Abnormality*
U/L for ALT and AST,
µmol/L for Total 
Bilirubin
no lower limit
ALT and/or AST > 3X 
ULN or Total Bilirubin 
> 2X ULN
Severe Liver Abnormality*
U/L for ALT and AST,
µmol/L for Total 
Bilirubin
no lower limit
ALT and/or AST > 3X 
ULN and Total Bilirubin 
> 2X ULN
Gamma Glutamine 
Transaminase (GGT)
U/L
no lower limit
> 3X ULN
Calcium
mmo1/L
< 0.8 X LLN
>1.2 X ULN
Creatinine
µmo1/L
>1.5 X Baseline$
Potassium
mmo1/L
< 0.75 X LLN
>1.2 X ULN
Sodium
mmo1/L
< 0.9 X LNL
>1.1 X ULN
Total Protein
g/L
< 0.9 X LNL
>1.1 X ULN
Blood Urea Nitrogen (BUN)
mmo1/L
>1.5 X Baseline$
Neutrophils
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).
$ Criteria of > nX baseline only applicable for post-baseline assessments.
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:
●
Alanine Aminotransferase (ALT) > 3X ULN
●
Aspartate Aminotransferase (AST) > 3X ULN
●
Total Bilirubin > 1.5 X ULN 
For each above potentially clinically significant laboratory criteria, the time to occurrence of 
an abnormality for a subject with an abnormality at any moment during the Safety Emergent 
Period (see Section 6.2) will be calculated (in years) as defined in Section 6.2.2
Time to censoring will be defined (in years) as:
(Date of last laboratory assessment where parameter analyzed is non-missing during the 
Safety Emergent Period – Analysis date of first dose intake +1) / 365.25
6.2.3.2 Laboratory assessments
For all laboratory parameters, the minimum and the maximum values on treatment (see 
Section 6.2) will be defined.
In addition, each laboratory result will be classified as low (L), normal (N), or high (H) at 
each visit according to the laboratory supplied reference ranges.
Change from baseline will be calculated as the measurement taken at the specific visit minus 
the measurement at baseline visit. 
Baseline is defined as the assessment on Day 1 (prior to dosing), except for Hb (see 
Section 6.1.1.1). If Day 1 is missing, the screening or unscheduled assessment (prior to 
dosing) that is closest to Day 1 will be used.
Screening is defined as the screening or unscheduled assessment (during screening) that is 
closest to Day 1.
For the lipid panel and glucose parameter, two baseline values will be defined based on 
fasting status: regardless of fasting and fasted.
6.2.4
Physical Examination
A comprehensive physical examination will be conducted during the screening period and at 
the EOT visit and recorded in the source documents. This examination will include general 
appearance and the following body regions and systems: head, eyes, ears, neck and throat 


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(HEENT), lungs, heart, chest and back, abdomen, genitourinary, extremities, skin and any 
other, if deemed necessary.
A targeted examination (e.g., respiratory and cardiovascular) will be conducted and recorded 
in the source documents.
Only the date of the physical examination will be recorded in the eCRF. There will be no 
table or listing for the physical examination. Any clinically relevant adverse change will be 
recorded as an AE in the eCRF.
6.2.5
12-lead Electrocardiogram (ECG)
The 12-lead ECG measurements will be performed on all subjects at specific times. A single 
ECG measurement will be taken with the subject in the supine position, after the subject has 
been lying quietly for 5 minutes. Clinically significant abnormalities will be reported as an 
AE.
The visit, ECG date, Pulse, RR Interval, PR interval, QRS Interval, QT Interval, overall 
interpretation and relevant comments will be recorded in the eCRF.
Baseline assessment is the assessment from day 1 visit. If day 1 assessment is missing, 
screening period assessment will be used in the analysis.
QTc interval will be calculated using both 
●
Bazett (QTcB = QT/(RR Interval)'/*) and 
●
Fridericia (QTcF = QT/(RR Interval)'/) corrections, 
where QT is in msec and RR Interval in seconds; and if RR Interval is not available, it will be 
replaced with 60/HR.
For all ECG parameters, the maximum post-baseline value on treatment will be defined (see 
Section 6.2).
The QTc interval will be categorized at baseline and at each treatment visit using the range 
criteria defined in Table 9 below. This will be done for both Bazett and Fridericia correction 
formulas. The QTc interval changes from baseline will be categorized at each visit using the 
criteria defined in Table 9 below:
ECG values are potentially clinically significant (PCS) if they meet or exceed the upper limit 
values listed in Table 9 below.
Table 9
QTc Interval Classification
ECG Parameter
Classification
QTc interval (msec)
> 450 msec, > 480 msec, > 500 msec
QTc interval change (msec)
> 30 msec and > 60 msec
QRS and PR interval will also be categorized at baseline and at each treatment visit as 
defined in Table 10 below:


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Table 10
Other ECG Parameters Classification
ECG Parameter
Classification
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
6.2.6
Vascular Access Thrombosis (VAT)
For each AE marked as VAT, additional information regarding the event will be listed.
Time to first VAT will be derived similarly to time to first occurrence of a TEAE, in 
Section 6.2.1.3, with first event date corresponding to the Date of first VAT. Censoring rules 
will be the same as without an event of interest.
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.


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Age at baseline is calculated as Age= (DFirst-DB)/365.25, with DB as the Date of Birth and 
DFirst as the Date of First Dose intake.  If the Date of First Dose intake is not available, the 
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 follows:
average maximum quantity per day x 7
If the frequency is “/Month”, the average maximum quantity of tobacco per week will be 
determined as follows:
average maximum quantity per month / 4.3482
Screening Hb will be defined as the mean of the three latest central laboratory Hb values 
prior to the day of randomization.
Baseline Hb is defined in Section 6.1.1.1
Based on the mean screening Hb value, two categories will be defined: 
●
≤11.0 g/dL
●
> 11.0 g/dL
History of cardiovascular, cerebrovascular or thromboembolic diseases at baseline will be 
defined for subjects with any of the diseases that have been reported in the Cardiovascular 
Disease History eCRF. History will be categorized as:
●
Yes
●
No
Countries and Regions
Subjects will be enrolled from the following 17 countries: 
Region A (Western Europe)
●
Belgium
●
France


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●
Germany 
●
Italy
●
Portugal
●
Spain
●
UK
Region B (Central and Eastern Europe)
●
Bulgaria
●
Croatia
●
Hungary
●
Poland
●
Romania
●
Russia
●
Serbia
●
Czech Republic
●
Slovakia
●
Georgia
Randomization will be stratified by region using two categories: 
●
Region A: Western Europe
●
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 Treatment Discontinuation’-‘Analysis 
date of first dose intake’+1)/365.25
In case a subject completed the treatment period, time to censoring will be calculated as:
(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


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Time from Diagnosis of Targeted Medical History
Onset date and the start date of analysis for the study drug are collected and the time from 
diagnosis of targeted medical history in years is defined as
Time from Diagnosis of Targeted Medical History (years) =
(‘Analysis date of first dose intake’– ‘Onset Date’)/365.25
In case of partial dates, imputation rules apply and are detailed in Section 7.11.2
This will be calculated for each patient who was diagnosed with the targeted medical history:
hypertension, diabetes mellitus type 1, type 2 and combined, dyslipidemia and vascular 
access.
Iron Repletion at Screening
Subjects will be classified in one of the following 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%
●
Other
Iron Repletion at Baseline
Subjects will be classified in one of the following 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%
●
Other
If no Day 1 assessment is available, Iron Repletion at Screening will be used.
Average weekly ESA dose before randomization.
All subjects randomized will be classified into two groups:
●
Subjects with lower average weekly ESA dose prior to randomization (≤200 IU/kg 
epoetin or ≤ 1 μg/kg darbepoetin alfa), versus 
●
Subjects with higher average weekly ESA dose prior to randomization (>200 IU/kg 
epoetin or > 1 μg/kg darbepoetin alfa).
It will be derived using data in ‘Treatment History of Anemia’ eCRF. The methodology to 
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Dialysis type
Dialysis type is recorded in the eCRF Cumulative form: Dialysis method. All subjects will be 
classified into two groups (if two types of dialysis are reported, the latest one prior to first 
dosing will be used):
●
Hemodialysis subjects (including hemodiafiltration), versus
●
Peritoneal dialysis subjects (continuous ambulatory and automated)
Previous ESA treatment.
In the form Screening Procedures - Treatment history for Anemia and ESA Treatment history 
for Anemia, if the variable ‘Medication type’=’ESA’ and ‘Specify type of 
ESA’=’Darbepoetin Alfa’ then the variable ‘Previous ESA Treatment will be coded as 
‘Darbepoetin Alfa’. 
For all other values, as there are several epoetin types, it will take the value ‘Epoetin’.
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 end of 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 
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.
Renal transplant status (Yes or No), and the date of renal transplant (if applicable) will be 
derived. Similarly, ESA use after study treatment (Yes or No), and the start date of ESA use
after study treatment (if applicable) will be derived.
6.5.4
Variables related to study drugs
Randomization/Treatment Arms
Table 11 below presents the groups to which subjects are randomized.


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Table 11
Treatment arms
Randomization Arm Code (ARMCD)
Randomization Arm (ARM)
A
Roxadustat - TIW 
B
ESA (Darbepoetin Alfa or Epoetin Alfa)
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.
Duration of exposure in days
For each subject, the Length of Time on treatment will be calculated in days, using the 
following formula:
(‘Analysis Date of Last Dose’ - ‘Analysis Date first dose intake’) + 1
Amount of Prescribed (planned) 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. For first administration, the IRS reported dose and frequency will be used. 
The prescribed weekly dose at each visit (including unscheduled visits) will be calculated as
prescribed dose x 3 as the prescribed frequency is TIW for roxadustat.
Each visit will have an associated start and end date as follows:
●
Each visit (including unscheduled) will have an associated 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. 
Time periods of interest are defined below (monthly is defined as a period of 4 weeks or 
28 days) as follows:


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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
Treatment Period
Day 1
Day of EOT
Day 1 - Week 28
Day 1
End Day of Month 7 (day 196)
Day 1 – Week 36
Day 1
End Day of Month 9 (day 252)
*or EOT whichever is first
This will allow us to calculate the amount of prescribed medication in a time period as the 
sum of the daily prescribed amount within the time windows defined above.
In addition, amount of prescribed medication in mg/kg will be calculated. To convert a dose 
given in mg into a dose in mg/kg, the body weight recorded at day 1 will be used.
Darbepoetin alfa and epoetin alfa
The same methodology will be used for darbepoetin alfa and epoetin alfa. Note that 
prescribed frequency for darbepoetin alfa is once weekly, once every other week, or once 
every four weeks, and the prescribed frequency for epoetin alfa is: once weekly, twice 
weekly, three times weekly, or once every other week. The unit for darbepoetin alfa is 
microgram (µg), the unit for epoetin alfa is IU. 
In addition, amount of prescribed medication in µg/kg and IU/kg will be calculated. To 
convert a dose given in µg into a dose in µg/kg or in IU into a dose in IU/kg, the body weight 
recorded at day 1 will be used.
Amount of Consumed Medication
Roxadustat
The consumed Investigational Product Medication is captured in the Study Drug Roxadustat
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


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●
Amount consumed for each kit: amount dispensed – amount returned
●
Daily consumed dose for each kit: amount consumed/(end day of exposure-start day of 
exposure +1)
The same methodology as described for Amount Prescribed (planned) Medication will apply 
to calculate amount of consumed medication for each time period by summing up the 
different daily consumed amount of the different kits on a given day (subjects will be 
dispensed more than one kit on a given visit).
In addition, amount of consumed medication in mg/kg will be calculated. 
Darbepoetin alfa and epoetin alfa
The same methodology will be used for darbepoetin alfa and epoetin 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 
the ESA was dispensed – 1 Day
In addition, amount of consumed medication in µg/kg (darbepoetin alfa) and IU/kg (epoetin
alfa) will be calculated.
Compliance 
Compliance will be calculated for the time periods defined in Amount of Prescribed 
(planned) Medication. Compliance in % will be calculated for each time period (not reported 
cumulatively) as:
Amount consumed during time period
Amount prescribed during time period ×  100
The following compliance categories will be defined:
●
less than 50% (significant drug noncompliance)
●
at least 50%, less than 75% (moderate drug noncompliance)
●
at least 75% (acceptable compliance)
●
unknown
Dose Changes for roxadustat, darbepoetin alfa and epoetin alfa
Dosing changes are collected in the Study Drug Roxadustat - Dosing Decisions eCRF for 
roxadustat, in the Study Drug Darbepoetin - Dosing Decisions eCRF for darbepoetin alfa and 
in the Study Drug Epoetin alfa- Dosing Decisions eCRF for epoetin alfa. 
For example, for roxadustat, a change from 200 TIW to 250 TIW is a change of 600 mg to 
750 mg per week.
The same applies for darbepoetin alfa and epoetin alfa, but not weekly as it could be 
administered weekly, bi-weekly, monthly, or other frequencies. 


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For each subject the total number of dose changes, dose increases, dose decreases, and dose 
holds will be calculated.
7
STATISTICAL METHODOLOGY
7.1
General Considerations
●
All statistical comparisons will be made using two sided tests at the =0.05 significance 
level unless specifically stated otherwise. Null hypotheses for superiority testing will be 
of no treatment difference and corresponding alternative hypothesis will be two-sided. 
Null hypotheses for non-inferiority testing will be of inferiority of roxadustat treatment 
and will be one-sided at the =0.025.
●
All data processing, summarization, and analyses will be performed using SAS® 
Version 9.3 (SAS Enterprise Guide 4.3) or higher. Specifications for tables, data listings 
and figures (TLFs) formats can be found in the TLF Specifications for this study.  
●
All data will be summarized by treatment arm (roxadustat and ESA), type of ESA 
treatment (darbepoetin alfa and epoetin alfa) and for the total, unless specified otherwise.
For all results split by type of ESA treatment, previous ESA treatment before 
randomization will be separated in two categories (darbepoetin alfa or epoetin), unless 
specified otherwise. 
●
For continuous variables that are recorded as “< X” or “> X”, the value of “X” will be 
used in the calculation of summary statistics. The original values will be used for the 
listings.
●
All percentages will be rounded to one decimal place and lined up by the decimal place. 
The percentage will be suppressed when the count is zero.
●
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 frequency 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).
●
Pre-dialysis vital signs including blood pressure measurement will be used for analysis, 
unless otherwise specified.
●
For the SAF population analyses, the actual treatment will be used. For all other analysis 
populations, the planned treatment will be used.
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 violating criteria at subject level from Table 4. See Section 5.3
and Classification specifications for more details.


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7.2.1
Disposition of Subjects
The following subject data will be summarized and presented:
●
Number and percentage of subjects with informed consent, who discontinued before 
randomization and randomized (overall only),
●
Number and percentage of subjects randomized in each analysis set, by treatment arm, 
type of ESA treatment and overall,
●
Number and percentage of subjects who completed and discontinued treatment, by 
primary reason for treatment discontinuation, by treatment arm and type of ESA 
treatment for randomized subjects, SAF, FAS and PPS; 
●
Number and percentage of subjects who completed and discontinued the study, by 
primary reason for study discontinuation, by treatment arm and type of ESA treatment,
for randomized subjects, SAF, FAS and PPS; 
●
Number and percentage of subjects who completed the post study safety follow-up 
period, for all subjects who prematurely discontinued the study; 
●
Number and percentage of subjects for post study follow-up status, for all randomized
subjects within 2 years; and
●
Number and percentage of subjects excluded from PPS by reason for exclusion defined 
in Section 5.3, by treatment arm and type of ESA treatment, for the FAS.
The following data will be presented graphically by treatment arm and type of ESA treatment
for the SAF and PPS: 
●
Treatment discontinuation by reason using bar chart;
●
Treatment discontinuation by time interval and reason using bar chart; and
●
Time to treatment discontinuation using a Kaplan-Meier plot. 
In addition, the following graphs will be done to explore missing patterns and support 
efficacy analyses, by treatment arm, for the All Randomized and PPS:
●
Treatment discontinuation for lack of efficacy, using a cumulative incidence plot; 
●
Treatment discontinuation for adverse event, using a cumulative incidence plot;
●
Treatment discontinuation for withdrawal by subject, using a cumulative incidence plot.
Time intervals will be analyzed using the following categories:
●
Less than 2 weeks
●
At least 2 weeks, less than 4 weeks
●
At least 4 weeks, less than 12 weeks
●
At least 12 weeks, less than 24 weeks
●
At least 24 weeks, less than 36 weeks
●
At least 36 weeks, less than 52 weeks
●
At least 52 weeks, less than 78 weeks
●
At least 78 weeks, less than 104 weeks
●
104 weeks or more
●
Unknown.


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In addition, the randomization stratification strata from both sources (CRF and IRS) will be 
reported by treatment arm. Discrepancy between stratification from CRF and IRS will be 
summarized and the total number of patients with discrepancy overall and for each 
stratification factor will be provided.
Subjects who had a screen failure will be listed.
All other available data 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, type of ESA 
treatment 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,
o
PD2_1 Withdrawal of consent
o
PD2_2 Pregnancy
o
PD2_3 Significant non compliance
o
PD2_4 ESA rescue therapy (roxadustat subjects)
o
PD2_5 Organ transplant
●
PD3 – Received wrong treatment or incorrect dose
o
PD3_1- Received wrong treatment kit
o
PD3_2- Received incorrect dose
o
PD3_3- Study drug non compliance
●
PD4 – Received excluded concomitant treatment
o
PD4_1- Received prohibited medication
o
PD4_2- Received restricted medication
7.2.3
Demographic and Other Baseline Characteristics
Demographic and other baseline/screening characteristics will be summarized by descriptive 
statistics and frequency tabulations.
Number and percentage of subjects randomized in each country and site will be presented for 
the SAF, FAS, All Randomized and PPS.


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Descriptive statistics for age, weight, body mass index (BMI) and height at screening 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: 
●
Average screening Hb value as continuous and categorical (≤ 11.0 g/dL versus >11.0 
g/dL),
●
Baseline Hb as continuous,
●
Iron repletion at baseline, as a categorical value (see Section 6.5.2).
Demographic and baseline characteristics summaries above will be done for the All 
Randomized, SAF, FAS and PPS. This table will be repeated for subjects randomized after 
amendment 2.0 (or any further amendment) is implemented.
Selected demographics collected at screening will be done on Screen Failure subjects.
All Medical History will be analyzed using the SAF, as described below:
Medical History including anemia, chronic kidney disease (CKD), cardiovascular disease and 
targeted medical history are coded in MedDRA, they will be summarized by System Organ 
Class (SOC) and Preferred Term (PT).
Anemia history, CKD history, targeted medical history (diabetes type I and II, hypertension 
and dyslipidemia), cardiovascular disease history, tobacco history and family history of 
cardiovascular disease will be summarized. 
The number and proportion of subjects with each typical symptom for CKD will be 
described, as well as the number and proportion of subjects with each typical symptom for 
anemia.
Demographic and baseline data will also be listed. 
7.2.4
Previous and Concomitant Medications
Previous and concomitant medications are coded with WHO-DD, and will be summarized by
therapeutic subgroup (ATC 2nd level), chemical subgroup (ATC 4th level) and preferred 
WHO name for the SAF. 
Subjects taking the same medication multiple times will be counted once per medication. 
Treatment history for anemia will be summarized separately.
Missing dates' imputation rules are detailed in Section 7.11.2
7.3
Study Drugs
Roxadustat (=Investigational Product Medicine) is for oral administration and supplied as red 
coated oval tablets of 20, 50 and 100 mg.
Darbepoetin alfa (=Comparative Medicine) is administered by SC or IV injection, and 
supplied as a solution for injection in a pre-filled syringe of 10, 20, 30, 40, 60 and 100 µg.


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Epoetin alfa (=Comparative Medicine) is administered by SC or IV injection, and supplied as 
a solution for injection in a pre-filled syringe of 1000, 2000, 3000, 4000, 6000 and 8000 IU.
7.3.1
Exposure
The following information on drug exposure will be presented by treatment arm and type of 
ESA treatment, for the SAF.
Exposure related variables are defined in Section 6.5.4  
Descriptive statistics will be produced for:
●
The average weekly dose (roxadustat, darbepoetin alfa and epoetin alfa) the subject was 
exposed to during the treatment period (in mg, µg or IU and in mg/kg, µg/kg or IU/kg), 
by month, during the first 28, 36, and 52 weeks; and overall.
●
Number and percentage of subjects with dose changes, dose increases, dose decreases or 
dose hold.
●
Number of times for dose changes, dose increases, decreases or dose hold.
Duration of exposure will be summarized in two ways:
●
Descriptive statistics and frequency tabulations will be presented; 
●
Exposure time will be categorized according to 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
At least 78 weeks, less than 104 weeks
o
104 weeks or more
o
Unknown.
Counts and percentages of subjects in each of these categories will be summarized.
For roxadustat, box-plots of average weekly dose and average weekly dose/kg by month will 
be produced. Separate box-plots for darbepoetin alfa will be produced, using a different unit 
(µg instead of mg), and separate box-plots will be produced for epoetin alfa too, using IU 
instead of mg. In the box-plots, the prescribed amount will be used.
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 ESA, 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.


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7.3.2
Treatment Compliance
Overall compliance with the dosing schedule will be examined for subjects in the SAF whose 
total study drug count and first and last days of treatment are known.
Percent overall compliance will be summarized in two ways, during the first 28 weeks, 
36 weeks, 52 weeks and overall:
●
Descriptive statistics will be presented,
●
Percent compliance categories will be categorized according to the categories defined in 
Section 6.5.4
Counts and percentages of subjects in each of these categories will be summarized.
Results will be displayed by treatment arm and type of ESA treatment.
7.4
Analysis of Efficacy 
For all continuous efficacy variables, in addition to inferential analyses, descriptive statistics 
will be produced for the actual values and for the changes from baseline (BL) by visit.
Similarly, for all categorical efficacy variables, frequencies and proportions will be produced 
by analysis visit.
Quantitative endpoints with repeated measures over time will be analyzed using MMRM and 
ANCOVA with MI, as the preferred methods for imputation of missing data.
For this section, unless specified otherwise, PPS refers to the analysis set which excludes 
from the FAS all the subjects violating criteria at subject level from Table 4. See Section 5.3
and Classification specifications for more details.
Unless otherwise specified, the efficacy analyses will be performed for All subjects, and by 
Type of ESA treatment (Darbepoetin Subjects and Epoetin Subjects).
For efficacy analyses by treatment arm (Roxadustat versus ESA), the covariates list will 
include the variable Previous ESA treatment (epoetin versus darbepoetin alfa). But for 
efficacy analyses by Type of ESA treatment (Subgroup Darbepoetin and Subgroup Epoetin), 
because the Type of ESA treatment is based on the Previous ESA treatment, then this 
variable Previous ESA treatment will not be included in the covariates list.
For the efficacy analyses by subgroup, the subgroup analysis by Previous ESA treatment will
not be presented in tables, as this analysis is already performed by Type of ESA treatment
(Subgroup Darbepoetin and Subgroup Epoetin).
Analysis visits windows 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(s)
There are two separate regionally based primary efficacy endpoints in this study, depending 
upon whether the data are being filed to support submission to the US FDA or to Ex-US 
health authorities, such as the European Medicines Agency (EMA).


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7.4.1.1 EU (EMA) Primary Endpoint
7.4.1.1.1
Primary Analysis of the EU (EMA) Primary Endpoint
The primary EU (EMA) efficacy endpoint will be analyzed using the PPS.
The change from baseline to the average Hb of weeks 28 to 36, without having received
rescue therapy within 6 weeks prior to and during this 8-week period, will be computed from 
the Mixed Model of Repeated Measures method (MMRM), adjusting for stratification factors
(covariates defined below), comparing roxadustat to ESA (pooled darbepoetin alfa and 
epoetin alfa). After fitting the data, a computation statement will be added to the model to 
calculate the average Hb values estimate during the period under consideration.
Difference of least square means (roxadustat minus ESA) and its 2-sided 100*(1-α*2)% 
confidence interval will be estimated for the change from baseline to the average of weeks 28 
to 36. The significance level α is fixed by the parametric chain procedure explained below.
The primary analysis of the EU (EMA) primary efficacy endpoint will be tested both in the 
overall population and in the subset of patients defined as subjects with an average prescribed 
weekly epoetin or darbepoetin dose within the last four weeks prior to randomization 
≤ 200 IU/kg or ≤ 1 μg/kg respectively, following a parametric chain procedure.
The two null hypotheses to be tested are:
●
HA0: Hb change from baseline to the average of weeks 28 to 36 in the roxadustat arm 
≤ Hb change from baseline to the average of weeks 28 to 36 in the ESA arm minus
0.75 g/dL in the total study population
●
HB0: Hb change from baseline to the average of weeks 28 to 36 in the roxadustat arm 
≤ Hb change from baseline to the average of weeks 28 to 36 in the ESA arm minus 
0.75 g/dL in the subset population
The alternative hypotheses HA1 and HB1 are defined as the negation of the null hypotheses
HA0 and HB0 respectively. The information fraction (subjects in the subset population/total 
study population) will be calculated at the time of database hardlock.
The overall one-sided significance level (alpha) is fixed at 0.025. The overall alpha will be 
equally allocated to each of the two null hypotheses defined above. In case of an information 
fraction of 0.80, this rule will lead to a significance level of 0.0174.
The following table (Table 12) lists a selection of one-sided significance levels (alpha) to be 
considered should the IF varies from the protocol.


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Table 12
Information Fraction (IF) and One Sided Significance Level (alpha) for 
the Primary Endpoint
Information Fraction (IF)
alpha (1-sided)
0.5
0.0147
0.6
0.0154
0.7
0.0162
0.8
0.0174
0.9
0.0191
0.97
0.0216
Following the parametric chain procedure, if at least one of the two null hypotheses is 
rejected at the significance level of 0.0174, the other one can be tested at a significance level 
of 0.025 while still controlling the overall type I error. The study will be successful for the 
EU primary efficacy endpoint if either of the null hypotheses is rejected, i.e., if the lower 
limit of the two-sided 100*(1-α*2)% CI for the difference in least square means from the 
MMRM model is greater than -0.75g/dL. 
If both null hypotheses are rejected, secondary endpoints will be assessed on the overall 
population. Otherwise, secondary endpoints will not be formally tested.
The covariates will be: 
●
Previous ESA treatment (epoetin versus darbepoetin alfa);
●
Region (region A versus region B);
●
History of cardiovascular, cerebrovascular or thromboembolic diseases (Yes versus 
No)#;
●
Average prescribed weekly ESA dose prior to randomization (≤200 IU/kg epoetin or 
≤ 1 μg/kg darbepoetin alfa versus >200 IU/kg epoetin or > 1 μg/kg darbepoetin alfa)*;
●
Baseline Hb value (Continuous).
#: This covariate is derived according to a list of cardiovascular disease preferred terms 
received from the study physician after softlock. 
*: For the analyses, the average prescribed weekly ESA dose prior to randomization will be 
taken from the screening procedure form, in the eCRF. Upon review of data, this covariate 
was excluded from analysis as number of subjects in the high dose group was too low for the 
variable to be meaningful.
For these covariates, the IRS value used at randomization will be compared to the eCRF 
value.
In case of stratification errors during the randomization process, the analysis will use the 
correct covariates as recorded on the eCRF for the subject. 
MMRM model:
An MMRM model will be run for the purpose of implicit imputation of missing data by using 
all the available information from the observed data via the within-patient correlation 


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structure. The analysis will be based on the estimated difference between the two treatment 
arms overall mean effects throughout the evaluation period (weeks 28 to 36) based on this 
MMRM model.
The model will contain treatment arm, region, CV History, previous ESA treatment, visits
and visit by treatment as categorical variables. It will also contain baseline Hb and baseline 
Hb by visit as continuous variable.
The unstructured covariance pattern model will be used. If the algorithm for unstructured 
covariance pattern does not converge, then heterogeneous Toeplitz structure will be used. If 
this later model does not converge either, then the (homogeneous) Toeplitz structure will be 
tried. Finally, if none of them converge, first order autoregressive (AR (1)) as a covariance 
structure will be used to achieve convergence.
A similar model as the general example below will be used:
cikjn = intercept + ßn Mbaseline,ikjn + τi + αn+ (ατ)in + γk + εikjn
where
●
cikjn is each analysis visit change from baseline of subject j in treatment arm i, and
stratum k at time n,
●
ßn is the slope of cikjn at visit n as a function of the baseline Hb, 
●
Mbaseline,ikjn is the baseline measurement of subject j in treatment arm i and stratum k at 
time n,
●
τi , is the mean effect of treatment arm i,
●
αn is the mean effect at time n,
●
(ατ)in is the interaction term between treatment arm i and time n,
●
γk is the mean effect of stratum k,
●
εikjn is the residual at time n for subject j in treatment arm i and stratum k.
The SAS procedure will be similar to the following:
proc mixed;
class subject_id treatment previous_ESA_treatment region cv_history    
visit;
model change = treatment previous_ESA_treatment region cv_history  
baseline_Hb visit treatment*visit;
repeated visit /subject = subject id type=un;
lsmeans visit*treatment / cl alpha = 0.05;
estimate ‘Roxadustat v.s. ESA averaged at weeks 28-36’ 
treatment 1 -1
treatment*visit 0 0 0 0 .. 0.2 0.2 0.2 0.2 0.2 -0.2 -0.2 -0.2 
-0.2  / cl;
where visit in (’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 and Table 32.


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Subjects receiving rescue therapy treatment within 6 weeks prior to and during this 8-week
period will be set to missing and imputed similarly in the model (see Section 7.11.1 for 
imputation details).
In addition, MMRM least square means and 2-sided 95% confidence intervals will be 
calculated for each visit for the difference in treatment arms. The results will be presented as 
least square means and 95% confidence intervals for treatment differences, and also present 
the nominal p-values for non-inferiority and superiority. MMRM least square means and 
their 95% confidence intervals will be plotted versus time.
Model checking:
Residual plots will be produced showing the following:
●
Model residuals in the y-axis and model predictions in the x-axis,
●
Model residuals in the y-axis and baseline Hb in the x-axis.
Different dot styles will be used for the two treatment arms. Solid black symbols will be used 
for roxadustat and non-solid red symbols will be used for ESA.
Residual plots will be done for the MMRM analysis. The plot will be repeated by visit at 
Weeks 28, 30, 32, 34 and 36.
In addition, an empirical cumulative distribution function of the residuals will be plotted for 
the MMRM analysis.
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.
7.4.1.1.2
Secondary Analyses (sensitivity) of the EU (EMA) Primary Endpoint
The following analyses will be done as sensitivity analyses of the EU (EMA) primary 
endpoint:
●
The primary analysis will be repeated on the FAS and All Randomized;
●
The primary endpoint will be analyzed similarly as for the primary analysis, but 
regardless of rescue therapy, on the PPS and FAS.
●
The primary endpoint will be analyzed using an ANCOVA and Multiple Imputation 
(MI) of data, and including the same covariates, on the PPS.
●
The primary endpoint will be analyzed using different Pattern Mixture Models (PMM)
with different assumptions for missing patterns, including the same covariates, on the 
PPS.


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All sensitivity analyses will be done on the total population.
The analysis using MMRM will be similar to the one provided in Section 7.4.1.1.1
For all sensitivity analyses, no hypothesis testing will be done, only confidence intervals
presented and graphically represented in a forest plot.
Table 13 summarizes all sensitivity analyses to be performed with the EU (EMA) primary 
endpoint.
Table 13
Primary and Sensitivity Analyses for the EU (EMA) Primary Endpoint
Code
Set
Population
Endpoint
Model
Covariates*
Primary
PPS
Total
Change to the 
Average Hb in 
weeks 28-36, 
without rescue 
therapy
MMRM
Region, History of CV, 
Previous ESA 
treatment, Visits and 
Visit by Treatment, BL 
Hb by visit, BL Hb
S1
FAS
Total 
Change to the 
Average Hb in 
weeks 28-36, 
without rescue 
therapy
MMRM
Region, History of CV, 
Previous ESA 
treatment, Visits and 
Visit by Treatment, BL 
Hb by visit, BL Hb
S2
All 
Randomized
Total 
Change to the 
Average Hb in 
weeks 28-36, 
without rescue 
therapy
MMRM
Region, History of CV, 
Previous ESA 
treatment, Visits and 
Visit by Treatment, BL 
Hb by visit, BL Hb
S3
PPS
Total 
Change to the 
Average Hb in 
weeks 28-36, 
regardless of 
rescue therapy
MMRM
Region, History of CV, 
Previous ESA 
treatment, Visits and 
Visit by Treatment, BL 
Hb by visit, BL Hb
S4
FAS
Total 
Change to the 
Average Hb in 
weeks 28-36, 
regardless of 
rescue therapy
MMRM
Region, History of CV, 
Previous ESA 
treatment, Visits and 
Visit by Treatment, BL 
Hb by visit, BL Hb
S5
PPS
Total 
Change to the 
Average Hb in 
weeks 28-36, 
without rescue 
therapy
ANCOVA with 
MI
Region, History of CV, 
Previous ESA 
treatment, BL Hb
S6
PPS
Total 
Change to the 
Average Hb in 
weeks 28-36, 
without rescue
therapy
PMM (Last 
mean carried 
forward)
Region, History of CV, 
Previous ESA 
treatment, BL Hb
S7
PPS
Total 
Change to the 
Average Hb in 
weeks 28-36, 
without rescue 
therapy
PMM – Last 
Mean Carried 
Forward for 
Roxadustat and 
Randomized 
arm MAR for 
ESAs
Region, History of CV, 
Previous ESA 
treatment, BL Hb


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ANCOVA with MI:
The sensitivity analysis using ANCOVA with MI will be similar to the primary analysis of 
the US endpoint, provided in Section 7.4.1.2.1
Pattern Mixture Models (PMM)
Pattern Mixture models will be used as an alternative to impute missing values, using 
different assumptions for missing patterns.
PMMs provide a general and flexible framework for sensitivity analyses that allows 
formulating assumptions regarding missing data in a transparent and clinically interpretable 
manner. This is expected to address the possibility of the data being missing not at random.
All factors mentioned in the primary analysis will be included in the PMM (refer to 
Section 7.4.1.1.1).
The following aspects of data missingness, may affect the estimates.
●
Timing and extent of missingness 
●
Assumed underlying mechanism for data missingness
A. Timing and Extent of Missing Data
To assess the potential effect of data missingness on the estimate of treatment effect, subjects 
will be classified as full data or missing data cases. Patterns of missingness will be based on 
non-missing hemoglobin before the end of the evaluation period.
●
Full data cases are defined as subjects with non-missing hemoglobin for all scheduled 
weeks of the Treatment period. 
●
Missing data cases are defined as subjects with a missing hemoglobin on at least one 
scheduled Week of the treatment period. The missing data cases are further grouped into 
intermittent missing and monotone missing cases.
o
Intermittent missing hemoglobin cases are defined as subjects with a missing 
hemoglobin for at least one scheduled week of but not on consecutive 
scheduled weeks up to end of the evaluation period.
o
Monotone missing hemoglobin cases are defined as subjects who have 
consecutive scheduled Weeks with missing hemoglobin up to the end of 
evaluation period. A subject who is a Monotone missing case could have 
intermittent missing hemoglobin prior to the ending Week. 
Subjects will be grouped as follows:
●
Full data cases 
●
Intermittent missing data cases 
●
Monotone missing data cases 
Should the incidence of monotone missing data cases and intermittent missing data cases be 
relatively small, then those cases will be combined so that the groups are full data cases and 
missing data cases. The summary of missing patterns in the first 36 scheduled visits will be 
presented in a table/graph.


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B. Assumptions on Missing Data Mechanism 
In addition to the extent of data missingness, the mechanism under which missing data occur 
may affect the estimate of the parameter of interest. 
The potential impact of missing efficacy endpoints on the estimates of treatment effects will 
be assessed using alternative statistical models with different underlying assumptions on the 
missing data mechanism for Missing Not AT Random (MNAR) (Little and Rubin, 1987).
C. PMM - Last Mean Carried Forward
A pattern-mixture model using a last mean carried forward multiple imputation method 
(Carpenter et al, 2013) will be used as another sensitivity analysis to explore the robustness 
of the MMRM and ANCOVA with MI results for the primary efficacy variable. Using this 
method, missing data after ending week will be imputed based on the last non-missing mean 
from its own treatment group.
D. PMM –Mixed (Last Mean Carried Forward for Roxadustat and Randomized
Arm MAR for Active Comparator)
This method is a combination of PMM-Last Mean Carried forward for Roxadustat and 
PMM-Randomized Arm Missing At Random (MAR) for ESA group. The imputation data 
will be generated based on last mean carried forward method described above for the 
Roxadustat treatment group, while for the ESA group, the imputation data will be generated 
using the Randomized Arm MAR group described below.
The Randomized Arm MAR is similar to PMM-Last Mean Carried Forward except that the 
joint distribution of the patient’s observed and missing data is multivariate normal with mean 
and covariance matrix from their randomized treatment group. 
The ANCOVA model will then be performed for each combined imputed complete data set. 
Similarly, the Rubin’s method will be then used to combine the estimates and the differences 
between the least square mean differences between the two treatment groups from each of the 
ANCOVA analyses. 
Model checking:
Residual plots will be produced showing the following:
●
Model residuals in the y-axis and model predictions in the x-axis,
●
Model residuals in the y-axis and baseline Hb in the x-axis.
Different dot styles will be used for the two treatment arms. Solid black symbols will be used 
for roxadustat and non-solid red symbols will be used for ESA.
Residual plots will be done for the ANCOVA analysis. In addition, an empirical cumulative 
distribution function of the residuals will be plotted for the same ANCOVA analysis.
If a relevant baseline variable is identified for which a clinically important imbalance exists 
at baseline between treatment groups, additional sensitivity analyses of the primary endpoint


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may be performed using an ANCOVA model adjusting for this baseline variable. This will 
allow us to assess the impact of these imbalances on the treatment comparisons.
7.4.1.1.3
Additional Analyses of the EU (EMA) Primary Endpoint
In addition to the main estimates cited in Section 7.4.1.1.1, supportive estimates for each 
ESA treatment (darbepoetin alfa and epoetin alfa), will be presented for the primary analysis, 
on the PPS. Differences between treatments change from BL (roxadustat randomized 
subjects on epoetin before randomization minus epoetin alfa randomized subjects, and 
similarly for darbepoetin alfa) will be presented with indicative p-values, to support the 
analysis. 
The analysis of the primary endpoint will be repeated by subgroup of interest. For definitions 
of subgroups of interest, see Section 7.8
The subgroups with a potential impact on Hb will be analyzed to check if there is an 
imbalance between the groups. If one of the subgroups is the same as a stratification factor, 
the factor will be omitted from the model. 
Table 14
Additional Analyses of the EU (EMA) Primary Endpoint, by Subgroup
Code
Set
Population
Endpoint
Model
Covariates*
A1
PPS
Total
Change to the Average Hb 
in weeks 28-36, without 
rescue therapy by 
Subgroup
MMRM
Region, History of CV, 
Previous ESA treatment, Visits 
and Visit by Treatment, BL Hb
Subgroup analyses will be done by producing separate summaries similar to those produced 
for the primary analysis. In addition, forest plots will be generated per each subgroup 
showing subgroup factors on the y-axis and change from baseline and their 95% confidence 
interval on the x-axis.
The potential existence of subgroup by treatment interaction will be visually inspected.
7.4.1.2 US (FDA) Primary Endpoint
7.4.1.2.1
Primary Analysis of the US (FDA) Primary Endpoint
The US (FDA) primary efficacy endpoint will be analyzed using the All Randomized.
The change from baseline to the average Hb of weeks 28 to 52 regardless of rescue therapy
will be computed from an ANCOVA model with MI, adjusting for covariates defined in 
Section 7.4.1.1.1, comparing treatments (roxadustat vs. ESA).
The null hypothesis to be tested for the US primary efficacy analysis is:
●
H0: Hb change from baseline in the roxadustat arm ≤ Hb change from baseline in the 
ESA arm minus 0.75 g/dL
The alternative hypothesis H1 is defined as the negation of the null hypothesis H0. The overall 
one-sided significance level (alpha) is fixed as 0.025. The study will be successful for the US 
primary endpoint if the null hypothesis is rejected.


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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 28-52 of subject j in 
treatment 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 treatment region CV_history previous_ESA_treatment;
   model change = treatment previous_ESA_treatment region cv_history  
baseline_Hb;
run;
ANCOVA with MI model:
The MI ANCOVA model will be used to compare the roxadustat and ESA groups in a fixed 
sequence procedure: 
The following steps will be used to conduct the primary analysis. 
1.
Generate 1000 datasets, using seed 253056, where intermittent missing hemoglobin data 
will be imputed for each treatment relying on  non-missing data from all subjects within 
each treatment group using the Monte Carlo Markov Chain (MCMC) imputation model 
with treatment, baseline hemoglobin, randomization stratification factors and the 
available non missing hemoglobin for each scheduled Week. 
The MCMC statement in the SAS PROC MI procedure with monotone option will be 
used. As a result, each dataset will only have missing ending data, or a monotone 
missing data pattern. 
2.
For each dataset from step 1, missing ending data (hemoglobin up through end of 
evaluation period) will be imputed using seed 35286853. As a result, 1000 imputed 
complete datasets will be generated.
●
Missing data at Week 1 will be imputed using the regression imputation model with 
baseline stratification factor, baseline and hemoglobin from Week 1, using the SAS 
PROC MI procedure with the REGRESSION option in the MONOTONE statement. 
●
The SAS PROC MI procedure will use data separately from each treatment subjects to 
impute the missing data for a specific Week (i.e. only those that need the imputation for 
the Week). Since subjects from the different treatment groups for that Week are 
excluded from the step, they will not contribute to the imputation for the Week.


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●
Repeat for all other scheduled Weeks sequentially (Week 2 to the end of evaluation 
period). Subjects whose missing data were imputed for previous Weeks will contribute to 
the imputation for the current Week. 
The regression imputation model includes an intercept and the slopes of the hemoglobin 
from previous Weeks and the stratification factors. 
3.
Analyze each imputed dataset using the ANCOVA using the mean of all observed or 
imputed Hb values within the evaluation period. The model will contain terms for 
baseline Hb measurement as a covariate and treatment arm and the other randomization 
stratification factors except screening Hb (≤11 vs >11) as fixed effects.
4.
Combine estimates from the results of each of the 1000 ANCOVA runs using SAS 
PROC MIANALYZE. 
Report the results of the least-squares mean estimates of the change from baseline in 
hemoglobin during the evaluation period, the estimates of treatment effect (e.g., least-squares 
mean change form baseline in hemoglobin for the treatment group minus the least-squares 
mean change from baseline in hemoglobin for the ESA group) and the corresponding 
p-values and 95% CIs during the evaluation period. Summary statistics for the imputed data
by MI will be presented too.
All available Hb values will be used for the calculation of the average in weeks 28 to 52, as 
defined in analysis windows in Section 7.11.4.
A forest plot will be generated showing subgroup factors on the y-axis and differences in 
mean changes from BL to the average in week 28-52 and their 95% confidence interval on 
the x-axis.
If a relevant baseline variable is identified for which a clinically important imbalance exists 
at baseline between treatment groups, additional sensitivity analyses of the primary endpoint 
may be performed using an ANCOVA model adjusting for this baseline variable. This will 
allow us to assess the impact of these imbalances on the treatment comparisons.
Descriptive analyses
In addition to the inferential analysis, central laboratory and HemoCue hemoglobin Hb 
values and their associated change from baseline, will be reported descriptively by visit. For 
central lab Hb values, the average of weeks 28-52 will also be reported.
The following data will be presented graphically, by treatment arm: 
●
Hb results using mean values (+/- 95% CI) plot
●
Hb change from baseline results using mean values (+/- 95% CI) plot.
7.4.1.2.2
Secondary Analyses (sensitivity) of the US (FDA) Primary Endpoint
Table 15 summarizes all sensitivity analyses to be performed with the US (FDA) primary 
endpoint. No analysis will be performed on the subset population with lower ESA doses, 
only the total population.


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Table 15
Primary and Sensitivity Analysis for the US (FDA) Primary Endpoint
Code
Set 
Endpoint
Method
Covariates
Primary
All 
Randomized
Change to the Average 
Hb in weeks 28-52, 
regardless rescue therapy
ANCOVA with 
MI
Region, History of CV, 
Previous ESA treatment, BL 
Hb
S1
FAS
Change to the Average 
Hb in weeks 28-52, 
regardless rescue therapy
ANCOVA with 
MI
Region, History of CV, 
Previous ESA treatment, BL 
Hb
S2
PPS 
Change to the Average 
Hb in weeks 28-52, 
regardless rescue therapy
ANCOVA with 
MI
Region, History of CV, 
Previous ESA treatment, BL 
Hb
S3
All 
Randomized
Change to the Average 
Hb in weeks 28-52, 
regardless rescue therapy
MMRM
Region, History of CV, 
Previous ESA treatment, Visits 
and Visit by Treatment, BL Hb 
by visit, BL Hb
S4
FAS
Change to the Average 
Hb in weeks 28-52, 
regardless rescue therapy
MMRM
Region, History of CV, 
Previous ESA treatment, Visits 
and Visit by Treatment, BL Hb 
by visit, BL Hb
S5
FAS 
Change to the Average 
Hb in weeks 28-52, 
without rescue therapy
ANCOVA with 
MI
Region, History of CV, 
Previous ESA treatment, BL 
Hb
S6
All 
Randomized
Change to the Average 
Hb in weeks 28-52, 
regardless rescue therapy
PMM (Last 
mean carried 
forward)
Region, History of CV, 
Previous ESA treatment, BL 
Hb
S7
All
Randomized
Change to the Average 
Hb in weeks 28-52, 
regardless rescue therapy
PMM – Last 
Mean Carried 
Forward for 
Roxadustat and 
Randomized 
arm MAR for 
ESA
Region, History of CV, 
Previous ESA treatment, BL 
Hb
For all sensitivity analyses, no hypothesis testing will be done, only confidence intervals 
presented and graphically represented in a forest plot. 
MMRM:
The analysis using MMRM model will be similar to the one provided in Section 7.4.1.1.1
One analysis Hb value for each visit will be used, as defined in analysis windows in 
Section 7.11.4 and Table 32.
Pattern Mixture Model (PMM)
Pattern Mixture models will be used as an alternative to impute missing values, using 
different assumptions for missing pattern. The PMM analysis method is described in 
Section 7.4.1.1.2, the analyses will be similar:
●
PMM –Last Mean Carried Forward
●
PMM – Last Mean Carried Forward for Roxadustat and Randomized arm MAR for ESA


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Model checking:
Residual plots will be produced showing the following:
●
Model residuals in the y-axis and model predictions in the x-axis,
●
Model residuals in the y-axis and baseline Hb in the x-axis.
Different dot styles will be used for the two treatment arms. Solid black symbols will be used 
for roxadustat and non-solid red symbols will be used for ESA.
Residual plots will be done for the ANCOVA analysis. In addition, an empirical cumulative 
distribution function of the residuals will be plotted for the same ANCOVA analysis.
If a relevant baseline variable is identified for which a clinically important imbalance exists 
at baseline between treatment groups, additional sensitivity analyses of the primary endpoint
may be performed using an ANCOVA model adjusting for this baseline variable. This will 
allow us to assess the impact of these imbalances on the treatment comparisons.
7.4.1.2.3
Additional Analyses of the US (FDA) Primary Endpoint
In addition to the main estimates cited in Section 7.4.1.2.1, supportive estimates for each 
ESA treatment (darbepoetin alfa and epoetin alfa), will be presented for the primary analysis, 
on the All Randomized.
The analysis of the US (FDA) primary endpoint will be repeated by subgroup of interest. For 
definitions of subgroups of interest, see Section 7.8
The subgroups with a potential impact on Hb will be analyzed to check if there is an 
imbalance between the groups. If one of the subgroups is the same as a stratification factor, 
the factor will be omitted from the model.
Table 16
Additional Analyses of the US (FDA) Primary Endpoint, by Subgroup.
Code
Set
Endpoint
Model
Covariates
A1
All 
Randomized
Change to the Average Hb 
in weeks 28-52 by 
Subgroup
ANCOVA 
with MI
Region, History of CV, Previous 
ESA treatment, BL Hb
Subgroup analyses will be done by producing separate summaries similar to those produced 
for the primary analysis. In addition, forest plots will be generated per each subgroup 
showing subgroup factors on the y-axis and change from baseline and their 95% confidence 
interval on the x-axis.
The potential existence of subgroup by treatment interaction will be visually inspected.
7.4.2
Analysis of Key Secondary Endpoints 
Once the null hypothesis has been rejected for the EU (EMA) primary efficacy endpoint for 
both the total population and the subset population, the key secondary endpoints will be 
tested for the total population, as described below.


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The EU (EMA) primary analysis set for the analysis of the key secondary endpoints will be 
the PPS for the non-inferiority tests and the FAS for the superiority tests.
All inferential analyses will evaluate the difference between the treatment arms: roxadustat 
versus ESA (i.e. pooled darbepoetin alfa and epoetin alfa).
The key secondary endpoints will be tested using a fixed sequence testing procedure, as 
depicted in Table 17 in order to maintain the overall one-sided type I error rate for the set of 
key secondary endpoints at 0.025. If the null hypothesis is rejected for a test, 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 17
Key Secondary Endpoints Fixed Sequence Testing Procedure
Test
Analysis 
sets
Endpoint
Comparison
1
PPS
Hb response defined as mean Hb during weeks 
28 to 36 within the target range of 10.0 to 12.0 
g/dL without having received rescue therapy 
within 6 weeks prior to and during this 8-week 
evaluation period.
Non-inferiority of roxadustat versus ESA 
(the non-inferiority margin for the 
difference between groups is -15% 
2
FAS
Change from BL in Low Density Lipoprotein 
(LDL) cholesterol to the average LDL 
cholesterol of weeks 12 to 28.
Superiority of roxadustat versus ESA
3
FAS
Mean monthly IV iron use (mg) during day 1 
to week 36 (monthly defined as a period of 
4 weeks).
Superiority of roxadustat versus ESA
4
PPS
Change from BL in SF-36 Physical 
Functioning (PF) sub-score to the average PF 
sub-score of weeks 12 to 28.
Non-inferiority of roxadustat versus ESA 
(the non-inferiority margin is fixed as -3)
5
PPS
Change from BL in SF-36 Vitality (VT) sub-
score to the average VT sub-score of weeks 12 
to 28.
Non-inferiority of roxadustat versus ESA 
(the non-inferiority margin is fixed as -3)
6
PPS
Change from BL in mean arterial pressure 
(MAP) to the average MAP value of weeks 20 
to 28.
Non-inferiority of roxadustat versus ESA 
(the non-inferiority margin for the 
difference between groups is 1 mmHg)
7
PPS
Time to first occurrence of an increase in blood 
pressure: An increase from BL of ≥ 20 mm Hg 
systolic blood pressure (SBP) and SBP ≥ 170 
mmHg or an increase from baseline of 
≥15 mmHg diastolic blood pressure (DBP) and 
DBP ≥ 100 mmHg during weeks 1 to 36.
Non-inferiority of roxadustat versus ESA 
(the non-inferiority margin for the 
difference between groups is fixed as a 
hazard ratio of 1.3).
8
FAS
Change from BL in mean arterial pressure 
(MAP) to the average MAP value of weeks 20 
to 28.
Superiority of roxadustat versus ESA
9
FAS
Time to first occurrence of an increase in blood 
pressure: An increase from BL of ≥ 20 mm Hg 
systolic blood pressure (SBP) and SBP ≥ 170 
mmHg or an increase from baseline of 
≥15 mmHg diastolic blood pressure (DBP) and 
DBP ≥ 100 mmHg during weeks 1 to 36).
Superiority of roxadustat versus ESA


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Details of the analysis for each of these secondary endpoints are given below.
Descriptive statistics and frequency tabulations will be reported.
7.4.2.1 Hb response defined as mean Hb during weeks 28 to 36 within the target range 
of 10.0 to 12.0 g/dL without having received rescue therapy within 6 weeks 
prior to and during this 8-week evaluation period.
The difference in the proportion of responders between the treatment arms will be analyzed
using a Miettinen & Nurminen (MN) approach and adjusting for covariates defined below:
The covariates will be: 
●
Previous ESA treatment (epoetin versus darbepoetin alfa);
●
Region (region A versus region B);
●
History of cardiovascular, cerebrovascular or thromboembolic diseases (Yes versus No);
●
Average prescribed weekly ESA dose prior to randomization (≤200 IU/kg epoetin or ≤ 1 
μg/kg darbepoetin alfa versus >200 IU/kg epoetin or > 1 μg/kg darbepoetin alfa) *;
●
Baseline Hb value (<11.0 g/dL versus >11.0 g/dL).
*: The average prescribed weekly ESA dose prior to randomization will not be used in the 
analysis due to the number of subjects in the high dose group was too low for the variable to 
be meaningful.
The SAS code will be similar to the one below:
proc freq;
  tables  ESA_trt*region*CV_history* Hb_category*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 ESA_trt region CV_history; 
  model response=ESA_trt region CV_history Hb_continuous arm
/dist=bin link=identity; 
  lsmeans arm / diff cl;
run;
This endpoint will be analyzed using the PPS. See Section 7.11.1 for imputation rules, in case 
of missing values in the evaluation period or in case of rescue therapy within 6 weeks prior to 
and during this 8-week evaluation period.
The point estimates for the proportion of responders in the roxadustat group and the ESA
group and the difference in proportions between these rates will be calculated (roxadustat –


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ESA). The MN method will be used to calculate the two-sided 95% CI for the difference in 
rates, adjusting for covariates. If the resulting lower bound of the two-sided 95% CI between 
roxadustat and ESA (roxadustat minus ESA) is > -15%, non-inferiority will be concluded.
Two sensitivity analyses (not part of the sequence) will be performed, one on All 
Randomized and the other one on the PPS regardless the use of rescue therapy.
In addition, a 95% confidence interval for the proportion of roxadustat and ESA responders 
based on the exact method of Clopper-Pearson will be calculated and presented, for all 
analyses.
The average Hb value of weeks 28-36 will also be reported.
A forest plot will be generated showing subgroup factors on the y-axis and differences in 
proportions and their 95% confidence interval on the x-axis.
Table 18
Primary and Sensitivity Analysis for the Hb Response
Code
Set 
Rescue Therapy 
Endpoint
Method
Covariates
Primary
PPS
Without rescue 
therapy
Hb response 
Miettinen & 
Nurminen 
(MN) 
approach
Region, History of 
CV, Previous ESA 
treatment, BL Hb
(categorical)
S1
FAS
Without rescue 
therapy
Hb response 
Miettinen & 
Nurminen 
(MN) 
approach
Region, History of 
CV, Previous ESA 
treatment, BL Hb
(categorical)
S2
PPS
Regardless rescue 
therapy
Hb response 
Miettinen & 
Nurminen 
(MN) 
approach
Region, History of 
CV, Previous ESA 
treatment, BL Hb
(categorical)
7.4.2.2 Change from BL in Low Density Lipoprotein (LDL) cholesterol to the average 
LDL cholesterol of weeks 12 to 28.
LDL change from baseline to the average LDL value in weeks 12-28 will be compared by 
treatment arms using a MMRM model as in Section 7.4.1.1.1 (with the addition of LDL at 
baseline as a continuous covariate).
The analysis will be similar to the primary analysis provided in Section 7.4.1.1.1, 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 (roxadustat minus ESA) is lower than 0.
The analysis will be done on the FAS. An additional analysis (not part of the sequence) will 
be done on All Randomized.
For missing LDL imputation rules, refer to Section 7.11.1.
Theses analyses will be done on all values (regardless of fasting status).


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In addition to the inferential analysis, LDL cholesterol and LDL cholesterol change from 
baseline will be reported descriptively by visit for fasted values. The average of weeks 12-28
will also be reported.
Residual plots will be produced showing the following:
●
Model residuals in the y-axis and model predictions in the x-axis,
●
Model residuals in the y-axis and baseline LDL-cholesterol in the x-axis. 
Table 19
Primary and Sensitivity Analysis for Change from BL in LDL to the 
Average LDL of weeks 12 to 28
Code
Set 
Endpoint
Method
Covariates
Primary
FAS
Change from BL in Low Density 
Lipoprotein (LDL) cholesterol to 
the average LDL cholesterol of 
weeks 12 to 28.
MMRM
Region, History of CV, 
Previous ESA treatment, Visits 
and Visit by Treatment, BL 
Hb, BL LDL
S1
All 
Randomized
Change from BL in Low Density 
Lipoprotein (LDL) cholesterol to 
the average LDL cholesterol of 
weeks 12 to 28.
MMRM
Region, History of CV, 
Previous ESA treatment, Visits 
and Visit by Treatment, BL 
Hb, BL LDL
7.4.2.3 Mean monthly IV iron use (mg) during Day 1 to Week 36 (monthly defined as a 
period of 4 weeks).
The average monthly IV iron use (mg) during Day 1 to Week 36 will be compared by
treatment arm using an ANCOVA model, as in Section 7.4.1.2.1 (except that it will be done 
on the total average of weeks 1 to 36 and that there will be no imputation). Subjects on study 
with no medication record of IV Iron will be assumed that they received no IV Iron. For 
those subjects (on study), monthly IV iron use will be set to zero mg.
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 (roxadustat minus ESA) is lower than 0.
An additional analysis (not part of the sequence) will be performed on All Randomized. 
Furthermore, the mean monthly IV iron use will be reported for Day 1 to Week 36, weeks 37
to 52, and weeks 53 to 104. Number and percentage of subjects took IV iron and/or Oral Iron
at any time and during Day 1 to week 36, weeks 37 to 52, and weeks 53 to 104 will be 
summarized.
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Table 20
Primary and Sensitivity Analysis for Mean Monthly IV Iron use (mg) 
During Day 1 to Week 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, Previous 
ESA treatment, BL Hb
S1
All Randomized
Mean monthly IV iron 
use (mg) during Day 1 
to Week 36
ANCOVA
Region, History of CV, Previous 
ESA treatment, BL Hb
S2
FAS 
Occurrence and time to 
first use of IV iron in 
day 1 to week 36
Cox 
regression + 
Kaplan Meier
Stratified on Region, History of 
CV, Previous ESA treatment, and 
adjusted on BL Hb as continuous 
covariate
7.4.2.4 Change from BL in SF-36 Physical Functioning (PF) sub-score to the average 
PF sub-score of weeks 12 to 28.
Change from baseline in PF subscore of SF-36 to the average of weeks 12–28 will be 
compared by treatment arm, for the PPS. It will be done using a MMRM method using 
region, history of CV, previous ESA treatment as categorical covariates and baseline SF-36 
PF subscore, baseline Hb as continuous covariates. Non-inferiority can be concluded if the 
lower bound of the two-sided 95% CI of the difference between the two treatment arms
(roxadustat minus ESA) is greater than -3 points.
The analysis will be similar to the one provided in Section 7.4.1.1.1
Residual plots will be produced showing the following:
●
Model residuals in the y-axis and model predictions in the x-axis,
●
Model residuals in the y-axis and baseline SF-36 PF subscore in the x-axis.
An additional analysis (not part of the sequence) will be done on All Randomized. 
The analysis will be repeated in the subsets of subjects with baseline PF subscore below 40 
and equal or above 40.
In addition to the inferential analyses, SF-36 PF and SF-36 PF change from baseline will be 
reported descriptively by visit, using all available data for PPS and FAS. The average of 
weeks 12-28 will also be reported.


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Table 21
Primary and Sensitivity Analysis for Change from BL in SF-36 PF Sub-
score to the Average PF Sub-score of weeks 12 to 28
Code
Set 
Endpoint
Method
Covariates
Primary
PPS
Change from BL in SF-36 
PF sub-score to the average 
PF sub-score of weeks 12 to 
28
MMRM
Region, History of CV, Previous ESA 
treatment, Visits and Visit by 
Treatment, BL SF-36 PF subscore, BL 
Hb
S1
FAS
Change from BL in SF-36 
PF sub-score to the average 
PF sub-score of weeks 12 to 
28
MMRM
Region, History of CV, Previous ESA 
treatment, Visits and Visit by 
Treatment, BL SF-36 PF subscore, BL 
Hb
7.4.2.5 Change from BL in SF-36 VT subscore to the average in weeks 12–28
Change from baseline in VT subscore of SF-36 to the average of weeks 12–28 will be
compared by treatment arm, for the PPS. It will be done using a MMRM method using 
region, history of CV, previous ESA treatment as categorical covariates and baseline SF-36 
VT subscore, baseline Hb as continuous covariates. Non-inferiority can be concluded if the 
lower bound of the two-sided 95% CI of the difference between the two treatment arms 
(roxadustat minus ESA) is greater than -3 points.
The analysis will be similar to the one provided in Section 7.4.1.1.1  
Residual plots will be produced showing the following:
●
Model residuals in the y-axis and model predictions in the x-axis,
●
Model residuals in the y-axis and baseline SF-36 VT subscore in the x-axis.
An additional analysis (not part of the sequence) will be done on All Randomized. 
The analysis will be repeated in the subsets of subjects with baseline vitality subscore below 
50 and equal or above to 50.
In addition to the inferential analyses, SF-36 VT and SF-36 VT change from baseline will be 
reported descriptively by visit, using all available data for PPS and FAS. The average of 
weeks 12-28 will also be reported.
Table 22
Primary and Sensitivity Analysis for Change from BL in SF-36 VT
Sub-score to the Average VT Sub-score of weeks 12 to 28
Code
Set 
Endpoint
Method
Covariates
Primary
PPS
Change from BL in SF-36 
VT sub-score to the average 
VT sub-score of weeks 12 
to 28
MMRM
Region, History of CV, Previous ESA 
treatment, Visits and Visit by 
Treatment, BL SF-36 VT subscore, BL 
Hb
S1
FAS
Change from BL in SF-36 
VT sub-score to the average 
VT sub-score of weeks 12 
to 28
MMRM
Region, History of CV, Previous ESA 
treatment, Visits and Visit by 
Treatment, BL SF-36 VT subscore, BL 
Hb


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7.4.2.6 Change from BL in pre-dialysis mean arterial pressure (MAP) to the average 
MAP value of weeks 20 to 28.
The blood pressure effect is shown by use of the change from baseline in MAP. MAP values 
are pre-dialysis MAP values.
MAP change from baseline to the average MAP value in weeks 20-28 will be analyzed using 
a MMRM model as in Section 7.4.1.1.1 (with the addition of MAP at baseline as continuous 
covariate).
For missing MAP imputation rules, refer to Section 7.11.1
Non-inferiority (by the absence of a rise in MAP) can be concluded if the upper bound of the 
two-sided 95% CI of the difference between the two treatment arms (roxadustat minus ESA) 
is lower than 1 mm Hg. This will be calculated on the PPS.
As per Table 17, once the non-inferiority is concluded, superiority will be checked for this 
variable on the FAS as part of the fixed sequence testing procedure. Superiority can be 
concluded if the upper bound of the two-sided 95% CI of the difference between roxadustat 
and ESA (roxadustat minus ESA) is lower than 0 mmHg.
A sensitivity analysis will be done on All Randomized.
In addition to the inferential analyses, MAP and MAP change from baseline will be reported 
descriptively by visit, using all available data. The average of weeks 20-28 will also be 
reported.
Residual plots will be produced showing the following:
●
Model residuals in the y-axis and model predictions in the x-axis,
●
Model residuals in the y-axis and baseline MAP-cholesterol in the x-axis. 
Table 23
Primary and sensitivity analysis for change from BL in MAP to the 
average MAP value of weeks 20 to 28
Code
Set 
Endpoint
Method
Covariates
Primary
PPS
Change from BL in 
MAP to the average 
MAP value of weeks 20 
to 28
MMRM
Region, History of CV, Previous ESA 
treatment, Visits and Visit by 
Treatment, BL Hb, BL MAP
Primary
FAS
Change from BL in 
MAP to the average 
MAP value of weeks 20 
to 28
MMRM
Region, History of CV, Previous ESA 
treatment, Visits and Visit by 
Treatment, BL Hb, BL MAP
S1
All 
Randomized
Change from BL in 
MAP to the average 
MAP value of weeks 20 
to 28
MMRM
Region, History of CV, Previous ESA 
treatment, Visits and Visit by 
Treatment, BL Hb, BL MAP


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7.4.2.7 Time to first occurrence of an increase in pre-dialysis blood pressure: An 
increase from BL of ≥ 20 mm Hg systolic blood pressure (SBP) and SBP ≥ 170 
mmHg or an increase from baseline of ≥15 mmHg diastolic blood pressure 
(DBP) and DBP ≥ 100 mmHg during weeks 1 to 36.
Time to first occurrence of an increase in blood pressure during the first 36 weeks, including 
time to censoring, defined in Section 6.1.2.7, will be used in a Cox Proportional Hazards 
regression analysis. It will compare treatment arms, using covariates defined in 
Section 7.4.1.1.1, and provide hazard ratio and their 95% confidence intervals.
Blood pressures are pre-dialysis blood pressures.
Non-inferiority will be declared if the upper bound of the 2-sided 95% confidence interval of 
the hazard ratio (roxadustat as relative to ESA), calculated on the PPS, is lower than 1.3. As 
per Table 17, once the null hypothesis is rejected, superiority will be checked for this variable 
on the FAS, as part of the fixed sequence testing procedure. Superiority will be concluded if 
the upper bound of the two-sided 95% CI of the hazard ratio of the two treatment arms 
(roxadustat as relative to ESA) is lower than 1.
A sensitivity analysis will be done on All Randomized.
The Cox Model can be written: 



)z
exp(
t
x
;t
j0
j




where
j - indicator for stratum 
z – treatment indicator – which is either roxadustat or ESA
The SAS procedure for the Cox regression will be similar to the following:
proc phreg;
  model time_to_event*cens_var(1) = treatment Hb_base / rl;
  strata previous_ESA_treatment region cv_history;
where visit in 
(‘Day1’,’Week1’,’Week2’,...,’Week8’,’Week10’,...,’Week36’);
run;
In addition, the cumulative incidence curve of subjects with an increase in blood pressure
from baseline will be plotted by treatment arm and type of ESA treatment.
The cumulative incidence will be calculated as one minus the Kaplan-Meier estimate of the 
survival function. Two types of analyses can be performed: modeling the cause specific 
hazard or modeling the hazard of the sub-distribution. The first approach has been chosen in 
this SAP, because competing risks are assumed not to exist, since the main interest is to study 
the treatments effect and this method provides results to be generalized across datasets with 
different competing risks. One minus the Kaplan-Meier estimate can be interpreted as the 
probability that an event of interest occurs to a subject by time t, in the absence of any 
competing risk. 


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In addition to the cumulative incidence plot, the cumulative incidence at 0.25, 0.5 and 
0.75 year 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. 
The proportional hazards assumption will also be tested by fitting a Cox Proportional 
Hazards regression, stratified for region, history of CV, previous ESA treatment, and 
adjusted for baseline Hb (continuous) with one dependent variable: treatment (0 for ESA, 1 
for roxadustat). 
Table 24
Primary and Sensitivity Analysis for the time to First Occurrence of an 
Increase in Blood Pressure in the First 36 weeks
Code
Set 
Endpoint
Method
Strata/Covariates
Primary
PPS 
Occurrence and time to 
first occurrence of 
increase in blood 
pressure in week 1 to 
36
Cox regression 
+ Kaplan 
Meier
Stratified on Region, History of CV, 
Previous ESA treatment, and adjusted 
on BL Hb as continuous covariate
Primary
FAS
Occurrence and time to 
occurrence of increase 
in blood pressure in 
week 1 to 36
Cox 
regression+ 
Kaplan Meier
Stratified on Region, History of CV, 
Previous ESA treatment, and adjusted 
on BL Hb as continuous covariate
S1
All 
Randomized
Occurrence and time to 
occurrence of increase 
in blood pressure in 
week 1 to 36
Cox 
regression+ 
Kaplan Meier
Stratified on Region, History of CV, 
Previous ESA treatment, and adjusted 
on BL Hb as continuous covariate
In addition, the number and percentage of subjects with an increase from baseline in blood 
pressure during weeks 1 to 36 will be reported by treatment arm and type of ESA treatment, 
on the PPS. They will also be reported for the total duration of the study. For subjects who 
have experienced more than one increase in blood pressure, only their first event following 
study treatment will be used in the analysis.
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.
7.4.2.8 Additional Analyses of the Key Secondary Endpoints
In addition to the main estimates cited in Sections 7.4.2.1 to 7.4.2.7, descriptive supportive 
estimates for each type of ESA treatment (darbepoetin alfa and epoetin alfa) will be 
presented for the primary analysis of all key secondary endpoints.


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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.
Forest plots will be produced where all subgroup factors will appear in the y-axis and the 
appropriate statistic comparing roxadustat to ESA and the 95% confidence interval will
appear in the x-axis.
Table 25
Additional Analyses of the Key Secondary Endpoints
Code
Analysis 
sets 
Endpoint
Method
Covariates
A1
PPS
Hb response defined as mean Hb during 
weeks 28 to 36 within the target range of 
10.0 to 12.0 g/dL without having received 
rescue therapy within 6 weeks prior to and 
during this 8-week evaluation period by 
Subgroup
MN method
Region, History of 
CV, Previous ESA 
treatment, BL Hb
(categorical)
A2
FAS
Change from BL in Low Density 
Lipoprotein (LDL) cholesterol to the 
average LDL cholesterol of weeks 12 to 28 
by Subgroup.
MMRM
Region, History of 
CV, Previous ESA 
treatment, Visits and 
Visit by Treatment, 
BL Hb, BL LDL
A3
FAS
Mean monthly IV iron use (mg) during day 
1 to week 36 (monthly defined as a period 
of 4 weeks) by Subgroup.
ANCOVA 
Region, History of 
CV, Previous ESA 
treatment, BL Hb
A4
PPS
Change from BL in SF-36 Physical 
Functioning (PF) sub-score to the average 
PF sub-score of weeks 12 to 28 by 
Subgroup.
MMRM
Region, History of 
CV, Previous ESA 
treatment, Visits and 
Visit by Treatment, 
BL SF-36 PF 
subscore,  BL Hb
A5
PPS
Change from BL in SF-36 Vitality (VT) 
sub-score to the average VT sub-score of 
weeks 12 to 28 by Subgroup.
MMRM
Region, History of 
CV, Previous ESA 
treatment, Visits and 
Visit by Treatment, 
BL SF-36 VT 
subscore, BL Hb
A6
PPS
Change from BL in mean arterial pressure 
(MAP) to the average MAP value of weeks 
20 to 28 by Subgroup.
MMRM
Region, History of 
CV, Previous ESA 
treatment, Visits and 
Visit by Treatment, 
BL Hb, BL MAP
Table continued on next page


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Code
Analysis 
sets 
Endpoint
Method
Covariates
A7
PPS
Time to an increase in blood pressure: An 
increase from BL of ≥ 20 mm Hg systolic 
blood pressure (SBP) and SBP 
≥170 mmHg or an increase from baseline 
of  ≥15 mmHg diastolic blood pressure 
(DBP) and DBP ≥ 100 mmHg during weeks 
1 to 36 by Subgroup.
Cox 
regression
Stratified on Region, 
History of CV, 
Previous ESA 
treatment, and 
adjusted on BL Hb as 
continuous covariate
A8
FAS
Change from BL in mean arterial pressure 
(MAP) to the average MAP value of weeks 
20 to 28 by Subgroup.
MMRM
Region, History of 
CV, Previous ESA 
treatment, Visits and 
Visit by Treatment, 
BL Hb, BL MAP
A9
FAS
Time to an increase in blood pressure: An 
increase from BL of ≥ 20 mm Hg systolic 
blood pressure (SBP) and SBP ≥ 
170 mmHg or an increase from baseline of  
≥15 mmHg diastolic blood pressure (DBP) 
and DBP ≥ 100 mmHg during weeks 1 to 
36 by Subgroup.
Cox 
regression
Stratified on Region, 
History of CV, 
Previous ESA 
treatment, and 
adjusted on BL Hb as 
continuous covariate
7.4.3
Analysis of Additional Secondary Efficacy Endpoints 
All the analyses below will be superiority tests. These inferential analyses will be performed 
on the FAS and present the treatment effect of Roxadustat versus ESA.
The analyses will be performed on the total population.
Descriptive statistics will be presented by treatment arm and type of ESA treatment, when 
applicable.
7.4.3.1 Hb response regardless of use of rescue therapy. 
This analysis is identical to the one defined in Section 7.4.2.1, except that it is regardless of 
rescue therapy and a superiority test will be performed on the FAS.
The two-sided 95% CI for the difference in rates will be calculated similarly. If the resulting 
lower bound of the two-sided 95% CI between roxadustat and ESA is > 0, superiority will be 
concluded.
Hb responses (defined as mean Hb values between 10.0 to 12.0 g/dL and also defined as
mean Hb values >=10.0 g/dL) during weeks 28 to 36, and during weeks 28 to 52 will be 
analyzed similarly.
For Hb response (mean Hb between 10.0 to 12.0 g/dL) during weeks 28 to 52 will be 
analyzed using logistic regressions too, the odds ratio (roxadustat vs. ESA) and their 95% 
confidence intervals will be produced, if convergence achieved.
The SAS procedure will be similar to the following:


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proc logistic;
class treatment previous_ESA_treatment region CV_history;
model response = treatment previous_ESA_treatment region cv_history 
baseline_Hb;
run;
7.4.3.2 Hb change from BL to each post-dosing time point. 
Hb value and change from BL Hb to each post dosing time point will be described by 
treatment arm on the FAS.
The analysis will be similar to the one provided in Section 7.4.1.1.1
7.4.3.3 Hb level averaged over weeks 28 to 36, 44 to 52, and 96 to 104 without use of 
rescue therapy within 6 weeks prior to and during these 8-week evaluation 
periods.
Averaged Hb over weeks 28-36, 44 to 52 and 96 to 104 will be described by treatment arm
on the FAS. 
The analysis will be similar to the one provided in Section 7.4.1.1.1
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 g/dL, 
10-12 g/dL and >12 g/dL categories will be reported. 
7.4.3.4 Hb change from BL to the average Hb value of weeks 28 to 36, 44 to 52, and 96 
to 104 regardless of the use of rescue therapy.
The analysis will be done similarly as in Section 7.4.1.1.1, on the FAS except that it will be 
for weeks 28-36, 44-52 and 96-104.  
7.4.3.5 Categorical analysis for Hb values
For the analyses below, results will be displayed by treatment arm and type of ESA 
treatment.
Proportion of Hb values:
The proportion of Hb values >=10 g/dL and within 10-12 g/dL is a quantitative variable in 
the 0 – 100 range for each subject. Descriptive statistics for this variable will be presented. 
This variable will be presented in weeks 28-36, in weeks 44-52 and in weeks 96 -104, on the 
FAS. 
Percentage of time during the Efficacy Emergent Period: 
Descriptive statistics for the percentage of time with Hb values falling in each interval 
(<10.0 g/dL, >=10 g/dL, within 10.0-12.0 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.
The number and percentage of subjects, and the number of events, will be reported by for the 
following potential EH events of interest, based on Hb values from the central laboratory: 


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●
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).
Subjects with at least one Hb value > 13g/dL during the treatment period will be 
summarized.
7.4.3.6 Occurrence (number) of hospitalizations, number of days of hospitalization per 
year and time to first hospitalization during the study.
The number and percentage of subjects with hospitalization will be reported. Descriptive 
statistics and frequency tabulations by treatment arm and type of ESA treatment of the total 
duration of hospitalization (days), the average duration of each hospitalization (days), the 
number of hospitalizations, number of days of hospitalization per year and reason for 
hospitalization will also be reported.
Time to first hospitalization will also be analyzed similarly as in Section 7.4.2.7 (except that 
all data during the Efficacy Emergent Period will be taken into account for the analysis).
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.
The analysis will be done on the FAS.
7.4.3.7 Occurrence and time to first use of rescue therapy, 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 rescue therapy will be reported by treatment arm
and type of ESA treatment. 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).
Mean monthly number of RBC packs and volume of RBC transfused during the Efficacy 
Emergent Period will be compared by treatment arm using an ANCOVA model as in 
Section 7.4.1.2.1  Subjects with no medication record of RBC will be assumed that they 
received no RBC and therefore number of packs and volume will be set to 0.
The 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.
In addition, the number and percentage of subjects with RBC transfusion will be reported. 
Descriptive statistics by treatment arm and type of ESA treatment for number of RBC packs 
and volume of blood transfused will be reported. Time to first use of RBC transfusion will be 
analyzed similarly as in Section 7.4.2.7 (except that all data during the Efficacy Emergent
Period will be taken into account for the analysis).


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The number and percentage of roxadustat subjects with ESA use as rescue therapy, and the 
number of ESA-weeks will be reported descriptively for the roxadustat treatment arm only.
7.4.3.8 Occurrence of iron supplementation. 
The number and percentage of subjects who received IV Iron and the total amount of IV Iron 
used during the study will be reported descriptively by treatment arm and type of ESA 
treatment.
The incidence and cumulative incidence of subjects receiving IV Iron will be calculated 
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).
Mean monthly IV iron (mg) per subject during weeks 37-52 and weeks 53-104 will be 
compared by treatment arm and analyzed similarly as in Section 7.4.2.3
The analysis will be done on the FAS.
7.4.3.9 Change from BL to each post-dosing study visit in Total cholesterol, 
LDL/High-density Lipoprotein (HDL) ratio, Non-HDL cholesterol, 
Triglycerides, Apolipoproteins A1 and B, ApoB/ApoA1 ratio. 
Descriptive statistics (value, change from baseline) by visit, treatment arm and type of ESA 
treatment will be presented regardless of fasting status, including averages in week 12-28.
Descriptive statistics will also be reported with fasted values.
7.4.3.10 Occurrence of mean LDL cholesterol <100 mg/dL calculated over weeks 12 to 
28.
The number and percentage of subjects with mean LDL cholesterol less than 100 mg/dL
(2.59 mmol/L) (regardless fasting status) on average in weeks 12-28 will be reported by 
treatment arm and type of ESA treatment. Descriptive statistics and frequency tabulations 
will also be reported on fasted values, and regardless of fasting status.
7.4.3.11 Occurrence of achieved antihypertensive treatment goal in CKD subjects 
(SBP< 140 mmHg and DBP< 90 mmHg) based on the mean SBP and mean 
DBP calculated over weeks 12 to 28.
The number and percentage of subjects with achieved antihypertensive treatment goal over 
an evaluation period defined as the average of available values in weeks 12-28 will be 
reported by treatment arm and type of ESA treatment.
7.4.3.12 Health related Quality of Life Questionnaires Change from BL to the average 
value of weeks 12 to 28 
The following questionnaires will be analyzed:
●
SF-36 (Physical Component Score (PCS));
●
FACT-An (Anemia Subscale (“Additional Concerns”), Total FACT-An Score);
●
EQ-5D 5L (VAS Score);
●
Patients’ Global Impression of Change (PGIC).


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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, treatment arm and type of ESA treatment. Mean values will also be plotted 
over time and by treatment arm.
In addition, for the average value in weeks 12-28, an inferential analysis, similar to the one 
defined in Section 7.4.1.1.1 will be performed for the following endpoints:
●
Physical Component Scores of SF-36 (SF-36 PCS)
●
Anemia Subscale (“Additional Concerns”) of FACT-An Scores
●
Total FACT-An Scores
●
Fatigue
For SF-36, at each visit, the frequency and proportion of subjects with a change from 
baseline <3/>= 3 points and <5/>=5 points will be reported for Physical Functioning, Vitality
and Physical Component scores. 
In addition to this, change from BL to the average value of weeks 36 to 52 will be 
summarized similarly as for change from BL to the average value of week 12 to 28. 
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.
For the 5 EQ-5D 5L qualitative domains, the number and percentage of subjects in each 
response level value will be reported by visit, treatment arm and type of ESA treatment.
7.4.3.13 Patients’ Global Impression of Change (PGIC)
Patients’ Global Impression of Change will be summarized descriptively by visit, treatment 
arm and type of ESA treatment. 
7.4.3.14 Changes from BL to each study visit (when measured) in Serum hepcidin, 
Serum ferritin, TSAT and HbA1c level.
Changes from baseline to each study visit will be calculated for these parameters:

Serum hepcidin

Serum ferritin

TSAT

Serum Iron

TIBC

HbA1c level (Subjects with diabetes, Subjects without diabetes, and overall)
Descriptive statistics and frequency tabulations will be presented for these parameters and for 
the change from baseline by visit, treatment arm and type of ESA treatment. Mean values 
will also be plotted versus visit by treatment arm.


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7.4.4
Analysis of Exploratory Variables: hs-CRP (High Sensitivity C-Reactive 
Protein) and Post-dialysis BP.
For each visit, descriptive statistics with the absolute values and change from baseline for hs-
CRP will be displayed by treatment arm and type of ESA treatment.
Genotyping will be shipped to a delegated CRO and analyzed under the responsibility of 
Bioanalysis-Europe of Astellas Pharma Europe B.V. A separate report will be provided.
The BP-related key secondary endpoints will be analyzed using the post-dialysis BP 
assessments: MAP and time to first occurrence of increase in blood pressure, similarly with 
the analyses in Sections 7.4.2.6 and 7.4.2.7, excluding the analysis using All randomized 
subjects and subgroup analysis.
7.5
Analysis of Safety
Safety analyses will be performed using the Safety Analysis Set (SAF). 
Missing dates' imputation rules for AE onset date and stop date are detailed in Section 7.11.2
For each safety parameter, the last non-missing assessment prior to the first dose of study 
drug will be used as the baseline for all analyses, unless specified otherwise.
For the safety analyses by subgroup, the subgroup analysis by Previous ESA treatment will 
not be presented in tables, as this analysis is already performed by Type of ESA treatment
(Subgroup Darbepoetin and Subgroup Epoetin). In forest plots, results for this subgroup 
factor Previous ESA treatment will be included.
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 and type of ESA 
treatment:
●
Number and percentage of subjects with TEAEs,
●
Number and percentage of subjects with causally drug related TEAEs,
●
Number and percentage of subjects with serious TEAEs,
●
Number and percentage of subjects with serious drug related TEAEs,
●
Number and percentage of subjects with TEAEs leading to permanent discontinuation of 
study drug, 
●
Number and percentage of subjects with causally drug related TEAEs leading to 
permanent discontinuation of study drug, 
●
Number and percentage of subjects with NCI CTC Grade 3 or higher TEAEs,
●
Number and percentage of subjects with TEAEs leading to death, 
●
Number and percentage of subjects with drug related TEAEs leading to death and
●
Number of deaths occurring during the Safety Emergent Period and overall.


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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 and type of ESA treatment. Summaries will be provided for:
●
TEAEs,
●
TEAEs (by PT only),
●
Drug related TEAEs, 
●
TEAEs with NCI CTC Grade 3 or higher,
●
TEAEs by severity,
●
Drug related TEAEs by severity,
●
Serious TEAEs, 
●
Drug related serious TEAEs, 
●
TEAEs leading to permanent discontinuation of study drug, 
●
Drug related TEAEs leading to permanent discontinuation of study drug, 
●
TEAEs 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 (roxadustat or ESA), 
●
Common TEAEs that equal to or exceed a threshold of 5.0% in any treatment arm 
(roxadustat or ESA). 
●
TEAEs by relationship to the study drug,
●
AEs occurring during the post study follow up period,
●
Serious AEs 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 (see Section 6.2).
No queries will be done for SMQs.
7.5.1.3 Number of Events/100 Patient Exposure Year (PEY)
The number of events and number of events/Patient Exposure Year (PEY) 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, 


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7.5.1.4 Incidence Rates and Cumulative Incidence
Since the percentage of adverse events might be different between treatment arms due to the 
difference in the discontinuation rates, in addition to the frequency tables above, the 
incidence rate (per 100 subject years at risk) and the cumulative incidence at 0.5 year, 1 year, 
1.5 years & 2 years with the 95% confidence interval, using Greenwood’s formula, will be 
reported by treatment arm and type of ESA treatment.
It will be done for each of the following event types of special interest: 
●
Serious TEAEs, 
●
Deaths occurring during the Safety Emergent Period, 
●
All deaths during study period and post study safety follow up period,
●
Related serious TEAEs, 
●
TEAEs 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, history of CV, previous ESA 
treatment and adjusted on baseline Hb as continuous covariate. Hazard ratios (roxadustat as
relative to ESA) 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 category on the y-
axis. The incidence rates by treatment arm, the stratified Cox hazard ratios (roxadustat as 
relative to ESA) and their 95% CI will be shown on the x-axis.
In addition, cumulative incidence plots for subjects experiencing each of the TEAE 
categories above will be produced by treatment arm and type of ESA treatment.
Incidence rate (per 100 subject years at risk) for most common PT (>=5% in the total 
population) by SOC and the cumulative incidences of TEAE by SOC will also be produced 
for TEAEs in each treatment arm: Cumulative Incidence plots of subjects experiencing each 
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
7.5.1.6 Adverse events up to 7 days after last dose
Additional summaries or analyses with treatment emergent adverse events to be considered 
restricted to any event starting up to Analysis Date of Last Dose + 7 days considering the last 
dosing frequency:
●
Overview summary table of subjects with AEs
●
Number and percentage of subjects with AEs leading to death, as classified by PT


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●
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)
●
Number and percentage of subjects with AEs by SOC and PT.
Pre-specified adjudicated cardiovascular and thrombo-embolic events will be analyzed in 
meta-analyses across multiple phase 3 studies and compared between treatment groups. The 
statistical method for analysis of the composite safety endpoint (CSE) pooling studies will be 
detailed in a Meta-Analysis Statistical Analysis Plan. The results will be presented in a 
separate report.
7.5.2
Clinical Laboratory Evaluation
Descriptive statistics for laboratory values (in SI units) and changes from baseline at each 
assessment time point and for the maximum and minimum on-treatment (i.e., during Safety 
Emergent Period) value will be presented by treatment arm and treatment for the quantitative 
laboratory parameters. 
Maximum and minimum on-treatment values will be determined using all the original values 
and not the derived windows.
Shift tables and number and percentage of subjects with shift to low and shift to high will be
reported by treatment arm and type of ESA treatment for the quantitative laboratory 
parameters. 
Box plots of quantitative laboratory values (in SI units) versus visit will be produced by 
treatment arm (two arms in one page) and type of ESA treatment (darbepoetin alfa and 
epoetin alfa in another page).
Summary by visit for qualitative laboratory parameters will be provided by treatment arm.
All clinical laboratory data will also be listed. 
Potentially clinically significant (PCS) laboratory abnormalities
For each potentially clinically significant (PCS) criterion defined in Section 6.2.3.1, the 
percentage of subjects with abnormalities by visit and at any moment during the Safety 
Emergent Period and who did not meet the criteria at baseline will be reported by treatment 
arm and type of ESA treatment.
Incidence rate (per 100 subject years at risk) and the cumulative incidence at .5 year, 1 year, 
1.5 years & 2 years with the 95% confidence interval using Greenwood’s formula of PCS 
abnormalities will also be reported, using only subjects who did not meet the criteria at 
baseline, by treatment arm and type of ESA treatment. Risk of PCS abnormalities will be 
compared using the same Cox model as used on Section 7.5.1. Hazard ratio and its 95% will 
be calculated for the frequency of roxadustat as relative to ESA. A dot-and-forest plot will be 
produced showing the PCS abnormalities above in the y-axis and the incidence rates, the Cox 
hazard ratio and their 95% CI in the x-axis. 


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In addition, cumulative incidence plots for subjects experiencing each PCS abnormality will 
be produced by treatment arm (two arms in one page) and type of ESA treatment
(darbepoetin alfa and epoetin alfa in another 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.
In addition, a matrix scatter plot of Liver Enzymes and Bilirubin 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 ESA.
Individual displays of Liver Enzymes and Bilirubin parameters, listed in Section 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 the Safety Emergent Period.
For subjects who require further liver function investigations, additional information will be 
collected and listed.
7.5.3
Vital Signs
Descriptive and changes from baseline for vital signs (systolic blood pressure, diastolic blood 
pressure, respiratory rate, weight and pulse) at each assessment time point and for the 
maximum and minimum on-treatment (i.e during Safety Emergent Period) value will be 
presented by treatment arm and type of ESA treatment.
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) and type of ESA treatment (darbepoetin alfa and epoetin alfa in 
another page) for pre-dialysis and post-dialysis values. 
PCS Vital signs criteria (10 Combined) will be analyzed in the same way as explained in 
Section 7.5.2 for PCS laboratory abnormalities.
All vital signs data will also be listed. 
7.5.4
Electrocardiograms (ECGs) 
Descriptive and changes from baseline for ECG parameters (Pulse, PR Interval, RR Interval, 
QRS interval, QT interval, and QTc interval) at each assessment time point and for the 
maximum - on-treatment (i.e during Safety Emergent Period) value will be presented by 
treatment arm and type of ESA treatment.
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 9 and 
Table 10) will be tabulated by treatment group and type of ESA treatment. The percentages 
are to be calculated relative to the number of subjects with available baseline and at least one 


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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 Potentially Clinically Significant (PCS) QTc Criteria (both QTcB and QTcF) :
-
QTc > 500 msec 
-
Change from baseline in QTc > 60 msec
will be analyzed 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) and type of ESA treatment (darbepoetin alfa and epoetin alfa in 
another 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
Vascular Access Thrombosis (VAT)
Time to first VAT will be analyzed similarly as in Section 7.5.1.4 (Time to event analysis for 
TEAEs).
7.5.6
Pregnancies
A listing of pregnancy test results will be provided.
7.6
Analysis of PK
The statistical methods for PK data will be described in a separate analysis plan. Results of 
the population PK analysis will not be reported in the Clinical Study Report but in a separate 
population PK report.
Plasma concentration data of roxadustat will be listed. In addition, concentration of 
roxadustat in dialysates will also 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 26


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Table 26
Subgroups of Interest
Grouping variables
Subgroups
Age group
< 65 years
65 - 74 years
≥75 years
Sex
Female
Male
Previous ESA treatment
Darbepoetin alfa
Epoetin
Region
Western Europe
Central and Eastern Europe
Baseline Hb
≤11 g/dL
>11 g/dL
Dialysis type*
Hemodialysis
Peritoneal dialysis
History of cardiovascular, cerebrovascular or 
thromboembolic diseases #
Yes
No
Baseline hs-CRP
<=ULN
>ULN
*: Only for primary Hb analyses.
#: This subgroup is derived according to a list of cardiovascular disease preferred terms received from the study 
physician after softlock.
7.9
Other Analyses
No other analyses are planned.
7.10
Interim Analysis (and Early Discontinuation of the Clinical Study)
The study will have no interim analysis with statistical inference. Safety data and dosing 
decisions will be monitored on an ongoing basis. Ongoing review of safety data will be 
completed by an independent Data and Safety Monitoring Board (DSMB). 
7.11
Handling of Missing Data, Outliers, Visit Windows, and Other  
Information
7.11.1
Missing Data
For relevant analyses without rescue therapy, for subjects who used rescue therapy, the 
reported Hb values after the initiation of rescue therapy will be set to missing (instead of the 
reported values) for 6 weeks from the start date of rescue therapy (or the end in case the 
duration of rescue therapy > 1 day).
For response variables, if no Hb value is available during the reference period, an imputation 
technique will be used, with the mean of all available values from Day 1 to minimum (End of 
Efficacy Emergent Period, End of the reference period) carried forward.
The following imputations will be performed for the continuous endpoints, unless specified 
otherwise:


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●
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.
●
An ANCOVA model with multiple imputations (MI) will also be run (refer to 
Section 7.4.1.2.1).
●
PMM models with different missingness patterns assumptions will be run, in addition 
(refer to Section 7.4.1.1.2).
7.11.2
Missing Dates
As a general rule, the worst case scenario imputation rule is usually used. A start date is 
generally imputed to the first possible day, unless the available information in the partly 
missing date is equal to the one in the reference date. In this case, the substituted date is set to 
the reference date. An end date is generally imputed to the last possible day.
Completely missing dates will not be imputed.
Diagnosis of anemia, CKD and Targeted Medical History
The following rules will be applied to impute partially missing dates of diagnosis of Anemia, 
CKD and targeted medical history, as defined in Table 27 below.
Table 27
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, partially missing 
start dates and/or stop dates will be imputed as defined in Table 28 and Table 29 below:
Table 28
Definitions of the Previous or Concomitant Medication Analysis Start 
Date
Reported Date (from the eCRF)
Analysis Date (Derived)
--/MM/YYYY
01/MM/YYYY
--/--/YYYY 
01/01/YYYY
DD/--/----, or
--/MM/----, or
--/--/----
No imputation
If the imputed start date is after the stop date, then the imputed start date will be one day 
prior to the stop date.


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Table 29
Definitions of the Previous or Concomitant Medication Analysis Stop 
Date
Reported Date (from the eCRF)
Analysis Date (Derived)
--/MM/YYYY
31/MM/YYYY, or
30/MM/YYYY, or
29/MM/YYYY, or
28/MM/YYYY
--/--/YYYY 
31/12/YYYY
DD/--/----, or
--/MM/----, or
--/--/----
No imputation
AE Onset date
For adverse events, partially missing start dates and/or stop dates will be imputed as defined 
in Table 30 and Table 31 below:
Table 30
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 31
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.


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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 32 below, will be used for the following study 
assessments reported by visit:
●
Central laboratory parameters (except Lipid Panel),
●
Vital Signs,
●
ECG parameters.
Table 32
Analysis Visit Windows
CRF Visit
Target DEFE
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 – 7
Day 7 * (Week #) + 1
[Target Day ± 3]
Week 2 - 7
Week 8
Day 7 * (Week #) + 1
[Target Day – 3, Target Day + 6]
Week 8
Week 10 - 34
Day 7 * (Week #) + 1
[Target Day – 7, Target Day +6]
Week 10 - 34
Week 36
Day 7 * (Week #) + 1
[Target Day – 7, Target Day +13]
Week 36
Week 40 – 100
Day 7 * (Week #) + 1
[Target Day – 14, Target Day + 13]
Week 40 - 100
Week 104/EOT 
(for completers)
Day 7 * (Week #) + 1
[Target Day – 14, Target Day + 28]
Week 104
EOT Visit (for 
premature 
discontinuations)
NA
NA
Analysis Visit 
corresponding to the 
actual visit window
EOT + 2 Weeks 
Visit
14 Days after EOT Visit 
date
[DAY of EOT + 1, DAY of EOT +20]
EOT + 2 Weeks
EOS Visit
28 Days after EOT Visit 
date
[DAY of EOT + 21, DAY of EOT + 31]
EOS
Unscheduled
NA
NA
Analysis Visit 
corresponding to the 
actual visit window
a:  Relative to Day 1 (first dose date of study medication)
Analysis Visit windows, as depicted in Table 33 below, will be used for the quality of life 
efficacy study assessments:


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Table 33
Analysis Visit Windows for QoL
CRF Visit
Target DEFE
Analysis Visit Windows Actual
Assessment Day
Analysis Visit
Day 1
Day 1
Day 1
Baseline
Week 8
Day 7 * (Week #) + 1
[Target Day – 14, Target Day + 13]
Week 8
Week 12
Day 7 * (Week #) + 1
[Target Day – 14, Target Day + 27]
Week 12
Week 28
Day 7 * (Week #) + 1
[Target Day – 28, Target Day + 27]
Week 28
Week 36
Day 7 * (Week #) + 1
[Target Day – 28, Target Day +27]
Week 36
Week 52
Day 7 * (Week #) + 1
[Target Day – 56, Target Day + 83]
Week 52
Week 76
Day 7 * (Week #) + 1
[Target Day – 84, Target Day + 97]
Week 76
Week 104/EOT
(for completers)
Day 7 * (Week #) + 1
[Target Day – 98, Target Day + 28]
Week 104/EOT
EOT Visit (for 
premature 
discontinuations)
NA
NA
Analysis Visit 
corresponding to the 
actual visit window
Unscheduled
NA
NA
Analysis Visit 
corresponding to the 
actual visit window
a:  Relative to Day 1 (first dose date of study medication) 
Analysis Visit windows, as depicted in Table 34 below, will be used for the Lipid Panel, 
including LDL cholesterol efficacy study assessment:
Table 34
Analysis Visit Windows for Lipid Panel
CRF Visit
Target DEFE
Analysis Visit Windows Actual 
Assessment Day
Analysis Visit
Day 1
Day 1
Day 1
Baseline
Week 4
Day 7 * (Week #) + 1
Day 2 to Day 42
Week 4
Week 8
Day 7 * (Week #) + 1
[Target Day – 14, Target Day + 13]
Week 8
Week 12
Day 7 * (Week #) + 1
[Target Day – 14, Target Day + 27]
Week 12
Week 20
Day 7 * (Week #) + 1
[Target Day – 28, Target Day + 27]
Week 20
Week 28
Day 7 * (Week #) + 1
[Target Day – 28, Target Day + 27]
Week 28
Week 36
Day 7 * (Week #) + 1
[Target Day – 28, Target Day + 27]
Week 36
Week 44
Day 7 * (Week #) + 1
[Target Day – 28, Target Day + 27]
Week 44
Week 52
Day 7 * (Week #) + 1
[Target Day – 28, Target Day + 55]
Week 52
Week 68
Day 7 * (Week #) + 1
[Target Day – 56, Target Day + 55]
Week 68
Week 84
Day 7 * (Week #) + 1
[Target Day – 56, Target Day + 69]
Week 84
Week 104/EOT 
(for completers)
Day 7 * (Week #) + 1
[Target Day – 70, Target Day + 28]
Week 104/EOT
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) 


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For the MMRM analyses, which require one value per visit, one analysis value for each 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 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.
The value of x days is defined to standardize to 3 times per week,:
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 days.
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 is defined as the treatment period up to 
the EOT Visit. Only exception for subjects who discontinued due to death, the last Hb 
assessment is taken as per convention the date of death is the EOT visit.


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8
DOCUMENT REVISION HISTORY 
Version
Date
Changes
Comment/rationale for change
1.0
04-Dec-2014
NA
Document finalized
2.0
22-Mar-2016
1)
Reduction of the number of 
sensitivity analyses for the 
secondary endpoints.
2)
Revise the ordering for the key 
secondary endpoints by moving 
up the QoL endpoints.
3)
Implementation of the Time to 
event approach for the PPS and 
adjustment of the relevant 
sections.
4)
Change from ITT to All 
Randomized as per Astellas 
standard. Definition remains 
unchanged.
5)
Use of the Safety Emergent Period 
(i.e., last dose + 28 days) as 
evaluation period by default for 
the safety endpoints.
6)
Use of the Efficacy Emergent 
Period (i.e last dose + 7 days) as 
evaluation period by default for 
most of the efficacy time to event 
endpoints.
7)
Use of “Time to censoring” 
instead of  ”time at risk” for 
patient with no event for more 
clarity.
8)
Clarification of time to censoring
for events evaluated during the 
Safety Emergent Period/Efficacy 
Emergent Period.
9)
Time to PCS vital signs added.
10) Time to PCS ECG focused to QTc 
instead of all ECG assessments.
11) Update regarding derivation of 
MAP values: average of the 3 
measurements instead of 2 (now 
in line with FG SAP).
12) Implementation of the primary 
efficacy endpoint for the US 
1)
To limit the additional 
analyses.
2)
Due to the importance and 
relevance of the QoL 
endpoints 
3)
PPS definition has been 
revised in order to limit the 
exclusion of data by using a 
time to event approach rather 
than creating one PPS set for 
each period of interest.
4)
Astellas standards 
requirement.
5)
Clarify a consistent approach 
for all the safety endpoints by 
defining the evaluated period 
up to 28 days after last dose, 
which matched the AE 
analyses.
6)
Clarify 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 definitions of 
Efficacy/Safety Emergent 
period, time to censoring for 
all time to events have been 
updated accordingly.
9)
Time to PCS were already 
planned for lab and ECG but 
not for Vital signs. This was 
added to maintain a consistent 
approach.
10) Time to event for PCS ECG 
other than QTc was 
considered not of interest.
11) Using the average of all 3 
measurements is more 
efficient and is consistent  
with the other studies 
12) This specific endpoint has 


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Version
Date
Changes
Comment/rationale for change
submission (change in Hb from 
baseline to the average level 
between week 28 and week 52) 
with the description of the 
statistical analyses including 
sensitivity analyses for missing 
data.
13) Interim analysis changed from 
week 36 to week 52. 
14) Implementation of time to first 
hospitalization and time to first 
potential EH .
15) Update regarding the analysis on 
cholesterol data: use of all data as 
main analysis and fasted only as 
additional..
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 descriptive analysis 
on the categorical change form 
baseline in Total FACT-An Score.
20) Addition of an analysis on a 
subset of subjects with baseline 
PF subscore <40 and ≥40, and 
baseline VT subscore <50 and ≥ 
50.
21) Updated rule for complete missing 
start date and end date for 
concomitant medications. In that 
case, the medication will be 
considered as both previous and 
concomitant instead of only 
concomitant.
22) For the analysis of monthly IV 
Iron use, MMRM has been 
replaced by ANCOVA.
23) Additional tables run on group of 
subjects enrolled after protocol 
been added in protocol 
amendment 1.0.Sensitivity 
analyses for missing data were 
added following FDA 
feedback on the Fibrogen 064
study. 
13) This has been changed in 
protocol amendment 1.0.
14) Due to harmonization with 
Fibrogen 064 study SAP and 
the expected difference in 
treatment durations
15) Due to the assumption that 
most samples were not taken 
fasted and harmonization with 
Fibrogen 064 study SAP.
16) To limit the total number of 
analyses and the volume of 
tables
17) The concept of percentage of 
time with high Hb values was 
implemented in order to 
account for differences in 
individual treatment 
durations.
18) Inferential analysis for RBC 
was missing in the v1.0.
19) Descriptive statistics for 
categorical change not 
necessary since analysis on 
absolute change already 
planned and considered 
sufficient.
20) Due to harmonization with 
Fibrogen 064 study SAP.
21) Previous rule considered too 
conservative since a missing 
year of start is usually for 
previous medications than 
concomitant. Decision was 
taken to consider such 
medications as both previous 
and concomitant.
22) MMRM model for monthly 
IV Iron was not adapted due 
the data distribution. Since 
monthly average will be 
calculated, ANCOVA is more 
appropriate.
23) Added in order to assess the 


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Version
Date
Changes
Comment/rationale for change
amendment implementation
24) Addition of response endpoint up 
to week 52, regardless of rescue 
therapy in the additional 
secondary endpoint
25) Addition of a week 36 to 52 
endpoints, in the additional 
secondary endpoints for Quality of 
Life.
26) Removal of ANCOVA with 
LOCF for the primary endpoint 
sensitivity analysis, and addition 
of ANCOVA with MI and PMM.
impact of substantial protocol 
amendment 1.0.
24) Corresponding with the 
endpoint for the US
25) Clinically relevant to have an 
endpoint to measure long term 
effect on quality of life.
26) Sensitivity analyses for 
missing data were added 
following FDA feedback on 
the Fibrogen 064 study.
3.0
10-Sep-2018
1) Updating the safety and efficacy 
periods
2) Additional Hb response definition 
as the average Hb>=10.
3) Add MMRM analyses regardless 
of rescue therapy using FAS for 
primary EU endpoint 
4) Removed analysis using all Hb 
values using All Randomized.
5) Added time to first IV iron during 
day 1 to week 36
6) Added the analysis of Time to first 
VAT
7) Details were added in All 
Randomized section regarding 
exclusion of subjects from site 
8) Additional analyses on adverse 
event were added considering 
events occurring up to last dose +7 
days
9) The unique identifiers of protocol 
deviations are updated
10) Removed other baseline factors 
except baseline Hb and 
randomization stratification factors 
in ANCOVA with MI
1) Adjusting for the different 
dosing frequencies, especially 
for darbepoetin.
2) To include Hb values above 
12.0 (e.g. 12.3) also as a good 
response.
3) Harmonization of Phase 3 
studies.
4) Duplicate analysis
5) Majority of subjects did not 
use IV iron; therefore, time to 
first use proposed as 
alternative to the actual dose of 
IV iron.   
6) Included VAT AE specific 
safety analysis.  
7) Site 
 was terminated due 
to GCP violations and it is now 
clearly mentioned in the 
population section that those 
subjects are excluded from all 
analysis set.
8) Due to harmonization with 
Fibrogen 064 study SAP.
9) Updated according to latest
protocol deviations
10) Per team discussion, other 
baseline factors will not be 
included for ANCOVA with 
MI


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9
REFERENCES
Cella D. The functional assessment of Cancer Therapy-Anemia (FACT-An) Scale: A new tool for the 
assessment of outcome in cancer anemia and fatigue. Hematology Seminars 1997; 34: 13-19 
Gart J., and Nam J. Approximate Interval Estimation of the Difference in Binomial Parameters: 
Correction for Skewness and Extension to Multiple Tables. Biometrics 1990,46:637-643.
Ge M, Durham LK, Meyer RD, Xie W and Thomas N. Covariate-Adjusted Difference in Proportions 
from Clinical Trials Using Logistic Regression and Weighted Risk Differences. Drug 
Information Journal 2011; 45: 481
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)
Miettinen, O. and Nurminen, M., Comparative Analysis of Two Rates, Statistics in Medicine, 4, 213–
226, 1985
Millen BA, Dmitrienko A. Chain procedures: A class of flexible closed testing procedures with 
clinical trial applications. Statistics in Biopharmaceutical Research. 2011;3:14-30.
Spiessens B, Debois M. Adjusted significance levels for subgroup analyses in clinical trials. 
Contemporary Clinical Trials, Volume 31, Issue 6; November 2010.
Webster K, Cella D and Yost K. The Functional Assessment of Chronic Illness Therapy (FACIT) 
Measurement System: properties, applications, and interpretation. Heath and Quality of Life 
Outcomes 2003; 1: 79. 


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10
APPENDICES
10.1
Appendix 1: SF-36 v2


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SF-36 v2


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SF-36 v2


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SF-36 v2


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SF-36 v2


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SF-36 v2


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SF-36 Model


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


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FACT-An (Version 4)


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FACT-An (Version 4)


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


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


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To Derive a FACT-An total score:
     _________ + __________ + __________ + __________ + __________ =________=FACT-An Total score
                (PWB score)  (SWB score)   (EWB score)  (FWB score)   (AnS score)
*For guidelines on handling missing data and scoring options, please refer to the Administration and Scoring 
Guidelines in the manual or on-line at www facit.org.
Score range: 0-188


Sponsor: Astellas Pharma Europe B.V.
SAP Final Version 3.0 10 Sep 2018
ISN/Protocol 1517-CL-0613
Astellas
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10.3
Appendix 3:
EQ-5D 5L v2
EQ-5D 5L v2
10.4
Appendix 4: 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


Sponsor: Astellas Pharma Europe B.V.
SAP Final Version 3.0 10 Sep 2018
ISN/Protocol 1517-CL-0613
Astellas
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10.5
Appendix 5: Medication WHO Drug Dictionary Codes
Name
Code
ESA except darbepoetin alfa 
ATC level 4 = B03XA
Darbepoetin alfa
ATC level 4 = B03XA
IV Iron or Oral Iron
ATC Level 3 = “IRON PREPARATIONS” and 
Route = “INTRAVENOUS” or “ORAL”
RBC transfusion
ATC level 4 = B05AX
Any investigational drug
WHODD drug code = 99999701001
Hypoxia-inducible factor HIF-PHI
ATC level 4 = B03XA
Iron-chelating agents
ATC level 4 = B03AA, B03AD, B03AE, A12CX
Androgens
ATC level 3 = G03B and G03E
Dapsone 
ATC level 4 = J04BA
Acetaminophen/paracetamol
ATC level 4 = N02BE


Sponsor: Astellas Pharma Europe B.V.
SAP Final Version 3.0 10 Sep 2018
ISN/Protocol 1517-CL-0613
Astellas
Page 124 of 125
10.6
Appendix 6: Signatures
List of Key Contributors and Approvers
Key Contributors
The following contributed to or reviewed this Statistical Analysis Plan as relevant to their 
indicated discipline or role.
Primary author
Contributors and Reviewers
Data Science
Data Science
Clinical Science
Medical Science
Medical Science
Medical Science