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

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

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 1 of 160
Version 3.0, Incorporating Substantial Amendment 2
A Phase 3, Randomized, Open-Label, Active-Controlled Study 
to Evaluate the Efficacy and Safety of Roxadustat in 
the Treatment of Anemia in Chronic Kidney Disease 
Patients Not on Dialysis
Protocol for Phase 3 Study of Roxadustat (ASP1517/FG-4592) a
ISN/Protocol 1517-CL-0610
Version 3.0
Incorporating Substantial Amendment 2 [See Attachment 1]
31 March 2016
EudraCT number 2013-000951-42
Sponsor:
Astellas Pharma Europe B.V.
Sylviusweg 62, 2333 BE Leiden
The Netherlands
Protocol History:
Version 1.0 [14 Aug 2013]
Version 2.0 [18 May 2015]
                                                
a The originator of the compound under study is FibroGen Inc and the code name used by FibroGen Inc is 
FG-4592. Astellas is the development partner and uses the code name ASP1517. The sponsor of this study is 
Astellas. The compound has received the International Nonproprietary Name (INN) roxadustat.

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

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

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

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

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

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 7 of 160
Version 3.0, Incorporating Substantial Amendment 2
10.1
Independent Data and Safety Monitoring Board (DSMB) ····························· 106
10.2
Independent Event Review Committee (IERC) ········································· 106
10.3
Other Study Organization ·································································· 106
11
REFERENCES ·················································································· 107
12
APPENDICES ··················································································· 110
12.1
List of Prohibited Concomitant Medication·············································· 110
12.2
Liver Safety Monitoring and Assessment ················································ 111
12.3
Instructions for Subjects Moving from Protocol v1.0 to Protocol v2.0··············· 114
12.3.1
Visit Schedule·········································································· 114
12.3.2
Dosing Instructions for Subjects Moving from Protocol v1.0 to Protocol 
v2.0······················································································ 114
12.3.3
ESA Rescue Therapy ································································· 115
12.4
Instructions for Subjects Requiring Dialysis············································· 116
12.4.1
Dosing ·················································································· 116
12.4.2
Dose Adjustment ······································································ 116
12.4.3
ESA Rescue Therapy ································································· 116
12.4.4
Supplemental Iron Use································································ 116
12.4.5
Health Related Quality of Life······················································· 116
12.4.6
Timing of Study Assessments ······················································· 116
12.5
Short Form-36 Health Survey (SF-36) ··················································· 117
12.6
Functional Assessment of Cancer Therapy- Anemia (FACT-AN)···················· 123
12.7
EuroQol Questionnaire (EQ-5D-5L)······················································ 126
12.8
Subjects’ Global Impression of Change (PGIC) Scale ································· 129
12.9
Work Productivity and Activity Impairment Questionnaire: Anemic Symptoms 
(WPAI:ANS) ················································································ 130
13
ATTACHMENT 1:   SUBSTANTIAL AMENDMENT 2 ······························· 132
14
SPONSOR’S SIGNATURES·································································· 160
List of In-Text Tables
Table 1
Schedule of Assessments·····································································34
Table 2
Treatment Arms and Dosing Frequency····················································50
Table 3
Expected Number of Subjects Randomized················································51
Table 4
Initial Dosing of Roxadustat (TIW)·························································63
Table 5
Dose Adjustment Rules for Roxadustat ····················································64
Table 6
Proposed Maximum Daily Dose of Statins Not to Be Exceeded························67

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 8 of 160
Version 3.0, Incorporating Substantial Amendment 2
Table 7
Laboratory Tests ··············································································77
Table 8
Examples of Sampling Schedules for Population PK·····································86
Table 9
Sample Size Calculations per Treatment Arm·············································89
Table 10
Secondary Endpoints Fixed Sequence Testing Procedure································93
List of In-Text Figures
Figure 1
HIF-PHI Mechanism of Action······························································40

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 9 of 160
Version 3.0, Incorporating Substantial Amendment 2
I.
SIGNATURES
1.
SPONSOR’S SIGNATURES
Required signatures (e.g., Protocol authors, Sponsor’s reviewers and contributors) are located 
in Section 14, Sponsor’s Signatures; e-signatures (when applicable) are located at the end of 
this document.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 10 of 160
Version 3.0, Incorporating Substantial Amendment 2
2.
COORDINATING INVESTIGATOR’S SIGNATURE
A Phase 3, Randomized, Open-Label, Active-Controlled Study to Evaluate the 
Efficacy and Safety of Roxadustat in the Treatment of Anemia in Chronic 
Kidney Disease Patients Not on Dialysis
ISN/Protocol 1517-CL-0610
Version 3.0 / Incorporating Substantial Amendment 2
31 March 2016
I have read all pages of this clinical study protocol for which Astellas is the Sponsor. I agree that it 
contains all the information required to conduct this study.
Coordinating Investigator:
Signature:
<Insert name, department/affiliation, name of institution>
Date (DD Mmm YYYY)
Printed Name:
Address:

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 11 of 160
Version 3.0, Incorporating Substantial Amendment 2
3.
INVESTIGATOR’S SIGNATURE
A Phase 3, Randomized, Open-Label, Active-Controlled Study to Evaluate the 
Efficacy and Safety of Roxadustat in the Treatment of Anemia in Chronic 
Kidney Disease Patients Not on Dialysis
ISN/Protocol 1517-CL-0610
Version 3.0 / Incorporating Substantial Amendment 2
31 March 2016
I have read all pages of this clinical study protocol for which Astellas is the Sponsor. I agree 
to conduct the study as outlined in the protocol and to comply with all the terms and 
conditions set out therein. I confirm that I will conduct the study in accordance with ICH 
GCP guidelines and applicable local regulations. I will also ensure that sub-investigator(s) 
and other relevant members of my staff have access to copies of this protocol and the ICH 
GCP guidelines to enable them to work in accordance with the provisions of these 
documents.
Principal Investigator:
Signature:
<Insert name and qualifications of the Investigator>
Printed Name:
Date (DD Mmm YYYY)
Address:

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 13 of 160
Version 3.0, Incorporating Substantial Amendment 2
III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AE
Adverse Event
α1-AGP
Alpha 1-Acid Glycoprotein
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
AnS
Anemia Subscale
anti-HCV Ab
Anti-hepatitis C Virus 
APEB
Astellas Pharma Europe BV
ASP1517
= FG-4592 (codename of investigational product) or roxadustat (international 
nonproprietary name)
AST
Aspartate Aminotransferase
AT
Aminotransferases
AUC
Area under the plasma concentration – time curve
BIW
twice weekly
BL
Baseline
BL Hb
Baseline Hemoglobin (please refer to key definitions for information)
BP
Blood Pressure
CA
Competent Authority 
CBC
Complete Blood Count
CHMP
Committee for Medicinal Products for Human Use
CHOIR
Correction of Hemoglobin and Outcomes in Renal Insufficiency
CHr
Hemoglobin content of reticulocytes
CKD
Chronic Kidney Disease
CL/F
Apparent total body clearance
Cmax
Maximum concentration
CRO
Contract Research Organization
CYP
Cytochrome P450
DBP
Diastolic Blood Pressure
DD-CKD
Dialysis-dependent chronic kidney disease
DNA
Deoxyribonucleic Acid
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
eCRF
Electronic CRF
EDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate
ELISA
Enzyme-Linked ImmunoSorbent Assay
EOS
End of Study
EOT
End of Treatment
EPAR
European Public Assessment Report
EPO
Erythropoietin
EQ-5D 5L
Health Related Quality of Life Questionnaire Consisting of Five Levels
ESA
Erythropoiesis Stimulating Agent
ESRD
End Stage Renal Disease
EU
European Union
EWB
Emotional Well being

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 14 of 160
Version 3.0, Incorporating Substantial Amendment 2
Abbreviations
Description of abbreviations
FACT-An
Functional Assessment of Cancer Therapy-Anemia
FACT-G
Functional Assessment of Cancer Therapy-General
FDA
Food and Drug Administration
FAS
Full Analysis Set
FG-4592
= ASP1517 (codename of investigational product) or roxadustat (international 
nonproprietary name) 
FWB
Functional Well-being
GCP
Good Clinical Practice
GDS
Global Data Science
GGT
Gamma Glutamyl Transferase
GMP
Good Manufacturing Practice
Hb
Hemoglobin
HbA1c
Hemoglobin A1c; Glycated hemoglobin
HBsAg
Hepatitis B Surface Antigen
Hct
Hematocrit
HD
Hemodialysis 
HDF
Hemodiafiltration
HDL
High-density Lipoprotein
HEENT
Head, Eyes, Ears, Neck and Throat
HIF
Hypoxia-inducible factor
HIF-PH
Hypoxia-inducible factor prolyl hydroxylase
HIF-PHI
Hypoxia-inducible factor prolyl hydroxylase inhibitor
HIV
Human Immunodeficiency Virus
HR
Heart Rate
HRQoL
Health-Related Quality of Life
hs-CRP
High Sensitivity C-reactive protein
ICF
Informed Consent Form
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IERC
Independent Event Review Committee
IMP
Investigational Medicinal Product
IMPD
Investigational Medicinal Product Dossier
IND
Investigational New Drug (Application)
INN
International Nonproprietary Name
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intra Uterine Device 
IUS
Intra Uterine System
ISN
International Study Number
IV
Intravenous(ly)
ka
First order absorption rate constant
KDIGO
Kidney Disease Improving Global Outcomes
KDOQI
Kidney Disease Outcomes Quality Initiative
kg
Kilogram
LDL
Low-density Lipoprotein
LA-CRF
Liver Abnormality Case Report Form
LFT
Liver Function Tests

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 15 of 160
Version 3.0, Incorporating Substantial Amendment 2
Abbreviations
Description of abbreviations
LOCF
Last Observation Carried Forward
LLN
Lower Limit of Normal 
LSO
Last Subject Out
MAP
Mean Arterial Pressure
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram 
MI
Myocardial Infarction
mL
Milliliters 
MMRM
Mixed Model of Repeated Measures
MTD
Maximum Tolerated Dose
NASH
Non-alcoholic steatohepatitis
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria for Adverse Events
NDD-CKD
Nondialysis-dependent chronic kidney disease
NONMEM
Non-linear Mixed Effects Modeling
OATP1B1
Organic anion transporting polypeptide 1B1
PCS
Physical Component Scores
PD
Pharmacodynamic
PF
Physical Functioning
PGIC
Patients’ Global Impression of Change
PHI
Protected Health Information
PK
Pharmacokinetic
PKAS
Pharmacokinetic Analysis Set
PL
Package Leaflet
PPK
Population Pharmacokinetics
PPKPD
Population Pharmacokinetic/Pharmacodynamic
PPS
Per Protocol Set
PR
Partial Response
PWB
Physical Well-being
QoL
Quality of Life
QRS 
QRS interval 
QTc
QT Interval corrected for heart rate
QW
Once weekly
RBC
Red Blood Cell
r-HuEPO
Recombinant Human Erythropoietin
RRT
Renal Replacement Therapy
SAE
Serious AE
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SC
Subcutaneous(ly)
SI
International System of Units 
SF-36
Short Form 36
SmPC
Summary of Product Characteristics
SOC
System Organ Class
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SWB
Social Well-being
t½
Apparent Terminal Elimination Half-life

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 16 of 160
Version 3.0, Incorporating Substantial Amendment 2
Abbreviations
Description of abbreviations
TBL
Total Bilirubin 
TEAE
Treatment-Emergent Adverse Event
TESAE
Treatment-Emergent Serious Adverse Event
TIBC
Total Iron-Binding Capacity
TIW
Three times weekly
tmax
Time to Attain Cmax
TREAT
Trial to Reduce Cardiovascular Events with Aranesp Therapy
TSAT
Transferrin Saturation (also known as FeSAT, iron saturation) 
UACR
Urine albumin/creatinine ratio
ULN
Upper Limit of Normal
USRDS
United States Renal Data System
VAS
Visual Analogue Scale
V/F
Apparent volume of distribution
VT
Vitality
WBC
White Blood Cell
Wk(s)
Week(s)
WPAI:ANS
Work Productivity and Activity Impairment questionnaire: Anemic Symptoms

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 17 of 160
Version 3.0, Incorporating Substantial Amendment 2
List of Key Study Terms
Terms
Definition of terms
Adverse Event
An adverse event (AE) is as any untoward medical occurrence in a subject 
administered roxadustat or darbepoetin alfa, and which does not necessarily 
have a causal relationship with this treatment. AE collection starts after 
obtaining signed informed consent and continues until the End of Study visit. 
AEs will not be collected during the period where a subject has failed 
screening and first rescreening visit.
Baseline
1) Observed values/findings which are regarded as calibrated zero status in the 
present study; 2) Time when ‘Baseline’ is observed.
Baseline 
hemoglobin (Hb) 
value
Mean of three Hb values: the last two Hb values during screening and the Hb 
value at the day of randomization (day 1), all assessed by the central 
laboratory. 
Discontinuation
A discontinuation is a subject who enrolled into the study and for whom study 
treatment is permanently discontinued prematurely for any reason. Four 
categories of discontinuation are distinguished: a) dropout: Active 
discontinuation by a subject (also a noun referring to such a discontinued 
subject); b) investigator-initiated discontinuation (e.g., for cause); c) loss to 
follow-up: cessation of participation without notice or action by the subject; 
d) Sponsor-initiated discontinuation. Note that subject discontinuation does not 
necessarily imply exclusion of subject data from analysis. “Termination” has a 
history of synonymous use, but is now considered non-standard.
Enroll
To register or enter into a clinical trial; transitive and intransitive. Informed 
consent precedes enrollment, which precedes randomization.
Hb Correction
Hemoglobin level ≥11.0 g/dL and a Hb increase from baseline 
BL Hb ≥1.0 g/dL as assessed by the central laboratory at two consecutive 
study visits separated by at least 5 days in the correction period.
Hb Response
Hemoglobin level ≥11.0 g/dL and a Hb increase from baseline 
BL Hb ≥1.0 g/dL in case BL Hb was > 8.0 g/dL, or an increase in Hb from 
BL Hb by ≥2.0 g/dL in case BL Hb was ≤8.0 g/dL, as assessed by the central 
laboratory at two consecutive study visits separated by at least 5 days.
Post study 
follow-up
Period of time from EOS visit to projected week 108 or until consent 
withdrawn. This period is only applicable to subjects who prematurely 
discontinued treatment. These subjects will be followed up every 6 months for 
vital status, serious adverse events (SAEs), cardiovascular and thromboembolic 
adverse events (AEs). 
Randomization
The process of assigning trial subjects to treatment or control groups using an 
element of chance to determine assignments in order to reduce bias.
(After randomization subjects receive either roxadustat or darbepoetin alfa 
from day 1 until End Of Treatment [EOT].) 
Rescreening
Process of repeating screening. If subject fails screening they may be re-
screened once if deemed appropriate; all screening procedures will be repeated. 
Rescreening failure
Subject who is rescreened, but did not fulfill protocol inclusion and/or 
exclusion criteria for a second time and failed to receive randomized treatment, 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 18 of 160
Version 3.0, Incorporating Substantial Amendment 2
Terms
Definition of terms
or decided not to participate anymore (withdrew consent) prior to the treatment
period. 
Screening
1) Process for retrieving candidates for the study. 2) Process for checking the 
eligibility of subjects usually done during the “pre-investigational period.”
Screen failure
Potential subject who did not meet one or more inclusion and/or exclusion
criteria required for participation in a trial. See also screening of subjects.
Serious Adverse 
Event
An adverse event is considered “serious” if, in the view of either the 
investigator or Sponsor, it results in any of the following outcomes: results in 
death, is life threatening, results in persistent or significant disability/incapacity 
or substantial disruption of the ability to conduct normal life functions, results 
in congenital anomaly, or birth defect, requires in-subject hospitalization or 
leads to prolongation of hospitalization, or a medically important event.
Study period
Period of time from first subject screened to end of the last scheduled visit of 
the last subject randomized
Subject
An individual who participates in a clinical trial
TEAE
A treatment-emergent adverse event (TEAE) is an AE that started during the 
treatment period and was not present prior to the first dose of study drug, or the 
AE was present prior to the first dose of study drug but increased in severity 
during the treatment period. An AE that occurs more than 28 days after the last 
dose of study medication will not be counted as a TEAE.
Treatment period
It is the period of time - between first dose of the test drug and EOT visit -
where major interests of protocol objectives are observed, and where 
roxadustat (study drug) or darbepoetin alfa (comparative drug) is given to a 
subject. The treatment period consists of the correction and maintenance 
periods.
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 19 of 160
Version 3.0, Incorporating Substantial Amendment 2
IV.
SYNOPSIS
Date and Version # of Protocol Synopsis:
31 March 2016 / Version 3.0
Sponsor:
Astellas Pharma Europe B.V. (APEB)
Protocol Number:
1517-CL-0610
Name of Study Drug:
Roxadustat (ASP1517/FG-4592)
Phase of Development:
Phase 3
Title of Study:
A Phase 3, Randomized, Open-Label, Active-Controlled Study to Evaluate the Efficacy and Safety of 
Roxadustat in the Treatment of Anemia in Chronic Kidney Disease Patients Not on Dialysis
Planned Study Period:
From 1Q2014 to 2Q2021
Study Objectives:
The primary objective of this study is to evaluate the efficacy of roxadustat compared to darbepoetin 
alfa in the treatment of anemia in nondialysis-dependent Chronic Kidney Disease (NDD-CKD) 
subjects.
The secondary objectives of this study are to:
Evaluate the safety of roxadustat compared to darbepoetin alfa in the treatment of anemia in 
NDD-CKD subjects.
Evaluate the health-related quality of life (HRQoL) benefit of roxadustat compared to darbepoetin 
alfa in the treatment of anemia in NDD-CKD subjects.
Planned Total Number of Study Centers and Locations:
Approximately 200 study centers globally.
Study Population:
The study population consists of subjects with CKD stages 3, 4, and 5 (estimated glomerular filtration 
rate [eGFR] < 60 mL/min/1.73 m2) who are anemic and not on dialysis. 
Number of Subjects to be Randomized:
Approximately 570 subjects will be randomized; this will lead to approximately 450 subjects in the 
Per Protocol Analysis Set (PPS).
Study Design Overview:
This is a multicenter, randomized, open-label, active-controlled study.
The study will consist of three study periods:
Screening period: up to 6 weeks
Treatment period: 104 weeks
Follow-up period: 4 weeks
Subjects that have discontinued treatment prior to their projected week 104 will continue to be 
followed for vital status, serious adverse events (SAEs), cardiovascular and thromboembolic adverse 
events (AEs) in a post study follow-up period.
During the course of the study, visits and assessments will be performed as defined in the Schedule of 
Assessments. During the treatment period, subjects will attend weekly study visits from day 1 to 
week 2, followed by every other week study visits from weeks 4 to 24 and thereafter every four weeks 
until the end of treatment (EOT).
Subjects will receive study treatment - roxadustat or darbepoetin alfa - for 104 weeks.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 20 of 160
Version 3.0, Incorporating Substantial Amendment 2
Screening Period
During the screening period (up to 42 days duration), hemoglobin (Hb) levels will be assessed in a 
central laboratory for matching the inclusion criterion (mean of two Hb values must be ≤10.5 g/dL, 
see inclusion criterion 4 below). Subjects meeting all of the inclusion criteria and none of the 
exclusion criteria will be randomized at day 1, which marks the end of screening period and start of 
the treatment period. If a subject fails screening, the subject may be rescreened once (immediately or 
later) if deemed appropriate by the investigator. The subject must be re-consented. A new 
rescreening period will start and all screening procedures must be repeated.
Treatment Period (Correction Period and Maintenance Period)
The treatment period consists of a correction period and a maintenance period. Subjects are 
randomized to 1 of 2 treatment arms in a 1:1 ratio: one treatment arm will receive roxadustat 
administered orally and one treatment arm will receive darbepoetin alfa administered subcutaneously 
(SC) or intravenously (IV). Study treatment administration is implemented in an open-label manner.
Table 1: Treatment Arms and Dosing Frequency
Treatment Arm
Study Treatment
Dosing Frequency in Treatment Period
Correction Period
Maintenance Period
1
Roxadustat
TIW
TIW
2
Darbepoetin alfa
Dosing per European (EU) SmPC
SmPC = Summary of Product Characteristics; TIW = three times weekly
Correction Period
The aim of the correction period is to correct Hb levels to ≥11.0 g/dL and a Hb increase from 
BL Hb ≥1.0 g/dL as measured at two consecutive study visits separated by at least 5 days (as 
assessed by central laboratory).
Dosing and dose adjustments of roxadustat will follow prespecified dose adjustment rules. Dosing 
and dose adjustments of darbepoetin alfa will be per EU approved Summary of Product 
Characteristics (SmPC).
Once Hb is corrected (Hb ≥11.0 g/dL or higher, and a Hb increase from BL Hb ≥1.0 g/dL) the 
subjects will enter into the maintenance period.
Maintenance Period
The aim of the maintenance period is to treat to a Hb target level of 11.0 g/dL by maintaining the Hb 
level between 10.0 g/dL and 12.0 g/dL.
Dose adjustments of roxadustat will follow prespecified dose adjustment rules.
Dose adjustments of darbepoetin alfa will be per EU approved Summary of Product Characteristics 
(SmPC).
Follow-up Period
After the treatment period, subjects proceed to the 4-week follow-up period.
Post Study Follow-up (for premature treatment discontinued subjects only)
Subjects that have prematurely discontinued study treatment will complete the EOT visits (EOT visit 
and EOT + 2 weeks visit) and end of study (EOS) visit. Thereafter, these subjects (only if they have 
taken at least one dose of study drug) will continue to be followed up every 6 months for vital status, 
SAEs, cardiovascular and thromboembolic AEs until their projected date of completion of the follow-
up period (i.e., projected week 108 date) or until consent withdrawn.
Data Safety Monitoring Board
A Data Safety Monitoring Board (DSMB) will review prespecified safety data periodically in 
collaboration with the Sponsor to ensure subject safety. Details will be specified in a DSMB charter.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 21 of 160
Version 3.0, Incorporating Substantial Amendment 2
Independent Event Review Committee
An Independent Event Review Committee (IERC) will adjudicate all prespecified cardiovascular and 
cerebrovascular events in a blinded manner to ensure a consistent safety assessment. Details will be 
specified in an IERC charter.
Inclusion Criteria:
Subject is eligible for the study if all of the following apply:
1.
Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written 
Informed Consent and privacy language as per national regulations has been obtained from the 
subject or legally authorized representative prior to any study-related procedures (including 
withdrawal of prohibited medication, if applicable).
2.
Subject age is ≥18 years.
3.
Subject has a diagnosis of CKD, with Kidney Disease Outcomes Quality Initiative (KDOQI) 
Stage 3, 4 or 5, not on dialysis; with an eGFR < 60 mL/min/1.73 m2 estimated using the 
abbreviated 4-variable Modification of Diet in Renal Disease (MDRD) equation.
4.
The mean of the subject’s two most recent (prior to randomization) Hb values during the 
screening period, obtained at least 4 days apart, must be ≤10.5 g/dL, with a difference of 
≤1.0 g/dL. The last Hb value must be within 10 days prior to randomization.
5.
Subject is deemed suitable by the investigator for treatment with erythropoiesis stimulating agents 
(ESA) using the criteria specified in the Kidney Disease Improving Global Outcomes (KDIGO)
2012 recommendation considering the rate of fall of Hb concentration, prior response to iron 
therapy, the risk of needing a transfusion, the risks related to ESA therapy and the presence of 
symptoms attributable to anemia.
6.
This criterion has been removed.
7.
This criterion has been removed.
8.
Subject has a serum folate level ≥ lower limit of normal (LLN) at screening.
9.
Subject has a serum vitamin B12 level ≥LLN at screening.
10. Subject’s alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are ≤3 x upper 
limit of normal (ULN), and total bilirubin (TBL) is ≤1.5 x ULN.
11. Subject’s body weight is 45.0 kg to a maximum of 160.0 kg.
12. Female subject is either:
Of non-childbearing potential:
post-menopausal (defined as at least 1 year without any menses) prior to screening,
or
documented surgically sterile
Or if of childbearing potential:
agree not to try to become pregnant during the study and for 28 days after the final study drug 
administration
must have a negative serum pregnancy test at screening and
if heterosexually active, agree to consistently use a highly effective form of birth control* 
starting at screening and throughout the study period, and continue to do so for 28 days after 
final study treatment administration. If required by local law, 2 highly effective methods of 
birth control must be used, 1 of which must be a barrier method.
13. Female subject must not be breastfeeding at screening or throughout the study period, and for 
28 days after the final study treatment administration.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 22 of 160
Version 3.0, Incorporating Substantial Amendment 2
14. Female subject must not donate ova starting at screening and throughout the study period and for 
28 days after final study drug administration.
15. Male subject and their female spouse/partner(s) who are of childbearing potential must be using a 
highly effective form of birth control* starting at screening and continue to do so throughout the 
study period and for 12 weeks after final study treatment administration. If required by local law, 
2 highly effective methods of birth control must be used, 1 of which must be a barrier method.
16. Male subject must not donate sperm starting from screening, throughout the study period and up 
to 12 weeks after final study drug administration.
17. Subject agrees not to participate in another interventional study from the time of signing informed 
consent until the End of Study visit (EOS).
*Highly effective forms of birth control include:

Consistent and correct usage of established oral contraception. 

Injected or implanted hormonal methods of contraception.

Established intrauterine device (IUD) or intrauterine system (IUS).

Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository (if allowed by local regulations).

Any male partner that has undergone effective surgical sterilization.

Any female partner that has undergone effective surgical sterilization, if applicable.
Waivers to the inclusion criteria will NOT be allowed.
Exclusion Criteria:
Subject will be excluded from participation if any of the following apply:
1.
Subject has received any ESA treatment within 12 weeks prior to randomization.
2.
Subject has received any dose of IV iron within 6 weeks prior to randomization.
3.
Subject has received a Red Blood Cell (RBC) transfusion within 8 weeks prior to randomization.
4.
Subject has a known history of myelodysplastic syndrome or multiple myeloma.
5.
Subject has a known hereditary hematologic disease such as thalassemia or sickle cell anemia, 
pure red cell aplasia, or other known causes for anemia other than CKD.
6.
Subject has a known hemosiderosis, hemochromatosis, coagulation disorder, or hypercoagulable 
condition.
7.
Subject has a known chronic inflammatory disease that could impact erythropoiesis (e.g., 
systemic lupus erythematosus, rheumatoid arthritis, celiac disease) even if it is currently in 
remission.
8.
Subject is anticipated to undergo elective surgery that is expected to lead to significant blood loss 
during the study period or anticipated elective coronary revascularization.
9.
Subject has active or chronic gastrointestinal bleeding.
10. Subject has received any prior treatment with roxadustat or a hypoxia-inducible factor prolyl 
hydroxylase inhibitor (HIF-PHI). 
11. Subject has been treated with iron-chelating agents within 4 weeks prior to randomization.
12. Subject has a history of chronic liver disease (e.g., cirrhosis or fibrosis of the liver).
13. Subject has known New York Heart Association Class III or IV congestive heart failure.
14. Subject has had a myocardial infarction, acute coronary syndrome, stroke, seizure, or a 
thrombotic/thromboembolic event (e.g., deep vein thrombosis or pulmonary embolism) within 
12 weeks prior to randomization.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 23 of 160
Version 3.0, Incorporating Substantial Amendment 2
15. Subject has one or more contraindications for treatment with darbepoetin alfa:
Uncontrolled hypertension in the opinion of the investigator, or two or more blood pressure 
values of systolic blood pressure (SBP) ≥160 mmHg or diastolic blood pressure (DBP) 
≥95 mmHg (within 2 weeks prior to randomization).
Known hypersensitivity to darbepoetin alfa, recombinant human erythropoietin, or any of the 
excipients.
16. Subject has a diagnosis or suspicion (e.g., complex kidney cyst of Bosniak Category 2F or higher) 
of renal cell carcinoma as shown on renal ultrasound within 12 weeks prior to randomization.
17. Subject has a history of malignancy, except for the following: cancers determined to be cured or 
in remission for ≥5 years, curatively resected basal cell or squamous cell skin cancers, cervical 
cancer in situ, or resected colonic polyps.
18. Subject is positive for any of the following: 
human immunodeficiency virus (HIV).
hepatitis B surface antigen (HBsAg).
or anti-hepatitis C virus antibody (anti-HCV Ab).
19. Subject has an active clinically significant infection that is manifested by White Blood Count 
(WBC) > ULN, and/or fever, in conjunction with clinical signs or symptoms of infection within 
one week prior to randomization.
20. Subject has a known untreated proliferative diabetic retinopathy, diabetic macular edema, macular 
degeneration or retinal vein occlusion.
21. Subject has had any prior organ transplant (that has not been explanted),  subject is scheduled for 
organ transplantation, or subject is likely to initiate renal replacement therapy including dialysis 
within the first year of the study in the opinion of the investigator.
22. Subject will be excluded from participation if any of the following apply:
a. subject has received investigational therapy within 30 days or 5 half lives or limit set by 
national law, whichever is longer, prior to initiation of screening, or
b. any condition which, in the investigator’s opinion, makes the subject unsuitable for study 
participation.
23. Subject has an anticipated use of dapsone in any dose amount or chronic use of 
acetaminophen/paracetamol > 2.0 g/day during the treatment or follow-up period of the study.
24. Subject has a history of alcohol or drug abuse within 2 years prior to randomization.
25. Subject has any medical condition that in the opinion of the investigator may pose a safety risk to 
a subject in this study, which may confound efficacy or safety assessment, or may interfere with 
study participation.
Waivers to the exclusion criteria will NOT be allowed.
Investigational Product:
Roxadustat (ASP1517/FG-4592)

Tablets

Strengths of 20 mg, 50 mg and 100 mg
Mode of Administration:

Oral
Doses:
The initial study drug (roxadustat) dose (per dose amount) is based on the tiered, weight-based dosing 
scheme shown in the table below:

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 25 of 160
Version 3.0, Incorporating Substantial Amendment 2

Next dose adjustment review is 4 weeks after dose resumption and in 4-weekly intervals 
thereafter.
Dose Adjustment for Excessive Hematopoiesis
If at any time during the treatment period Hb increases by > 2.0 g/dL within 4 weeks:

The dose should be reduced by one dose step

Only one dose reduction for excessive hematopoiesis is recommended within a period of 4 weeks.
If a blood transfusion or ESA treatment has been performed within 2 weeks of meeting the 
criteria for excessive hematopoiesis, it is recommended not to perform a dose reduction for 
excessive hematopoiesis.

After a dose adjustment due to excessive hematopoiesis, the subject’s next dose adjustment 
review will occur 4 weeks later, and in 4-weekly intervals thereafter.
Comparative Drug:

Darbepoetin alfa (Aranesp®) solution for injection in a pre-filled syringe.

Range of strengths: 20, 30, 40, 60 and 100 μg.
Mode of Administration:

Subcutaneous (SC) or intravenous (IV) as judged appropriate by the investigator.
Dose:
Darbepoetin alfa dosing is to follow the EU SmPC. All administrations will be performed by the 
investigator or a qualified member of the site staff or, after 36 weeks of treatment, by the subject 
themselves or caregiver, e.g., relative, if well trained and willing to self-administer.

Initial dose:
0.45 μg/kg body weight as a single SC or IV injection once weekly; alternatively 0.75 μg/kg 
body weight SC once every two weeks.

Dose adjustment:
If the increase in Hb is inadequate (less than 1.0 g/dL within 4 weeks) increase the dose by 
approximately 25%. During the correction period, dose increases must not be made more 
frequently than once every four weeks; during the maintenance period, dose changes should not 
be made more frequently than every two weeks.
If the rise in Hb is greater than 2.0 g/dL in 4 weeks, reduce the dose by approximately 25%.
Once the target Hb level has been achieved with once every 2-week dosing, darbepoetin alfa 
may be administered SC once monthly using an initial dose equal to twice the previous once 
every 2-week dose.
All dose adjustments are made based on Hb values assessed using the HemoCue® device.
Target of treatment is achieving Hb response (defined as Hb values of ≥11.0 g/dL and Hb increase 
from BL Hb ≥1.0 g/dL at 2 consecutive study visits separated by at least 5 days [as assessed by the 
central laboratory]) and thereafter maintaining Hb in the target range of 10.0 to 12.0 g/dL.
Rescue Therapy Guidelines:
Rescue therapy guidelines are provided to optimize standardization of the use of rescue therapy by 
investigators and to ensure safety of the individual study subjects.
1.
RBC Transfusion (for all subjects)
In the event of acute or severe blood loss, RBC transfusion is allowed if clinically indicated. In a 
situation where there is no obvious blood loss, RBC transfusion will be permitted if the subject has 
moderate to severe symptom(s) from his/her anemia, e.g., dyspnea at rest or on mild exertion, and the 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 26 of 160
Version 3.0, Incorporating Substantial Amendment 2
investigator is of the opinion that the blood transfusion is a medical necessity. Study treatment may be 
continued even if a blood transfusion has been administered.
2.
ESA (only for subjects treated with roxadustat)
If the investigator considers administration of ESA as a medical necessity, darbepoetin alfa may be 
initiated if the following criteria are met:

the subject’s Hb level is < 9.0 g/dL (HemoCue) as confirmed at two consecutive visits,
and

the subject’s Hb level has not responded adequately despite 2 or more roxadustat dose 
increases in the previous 8 weeks, or the roxadustat dose reached the maximum dose limit,
and

reducing the risk of alloimmunization in transplant eligible subjects and/or reduction of other 
RBC transfusion-related risks is a goal.
Prior to the initiation of darbepoetin alfa, the subject’s Hb response, as well as factors influencing the 
Hb response, such as iron status, inflammatory status, hemolysis, blood loss or other potential reasons 
for Hb decrease should be considered and, where applicable, be addressed by the investigator.
The subject may continue in the study while on rescue treatment with darbepoetin alfa, however, it is 
not allowed to administer roxadustat during the same time period.
The course of darbepoetin alfa (i.e., the amount that may be administered) will be limited by duration 
of therapy and effect on Hb. The course of darbepoetin alfa rescue treatment will not exceed 4 weeks 
in duration, and darbepoetin alfa rescue will be stopped as soon as Hb ≥9.0 g/dL. To continue study 
participation, treatment with roxadustat study drug should be resumed within one week after the last 
administration of darbepoetin alfa at the dose level the subject was on prior to initiating darbepoetin 
alfa rescue therapy.
If a subject requires a second course of rescue darbepoetin alfa, the subject must be discontinued from 
treatment.
Doses:
The doses of rescue therapies are per investigator’s discretion.
Emergency Procedure:
Therapeutic Phlebotomy
If there are clinical concerns for a subject’s high Hb levels, the investigator may decide to perform a 
therapeutic phlebotomy instead of, or in addition to, a study treatment dose hold (stop dosing). The 
therapeutic phlebotomy should be documented in the eCRF and source documentation, and discussed 
with the Medical Monitor.
Concomitant Medication Restrictions and/or Requirements:
Supplemental Iron Use
For subjects receiving roxadustat
i.
Oral iron
For subjects receiving roxadustat, oral iron is recommended for supplementation to support 
erythropoiesis and as the first-line treatment for iron deficiency, unless the subject is 
intolerant to this treatment. The recommended daily dose is 200 mg of elemental iron.
Administration of roxadustat between -1 hour and +1 hour of intake of oral iron is not 
recommended.
ii.
Intravenous iron
For subjects receiving roxadustat, IV iron supplementation is only allowed if all of the 
following criteria are met:

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 27 of 160
Version 3.0, Incorporating Substantial Amendment 2

The subject has not responded adequately to 2 or more dose increases of roxadustat or has 
reached the maximum dose limit, and

The subject has iron deficiency (either ferritin < 100 ng/mL [< 220 pmol/L] or 
TSAT < 20%) or the subject does not tolerate oral iron therapy.
Treatment with roxadustat may continue during IV iron administration. Discontinuation of 
IV iron administration is recommended once ferritin levels are ≥100 ng/mL (≥220 pmol/L)
and TSAT ≥20%.
For subjects receiving darbepoetin alfa
For subjects treated with darbepoetin alfa, oral or IV iron supplementation is required to maintain iron 
repletion. IV iron should only be administered if ferritin is < 100 ng/mL (< 220 pmol/L) or TSAT is 
< 20%. IV iron may be administered per local practice. Discontinuation of IV iron therapy is 
recommended once ferritin levels are ≥100 ng/mL (≥220 pmol/L) and TSAT ≥20%.
Anti-hypertensive Medication
To avoid confounding effects on study endpoints, changes to anti-hypertensive medications should be 
minimized, and made only if deemed medically necessary by the investigator or if pre-specified 
changes in blood pressure are met.
Prohibited Medication
The following medications are prohibited during the period identified:

Any ESA: within 12 weeks prior to randomization until EOT.

IV iron: within 6 weeks prior to randomization.

RBC transfusion: within 8 weeks prior to randomization.

Any investigational drug: within 30 days or 5 half lives or limit set by national law (whichever is 
longer), prior to screening until EOS.

Roxadustat or another HIF-PHI: at any time prior to randomization. After randomization any 
HIF-PHI other than roxadustat, as allocated by randomization, until EOS.

Iron-chelating agents (e.g., deferoxamine, deferiprone, or deferasirox therapy): from 4 weeks 
prior to randomization until EOS.

Androgens from day of randomization until EOS.

Dapsone in any dose amount or chronic use of acetaminophen/paracetamol >2.0 g/day from the 
day of randomization until EOS.
Duration of Treatment:
104 weeks
Formal Stopping Rules:
Subjects should be prematurely discontinued from study treatment for any of the following reasons:

Subject no longer consents to participate in the treatment phase of the study.

Physician decision that it is in the best interest of the subject to be discontinued from study 
treatment.

Significant noncompliance with study procedures, as determined by principal investigator and/or 
Sponsor.

Pregnancy in a study subject.

Subjects randomized to roxadustat: requirement of a second course of rescue therapy with 
darbepoetin alfa deemed necessary by the investigator based upon the criteria for use of rescue 
treatment.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 28 of 160
Version 3.0, Incorporating Substantial Amendment 2

Subject receives an organ transplant.
Subjects that have prematurely discontinued study treatment will complete the EOT visits (EOT visit 
and EOT + 2 weeks visit) and EOS visit. Thereafter, these subjects who have taken at least one dose 
of study drug will continue to be followed up every 6 months for vital status, SAEs, cardiovascular 
and thromboembolic AEs until their projected date of completion of follow-up period (i.e., projected 
week 108 date) or until consent is withdrawn.
Subjects should be withdrawn from the study for any of the following reasons:

Subject no longer consents to participate in the study.

Subject is lost to follow-up despite reasonable efforts by the investigator to contact the subject.

Death of a study subject.

The Sponsor may decide to prematurely stop the study, e.g., for safety considerations.
Endpoints for Evaluation
Primary:
The primary efficacy variable is:

Hb response defined as: Hb ≥11.0 g/dL and a Hb increase from BL Hb by ≥1.0 g/dL in any 
subject with BL Hb > 8.0 g/dL, OR an increase from BL Hb by ≥2.0 g/dL in any subject with 
BL Hb ≤8.0 g/dL as measured at 2 consecutive visits separated by at least 5 days during the first 
24 weeks of treatment without administration of rescue therapy prior to Hb response.
Key Secondary:

Hb change from BL to the average Hb of weeks 28 to 36, without having received rescue therapy 
within 6 weeks prior to and during this 8-week evaluation period.

Change from BL in Low-Density Lipoprotein (LDL) cholesterol to the average LDL cholesterol 
of weeks 12 to 28.

Mean monthly IV iron use (mg) per subject during weeks 1 to 36 (monthly defined as a period of 
4 weeks). 

Change from BL in SF-36 Physical Functioning (PF) sub-score to the average PF sub-score of 
weeks 12 to 28.

Change from BL in SF-36 Vitality (VT) sub-score to the average VT sub-score of weeks 12 
to 28.

Blood pressure effect: 
o Change from BL in mean arterial pressure (MAP) to the average MAP value of 
weeks 20 to 28.
o Occurrence and time to occurrence of hypertension (defined as either systolic blood pressure 
[SBP] > 170 mmHg AND an increase from BL of ≥20 mmHg SBP or diastolic blood 
pressure [DBP] >110 mmHg AND an increase from BL of ≥15 mmHg DBP on 
2 consecutive visits) during weeks 1 to 36.
Additional Secondary:
Hb correction and maintenance:

Hb change from BL to the average Hb value of weeks 28 to 52 regardless of the use of rescue 
therapy.

Time (weeks) to achieve the first Hb response as defined by primary endpoint.

Hb response defined as: Hb ≥11.0 g/dL and a Hb increase from BL Hb by ≥1.0 g/dL in any 
subject with BL Hb > 8.0 g/dL, OR an increase from BL Hb by ≥2.0 g/dL in any subject with 
BL Hb ≤8.0 g/dL as measured at 2 consecutive visits separated by at least 5 days during the first 
24 weeks of treatment regardless of administration of rescue therapy prior to Hb response.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 29 of 160
Version 3.0, Incorporating Substantial Amendment 2

Hb averaged over weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104, without use of rescue therapy 
within 6 weeks prior to and during this evaluation period.

Hb value and Hb change from BL at each post-dosing time point.

Hb change from BL to the average Hb value of weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104, 
regardless of the use of rescue therapy.

Proportion of Hb values within 10.0 to 12.0 g/dL in weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104, 
without use of rescue therapy within 6 weeks prior to and during this 8-week evaluation period.
Hospitalizations

Occurrence (number) of hospitalization(s).

Number of days of hospitalization.
Rescue therapy use

Having received rescue therapy (either RBC transfusions [for all subjects] or darbepoetin alfa use 
[for roxadustat treated subjects only])

Having received RBC transfusions.

Number of RBC packs per subject.

Volume of RBC transfused per subject.
Changes in cholesterol levels

Change from BL to each post-dosing scheduled measurement in:
o Total cholesterol
o LDL/High-density Lipoprotein (HDL) ratio
o Non-HDL cholesterol
o Apolipoproteins A1 and B, and ApoB/ApoA1 ratio

Occurrence of mean LDL cholesterol < 100 mg/dL (mean LDL calculated over weeks 12 to 28, 
and weeks 36 to 52 of treatment).
Blood pressure effect

Occurrence of achieved antihypertensive treatment goal (SBP < 130 mmHg systolic and 
DBP < 80 mmHg) based on the mean SBP and mean DBP calculated over weeks 12 to 28 and 
36 to 52 of treatment with study drug.
HRQoL and EQ5D 5L benefits

Change from BL to the average value of weeks 12 to 28 and 36 to 52 in:
o Physical Component Score (PCS) of SF-36
o Anemia Subscale (“Additional Concerns”) of Functional Assessment of Cancer 
Therapy-Anemia (FACT-An) Score
o Total FACT-An Score
o EQ-5D 5L VAS Score
o WPAI:ANS Score

PGIC (qualitatively by assessment)
Iron, HbA1c, and CKD progression

Changes from BL to each scheduled measurement in:
o Serum ferritin
o TSAT
o HbA1c level
o Fasting blood glucose
o eGFR (including eGFR slope over time)
o Urine albumin/creatinine ratio

Serum creatinine having doubled during the study in comparison with baseline

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 30 of 160
Version 3.0, Incorporating Substantial Amendment 2

Occurrence of End Stage Renal Disease (ESRD)
Safety:
Safety will be assessed by evaluating the following:

Occurrence of AEs, SAEs, treatment emergent adverse events (TEAEs), treatment emergent 
serious adverse events (TESAEs), and clinically significant changes in laboratory values from BL.

Changes from BL in vital signs, electrocardiogram (ECG) findings, and clinical laboratory values.

Occurrence of prespecified adjudicated cardiovascular and cerebrovascular events.
Statistical Methods
Sample Size Justification:
Approximately 570 subjects will be randomized to receive roxadustat or darbepoetin alfa as follows:
Table 4: Sample Size Calculations per Treatment Arm 
Treatment Group
Protocol version 1.0
Protocol versions 2 and 3
Total
Randomized
PPS
Randomized†
PPS
Randomized
PPS
Roxadustat
100
80
210
168
310
248
Darbepoetin alfa
50
40
210
168
260
208
Total
150
120
420
336
570
456
† The number of subjects under protocol v2 and v3 will depend on the number of subjects randomized under 
protocol v1.
Randomization will be stratified by the following four factors:

Region: region A versus region B*
* Assignment to region will be determined based on health care comparability.

Screening Hb values (≤8.0 g/dL versus > 8.0 g/dL)

History of cardiovascular, cerebrovascular or thromboembolic diseases (Yes versus No)

eGFR (< 30 mL/min/1.73 m2 versus ≥30 mL/min/1.73 m2).
Assuming that the PPS analysis will consist of 80% of subjects in the Full Analysis Set (FAS), 
570 randomized subjects in the FAS will lead to 456 subjects in the PPS. Two hundred and forty 
eight (248) subjects for the roxadustat treatment group and 208 subjects for the darbepoetin alfa 
treatment group will provide at least 98% test power to demonstrate statistically non-inferiority of 
roxadustat versus darbepoetin alfa in the primary endpoint assuming that the proportion of subjects 
with response in both groups is the same and at least 80% and a non-inferiority margin for the 
difference of proportions of 15%. The power for the sensitivity analysis of post-amendment data 
(336 subjects) will be at least 93%.
Analysis Sets
The following analysis sets are defined and will be used for the statistical analysis:

Intent-to-Treat (ITT)

Full Analysis Set (FAS)

Per-Protocol Set (PPS)

Safety Analysis Set (SAF)

Pharmacokinetic Analysis Set (PKAS)
Efficacy:
Analysis of Primary Endpoint 
The difference in the proportion of responders in the primary efficacy endpoint between pooled 
roxadustat and darbepoetin alfa will be calculated using Mattinen & Nurminen approach adjusting for 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 31 of 160
Version 3.0, Incorporating Substantial Amendment 2
the stratification factors. The primary hypothesis to be tested for the primary efficacy analysis is:
H0: Hb responder rate in the pooled roxadustat group < Hb responder rate in the darbepoetin alfa 
group minus 15%
versus
H1: Hb responder rate in the pooled roxadustat group ≥Hb responder rate in the darbepoetin alfa 
group minus 15%
This null hypothesis will be rejected if the two-sided 95% confidence interval for the difference of 
proportions lies entirely above -15%.
In addition, a 95% CI will be calculated for the proportion of responders on roxadustat and
darbepoetin alfa based on the exact method of Clopper-Pearson. Sensitivity analyses will be 
conducted to assess the consistency of the results before and after protocol amendments 1 and 2.
Efficacy:
Analysis of Key Secondary Endpoints
Once the primary hypothesis has been rejected for the primary endpoint, the key secondary variables 
will be tested using a fixed sequence testing procedure as follows:
1.
Hb change from BL to the average Hb of weeks 28 to 36 (non-inferiority of pooled roxadustat 
versus darbepoetin alfa) without having received rescue therapy within 6 weeks prior to and 
during this 8-week evaluation period. The non-inferiority margin for the difference between 
groups is 0.75 g/dL.
2.
LDL cholesterol change from BL to the average of weeks 12 to 28 (superiority of pooled 
roxadustat versus darbepoetin alfa).
3.
Mean monthly IV iron (mg) use per subject during weeks 1 to 36 (superiority of pooled 
roxadustat versus darbepoetin alfa).
4.
SF-36 PF sub-score change from BL to the average of weeks 12 to 28 (non-inferiority of pooled 
roxadustat versus darbepoetin alfa). The non-inferiority margin is fixed as a difference of 3 points.
5.
SF-36 VT sub-score change from BL to the average of weeks 12 to 28 (non-inferiority of pooled 
roxadustat versus darbepoetin alfa). The non-inferiority margin is fixed as a difference of 3 points.
6.
MAP change from BL to the average MAP of weeks 20 to 28 (non-inferiority of pooled 
roxadustat versus darbepoetin alfa). The non-inferiority margin for the difference between groups 
is 1 mmHg.
7.
Incidence of hypertension (non-inferiority of pooled roxadustat versus darbepoetin alfa). The non-
inferiority margin is fixed as a hazard ratio of 1.3.
8.
MAP change from BL to the average MAP of weeks 20 to 28 (superiority of pooled roxadustat 
versus darbepoetin alfa).
9.
Incidence of hypertension (superiority of pooled roxadustat versus darbepoetin alfa).
The primary analysis set will be PPS for the non-inferiority tests and FAS for the superiority tests.
Pharmacokinetics:
Population PK data will be generated for roxadustat from a timed blood sampling scheme. All details 
of the population PK (PPK) analysis will be described in a separate analysis plan and a separate PPK 
modeling report will be written.
Pharmacodynamics:
Pharmacodynamic data may be submitted to population pharmacodynamic or population 
pharmacokinetic/pharmacodynamic (PPKPD) modeling. When deemed necessary, data from this 
study may be combined with data from other studies. Results will be reported in a separate PPKPD 
modeling report.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 32 of 160
Version 3.0, Incorporating Substantial Amendment 2
Safety:
Safety analyses will be performed using the Safety Analysis Set (SAF). Safety parameters include 
AEs, SAEs, laboratory parameters (with special emphasis on excessive Hb response and liver 
function tests [LFTs]), vital signs, and ECG parameters.
The number and percentage of subjects reporting TEAEs and TESAEs in each treatment group will be 
tabulated. Descriptive statistics will be presented for laboratory parameters, vital signs values and 
ECG parameters by visit and for the changes from BL to each visit.
The statistical method for analysis of adjudicated safety data will be detailed in a pooled
cardiovascular safety Statistical Analysis Plan (SAP).
Safety data and dosing decisions will be monitored on an ongoing basis. Ongoing review of safety 
data will be conducted by an independent DSMB.
Interim Analyses:
An interim analysis will be performed when all subjects have completed 36 weeks of treatment;
efficacy and safety data will be analyzed and reported, excluding the endpoints measured after 
36 weeks. Since all primary and secondary analyses have been defined over this period of time, no 
multiplicity adjustment is required as the information fraction at the interim analysis is 100%.
In addition, a descriptive analysis on both safety and efficacy will be performed to provide 
information from this study for regulatory filings of roxadustat in case the planned interim analysis 
has not been reached. This will include only descriptive statistics by arm (i.e., without formal 
hypothesis testing).
Once the study is completed, efficacy and safety will be analyzed again and reported including the 
complete study treatment of 104 weeks.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 33 of 160
Version 3.0, Incorporating Substantial Amendment 2
V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS
Flow Chart
STUDY DESIGN 3.0

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 34 of 160
Version 3.0, Incorporating Substantial Amendment 2
Table 1
Schedule of Assessments
Assessments
Screening 
Period
Treatment Period
(Correction Period and Maintenance Period)
Follow-up Period
Unscheduled 
Visits
Post study 
Follow-up c
Visit / Week
Up to6 
weeks a
Day 1b
Weekly
(wks 1 - 2)
± 2 days
Every 2 Weeks 
(wks 4 - 24)
± 2 days
Every 4 Weeks 
(wks 28 - 100)
± 3 days
EOT c
(wk 104)
± 3 days
EOTc + 2 wks
± 3 days
EOS c
(EOT + 4 wks)
± 3 days
Every 6 months 
until projected 
wk 108
S1
S2
Written informed consent
X
Randomization
X
Eligibility criteria
X
X
Demographics
X
Medical history
X
Physical examination  
X
X
wks 12d, 24d 
wks 36d, 52d, 76d
X
Xd
Od
Heighte, weight
X
X
wks 12, 24
wks 36, 52, 76
X
X
O
Blood pressuref, heart ratef, respiratory rateg
X
X
X
X
X
X
X
X
O
CBC with WBC diff, red cell indices and 
platelets
X
X
X
wks 4, 8, 12, 20
wks 28, 36, 44, 52, 
60, 68, 76, 84, 92, 
100
X
X
O
Hemoglobinh
Xi
X
X
X
Oi1
HemoCue assessmentj
X
X
X
X
O
Reticulocyte count and Hb in reticulocytes 
(CHr)
X
X
X
wks 4, 6, 8, 12, 16, 
20
wks 28, 36, 44, 52, 
60, 68, 76, 84, 92, 
100
X
X
O
12-lead ECG 
X
X
wks 12, 24
wks 36, 52, 76
X
O
Serum chemistry
X
X
wks 4, 8, 12, 20
wks 28, 36, 44, 52, 
60, 68, 76, 84, 92, 
100
X
X
X
O
LFTsk
wk 2
wks 6, 16
O
Renal ultrasoundl
X
O
Serum lipid panelm
X
X
wks 4, 8, 12, 20 wks 28, 36, 44, 52, 
68, 84
X
X
O
Serum iron, ferritin, TIBC, TSAT
X
X
wks 4, 8, 12, 20
wks 28, 36, 44, 52, 
60, 68, 76, 84, 92, 
100
X
X
O
HbA1c
X
X
wk 12
wks 28, 36, 44, 60, 
84
X
X
O
Vitamin B12, folate
X
HIV immunoassay, HBsAg, 
anti-HCV antibody
X
Serum pregnancy testn
X
wks 12, 24
wks 36, 48, 60, 72, 
84, 96
X
O
Table continued on next page

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 35 of 160
Version 3.0, Incorporating Substantial Amendment 2
Assessments
Screening 
Period
Treatment Period
(Correction Period and Maintenance Period)
Follow-up Period
Unscheduled 
Visits
Post study 
Follow-up c
Visit / Week
Up to6 
weeks a
Day 1b
Weekly
(wks 1 - 2)
± 2 days
Every 2 Weeks 
(wks 4 - 24)
± 2 days
Every 4 Weeks 
(wks 28 - 100)
± 3 days
EOT c
(wk 104)
± 3 days
EOTc + 2 wks
± 3 days
EOS c
(EOT + 4 wks)
± 3 days
Every 6 months 
until projected 
wk 108
S1
S2
eGFRo
X
X
wk 20
wks 36, 52, 68, 84
X
X
O
hs-CRP
X
wks 4, 12, 20
wks 36, 52
X
X
Archival serum samples for biomarkersp
X
wks 4, 12, 20
wks 52, 76
Blood sample for PKq
wks 2 to 8
Genotypingr
O
QoL questionnairess
X
wks 8, 12 
wks 28, 36, 52, 76
X
O
Urinary testingt
X
wks 12, 24
wks 36, 52, 64, 76, 
88
X
O
Archival urine samples for biomarkers
X
wk 24
wks 52, 76
Study drug dispensingu
├────────────────────────────┤
O
Dose adjustment reviewv
X
X
X
O
Hospitalization recordingw
X
X
◄─────────────────────────────────────────────────────────────►
X
AE recording
X
X
◄─────────────────────────────────────────────────────────────►
Concomitant medication, procedure and non-
drug therapy recording
X
X
◄─────────────────────────────────────────────────────────────►
Vital status, SAEs, cardiovascular and 
thromboembolic AEsw
X
S1/S2 = Screening visit 1and 2; EOT = End of Treatment; EOS = End of Study; Wk(s) = Week(s); X = mandatory test/assessment; O = optional test/assessment.
Note: see Appendix 12.4 Instructions for Subjects Requiring Dialysis.
a The requirement of a 4-day separation between the screening Hb values defines the minimum duration of the screening period. The maximum duration of the screening period is 6 
weeks. Sites are recommended to schedule the two screening visits in the shortest time span possible.
b All study assessments are to be performed prior to first study drug administration.
c In case of premature treatment discontinuation or withdrawal during the treatment period, subjects will complete the EOT visits (EOT visit and EOT + 2 weeks visit) and EOS 
visit. Thereafter, subjects who have taken at least one dose of study drug will continue to be followed up at a 6-monthly frequency for vital status, SAEs, cardiovascular and 
thromboembolic AEs until their projected date of completion of the follow-up period (i.e., projected week 108 date) or until consent withdrawn.
d Targeted physical examination only (e.g., respiratory and cardiovascular).
e Height measurement only required at first screening visit.
Footnotes continued on next page

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 36 of 160
Version 3.0, Incorporating Substantial Amendment 2
f Blood pressure and heart rate measured singly during the screening period, and in triplicate at all other visits. It is recommended during the treatment period that measurements 
should occur prior to study drug administration if study medication is taken on same day of visit; except for visits where subjects are instructed to take study medication at home 
for PK sampling purpose. For subjects requiring dialysis, BP and heart rate will be recorded prior to and after dialysis (hemodialysis [HD]/hemodiafiltration [HDF] subjects only).
g Respiratory rate measured singly during screening period and all other visits. It is recommended during the treatment period that measurement should occur prior to study drug 
administration except for visits where subjects are instructed to take study medication at home for PK sampling purposes. For subjects requiring dialysis, respiratory rate will be 
recorded prior to dialysis (HD/HDF subjects only).
h Separate Hb should be collected at all the visits where Complete Blood Count (CBC) is not collected (i.e., Hb at weeks 6, 10 until the end of the study).
i An additional (third) Hb value may be collected if necessary. Only for subjects who are switched from protocol version 2.0 to 3.0 during (re) screening can a fourth Hb value be 
collected, as was applicable under protocol version 2.0.
i1 If during an unscheduled visit, Hb needs to be assessed, this should always be done with the HemoCue AND a central laboratory Hb assessment.
j If during an unscheduled visit Hb needs to be assessed, this should always be done with the HemoCue AND a central laboratory Hb assessment. This HemoCue assessment should 
be done on the blood sample that is collected for Hb analysis for the central laboratory.
k In addition to LFTs collected as part of Serum Chemistry, LFTs will separately be collected at the indicated weeks.
l Renal ultrasound examination within 12 weeks prior to randomization. Not required if results of a previous renal ultrasound (or other renal imaging modality such as CT scan or 
MRI) within 12 weeks prior to randomization is available and ruling out renal cell carcinoma. If other imaging modality, a conclusive report on the kidney should be available.
m Fasting whenever possible.
n Collect from female subjects of childbearing potential only.
o Using Modification of Diet in Renal Disease (MDRD) formula; calculated by the central laboratory.
p At day 1, week 20, 52, and 76, two equal volume samples should be collected.
q Sampling roxadustat will be done at 6 time points over 1 to 3 visits between weeks 2 and 8. See Section 5.6. At each pharmacokinetic visit, one additional sample will be collected 
for determination of Alpha 1-Acid Glycoprotein (α1-AGP) and albumin concentration.
r Optional assessment for subjects treated with roxadustat. A separate informed consent form must be signed before genotyping sample is collected. Sample collection can be done 
at any timepoint throughout the treatment period of the study.
s Including SF-36, FACT-An, EQ-5D 5L, PGIC and WPAI:ANS. PGIC will not be performed on day 1. Questionnaires to be completed by the subject preferably prior to any study 
assessments. When subjects need dialysis therapy, Quality of Life (QoL) questionnaires will be completed on the day of first dialysis (preferably before the dialysis is started), 4 
weeks later and 12 weeks later.
t Ideally, the sample should be from the first morning void. Urinary testing includes qualitative testing with dipstick testing (for protein, pH, glucose) and quantitative assessment of 
albumin and creatinine for calculation of albumin/creatinine ratio.
u Dosing of darbepoetin alfa per EU SmPC.
v Subjects randomized to roxadustat: dose adjustment review from week 4 onward, and every 4 weeks thereafter until EOT (wks 4, 8, 12 etc), except in the event of excessive 
hematopoiesis or Hb ≥13.0 g/dL. If next dose adjustment interval falls on a non-visit study week, the dose adjustment review should be performed at the next scheduled visit.
w Telephone or in-person follow-up call with subject.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 37 of 160
Version 3.0, Incorporating Substantial Amendment 2
1
INTRODUCTION
1.1
Background
1.1.1
Epidemiology of Chronic Kidney Disease and End Stage Renal Disease
Chronic Kidney Disease (CKD) is a growing worldwide public health challenge associated 
with significant morbidity and mortality, yet it is under-diagnosed and under-treated. It is 
characterized by progressive loss of kidney function, ultimately resulting in premature death 
or renal replacement therapy (kidney transplant or dialysis). In 2007, CKD affected 13% of 
the US adult population (approximately 29 million US adults) and its prevalence is growing 
rapidly [Coresh et al, 2007]. In Europe, the average prevalence of CKD regardless of age lies 
between 5 and 11% [Zoccali et al, 2010]. All-cause mortality risk increases exponentially as 
CKD stages advance [Tonelli et al, 2006]. 
The number of CKD patients suffering from End Stage Renal Disease (ESRD) also continues 
to increase worldwide. The US has one of the highest prevalence rates of ESRD in the 
world: in 2010, the US had over 1700 ESRD patients per million population, a 23% increase 
compared to 10 years prior (United States Renal Data System [USRDS, 2011]. In 2009, 
there were approximately 570,000 ESRD patients in the US, of whom 370,000 were 
receiving hemodialysis, 27,000 were receiving peritoneal dialysis, and 173,000 had a 
functioning kidney transplant [USRDS, 2011]. In Europe, over the period 1992–2005, the 
overall crude prevalence of renal replacement therapy (RRT) for ESRD increased from 480 
to 807 patients per million population [Zoccali et al, 2010].
The average expected remaining lifetime of a dialysis patient in the US is 5.9 years, 
compared to 16.4 years for a transplant patient, and 25.2 years for someone of comparable 
age in the general population [USRDS, 2009]. The prevalence of ESRD is projected to grow 
to 774,000 by the year 2020 [USRDS, 2009]. Data from selected countries in Europe 
indicate that the five-year mortality rates in incident RRT patients are 52% in all patients, and 
21%, 32% and 73% for patients 0 to 14, 15 to 64 and over 65 years of age, respectively 
[Zoccali et al, 2010].
1.1.2
Anemia Associated with CKD
Anemia is a common complication in patients with CKD, and although its pathogenesis is 
multi-factorial, the decreased production of erythropoietin (EPO), a hormone produced 
primarily in the kidneys, is considered an important etiologic factor. The impaired ability of 
the body to absorb and utilize iron is likely another etiologic factor.
Anemia may first present in early stages of CKD, and its prevalence increases as CKD 
progresses. Anemia is present in 17% of patients with late Stage 3 CKD; this increases to 25% 
in patients with Stage 4 CKD, and 49% in patients with Stage 5 CKD who have not yet 
progressed to requiring dialysis [Coresh et al, 2007; Go et al, 2004]. Over 90% of patients 
undergoing dialysis are anemic: 50.1% of the dialysis patients had hemoglobin (Hb) levels 
below 10 g/dL and approximately 28% had Hb below 9 g/dL [USRDS, 2003]. Some studies
from Europe provide data on anemia rates in patients who have been under care of 
nephrologists. In 1999 Jungers prospectively studied 403 consecutive ambulatory pre-dialysis 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 38 of 160
Version 3.0, Incorporating Substantial Amendment 2
patients and found that 60% of patients with a creatinine clearance of < 20 mL/min/1.73 m2
were anemic (Hb <11 g/dL) [Jungers et al, 2002]. Between 2003 and 2005 Thilly studied 
pre-dialysis anemia care in 6271 incident dialysis patients. The average level of pre-dialysis 
Hb was 10.3 g/dL and 63.6% of the patients had a Hb value lower than 11 g/dL [Thilly et al, 
2008].
The clinical consequences of anemia in patients with CKD have been studied extensively. 
Because the main impact of anemia on organ function is reduced oxygen delivery to tissues, 
it affects almost every organ system.
Anemia contributes to the excess morbidity and mortality in CKD and ESRD. In patients 
with CKD, the severity of anemia correlates directly with the risk of hospitalization, 
cardiovascular disease, and death [Collins et al, 1998]. Patients with the lowest Hb have 
worse outcomes, as was discussed in the post hoc analysis of mortality by Hb quintiles for 
the Normal Hematocrit and Correction of Hemoglobin and Outcomes in Renal Insufficiency 
(CHOIR) studies in the Food and Drug Administration (FDA) briefing document for the 
October 2007 Cardiovascular and Renal Drugs Advisory Committee [Unger, 2007]. Similar 
data are found in the USRDS mortality data stratified by Hb. All-cause mortality stratified 
by Hb (1993–1996) showed significantly higher first-year death rates in patients with Hb 
levels < 9 and 9 to < 10 g/dL, compared to 11 to <12 g/dL. This trend continued to worsen, 
as reflected in 1998–1999 data, where the death rate rose by approximately 75% compared to 
the 1993-1996 period [USRDS, 2000; USRDS, 2002]. This increase coincides with the 
introduction of the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines in 1997. 
The relative risk of all-cause mortality for patients with Hb <9 g/dL is twice that of patients 
with Hb > 12 g/dL [USRDS, 2002]. The relative risk of cardiovascular hospitalization 
increased significantly to 1.26 in patients with Hb levels < 9 g/dL compared to those with Hb 
at 11 to 12 g/dL [USRDS, 2001].
Multiple studies have shown that treatment of anemia reduces the need for blood transfusions 
and improves health-related quality of life (HRQoL) [NKF KDOQI, 2007].
1.1.3
Treatment of Anemia
In less severe anemia first-line therapy consists of iron monotherapy (oral or intravenously). 
However, therapy with erythropoiesis-stimulating agents (ESAs) in combination with iron 
supplementation is a major alternative to transfusion in managing more severe anemia 
associated with CKD. Anemic patients with CKD or ESRD will require life-long treatment. 
For those patients not resistant to ESAs, parenteral administration of exogenous recombinant 
human erythropoietin (epoetin alfa or beta) or pegylated analogues has been a widely 
accepted approach for treatment of anemia in patients with CKD [Eschbach et al, 1987; 
Eschbach & Adamson, 1989; Winearls et al, 1986; US Recombinant Human Erythropoietin 
Predialysis Study Group, 1991], despite the documented safety risks such as hypertension 
and thrombosis.
Although the treatment of anemia in CKD and ESRD is thought to contribute positively to a 
patient’s quality of life (QoL), functional well-being and physical performance, several 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 39 of 160
Version 3.0, Incorporating Substantial Amendment 2
studies in ESRD and nondialysis-dependent chronic kidney disease (NDD-CKD) patients 
have shown higher mortality or trends in that direction in the higher-dosed ESA-treated 
cohorts when the protocol objective was to treat to high target Hb levels [Besarab et al, 1998; 
Drüeke et al, 2006; Singh et al, 2006].
An ESA dose relationship to mortality has been reported in a review of the USRDS database 
[Zhang et al, 2004] of ESRD patients who received higher ESA doses. A treatment option 
that avoids supraphysiologic levels of circulating plasma EPO levels may be a safer 
alternative.  Additionally, ESA therapy for anemia in ESRD patients on hemodialysis usually 
requires concomitant intravenous (IV) iron supplementation.
There is currently an unmet medical need for an oral treatment that will correct anemia in 
NDD-CKD and dialysis-dependent chronic kidney disease (DD-CKD) patients to a target Hb 
level that is safe and well tolerated.
Roxadustatb is an oral medication that could potentially deliver effective treatment for 
CKD-related anemia with less need for iron supplementation and without producing 
supraphysiologic levels of circulating EPO.
1.2
Non-clinical and Clinical Data
1.2.1
Mechanism of Action of Roxadustat
Virtually all tissues depend on a sufficient supply of oxygen for survival. Lack of oxygen 
associated with hypoxic, ischemic, and anemic conditions triggers a series of homeostatic 
responses (Figure 1). Hypoxia-inducible factor (HIF) is a transcription factor that is believed 
to be the key element in the body’s oxygen sensing mechanism [Semenza, 2000]. HIF 
regulates expression of genes that modulate both the acute and chronic response to hypoxia,
and HIF-responsive genes regulate processes as diverse as erythropoiesis, iron metabolism, 
oxidation, cellular metabolism, glycolysis, vasculogenesis, cell cycle progression, and 
apoptosis. Chronic hypoxia and intermittent hypoxia induce different sets of genes 
associated with HIF transcriptional activity [Fan et al, 2005]. HIF is a heterodimeric 
transcription factor family comprising three oxygen-sensitive isoforms (HIF-1, HIF-2and 
HIF-3), and a constitutively expressed HIF-1subunit, with each heterodimeric isoform 
responsible for the induction of specific sets of genes [Greijer et al, 2005; Hu et al, 2003].
For example, HIF-1has been shown to regulate vascular endothelial growth factor 
expression [Gray et al, 2005; Büchler et al, 2003], while HIF-2is critical for the induction 
of the EPO gene and erythropoiesis [Warnecke et al, 2004; Scortegagna et al, 2005].
                                                
b The originator of the compound under study is FibroGen Inc and the code name used by FibroGen Inc is 
FG-4592. Astellas is the development partner and uses the code name ASP1517. The sponsor of this study is 
Astellas. The compound has received the INN roxadustat.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 40 of 160
Version 3.0, Incorporating Substantial Amendment 2
Figure 1
HIF-PHI Mechanism of Action
Source: Epstein, et al. Cell, 2001.
HIF target genes are expressed when the active heterodimer binds to a conserved 
deoxyribonucleic acid (DNA) motif found within all HIF target genes, termed the hypoxia 
response element, and in cooperation with other co-activators initiates de novo transcription. 
One of the most sensitive and well-studied HIF-responsive genes is the EPO gene. Increased 
transcription of the EPO gene leads to increased circulating levels of EPO, which acts at sites 
of erythropoiesis to enhance the differentiation and proliferation of red blood cell (RBC)
precursors.
Although HIF-isoforms are constitutively produced, their accumulation under normoxic 
conditions is prevented by recruitment and binding by the Von Hippel-Lindau protein, which 
targets HIF-isoforms for degradation through the ubiquitin-proteasome pathway. The 
molecular mechanism for oxygen-dependent degradation of HIF-is based on the 
hydroxylation of specific proline residues, as catalyzed by a family of hypoxia-inducible 
factor prolyl hydroxylases (HIF-PH) that utilize molecular oxygen as the substrate for 
hydroxylation. Thus, HIF-PH constitutes the body’s main oxygen sensor by regulating the 
prevalence and activity of nuclear HIF protein. Under hypoxic conditions, HIF-PHs are 
inactive and lead to initiation of the HIF-responsive transcriptional cascade [Wang et al, 
1995; Semenza, 1998].
Roxadustat is a potent and reversible hypoxia-inducible factor prolyl hydroxylase inhibitor 
(HIF-PHI) that transiently induces HIF stabilization and leads to a functional HIF 
transcriptional response that mimics the erythropoietic response associated with exposure of 
humans to intermittent hypoxia. HIF induces expression of not only EPO, but also the EPO 
receptor and proteins that promote iron absorption and recycling [Peyssonnaux et al, 2008].  
Thus, roxadustat pharmacologically stimulates erythropoiesis via the HIF pathway and in a 
manner consistent with the body’s normal homeostatic response to anemia, but under 
normoxic conditions.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 41 of 160
Version 3.0, Incorporating Substantial Amendment 2
Roxadustat also has the potential to effectively treat anemias caused by inflammation-
induced functional iron deficiency, which are typically hyporesponsive to ESAs. In these 
conditions, iron availability for erythropoiesis is reduced due to a number of inflammatory 
mediators. Because HIF-PHIs such as roxadustat alter expression not only of the EPO gene 
but also of genes regulating iron metabolism, it is postulated that roxadustat may be effective 
in treating these anemias as well [Langsetmo et al, 2005].
Chronic hypoxia and intermittent hypoxia induce different sets of genes associated with HIF 
transcriptional activity, presumably because intermittent stimulation allows the restoration of 
HIF degradation, turnover, and inactivation. Transient activation of HIF thereby precludes 
sustained gene expression and the induction of genes that are expressed late after HIF 
activation, as well as expression of additional genes that are secondary to activation of 
HIF-dependent genes. Both non-clinical and clinical studies of roxadustat have successfully 
used the intermittent dosing paradigm to induce selective erythropoiesis and to optimize the 
Hb dose response. Furthermore, roxadustat was selected for development over other 
HIF-PH-inhibiting candidate molecules based on an optimal biodistribution profile that 
enhances its selective actions. The specific tissues where roxadustat enters the cytoplasm 
and triggers gene expression reside in the main target organs for erythropoiesis: the kidney 
(EPO production), the bone marrow (increase in EPO receptors), the duodenum 
(transepithelial iron transport), and the liver (EPO production and down-regulation of 
hepcidin production); roxadustat distributes preferentially to these organs.
1.2.2
Clinical Experience with Roxadustat
Roxadustat is currently being studied in DD-CKD and NDD-CKD subjects with anemia. 
Numerous Phase 1 and 2 clinical studies have been completed in the United States, Europe 
and Asia. Information from these studies is provided in the Investigator’s Brochure. As of 
07 September 2014, an estimated total of 1,485 subjects have been exposed to roxadustat in 
the clinical development program, comprising 571 healthy subjects and an estimated 
483 subjects with NDD-CKD and 431 subjects with DD-CKD. In completed studies, 
subjects with CKD have received up to 24 weeks of roxadustat, in doses of up to 3.0 mg/kg.
In completed Phase 1 studies, healthy subjects received single doses of roxadustat up to 
4.0 mg/kg and repeat doses up to 3.75 mg/kg three times a week for 4 weeks. In a completed 
thorough QT study in healthy subjects, single doses up to 5 mg/kg were administered, 
without evidence of QT prolongation. The clinical data collected thus far suggest that 
roxadustat is generally safe and well tolerated in healthy adult subjects, and in DD-CKD and 
NDD-CKD subjects with anemia who have been treated in the completed and ongoing 
studies.
1.2.2.1 Pharmacokinetics and Pharmacodynamics
The pharmacokinetics (PK) and pharmacodynamics (PD) of roxadustat were characterized in 
studies in healthy subjects and in DD-CKD and NDD-CKD subjects. Roxadustat showed 
generally dose proportional PK (except at the lowest dose of 0.3 mg/kg); t1/2 was 12 to 
14 hours in healthy subjects, and 15 to 19 hours in dialysis subjects (after single doses of 
1 and 2 mg/kg). The exposure was higher in dialysis subjects compared to healthy subjects.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 42 of 160
Version 3.0, Incorporating Substantial Amendment 2
A relative bioavailability study was conducted in 24 healthy subjects comparing the capsule 
formulation, which was used in phase 1 and phase 2, with the tablet formulation which was 
developed for phase 3. PK parameters were comparable between the two formulations.
With an intermittent dose regimen of once weekly (QW), twice weekly (BIW) or three times 
weekly (TIW), no or limited accumulation in mean area under the plasma concentration (AUC) 
or maximum concentration (Cmax) was observed. Furthermore no evidence was found for time-
dependent PK (no auto-induction or inhibition). Roxadustat is highly protein bound and the PK 
of roxadustat is not affected by dialysis. Metabolites found in urine suggested phase 2 
metabolism as the major metabolic pathway. In plasma, parent roxadustat is the main 
component. The inhibitory potential of roxadustat on cytochrome P450 (CYP) enzymes, based 
on in vitro studies is limited, and the lowest inhibition constant (Ki) value was observed for 
CYP 2C8 (16 μM). In a clinical drug-drug interaction study with rosiglitazone, a probe drug 
for CYP 2C8, roxadustat did not show any inhibitory potential on CYP 2C8 in vivo.
Roxadustat increases the AUCinf of simvastatin 1.9-fold; of rosuvastatin 2.9-fold; and of 
atorvastatin 2.0-fold. The AUCinf of roxadustat is decreased 2.9-fold and 1.8-fold 
respectively by simultaneous administration with the phosphate-binders sevelamer carbonate 
and calcium acetate. Administration of roxadustat at least 1 hour before or 1 hour after the 
phosphate binder minimized the interactions.
In healthy adult male volunteers (Study FGCL-SM4592-016), roxadustat administered orally 
as a single dose up to 4.0 mg/kg, and QW, BIW, or TIW for 4 weeks at doses up to 
3.75 mg/kg, was pharmacodynamically active as evidenced by dose-dependent transient 
increases in endogenous EPO (starting from single doses of 0.3 mg/kg), increases in 
reticulocytes (starting from doses of 2 mg/kg), and Hb responses (starting at 3 mg/kg). The 
mean peak level of plasma EPO following the day 26 dose of 2.0 mg/kg TIW (the high 
therapeutic dose studied) was 326.3 ± 197.0 mIU/mL.
In PD studies conducted with roxadustat in CKD subjects not on dialysis 
(Study FGCL-4592-017), the mean maximum EPO increase from BL ranged from 82-443 
and 492-554 mIU/mL after a single 1 and 2 mg/kg dose, respectively. In dialysis subjects
(Study FGCL-4592-039), comparable dose-dependent increases in EPO levels were 
observed, both pre-dialysis and post-dialysis. These increases in endogenous EPO were 
transient and the effect disappeared within approximately 48 hours.
In contrast, EPO levels associated with therapeutic ESA dosing range from 1,500 to over 
10,000 mIU/mL [Besarab et al, 2009]. In a clinical study with dialysis subjects, the reported 
mean administered individual ESA dose was 8,000 IU, which would correspond to plasma 
EPO Cmax levels exceeding 3,000 mIU/mL [Fishbane & Besarab, 2007]. This is approximately 
10-fold higher than the physiologic range.
1.2.2.2 Efficacy
Data from a 4-week treatment study in anemic CKD subjects not on dialysis 
(Study FGCL-SM4592-017) showed that roxadustat promoted erythropoiesis at lower doses 
in CKD subjects than in healthy volunteers. In contrast to the classical paradigm suggesting 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 43 of 160
Version 3.0, Incorporating Substantial Amendment 2
that anemia in CKD subjects is caused by the inability of these subjects to produce EPO, the 
results of this study suggest that the EPO production in this patient population is sufficient to 
achieve a robust erythropoiesis. With roxadustat 0.7 mg/kg TIW dosing, mean maximum Hb 
increased by 1.0 g/dL over a 6-week period in anemic CKD subjects who completed 4 weeks 
of dosing; more robust mean Hb increases of 2.0 to 2.3 g/dL occurred at roxadustat doses of 
1.5 and 2.0 mg/kg TIW, respectively. Hemoglobin responder (Hb increase of ≥1.0 g/dL) 
rates were 62%, 60%, 91%, and 100% in the roxadustat 0.7, 1.0, 1.5, and 2.0 mg/kg TIW 
cohorts, respectively. The Hb responses were also robust at the higher roxadustat doses (1.5 
to 2.0 mg/kg) in the BIW dosing groups. With the additional criterion that Hb achieves a 
level of ≥11.0 g/dL as well as increasing by ≥1.0 g/dL, the Hb responder rate with 
roxadustat 2.0 mg/kg was 89% and 91% in BIW and TIW dosing, respectively. The rapid 
rates of rise in Hb with roxadustat treatment were not accompanied by elevations in blood 
pressure, as has been reported with ESA treatment [Eschbach et al, 1989].
Data from a completed 16- to 24-week treatment study in CKD subjects not on dialysis 
(Study FGCL-4592-041) showed absolute and weight-based doses of roxadustat, administered 
TIW and BIW, effectively corrected Hb levels in these subjects. Corrected Hb levels were 
maintained within target range for the 16- or 24-week treatment period at TIW and BIW 
dosing and were generally maintained even with conversion to once weekly dosing. The 
median time to Hb response was 28 days for subjects who received adequate weight-based or 
absolute starting doses of roxadustat and longer for those who received a lower absolute 
starting dose. Treatment with roxadustat in these anemic CKD patients led to positive changes 
or trends for positive changes from baseline in subscales of the SF-36 QoL questionnaire 
(Vitality, Mental Component, and Social Functioning). Dose-response trends suggested that 
starting doses of 1.0−1.6 mg/kg roxadustat administered TIW are appropriate to correct Hb 
levels during 4 weeks of treatment in NDD-CKD subjects. Dosing frequency reduction, once 
Hb correction is achieved, appears to be feasible to maintain Hb in the target range.
Data from a 6- and 19-week treatment study in ESRD subjects on dialysis showed the feasibility 
of converting subjects from a stable ESA dose to roxadustat (Study FGCL-4592-040). In the 
6-week dose range portion of this conversion study (during which roxadustat doses were mostly 
fixed upon switching from stable doses of epoetin alfa), dose response was observed. The 
1.0 mg/kg roxadustat dose was comparable to the epoetin alfa control, which had a small decline 
in Hb levels from BL and a lower percent Hb responder rate compared to the higher doses of 
roxadustat. The 1.5 and 2.0 mg/kg roxadustat dose arms resulted in a Hb increase of about 
1 g/dL from BL and an 89% response rate, more than double that of the epoetin alfa arm, despite 
the absence of IV iron supplementation; no restriction was made in the study protocol for the use 
of oral iron. Regression slope analyses of Hb values over time showed that the estimated rate of 
Hb rise was positive and statistically significant for the 1.5 and 2.0 mg/kg dose cohorts, with a 
Hb increase of 0.22 g/dL (p=0.0040) and 0.18 g/dL (p=0.0146) per week, respectively. In the 
19-week portion of the study, during which dose-titration was allowed, Hb maintenance was 
demonstrated to be durable in roxadustat treatment arms (combined) over a 19-week period.
For further information, refer to the most recent version of the Investigator Brochure.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 44 of 160
Version 3.0, Incorporating Substantial Amendment 2
1.2.2.3 Summary
In summary, roxadustat is an orally active HIF-PH inhibitor with potent erythropoietic 
effects. Repeated intermittent dosing of roxadustat results in intermittent activation of HIF, 
intermittent induction of endogenous EPO, and a dose-dependent erythropoiesis. The clinical 
data collected thus far suggest that roxadustat is generally safe and well tolerated in healthy 
adult subjects, and in DD-CKD and NDD-CKD subjects with anemia who have been 
enrolled and treated in completed and ongoing clinical studies. Roxadustat leads to a robust 
dose-related erythropoietic response in subjects with CKD-associated anemia. Roxadustat 
dosing induces a transient elevation in endogenous EPO level that is close to the physiologic 
range, but much lower than the plasma EPO level associated with IV ESA dosing, suggesting 
a coordinated erythropoiesis mechanism that is different from that of ESA therapy.
1.2.3
Clinical Experience with Darbepoetin alfa
The comparative drug darbepoetin alfa (Aranesp®) is approved since 2001 in the European 
Union (EU) for the treatment of anemia associated with chronic renal failure in adults and 
pediatric subjects. It is a commonly used ESA in Europe for the treatment of anemic 
NDD-CKD subjects and has demonstrated its ability to correct and maintain Hb in subjects in 
several controlled randomized trials.
Two exploratory dose- and schedule-finding studies (NESP-960245 and NESP-960246) 
investigated the effects of darbepoetin alfa for correction of anemia in hemodialysis (HD) and 
peritoneal dialysis subjects by IV and subcutaneous (SC) injection respectively. The results of 
both studies showed a clear dose-related effect of darbepoetin alfa by IV as well as by SC route 
and independent of the schedule (once or three times weekly). At two of the selected dose 
levels, 60% to 70% of subjects produced an optimal rate of rise in Hb, which was the primary 
endpoint, within the first 4 weeks (1g/dL). Based on the results of these studies it was 
concluded that 0.45 to 0.75 μg/kg of darbepoetin alfa administered once weekly IV or SC is the 
most appropriate starting dose for treatment of anemia in CKD subjects [Macdougall et al, 
2003].
The pharmacokinetic PK studies showed that darbepoetin alfa has a slower clearance and a 
significantly longer terminal half-life in CKD subjects when compared to recombinant 
human erythropoietin (r-HuEPO). There was no evidence of accumulation of darbepoetin 
alfa over time. There are no special precautions for use based on the pharmacokinetic PK 
data, although darbepoetin alfa should be used with caution in subjects with acute hepatic 
failure, as the liver is a likely route for drug elimination.
The two multi-center randomized open-label trials explored the correction of anemia in 
subjects on dialysis (NESP-980211) or pre-dialysis (NESP-980202). The aim of the studies 
was to correct anemia and maintain Hb concentration within a predefined target range for up to 
20 and 24 weeks, respectively. Subjects were randomized to receive darbepoetin alfa or 
r-HuEPO. The primary endpoint for both studies was defined as the proportion of subjects that 
achieved a Hb response (Hb increase of ≥1.0 g/dL from baseline and a Hb concentration of 
≥11.0 g/dL during the initial 24 weeks of treatment). The selected starting dose was 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 45 of 160
Version 3.0, Incorporating Substantial Amendment 2
0.45 μg/kg once weekly for darbepoetin alfa as suggested by the exploratory dose finding 
studies. The starting dose for r-HuEPO was approximately equivalent to this dose in 
study NESP-980202 (50 U/kg twice weekly), and 40% higher than this dose in NESP-980211 
(50 U/kg three times weekly) [Locatelli et al, 2001; EMEA, EPAR Aranesp, 2004].
In the first pivotal correction study (NESP-980202) r-HuEPO-naive subjects were not yet on 
dialysis and study drugs were administered by SC injection. A total of 129 subjects received 
darbepoetin alfa, 37 received r-HuEPO. A Hb response was achieved in 93% of subjects in the 
darbepoetin alfa group and 92% in the rHuEPO group. Subjects from this study had the option 
to extend dosing up to 104 weeks and were so eligible for long-term efficacy and safety.
In the second pivotal correction of anemia study (NESP-980211, US trial) subjects were on 
dialysis (mainly hemodialysis) and received study drugs by SC or IV injection route. A total 
of 122 subjects were randomized (darbepoetin alfa: 91; r-HuEPO: 31). A Hb response was 
achieved in 72% of subjects in the darbepoetin alfa group and 84% in the r-HuEPO group. 
This reflects the 40% higher starting dose for r-HuEPO in this trial.
Two pivotal phase 3 studies (NESP-970200 conducted in Europe and Australia with a study 
duration of 52 weeks, and NESP-980117 conducted in United states and Canada with a study
duration of 28 weeks) evaluated the ability of darbepoetin alfa to maintain hemoglobin in the 
predefined target range, when CKD subjects on dialysis and stable on r-HuEPO therapy, 
were converted to darbepoetin alfa therapy. Both studies indicate that darbepoetin alfa was 
not inferior to r-HuEPO. The lower boundary of the 95% CI for the difference in mean 
change in hemoglobin (darbepoetin alfa minus r-HuEPO) was far above the prespecified 
clinical acceptable difference of –1.0 g/dL for NESP-980117 as well as above the more 
rigorous criteria of –0.5 g/dL for the NESP-970200. This applied equally to per protocol and 
intention to treat analysis sets and demonstrates that darbepoetin alfa is not inferior to 
r-HuEPO for maintaining subjects Hb concentration within the predefined target range.
Data from one uncontrolled long-term safety study demonstrated that darbepoetin alfa once 
weekly/once every two weeks by the IV or SC route is safe and effective in maintaining Hb 
in subjects with CKD undergoing dialysis. Data from a long-term safety of darbepoetin alfa 
in subjects who had completed one year of treatment on a previous darbepoetin alfa clinical 
trial show that for subjects who have already received 52 weeks of darbepoetin alfa 
treatment, the Hb concentration can be safely maintained at a stable level without changes in 
the average weekly darbepoetin alfa dose [EMEA, 2004; EMEA, 2003].
1.3
Summary of Key Safety Information for Study Drugs
1.3.1
Roxadustat
The overall frequency and type of treatment-emergent adverse events (TEAEs) and serious 
adverse events (SAEs) observed in the clinical studies conducted with roxadustat reflect 
events that would be expected to occur in CKD subjects. The most commonly reported AEs 
in healthy subjects were headache, pharyngolaryngeal pain, and nasal congestion. The most 
commonly reported AEs (> 5%) in CKD subjects not on dialysis were diarrhea, nausea, 
urinary tract infection, nasopharyngitis, peripheral edema, hyperkalemia, headache and 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 46 of 160
Version 3.0, Incorporating Substantial Amendment 2
hypertension. The most commonly reported adverse events (AEs) (> 3%) in CKD subjects 
on dialysis were diarrhea, nausea, hypertension and upper respiratory tract infection. The 
only expected non-serious adverse drug reaction was heart rate (HR) increase.
Safety analyses did not reveal any association between the rates of occurrence of 
cardiovascular events with roxadustat, or any effect on AE rates related to either increasing 
Hb levels or on the rate of change of Hb levels.
AEs commonly reported with ESA use have been reported at lower rates such as 
hypertension (1% in Study FGCL-SM4592-017, and 6.9% in Study FGCL-4592-041) and 
thrombosis (overall incidence < 1%). No increased cancer risk has been noted with 
roxadustat treatment, though it should be noted that the study program was not powered to 
detect absence of cancer risk.
Liver enzymes were monitored closely throughout the roxadustat clinical development 
program. Increases in liver enzymes were infrequently seen, and were generally mild and 
transient in nature. No case of Hy’s Law was observed throughout the program. An 
independent data and safety monitoring committee concluded that there was no concern for 
hepatotoxicity with roxadustat.
Five pancreatitis events were noted during the roxadustat phase 2 clinical development 
program, the majority of which have been associated with gallstones or biliary sludge; one of 
which was due to a pancreatic duct stricture, and another case had multiple risk factors for 
pancreatitis. Only one of the pancreatitis cases was considered as possibly related by the 
investigator. Amylase levels were routinely measured in the FGCL-4592-040 study and 
mean levels were not found to be elevated during the course of the study. A higher incidence 
of pancreatitis in subjects with type 2 diabetes mellitus, and CKD, has been well defined in 
the literature.
For further information please refer to the most recent version of the Investigator Brochure.
1.3.2
Darbepoetin alfa
The safety profile of darbepoetin alfa was assessed in 1578 CKD subjects treated with 
darbepoetin alfa and 591 treated with r-HuEPO. Out of the 1578 subjects 847 (54%) 
received SC darbepoetin alfa. AEs were consistent across all studies and were similar in the 
two treatment groups – darbepoetin alfa and r-HuEPO. The majority of AE were due to 
underlying disease. Only hypertension, vascular access thrombosis and injection site pain 
(SC route) were consistently reported as related to study drug. As hypertension is the most 
common AE with both darbepoetin alfa and r-HuEPO, and as most deaths were due to 
cardiac events, control of blood pressure is an important consideration in all CKD subjects.
There were no overall changes in blood pressure or HR in the study although there was 
considerable variability in individual blood pressure measurements.
The clinical results showed that the safety profile of darbepoetin alfa is similar to that of 
r-HuEPO when administered by the IV or SC route. The odds-ratio (95% CI) between 
darbepoetin alfa and r-HuEPO for the incidence of AEs showed that there is no evidence that 
AEs occurred more frequently with IV darbepoetin alfa compared to r-HuEPO therapy. 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 47 of 160
Version 3.0, Incorporating Substantial Amendment 2
When administered by the SC route, the only event that occurred more frequently during 
darbepoetin alfa treatment was injection site pain.
The AEs observed during post marketing experience with darbepoetin alfa were: aggravated 
hypertension, cerebrovascular disorders, myocardial infarction, angina pectoris and skin 
reactions. A warning on possible cross reactivity of epoetin antibodies with different 
epoetins and to a number of adverse drug reactions was also added in the Summary of 
Product Characteristics (SmPC). Furthermore a warning was included in section 4.4 of the 
SmPC to specify that cases of severe hypertension, including hypertensive crisis, 
hypertensive encephalopathy, and seizures, have been observed in CKD subjects treated with 
darbepoetin alfa. Further to the request of the Committee for Medicinal Products for Human 
Use (CHMP) regarding the assessment of outcome of Study 20010184 "Trial to Reduce 
Cardiovascular Events with Aranesp® Therapy" (TREAT) in March 2010, additional 
warnings and the results of the TREAT study were included into the current product 
information for darbepoetin alfa. Also, the specific section of the Aranesp Package Leaflet 
(PL), section 2 "Before you use Aranesp®" was updated to align it with the SmPC, reflecting 
the concern that elevated hemoglobin concentrations could increase the risk of myocardial 
infarction, stroke and death [EMEA, 2004].
1.4
Risk-Benefit Assessment
Based upon the results of the studies described above, the expected benefit of roxadustat is 
the correction of anemia and relief of signs and symptoms of anemia resulting in an increased 
quality of life, improved physical functioning and performance. Treatment with roxadustat 
triggers a pharmacodynamic response which translates into correction of anemic Hb levels 
and maintenance of these corrected Hb levels.
An established dose adjustment algorithm, similar to the one used in phase 2 studies with 
roxadustat, will be used during the current study to titrate roxadustat doses to enable subjects 
to achieve and maintain Hb levels within target range, while allowing investigators to closely 
monitor the rate of rise of Hb levels. Roxadustat doses may be held and/or the use of 
therapeutic phlebotomy is allowed in the event of excessive hematopoiesis. In case of 
insufficient response to study drug roxadustat rules for the use of supplemental IV iron and 
rescue treatments such as darbepoetin alfa (for roxadustat treated subjects) or RBC 
transfusion are in place in order to assure safety of the affected study subjects.
In PK studies with roxadustat there was no evidence of drug accumulation with the proposed 
clinical regimen of up to three times weekly dosing. The overall frequency and nature of 
AEs and SAEs observed in clinical studies thus far generally reflect events what would be 
expected to occur in the DD-CKD and NDD-CKD patient populations, and did not reveal any 
particular safety concern.
A drug interaction with statins is a potential risk. To mitigate this risk, recommendations for 
maximum statin doses are included in the study protocol. Also, the protocol includes a 
recommendation for the investigator to consider the posology of other concomitantly 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 48 of 160
Version 3.0, Incorporating Substantial Amendment 2
administered drugs that are substrates of the organic anion transporting polypeptide 1B1
(OATP1B1) and to refer to the SmPCs of these drugs.
Furthermore, there is a drug interaction with phosphate binders: concomitant intake of 
phosphate binders and roxadustat reduces the absorption of roxadustat. Subjects should take 
roxadustat in a consistent manner relative to their phosphate binder intake, and discuss with 
the investigator before changing their phosphate binder dose or dosing time. As a further risk 
mitigation this study protocol includes a recommendation that roxadustat be taken separately 
from phosphate binders. 
As it is anticipated that other multivalent cation-containing drugs and mineral supplements 
(e.g., iron, calcium, magnesium, aluminium), sucralfate or magnesium- or aluminium-
containing antacids would produce a similar interaction, the study protocol includes the 
advice that roxadustat be taken separately from these drugs.
Darbepoetin alfa has been chosen as comparator to adequately assess the efficacy, safety and 
benefit of achieving Hb correction and maintenance in anemic subjects treated with 
roxadustat. It is a commonly used ESA in Europe for the treatment of anemic NDD-CKD 
subjects and has demonstrated its ability to correct and maintain Hb in subjects in several 
controlled randomized trials.
The rules for dose adjustment and for events of excessive hematopoiesis in the present study 
will follow the approved posology of darbepoetin alfa. In case of insufficient response to 
darbepoetin alfa, rules for RBC transfusions are in place in order to assure safety of the 
affected study subjects.
The safety of treatment with roxadustat and darbepoetin alfa in this study will be carefully 
monitored to include AEs and SAEs, laboratory parameters such as electrolytes, liver 
enzymes, serum lipase and iron indices. Emphasis will be placed on cardiovascular, 
cerebrovascular, and thrombo-embolic events, which are not uncommon in the study 
population; an independent event review committee (IERC) will assess and adjudicate all 
significant occurrences of such events. In addition, an independent Data and Safety 
Monitoring Board (DSMB) will perform regular, periodic assessments of blinded and 
unblinded data to detect any potential safety signals that may arise during the study and 
advise the Sponsor accordingly.
Based on the clinical and non-clinical experimental results of the orally administered 
roxadustat to date, it is anticipated that roxadustat will be comparable in safety and efficacy 
to the marketed, parenterally administered darbepoetin alfa in the treatment of anemia of 
CKD. The risk mitigation measures applied in this protocol are deemed to sufficiently assure 
that major risks for the subject can be avoided. The benefit-risk profile for the participation 
of subjects in this study is therefore considered to be acceptable.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 49 of 160
Version 3.0, Incorporating Substantial Amendment 2
2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS
2.1
Study Objectives
2.1.1
Primary Objective
The primary objective of this study is to evaluate the efficacy of roxadustat compared to 
darbepoetin alfa in the treatment of anemia in NDD-CKD subjects.
2.1.2
Secondary Objectives
The secondary objectives of this study are to:

Evaluate the safety of roxadustat compared to darbepoetin alfa in the treatment of anemia 
in NDD-CKD subjects.

Evaluate the HRQoL benefit of roxadustat compared to darbepoetin alfa in the treatment 
of anemia in NDD-CKD subjects.
2.2
Study Design and Dose Rationale
2.2.1
Study Design
2.2.1.1 General
This is a phase 3, multi-center, randomized, open-label, active-controlled study. This study 
is planned to recruit approximately 570 subjects from approximately 200 study centers 
globally.
The study is planned to provide key efficacy and safety data for the approval of roxadustat in
the treatment of anemia associated with CKD.
2.2.1.2 Study Population
The study population consists of subjects with CKD stages 3, 4, and 5 (eGFR 
< 60 mL/min/1.73 m2) who are anemic and not on dialysis. Anemia is defined by mean Hb 
≤10.5 g/dL upon repeated screening measurements. Anemia of non-renal origin is to be 
excluded. Washout periods of at least 12 weeks for any prior ESA, at least 6 weeks for any 
IV iron treatment, and at least 8 weeks for any RBC transfusion prior to randomization have 
been mandated in order to exclude a potential impact of these extraneous anemia treatments 
on the assessment of efficacy.
2.2.1.3 Description of Study
Subjects assigned to roxadustat treatment will be administered roxadustat orally as a 
combination of tablets of different strengths. Subjects assigned to darbepoetin alfa treatment 
will be administered darbepoetin alfa subcutaneously (SC) or intravenously (IV) by the 
investigator or a qualified member of the site staff or, after 36 weeks of treatment, by the 
subject themselves or caregiver, e.g., relative, if well trained and willing to self-administer.
Study treatment administration is implemented in an open-label manner.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 50 of 160
Version 3.0, Incorporating Substantial Amendment 2
The study will consist of three study periods as follows:

Screening period: up to 6 weeks

Treatment period: 104 weeks

Follow-up period: 4 weeks
Subjects that have discontinued treatment prior to their projected week 104 will continue to 
be followed for vital status, SAEs, cardiovascular and thromboembolic AEs in a post study 
follow-up period.
During the course of the study, visits and assessments will be performed as defined in the 
Schedule of Assessments.
Screening Period
During the screening period (up to 42 days duration), Hb levels will be assessed in a central 
laboratory for matching the inclusion criterion (mean of two Hb values must be ≤10.5 g/dL, 
see inclusion criterion 4). Subjects meeting all of the inclusion criteria and none of the 
exclusion criteria will be randomized at day 1, which marks the end of screening period and 
start of the treatment period. If a subject fails screening, the subject may be rescreened once 
(immediately or later) if deemed appropriate by the investigator. The subject must be 
re-consented. A new rescreening period will start and all screening procedures must be 
repeated.
Treatment Period (Correction and Maintenance Period)
After subjects have been confirmed eligible for study participation, subjects are randomized 
to 1 of 2 treatment arms (1:1 ratio) as illustrated in Table 2 The randomization will occur 
through Interactive Response Technology (IRT). The randomization will result in a 1:1 ratio 
of subjects receiving roxadustat administered orally or darbepoetin alfa administered by SC
or IV injection.
Table 2
Treatment Arms and Dosing Frequency
Treatment 
Arms
Study Treatment
Dosing Frequency in Treatment 
Period
Correction 
Period
Maintenance Period
1
Roxadustat
TIW
TIW
2
Darbepoetin alfa
Dosing per EU SmPC
SmPC: Summary of Product Characteristics; TIW: three times weekly
In protocol version 1 subjects were randomized in a ratio of 2:1 receiving roxadustat versus 
darbepoetin alfa. The expected number of subjects randomized on protocol version 1, 
protocol versions 2 and 3 and the total number of randomized subjects per treatment arm are 
represented in the following table.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 51 of 160
Version 3.0, Incorporating Substantial Amendment 2
Table 3
Expected Number of Subjects Randomized 
Treatment 
Arms
Study Treatment
Expected Number of 
Protocol v1 Subjects 
Randomized (Ratio 
2:1)
Expected Number of 
Protocol v2 and 3
Subjects Randomized
(Ratio 1:1)†
Total Expected 
Number of 
Subjects 
Randomized per 
Treatment Arm
1
Roxadustat
100
210
310
2
Darbepoetin alfa
50
210
260
Total
150
420
570
† The number of subjects under protocol v2 and v3 will depend on the number of subjects randomized under 
protocol v1.
During the treatment period, subjects will attend weekly study visits from day 1 to week 2, 
followed by every other week study visits from weeks 4 to 24. From week 24 onwards, visits 
will occur every four weeks until the end of treatment (EOT).
Subjects will receive study treatment (roxadustat or darbepoetin alfa) for 104 weeks.
Correction Period
The aim of the correction period is to correct Hb levels to ≥11.0 g/dL and a Hb increase 
from BL Hb ≥1.0 g/dL as measured at two consecutive study visits separated by at least 
5 days (as assessed by central laboratory). Dosing and dose adjustments of roxadustat will 
follow prespecified dose adjustment rules. Dosing and dose adjustments of darbepoetin alfa 
will be per EU approved Summary of Product Characteristics (SmPC).
Once Hb is corrected the subjects will enter into the maintenance period.
Maintenance Period
The aim of the maintenance period is to treat to a Hb target level of 11.0 g/dL by maintaining 
the Hb levels between 10.0 g/dL and 12.0 g/dL. Dose adjustments of roxadustat will follow 
prespecified dose adjustment rules. Dose adjustments of darbepoetin alfa will be per EU 
approved Summary of Product Characteristics (SmPC).
Follow-up Period
After the end of the treatment period, subjects proceed to the 4-week follow-up period.
Post study Follow-up (for premature treatment discontinued subjects only)
Subjects that have prematurely discontinued study treatment will complete the EOT visits 
(EOT visit and EOT +2 weeks visit) and EOS visit. Thereafter, these subjects who have 
taken at least one dose of study drug will continue to be followed up every 6 months for vital 
status, SAEs, cardiovascular and thromboembolic AEs until their projected date of 
completion of the follow-up period (i.e., projected week 108 date) or until consent 
withdrawn.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 52 of 160
Version 3.0, Incorporating Substantial Amendment 2
2.2.1.4 Randomization and Open-Label
A randomized design has been chosen in order to ensure a balanced allocation of study 
subjects to the treatment arms and to minimize bias in therapeutic management and in 
outcomes assessment.
An open label design was chosen since the investigational and comparator drug are provided 
via different routes of administration and have a different requirement for iron 
supplementation.
2.2.1.5 Comparator
Darbepoetin alfa supplied as a solution for injection in a pre-filled syringe, and is 
administered by SC or IV injection. Once the route of administration is chosen (IV or SC), it 
is recommended to keep the same administration route for a subject throughout the study. It 
is administered in combination with IV or oral iron to maintain iron repletion. 
2.2.2
Roxadustat Dose Rationale
Starting doses of roxadustat were studied in three ways in phase 2:

using a strict weight-based dosing approach by dosing in mg/kg that was useful in the 
proof of concept stage

using a tiered weight-based approach where a subject’s starting dose was selected based 
on categorizing the subject’s body weight as low (45 to 60 kg), medium (>60 to 90 kg),
or high (>90 to 140 kg)

using an absolute starting dose regardless of body weight
The tiered weight-based approach has been chosen for the development of roxadustat in the 
phase 3 program to provide the best opportunity for managing subjects’ controlled correction 
to target Hb values.
Based upon simulations derived from a kinetic-pharmacodynamic model built from 
phase 2 data a tiered weight-based approach with starting doses of 70 mg given TIW for 
subjects weighing up to 70 kg and 100 mg given TIW for subjects weighing more than 70 kg 
has been chosen for the development of roxadustat. This approach is a variation of the tiered 
weight-based starting approach used in phase 2 and is expected to provide the best opportunity 
for managing subjects’ controlled individualized correction to target Hb values by achieving a 
steady Hb increase associated with moderate rates of Hb overshoots.
Based on the phase 2 data, it is expected that subjects who receive these starting doses to 
correct anemia will require in the maintenance period a total weekly dose reduction in the 
order of 22% to 35% after achieving response. This dose reduction will be achieved by 
adjustment of the single dose. The phase 2 studies evaluated the need for dose adjustments for 
correcting and maintaining Hb. Dose adjustments were allowed at regular 4-week intervals to 
maintain, increase or decrease the dose according to prespecified rules. Prespecified dosing 
steps were used to correct and maintain Hb levels within treatment thresholds based on 
absolute Hb levels and change of Hb in the previous 4 weeks. Additional rules for dose 
adjustment were provided to minimize excessive hematopoiesis. These dose adjustment rules 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 53 of 160
Version 3.0, Incorporating Substantial Amendment 2
were successful in Hb correction and Hb maintenance and will be adopted in this study with 
minor modifications.
The maximum allowed roxadustat dose in this study is set at 3.0 mg/kg or 300 mg per 
administration, whichever is lower. For randomized subjects who require chronic dialysis 
during the treatment period, the maximum dose step is the dose step corresponding to 
3.0 mg/kg per administration or 400 mg, whichever is lower. The highest dose tested in 
healthy volunteers is 5 mg/kg single dose and 3.75 mg/kg TIW; the highest dose tested in 
phase 2 studies was 3.0 mg/kg. The doses were safe and well tolerated with transient dose 
dependent HR increases observed. No maximum tolerated dose (MTD) was reached in the 
clinical development of roxadustat based on the observed pharmacodynamic response (plasma 
EPO levels) and the predicted relation between EPO levels and Hb response; therefore, 
exploration of higher doses was not conducted. Plasma EPO levels increased in a supra-linear 
fashion with increasing roxadustat doses. It is expected that the majority of the subjects will 
show adequate Hb response (correction and maintenance) at substantially lower doses than the 
maximum allowed dose.
The treatment period of 104 weeks will provide sufficient data on the efficacy and safety of 
long term treatment of anemic CKD subjects with roxadustat.
2.3
Endpoints
2.3.1
Primary Endpoints
The primary efficacy endpoint is Hb response. Hb response is defined as:

Hb ≥11.0 g/dL and a Hb increase from BL Hb by ≥1.0 g/dL in any subject with 
BL Hb >8.0 g/dL, OR

An increase from BL Hb by ≥2.0 g/dL in any subject with BL Hb ≤8.0 g/dL
as measured at 2 consecutive visits separated by at least 5 days during the first 24 weeks of 
treatment without administration of rescue therapy prior to Hb response.
2.3.2
Key Secondary Endpoints
The secondary efficacy endpoints in this study are:

Hb change from BL to the average Hb of weeks 28 to 36, without having received rescue 
therapy within 6 weeks prior to and during this 8-week evaluation period

Change from BL in Low Density Lipoprotein (LDL) cholesterol to the average LDL 
cholesterol of weeks 12 to 28

Mean monthly IV iron (mg) use per subject during weeks 1 to 36 (monthly defined as a 
period of 4 weeks)

Change from BL in SF-36 Physical Functioning (PF) sub-score to the average PF 
sub-score of weeks 12 to 28

Change from BL in SF-36 Vitality (VT) sub-score to the average VT sub-score of 
weeks 12 to 28 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 54 of 160
Version 3.0, Incorporating Substantial Amendment 2

Blood pressure effect:
o
Change from BL in mean arterial pressure (MAP) to the average MAP value of
weeks 20 to 28
o
Occurrence and time to occurrence of hypertension (defined as either SBP 
> 170 mmHg AND an increase from BL of ≥20 mmHg SBP or DBP > 110 mmHg 
AND an increase from BL of ≥15 mmHg DBP on 2 consecutive visits) during 
weeks 1 to 36
2.3.3
Additional Secondary Endpoints
2.3.3.1 Efficacy Endpoints
Hb correction and maintenance:

Hb change from BL to the average Hb value of weeks 28 to 52 regardless of rescue 
therapy

Time (weeks) to achieve the first Hb response as defined by primary endpoint.

Hb response defined as: Hb ≥11.0 g/dL and a Hb increase from BL Hb by ≥1.0 g/dL in 
any subject with BL Hb > 8.0 g/dL, OR an increase from BL Hb by ≥2.0 g/dL in any 
subject with BL Hb ≤8.0 g/dL as measured at 2 consecutive visits separated by at least 
5 days, during the first 24 weeks of treatment regardless of administration of rescue 
therapy prior to Hb response.

Hb averaged over weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104, without use of rescue 
therapy within 6 weeks prior to and during this evaluation period.

Hb value and Hb change from BL to each post-dosing time point.

Hb change from BL to the average Hb value of weeks 28 to 36, 44 to 52, 72 to 80, 96 to 
104 regardless of the use of rescue therapy 

Proportion of Hb values within 10.0 to 12.0 g/dL in weeks 28 to 36, 44 to 52, 72 to 80, 
96 to 104 without use of rescue therapy within 6 weeks prior to and during this 8-week 
evaluation period.
Hospitalizations

Occurrence (number) of hospitalization(s)

Number of days of hospitalization
Rescue therapy use

Having received rescue therapy (composite of RBC transfusions [all subjects] and 
darbepoetin alfa use [roxadustat treated subjects only])

Having received RBC transfusions

Number of RBC packs per subject

Volume of RBC transfused per subject
Changes in cholesterol levels

Change from BL to each scheduled measurement in:
o
Total cholesterol
o
LDL/High-density Lipoprotein (HDL) ratio

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 55 of 160
Version 3.0, Incorporating Substantial Amendment 2
o
Non-HDL cholesterol
o
Apolipoproteins A1 and B, and ApoB/ApoA1 ratio

Occurrence of mean LDL cholesterol < 100 mg/dL (mean LDL calculated over weeks 12 
to 28, and weeks 36 to 52 of treatment).
Blood pressure effect

Occurrence of achieved anti-hypertensive treatment goal (SBP < 130 mmHg and DBP 
< 80 mmHg) based on the mean SBP and mean DBP calculated over weeks 12 to 28 and 
36 to 52 of treatment with study drug.
HRQoL and EQ5D 5L benefits

Change from BL to the average value of weeks 12 to 28 and 36 to 52 in:
o
Physical Component Score (PCS) of SF-36
o
Anemia Subscale (“Additional Concerns”) of Functional Assessment of Cancer   
Therapy-Anemia (FACT-An) Score
o
Total FACT-An Score
o
EQ-5D 5L VAS Score
o
WPAI:ANS Score (Work Productivity and Activity Impairment Questionnaire)

PGIC (qualitatively by assessment)
Iron, HbA1c, and CKD progression

Change from BL to each scheduled measurement in:
o
Serum ferritin
o
TSAT
o
HbA1c level
o
Fasting blood glucose
o
eGFR (including eGFR slope over time)
o
Urine albumin/creatinine ratio (UACR)

Serum creatinine having doubled during the study in comparison with baseline

Occurrence of ESRD
2.3.3.2 Safety Endpoints
Safety will be assessed by evaluating the following:

Occurrence of Treatment Emergent AEs (TEAEs), and clinically significant changes in 
laboratory values from BL

Changes from BL in vital signs, electrocardiogram (ECG) findings, and clinical 
laboratory values

Occurrence of prespecified adjudicated cardiovascular and cerebrovascular events.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 56 of 160
Version 3.0, Incorporating Substantial Amendment 2
3
STUDY POPULATION
3.1
Selection of Study Population
The study population consists of subjects with CKD as defined by CKD stages 3, 4 and 5 
(eGFR < 60 mL/min/1.73 m2) who are anemic and not in need of dialysis.
3.2
Inclusion Criteria
Subject is eligible for the study if all of the following apply:
1.
Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved 
written Informed Consent and privacy language as per national regulations has been
obtained from the subject or legally authorized representative prior to any study-related 
procedures (including withdrawal of prohibited medication, if applicable).
2.
Subject age is ≥18 years.
3.
Subject has a diagnosis of CKD, with Kidney Disease Outcomes Quality Initiative 
(KDOQI) Stage 3, 4 or 5, not on dialysis; with an eGFR < 60 mL/min/1.73 m2
estimated using the abbreviated 4-variable Modification of Diet in Renal Disease 
(MDRD) equation.
4.
The mean of the subject’s two most recent (prior to randomization) Hb values during the 
screening period, obtained at least 4 days apart, must be ≤10.5 g/dL, with a difference of 
≤1.0 g/dL. The last Hb value must be within 10 days prior to randomization.
5.
Subject is deemed suitable by the investigator for treatment with ESA using the criteria 
specified in the KDIGO 2012 recommendation considering the rate of fall of Hb 
concentration, prior response to iron therapy, the risk of needing a transfusion, the risks 
related to ESA therapy and the presence of symptoms attributable to anemia.
6.
This criterion has been removed.
7.
This criterion has been removed.
8.
Subject has a serum folate level ≥ lower limit of normal (LLN) at screening.
9.
Subject has a serum vitamin B12 level ≥LLN at screening.
10. Subject’s alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are 
≤3 x upper limit of normal (ULN), and total bilirubin (TBL) is ≤1.5 x ULN. 
11. Subject’s body weight is 45.0 kg to a maximum of 160.0 kg.
12. Female subject is either:
Of non-childbearing potential:

post-menopausal (defined as at least 1 year without any menses) prior to screening,
or

documented surgically sterile 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 57 of 160
Version 3.0, Incorporating Substantial Amendment 2
Or if of childbearing potential:

agree not to try to become pregnant during the study and for 28 days after the final 
study drug administration

must have a negative serum pregnancy test at screening and

if heterosexually active, agree to consistently use a highly effective form of birth 
control* starting at screening and throughout the study period, and continue to do so 
for 28 days after final study treatment administration. If required by local law, 
2 highly effective methods of birth control must be used, 1 of which must be a 
barrier method.
13. Female subject must not be breastfeeding at screening or throughout the study period, 
and for 28 days after the final study treatment administration.
14. Female subject must not donate ova starting at screening and throughout the study 
period and for 28 days after final study drug administration. 
15. Male subject and their female spouse/partner(s) who are of childbearing potential must 
be using a highly effective form of birth control* starting at screening and continue to 
do so throughout the study period and for 12 weeks after final study treatment 
administration. If required by local law, 2 highly effective methods of birth control 
must be used, 1 of which must be a barrier method.
16. Male subject must not donate sperm starting from screening, throughout the study 
period and up to 12 weeks after final study drug administration.
17. Subject agrees not to participate in another interventional study from the time of signing 
informed consent until the end of study visit (EOS).
* Highly effective forms of birth control include:

Consistent and correct usage of established oral contraception

Injected or implanted hormonal methods of contraception

Established intrauterine device (IUD) or intrauterine system (IUS)

Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository (if allowed 
by local regulations)

Any male partner that has undergone effective surgical sterilization

Any female partner that has undergone effective surgical sterilization, if applicable
Waivers to the inclusion criteria will NOT be allowed.
3.3
Exclusion Criteria
Subject will be excluded from participation if any of the following apply:
1.
Subject has received any ESA treatment within 12 weeks prior to randomization.
2.
Subject has received any dose of IV iron within 6 weeks prior to randomization.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 58 of 160
Version 3.0, Incorporating Substantial Amendment 2
3.
Subject has received a Red Blood Cell (RBC) transfusion within 8 weeks prior to 
randomization.
4.
Subject has a known history of myelodysplastic syndrome or multiple myeloma.
5.
Subject has a known hereditary hematologic disease such as thalassemia or sickle cell 
anemia, pure red cell aplasia, or other known causes for anemia other than CKD.
6.
Subject has a known hemosiderosis, hemochromatosis, coagulation disorder, or 
hypercoagulable condition.
7.
Subject has a known chronic inflammatory disease that could impact erythropoiesis 
(e.g., systemic lupus erythematosus, rheumatoid arthritis, celiac disease) even if it is 
currently in remission.
8.
Subject is anticipated to undergo elective surgery that is expected to lead to significant 
blood loss during the study period or anticipated elective coronary revascularization.
9.
Subject has active or chronic gastrointestinal bleeding.
10. Subject has received any prior treatment with roxadustat or a HIF-PHI. 
11. Subject has been treated with iron-chelating agents within 4 weeks prior to 
randomization.
12. Subject has a history of chronic liver disease (e.g., cirrhosis or fibrosis of the liver).
13. Subject has known New York Heart Association Class III or IV congestive heart failure.
14. Subject has had a myocardial infarction, acute coronary syndrome, stroke, seizure, or a 
thrombotic/thromboembolic event (e.g., deep vein thrombosis or pulmonary embolism) 
within 12 weeks prior to randomization.
15. Subject has one or more contraindications for treatment with darbepoetin alfa:
Uncontrolled hypertension in the opinion of the investigator, or two or more blood 
pressure values of SBP ≥160 mmHg or DBP ≥95 mmHg (within 2 weeks prior to 
randomization).
Known hypersensitivity to darbepoetin alfa, recombinant human erythropoietin, or any 
of the excipients.
16. Subject has a diagnosis or suspicion (e.g., complex kidney cyst of Bosniak Category 2F
or higher) of renal cell carcinoma as shown on renal ultrasound within 12 weeks prior to 
randomization.
17. Subject has a history of malignancy, except for the following: cancers determined to be 
cured or in remission for ≥5 years, curatively resected basal cell or squamous cell skin 
cancers, cervical cancer in situ, or resected colonic polyps.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 59 of 160
Version 3.0, Incorporating Substantial Amendment 2
18. Subject is positive for any of the following:
human immunodeficiency virus (HIV).
hepatitis B surface antigen (HBsAg).
or anti-hepatitis C virus antibody (anti-HCV Ab).
19. Subject has an active clinically significant infection that is manifested by White Blood 
Count (WBC) > ULN, and/or fever, in conjunction with clinical signs or symptoms of 
infection within one week prior to randomization.
20. Subject has a known untreated proliferative diabetic retinopathy, diabetic macular 
edema, macular degeneration or retinal vein occlusion.
21. Subject has had any prior organ transplant (that has not been explanted),  subject is 
scheduled for organ transplantation, or subject is likely to initiate renal replacement 
therapy including dialysis within the first year of the study in the opinion of the 
investigator.
22. Subject will be excluded from participation if any of the following apply:
a. subject has received investigational therapy within 30 days or 5 half lives or limit 
set by national law, whichever is longer, prior to initiation of screening, or 
b. any condition which, in the investigator’s opinion, makes the subject unsuitable for 
study participation. 
23. Subject has an anticipated use of dapsone in any dose amount or chronic use of
acetaminophen/paracetamol > 2.0 g/day during the treatment or follow-up period of the 
study.
24. Subject has a history of alcohol or drug abuse within 2 years prior to randomization.
25. Subject has any medical condition that in the opinion of the investigator may pose a 
safety risk to a subject in this study, which may confound efficacy or safety assessment, 
or may interfere with study participation.
Waivers to the exclusion criteria will NOT be allowed.
4
TREATMENT(S)
4.1
Identification of Investigational Product(s)
4.1.1
Test Drug
Roxadustat is supplied as red, film-coated, oval tablets for oral administration, in strengths of 
20, 50 and 100 mg. All ingredients used for the manufacture of roxadustat tablets comply 
with US and EU compendial or regulatory standards.  Tablet strengths are different in size 
and debossing reflects the strength (i.e., 20, 50 or 100 mg).

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 60 of 160
Version 3.0, Incorporating Substantial Amendment 2
The excipients include lactose monohydrate, microcrystalline cellulose, povidone, 
croscarmellose sodium, magnesium stearate, and colorant Red Opadry II.
4.1.2
Comparative Drug
Darbepoetin alfa is supplied as a solution for SC or IV injection in a pre-filled syringe. It is 
centrally provided in the following strengths 20, 30, 40, 60 and 100 µg and needs to be 
administered in combination with IV or oral iron to maintain iron repletion. All administrations 
will be performed by the investigator or a qualified member of the site staff or, after 36 weeks 
of treatment, by the subject themselves or caregiver, e.g., relative, if well trained and willing to 
self-administer. Darbepoetin alfa (Aranesp®) should be administered IV or SC according to 
the Package Insert or SmPC (EU SmPC for Aranesp®). Copies of this SmPC will be 
distributed as part of the study materials.
4.2
Packaging and Labeling
All supplied medication used in this study will be prepared, packaged, and labeled under the 
responsibility of qualified staff at Astellas Pharma Europe B.V. (APEB) or Sponsor’s 
designee in accordance with APEB or Sponsor’s designee Standard Operating Procedures 
(SOPs), Good Manufacturing Practice (GMP) guidelines, ICH GCP guidelines, and 
applicable local laws/regulations.
The medication will bear a label conforming to regulatory guidelines, Good Manufacturing 
Practice and local laws and regulations that identifies the contents as investigational drug.
A Qualified Person of Astellas Pharma Europe B.V. (APEB) or Sponsor’s designee will 
perform the final release of the medication according to Directive 2003/94/EC annex 13.
Roxadustat study drug tablets are presented in white high-density polyethylene bottles with a 
black lining, for optimal light protection, and closed with a foil induction seal and a white, 
child resistant cap. Due to the light sensitive nature of roxadustat and to minimize exposure 
of the active pharmaceutical ingredients to light, tablets should remain in the original 
packaging until time of administration and be administered as intact tablets only.
Darbepoetin alfa will be provided as a solution for injection in pre-filled syringes. Each 
pre-filled syringe will be packaged in a single box.
For storage and administration purposes, please refer to the EU SmPC to warrant correct use.
4.3
Study Drug Handling
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries
from the Sponsor are received by the investigator/or designee and that:

such deliveries are recorded

study drug is handled and stored according to labeled storage conditions

study drug with appropriate expiry/retest and is only dispensed to study subjects in 
accordance with the protocol, and

any unused study drug is returned to the Sponsor

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 61 of 160
Version 3.0, Incorporating Substantial Amendment 2
Drug inventory and accountability records for the study drugs will be kept by the 
investigator/or designee. Study drug accountability throughout the study must be 
documented and reconciled. The following guidelines are therefore pertinent:

The investigator agrees not to supply study drugs to any persons except the eligible 
subjects in this study in accordance with the protocol.

The investigator or designee will keep the study drugs in a pharmacy or other locked and 
secure storage facility under controlled storage conditions, accessible only to those 
authorized by the investigator to dispense the study drugs.

A study drug inventory will be maintained by the investigator or designee. The inventory 
will include details of material received and a clear record of when they were dispensed 
and to which subject.

At the conclusion or termination of the study, the investigator or designee agrees to 
conduct a final drug supply inventory and to record the results of this inventory on the 
Drug Accountability Record. It must be possible to reconcile delivery records with those 
of used and/or returned medication. Any discrepancies must be accounted for and 
documented. Appropriate forms of deliveries and returns must be signed by the site staff 
delegated this responsibility.

The site must return study drug to the Sponsor or designee at the end of the study or upon 
expiration. Only if agreed by the Sponsor, can standard procedures for the alternative 
disposition of the unused study drug be followed, after drug accountability has been 
conducted by the Sponsor or representative. A copy of the standard institutional 
procedure for destroying investigational drugs will be provided to the Sponsor or 
designee upon request.
4.4
Blinding
This section is not applicable as this is an open-label study.
4.5
Assignment and Allocation
Randomization and treatment assignments will be performed via IRT prepared on behalf of 
the Sponsor (under the responsibility of the Global Data Science [GDS] Department of 
APEB). Specific procedures for randomization through the IRT are contained in the study 
procedures manual.
Approximately 570 subjects will be randomized to receive roxadustat TIW or darbepoetin 
alfa as shown in Table 9 assuming 150 subjects will be randomized pre-amendment.
Randomization will be stratified by the following four factors:

Region: region A versus region B*
* Assignment to region will be determined based on health care comparability.

Screening Hb values (Hb ≤8.0 g/dL versus > 8.0 g/dL)

History of cardiovascular, cerebrovascular or thromboembolic diseases (Yes versus No)

eGFR (< 30 mL/min/1.73 m2 versus > 30 mL/min/1.73 m2)

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 62 of 160
Version 3.0, Incorporating Substantial Amendment 2
5
TREATMENTS AND EVALUATION
Subjects must be consented and registered in IRT before any screening tests or assessments 
are performed. Participating study sites are required to document all screened candidates 
initially considered for inclusion in this study. If a subject is excluded from the study, the 
reasons for exclusion will be documented in the subject’s source documents in the eCRF.
Registration of subjects into the study, assignment of subject identification numbers, and 
randomization will take place using a centralized IRT. After obtaining consent, and prior to 
the start of screening assessments, the investigator will register the subject in IRT, which 
starts the screening period, and a subject identification number will be assigned.  No 
screening tests or assessments should be performed prior to registration and assignment of a 
unique subject identification number by IRT. Any subject identification numbers that are 
assigned will not be reused even if the subject does not receive treatment.
If a subject’s laboratory results do not meet the inclusion criteria or meet the exclusion 
criteria at screening, any laboratory assessment may be repeated once within the 42-day 
screening period. This includes an additional (third) Hb value that may be collected if 
necessary. The mean of 2 most recent Hb values during the screening period, obtained at 
least 4 days apart, will be used to assess the subject’s eligibility.
If a subject fails screening, they will be registered in IRT as a screen failure and considered 
out of the study. However, the subject may be re-screened once (immediately or later) if 
deemed appropriate by the investigator. When a subject will be re-screened, the subject must 
be re-consented, a new rescreening period starts and all screening procedures must be 
repeated. Subject must also be registered in IRT as re-screened under the same subject 
identification number as first screening.
Subjects confirmed not eligible after re-screening, should be registered in IRT as a re-screen 
failure.
5.1
Dosing and Administration of Study Drugs and Other Medication
5.1.1
Dose/Dose Regimen and Administration Period
Following the screening period, eligible subjects will enter the treatment period upon 
randomization (day 1).
Subjects will be randomized via IRT to receive roxadustat or darbepoetin alfa. The first 
study treatment should be on the day of randomization, i.e., day 1, after all study assessments 
have been completed.
All subjects will be treated for 104 weeks.
Subjects receiving roxadustat
Roxadustat tablets will be dispensed to subjects at each study visit during the treatment 
period with instructions for self-administration, according to the dosing schedule. The study 
drug tablets are to be swallowed whole with room-temperature drinking water. 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 63 of 160
Version 3.0, Incorporating Substantial Amendment 2
The initial roxadustat dose (per dose amount) is based on the tiered, weight-based dosing 
scheme shown in the table below.
Table 4
Initial Dosing of Roxadustat (TIW)
Study Drug
(Dose Frequency)
Weight
(≥45.0 to ≤70.0 kg)
Weight
(> 70.0 to ≤160.0 kg)
Roxadustat (TIW)
70 mg
100 mg
All subjects will administer study drug doses TIW. The period between two roxadustat 
administrations should be at least 36 hrs and no more than 4 days apart.
Investigators and subjects should make every effort to keep dosing days and dosing times 
consistent throughout the study. 
The roxadustat treated subjects that had entered the study under protocol v1.0, upon signing 
the informed consent for the amendment 1, had their dose frequency (on QW and BIW under 
protocol v1.0) and dose amount adjusted according to the instructions in Appendix 12.3
Section 5.1.2 describes the dose adjustment rules within this protocol to enable investigators 
to adjust the dose for their subjects to achieve Hb correction and to maintain their Hb levels 
within the predefined target range in this study.
Subjects receiving darbepoetin alfa
Darbepoetin alfa dosing is to follow the EU SmPC. The initial dosing is weight based. 
Darbepoetin alfa will be administered by SC or IV injection by the investigator or a qualified 
member of the site staff or, after 36 weeks of treatment, by the subject themselves or 
caregiver, e.g., relative, if well trained and willing to self-administer.
Similar to roxadustat treatment, the target of treatment is achieving Hb correction (defined as 
Hb values of ≥11.0 g/dL and Hb increase from BL Hb ≥1.0 g/dL at 2 consecutive study 
visits separated by at least 5 days [as assessed by the central laboratory]) and thereafter 
maintaining Hb in the target range of 10.0 to 12.0 g/dL.
5.1.2
Changes in Study Drug Dose
5.1.2.1 Dose Adjustment Rules for Subjects Receiving Roxadustat
Dose adjustments are permitted from week 4 onward, and every 4 weeks thereafter. All dose 
adjustments are made to maintain study subjects’ Hb level within the predefined target range.
Dose adjustments will follow unique dose adjustment rules [Table 5].

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 65 of 160
Version 3.0, Incorporating Substantial Amendment 2
Dose Adjustment for Excessive Hematopoiesis
If at any time during the treatment period Hb increases by > 2.0 g/dL at any time within 
4 weeks, the dose should be reduced by one dose step.
Note: Only one dose reduction for excessive hematopoiesis is recommended within a period 
of 4 weeks. If a blood transfusion or ESA treatment has been performed within 2 weeks of 
meeting the criteria for excessive hematopoiesis, it is recommended not to perform a dose 
reduction for excessive hematopoiesis.
After a dose adjustment due to excessive hematopoiesis, the subject’s next dose adjustment 
review will occur 4 weeks later, and in 4-weekly intervals thereafter.
5.1.2.2 Dose Adjustment Rules for Subjects Receiving Darbepoetin Alfa
The initial dose is weight-based according to the EU SmPC and either 0.45 μg/kg body 
weight, as a single SC or IV injection once weekly or 0.75 μg/kg body weight, as a single SC 
injection once every two weeks, as judged appropriate by the investigator. Dose adjustment 
should be made according to the EU SmPC.
If the rise in Hb is greater than 2.0 g/dL in 4 weeks, the dose is to be reduced by 
approximately 25%. Once the target Hb level has been achieved with once every 2-week 
dosing, darbepoetin alfa may be administered SC once monthly using an initial dose equal to 
twice the previous once every 2-week dose.
All these dose adjustments are made based on Hb values using HemoCue in both the 
correction and the maintenance period.
Target of treatment is achieving Hb correction (defined as Hb values of ≥11.0 g/dL and Hb 
increase from BL Hb ≥1.0 g/dL at 2 consecutive study visits separated by at least 5 days [as 
assessed by the central laboratory]) and thereafter maintaining Hb in the target range of 
10.0 to 12.0 g/dL.
5.1.3
Previous and Concomitant Treatment
5.1.3.1 Previous Medication
Previous medications are any prescription or over-the-counter preparations, including herbal 
products and “natural remedies”, used by a subject prior to screening.
If not specified differently, intake of any medication within four months prior to 
randomization should be documented in the eCRF. The medication name, start and stop date, 
route, dose and frequency, and indication for each medication will be entered in the eCRF.
The last treatment course of any previous treatment type received for anemia (medication or 
procedures such as ESAs, iron (IV or oral), and RBC transfusions) within 12 months prior to 
randomization will be documented in the eCRF. The medication name, start and stop date, 
route, dose and frequency, and indication for each medication will be entered in the eCRF.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 66 of 160
Version 3.0, Incorporating Substantial Amendment 2
Certain previous medications are prohibited for a specified time frame prior and/or during the 
study treatment period and/or until EOS. These medications and restrictions are described in 
Section 5.1.3.3
5.1.3.2 Concomitant Medication
Concomitant medications are any prescription or over-the-counter preparations, including 
herbal products and “natural remedies”, used by a subject from informed consent to EOS 
visit. The medication/therapy name, start and stop date, route (if applicable), total daily dose 
(if applicable) and indication for each medication/therapy will be entered in the eCRF.
For all concomitant medication use, from screening visit to EOS visit, the study site must 
provide an indication for its use. If the stated indication is a non-specific condition, e.g.,
“rash”, documentation of the condition, as specific as possible, should be maintained in the 
subject’s clinical study records as source documentation.
5.1.3.2.1
Supplemental Iron Use
Subjects receiving roxadustat
i. Oral iron
For subjects receiving roxadustat, oral iron is recommended for dietary supplementation to 
support erythropoeisis and as the first-line for prevention and treatment of iron deficiency,
unless the subject is intolerant to this treatment. The recommended daily dose is 200 mg of 
elemental iron. Subjects should be advised to take roxadustat at least one hour before or one 
hour after oral iron.
ii. IV iron
For subjects receiving roxadustat, IV iron supplementation is allowed if all of the following 
criteria are met:

The subject has not responded adequately in terms of hemoglobin response to 2 or more 
consecutive dose increases of roxadustat or reached the maximum dose limit, and

The subject has iron deficiency (either ferritin < 100 ng/mL [< 220 pmol/L] or 
TSAT < 20%) or the subject is intolerant of oral iron therapy.
Treatment with roxadustat may continue during IV iron administration. Discontinuation of 
IV iron administration is recommended once ferritin levels are ≥100 ng/mL (≥220 pmol/L) 
and TSAT ≥20%.
Subjects receiving darbepoetin alfa
For subjects treated with darbepoetin alfa, oral or IV iron supplementation is required to 
maintain iron repletion. IV iron should only be administered if ferritin < 100 ng/mL
(< 220 pmol/L) or TSAT < 20%. IV iron may be administered per local practice. 
Discontinuation of IV iron therapy is recommended once ferritin levels are ≥100 ng/mL 
(≥220 pmol/L) and TSAT ≥20%. 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 67 of 160
Version 3.0, Incorporating Substantial Amendment 2
5.1.3.2.2
Statins and Other Substrates for OATP1B1
For subjects receiving roxadustat
There is a risk that roxadustat will increase the plasma levels of statins and other drugs that 
are substrates of OATP1B1, based on results from drug drug interaction studies. Because 
statin dose has been known to be associated with the risk for side effects such as myopathy, 
(e.g., myalgia, myositis and rhabdomyolysis), the investigator is advised to consider this 
potential interaction between roxadustat and statins when deciding on the appropriate dose of 
statins based on efficacy and safety of statin therapy. Switching to a non-interacting statin 
(e.g., pravastatin) may be considered. Furthermore, it is recommended not to exceed the 
proposed maximum daily dose of statins as outlined in [Table 6].
The investigator is also advised to consider this potential interaction between roxadustat and 
other drugs that are substrates for OATP1B1 when deciding on the appropriate posology of 
these drugs. Examples of these drugs are atrasentan, bosentan, ezetimibe, repaglinide, 
glyburide, SN-38 (active metabolite of irinotecan), rifampin, valsartan and olmesartan. It is 
recommended to refer to the SmPCs of these drugs for further details and guidance.
Table 6
Proposed Maximum Daily Dose of Statins Not to Be Exceeded
Statin
Proposed maximum dose (mg/day)
Simvastatin
20
GFR < 30 mL/min: 5
Atorvastatin
40
Rosuvastatin
10
Severe renal impairment:* no recommendation as 
contraindicated in this case
Fluvastatin
40
GFR < 30 mL/min: 20
Pravastatin
40
Pitavastatin
2
GFR < 30 mL/min: 1
* The rosuvastatin SmPC defines severe renal impairment as GFR < 30 mL/min.
5.1.3.2.3
Phosphate Binders and Other Multivalent Cation-containing Drugs and 
Mineral Supplements
For subjects receiving roxadustat
Results from a drug-drug interaction study demonstrated a significant reduction in roxadustat 
plasma exposure when a single dose of roxadustat was administered simultaneously with the 
phosphate binders sevelamer carbonate or calcium acetate.
Subjects should take roxadustat in a consistent manner relative to their phosphate binder 
intake, and discuss with the investigator before changing their phosphate binder dose or 
dosing time. To reduce the effect of phosphate binders on roxadustat exposure, subjects 
should take roxadustat at least one hour before or one hour after their phosphate binder.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 68 of 160
Version 3.0, Incorporating Substantial Amendment 2
It is anticipated that other multivalent cation-containing drugs and mineral supplements (e.g.,
iron, calcium, magnesium, aluminium), sucralfate or magnesium- or aluminium-containing 
antacids would produce a similar interaction; therefore, subjects should take roxadustat at 
least one hour before or one hour after intake of these preparations.
5.1.3.2.4
Anti-hypertensive Medications
To avoid confounding effects on study endpoints, changes to anti-hypertensive medications 
should be minimized, and made only if deemed medically necessary by the investigator or if 
prespecified changes in blood pressure are met.
5.1.3.3 Prohibited Medication
The following medications are prohibited during the period identified (see also 
Appendix 12.1):

Any ESA: within 12 weeks prior to randomization until EOT

IV iron: within 6 weeks prior to randomization. 

RBC transfusion: within 8 weeks prior to randomization. 

Any investigational drug: within 30 days or 5 half lives or limit set by national law 
(whichever is longer), prior to screening until EOS

Roxadustat or another HIF-PHI: at any time prior to randomization. After randomization 
any HIF-PHI other than roxadustat, as allocated by randomization, until EOS

Androgens from day of randomization until EOS

Iron-chelating agents (e.g., deferoxamine, deferiprone, or deferasirox therapy): from 
4 weeks prior to randomization until EOS

Dapsone in any dose amount or chronic use of acetaminophen/paracetamol > 2.0 g/day 
from the day of randomization until EOS
Use of herbal medicine is not prohibited but strongly discouraged during the course of the 
study.
5.1.3.4 Procedure and Non-drug Therapy Recording
Any other procedures or non-drug therapies need to be recorded from informed consent until 
EOT. This also includes the recording of hospitalizations until the projected date of week 108.
5.1.4
Treatment Compliance
For subjects randomized to roxadustat, the quantity of study drug dispensed to and returned 
by the subject will be counted and recorded in the eCRF (see Section 5.1.1). If the subject is 
not compliant with study drug intake, the investigator should discuss this with the subject.
Deviations from the prescribed dose should be entered into the eCRF and require notification 
to the Sponsor. All roxadustat bottles dispensed to the subject should be returned by the 
subject to the site, including empty bottles for reconciliation by the study monitor.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 69 of 160
Version 3.0, Incorporating Substantial Amendment 2
For subjects randomized to darbepoetin alfa the administration of each dose at site will be 
recorded in the eCRF with information on dose and route and reasons for each dose change.
All administrations will be performed by the investigator or a qualified member of the site 
staff or, after 36 weeks of treatment, by the subject themselves or caregiver, e.g., relative, if 
well trained and willing to self-administer.
The quantity and dose of syringes dispensed to and taken by the subject will be counted and 
recorded in the eCRF. The empty packages of darbepoetin alfa should be stored at site for 
reconciliation by the study monitor. In case of self-administration after 36 weeks of treatment, 
the empty packages of darbepoetin alfa should be returned by the subject to the site.
5.1.5
Rescue Therapy Guidelines
Rescue therapy guidelines are provided to optimize standardization of the use of rescue 
therapy by investigators and to ensure safety of the individual study subjects.  Use of rescue 
therapy and reason for rescue therapy should be recorded in the eCRF.
1) RBC Transfusion (for all subjects)
In the event of acute or severe blood loss, RBC transfusion is allowed if clinically indicated. 
In a situation where there is no obvious blood loss, RBC transfusion will be permitted if the 
subject has moderate to severe symptom(s) from his/her anemia, e.g., dyspnea at rest or on 
mild exertion, and the investigator is of the opinion that the blood transfusion is a medical 
necessity. Study treatment may be continued even if a blood transfusion has been 
administered.
2) ESA (only for subjects treated with roxadustat)
If the investigator considers administration of ESA as a medical necessity, darbepoetin alfa 
may be initiated if the following criteria are met:

the subject’s Hb level is < 9.0 g/dL (HemoCue) as confirmed at two consecutive 
visits,
AND

the subject’s Hb level has not responded adequately despite 2 or more roxadustat dose 
increases in the previous 8 weeks, or the roxadustat dose reached the maximum dose 
limit,
AND

reducing the risk of alloimmunization in transplant eligible subjects and/or reduction 
of other RBC transfusion-related risks is a goal.
Prior to the initiation of darbepoetin alfa, the subject’s Hb response, as well as factors 
influencing the Hb response, such as iron status, inflammatory status, hemolysis, blood loss 
or other potential reasons for Hb decrease should be considered and, where applicable, be 
addressed by the investigator.
The subject may continue in the study while on rescue treatment with darbepoetin alfa, 
however, it is not allowed to administer roxadustat during the same time period.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 70 of 160
Version 3.0, Incorporating Substantial Amendment 2
The course of darbepoetin alfa (i.e., the amount that may be administered) will be limited by 
duration of therapy and effect on Hb. The course of darbepoetin alfa rescue treatment will 
not exceed 4 weeks in duration, and darbepoetin alfa rescue will be stopped as soon as 
Hb ≥9.0 g/dL. To continue study participation, treatment with roxadustat study drug should 
be resumed within one week after the last administration of darbepoetin alfa at the dose level 
the subject was on prior to initiating darbepoetin alfa rescue therapy.
If a subject requires a second course of rescue darbepoetin alfa, the subject must be 
discontinued from treatment.
5.1.6
Emergency Procedures
Therapeutic Phlebotomy
If there are clinical concerns for a subject’s high Hb levels, the investigator may decide to 
perform a therapeutic phlebotomy instead of, or in addition to, a study treatment dose hold. 
This should be documented in the eCRF and source documentation, and discussed with the
Medical Monitor.
5.1.7
Restrictions During the Study
Subjects are not permitted to consume more than three alcohol-containing drinks per day 
during the treatment or follow-up periods.
Female subjects of childbearing potential must agree to not try to become pregnant during the 
study and for 28 days after the final study drug administration, AND must have a negative 
serum pregnancy test at screening AND, if heterosexually active, must agree to use a highly 
effective form of birth control as stated in the inclusion criteria. If required by local law, 
2 highly effective methods of birth control must be used, 1 of which must be a barrier method.
Contraception must be practiced from start of screening until 28 days (female subjects), and 
until 12 weeks (male subjects with female partners of childbearing potential) after the last 
dose of study treatment. If a subject discontinues prematurely, contraception must be 
practiced for 12 weeks (male subjects) and 28 days (female subjects) following final 
administration of study treatment.
Pregnancy, spontaneous or therapeutic abortion, or events related to pregnancy must be 
reported (see Section 5.5.7).
5.2
Demographics and Baseline Characteristics
5.2.1
Demographics
Demographic data recorded during screening, including date of birth (depending on local 
regulations; if full date of birth cannot be recorded, only year of birth will be recorded), sex, 
race, height, and body weight will be recorded in the eCRF.
5.2.2
Medical History
A detailed medical history, including detailed cardiovascular history, will be obtained at 
screening. All relevant past and present conditions as well as prior surgical procedures, and 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 71 of 160
Version 3.0, Incorporating Substantial Amendment 2
previous and current tobacco use will be recorded in the subject’s eCRF. Relevant conditions 
include conditions that have been treated with medication within four months prior to 
randomization. Additionally, family history of cardiovascular diseases in first degree 
relatives (occurring before the age of 60) will be obtained.
5.2.3
Renal Ultrasound
A renal ultrasound examination should be performed within 12 weeks prior to randomization. 
This is not required if results of a previous renal ultrasound (or other renal imaging modality 
such as CT scan or MRI) within 12 weeks prior to randomization are available and it 
conclusively excludes the presence of renal cell carcinoma. Renal ultrasound findings are 
required prior to randomization to exclude subjects with a presence or suspicion of renal cell 
carcinoma (exclusion criterion 16). Sites are reminded to schedule the renal ultrasound, 
following the first screening visit and prior to randomization, only for those subjects that 
have not had a renal ultrasound, or other renal imaging modality, in the specified period. The 
date of the renal ultrasound examination and the assessment of the presence or suspicion of 
renal cell carcinoma will be collected in the eCRF.
5.2.4
Diagnosis of the Target Disease, Severity, and Duration of Disease
A detailed anemia and CKD history for each subject will be obtained at screening and 
recorded in the eCRF. This includes date of diagnosis and symptoms of anemia, the date of 
diagnosis of CKD, CKD stage and etiology. Also the non-drug therapy history and 
medication history for anemia in the last 12 months prior to randomization will be obtained.
CKD stages 3, 4 and 5 is defined as eGFR < 60 mL/min/1.73 m2 for ≥3 months, with or 
without kidney damage and not requiring dialysis. This is in line with the diagnosis criterion 
for CKD as defined by KDOQI. Documentation of reduced eGFR should be available in the 
subject’s source documentation. In addition, calculation of eGFR to confirm the degree of 
CKD will be performed by the central laboratory at screening for eligibility and on day 1.
eGFR will be calculated using the following MDRD equation: GFR (mL/min per 1.73 m2) = 
175 × Serum Cr –1.154 × age–0.203 × (0.742, if female) × (1.212, if black).
Anemia will be measured by repeated Hb measurements (central laboratory assessment) 
during screening; the mean of the 2 most recent Hb values during the screening period, 
obtained at least 4 days apart, must be ≤10.5 g/dL with a difference of ≤1.0 g/dL. The last 
Hb value must be within 10 days prior to randomization.
Exclusion of other causes of anemia should be based upon assessments of

Complete blood count (CBC), which will include Hb concentration, RBC indices, WBC 
count and differential, platelet count and reticulocyte count

Iron status

Serum vitamin B12 and folate levels.
For more details on the laboratory tests, please see Section 5.4.3

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 72 of 160
Version 3.0, Incorporating Substantial Amendment 2
5.2.5
Further Laboratory Testing Prior to Randomization
Other laboratory tests mandatory prior to randomization of a subject include immunoassay
for HIV, Hepatitis B (HBsAg) and hepatitis C antibody (anti-HCV Ab) and serum pregnancy 
test for women of childbearing potential only, serum chemistry and serum lipid panel.
For more details on the laboratory tests please refer to Section 5.4.3.3
5.3
Efficacy Assessment
5.3.1
Primary Efficacy Assessment
Efficacy assessment of treatment with study treatment will be based primarily upon Hb as 
assessed by central laboratory from IV blood sampling.
For the exact timing of Hb assessments refer to the Schedule of Assessments, [Table 1].
The use of rescue medication (as recorded in the eCRF) will be taken into account for the 
evaluation of the primary efficacy assessment.
5.3.2
Additional Efficacy Assessments
5.3.2.1 Blood Pressure
Blood pressure will be assessed as per schedule of assessment, SBP and DBP will be 
measured and MAP will be calculated. For measurement of blood pressure refer to 
Section 5.4.1.1
5.3.2.2 Serum Lipid Panel
Blood sampling for serum lipids should be done in a fasting condition, wherever possible. 
The following parameters will be assessed: total cholesterol, LDL-cholesterol, 
HDL-cholesterol, triglycerides, apolipoproteins A1 and B.
5.3.3
Additional Assessments
5.3.3.1 Health Related Quality of Life Questionnaires
All study subjects will be required to complete Quality of Life (QoL) questionnaires as 
indicated in the Schedule of Assessments (Table 1): SF-36, FACT-An, EQ-5D 5L, PGIC and 
WPAI:ANS (see Appendices 12.4-12.9). The QoL questionnaires are to be completed by the 
subject prior to any other study assessments on the study visits.
5.3.3.1.1
Short Form-36 Health Survey (SF-36)
The SF-36 is a QoL instrument designed to assess generic health concepts relevant across 
age, disease, and treatment groups. The SF-36 consists of eight domains of health status: 
Physical functioning (10 items), Role-physical (4 items), Bodily pain (2 items), General 
health (5 items), Vitality (4 items), Social functioning (2 items), Role emotional (3 items) and 
Mental health (5 items). Two component scores, the Physical Component Summary and the 
Mental Component Summary can also be calculated. For both the SF-36 domain scores and 
summary scores, higher scores indicate better health status. The SF-36 has a recall period of 
the ‘past four weeks’.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 73 of 160
Version 3.0, Incorporating Substantial Amendment 2
5.3.3.1.2
Functional Assessment of Cancer Therapy –Anemia (FACT-An)
The Functional Assessment of Cancer Therapy- General (FACT-G) Version 4 contains 
27 items that cover four dimensions of physical well being (PWB)—7 items, functional 
(FWB)—7 items, social/family (SWB)—7 items each, and emotional (EWB)—6 items. A 
subscale of 13 fatigue specific items (the Fatigue Subscale) plus seven additional items 
related to anemia were developed for use in conjunction with the FACT-G [Cella, 1997]. 
The 13 fatigue items plus the seven additional items related to anemia comprise the Anemia 
Subscale (AnS). Administration of the FACT-G plus the AnS is referred to as the FACT-An
(see Appendix 12.6). The FACT-An has a recall period of the ‘past seven days’. 
Respondents are asked to provide responses, (i.e., ‘Not at all’, ‘A little bit’, ‘Somewhat’, 
‘Quite a bit’ and ‘Very much’), to a list of statements which are either positively or 
negatively phrased. For all FACT-An scales, a higher score indicates better QoL.
5.3.3.1.3
EuroQol Questionnaire – 5 Dimensions 5 Levels (EQ-5D-5L)
The EuroQol Questionnaire - 5 Dimensions -5 Levels (EQ-5D-5L) is a self-reported 
questionnaire. The EQ-5D is being used as a measure of respondents' Health Related Quality 
of Life (HRQoL) and utility values. The EQ-5D consists of the EQ-5D descriptive system 
and the EQ visual analogue scale (VAS). The EQ-5D descriptive system comprises 
5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate 
problems, severe problems, extreme problems. The VAS records the respondent's self-rated 
health status on a graduated (0–100) scale, where the endpoints are labeled ‘Best imaginable 
health state’ and ‘Worst imaginable health state’ with higher scores for higher HRQoL. 
EQ-5D health states, defined by the EQ-5D descriptive system, may be converted into a 
single summary index by applying a formula that essentially attaches values (also called 
weights) to each of the levels in each dimension. The index can be calculated by deducting 
the appropriate weights from 1, the value for full health (i.e., state 11111). The EQ-5D-5L is 
shown in Appendix 12.7
5.3.3.1.4
Patient Global Impression of Change Scale (PGIC)
The PGIC (Appendix 12.8) is a subject-rated instrument that measures change in subjects’ 
overall status on a 7-point scale ranging from 1 (very much improved) to 7 (very much 
worse), when compared to the start of the study treatment.
5.3.3.1.5
Work Productivity and Activity Impairment Questionnaire: Anemic 
Symptoms (WPAI:ANS)
The objective of the WPAI:ANS (version 2) is to measure work and activity impairment 
during the past seven days due to anemia [Reilly et al, 1993].  It is self-assessed. The 
2 domains covered by the questionnaire are work and daily activities. The WPAI: ANS 
consists of 6 questions, including asking if the subject is working, how many hours the person 
missed work due to anemic symptoms, how many hours the subject actually worked and how 
the anemic symptoms impacted the productivity and ability to do daily activities. The 
WPAI:ANS is shown in Appendix 12.9

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 74 of 160
Version 3.0, Incorporating Substantial Amendment 2
5.3.3.2 Hospitalizations
Details on hospitalizations will be collected at each study visit as indicated in the Schedule of 
Assessments. Reason, admission and discharge dates and type and reason for hospitalization 
will be recorded in the eCRF.
Details of hospitalizations will also be collected at post-study follow-up visits in subjects 
who prematurely discontinued treatment (only if they have taken at least one dose of study 
drug), until the projected date of the EOS visit (week 108).
5.3.3.3 Iron Status, HbA1c, CKD Progression and UACR
Serum iron, TSAT, ferritin, HbA1c, fasting blood glucose, eGFR and UACR will be assessed 
(central laboratory) according to the Schedule of Assessments, Table 1
5.3.3.4 Additional Assessments
Exploratory assessments in this study include the following parameters:

High Sensitivity C-reactive protein (hs-CRP)

Relevant selected biomarkers may be assessed from archived serum/plasma samples and 
urine samples

PGIC Score

WPAI:ANS Score
5.4
Safety Assessment
5.4.1
Vital Signs
The vital signs blood pressure, HR and respiratory rate will be assessed at the visits as 
described in the Schedule of Assessments, [Table 1].
See additional information in Appendix 12.4.
5.4.1.1 Blood Pressure
Blood pressure measurement will be done with the subject comfortably seated in a chair, with 
the legs uncrossed, and the back and arm supported, such that the middle of the cuff on the 
upper arm is at the level of the right atrium (the midpoint of the sternum). The subject will 
be instructed to relax as much as possible and to not talk during the measurement procedure; 
ideally, 5 minutes should elapse before the first reading is taken. Preferably measurement 
will be done with an electronic automated oscillometric device. The same device should 
preferably be used for the subject during the course of the study, timing as indicated in the 
Schedule of Assessments.
Blood pressure (systolic and diastolic) will be measured singly on the 2 visits during the 
screening period, and in triplicate with a least two minute intervals for all other visits. The 
same arm should be used consistently for measurements throughout the study.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 75 of 160
Version 3.0, Incorporating Substantial Amendment 2
5.4.1.2 Heart Rate
Measurement of HR will be done at rest in a sitting position wherever possible. It can be 
performed with an oscillometric device as used for blood pressure measurement (see 
Section 5.4.1.1), by using any other suitable device or manually (wrist HR within 
one minute). The same methodology and device should preferably be used for the subject 
throughout the study, timing as indicated in the Schedule of Assessments.
HR will be measured singly on the 2 visits during the screening period, and in triplicate with 
at least two minute intervals for all other visits. All values will be reported in the eCRF.
5.4.1.3 Respiratory Rate
Measurement of respiratory rate will be done at rest in a sitting position wherever possible. It 
can be performed with any suitable device or manually (number of breathing cycles within 
one minute). The same methodology and device should preferably be used for the subject 
throughout the study, timing as indicated in the Schedule of Assessments. Respiratory rate 
will be measured singly during all visits and reported in the eCRF.
5.4.2
Adverse Events
Adverse Events (AEs) will be collected at all study visits. See Section 5.5 for detailed 
information regarding AE collection and data handling. AE collection starts after obtaining 
signed informed consent and continues until the EOS visit. For subjects who continue in the 
post study follow-up period, SAEs and cardiovascular and thromboembolic AEs will be 
collected. AEs will not be collected during the period between first screen where subject has 
failed screening and first rescreening visit.
The description of the collection and adjudication of prespecified cardiovascular and 
cerebrovascular events will be detailed in a separate adjudication charter. For submission of 
documentation for events that require adjudication, the ICON SQUARE system will be used.
A site manual for the submission of packages for events requiring adjudication will be 
provided to each site and a dedicated staff member (and one back-up person) will be required 
to review the manual prior to getting access to the system.
5.4.2.1 Adverse Events of Possible Hepatic Origin
Subjects with AEs of hepatic origin accompanied by Liver Function Test (LFT)
abnormalities should be carefully monitored.
See Appendix 12.2 Liver Safety Monitoring and Assessment for detailed information on liver 
abnormalities, monitoring and assessment, if the AE for a subject enrolled in a study and 
receiving study drug is accompanied by increases in liver function testing (LFT, e.g.: AST, 
ALT, bilirubin, etc.) or is suspected to be due to hepatic dysfunction.
In the event of a confirmed, severe hepatic abnormality as defined in Appendix 12.2 it is the 
investigator’s responsibility to ensure contact with the Sponsor/delegated CRO (Contract 
Research Organization) by telephone or fax immediately (i.e., within 24 hours of awareness).

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 76 of 160
Version 3.0, Incorporating Substantial Amendment 2
5.4.3
Laboratory Assessments
5.4.3.1 HemoCue
Hb values obtained by HemoCue are used to allow “real-time” dose adjustments for all 
subjects. Date and results of HemoCue measurement will be collected in the eCRF at visits 
specified in the Schedule of Assessments [Table 1]. The HemoCue assessment of Hb will be 
performed on the venous blood sample collected for central laboratory Hb assessment.
5.4.3.2 Urinalysis
Dipstick analysis will be performed for protein, pH and glucose. A quantitative assessment 
of albuminuria (UACR) will be performed by the central laboratory. Ideally, the sample 
should be from the first morning void.
5.4.3.3 Central Laboratory
All safety related tests of blood specimens will be performed by a central laboratory.
Central laboratory results should be reviewed by the investigator or another qualified study 
staff member. Subject management is dependent upon close review of the laboratory data.
Any changes in laboratory values are to be evaluated by the investigator. Clinically relevant 
changes will be recorded as AEs in the eCRF.
Unscheduled and repeat laboratory tests will also be performed by the central laboratory. 
However, in no case should prudent or necessary testing be delayed if it is not possible to 
send a sample to the central laboratory or if the turnaround time from the central laboratory is 
not sufficiently rapid for clinical management of the subject. In such emergency/urgent 
situations local laboratory test results may be used to make clinical judgments that affect the 
safety of the study subject.
A central laboratory manual with instructions on specimen collection, processing, storage and 
shipping to the central laboratory will be provided to all participating sites before they start 
the study.
In Table 7, the laboratory tests that will be performed during the conduct of the study are listed. 
The exact timing of all assessments can be found in [Table 1] Schedule of Assessments.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 77 of 160
Version 3.0, Incorporating Substantial Amendment 2
Table 7
Laboratory Tests
Lab assessment type
Parameters to be analyzed
Hematology
CBC with WBC differential
Hemoglobin (Hb)
Hematocrit (Hct)
Erythrocytes (RBC)
Mean corpuscular volume
Mean corpuscular Hb
Mean corpuscular Hb concentration
Leukocytes (WBC) 
Differential WBC

Neutrophils

Lymphocytes

Monocytes

Eosinophils

Basophils
Platelet count 
Reticulocyte count and Hb in reticulocytes (CHr)
Serum Chemistry
Sodium
Potassium
Calcium
Chloride
Glucose (fasting condition wherever possible)
Creatinine
Magnesium
Bicarbonate
Phosphorus
Uric Acid
Albumin
Total protein
Lactate dehydrogenase
Blood urea nitrogen
Lipase
Liver Function Tests:

AST

ALT

Bilirubin (Total and direct)

GGT

ALP
Lipid Panel (in fasting condition wherever possible):

Total Cholesterol

LDL

HDL

Triglycerides

Apolipoproteins A1, B and ApoB/ApoA1 ratio
Serum iron
Ferritin 
TIBC
TSAT (= measured as FESAT)
Pregnancy test (for female subjects of child bearing potential only)
HbA1c
Vitamin B12
Folate
Table continued on next page

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 78 of 160
Version 3.0, Incorporating Substantial Amendment 2
Lab assessment type
Parameters to be analyzed
Serology (Immunology):

HIV Immunoassay

HBsAg 

Anti-HCV antibody 
Special Laboratory Analytes
hs-CRP
Serum Biomarkers
Archival of serum samples for biomarkers
PK analysis
Level of roxadustat
Covariates for PK

Albumin 

α1-AGP 
Whole Blood
Genotyping
Urinalysis
Qualitative

Protein

pH

Glucose
Quantitative

Creatinine

Albumin

UACR
Archival of urine samples for biomarkers
5.4.4
Physical Examination
A comprehensive physical examination will be conducted during the screening visit, day 1
and at the EOT visit and recorded in the source documents. This examination will include 
general appearance and the following body regions and systems: head, eyes, ears, neck and 
throat (HEENT), lungs, heart, chest and back, abdomen, genitourinary, extremities, skin, and 
any other, if deemed necessary.
A targeted physical examination (e.g., respiratory and cardiovascular) will be conducted
throughout the study as described in Schedule of Assessments, and recorded in the source 
documents.
Only the date of the physical examination will be recorded in the eCRF. Any clinically 
relevant adverse change will be recorded as an AE in the eCRF (see Section 5.5.1).
Height is measured only at screening. Weight is measured at screening, day 1, weeks 24, 36, 
52, 76, EOT and EOS.
5.4.5
Electrocardiogram (ECG)
Local 12-lead ECGs will be performed on all subjects at specific time points as described in
Table 1, Schedule of Assessments. A single ECG will be taken with the subject in the supine 
position, after the subject has been lying quietly for 5 minutes. Any abnormalities must be 
evaluated in clinical context (based on subject’s medical history and concomitant medication) 
and the investigator should determine if it is clinically significant. Clinically significant 
abnormalities should be reported as an AE.
Only the visit, ECG date, HR, PR interval, QRS Interval, QT Interval, overall interpretation 
and relevant comments will be recorded in the eCRF. The RR interval will be calculated 
using the HR in the eCRF. ECG recording will be kept as source documents.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 79 of 160
Version 3.0, Incorporating Substantial Amendment 2
5.5
Adverse Events and Other Safety Aspects
Safety will be assessed throughout the study. A complete BL profile of each subject will be 
established through medical history, clinical laboratory values, vital signs, physical 
assessments and ECGs. During the course of the study, vital signs, complete and targeted 
physical assessments, laboratory tests and ECGs will be performed at several intervals. Any 
medically significant changes from BL will be monitored throughout the study and appropriate 
interventions will be taken accordingly. Clinical laboratory tests may be assessed at additional 
times on unscheduled visits for safety reasons.
AEs, SAEs, and ongoing concomitant medication usage will be monitored and recorded 
throughout the study.
5.5.1
Definition of Adverse Events (AEs)
An AE is defined as any untoward medical occurrence in a subject administered a study drug 
or has undergone study procedures and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product.
Some countries may have additional local requirements for events that are required to be 
reported as AEs or in an expedited manner similar to an SAE. In these cases, it is the 
investigator’s responsibility to ensure these AEs or other reporting requirements are followed 
and the information is appropriately recorded in the (e)CRF accordingly.
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG 
data, physical exam) should be defined as an AE only if the abnormality meets one of the 
following criteria:

Induces clinical signs or symptoms

Requires active intervention

Requires interruption or discontinuation of study medication

The abnormality or investigational value is clinically significant in the opinion of the 
investigator.
AEs present prior to study treatment will be considered as ‘non-treatment emergent’.
Baseline conditions that worsen during the study will be recorded as AEs. AEs with a start 
date after subjects have completed EOS procedures will not be captured.
For AEs that resolve during the subject’s participation in the study, a resolution date will be 
documented in the eCRF.  AEs will be followed until resolved, stable, or until the subject’s 
last study visit or lost to follow up. AEs ongoing at the EOS visit will be followed up for as 
long as necessary to adequately evaluate the subject’s safety or until the event stabilizes and 
documented in source documents only.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 80 of 160
Version 3.0, Incorporating Substantial Amendment 2
Data to be recorded in the eCRF include a description of the event, date of onset, onset status 
(onset before/after first dose of study medication), end of the event, severity, SAE, 
seriousness criteria, action with respect to study medication, treatment required, relationship 
to study treatment and outcome of the event.
The study period during which all AEs and SAEs must be reported begins after informed 
consent is obtained and ends 28 days after the last dose of study treatment or through to EOS, 
except for pregnancy reporting (see Section 5.5.7). For subjects that continue into the post 
study follow-up period, SAEs, cardiovascular and thromboembolic AEs will be captured
until their projected date of completion of the follow-up period (i.e., projected week 108).
During the AE reporting period, study site personnel will query each subject at each visit to 
actively solicit any AE occurring since the previous visit. All AEs will be collected in 
response to a general question about the subject’s well-being and any possible changes from 
the BL or previous visit, but shall not be specifically solicited. There will be no directed 
questioning for any specific AE. This does not preclude the site from collecting and 
recording any AEs reported by the subject to site personnel at any other time.
Whenever possible, diagnoses should be recorded when signs and symptoms are due to a 
common etiology as determined by qualified medical study staff. New indications for 
medications started after informed consent until 28 days after the last dose of study treatment
or through to EOS visit, will be recorded as AEs; recurrence or worsening of medical history 
problems requiring new or changes in concomitant medication, will also be recorded as AEs. 
Abnormal, clinically significant laboratory results, physical examination findings, and ECGs 
will be recorded as AEs if they are deemed by the investigator to meet criteria.
5.5.2
Definition of Serious Adverse Events (SAEs)
An AE is considered “serious” if, in the view of either the investigator or Sponsor, it results 
in any of the following outcomes:

Results in death

Is life threatening (an AE is considered “life-threatening” if, in the view of either the 
investigator or Sponsor, its occurrence places the subject at immediate risk of death. It 
does not include an AE that, had it occurred in a more severe form, might have caused 
death)

Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 

Results in congenital anomaly, or birth defect

Requires inpatient hospitalization or leads to prolongation of hospitalization 
(hospitalization for treatment/observation/examination caused by AE is to be considered 
as serious) 

Other medically important events
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the subject 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 81 of 160
Version 3.0, Incorporating Substantial Amendment 2
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These events, including those that may result in disability/incapacity, should also usually be 
considered serious. Examples of such events are intensive treatment in an emergency room or 
at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. Additionally, Astellas 
requests that all medical events listed in Appendix 12.2 (Liver Safety Monitoring and 
Assessment) be reported by the Investigator as SAEs, even if none of the above criteria apply.
Safety events of interest (“Special Situations”) on the medicinal products administered to the 
subject as part of the study (e.g., study drug, comparator, background therapy) that may 
require expedited reporting and/or safety evaluation include, but are not limited to:

Overdose of the medicinal product

Suspected abuse/misuse of the medicinal product

Inadvertent or accidental exposure to the medicinal product

Medication error involving the medicinal product (with or without subject/patient 
exposure to the Sponsor medicinal product, e.g., name confusion)

Drug-drug interactions
Concerning other special situations:  lack of efficacy is not to be recorded or reported as an 
AE in this study, as the study end point monitors the effect of the study drug. Due to the 
method of oral administration of roxadustat the risk of transmission of infectious agents is 
limited for which these events do not need to be reported. Off-label use of roxadustat can be 
excluded for reporting as the product is under development.
All of the events of interest noted above should be recorded on the SAE and/or Special 
Situation worksheet and within the timelines of reporting SAEs, thus within 24 hours of 
becoming aware of this event, regardless whether or not a (S)AE occurred. The above special 
situations will not be captured on the AE form in the eCRF, instead they will be captured in 
the dosing and accountability forms within the eCRF.
If a special situation also induces an adverse event, this AE should be recorded on the AE 
page of the eCRF. Note, the seriousness criteria described in this section do not apply for the 
above special situations themselves but only for their potentially induced adverse events. 
This means that on the SAE worksheet the seriousness criteria for a special situation only 
should be left blank.
The Sponsor has a list of events that they classify as “always serious” events. If an AE is 
reported that is considered to be an event per this classification as “always serious”, 
additional information on the event may be requested as well as expedited reporting within 
the timelines as demanded for SAEs.
If a subject becomes pregnant during treatment, this should be reported as if it were a SAE. 
Refer to Section 5.5.7

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 82 of 160
Version 3.0, Incorporating Substantial Amendment 2
5.5.3
Criteria for Causal Relationship to the Study Drug
AEs that fall under either "Possible" or "Probable" should be defined as "AEs whose 
relationship to the study drugs could not be ruled out".
Causal relationship to 
the study drug
Criteria for causal relationship
Not Related
A clinical event, including laboratory test abnormality, with a 
temporal relationship to drug administration which makes a causal 
relationship improbable, and/or in which other drugs, chemicals or 
underlying disease provide plausible explanations.
Possible
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, but which 
could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking or 
unclear.
Probable
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely to 
be attributed to concurrent disease or other drugs or chemicals, and 
which follows a clinically reasonable response on re-administration 
(rechallenge) or withdrawal (dechallenge).
5.5.4
Criteria for Defining the Severity of an Adverse Event
AEs, including abnormal clinical laboratory values, will be graded using the National Cancer 
Institute-Common Terminology Criteria for AE (NCI-CTCAE) guidelines (Version 4.03). 
The items that are not stipulated in the NCI-CTCAE Version 4.03 will be assessed according 
to the criteria below and entered into the eCRF:
Grade
Assessment Standard
1-Mild
Asymptomatic, or mild symptoms, clinical or diagnostic observations 
noted; intervention not indicated.
2-Moderate
Local or noninvasive intervention indicated.
3-Severe
Medically significant but not immediately life threatening, 
hospitalization or prolonged hospitalization.
4-Life Threatening
Life threatening consequences, urgent intervention indicated
5-Death
Death related to AE
5.5.5
Reporting of Serious Adverse Events (SAEs)
In the case of a serious adverse event (SAE), the investigator must contact his/her respective
delegated CRO (INC Drug Safety or other CRO as specified in the Investigator Site File) by 
telephone or fax immediately (within 24 hours of awareness).
The investigator should complete and submit an SAE worksheet containing all information that 
is required by the Regulatory Authorities to the delegated CRO by fax or email immediately 
(within 24 hours of awareness).  If the faxing or e-mailing of an SAE Worksheet is not 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 83 of 160
Version 3.0, Incorporating Substantial Amendment 2
possible or is not possible within 24 hours, the local drug safety contact should be informed by 
phone.
The SAE worksheet should be sent to the delegated CRO that is responsible for the 
investigator’s country:
INC Drug Safety or other CRO as specified in the Investigator Site File:
Email: INCDrugSafety@INCResearch.com
Fax: toll-free numbers will be provided for each country; the specific fax number can be 
found on the SAE form fax cover sheet
Tel: +49 89 99 39 13 198
After checking for completeness and accuracy, the delegated CRO will send the SAE 
worksheet and (when present) source documents (within 24 hours of receipt) to the Sponsor. 
If there are questions, or if clarification is needed regarding the SAE, please contact the 
Sponsor’s Medical Monitor or his/her designee or the delegated CRO that is responsible for 
the investigator’s country (for contact details, see Section II of the protocol and as specified 
on the contact list in the Investigator Site File).
Follow-up information for the event should be sent promptly (within 7 days of the initial 
notification).
Full details of the SAE should also be recorded on the medical records and on the eCRF.  
The following minimum information is required to be completed on the SAE Worksheet:

The ISN/Study number 1517-CL-0610

Subject number, sex and age

The date of report

A description of the SAE (event, seriousness of the event), and

Causal relationship to the study drug
All SAEs, including death, should be reported, when occurring up to EOS visit or up to 
28 days after the last intake of study medication, whichever is last. In addition, any event 
leading to hospitalization and/or death during the post-study follow-up period should also be 
reported as an SAE.
The Sponsor or Sponsor's designee will submit expedited safety reports to the regulatory 
agencies as necessary, and will inform the investigators of such regulatory reports. 
Investigators must submit safety reports as required by their Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) within timelines set by regional regulations (i.e., 
EU). Documentation of the submission to and receipt by the IRB/IEC of expedited safety 
reports should be retained by the site.
The CRO will notify all investigators responsible for ongoing clinical studies with the study 
drug of all SAEs which require submission per local requirements IEC.
The investigators should provide written documentation of IRB/IEC notification for each 
report to the Sponsor.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 84 of 160
Version 3.0, Incorporating Substantial Amendment 2
Please contact the Sponsor's Medical Monitor for any other problem related to the safety, 
welfare, or rights of the subject.
5.5.6
Follow-up of Adverse Events
All AEs occurring during or after the subject has discontinued the study are to be followed up 
until resolved or judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized.
If during AE follow-up, the AE progresses to an "SAE", or if a subject experiences a new 
SAE, the investigator must immediately report the information to the Sponsor.
Please refer to Appendix 12.2 for detailed instructions on Drug Induced Liver Injury.
5.5.7
Procedure in Case of Pregnancy
If a female subject or female partner of a male subject becomes pregnant during the study 
dosing period or within 12 weeks from the discontinuation of dosing, the investigator should 
report the information to the delegated CRO as if it is an SAE. Besides completion of the SAE 
Worksheet, a separate Pregnancy Form should be completed: part A at time of pregnancy 
reporting and part B when outcome of pregnancy is known. The expected date of delivery or 
expected date of the end of the pregnancy, last menstruation, estimated fertility date, pregnancy 
result and neonatal data etc., should be included in this information.  Additional details should 
be provided in part C during the pregnancy and/or after the delivery.
The investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE and will report the outcome to the Sponsor.
When the outcome of the pregnancy falls under the criteria for SAEs (spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly [including anomaly in a 
miscarried fetus]), the investigator should respond in accordance with the report procedure for 
SAEs. Additional information regarding the outcome of a pregnancy (which is categorized as 
an SAE) is mentioned below.

"Spontaneous abortion" includes miscarriage, abortion and missed abortion

Death of an infant within 1 month after birth should be reported as an SAE regardless of 
its relationship with the study drug

If an infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by 
the investigator

In the case of a delivery of a living newborn, the "normality" of the infant is evaluated at 
the birth

Unless a congenital anomaly are identified prior to spontaneous abortion or miscarriage, 
the embryo or fetus should be assessed for congenital defects by visual examination
If during the conduct of a clinical trial, a male subject makes his partner pregnant, the subject 
should report the pregnancy to the investigator. The investigator will report the pregnancy to 
the delegated CRO as an SAE.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 85 of 160
Version 3.0, Incorporating Substantial Amendment 2
5.5.8
Emergency Procedures and Management of Overdose
In the event of suspected roxadustat overdose, the subject should receive supportive care and 
monitoring. If clinically indicated, phlebotomy may be performed. The Medical Monitor 
should be contacted as applicable.
In the event of suspected darbepoetin alfa overdose, refer to the approved EU SmPC.
The therapeutic margin of darbepoetin alfa is very wide. Even at very high serum levels, no 
symptoms of overdose have been observed. In the event of polycythemia, darbepoetin alfa 
should be temporarily withheld. If clinically indicated, phlebotomy may be performed.
5.5.9
Supply of New Information Affecting the Conduct of the Study
When new information becomes available necessary for conducting the clinical study 
properly, the Sponsor will inform all investigators involved in the clinical study as well as the 
regulatory authorities. Investigators should inform the IRB/IEC of such information when 
needed.
5.6
Test Drug Concentration
For the purpose of evaluation of the population PK, blood samples will be obtained from the 
subjects that are treated with roxadustat. The intention is to collect 6 blood samples per 
roxadustat-treated subject at the following time points:
A: 2 to 0 hours prior to dosing
B: 1 to 2 hours after dosing
C: 2 to 3 hours after dosing, at least 60 minutes after sample B
D: 3 to 5 hours after dosing, at least 60 minutes after sample C 
E: 4 to 6 hours after dosing, at least 60 minutes after sample D
F: 6 to 10 hours after dosing, at least 2 hours after sample E.
The blood samples can be collected at one visit, or over 2 to 3 visits. These visits should take 
place between weeks 2 and 8 of the treatment period:

Samples A, B and C should be collected during the same visit

Samples D and E should be collected on the same visit 

Sample F can be collected during the same visit as samples D and E, or during a separate 
visit. Sample F should be collected as late as possible during the PK visit (last assessment 
of the visit).
The investigator is free to choose at which study visits, between week 2 and 8 of treatment, to 
draw the samples and in which order. The study site will agree with the subjects on timing 
and process of the sampling. Based on preference of the study site and the subject, there is a 
choice of three sampling schedules to perform the PK samples collection, see [Table 8].
During weeks 1 to 8, subjects treated with roxadustat will be instructed to record the date and 
time of study drug intake in the study medication diary. The information will be used to record 
the date and time of roxadustat intake on the dosing day prior to PK sampling and on the day 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 86 of 160
Version 3.0, Incorporating Substantial Amendment 2
of PK sampling in the eCRF. The date and time of PK sampling and the actual study drug dose 
taken on the day of sampling will be recorded in the eCRF.
During the PK visits one additional sample will be collected for determination of alpha 
1-Acid Glycoprotein (α1-AGP) and albumin concentration.
Table 8
Examples of Sampling Schedules for Population PK
Schedule#
PK Visit 1
PK Visit 2
PK Visit 3
1
Collect pre-dose sample A.
Take study drug in clinic.
Collect samples B to F.
None
None
2
Collect pre-dose sample A.
Take study drug in clinic.
Collect samples B and C.
Take study drug.
Collect samples D to F.
None
3
Collect pre-dose sample A.
Take study drug in clinic.
Collect samples B and C.
Take study drug.
Collect sample D and E.
Take study drug.
Collect sample F.
# The order of the PK visits for schedule 2 and 3 is a decision for the investigator.
5.6.1
Blood Samples for Roxadustat PK Analysis
Samples of venous blood for bioanalysis of roxadustat, related metabolites of roxadustat and 
exploratory biomarkers will be collected into appropriately labeled tubes containing sodium-
heparin as anticoagulant.
All further details on the processing of the samples, storage and shipment conditions will be 
provided in the laboratory manual.
5.7
Other Measurements, Assessments or Methods
5.7.1
α1-AGP and Albumin in Serum
Serum levels of albumin and α1-AGP will be included as covariate in the PK analysis, since 
both albumin and α1-AGP is involved in plasma protein binding of roxadustat. Serum 
albumin and α1-AGP will be analyzed by the central laboratory using a standardized assay. 
To perform the analysis, 2 mL blood samples will be collected on the same day as PK 
sampling is performed (1-3 visits). If 1 or more PK samples are taken at a visit, one α1-AGP 
sample should be taken at that visit as well.
All details on the processing of the samples, storage and shipment conditions will be 
provided in the laboratory manual.
5.7.2
Archival of Serum Samples for Biomarker Analysis
Serum samples will be drawn at the timepoints as indicated in Table 1. The processed 
samples will be stored and archived for potential future analysis of relevant biomarkers, 
linked with the efficacy or safety of the study drugs, prognosis and outcomes. These archival 
samples will be destroyed (if not used in total), maximally 5 years after the last subject 
completed the study. All details on the processing of the samples, storage and shipment 
conditions will be provided in the central laboratory manual.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 87 of 160
Version 3.0, Incorporating Substantial Amendment 2
5.7.3
Archival of Urine Samples for Biomarker Analysis
Urine samples will be drawn at the timepoints as indicated in Table 1. The processed 
samples will be stored and archived for potential future analysis of relevant biomarkers.
These archival samples will be destroyed (if not used in total), maximally 5 years after the 
last subject completed the study. All details on the processing of the samples, storage and 
shipment conditions will be provided in the central laboratory manual.
5.7.4
Optional Genotyping Sample
It is now known that roxadustat is a substrate of various transporters as well as metabolizing 
enzymes. Some of these proteins are polymorphic, resulting in different phenotypes in the 
standard human population. In order to clarify and explain the possible differences observed 
in the study subjects, exploratory (and optional) genotyping sampling will be included in this 
study for subjects randomized to the roxadustat arm.
If a separate (optional) informed consent is signed by the subject, a 5 mL whole blood sample 
for genotyping can be done at any time during the study.  The sample will be collected into 
pre-labeled polypropylene collection tubes containing EDTA as anti-coagulant. The sample 
will be taken via venipuncture or cannulation of a forearm vein. The genotyping tube will 
not require any further processing. Genotyping samples will be stored at -20°C or lower until 
they are shipped to the delegated CRO and analyzed under the responsibility of Bioanalysis-
Europe of APEB. All details on the processing of the samples, storage and shipment 
conditions will be provided in the laboratory manual. The genotyping samples (whole blood 
and isolated DNA) will be managed in strictly secured condition and they will be destroyed 
in accordance with relevant guidelines and procedures, maximally 5 years after the last 
subject completed the study.
5.8
Total Amount of Blood
The total amount of blood to be collected per subject during the study, based on the subject’s 
screening period, the 104 weeks’ treatment period and the follow-up period and allowing full 
re-screening and unscheduled visits is estimated to be approximately 460 mL.
6
DISCONTINUATION
6.1
Discontinuation of Individual Subject(s)
A discontinuation is a subject who enrolled into the study and for whom study treatment is 
permanently discontinued prematurely for any reason.
The subject is free to discontinue from study treatment or withdraw from the study for any 
reason and at any time without giving reason for doing so and without penalty or prejudice. 
The investigator is also free to terminate a subject's involvement in the study at any time if 
the subject's clinical condition warrants it.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 88 of 160
Version 3.0, Incorporating Substantial Amendment 2
If a subject is discontinued from the study with an ongoing AE or an unresolved laboratory 
result that is significantly outside of the reference range, the investigator will attempt to 
provide follow-up until the condition stabilizes or no longer is clinically significant.
Discontinued subjects will complete the EOT visits (EOT visit and EOT + 2 weeks visit) and 
EOS visit procedures. The appropriate documentation must be entered on the eCRF.
Premature treatment discontinuation
Subjects should be prematurely discontinued from study treatment for any of the following 
reasons:

Subject no longer consents to participate in the treatment phase of the study

Physician decision that it is in the best interest of the subject to be discontinued from the 
study treatment

Significant noncompliance with study procedures, as determined by principal investigator 
and/or Sponsor

Pregnancy in a study subject

Subjects randomized to roxadustat: requirement of a second course of rescue therapy with 
darbepoetin alfa deemed necessary by the investigator based upon the criteria for use of 
rescue treatment

Subject receives an organ transplant
Subjects that have prematurely discontinued study treatment will complete the EOT visits 
(EOT visit and EOT + 2 weeks visit) and EOS visit. Thereafter, these subjects who have 
taken at least one dose of study drug will continue to be followed up every 6 months for vital 
status, SAEs, cardiovascular and thromboembolic AEs until their projected date of 
completion of the follow-up period (i.e., projected week 108 date) or until consent is
withdrawn.
Study withdrawal
Subjects should be withdrawn from the study for any of the following reasons:

Subject no longer consents to participate in the study

Subject is lost to follow-up despite reasonable efforts by the investigator to contact the 
subject

Death of a study subject

The Sponsor may decide to prematurely stop the study, e.g., for safety considerations
Women of childbearing potential who discontinue from treatment and/or withdraw from this 
study must continue contraception for at least 28 days following the last study drug 
administration. Male subjects with partners of childbearing potential must agree to use a 
medically acceptable method of contraception during the study and for at least 12 weeks 
following the last study drug administration.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 89 of 160
Version 3.0, Incorporating Substantial Amendment 2
6.2
Discontinuation of the Site
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the Sponsor.
6.3
Discontinuation of the Study
The Sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination. Advance notice is not required if the study is stopped due to safety concerns. If 
the Sponsor terminates the study for safety reasons, the Sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination.
7
STATISTICAL METHODOLOGY
The statistical analysis will be coordinated by the responsible biostatistician of APEB. A 
Statistical Analysis Plan (SAP) will be written to provide details of the analysis, along with 
specifications for tables, listings and figures to be produced. The SAP will be finalized 
before the database soft lock at the latest. Any changes from the analyses planned in SAP 
will be justified in the Clinical Study Report (CSR).
Prior to Database Lock, a Final Review of Data and Table Listings Figures Meeting will be 
held to allow a review of the clinical trial data and to verify the data that will be used for 
analysis set classification. If required, consequences for the statistical analysis will be 
discussed and documented. A meeting to determine analysis set classifications may also be 
held prior to database lock
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
standard deviation, minimum, median and maximum) for continuous endpoints, and 
frequency and percentage for categorical endpoints.
7.1
Sample Size
Approximately 570 subjects will be randomized to receive roxadustat or darbepoetin alfa as 
follows:
Table 9
Sample Size Calculations per Treatment Arm 
Treatment 
Group
Protocol version 1
Protocol versions 2 and 3
Total
Randomized
PPS
Randomized†
PPS
Randomized
PPS
Roxadustat
100
80
210
168
310
248
Darbepoetin alfa
50
40
210
168
260
208
Total
150
120
420
336
570
456
† The number of subjects under protocol v20 and v3 will depend on the number of subjects randomized under 
protocol v1.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 90 of 160
Version 3.0, Incorporating Substantial Amendment 2
Randomization will be stratified by the following four factors:

Region: region A versus region B*
* Assignment to region will be determined based on health care comparability.

Screening Hb values (≤8.0 g/dL versus > 8.0 g/dL)

History of cardiovascular, cerebrovascular or thromboembolic diseases (Yes versus No)

eGFR (< 30 mL/min/1.73 m2 versus > 30 mL/min/1.73 m2)
Assuming that the PPS analysis will consist of 80% of subjects in the Full Analysis Set (FAS), 
570 randomized subjects in the FAS will lead to 456 subjects in the PPS. Two hundred and 
forty eight (248) subjects for the roxadustat treatment group and 208 subjects for the 
darbepoetin alfa treatment group will provide at least 98% test power to demonstrate 
statistically non-inferiority of roxadustat versus darbepoetin alfa in the primary endpoint 
assuming that the proportion of subjects with response in both groups is the same and at least 
80% and a non-inferiority margin for the difference of proportions of 15%. The power for the 
sensitivity analysis of post-amendment data (336 subjects) will be at least 93%.
7.2
Analysis Set
Detailed criteria for analysis sets will be laid out in Classification Specifications and the 
allocation of subjects to analysis sets will be determined prior to database hard-lock
The following analysis sets are defined and will be used for the statistical analysis:

Intent-to-Treat Set (ITT)

Full Analysis Set (FAS)

Per-Protocol Set (PPS)

Safety Analysis Set (SAF)

Pharmacokinetic Analysis Set (PKAS)
7.2.1
Intent-to-Treat Set (ITT)
All randomized subjects will be included in the ITT.
The primary and secondary efficacy endpoints will be analyzed using the ITT as a sensitivity 
analysis.
7.2.2
Full Analysis Set (FAS)
All randomized subjects who received at least one dose of study drug and have at least 
one post-dose Hb assessment will be included in the FAS. 
The primary and secondary efficacy endpoints will be analyzed using the FAS.
7.2.3
Per Protocol Set (PPS)
All FAS subjects who received at least 2 weeks of study treatment with valid corresponding 
Hb measurements and without any criteria for PPS exclusion will be included in the PPS.  

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 91 of 160
Version 3.0, Incorporating Substantial Amendment 2
Criteria for PPS exclusion will be defined in the SAP. The primary and secondary efficacy 
endpoints will also be analyzed using the PPS. Additional PPS sub-populations (e.g., PPS-
36) will be described in the SAP.
7.2.4
Safety Analysis Set (SAF)
All subjects that received at least one dose of study drug will be included in the SAF. All 
safety data will be analyzed using the SAF.
7.2.5
Pharmacokinetic Analysis Set (PKAS)
The PKAS consists of all randomized subjects who meet the following criteria:

Received at least one dose of study drug, and

At least one quantifiable plasma concentration of roxadustat was obtained and dosing and 
sampling history has been recorded.
The PKAS will be used for all tables and graphical summaries of the PK data.
7.3
Demographics and Other Baseline Characteristics
Demographic (age, race, sex) and other baseline characteristics, including stratification 
factors, and subject disease characteristics will be summarized for the SAF, ITT, FAS and 
PPS populations.
Descriptive statistics will be calculated for continuous variables (e.g., age, weight, baseline 
Hb, body mass index and baseline eGFR) and frequency counts and percentages will be 
tabulated for categorical variables (e.g., sex, race, baseline Hb category, region, baseline 
eGFR category and history of cardiovascular disease or cerebrovascular disease) by study 
treatment arm, roxadustat group and overall.
7.4
Analysis of Efficacy
7.4.1
Analysis of Primary Endpoint 
The primary efficacy endpoint is:
Hb response defined as: Hb ≥11.0 g/dL and a Hb increase from BL Hb by ≥1.0 g/dL in any 
subject with BL Hb > 8.0 g/dL, or an increase from BL Hb by ≥2.0 g/dL in any subject with 
BL Hb ≤8.0 g/dL as measured at 2 consecutive visits separated by at least 5 days during the 
first 24 weeks of treatment without administration of rescue therapy prior to Hb response.
7.4.1.1 Primary Analysis
The primary analysis will be performed on the PPS.
The difference in the proportion of responders in the primary efficacy variable between 
pooled roxadustat and darbepoetin alfa will be calculated using Mattinen & Nurminen 
approach adjusting for the following stratification factors:

Region: region A versus region B*
* Assignment to region will be determined based on health care comparability.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 92 of 160
Version 3.0, Incorporating Substantial Amendment 2

Screening Hb values (≤8.0 g/dL versus > 8.0 g/dL)

History of cardiovascular, cerebrovascular or thromboembolic diseases (Yes versus No)

eGFR (< 30 mL/min/1.73 m2 versus > 30 mL/min/1.73 m2)
The primary hypothesis to be tested for the primary efficacy analysis is:
H0: Hb responder rate in the pooled roxadustat group < Hb responder rate in the 
darbepoetin alfa group minus 15%
versus
H1: Hb responder rate in the pooled roxadustat group ≥Hb responder rate in the 
darbepoetin alfa group minus 15%
This null hypothesis will be rejected if the two-sided 95% CI for the difference of proportions 
lies entirely above -15%.
In addition, a 95% CI will be calculated for the proportion of responders on roxadustat and 
darbepoetin alfa based on the exact method of Clopper-Pearson. Sensitivity analyses will be 
conducted to assess the consistency of the results before and after protocol amendments 1 
and 2 (e.g., protocol versions 2.0 and 3.0 respectively).
Justification of the non-inferiority margin.
In general an appropriate choice of margin should provide both:
a) Assurance that the test drug has a clinically relevant effect greater than zero (placebo). 
This aspect of the choice of margin is discussed in EMEA Guideline on the choice of the 
non-inferiority margin, section III [EMEA, 2005].
b) Assurance that the test product is not substantially inferior to the reference in EMA 
guideline. This aspect of the choice of margin is discussed in EMEA Guideline on the 
choice of the non-inferiority margin, section IV [EMEA, 2005].
Two randomized pivotal placebo controlled studies are planned in this population 
(FGCL-4592-060 and 1517-CL-0608) that will directly prove superiority over placebo. 
Since direct comparisons provide always a higher level of evidence than indirect tests, the 
main criterion to fix the NI-margin in the 1517-CL-0610 study is bullet b above, i.e., to prove 
that the difference between roxadustat and darbepoetin alfa is unimportant.
From a clinical point of view, a true response rate for roxadustat of 15% lower than the true 
response rate for darbepoetin alfa is regarded an unimportant loss in efficacy since roxadustat
is anticipated to have a number of advantages that have been shown during the phase 2
program: no need for IV iron supplementation, no increase of blood pressure and no increase 
of platelet counts. 
No regulatory guideline exists in this therapeutic indication recommending a non-inferiority 
margin. However, the selected non-inferiority margin of 15% is in line with the FDA 
guideline in the urinary tract infections indication, where a high responder rate was also 
expected and a non-inferiority margin of 15% was recommended [FDA, 1998].

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 93 of 160
Version 3.0, Incorporating Substantial Amendment 2
7.4.1.2 Secondary Analysis
The same analysis of the primary endpoint as described in [Section 7.4.1.1] will be repeated
using the FAS and ITT. A sensitivity analysis on the primary efficacy endpoint will be 
performed on the subgroup of subjects being randomized after the implementation of 
protocol v2.0 and v3.0.
7.4.1.3 Subgroup Analysis
The analysis of the primary variable will be repeated separately by gender, age group, region, 
BL Hb categories, iron repletion at BL, diabetes and eGFR categories. Other subgroup 
analyses might be added to the SAP.
7.4.2
Analysis of Secondary Endpoints
7.4.2.1 Primary Analysis
The primary analysis set will be PPS for the non-inferiority tests and FAS for the superiority 
tests.
Once the primary hypothesis has been rejected for the primary endpoint, the key secondary 
endpoints below (Table 10) will be tested using a fixed sequence testing procedure, as depicted 
in Table 10 in order to maintain the overall one-sided type I error rate at 0.025. If the one-
sided p-value from a test is < 0.025, the claim of superiority (or non-inferiority) will be 
considered successful and the test will progress to the next comparison in sequence as follows:
Table 10
Secondary Endpoints Fixed Sequence Testing Procedure
Test
Endpoint
Comparison*
1
Hb change from BL to the average Hb of weeks 28 to 36 
without having received rescue therapy within 6 weeks 
prior to and during this 8-week evaluation period (the 
non-inferiority margin for the difference between groups 
is 0.75 g/dL).
Non-inferiority of pooled 
roxadustat versus darbepoetin alfa
2
LDL cholesterol change from BL to the average of 
weeks 12 to 28
Superiority of pooled roxadustat 
versus darbepoetin alfa
3
Mean monthly IV iron (mg) use per subject during 
weeks 1 to 36
Superiority of pooled roxadustat 
versus darbepoetin alfa
4
SF-36 PF sub-score change from BL to the average of 
weeks 12 to 28
(the non-inferiority margin is fixed as a difference of 3
points)
Non-inferiority of pooled 
roxadustat versus darbepoetin alfa
5
SF-36 vitality sub-score change from BL to the average 
of weeks 12 to 28 (the non-inferiority margin is fixed as 
a difference of 3 points)
Non-inferiority of pooled 
roxadustat versus darbepoetin alfa
6
MAP change from BL to the average MAP of weeks 20 
to 28
(the non-inferiority margin for the difference between 
groups is 1 mmHg)
Non-inferiority of pooled 
roxadustat versus darbepoetin alfa
Table continued on next page

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 94 of 160
Version 3.0, Incorporating Substantial Amendment 2
Test
Endpoint
Comparison*
7
Incidence of hypertension (the non-inferiority margin is 
fixed as a hazard ratio of 1.3)
Non-inferiority of pooled 
roxadustat versus darbepoetin alfa 
8
MAP change from BL to the average MAP of weeks 20 
to 28
Superiority of pooled roxadustat 
versus darbepoetin alfa 
9
Incidence of hypertension 
Superiority of pooled roxadustat 
versus pooled darbepoetin alfa 
*Subjects randomized to roxadustat QW, BIW and TIW under protocol v1 will be pooled together.
1.
Hb change from BL to the average Hb of weeks 28-36 without having received rescue 
therapy within 6 weeks prior to and during this 8-week evaluation period (non-inferiority) 
will be analyzed using a Mixed Model of Repeated Measures (MMRM) with unstructured 
covariance matrix model (pooled roxadustat versus darbepoetin alfa). The model will 
contain terms for treatment arm, baseline measurement, visit, visit x treatment interaction 
and other stratification factors. The non-inferiority margin for the difference between 
groups is 0.75 g/dL. Non-inferiority can be concluded if the lower limit of the two-sided 
95% CI of the difference between the two treatment arms is above -0.75 g/dL.
2.
Change from BL in LDL cholesterol to the average value of LDL cholesterol of 
weeks 12-28 (superiority) will be compared (pooled roxadustat versus darbepoetin alfa) 
using an MMRM with unstructured covariance matrix model. The model will contain 
terms for treatment arm, baseline measurement, visit, visit x treatment interaction and 
other stratification factors.
3.
Monthly IV iron use (mg) during weeks 1 to 36 (superiority) will be compared (pooled 
roxadustat versus darbepoetin alfa) using a MMRM with unstructured covariance matrix 
model. The model will contain terms for treatment arm, baseline measurement, visit, visit 
x treatment interaction and other stratification factors.
4.
Change from BL in PF subscore of SF-36 to the average of weeks 12–28 (non-inferiority) 
will be compared (pooled roxadustat versus darbepoetin alfa) for all subjects, using an 
MMRM with unstructured covariance matrix model. The model will contain terms for 
treatment arm, baseline measurement, visit, visit x treatment interaction and other 
stratification factors. Non-inferiority can be concluded if the lower limit of the 2-sided 
95% CI of the difference between the 2 treatment arms is above -3 points.
5.
Change from BL in Vitality subscore of SF-36 to the average of weeks 12–28 will be 
compared (pooled roxadustat versus darbepoetin alfa) for all subjects, using an MMRM 
with unstructured covariance matrix model. The model will contain terms for treatment 
arm, baseline measurement, visit, visit x treatment interaction and other stratification 
factors. Non-inferiority can be concluded if the lower limit of the 2-sided 95% CI of the 
difference between the 2 treatment arms is above -3 points.
6.
Change from BL in MAP to the average of weeks 20–28 (non-inferiority) will be 
compared (pooled roxadustat versus darbepoetin alfa) using a MMRM with unstructured 
covariance matrix model. The model will contain terms for treatment arm, baseline 
measurement, visit, visit x treatment interaction and other stratification factors. 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 95 of 160
Version 3.0, Incorporating Substantial Amendment 2
Non-inferiority can be concluded if the lower limit of the two-sided 95% CI of the 
difference between the two treatment arms is below 1 mm Hg.
7.
Incidence rate (per 100 subject years at risk) and cumulative risk curve of subjects with 
hypertension from BL will be reported and compared (pooled roxadustat versus 
darbepoetin alfa) using stratified Cox Proportional Hazards regression adjusting for 
stratification factors. Hazard ratio and the two-sided 95% CI will be calculated for the 
frequency of pooled roxadustat as relative to darbepoetin alfa. Non-inferiority will be 
declared if the upper bound of the 2-sided 95% CI is below 1.3. 
8.
Change from BL in MAP to the average of weeks 20–28 (superiority) will be compared 
(pooled roxadustat versus darbepoetin alfa) using an MMRM with unstructured 
covariance matrix model (pooled roxadustat versus darbepoetin alfa). The model will 
contain terms for treatment arm, baseline measurement, visit, visit x treatment interaction 
and other stratification factors.
9.
Incidence rate (per 100 subject years at risk) and cumulative risk curve of subjects with 
hypertension from BL will be reported and compared (pooled roxadustat versus 
darbepoetin alfa) using stratified Cox Proportional Hazards regression adjusting for 
stratification factors. Hazard ratio and the two-sided 95% CI will be calculated for the 
frequency of pooled roxadustat as relative to darbepoetin alfa. 
7.4.2.2 Secondary Analysis
The analysis of the secondary endpoints as described in 7.4.2.1 will be repeated using (a) the 
FAS and ITT and (b) the PPS for both non-inferiority tests and superiority tests.
For all secondary variables analyzed using MMRM, an additional sensitivity analysis will be 
performed using an Analysis of Covariance (ANCOVA) model with Last Observation 
Carried Forward (LOCF) method using BL value and the stratification factors as covariates.
As an additional sensitivity analysis, the mean Hb change from BL, first secondary variable, 
will also be calculated using all Hb values regardless of rescue therapy (this is included 
among the additional endpoints). This will be analyzed using an MMRM model similar to 
the one described in Section 7.4.2.1
Additional sensitivity analyses will be defined in the SAP.
7.4.2.3 Subgroup Analysis
The analysis of selected secondary variables will be repeated separately by gender, age 
group, region, BL Hb categories, iron repletion at BL, diabetes and eGFR categories. Other 
subgroups analysis might be added to the SAP.
7.4.3
Analysis of Additional Endpoints 
The Hb change from BL to the average Hb of weeks 28 to 52 regardless of the use of rescue 
therapy will be analyzed on the ITT population using an MMRM with unstructured 
covariance matrix model. The model will contain terms for treatment arm, baseline 
measurement, visit, visit x treatment arm, and other stratification factors. Non-inferiority can 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 96 of 160
Version 3.0, Incorporating Substantial Amendment 2
be concluded if the lower limit of the two-sided 95% CI of the difference between the 
two treatment arms (roxadustat minus darbepoetin) is above -0.75 g/dL.
Statistical analysis for the other additional endpoints will be detailed in the SAP.
7.5
Analysis of Safety
Safety analyses will be performed using the SAF. Safety parameters include AEs, SAEs
laboratory parameters (with special emphasis on excessive Hb response and liver function 
tests [LFTs]), vital signs, and ECG parameters.
For each safety parameter, unless otherwise specified, the last assessment made prior to the 
first dose of study drug will be used as the baseline assessment for all analyses.
All safety analyses will be presented both by treatment group (pooled roxadustat and 
darbepoetin alfa) and by all 4 study arms, and by visit (if relevant).
The number and percentage of subjects reporting TEAEs and TESAEs in each treatment 
group will be tabulated. Descriptive statistics will be presented for laboratory, vital signs 
values and ECG parameters by visit and for the changes from BL to each visit. Further 
details will be described in the SAP. The statistical method for analysis of adjudicated safety 
data will be detailed in a pooled cardiovascular safety SAP.
Safety data and dosing decisions will be monitored on an ongoing basis. Ongoing review of 
safety data will be conducted by an independent DSMB.
7.5.1
Adverse Events
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA).
An AE (classified by preferred term) started during the treatment period will be considered a 
Treatment Emergent AE (TEAE) if it was not present prior to the first dose of study drug, or it 
was present prior to the first dose of study drug but increased in severity during the treatment 
period. An AE that occurs more than 28 days after the last dose of study medication will not 
be counted as a TEAE.
The number and percentage of subjects reporting TEAEs in each treatment group will be 
tabulated by system organ class (SOC) and preferred term; by SOC, preferred term, and 
severity; and by SOC, preferred term, and relationship to study medication. If more than one 
event occurs with the same preferred term for the same subject, the subject will be counted 
only once for that preferred term using the most severe and most related occurrence for the 
summarization by severity and by relationship to the study medication.
The overall distribution of TEAEs by severity and relationship to study medication will be 
summarized by treatment group.
The proportion of subjects with TESAE, fatal SAEs (i.e., events that caused death), and AEs 
leading to discontinuation of study drug will be summarized by SOC, preferred term and 
treatment group.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 97 of 160
Version 3.0, Incorporating Substantial Amendment 2
TEAEs will also be reported in terms of cumulative incidence versus time and as an incidence 
rate per subject-exposure-year.
Listings will be presented of subjects with SAEs, subjects with AEs leading to 
discontinuation and subjects who died.
7.5.2
Laboratory Assessments
For quantitative laboratory measurements, descriptive statistics will be used to summarize 
results (in International System of Units [SI]) and change from baseline by treatment group and 
time point. Shifts relative to normal ranges from baseline to each time point during treatment 
period in lab tests will also be tabulated. Laboratory data will be displayed in listings.
7.5.3
Vital Signs
Descriptive statistics for vital signs (e.g., systolic and diastolic blood pressure, HR) and their 
changes from BL at each visit and the end of study and for the maximum and minimum value 
on treatment will be presented by treatment group.
7.5.4
ECGs
Descriptive statistics for ECG parameters (HR, PR interval, QRS interval, QT interval and QTc 
interval) at BL, and changes from BL, at each assessment time point and for the maximum and 
minimum value on treatment will be presented by treatment group. QTc interval will be 
calculated using both Bazett (QTcB = QT/(RR)1/2) and Fridericia (QTcF = QT/(RR)1/3) 
corrections. Presence of potentially clinically significant ECG values will be reported using 
similar statistics as mentioned for TEAEs.
7.6
Analysis of Pharmacokinetics
Plasma concentration data of roxadustat will be subjected to population PK analysis. The 
aim of this analysis is to describe the PK behavior of roxadustat in the target population and 
to evaluate the effects of selected covariates on the PK of roxadustat. The results of the 
population PK analysis will not be reported in the Clinical Study Report but in a separate 
population PK modeling report.
7.7
Analysis of Pharmacodynamics
Pharmacodynamic data may be submitted to population pharmacodynamic or population 
pharmacokinetic/pharmacodynamic (PPKPD) modeling. When deemed necessary, data from 
this study may be combined with data from other studies. Results will be reported in a 
separate PPKPD report.
7.8
Protocol Deviations and Other Analyses
Protocol deviations as defined in Section 8.1.6 will be summarized for all randomized 
subjects by treatment group and total as well as by site. A data listing will be provided by 
site and subject.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 98 of 160
Version 3.0, Incorporating Substantial Amendment 2
The protocol deviation criteria will be uniquely identified in the summary table and listing. 
The unique identifiers will be as follows:
PD1 - Entered into the study even though they did not satisfy entry criteria
PD2 - Developed discontinuation criteria during the study and was not discontinued from 
study treatment
PD3 - Received wrong treatment or incorrect dose
PD4 - Received prohibited concomitant treatment
7.9
Interim Analysis
An interim analysis will be performed when all subjects have completed 36 weeks of
treatment; efficacy and safety data will be analyzed and reported, excluding the endpoints 
measured after 36 weeks. Since all primary and secondary analyses have been defined over 
this period of time, no multiplicity adjustment is required as the information fraction at the 
interim analysis is 100%. Once the study is completed, efficacy and safety will be analyzed 
again and reported including the complete study treatment of 104 weeks.
In addition, a descriptive analysis on both safety and efficacy will be performed to provide 
information from this study for regulatory filings of roxadustat in case the planned interim 
analysis has not been reached. This will include only descriptive statistics by arm (i.e.,
without formal hypothesis testing).
Safety data and dosing decisions will be monitored on an ongoing basis. Ongoing review of 
safety data will be completed by an independent Data and Safety Monitoring Board (DSMB)
(Section 10.1).
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
For the primary endpoint, subjects without at least two Hb values as measured at 2 consecutive 
visits separated by at least 5 days during the first 24 weeks of treatment will be classified as 
non-responders.
Main analysis of the efficacy endpoints with repeated measures over time will follow the
MMRM methodology. In addition, as a sensitivity analysis, an LOCF method will be fitted.
Visit time windows will be detailed in the SAP.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 99 of 160
Version 3.0, Incorporating Substantial Amendment 2
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS
8.1
Procedure for Clinical Study Quality Control
8.1.1
Data Collection
The investigator or site designee will enter data collected using an Electronic Data Capture 
(EDC) system. In the interest of collecting data in the most efficient manner, the investigator 
or site designee should record data (including laboratory values, if applicable) in the eCRF as 
soon as possible after the subject visit.
The investigator or site designee is responsible to ensure that all data in the eCRFs and 
queries are accurate and complete and that all entries are verifiable with source documents. 
These documents should be appropriately maintained by the site. Subject diaries and 
questionnaires will be completed by the subject on paper. The investigator or site designee 
should review the diaries and questionnaire data for correct completion while the subject is at 
the site. The investigator or site designee will enter only the relevant information from the 
medication diary (i.e., roxadustat intake data related to PK sampling) and all questionnaire 
data directly into the EDC system. eCRFs, diaries and questionnaires and any supporting 
documents should be available for review or retrieval at any given time.
The monitor should verify the data in the eCRFs with source documents and confirm that 
there are no inconsistencies between them.
Laboratory tests are performed at a central laboratory. Laboratory results will be provided to 
the investigator who will print, sign and retain the laboratory results. In addition all 
abnormalities will be checked and documented as clinically relevant or not clinically 
relevant. Laboratory data will be transferred electronically to the Sponsor or designee at 
predefined intervals during the study. The laboratory will provide the Sponsor or designee 
with a complete and clean copy of the data.
8.1.2
Specification of Source Documents
Source data must be available at the site to document the existence of the study subjects and to 
substantiate the integrity of study data collected. Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject.
The following information should be included in the source medical records:

Demographic data (date of birth, sex, race, height and body weight)

Inclusion and exclusion criteria details

The identification of the participation in study 

Original signed and dated informed consent forms 

Visit dates

Medical history and physical examination details

Key efficacy and safety data 

Results of HemoCue Hb assessments on all visits 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 100 of 160
Version 3.0, Incorporating Substantial Amendment 2

Decision on study drug dosing on all visits.

AEs and concomitant medication 

Results of relevant examinations such as ECG charts, renal ultrasound outcome.

Central laboratory printouts

Medication diaries (for roxadustat subjects only)

Paper questionnaires

Dispensing and return of study drug details

Reason for premature discontinuation from study treatment (if applicable)

Subject number

Method(s) of contraception for subjects or subject’s partner of childbearing potential.
8.1.3
Clinical Study Monitoring
The Sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that 
subject's human rights, safety, and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP, and study data reported by the 
investigator/sub-investigator are accurate and complete and that they are verifiable with 
study-related records such as source documents. The Sponsor is responsible for assigning 
study monitor(s) to this study for proper monitoring. They will monitor the study in 
accordance with planned monitoring procedures.
8.1.4
Direct Access to Source Data/Documents
The investigator and the study site must accept monitoring and auditing by the Sponsor or 
delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities. 
In these instances, they must provide all study-related records, such as source documents 
(refer to Section 8.1.2) when they are requested by the Sponsor monitors and auditors, the 
IRB/IEC, or regulatory authorities. The confidentiality of the subject's identities shall be well 
protected consistent with local and national regulations when the source documents are 
subject to direct access.
8.1.5
Data Management
Data Management will be coordinated by the GDS department of the Sponsor in accordance 
with the SOPs for data management. All study specific processes and definitions will be 
documented by Data Management. eCRF completion will be described in the eCRF 
Completion Guidelines. Coding of medical terms and medications will be performed using 
MedDRA and World Health Organization (WHO) Drug Dictionary respectively.
8.1.6
Protocol Deviations
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The investigator is responsible for ensuring 
the study is conducted in accordance with the procedures and evaluations described in this 
protocol and must protect the rights, safety, and welfare of subjects. The investigator should 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 101 of 160
Version 3.0, Incorporating Substantial Amendment 2
not implement any deviation from, or changes of, the protocol, unless it is necessary to 
eliminate an immediate hazard to trial subjects.
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited.
For the purposes of this protocol, deviations requiring notification to Sponsor are defined as 
any subject who:

Entered into the study even though they did not satisfy entry criteria

Developed discontinuation criteria during the study and not discontinued from study 
treatment

Received wrong treatment or incorrect dose

Received prohibited concomitant treatment
When a deviation from the protocol is identified for an individual subject, the investigator or 
designee must ensure the Sponsor is notified. The Sponsor will follow-up with the 
investigator, as applicable, to assess the deviation and the possible impact to the safety and / 
or efficacy of the subject to determine subject continuation in the study.
If a deviation impacts the safety of a subject, the investigator must contact the Sponsor 
immediately.
The investigator will also assure that deviations meeting IRB/IEC and applicable regulatory 
authorities’ criteria are documented and communicated appropriately. All documentation 
and communications to the IRB/IEC and applicable regulatory authorities will be provided to 
the Sponsor and maintained within the Trial Master File (TMF).
NOTE: Other deviations outside of the categories defined above that are required to be 
reported by the IRB/IEC in accordance with local requirements will be reported, as 
applicable.
8.1.7
End of Trial in All Participating Countries
The end of trial in all participating countries is defined as the Last Subject’s Last Visit.
8.2
Ethics and Protection of Subject Confidentiality
8.2.1
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) / 
Competent Authorities (CA)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, 
the Investigator’s Brochure, the informed consent and all other forms of subject information 
related to the study (e.g., advertisements used to recruit subjects) and any other necessary 
documents be reviewed by an IEC/IRB. The IEC/IRB will review the ethical, scientific and 
medical appropriateness of the study before it is conducted. IEC/IRB approval of the 
protocol, informed consent and subject information and/or advertising, as relevant, will be 
obtained prior to the authorization of drug shipment to a study site.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 102 of 160
Version 3.0, Incorporating Substantial Amendment 2
Any substantial amendments to the protocol will require IEC/IRB approval prior to 
implementation of the changes made to the study design at the site. The investigator will be 
required to submit, maintain and archive study essential documents according to ICH GCP.
Any serious AEs that meet reporting criteria, as dictated by local regulations, will be reported 
to both responsible Ethics Committees and Regulatory Agencies, as required. During the 
conduct of the study, the investigator should promptly provide written reports (e.g., ICH 
Expedited Reports, and any additional reports required by local regulations) to the IEC/IRB 
of any changes that affect the conduct of the study and/or increase the risk to subjects. 
Written documentation of the submission to the IEC/IRB should also be provided to Sponsor.
If required by local regulations, the investigator shall make accurate and adequate written 
progress reports to the IEC/IRB at appropriate intervals, not exceeding one year. The 
Sponsor shall submit a summary of the final clinical study report to the IRB/IEC and the 
Regulatory Agency within one year after last subject out (LSO) or termination of the study.
8.2.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki.
8.2.3
Informed Consent of Subjects
8.2.3.1 Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the subject or 
his/her guardian or legal representative, and answer all questions regarding this study. Prior to 
any study-related screening procedures being performed on the subject, the informed consent 
statement will be reviewed and signed and dated by the subject or his/her guardian or legal 
representative, the person who administered the informed consent and any other signatories 
according to local requirements. A copy of the signed informed consent form will be given to 
the subject and the original will be placed in the subject’s medical record. An entry must also 
be made in the subject’s dated source documents to confirm that informed consent was 
obtained prior to any study-related procedures and that the subject received a signed copy.
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor regulatory authorities and other applicable individuals 
upon request.
8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information
1.
The investigator or his/her representative will immediately inform the subject orally 
whenever new information becomes available that may be relevant to the subject’s 
consent or may influence the subject’s willingness to continue to participate in the study 
(e.g., report of serious drug adverse drug reaction). The communication must be 
documented in the subject’s medical records and must document whether the subject is 
willing to remain in the study or not.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 103 of 160
Version 3.0, Incorporating Substantial Amendment 2
2.
The investigator must update their ICF and submit it for approval to the IRB/IEC. The 
investigator or his/her representative must obtain written informed consent from the 
subject on all updated ICFs throughout their participation in the study. The investigator 
or his/her designee must re-consent subjects with the updated ICF even if relevant 
information was provided orally. The investigator or his/her representative who 
obtained the written informed consent and the subject should sign and date the informed 
consent form. A copy of the signed informed consent form will be given to the subject 
and the original will be placed in the subject’s medical record. An entry must be made 
in the subject’s records documenting the re-consent process.
8.2.4
Subject Confidentiality
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Such medical information may be 
given only after approval of the subject to the subject's physician or to other appropriate 
medical personnel responsible for the subject's well-being.
The Sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons.
The Sponsor affirms the subject's right to protection against invasion of privacy. Only a 
subject identification number and/or initials will identify subject data retrieved by the 
Sponsor. However, the Sponsor requires the investigator to permit the Sponsor, Sponsor's 
representative(s), the IRB/IEC and when necessary, representatives of the regulatory health 
authorities to review and/or to copy any medical records relevant to the study.
The Sponsor will ensure that the use and disclosure of protected health information obtained 
during a research study complies with the regional legislation related to the privacy and 
protection of personal information.
8.3
Administrative Matters
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the Investigator's Brochure and other pertinent information is confidential and remains 
the property of the Sponsor. Details should be disclosed only to the persons involved in the 
approval or conduct of the study. The investigator may use this information for the purpose 
of the study only. It is understood by the investigator that the Sponsor will use the 
information obtained during the clinical study in connection with the development of the 
drug and therefore may disclose it as required to other clinical investigators or to regulatory 
agencies. In order to allow for the use of the information derived from this clinical study, the 
investigator understands that he/she has an obligation to provide the Sponsor with all data 
obtained during the study.
Publication of the study results is described in the Clinical Study Agreement.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 104 of 160
Version 3.0, Incorporating Substantial Amendment 2
8.3.2
Documents and Records Related to the Clinical Study
The Sponsor will provide the investigator and/or institution with the following:
For EU:

Study protocol (and amendments, as applicable)

Investigator’s Brochure (and amendments, as applicable)

Investigational Medicinal Product Dossier (IMPD) 

Questionnaires and SAE Report Worksheet

Investigator’s File

Study drugs with all necessary documentation

Clinical Trial Agreement

Approval of regulatory authority and all documents related to submission.
In order to start the study, the investigator and/or study site is required to provide the 
following documentation to the Sponsor:
For EU:

Financial disclosure in compliance with federal regulation 21CFR Part 54

Signed and dated FDA form 1572, if conducted under a US IND

If the investigator submits to the IRB/IEC: Submission letter to the IRB/IEC

Signed confidentiality agreement

Signed Investigator's Statement in this protocol

Executed Study Contract

IEC/IRB approval of the protocol, protocol amendments (if applicable) and ICF (and 
separate authorization form, if appropriate), stating clearly the Sponsor's name, study 
number and study drug, including a membership list with names and qualifications

Current Curricula Vitae of all investigators (signed and dated, brief and in English.)

Medical/Laboratory/Technical procedures/tests certifications or accreditations or 
established quality control or other validation, where required.
At the end of the study, the Sponsor is responsible for the collection of:

Study documentation,

Unused study drug
The investigator will archive all study data (e.g., Subject Identification Code List, source 
data, CRFs, and Investigator's File) and relevant correspondence. These documents are to be 
kept on file for the appropriate term determined by local regulation: until at least 15 years 
after the last approval of a marketing application in an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region or at least 15 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product.
The Sponsor will notify the site/investigator if the MAA is approved or if the IMPD is 
discontinued.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 105 of 160
Version 3.0, Incorporating Substantial Amendment 2
The investigator agrees to obtain the Sponsor's agreement prior to disposal, moving, or 
transferring of any study-related records. The Sponsor will archive and retain all documents 
pertaining to the study according to local regulations.
Data generated by the methods described in the protocol will be recorded in the subjects' 
medical records and/or study progress notes. All data will be entered on the CRFs supplied 
for each subject.
The documents of the Efficacy and Safety Evaluation Committee (minutes and standard 
operating procedures and others) and the judgment committee outside the study sites 
(minutes and standard operating procedures and others) shall be retained by the Sponsor.
8.3.3
Protocol Amendment and/or Revision
Any changes to the study that arise after approval of the protocol must be documented as
protocol amendments: substantial amendments and/or non-substantial amendments.
Depending on the nature of the amendment, either IRB/IEC, Competent Authority approval 
or notification may be required. The changes will become effective only after the approval 
of the Sponsor, the investigator, the regulatory authority, and the IRB/IEC (if applicable).
Amendments to this protocol must be signed by the Sponsor and the investigator. Written 
verification of IRB/IEC approval will be obtained before any amendment is implemented 
which affects subject safety or the evaluation of safety, and/or efficacy. Modifications to the 
protocol that are administrative in nature do not require IRB/IEC approval, but will be 
submitted to the IRB/IEC for their information, if required by local regulations.
If there are changes to the Informed Consent, written verification of IRB/IEC approval must 
be forwarded to the Sponsor. An approved copy of the new Informed Consent must also be 
forwarded to the Sponsor.
8.3.4
Insurance of Subjects and Others
The Sponsor has covered this study by means of an insurance of the study according to 
national requirements. The name and address of the relevant insurance company, the certificate 
of insurance, the policy number and the sum insured are provided in the Investigator's File.
8.3.5
Signatory Investigator for Clinical Study Report
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study report 
which forms part of a marketing authorization application be signed by the representative for 
the Coordinating Investigator(s) or the Principal Investigator(s). The representative for the 
Coordinating Investigator (s) or the Principal Investigator(s) will have the responsibility to 
review the final study results to confirm to the best of his/her knowledge it accurately describes 
the conduct and results of the study. The representative for Coordinating Investigator(s) or the
Principal Investigator(s) will be selected from the participating investigators by the Sponsor
prior to database lock.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 106 of 160
Version 3.0, Incorporating Substantial Amendment 2
9
QUALITY ASSURANCE
The Sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that trials are conducted and data are generated, documented, 
recorded, and reported in compliance with the protocol, GCP, and applicable regulatory 
requirement(s).
The Sponsor or Sponsor's designee may arrange to audit the clinical study at any or all 
investigational sites and facilities. The audit may include on-site review of regulatory 
documents, case report forms, and source documents. Direct access to these documents will 
be required by the auditors.
10
STUDY ORGANIZATION
10.1
Independent Data and Safety Monitoring Board (DSMB)
A DSMB will review prespecified safety data periodically in collaboration with the Sponsor
to ensure subject safety. A separate DSMB charter will establish the process, meeting 
frequency and scope of responsibilities.
10.2
Independent Event Review Committee (IERC)
An Independent Event Review Committee (IERC) will adjudicate all prespecified 
cardiovascular and cerebrovascular events in a blinded manner to ensure a consistent safety 
assessment.
Details of event identification and process of adjudication will be described in an IERC 
charter.
10.3
Other Study Organization
Not applicable.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 107 of 160
Version 3.0, Incorporating Substantial Amendment 2
11
REFERENCES
Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, Schwab SJ, Goodkin 
DA. The effects of normal as compared with low hematocrit values in subjects with cardiac 
disease who are receiving hemodialysis and epoetin. N Engl J Med. 1998;339(9):584-590.
Besarab A, Frinak S and Yee J. "What is so bad about a hemoglobin level of 12 to 13 g/dL for chronic 
kidney disease subjects anyway?" Advances in Chronic Kidney Disease 2009;16 (2):131-142.
Büchler P, Reber HA, Büchler M, Shrinkante S, Büchler MW, Friess H, Semenza GL, Hines OJ. 
Hypoxia-inducible factor 1 regulates vascular endothelial growth factor expression in human 
pancreatic cancer. Pancreas 2003;26(1):56-64.
Cella D. The Functional Assessment of Cancer Therapy-Anemia (FACT-An) Scale: a new tool for the 
assessment of outcomes in cancer anemia and fatigue. Semin Hematol. 1997;34(3 Suppl 
2):13-19.
Collins AJ, Ma JZ, Xia A, Ebben J. Trends in anemia treatment with erythropoietin usage and patient 
outcomes. Am J Kidney Dis 1998;32(supl4):133-141.
Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, Van Lente F, Levey AS. Prevalence 
of Chronic Kidney Disease in the United States. JAMA. 2007;298(17):2038-2047. 
Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A. 
Normalization of hemoglobin level in subjects with chronic kidney disease and anemia. N Engl 
J Med. 2006;355(20):2071-2084.
EMEA. Aranesp Procedural steps taken and scientific information after the authorisation. Changes 
made after 2003. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Procedural_steps_taken_and_scientific_information_after_authorisation/human/000332/WC5
00026145.pdf.
EMEA. Aranesp European Public Assessment Report [EPAR]. 2004.
EMEA, Guideline on the choice of the non-inferiority margin,
Doc.Ref. EMEA/CPMP/EWP/2158/99, London, 27 July 2005.
Epstein ACR, Gleadle JM, McNeill LA, Hewitson KS, O’Rourke J, Mole DR, et al. Cell.
2001;107(1):43-54.
Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. Correction of the Anemia of End-
Stage Renal Disease with Recombinant Human Erythropoietin. N Engl J Med 1987; 316:73-78.
Eschbach JW, Adamson JW. Guidelines for recombinant human erythropoietin therapy. Am J Kidney 
Dis. Aug 1989;14;(2 Supl 1):2-8. 
Eschbach JW, Abdulhadi MH, Browne JK, Delano BG, Downing MR, Egrie JC, Evans RW, 
Friedman EA, Graber SE, Haley NR, et al. Recombinant human erythropoietin in anemic 
subjects with endstage renal disease. Results of a phase III multi-center clinical trial. Annals of 
Internal Medicine 1989;111(12):992-1000.
Fan C, Iacobas DA, Zhou D, Chen Q, Lai JK, Gavrialov O, Haddad GG. Gene expression and 
phenotypic characterization of mouse heart after chronic constant or intermittent hypoxia. 
Physiol Genomics 2005;22(3):292-307.
Fishbane S, Besarab A. Mechanism of increased mortality risk with erythropoietin treatment to higher 
hemoglobin targets. Clinical Journal of the American Society of Nephrology 2007;2(6):1274-1282.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 108 of 160
Version 3.0, Incorporating Substantial Amendment 2
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu C. Chronic Kidney Disease and the Risks of 
Death, Cardiovascular Events, and Hospitalization. N Engl J Med 2004;351:1296-1305.
Gray MJ, Zhang J, Ellis LM, Semenza GL, Evans DB, Watowich SS, Gallick GE. HIF-1alpha, 
STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates 
Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas.
Oncogene 2005;24(19):3110-3119.
Greijer AE, van der Groep P, Kemming D, Shvarts A, Semenza GL, Meijer GA, van de Wiel MA, 
Belien JA, van Diest PJ, van der Wall E. Up-regulation of gene expression by hypoxia is 
mediated predominantly by hypoxia-inducible factor 1 (HIF-1). J Pathol 2005;206(3):291-304.
Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC. Differential roles of hypoxia-inducible factor 
1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol 2003;
23(24):9361-9374.
Jungers PY, Robino C, Choukroun G, Nguyen-Khoa T, Massy ZA. Incidence of anaemia, and use of 
epoetin therapy in pre-dialysis subjects: a prospective study in 403 subjects. Nephrol Dial 
Transplant 2002;17(9):1621-1627.
Langsetmo I, Stephenson R, Jacob C, Zhang W, Klaus S, Lin A et al. Effect of FG-4592 in a Rat 
Model of Anemia of Chronic Disease. 301_05_3510_047 (ACD6). 2005.
Locatelli F, Olivares J, Walker R, Wilkie M, Jenkins B, Dewey C, Gray SJ; European/Australian 
NESP 980202 Study Group. Novel erythropoiesis stimulating protein for treatment of anemia 
in chronic renal insufficiency. Kidney Int. 2001 Aug;60(2):741-7
Macdougall IC, Matcham J, Gray SJ, NESP-960245/246 Study Group. Correction of anaemia with 
darbepoetin alfa in subjects with chronic kidney disease receiving dialysis. Nephrol Dial 
Transplant 2003 Mar;18(3):576-581.
National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI). KDOQI 
Clinical Practice Guideline and Clinical Practice Recommendations for Anemia in Chronic 
Kidney Disease: 2007 Update of Hemoglobin Target 
(http://www.kidney.org/professionals/KDOQI/guidelines_anemiaUP/guide1.htm )
Peyssonnaux C, Nizet V, Johnson RS. Role of the hypoxia inducible factors HIF in iron metabolism. 
Cell Cycle 2008;7(1): 28-32.
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and 
activity impairment instrument. PharmacoEconomics 1993; 4(5): 353-365.
Scortegagna M, Ding K, Zhang Q, Oktay Y, Bennett MJ, Bennett, Shelton JM, Richardson JA, Moe 
O, Garcia JA. HIF-2alpha regulates murine hematopoietic development in an erythropoietin-
dependent manner. Blood 2005;105(8):3133-3140.
Semenza GL. Hypoxia-inducible factor 1: master regulator of O2 homeostasis. Curr.Opin.Genet.Dev. 
1998;8(5):588-594.
Semenza, GL. HIF-1: mediator of physiological and pathophysiological responses to hypoxia. 
J.Appl.Physiol 2000;88(4):1474-1480.
Singh H, Reed J, Noble S, Cangiano JL, Van Wyck DB. Effect of Intravenous Iron Sucrose in 
Peritoneal Dialysis Patients Who Receive Erythropoiesis-Stimulating Agents for Anemia: A 
Randomized, Controlled Trial. Clin J Am Soc Nephrol 2006;1:475-482.
Temple R. Hy’s law: predicting serious hepatotoxicity. Pharmacoepidermiol Drug Saf 2006 
Apr;15(4):241-243.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 109 of 160
Version 3.0, Incorporating Substantial Amendment 2
The US Recombinant Human Erythropoietin Predialysis Study Group. Double-blind, placebo-
controlled study of the therapeutic use of recombinant human erythropoietin for anemia 
associated with chronic renal failure in predialysis subjects. Am J Kidney Dis. 1991 
Jul;18(1):50-59.
Thilly N, Stengel B, Boini S, Villar E, Couchoud C Frimat L. Evaluation and determinants of 
underprescription of erythropoiesis stimulating agents in pre-dialysis subjects with anaemia. 
Nephron Clin Pract. 2008;108(1):67-74.
Tonelli M, Wiebe N, Culleton B, House A, Rabbat C, Fok M, McAlister F, Garg AX. Chronic Kidney 
Disease and Mortality Risk: A Systematic Review. JASN 2006;17:(7): 2034-2047.
Unger E. F. FDA Department of Health and Human Services. Joint Meeting of the Cardiovascular 
and Renal Drugs Advisory Committee and the Drug Safety and Risk Management Advisory 
Committee. 2007.
United States Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER), Guidance for Industry: Complicated Urinary Tract 
Infections and Pyelonephritis – Developing Antimicrobial Drugs for Treatment, July 1998
United States Renal Data System (USRDS). Annual Data Report 2000 
(http://www.usrds.org/atlas00.aspx)
United States Renal Data System (USRDS). Annual Data Report 2001 
(http://www.usrds.org/atlas01.aspx)
United States Renal Data System (USRDS). Annual Data Report 2002 
(http://www.usrds.org/atlas02.aspx)
United States Renal Data System (USRDS). Annual Data Report 2003
(http://www.usrds.org/atlas02.aspx)
United States Renal Data System (USRDS). Annual Data Report 2009 
(http://www.usrds.org/atlas09.aspx)
United States Renal Data System (USRDS). Annual Data Report 2011 
(http://www.usrds.org/atlas11.aspx)
Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-
PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 1995;92(12):5510-
5514.
Warnecke C, Zaborowska Z, Kurreck J, Erdmann VA, Frei U, Wiesener M, Eckardt KU. 
Differentiating the functional role of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha 
(EPAS-1) by the use of RNA interference: erythropoietin is a HIF-2alpha target gene in Hep3B 
and Kelly cells. The FASEB Journal 2004;18(12):1462-1464.
Winearls CG, Oliver DO, Pippard MJ, Reid C, Downing MR, Cotes PM. Effect of human 
erythropoietin derived from recombinant DNA on the anaemia of subjects maintained by 
chronic haemodialysis. Lancet 1986;2(8517):1175-1178.
Zhang Y, Thamer M, Stefanik K, Kaufman J, Cotter DJ. Epoetin Requirements Predict Mortality in 
Hemodialysis Subjects. Am J Kidney Dis 2004;44(5):866-876.
Zoccali C, Kramer A, Jager KJ. Chronic kidney disease and end-stage renal disease – a review 
produced to contribute to the report ‘the status of health in the European union: towards a 
healthier Europe’. NDT Plus 2010;3(3):213-224.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 110 of 160
Version 3.0, Incorporating Substantial Amendment 2
12
APPENDICES
12.1
List of Prohibited Concomitant Medication
The following medications are prohibited during the period identified:

Any ESA: within 12 weeks prior to randomization until EOT

IV iron: within 6 weeks prior to randomization 

RBC transfusion: within 8 weeks prior to randomization

Any investigational drug: within 30 days or 5 half lives or limit set by national law 
(whichever is longer), prior to screening until EOS

Roxadustat or another HIF-PHI: at any time prior to randomization. After randomization 
any HIF-PHI other than roxadustat, as allocated by randomization, until EOS

Iron-chelating agents (e.g., deferoxamine, deferiprone, or deferasirox therapy): from 
4 weeks prior to randomization until EOS

Androgens from day of randomization until EOS

Dapsone in any dose amount from the day of randomization until EOS 

Chronic use of acetaminophen/paracetamol > 2.0 g/day from the day of randomization 
until EOS

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 111 of 160
Version 3.0, Incorporating Substantial Amendment 2
12.2
Liver Safety Monitoring and Assessment
Any subject enrolled in a clinical study with active drug therapy and reveals an increase of 
serum aminotransferases (AT) to > 3 × ULN, or bilirubin > 2 × ULN, should undergo 
detailed testing for liver enzymes (including at least ALT, AST, ALP, and TBL). Testing
should be repeated within 48-72 hours of notification of the test results. Alerts will be 
generated by the central lab regarding moderate and severe liver abnormality to inform the 
investigator, study monitor and study team. Subjects should be asked if they have any 
symptoms suggestive of hepatobiliary dysfunction.
Definition of Liver Abnormalities
Confirmed abnormalities will be characterized as moderate and severe where ULN:
ALT or AST
Total Bilirubin
Moderate
> 3× ULN 
or
> 2× ULN
Severe*)
> 3× ULN
and
> 2× ULN
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following:

ALT or AST > 8× ULN

ALT or AST > 5× ULN for more than 2 weeks

ALT or AST > 3× ULN and INR > 1.5 (If INR testing is applicable/evaluated).

ALT or AST > 3× ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%).
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring 
and follow-up.
Follow-up Procedures
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, 
physical examination and laboratory tests. The site should complete the Liver Abnormality 
Case Report Form (LA-CRF) that has been developed globally and can be activated for any 
study or an appropriate document. Subjects with confirmed abnormal liver function testing 
should be followed as described below.
Confirmed moderately abnormal LFTs should be repeated 2-3 times weekly then weekly or 
less if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic.
Severe hepatic liver function abnormalities as defined above, in the absence of another 
etiology, may be considered an important medical event and may be reported as a Serious AE
(SAE). The Sponsor should be contacted and informed of all subjects for whom severe 
hepatic liver function abnormalities possibly attributable to study drug are observed.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 112 of 160
Version 3.0, Incorporating Substantial Amendment 2
To further assess abnormal hepatic laboratory findings, the investigator is expected to:
Obtain a more detailed history of symptoms and prior or concurrent diseases. Symptoms and 
new onset-diseases should be recorded as ‘AEs’ on the AE page of the (e)CRF. Illnesses and 
conditions such as hypotensive events, and decompensated cardiac disease that may lead to 
secondary liver abnormalities should be noted. Non-alcoholic steatohepatitis (NASH) is seen 
in obese hyperlipoproteinemic, and/or diabetic subjects and may be associated with 
fluctuating aminotransferase levels. The investigator should ensure that the medical history 
form captures any illness that pre-dates study enrollment that may be relevant in assessing 
hepatic function.
Obtain a history of concomitant drug use (including non-prescription medication, 
complementary and alternative medications), alcohol use, recreational drug use, and special 
diets. Medications, including dose, should be entered on the concomitant medication page of 
the (e)CRF. Information on alcohol, other substance use, and diet should be entered on the 
LA-CRF or an appropriate document.
Obtain a history of exposure to environmental chemical agents.
Based on the subject’s history, other testing may be appropriate including: 
o
acute viral hepatitis (A,B, C, D, E or other infectious agents) 
o
ultrasound or other imaging to assess biliary tract disease
o
other laboratory tests including INR, direct bilirubin
Consider gastroenterology or hepatology consultations.
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document.
Study Discontinuation
In the absence of an explanation for increased LFT’s, such as viral hepatitis, pre-existing or 
acute liver disease or exposure to other agents associated with liver injury, the subject may be 
discontinued from the study. The investigator may determine that it is not in the subject’s 
best interest to continue study enrollment. Discontinuation of treatment should be considered 
if:
ALT or AST > 8 × ULN
ALT or AST > 5 × ULN for more than 2 weeks 
ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5) (If INR testing is 
applicable/evaluated)
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%).
In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, drug should be discontinued.
*) Hy’s Law Definition-Drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10–50% mortality 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 113 of 160
Version 3.0, Incorporating Substantial Amendment 2
(or transplant). The two “requirements” for Hy’s Law are: 1) Evidence that a drug can cause 
hepatocellular-type injury, generally shown by an increase in transaminase elevations higher 
3 times the upper limit of normal (“2 x ULN elevations are too common in treated and 
untreated subjects to be discriminating”); 2) Cases of increased bilirubin (at least 2 x ULN) 
with concurrent transaminase elevations at least 3x ULN and no evidence of intra- or extra-
hepatic bilirubin obstruction (elevated alkaline phosphatase) or Gilbert’s syndrome. [Temple 
R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf 2006 
Apr;15(4):241-3.]
Reference
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” 
issued by FDA on July 2009.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 114 of 160
Version 3.0, Incorporating Substantial Amendment 2
12.3
Instructions for Subjects Moving from Protocol v1.0 to Protocol v2.0
12.3.1
Visit Schedule
Subjects that have entered the study under protocol v1.0, upon signing the informed consent
for the amendment 1, will have their visit frequency adjusted according to Table 1, Schedule of 
Assessments. For example, if subject signs informed consent for protocol v2.0 at scheduled 
week 3 (according to protocol v1.0), subject will attend clinic at week 4, week 6 and all 
subsequent visits as per Schedule of Assessments.
12.3.2
Dosing Instructions for Subjects Moving from Protocol v1.0 to Protocol v2.0
Dosing
Study drug will be dosed TIW throughout the treatment period, unless otherwise specified.
Subjects that have entered the study under protocol version 1.0, upon signing the informed 
consent for the amendment 1, will have their dose frequency (on QW and BIW under 
protocol v1.0) and dose amount adjusted. Subjects randomized to roxadustat QW or BIW 
who do not agree to change to TIW, should be discontinued from the study treatment and 
continue in the post study follow-up period.
At this visit, it is first determined if the subject would need a dose titration according to the 
dose adjustment rules as per Section 5.1.2.1  Once that is established subjects are converted 
per the below instructions. The dose assigned must not exceed the maximum allowed dose of 
3.0 mg/kg bodyweight or 300 mg per administration, whichever is lower. For subjects on 
permanent dialysis dose assigned must not exceed 3.0 mg/kg (based on dry weight in 
hemodialysis subjects and weight minus abdominal fluid based on last filling in peritoneal 
dialysis subjects) or 400 mg per administration, whichever is lower.
a) Subjects in the correction period or maintenance period on TIW dosing, will continue on 
TIW dosing for the remainder of the treatment period. If needed their dose will be 
adjusted according to the conversion table below, at the visit when the updated informed 
consent is signed.
Current TIW dose (mg)
20
40
50
70
100
120
150
200
250
300
350
400
If no dose titration needed
20
40
50
70
100
100
150
200
250
300
300
300
If up titration needed*
40
50
70
100
150
150
200
250
300
300
300
300
If down titration needed*
#
20
40
50
70
100
100
150
200
250
300
300
b) Subjects in the maintenance period on BIW dosing will change to TIW dosing 
immediately, per conversion table below, at the visit when the informed consent for the 
amendment 1 is signed. 
Current BIW maintenance dose (mg)
20
40
50
70
100
120
150
200
250
300
350
400
If no dose titration needed
20
20
40
50
70
70
100
150
150
200
250
250
If up titration needed*
20
40
40
70
70 
100
150
150
200
250
250 300
If down titration needed*
#
20
20
40
50
70
70
100
150
150
200
200

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 115 of 160
Version 3.0, Incorporating Substantial Amendment 2
c) Subjects in the maintenance period on QW dosing will change to TIW dosing 
immediately, per conversion table below, at the visit when the updated informed consent 
is signed.
Current QW maintenance dose (mg)
20
40
50
70
100
120
150
200
250
300
350
400
If no dose titration needed
20
20
20
20
40
40
50
70
70
100
100
150
If up titration needed*
20 
20
20
40
40
50
70
70 
100
100
150
150
If down titration needed*
#
#
20
20
20
40
40
50
70
70
100
100
* Up or down titrations are only applicable when the criteria for dose reduction have been met.
#  Contact the medical monitor if down titration is needed.
12.3.3
ESA Rescue Therapy
If, upon implementation of protocol v2.0, a subject on roxadustat has already received 1 or 
more ESA treatments (under protocol v1.0), they can initially continue in the study. The
subject will, however, be discontinued from study treatment if a further ESA rescue treatment 
is required after implementation of protocol v2.0.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 116 of 160
Version 3.0, Incorporating Substantial Amendment 2
12.4
Instructions for Subjects Requiring Dialysis
Subjects who initiate temporary or permanent dialysis treatment are allowed to continue in the 
study. All modes of dialysis, i.e., hemodialysis (HD), hemodiafiltration (HDF) and peritoneal 
dialysis (PD) are allowed.
12.4.1
Dosing

Subjects should continue with the same dose and dose frequency of study drug as they 
were on prior to dialysis initiation.

For HD/HDF subjects, it is recommended that study drug is administered any time after 
completion of dialysis (if dosing is scheduled on a dialysis day) to avoid potential bias on 
certain study assessments.

For subjects treated with darbepoetin, the route of administration of darbepoetin is 
according to local standard of care for dialysis patients.
12.4.2
Dose Adjustment

The dose adjustment rules remain unchanged (see Section 5.1.2.1). 

The maximum allowed dose in subjects on permanent dialysis is 3.0 mg/kg (based on 
post-dialysis weight in HD subjects and weight minus abdominal fluid based on last
filling in PD subjects) or 400 mg per administration, whichever is lower.
12.4.3
ESA Rescue Therapy
If roxadustat subjects meet the criteria for ESA rescue therapy while on dialysis, darbepoetin 
alfa will be administered IV or SC according to its Package Insert or SmPC for dialysis 
subjects. The subject must be discontinued from study treatment if the subject requires a 
second course of rescue darbepoetin alfa.
12.4.4
Supplemental Iron Use
Iron supplementation rules are unchanged in subjects starting dialysis who are randomized to  
roxadustat (see Section 5.1.3.2.1). In subjects randomized to darbepoetin, IV iron 
supplementation will be given according to standard of care.
12.4.5
Health Related Quality of Life
Additional questionnaires will be completed on day of first dialysis, 4 weeks later and 
12 weeks later, prior to initiation of the procedure.
12.4.6
Timing of Study Assessments

If a study visit occurs on a dialysis day, all study assessments should be performed before 
start of dialysis. 

Blood pressure and HR should be measured in triplicate prior to and after end of dialysis 
(HD/HDF subjects only). 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 117 of 160
Version 3.0, Incorporating Substantial Amendment 2
12.5
Short Form-36 Health Survey (SF-36)
Your Health and Well-Being
This survey asks for your views about your health. This information will 
help keep track of how you feel and how well you are able to do your usual 
activities. Thank you for completing this survey!
1.
In general, would you say your health is:
Excellent
Very good
Good
Fair
Poor





1
2
3
4
5
2.
Compared to one year ago, how would you rate your health in 
general now?
Much better
now than one
year ago
Somewhat
better
now than one
year ago
About the
same as
one year ago
Somewhat
worse
now than one
year ago
Much worse
now than one
year ago





1
2
3
4
5

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 118 of 160
Version 3.0, Incorporating Substantial Amendment 2
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

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 119 of 160
Version 3.0, Incorporating Substantial Amendment 2
4.
During the past 4 weeks, how much of the time have you had any of 
the following problems with your work or other regular daily 
activities as a result of your physical health?
All of
the time
Most of
the time
Some of
the time
A little of
the time
None of
the time

a
Cut down on the amount of
time you spent on work or 
other activities.............................
1..........
2............
3............
4............
5
b
Accomplished less than you 
would like ...................................
1..........
2............
3............
4............
5
c
Were limited in the kind of 
work or other activities...............
1..........
2............
3............
4............
5
d
Had difficulty performing the
work or other activities (for 
example, it took extra effort) ......
1..........
2............
3............
4............
5
5.
During the past 4 weeks, how much of the time have you had any of 
the following problems with your work or other regular daily 
activities as a result of any emotional problems (such as feeling 
depressed or anxious)?
All of
the time
Most of
the time
Some of
the time
A little of
the time
None of
the time

a
Cut down on the amount of
time you spent on work or 
other activities.............................
1..........
2............
3............
4............
5
b
Accomplished less than you 
would like ...................................
1..........
2............
3............
4............
5
c
Did work or other activities
less carefully than usual..............
1..........
2............
3............
4............
5

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 120 of 160
Version 3.0, Incorporating Substantial Amendment 2
6.
During the past 4 weeks, to what extent has your physical health or 
emotional problems interfered with your normal social activities with 
family, friends, neighbours, or groups?
Not at all
Slightly
Moderately
Quite a bit
Extremely





1
2
3
4
5
7.
How much bodily pain have you had during the past 4 weeks?
None
Very mild
Mild
Moderate
Severe
Very severe






1
2
3
4
5
6
8.
During the past 4 weeks, how much did pain interfere with your 
normal work (including both work outside the home and 
housework)?
Not at all
A little bit
Moderately
Quite a bit
Extremely





1
2
3
4
5

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 121 of 160
Version 3.0, Incorporating Substantial Amendment 2
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

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 122 of 160
Version 3.0, Incorporating Substantial Amendment 2
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!

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 123 of 160
Version 3.0, Incorporating Substantial Amendment 2
12.6
Functional Assessment of Cancer Therapy- Anemia (FACT-AN)

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 124 of 160
Version 3.0, Incorporating Substantial Amendment 2

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 125 of 160
Version 3.0, Incorporating Substantial Amendment 2

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 126 of 160
Version 3.0, Incorporating Substantial Amendment 2
12.7
EuroQol Questionnaire (EQ-5D-5L)

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 127 of 160
Version 3.0, Incorporating Substantial Amendment 2

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 128 of 160
Version 3.0, Incorporating Substantial Amendment 2

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 129 of 160
Version 3.0, Incorporating Substantial Amendment 2
12.8
Subjects’ Global Impression of Change (PGIC) Scale

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 130 of 160
Version 3.0, Incorporating Substantial Amendment 2
12.9
Work Productivity and Activity Impairment Questionnaire: 
Anemic Symptoms (WPAI:ANS)
The following questions ask about the effect of your anaemic symptoms on your ability to work and 
perform normal daily activities. Please fill in the blanks or circle a number, as indicated.
1.
Are you currently employed (working for pay)? ______NO
______YES
If NO, tick “NO” and skip to question 6.
The next questions refer to the past seven days, not including today.
2.
During the past seven days, how many hours did you miss from work because of problems 
associated with your anaemic symptoms? Include hours you missed on sick days, times you 
went in late, left early, etc., because of your anaemic symptoms . Do not include time you 
missed to participate in this study.
______HOURS
3.
During the past seven days, how many hours did you miss from work because of any other 
reason, such as annual leave, holidays, time off to participate in this study?
______HOURS
4.
During the past seven days, how many hours did you actually work?
______HOURS (If “0”, skip to question 6)
5. 
During the past seven days, how much did your anaemic symptoms affect your productivity 
while you were working? 
Think about days you were limited in the amount or kind of work you could do, days you 
accomplished less than you would like, or days you could not do your work as carefully as 
usual. If anaemic symptoms affected your work only a little, choose a low number. Choose a 
high number if anaemic symptoms affected your work a great deal. 
Consider only how much anaemic symptoms affected 
productivity while you were working.
Anaemic symptoms had 
no effect on my work
Anaemic symptoms
completely prevented 
me from working
0
1
2
3
4
5
6
7
8
9
10

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 131 of 160
Version 3.0, Incorporating Substantial Amendment 2
CIRCLE A NUMBER
6. 
During the past seven days, how much did your anaemic symptoms affect your ability to 
perform your normal daily activities, other than work at a job?
By normal activities, we mean the usual activities you perform, such as working around the 
house, shopping, childcare, exercising, studying, etc. Think about times you were limited in 
the amount or kind of activities you could perform and times you accomplished less than you 
would like. If anaemic symptoms affected your activities only a little, choose a low number. 
Choose a high number if anaemic symptoms affected your activities a great deal. 
Consider only how much anaemic symptoms affected your ability
to do your normal daily activities, other than work at a job.
Anaemic symptoms had 
no effect on my daily 
activities
Anaemic symptoms
completely prevented 
me from doing my 
daily activities
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 132 of 160
Version 3.0, Incorporating Substantial Amendment 2
13
ATTACHMENT 1:  SUBSTANTIAL AMENDMENT 2
I.  The purpose of this amendment is:
Substantial Changes
1. Change in hemoglobin (Hb) eligibility criteria.
DESCRIPTION OF CHANGE:
The number of Hb values assessed during the screening period is reduced from three to two 
and the mean Hb entry threshold is increased from ≤10.0 g/dL to ≤10.5 g/dL. This results 
in a change in inclusion criterion 4 and texts throughout the protocol that refer to the mean 
Hb entry threshold.
RATIONALE:
Reducing the number of Hb screening values required to be assessed during the screening 
period from three to two reduces the number of screening visits, and is likely to shorten the 
screening period and accelerate the decision on patient eligibility concerning the Hb 
inclusion criterion. The Hb stability criterion defined by a maximum allowed difference 
between screening values of 1.0 g/dL remains unchanged to avoid unduly unstable Hb levels 
at baseline. 
The current Hb entry criterion (mean Hb ≤10.0 g/dL at screening) is reconsidered.  The 
current Hb value of ≤10.0 g/dL is considered too low and incongruent with contemporary 
clinical practice, especially in countries with high standard of care. Feedback from sites and 
investigators raise this criterion as the principal cause of screen failure, or alternatively, as a 
reason for not screening patients at all. This change will not bias or impact Hb-related 
endpoint assessments, nor does it affect other key elements of the trial design including the 
roxadustat dosing algorithm and principles for dose adjustments. The updated European 
Renal Best Practice (ERBP) position statement from a 2013 publication by Locatelli and 
colleagues provides valid support to increase the Hb threshold for inclusion: according to this 
statement the Hb levels should not routinely fall below 10 g/dL in all patients prior to 
initiation of erythropoiesis stimulating agent (ESA) therapy.  Consequently, the mean Hb 
entry threshold is increased to ≤10.5 g/dL. 
2. Update of the iron criteria: ferritin level ≥100 ng/mL and transferrin saturation 
(TSAT) level ≥20% at screening are removed.
DESCRIPTION OF CHANGE:
The iron criteria are updated to better reflect clinical practice, and as a result inclusion 
criteria 6 and 7 are removed.
RATIONALE:
The current iron repletion criteria do not always mimic clinical practice and are based on a
paradigm which dictates the requirement of full iron repletion prior to commencing ESA 
therapy. The proposed changes aim to better reflect clinical practice and allow for inclusion 
of patients with iron indices indicative of relative or functional iron deficiency, under the 
condition that they are deemed eligible in the opinion of the investigator as per the 2012 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 133 of 160
Version 3.0, Incorporating Substantial Amendment 2
Kidney Disease Improving Global Outcomes (KDIGO) anemia guidelines. These guidelines
recommend to check and correct iron deficiency prior to initiation of ESA therapy, but 
arguably without absolute requirement to achieve the thresholds of ferritin ≥100 ng/mL and 
TSAT ≥20%. The KDIGO anemia guidelines further advocate individualized assessments 
in the clinical decision to initiate ESA therapy, and it may not always be feasible to ensure 
full iron repletion in individual patients. Finally, the 6 week washout period of IV iron may 
also limit investigators to administer sufficient iron to achieve the key ferritin and TSAT 
thresholds.
3. Exclusion Criterion 21 extended to exclude patients who are close to initiating 
renal replacement therapy including dialysis.
DESCRIPTION OF CHANGE:
Exclusion criterion 21 is extended to exclude patients that are close to initiating renal 
replacement therapy including dialysis (within the first year of the study).
RATIONALE:
The primary objective of this study is to assess the efficacy and safety of roxadustat in non-
dialysis chronic kidney disease (CKD) patients. Currently there are no specific criteria that 
prevent randomization of patients who are close to initiating renal replacement therapy, 
including dialysis. Randomization of these patients leads to reduced exposure and less 
patients available for primary and key secondary endpoint assessments in the intended target 
population of this study. The revised exclusion criterion aims to increase awareness amongst 
investigators that patients predicted to undergo dialysis treatment, or be discontinued from 
the treatment phase due to renal transplantation during the first year of the study should not 
be randomized.
Non-Substantial Changes
1. Contact details of key sponsor personnel
DESCRIPTION OF CHANGE:
Medical Monitor is changed to 
.
RATIONALE:
 has taken over medical monitor responsibilities from 
.
2. Extension of the planned study period
DESCRIPTION OF CHANGE:
The planned study period is extended from 3Q2018 until 2Q2021.
RATIONALE:
Enrollment was slower than expected at the start of the study; therefore, the study duration
has been increased.  This increase in the duration of the trial is considered non-substantial as 
PPD
PPD
PPD

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 134 of 160
Version 3.0, Incorporating Substantial Amendment 2
exposure to the treatment with Investigational Medicinal Product (IMP) is not extended.  The 
definition of the end of the trial for the study subjects is unchanged and the monitoring 
arrangements are not changed.
3. Post-study follow-up visits
DESCRIPTION OF CHANGE:
In case of premature discontinuation, subjects were to complete the end of treatment (EOT) 
visit and end of study (EOS) visit. This has been reworded to: 2 EOT visits and 1 EOS visit.
RATIONALE:
In the current protocol it is not clear that there are in total 3 follow-up visits for subjects that 
prematurely discontinue study treatment.  The 3 follow-up visits are: 1. EOT visit, 2. EOT+2 
week visit, 3. EOS visit.  This is clarified throughout the protocol text and in Table 1: 
footnote c and the column EOT + 2 weeks.
4. Inclusion Criterion 5 has been extended
DESCRIPTION OF CHANGE:
Inclusion criterion 5 that addresses the suitability for treatment with ESA using the criteria 
specified in the KDIGO 2012 recommendation, has been further clarified.
RATIONALE:
Criteria of suitability for treatment with ESA are further explained in more detail in order to 
provide more clarity and guidance to the investigator.  These criteria are based upon the 
wording used in the KDIGO 2012 anemia management guidelines.  These guidelines request 
the treating physician to initiate the use of ESAs in non-dialysis CKD patients considering 
the rate of fall of Hb concentration, prior response to iron therapy, the risk of needing a 
transfusion, the risks related to ESA therapy and the presence of symptoms attributable to 
anemia.
5. Concomitant medication: Supplemental iron use 
DESCRIPTION OF CHANGE:
I. Oral iron: Rewording of supplemental iron use guidance for roxadustat-treated subjects in 
case of intolerance to oral iron.
II. Intravenous iron for all treated subjects: upon reaching iron repletion (once ferritin is 
≥100 ng/mL and TSAT ≥20%) it is recommended to discontinue IV iron supplementation.
RATIONALE:
Text updates have been made to align with other phase 3 protocols in the global program for 
consistency throughout the roxadustat development program. 
6. Prohibited medication
DESCRIPTION OF CHANGE:

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 135 of 160
Version 3.0, Incorporating Substantial Amendment 2
The list of prohibited medications is clarified and only to summarize the prohibited 
medication for the identified period.  In protocol version 1.0 for ESA, IV iron and red blood 
cell (RBC) transfusion, it was stated when these medications were prohibited, but also when 
these medications were allowed.  The time when these medications are allowed is removed.
RATIONALE:
ESA rescue therapy, IV iron and RBC transfusion are only prohibited during the screening 
period.  Within the treatment period these medications are restricted in use and follow certain 
criteria. These criteria are described under protocol sections of concomitant medication 
(Section 5.1.3) and rescue therapy guidelines (Section 5.1.5).  Therefore to avoid confusion, 
the references to the treatment period are being removed from the prohibited medication lists.
7. Additional efficacy secondary endpoint
DESCRIPTION OF CHANGE:
Additional secondary endpoint has been deleted : Iron use - Monthly oral iron (mg) use per 
subject during weeks 1 to 36, and weeks 36 to 52 (monthly defined as a period of 4 weeks)
RATIONALE:
Use of oral iron is not considered a clinically meaningful endpoint since the study protocol 
recommends supplementation of oral iron to support erythropoiesis and as the first-line 
treatment for iron deficiency in both treatment arms.
8. Changes in reference to pre- and post-amendment
DESCRIPTION OF CHANGE: 
The current tables (synopsis table 4, protocol table 3 and 10) refer to pre- and post-
amendment.  “Pre-amendment” are changed to “Protocol version 1” and “post-amendment” 
are changed to “Protocol version 2 and 3”.
RATIONALE:
With the current amendment these tables are updated to reflect the situation taking all 
protocol versions into account.
9. Primary Analysis: Sensitivity analyses on the primary analysis of the primary 
endpoint
DESCRIPTION OF CHANGE:
A sensitivity analysis on the results of the primary analysis of the primary endpoint before 
and after protocol amendment 1 and protocol amendment 2 is added.
RATIONALE:
This sensitivity analysis is added to evaluate the impact on the primary endpoint in both 
protocol amendments 1 and 2.  The changes implemented following both amendments could 
have led to inconsistent results between those patients included before amendment 1 versus 
those included after amendment 1, and patients included before amendment 2 versus those 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 136 of 160
Version 3.0, Incorporating Substantial Amendment 2
included after amendment 2.
10. Synopsis and interim analysis 
DESCRIPTION OF CHANGE: 
A descriptive analysis of both safety and efficacy data is added to support a regulatory 
submission in case the planned interim analysis is not reached. This includes only 
descriptive statistics.
RATIONALE:
Enrollment has been slower than expected at the start of the study.  It was anticipated that at 
the time of submission for marketing authorization, the currently planned interim analysis 
would not have been reached. In order to provide full disclosure of the results, a descriptive
analysis is included. Only summary data and both safety and efficacy (without inferential 
statistics) will be presented without any impact on the ongoing study.
11. Flow Chart
DESCRIPTION OF CHANGE:
The term “Absence of renal carcinoma per renal ultrasound” is deleted from the box 
describing the key selection criteria in the flow chart.
RATIONALE:
The purpose of the box in the flow chart describing key selection criteria is to inform on a 
high level about the most relevant criteria qualifying a subject for inclusion into the study.  In 
this context and keeping in mind that the protocol includes approximately 40 inclusion and 
exclusion criteria, the criterion “Absence of renal carcinoma per renal ultrasound” is not 
regarded as a key selection criterion. CKD stage, Hb entry value and the suitability for 
treatment with ESAs are considered the key selection criteria.
12. Schedule of Assessments
DESCRIPTION OF CHANGE:
Updates to the Schedule of Assessments to reflect changes made in this Amendment and to 
add other clarifications.
RATIONALE:
To provide up to date and accurate information.
13. Summary of key safety information for study design: roxadustat
DESCRIPTION OF CHANGE:
Five pancreatitis events were noted during the roxadustat clinical development program, the 
majority of which have been associated with gallstones or biliary sludge; one was due to a 
pancreatic duct stricture and another case had multiple risk factors for pancreatitis.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 137 of 160
Version 3.0, Incorporating Substantial Amendment 2
RATIONALE:
‘Phase 2’ is added to make clear that the ‘five pancreatitis events’ refer to data from the 
phase 2 development program.  Meanwhile the phase 3 program has been ongoing for more 
than 2 years
14. Three times weekly (TIW) dosing regimen of roxadustat
DESCRIPTION OF CHANGE:
The protocol described the roxadustat dosing schedule of TIW to be dosed at least 2 days 
apart (e.g., Monday, Wednesday, Friday). This changes into: the period between two 
roxadustat administrations should be at least 36 hrs. 
RATIONALE:
Alignment with phase 3 dialysis protocol and providing logic to dosing regimen TIW. 
15. Dose adjustment rules for subjects receiving darbepoetin alfa
DESCRIPTION OF CHANGE:
Deletion of Table 6: Recommended Dose Adjustment Rules for Darbepoetin Alfa
RATIONALE:
The principal reason for Table deletion is that the table does not fully reflect all elements of 
the Summary of Product Characteristics (SmPC).
16. Return of (un)used medication to site 
DESCRIPTION OF CHANGE:
Clarification on the return of empty medication packages for subjects treated with 
darbepoetin alfa who are self-administering the medication after 36 weeks of treatment.  A 
sentence is added with regard to treatment compliance for subjects randomized to 
darbepoetin:  In case of self-administration after 36 weeks of treatment, the empty packages 
of darbepoetin alfa should be returned by the subject to the site.
RATIONALE:
To clarify that in case subjects self-inject darbepoetin alfa (only following 36 weeks of 
treatment with darbepoetin alfa), they need to return the empty packages to perform the 
check on treatment compliance.
17. Safety Assessments
DESCRIPTION OF CHANGE:
The number of visits on which vital signs are measured is reduced and an average is not 
derived from the 2nd and 3rd readings.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 138 of 160
Version 3.0, Incorporating Substantial Amendment 2
RATIONALE:
As all three readings for the vital sign parameters will be used in the statistical analysis, an 
average of the 2nd and 3rd readings was no longer relevant and was inconsistent with the 
analysis.
18. Reporting of SAEs
DESCRIPTION OF CHANGE:
Deleted the contact details of MedPace for reporting of SAEs.
RATIONALE:
Contact details of MedPace as currently stated in the protocol are not applicable. 
19. Total blood volume
DESCRIPTION OF CHANGE:
The total volume of 440 mL is changed to 460 mL.
RATIONALE:
The blood volume is adjusted to better depict the total blood volume required by the current 
visit schedule.
20. Secondary analysis: additional sensitivity analysis
DESCRIPTION OF CHANGE:
In addition, this variable will be analyzed using the subset of subjects who have reached Hb 
≥11.0 g/dL prior to week 28.
RATIONALE:
While subgroup analysis based on baseline characteristics are scientifically sound and well 
accepted by regulatory guidelines, post-baseline responses affected by the treatment are not 
appropriate variables to define subgroups for investigation (see graft guideline on the 
investigation of subgroups in confirmatory clinical trials, EMA/CHMP/539146/2013). 
Therefore the subgroup analysis restricted to subjects who have reached 11 g/dL during the 
study has been removed from the protocol.
21. Appendix 12.4 Instructions for subjects requiring dialysis
DESCRIPTION OF CHANGE:
Addition of text to Appendix 12.4 to describe that: 1. The iron supplementation rules are 
unchanged (Section 5.1.3.2.1) in subjects starting dialysis.  2. The route of administration of 
darbepoetin is according to the local standard of care for dialysis patients.
RATIONALE:
Provides alignment with the phase 3 dialysis protocol and guidance in the applicable text 
regarding management of subjects after having initiated dialysis.  This change allows a 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 139 of 160
Version 3.0, Incorporating Substantial Amendment 2
switch in the application route if deemed required (e.g., from subcutaneous use to 
intravenous use).
22. Appendix 12.10 
DESCRIPTION OF CHANGE:
Appendix 12.10 has been deleted.
RATIONALE:
A general reference was added in the text to the KDIGO 2012 guideline.  Appendix 12.10 
did not add any further information and is therefore deleted.
23. Minor Administrative Changes
DESCRIPTION OF CHANGE: 
Includes minor administrative changes, e.g., typos, format, numbering, consistency 
throughout the protocol following the latest Astellas document consistency guidance.
RATIONALE:
Update the protocol to correct formatting and to provide clarifications to ensure complete 
understanding of study procedures.
II.  Amendment Summary of Changes: Substantial Changes
III List of Abbreviations and Definition of Key Terms, IV Synopsis, Study Design 
Overview and Inclusion Criteria, 2 Study Objective(s), Design, and Endpoints, 3 Study 
Population, and 5 Treatments and Evaluation
List of Key Study Terms, 2.2.1.2 Study Population, 2.2.1.3 Description of Study, 3.2 
Inclusion Criteria #4 and 5.2.4 Diagnosis of the Target Disease, Severity, and Duration of 
Disease
WAS:
The mean of the subject’s three most recent (prior to randomization) Hb values during the 
screening period, obtained at least 4 days apart, must be ≤10.0 g/dL, with a difference of 
≤1.0 g/dL between the highest and the lowest values. The last Hb value must be within 
10 days prior to randomization.
IS AMENDED TO:
The mean of the subject’s three two most recent (prior to randomization) Hb values during 
the screening period, obtained at least 4 days apart, must be ≤10.05 g/dL, with a difference 
of ≤1.0 g/dL between the highest and the lowest values. The last Hb value must be within 
10 days prior to randomization.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 140 of 160
Version 3.0, Incorporating Substantial Amendment 2
IV Synopsis, Inclusion Criteria and 3 Study Population
3.2 Inclusion criteria #6 and #7
WAS:
6. Subject has a ferritin level ≥100 ng/mL (≥220 pmol/L) at screening.
7. Subject has a transferrin saturation (TSAT) level ≥20% at screening.
IS AMENDED TO:
6. Subject has a ferritin level ≥100 ng/mL (≥220 pmol/L) at screening. This criterion has 
been removed.
7. Subject has a transferrin saturation (TSAT) level ≥20% at screening. This criterion has 
been removed.
IV Synopsis, Exclusion Criteria and 3 Study Population
3.2 Exclusion criterion #21
WAS:
Subject has had any prior organ transplant (that has not been explanted), or subject is 
scheduled for organ transplantation.
IS AMENDED TO:
Subject has had any prior organ transplant (that has not been explanted), or subject is 
scheduled for organ transplantation, or subject is likely to initiate renal replacement 
therapy including dialysis within the first year of the study in the opinion of the 
investigator.
V Flow Chart and Schedule of Assessments
Table 1: Schedule of Assessments
ADDED:
i An additional (third) Hb value may be collected if necessary. Only for subjects who 
are switched from protocol version 2.0 to 3.0 during (re) screening can a fourth Hb 
value be collected, as was applicable under protocol version 2.0.
2 Study Objective(s), Design, And Endpoints
2.2.1.2 Study Population
DELETED:
Subjects are iron replete; inclusion is permitted if ferritin ≥ 100 ng/mL (≥220 pmol/L) and 
Transferrin Saturation (TSAT) ≥ 20%.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 142 of 160
Version 3.0, Incorporating Substantial Amendment 2
WAS:
Subject is deemed suitable by the investigator for treatment with erythropoiesis stimulating 
agents (ESA) using the criteria specified in the KDIGO 2012 recommendation (see 
Appendix 12.10).
IS AMENDED TO:
Subject is deemed suitable by the investigator for treatment with erythropoiesis stimulating 
agents (ESA) using the criteria specified in the KDIGO 2012 recommendation (see 
Appendix 12.10). considering the rate of fall of Hb concentration, prior response to 
iron therapy, the risk of needing a transfusion, the risks related to ESA therapy and 
the presence of symptoms attributable to anemia.
IV Synopsis, Concomitant Medication Restrictions and/or Requirements, 2 Study 
Objective(s), Design, and Endpoints, and 5 Treatments and Evaluation
2.2.1.5 Comparator and 5.1.3.2.1 Supplemental Iron Use
WAS:
Subjects receiving roxadustat
i. Oral iron
For subjects receiving roxadustat, oral iron is recommended for dietary supplementation to 
support erythropoeisis and as the first-line for prevention and treatment of iron deficiency. 
The recommended daily dose is 200 mg of elemental iron; in case of iron intolerance or for 
other reasons a lower dose may be given. Subjects should be advised to take roxadustat at 
least one hour before or one hour after oral iron.
ii. IV iron
For subjects receiving roxadustat, IV iron supplementation is allowed if all of the following 
criteria are met:

The subject has not responded adequately in terms of hemoglobin response to 2 or more 
consecutive dose increases of roxadustat or reached the maximum dose limit, and

The subject has iron deficiency (either ferritin <100 ng/mL [<220 pmol/L] or 
TSAT < 20%) or the subject is intolerant of oral iron therapy.
Treatment with roxadustat may continue during IV iron administration. IV iron 
administration should be stopped once ferritin levels are ≥100 ng/mL (≥220 pmol/L) and 
TSAT ≥20%.
Subjects receiving darbepoetin alfa
For subjects treated with darbepoetin alfa, oral or IV iron supplementation is required to 
maintain iron repletion and will be administered only if ferritin <100 ng/mL (<220 pmol/L) 
or TSAT < 20%. The route of iron administration is up to the investigator’s discretion and 
follows the KDIGO 2012 recommendation for NDD-CKD subjects (see Appendix 12.10). 
Criteria such as the severity of iron deficiency, availability of venous access, response to
prior oral iron therapy, side effects with prior oral or IV iron therapy, and subject 
compliance will be considered.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 143 of 160
Version 3.0, Incorporating Substantial Amendment 2
IS AMENDED TO:
Subjects receiving roxadustat
i. Oral iron
For subjects receiving roxadustat, oral iron is recommended for dietary supplementation to 
support erythropoiesis and as the first-line for prevention and treatment of iron deficiency 
unless the subject is intolerant to this treatment.  The recommended daily dose is 200 mg 
of elemental iron; in case of iron intolerance or for other reasons a lower dose may be given. 
Subjects should be advised to take roxadustat at least one hour before or one hour after oral 
iron.
ii. IV iron
For subjects receiving roxadustat, IV iron supplementation is allowed if all of the following 
criteria are met:

The subject has not responded adequately in terms of hemoglobin response to 2 or more 
consecutive dose increases of roxadustat or reached the maximum dose limit, and

The subject has iron deficiency (either ferritin <100 ng/mL [<220 pmol/L] or 
TSAT < 20%) or the subject is intolerant of oral iron therapy.
Treatment with roxadustat may continue during IV iron administration.  Discontinuation of
IV iron administration should be stopped is recommended once ferritin levels are 
≥100 ng/mL (≥220 pmol/L) and TSAT ≥20%.
Subjects receiving darbepoetin alfa
For subjects treated with darbepoetin alfa, oral or IV iron supplementation is required to 
maintain iron repletion and will be administered only if ferritin <100 ng/mL (<220 pmol/L) 
or TSAT < 20%. The route of iron administration is up to the investigator’s discretion and 
follows the KDIGO 2012 recommendation for NDD CKD subjects (see Appendix 12.10). 
Criteria such as the severity of iron deficiency, availability of venous access, response to 
prior oral iron therapy, side effects with prior oral or IV iron therapy, and subject 
compliance will be considered.. IV iron should only be administered if ferritin < 100 
ng/mL (< 220 pmol/L) or TSAT < 20%. IV iron may be administered per local 
practice. Discontinuation of IV iron therapy is recommended once ferritin levels are 
≥100 ng/mL (≥220 pmol/L) and TSAT ≥20%.
IV Synopsis, Prohibited Medication, 5 Treatments and Evaluation and 12 Appendices
5.1.3.3 Prohibited Medication and 12.1 List of Prohibited Concomitant Medications
WAS:
The following medications are prohibited during the period identified:

Any ESA: within 12 weeks prior to randomization until EOT, except for darbepoetin 
alfa as part of randomized treatment or as rescue therapy.

IV iron: within 6 weeks prior to randomization. From day of randomization onwards IV 
iron is allowed as part of supplemental iron use, if protocol-specified criteria are met.

RBC transfusion: within 8 weeks prior to randomization. From the day of 

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 144 of 160
Version 3.0, Incorporating Substantial Amendment 2
randomization onwards RBC transfusions are allowed as part of the rescue therapy, if 
protocol-specified criteria are met.
IS AMENDED TO:
The following medications are prohibited during the period identified:

Any ESA: within 12 weeks prior to randomization until EOT, except for darbepoetin 
alfa as part of randomized treatment or as rescue therapy.

IV iron: within 6 weeks prior to randomization. From day of randomization onwards IV 
iron is allowed as part of supplemental iron use, if protocol specified criteria are met.

RBC transfusion: within 8 weeks prior to randomization. From the day of 
randomization onwards RBC transfusions are allowed as part of the rescue therapy, if 
protocol specified criteria are met.
IV Synopsis, Additional Secondary and 2 Study Objective(s), Design, and Endpoints
2.3.3.1 Efficacy Endpoints
DELETED:
Iron use

Monthly oral iron (mg) use per subject during weeks 1 to 36, and weeks 36 to 52 
(monthly defined as a period of 4 weeks)
IV Synopsis, Statistical Methods, 2 Study Objective(s), Design, and Endpoints and 7 
Statistical Methodology
2.2.1.3 Description of Study, 7.1 Sample Size
WAS:
In protocol version 1.0 (pre-amendment) subjects were randomized in a ratio of 2:1 
receiving roxadustat versus darbepoetin alfa. The expected number of subjects randomized 
pre-amendment, post-amendment and overall are represented in the following table.
Table 3 Expected Number of Subjects Randomized Pre-amendment and Post-amendment
Treatment 
Arms
Study Treatment
Expected Number of 
Pre-amendment 
Subjects Randomized 
(Ratio 2:1)*†
Expected Number of 
Post-amendment 
Subjects Randomized
(Ratio 1:1)
Total Expected 
Number of 
Subjects 
Randomized per 
Treatment Arm
1
Roxadustat
100
210
310
2
Darbepoetin alfa
50
210
260
Total
150
420
570
* The number of subjects post-amendment will depend on the number of subjects randomized pre-amendment. 
The number of subjects randomized pre-amendment is assumed to be 150.
† Subjects pre-amendment randomized to QW and BIW will be converted to the TIW arm according to the 
schedule as included in Appendix 12.3
IS AMENDED TO:

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 145 of 160
Version 3.0, Incorporating Substantial Amendment 2
In protocol version 1.0 (pre amendment) subjects were randomized in a ratio of 2:1 
receiving roxadustat versus darbepoetin alfa. The expected number of subjects randomized 
on protocol version 1, protocol versions 2 and 3 and the total number of randomized 
subjects per treatment arm pre amendment, post amendment and overall are represented 
in the following table.
Table 3 Expected Number of Subjects Randomized Pre amendment and Post amendment
Treatment 
Arms
Study Treatment
Expected Number of 
Pre amendment
Protocol v1
Subjects 
Randomized (Ratio 
2:1)*†
Expected Number of 
Post amendment
Protocol v2 and 3 
Subjects 
Randomized
(Ratio 1:1)†
Total Expected 
Number of 
Subjects 
Randomized per 
Treatment Arm
1
Roxadustat
100
210
310
2
Darbepoetin alfa
50
210
260
Total
150
420
570
* † The number of subjects under protocol v2 and v3 post amendment will depend on the number of subjects 
randomized under protocol v1 pre amendment. The number of subjects randomized pre amendment is 
assumed to be 150.
† Subjects pre amendment randomized to QW and BIW will be converted to the TIW arm according to the 
schedule as included in Appendix 12.3
IV Synopsis, Analysis of Primary Endpoint and 7 Statistical Methodology
7.4.1.1 Primary Analysis
ADDED:
Sensitivity analyses will be conducted to assess the consistency of the results before and 
after protocol amendments 1 and 2 (e.g., protocol versions 2.0 and 3.0 respectively).
IV Synopsis, Interim Analyses and 7 Statistical Methodology
7.9 Interim Analysis
ADDED:
In addition, a descriptive analysis on both safety and efficacy will be performed to 
provide information from this study for regulatory filings for roxadustat in case the 
planned interim analysis has not been reached. This will include only descriptive 
statistics by arm (i.e., without formal hypothesis testing).
V Flow Chart and Schedule of Assessments
Flow Chart
WAS:

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 146 of 160
Version 3.0, Incorporating Substantial Amendment 2
IS AMENDED TO:
STUDY DESIGN 3.0

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 147 of 160
Version 3.0, Incorporating Substantial Amendment 2
V Flow Chart and Schedule of Assessments
Table 1: Schedule of Assessments
WAS:
Assessments
Screening 
Period
Treatment Period
(Correction Period and Maintenance Period)
Follow-up Period
Unscheduled 
Visits
Post study 
Follow-up c
Visit / Week
2-6 weeks a
Day 1b
Weekly
(wks 1 - 2)
± 2 days
Every 2 Weeks 
(wks 4 - 24)
± 2 days
Every 4 Weeks 
(wks 28 - 100)
± 3 days
EOT c
(wk 104)
± 3 days
EOT + 2 wks
± 3 days
EOS c
(EOT + 4 wks)
± 3 days
Every 6 months 
until projected 
wk 108
S1
S2 S3
Written informed consent
X
Randomization
X
Eligibility criteria
X
X
Demographics
X
Medical history
X
Physical examination  
X
X
wks 12d, 24d 
wks 36d, 52d, 76d
X
Xd
Od
Heighte, weight
X
X
wks 12, 24
wks 36, 52, 76
X
X
O
Blood pressuref, heart ratef, respiratory rateg
X
X
X
X
X
X
X
X
X
X
CBC with WBC diff, red cell indices and 
platelets
X
X
X
wks 4, 8, 12, 20
wks 28, 36, 44, 
52, 60, 68, 76, 84, 
92, 100
X
X
O
Hemoglobinh
X
X
X
X
X
X
HemoCue assessmenti
X
X
X
X
X
Reticulocyte count and Hb in reticulocytes 
(CHr)
X
X
X
wks 4, 6, 8, 12, 
16, 20
wks 28, 36, 44, 
52, 60, 68, 76, 84, 
92, 100
X
X
O
12-lead ECG 
X
X
wks 12, 24
wks 36, 52, 76
X
O
Serum chemistry
X
X
wks 4, 8, 12, 20
wks 28, 36, 44, 
52, 60, 68, 76, 84, 
92, 100
X
X
X
O
LFTsj
wk 2
wks 6, 16
O
Renal ultrasoundk
X
X
O
Serum lipid panell
X
X
wks 4, 8, 12, 20 
wks 28, 36, 44, 
52, 68, 84
X
X
O
Serum iron, ferritin, TIBC, TSAT
X
X
wks 4, 8, 12, 20
wks 28, 36, 44, 
52, 60, 68, 76, 84, 
92, 100
X
X
O
HbA1c
X
X
wk 12
wks 28, 36, 44, 
60, 84
X
X
O
Vitamin B12, folate
X
HIV immunoassay, HBsAg, 
anti-HCV antibody
X

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 148 of 160
Version 3.0, Incorporating Substantial Amendment 2
Serum pregnancy testm
X
wks 12, 24
wks 36, 48, 60, 
72, 84, 96
X
O
Table continued on next page
eGFRn
X
X
wk 20
wks 36, 52, 68, 84
X
X
O
hs-CRP
X
wks 4, 12, 20
wks 36, 52
X
X
Archival serum samples for biomarkerso
X
wks 4, 12, 20
wks 52, 76
X
X
Blood sample for PKp
wks 2 to 8
Genotypingq
O
QoL questionnairesr
X
wks 8, 12 
wks 28, 36, 52, 76
X
O
Urinary testings
X
wks 12, 24
wks 36, 52, 64, 
76, 88
X
O
Archival urine samples for biomarkers
X
wk 24
wks 52, 76
X
Study drug dispensingt
├────────────────────────────┤
O
Dose adjustment reviewu
X
X
X
O
Hospitalization recordingv
X
X
X
◄─────────────────────────────────────────────────────────────►
X
AE recording
X
X
X
◄─────────────────────────────────────────────────────────────►
Concomitant medication, procedure and non-
drug therapy recording
X
X
X
◄─────────────────────────────────────────────────────────────►
Vital status, SAEs, cardiovascular and 
thromboembolic AEsv
X
S1/S2/S3 = Screening visit 1, 2 and 3; EOT = End of Treatment; EOS = End of Study; Wk(s) = Week(s); X = mandatory test/assessment; O = optional test/assessment.
Note:  see Appendix 12.3 Instructions for Subjects Moving from Protocol v1.0 to Protocol v2.0.
Note:  see Appendix 12.4 Instructions for Subjects Requiring Dialysis.
a Due to the requirement of 4-day separation between the screening Hb values, the screening period will last a minimum of 2 weeks but is allowed to be a maximum 6 weeks. Sites 
are recommended to schedule the three screening visits in the shortest time span possible.
b All study assessments are to be performed prior to first study drug administration.
c In case of premature treatment discontinuation or withdrawal during the treatment period, subjects will complete the EOT and EOS visits. Thereafter, subjects who have taken at 
least one dose of study drug will continue to be followed up at a 6-monthly frequency for vital status, SAEs, cardiovascular and thromboembolic AEs until their projected date of 
completion of the follow-up period (i.e., projected week 108 date) or until consent withdrawn.
d Targeted physical examination only (e.g., respiratory and cardiovascular).
e Height measurement only required at first screening visit.
Footnotes continued on next page
f Blood pressure and heart rate measured singly during the screening period, and in triplicate at all other visits. It is recommended during the treatment period that measurements 
should occur prior to study drug administration if study medication is taken on same day of visit; except for visits where subjects are instructed to take study medication at home 
for PK sampling purpose. For subjects requiring dialysis, BP and heart rate will be recorded prior to and after dialysis (hemodialysis [HD]/hemodiafiltration [HDF] subjects only).

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 149 of 160
Version 3.0, Incorporating Substantial Amendment 2
g Respiratory rate measured singly during screening period and all other visits. It is recommended during the treatment period that measurement should occur prior to study drug 
administration except for visits where subjects are instructed to take study medication at home for PK sampling purposes. For subjects requiring dialysis, respiratory rate will be 
recorded prior to dialysis (HD/HDF subjects only).
h Separate Hemoglobin should be collected at all the visits where Complete Blood Count (CBC) is not collected (i.e., Hb at weeks 6, 10 until the end of the study).
i HemoCue assessment is done on the blood sample that is collected for Hb analysis for the central laboratory.
j In addition to LFTs collected as part of Serum Chemistry, LFTs will separately be collected at the indicated weeks.
k Renal ultrasound examination within 12 weeks prior to randomization. Not required if results of a previous renal ultrasound (or other renal imaging modality such as CT scan or 
MRI) within 12 weeks prior to randomization is available and ruling out renal cell carcinoma. If other imaging modality, a conclusive report on the kidney should be available.
l Fasting whenever possible.
m Collect from female subjects of childbearing potential only.
n Using Modification of Diet in Renal Disease (MDRD) formula; calculated by the central laboratory.
o At day 1, week 20, 52, 76, and EOT, two equal volume samples should be collected.
p Sampling roxadustat will be done at 6 time points over 1 to 3 visits between weeks 2 and 8. See Section 5.6. At each pharmacokinetic visit, one additional sample will be collected 
for determination of Alpha 1-Acid Glycoprotein (α1-AGP) and albumin concentration.
q Optional assessment. A separate informed consent form must be signed before genotyping sample is collected. Sample collection can be done at any timepoint thought the 
treatment period of the study.
r Including SF-36, FACT-An, EQ-5D 5L, PGIC and WPAI:ANS. PGIC will not be performed on day 1. Questionnaires to be completed by the subject preferably prior to any study 
assessments. When subjects need dialysis therapy, Quality of Life (QoL) questionnaires will be completed on the day of first dialysis (preferably before the dialysis is started), 4 
weeks later and 12 weeks later.
s Ideally, the sample should be from the first morning void. Urinary testing includes qualitative testing with dipstick testing (for protein, pH, glucose) and quantitative assessment of 
albumin and creatinine for calculation of albumin/creatinine ratio.
t Dosing of darbepoetin alfa per EU SmPC.
u Subjects randomized to roxadustat: dose adjustment review from week 4 onward, and every 4 weeks thereafter until EOT (wks 4, 8, 12 etc), except in the event of excessive 
hematopoiesis or Hb ≥13.0 g/dL. If next dose adjustment interval falls on a non-visit study week, the dose adjustment review should be performed at the next scheduled visit.
v Telephone or in-person follow-up call with subject.
IS AMENDED TO:

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 150 of 160
Version 3.0, Incorporating Substantial Amendment 2
Assessments
Screening 
Period
Treatment Period
(Correction Period and Maintenance Period)
Follow-up Period
Unscheduled 
Visits
Post study 
Follow-up c
Visit / Week
Up to 2- 6 
weeks a
Day 1b
Weekly
(wks 1 - 2)
± 2 days
Every 2 Weeks 
(wks 4 - 24)
± 2 days
Every 4 Weeks 
(wks 28 - 100)
± 3 days
EOT c
(wk 104)
± 3 days
EOTc + 2 wks
± 3 days
EOS c
(EOT + 4 wks)
± 3 days
Every 
6 months until 
projected 
wk 108
S1
S2 S3
Written informed consent
X
Randomization
X
Eligibility criteria
X
X
Demographics
X
Medical history
X
Physical examination  
X
X
wks 12d, 24d 
wks 36d, 52d, 76d
X
Xd
Od
Heighte, weight
X
X
wks 12, 24
wks 36, 52, 76
X
X
O
Blood pressuref, heart ratef, respiratory rateg
X
X
X
X
X
X
X
X
XO
CBC with WBC diff, red cell indices and 
platelets
X
X
X
wks 4, 8, 12, 20
wks 28, 36, 44, 52, 
60, 68, 76, 84, 92, 
100
X
X
O
Hemoglobinh
Xi
X
X
X
X Oi1
HemoCue assessmentji
X
X
X
X
XO
Reticulocyte count and Hb in reticulocytes 
(CHr)
X
X
X
wks 4, 6, 8, 12, 16, 
20
wks 28, 36, 44, 52, 
60, 68, 76, 84, 92, 
100
X
X
O
12-lead ECG 
X
X
wks 12, 24
wks 36, 52, 76
X
O
Serum chemistry
X
X
wks 4, 8, 12, 20
wks 28, 36, 44, 52, 
60, 68, 76, 84, 92, 
100
X
X
X
O
LFTskj
wk 2
wks 6, 16
O
Renal ultrasoundlk
X
X
O
Serum lipid panelml
X
X
wks 4, 8, 12, 20 wks 28, 36, 44, 52, 
68, 84
X
X
O
Serum iron, ferritin, TIBC, TSAT
X
X
wks 4, 8, 12, 20
wks 28, 36, 44, 52, 
60, 68, 76, 84, 92, 
100
X
X
O
HbA1c
X
X
wk 12
wks 28, 36, 44, 60, 
84
X
X
O
Vitamin B12, folate
X
HIV immunoassay, HBsAg, 
anti-HCV antibody
X
Serum pregnancy testnm
X
wks 12, 24
wks 36, 48, 60, 72, 
84, 96
X
O
Table continued on next page

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 151 of 160
Version 3.0, Incorporating Substantial Amendment 2
Assessments
Screening 
Period
Treatment Period
(Correction Period and Maintenance Period)
Follow-up Period
Unscheduled 
Visits
Post study 
Follow-up c
Visit / Week
Up to 2- 6 
weeks a
Day 1b
Weekly
(wks 1 - 2)
± 2 days
Every 2 Weeks 
(wks 4 - 24)
± 2 days
Every 4 Weeks 
(wks 28 - 100)
± 3 days
EOT c
(wk 104)
± 3 days
EOTc + 2 wks
± 3 days
EOS c
(EOT + 4 wks)
± 3 days
Every 
6 months until 
projected 
wk 108
S1
S2 S3
eGFRon
X
X
wk 20
wks 36, 52, 68, 84
X
X
O
hs-CRP
X
wks 4, 12, 20
wks 36, 52
X
X
Archival serum samples for biomarkerspo
X
wks 4, 12, 20
wks 52, 76
X
X
Blood sample for PKqp
wks 2 to 8
Genotypingrq
O
QoL questionnairessr
X
wks 8, 12 
wks 28, 36, 52, 76
X
O
Urinary testingts
X
wks 12, 24
wks 36, 52, 64, 76, 
88
X
O
Archival urine samples for biomarkers
X
wk 24
wks 52, 76
X
Study drug dispensingut
├────────────────────────────┤
O
Dose adjustment reviewvu
X
X
X
O
Hospitalization recordingwv
X
X
◄─────────────────────────────────────────────────────────────►
X
AE recording
X
X
◄─────────────────────────────────────────────────────────────►
Concomitant medication, procedure and non-
drug therapy recording
X
X
◄─────────────────────────────────────────────────────────────►
Vital status, SAEs, cardiovascular and 
thromboembolic AEswv
X
S1/S2/S3 = Screening visit 1,and 2 and 3; EOT = End of Treatment; EOS = End of Study; Wk(s) = Week(s); X = mandatory test/assessment; O = optional test/assessment.
Note:  see Appendix 12.3 Instructions for Subjects Moving from Protocol v1.0 to Protocol v2.0.
Note:  see Appendix 12.4 Instructions for Subjects Requiring Dialysis.
a a
Due to tThe requirement of a 4-day separation between the screening Hb values, defines the minimum duration of the screening period. will last a minimum of 2 weeks 
but is allowed to be a The maximum duration of the screening period is 6 weeks. Sites are recommended to schedule the three two screening visits in the shortest time span 
possible.
bb
All study assessments are to be performed prior to first study drug administration.
c c
In case of premature treatment discontinuation or withdrawal during the treatment period, subjects will complete the EOT visits (EOT visit and EOT + 2 weeks visit) and 
EOS visits. Thereafter, subjects who have taken at least one dose of study drug will continue to be followed up at a 6-monthly frequency for vital status, SAEs, cardiovascular 
and thromboembolic AEs until their projected date of completion of the follow-up period (i.e., projected week 108 date) or until consent withdrawn.
d d
Targeted physical examination only (e.g., respiratory and cardiovascular).
e e
Height measurement only required at first screening visit.
Footnotes continued on next page

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 152 of 160
Version 3.0, Incorporating Substantial Amendment 2
f f       Blood pressure and heart rate measured singly during the screening period, and in triplicate at all other visits. It is recommended during the treatment period that 
measurements should occur prior to study drug administration if study medication is taken on same day of visit; except for visits where subjects are instructed to take study 
medication at home for PK sampling purpose. For subjects requiring dialysis, BP and heart rate will be recorded prior to and after dialysis (hemodialysis [HD]/hemodiafiltration 
[HDF] subjects only).
g g
Respiratory rate measured singly during screening period and all other visits. It is recommended during the treatment period that measurement should occur prior to study 
drug administration except for visits where subjects are instructed to take study medication at home for PK sampling purposes. For subjects requiring dialysis, respiratory rate 
will be recorded prior to dialysis (HD/HDF subjects only).
h h
Separate Hemoglobin should be collected at all the visits where Complete Blood Count (CBC) is not collected (i.e., Hb at weeks 6, 10 until the end of the study).
i An additional (third) Hb value may be collected if necessary. Only for subjects who are switched from protocol version 2 to 3 during (re) screening can a fourth Hb 
value be collected, as was applicable under protocol version 2.
i1 If during an unscheduled visit, Hb needs to be assessed, this should always be done with the HemoCue AND a central laboratory Hb assessment.
i j If during an unscheduled visit Hb needs to be assessed, this should always be done with the HemoCue AND a central laboratory Hb assessment.  The HemoCue 
assessment should be is done on the blood sample that is collected for Hb analysis for the central laboratory.
jk In addition to LFTs collected as part of Serum Chemistry, LFTs will separately be collected at the indicated weeks.
kl Renal ultrasound examination within 12 weeks prior to randomization. Not required if results of a previous renal ultrasound (or other renal imaging modality such as CT scan or 
MRI) within 12 weeks prior to randomization is available and ruling out renal cell carcinoma. If other imaging modality, a conclusive report on the kidney should be available.
lm
Fasting whenever possible.
m n
Collect from female subjects of childbearing potential only.
n o
Using Modification of Diet in Renal Disease (MDRD) formula; calculated by the central laboratory.
o p
At day 1, week 20, 52, and 76, and EOT, two equal volume samples should be collected.
p q
Sampling roxadustat will be done at 6 time points over 1 to 3 visits between weeks 2 and 8. See Section 5.6. At each pharmacokinetic visit, one additional sample will be 
collected for determination of Alpha 1-Acid Glycoprotein (α1-AGP) and albumin concentration.
qrOptional assessment for subjects treated with roxadustat. A separate informed consent form must be signed before genotyping sample is collected. Sample collection can be 
done at any timepoint throughout the treatment period of the study.
r s
Including SF-36, FACT-An, EQ-5D 5L, PGIC and WPAI:ANS. PGIC will not be performed on day 1. Questionnaires to be completed by the subject preferably prior to any 
study assessments. When subjects need dialysis therapy, Quality of Life (QoL) questionnaires will be completed on the day of first dialysis (preferably before the dialysis is 
started), 4 weeks later and 12 weeks later.
s tIdeally, the sample should be from the first morning void. Urinary testing includes qualitative testing with dipstick testing (for protein, pH, glucose) and quantitative assessment 
of albumin and creatinine for calculation of albumin/creatinine ratio.
t u
Dosing of darbepoetin alfa per EU SmPC.
u v
Subjects randomized to roxadustat: dose adjustment review from week 4 onward, and every 4 weeks thereafter until EOT (wks 4, 8, 12 etc), except in the event of excessive 
hematopoiesis or Hb ≥13.0 g/dL. If next dose adjustment interval falls on a non-visit study week, the dose adjustment review should be performed at the next scheduled visit.
v w 
Telephone or in-person follow-up call with subject.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 153 of 160
Version 3.0, Incorporating Substantial Amendment 2
1 Introduction
1.3.1 Roxadustat
WAS:
Five pancreatitis events were noted during the roxadustat clinical development program, the 
majority of which have been associated with gallstones or biliary sludge; one of which was 
due to a pancreatic duct stricture, and another case had multiple risk factors for pancreatitis. 
IS AMENDED TO:
Five pancreatitis events were noted during the roxadustat phase 2 clinical development 
program, the majority of which have been associated with gallstones or biliary sludge; one 
of which was due to a pancreatic duct stricture, and another case had multiple risk factors 
for pancreatitis. 
5 Treatments and Evaluation
Section 5.1.1 Dose/Dose Regimen and Administration Period
WAS:
All subjects will administer study drug doses TIW and study drug doses must be at least 2 
days apart (e.g., Monday Wednesday, Friday) and no more than 4 days apart.
Investigators and subjects should make every effort to keep dosing days and dosing times 
consistent throughout the study. 
The roxadustat treated subjects that have entered the study under protocol v1.0, upon 
signing the informed consent for the amendment 1, will have their dose frequency (on QW 
and BIW under protocol v1.0) and dose amount adjusted according to the instructions in 
Appendix 12.3. Subjects randomized to roxadustat QW or BIW who do not agree to change 
to TIW, should be discontinued from the study treatment and continue in the post study 
follow-up period.
IS AMENDED TO:
All subjects will administer study drug doses TIW and study drug doses must be at least 2 
days apart (e.g., Monday Wednesday, Friday).  The period between two roxadustat 
administrations should be at least 36 hrs and no more than 4 days apart.
Investigators and subjects should make every effort to keep dosing days and dosing times 
consistent throughout the study. 
The roxadustat treated subjects that have had entered the study under protocol v1.0, upon 
signing the informed consent for the amendment 1, will have had their dose frequency (on 
QW and BIW under protocol v1.0) and dose amount adjusted according to the instructions 
in Appendix 12.3. Subjects randomized to roxadustat QW or BIW who do not agree to 
change to TIW, should be discontinued from the study treatment and continue in the post 
study follow up period.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 154 of 160
Version 3.0, Incorporating Substantial Amendment 2
5 Treatments and Evaluation 
5.1.2.2 Dose Adjustment Rules for Subjects receiving Darbepoetin alfa
DELETED: 
Table 6: Dose Adjustment Rules for Darbepoetin Alfa
5 Treatments and Evaluation
5.1.4 Treatment Compliance
ADDED:
In case of self-administration after 36 weeks of treatment, the empty packages of 
darbepoetin alfa should be returned by the subject to the site.
5 Treatments and Evaluation
5.4 1.1 Blood Pressure
WAS:
Blood pressure (systolic and diastolic) will be measured singly on the three visits during the 
screening period, and in triplicate with a least two minute intervals for all other visits. An 
average of the SBP and DBP will be calculated from the 2nd and 3rd readings automatically 
within the eCRF. The same arm should be used consistently for measurements throughout 
the study.
IS AMENDED TO:
Blood pressure (systolic and diastolic) will be measured singly on the three 2 visits during 
the screening period, and in triplicate with a least two minute intervals for all other visits. 
An average of the SBP and DBP will be calculated from the 2nd and 3rd readings 
automatically within the eCRF. The same arm should be used consistently for 
measurements throughout the study.
5 Treatments and Evaluation
5.4 1.2 Heart Rate
WAS:
HR will be measured singly on the three visits during the screening period, and in triplicate 
with at least two minute intervals for all other visits. All values will be reported in the 
eCRF. An average will be calculated from the 2nd and 3rd readings automatically within the 
eCRF.
IS AMENDED TO:
HR will be measured singly on the three 2 visits during the screening period, and in 
triplicate with at least two minute intervals for all other visits. All values will be reported in 
the eCRF. An average will be calculated from the 2nd and 3rd readings automatically within 
the eCRF.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 155 of 160
Version 3.0, Incorporating Substantial Amendment 2
5 Treatments and Evaluation
5.5.2 Definition of Serious Adverse Events (SAEs)
WAS:
All of the events of interest noted above should be recorded on a SAE worksheet and within 
the timelines of reporting SAEs, thus within 24 hours of becoming aware of this event. The 
above special situations will not be captured on the AE form in the eCRF, instead they will 
be captured in the dosing and accountability forms within the eCRF.
IS AMENDED TO:
All of the events of interest noted above should be recorded on a the SAE and/or Special 
Situation worksheet and within the timelines of reporting SAEs, thus within 24 hours of 
becoming aware of this event, regardless whether or not a (S)AE occurred. The above 
special situations will not be captured on the AE form in the eCRF, instead they will be 
captured in the dosing and accountability forms within the eCRF.
5 Treatments and Evaluation
5.5.5 Reporting of Serious Adverse Events (SAEs)
WAS:
In the case of a Serious Adverse Event (SAE), the investigator must contact his/her 
respective delegated CRO (INC Drug Safety or Medpace Clinical Safety) by telephone or 
fax immediately (within 24 hours of awareness).
The investigator should complete and submit a SAE worksheet containing all information 
that is required by the Regulatory Authorities to the delegated CRO by fax or email 
immediately (within 24 hours of awareness).
If the faxing of an SAE Worksheet is not possible or is not possible within 24 hours, the 
local drug safety contact should be informed by phone.
The SAE worksheet should be sent to the delegated CRO that is responsible for the 
investigator’s country:
INC Drug Safety and as specified in the Investigator Site File:
Email: INCDrugSafety@INCResearch.com
Fax: toll-free numbers will be provided for each country; the specific fax number can be 
found on the SAE form fax cover sheet
Tel: +49 89 99 39 13 198
Medpace Clinical Safety and as specified in the Investigator Site File:
Medpace SAE hotline – USA:
Telephone: +1-800-730-5779, ext. 2999 or +1-513-579-9911, ext. 2999
Fax:  +1-866-336-5320 or +1-513-579-0444
Email: medpace-safetynotification@medpace.com
Or
Medpace SAE hotline – Europe:
Telephone: +49 89 89 55 718 44
Fax: +49 89 89 55 718 104
Email: medpace-safetynotification@medpace.com

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 156 of 160
Version 3.0, Incorporating Substantial Amendment 2
IS AMENDED TO:
In the case of a Sserious Aadverse Eevent (SAE), the investigator must contact his/her 
respective delegated CRO (INC Drug Safety or Medpace Clinical Safety or other CRO as 
specified in the Investigator Site File) by telephone or fax immediately (within 24 hours of 
awareness).
The investigator should complete and submit an SAE worksheet containing all information 
that is required by the Regulatory Authorities to the delegated CRO by fax or email 
immediately (within 24 hours of awareness).
If the faxing or e-mailing of an SAE Worksheet is not possible or is not possible within 24 
hours, the local drug safety contact should be informed by phone.
The SAE worksheet should be sent to the delegated CRO that is responsible for the 
investigator’s country:
INC Drug Safety and or another CRO as specified in the Investigator Site File:
Email: INCDrugSafety@INCResearch.com
Fax: toll-free numbers will be provided for each country; the specific fax number can be 
found on the SAE form fax cover sheet
Tel: +49 89 99 39 13 198
Medpace Clinical Safety and as specified in the Investigator Site File:
Medpace SAE hotline – USA:
Telephone: +1 800 730 5779, ext. 2999 or +1 513 579 9911, ext. 2999
Fax:  +1 866 336 5320 or +1 513 579 0444
Email: medpace-safetynotification@medpace.com
Or
Medpace SAE hotline – Europe:
Telephone: +49 89 89 55 718 44
Fax: +49 89 89 55 718 104
Email: medpace-safetynotification@medpace.com
5 Treatments and Evaluation
5.8 Total Amount of Blood
WAS:
The total amount of blood to be collected per subject during the study, based on the 
subject’s screening period, the 104 weeks’ treatment period and the follow-up period and 
allowing full re-screening and unscheduled visits is estimated to be approximately 440 mL.
IS AMENDED TO:
The total amount of blood to be collected per subject during the study, based on the 
subject’s screening period, the 104 weeks’ treatment period and the follow-up period and 
allowing full re-screening and unscheduled visits is estimated to be approximately 4460 mL.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 157 of 160
Version 3.0, Incorporating Substantial Amendment 2
7 Statistical Methodology
7.4.2.2 Secondary Analyses
DELETED:
In addition, this variable will be analyzed using the subset of subjects who have reached Hb 
≥11.0 g/dL prior to week 28.
11 References
WAS:
EMEA. Aranesp – Procedural steps taken and scientific information after the authorization 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Procedural_steps_taken_and_scientific_information_after_authorisation/human/00033
2/WC500026145.pdf 
EMEA. Aranesp European Public Assessment Report [EPAR] 2004; EMEA. Aranesp 
Procedural steps taken and scientific information after the authorisation. Changes made 
after 2003). 
EMEA, EPAR Aranesp 2004
IS AMENDED TO:
EMEA. Aranesp –Procedural steps taken and scientific information after the authorizsation. 
Changes made after 2003. 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Procedural_steps_taken_and_scientific_information_after_authorisation/human/00033
2/WC500026145.pdf.
EMEA. Aranesp European Public Assessment Report [EPAR]. 2004.; EMEA. Aranesp 
Procedural steps taken and scientific information after the authorisation. Changes made 
after 2003).
EMEA, EPAR Aranesp 2004
12 Appendices 
12.4 Instructions for Subjects Requiring Dialysis
WAS:
Subjects who initiate temporary or permanent dialysis treatment are allowed to continue in 
the study. All modes of dialysis, i.e., hemodialysis (HD), hemodiafiltration (HDF) and 
peritoneal dialysis (PD), are allowed.
12.4.1 Dosing

Subjects should continue with the same dose and dose frequency of study drug as 
they were on prior to dialysis initiation.

For HD/HDF subjects, it is recommended that study drug is administered any time 
after completion of dialysis (if dosing is scheduled on a dialysis day) to avoid 
potential bias on certain study assessments.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 158 of 160
Version 3.0, Incorporating Substantial Amendment 2
12.4.2 Dose Adjustment

The dose adjustment rules remain unchanged (see Section 5.1.2.1). 

The maximum allowed dose in subjects on permanent dialysis is 3.0 mg/kg (based 
on dry weight in HD subjects and weight minus abdominal fluid based on last filling 
in PD subjects) or 400 mg per administration, whichever is lower.
12.4.3 ESA Rescue Therapy
If roxadustat subjects meet the criteria for ESA rescue therapy while on dialysis, 
darbepoetin alfa will be administered IV or SC according to its Package Insert or SmPC for 
dialysis subjects. The subject must be discontinued from study treatment if the subject 
requires a second course of rescue darbepoetin alfa.
IS AMENDED TO:
Subjects who initiate temporary or permanent dialysis treatment are allowed to continue in 
the study. All modes of dialysis, i.e., hemodialysis (HD), hemodiafiltration (HDF) and 
peritoneal dialysis (PD), are allowed.
12.4.1 Dosing

Subjects should continue with the same dose and dose frequency of study drug as 
they were on prior to dialysis initiation.

For HD/HDF subjects it is recommended that study drug is administered any time 
after completion of dialysis (if dosing is scheduled on a dialysis day) to avoid 
potential bias on certain study assessments.

For subjects treated with darbepoetin, the route of administration of 
darbepoetin is according to local standard of care for dialysis patients.
12.4.2 Dose Adjustment

The dose adjustment rules remain unchanged (see Section 5.1.2.1). 

The maximum allowed dose in subjects on permanent dialysis is 3.0 mg/kg (based 
on dry weight post-dialysis weight in HD subjects and weight minus abdominal 
fluid based on last filling in PD subjects) or 400 mg per administration, whichever is 
lower.
12.4.3 ESA Rescue Therapy
If roxadustat subjects meet the criteria for ESA rescue therapy while on dialysis, 
darbepoetin alfa will be administered IV or SC according to its Package Insert or SmPC for 
dialysis subjects. The subject must be discontinued from study treatment if the subject 
requires a second course of rescue darbepoetin alfa.
12.4.4 Supplemental Iron Use
Iron supplementation rules are unchanged in subjects starting dialysis who are 
randomized to  roxadustat (see Section 5.1.3.2.1). In subjects randomized to 
darbepoetin, IV iron supplementation will be given according to standard of care.

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 159 of 160
Version 3.0, Incorporating Substantial Amendment 2
12 Appendices
12.10 KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease 2012 
(KDIGO 2012)
DELETED:
12.10  KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease 2012 
(KDIGO 2012)
Please refer for the KDIGO 2012 guidelines to:
VOLUME 2 | ISSUE 4 | AUGUST 2 2012
http://www.kidney international.org

Sponsor: APEB
ISN/Protocol 1517-CL-0610
EudraCT number 2013-000951-42
ASP1517/FG-4592
- CONFIDENTIAL -
31 Mar 2016
Astellas
Page 160 of 160
Version 3.0, Incorporating Substantial Amendment 2
14
SPONSOR’S SIGNATURES