Conditions: Anemia
Keywords: Renal, CKD, Epoetin alfa, Roxadustat, dialysis, anemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2133
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of roxadustat compared to epoetin alfa for the treatment of anemia in chronic kidney disease patients on dialysis.

Detailed description:
This is a Phase 3, multicenter, randomized, open-label, active-controlled study to evaluate the efficacy and safety of roxadustat compared to epoetin alfa for the treatment of anemia in dialysis patients. Patients on hemodialysis (HD) or peritoneal dialysis (PD) who have been treated with an erythropoietin analogue or have an indication for treatment with an erythropoietin analogue will be evaluated for eligibility and randomized at a 1:1 ratio to treatment with roxadustat (with discontinuation of prior erythropoietin analogue therapy) or to an active-control group treated with epoetin alfa

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Roxadustat intervention 2: Epoetin alfa
Intervention descriptions: intervention 1: Roxadustat will be administered orally three times a week (TIW) to achieve an Hb level of 11 g/dL and maintain a Hb level of 11±1 g/dL. intervention 2: Epoetin alfa will be administered TIW consistent with approved prescribing information for epoetin alfa to achieve an Hb level of 11 g/dL and maintain a Hb level of 11±1 g/dL.

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol (CSP), ANGEL
Version 7.0
Template Form Doc ID: LDMS_001_00026737
Parent Doc ID: SOP AZDoc0018580
Clinical Study Protocol 
Drug Substance
Roxadustat
Study Code
D5740C00002
Version
8.0
Date
19 September 2018
A Phase 3, Multicenter, Randomized, Open-Label, Active-Controlled Study 
of the Safety and Efficacy of Roxadustat in the Treatment of Anemia in 
Dialysis Patients
Sponsor: AstraZeneca AB, S-151 85 Södertälje, Sweden


Clinical Study Protocol
Drug Substance Roxadustat
Study Code D5740C00002
Version 8.0
Date 19 September 2018
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VERSION HISTORY
Global Clinical Study Protocol Version 8.0 is arising from:
Outside of US
Clinical Study Protocol version 7.0 (Outside of US)
US (only)
Clinical Study Protocol version 7.0 (US)
Clinical Study Protocol version 8.0
Rationale for protocol amendment:
Changes were made to clarify operational and statistical aspects of the protocol, including 
minor editorial changes throughout the document to correct typographical errors and improve 
consistency and clarity.
Changes to secondary efficacy in terms of addition of objectives and outcome measures as 
well as the ordering were made to harmonize D5740C00002 with the other phase 3 trials in 
the Roxadustat dialysis program (FG-4592-064, 1517-CL-0613 and FG-4592-063).
Adjudicated CV events from this study will be part of the pooled analysis across the study 
program. This strategy was adopted to ensure that the overall number of events is high enough 
to provide adequate power to address CV No harm. Thus, all analyses of CV safety will be 
conducted in accordance with the Pooled SAP (PSAP).
Summary of changes from Clinical Study Protocol version 7.0 (US) and Clinical Study 
Protocol version 7.0 (Outside of US) to version 8.0:
All below changes are updated in relevant sections of the study protocol.
General changes throughout the document:
Estimated date of study completion changed throughout the entire document to Q3 2018.
Rationale for change: Revision and clarification of estimated date of study completion.
Synopsis and Section 2.1. Primary safety objectives
The previous texts on primary objective is moved to the section on primary safety objective.
New texts stating that pooled CV safety analyses are now described in the PSAP.
Rationale for change:
Harmonizes D5740C00002 with the other phase 3 trials in the roxadustat CKD dialysis 
program, to serve as a pivotal study for confirming efficacy and safety, and facilitates 
assessment of pooled safety across the phase 3 program.
Synopsis and Section 2.1. Primary efficacy objectives
Previous primary efficacy objective and its outcome measures is designated for US FDA. 
Another outcome measure designated for EU health authority, namely, Hb change from 
baseline (BL) to the average Hb of weeks 28 to 36, without having received rescue therapy 
(i.e. RBC transfusion for all subjects and ESA for roxadustat subjects) within 6 weeks prior to 


Clinical Study Protocol
Drug Substance Roxadustat
Study Code D5740C00002
Version 8.0
Date 19 September 2018
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and during this 8-week evaluation period is added. 
Rationale for change:
Harmonizes D5740C00002 with the other phase 3 trials in the roxadustat CKD dialysis 
program, to serve as a pivotal study for confirming efficacy and safety, and facilitates 
assessment of pooled efficacy and safety across the phase 3 program.
Synopsis and Section 2.2. Secondary efficacy objectives
Here are the main changes as follows:
1. The efficacy of roxadustat based on the change from baseline in Hb averaged over 
Week 28-52 in inflamed subjects is added as a secondary efficacy objective.
2. Proportion of total time of Hb ≥10 g/dL from week 28 to week 52”, is added as a new 
outcome measure for the secondary efficacy objective based on Hb response and level 
during the study.
3. The secondary efficacy objective with its outcome measure related to composite 
rescue-therapy is replaced by a corresponding objective related to RBC transfusion.
Proportion and number of subjects receiving RBC transfusion as rescue therapy are 
also reported. 
4. The secondary efficacy objective with its outcome measure related to self-reported 
health status using EQ-5D-5L is removed
5. Additional secondary efficacy objectives with their outcome measures related to LDL 
cholesterol and IV iron are added. 
Rationale for change: 
To harmonize with the secondary objectives of the other phase 3 studies in the program.
Synopsis and Section 2.2. Secondary safety objectives
Two CV safety related secondary safety objectives are removed. 
Rationale for change:
They are to be addressed in the pooled analyses across the phase 3 program according to the 
PSAP.
Synopsis and Section 8.2 Sample size estimate
The description of the determination of the sample size related to CV safety has been 
shortened.
Rationale for change:
Reference to a more detailed description of the requirements for sample size to address CV 
safety for this indication is made to the pooled statistical analysis plan.
Section 3.1 Inclusion criteria
Clarification of inclusion criterion 3 in order to show wording in previous versions of the 
protocol prior to US amendment ver 6.0 and outside of US amendment ver 7.0 (changed to 
recruit incident dialysis patients only) as the inclusion criteria was changed to include incident 
dialysis patients only for the REMAINDER of the study.
Rationale for change: Clarification.
Section 3.9.2 Permanent discontinuation from investigational product


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Drug Substance Roxadustat
Study Code D5740C00002
Version 8.0
Date 19 September 2018
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Addition of reason for permanent discontinuation by investigator: “Patients who receive organ 
transplantation during the study”
Rationale for change: Clarification that subjects who receive organ transplantation should 
discontinue investigational products.
Section 3.9.3.2 Patient refuses to continue in-person study visits but agrees to undergo 
modified follow-up
Entire section clarified and elaborated.
Rationale for change: Clarification.
Section 3.9.3.3 Patient refuses any form of follow-up
Entire section clarified and elaborated consistently.
Rationale for change: Clarification.
Section 3.10 Criteria for withdrawal
Entire section clarified and elaborated consistently.
Rationale for change: Clarification.
3.10.2: Withdrawal of the informed consent
Added: “Patients who agree to continued study participation following investigational product 
discontinuation, including modified follow-up such as telephone calls or medical record 
review, have not withdrawn consent.”
Rationale for change: Clarification.
Section 5.1.1 Secondary efficacy assessments
The title of this section is changed to “Efficacy assessment”.
Rationale: 
Assessment of Hemoglobin level specified in 5.1.1.1 is for both the primary and some of the 
secondary efficacy endpoints.   
Section 5.2.1: Cardiovascular events
The texts in this section are simplified, the function of IERC is emphasized and the subsections 
5.2.1.1 to 5.2.1.9 are removed. 
Rationale: 
IERC contains more detail information on CV event adjudication
Table 1: Study Plan, Table 2: Laboratory Safety Variables from Section 5.2.2, and 
Section 5.7.1 Storage, use, re-use and destruction of biological samples
Added that hepcidin and hsCRP will be analyzed from biomarker samples.
Rationale for change: Hepcidin and hsCRP will be analyzed from biomarker samples.
Section 5.6.1 Collection of pharmacogenetic samples
 
Rationale for change: Clarification.
CCI


Clinical Study Protocol
Drug Substance Roxadustat
Study Code D5740C00002
Version 8.0
Date 19 September 2018
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Section 8.1 Statistical considerations
Change that preparation of a comprehensive SAP will take place before database lock, instead 
of before the first randomization.
Rationale:
To align with the timing for SAP finalization in the other phase 3 trials.
8.3.1 Full Analysis Set (FAS)
Here are the changes as follows: 
1.
This analysis set was previously termed as Full Analysis Set (FAS), this is now  
changed to Intention-To-Treat Analysis Set (ITT).
2.
The word “patients” is changed to “subjects”. This change is also for the rest of the 
section 8 where applicable. 
3.
Texts are updated to clarify how the event of interest will be counted in respect of 
study drug discontinuation according to ITT principle. 
Rationale for change:
To align with the definitions adopted in the other phase 3 trials in the study program.
8.3.2. Per Protocol Set (PPS)
Here are the changes as follows:
1. An additional criterion, “subjects receiving at least 8 weeks of study treatment”, 
has been added. 
2. Censoring rule for subjects with an important protocol deviation is clarified. 
3. Treatment groups to which PPS subjects belong to is specified.     
Rationale for change:
To align with the definitions adopted in the other phase 3 trials in the study program, and for 
clarification
8.3.3 Safety Analysis Set (SAS)
Treatment groups to which SAS subjects belong is further clarified, and the censoring rule of 
OT+28 is removed.
Rationale for change:
For clarification
Section 8.3.4 Full Analysis Set (FAS)
This section is newly added allowing for an additional analysis set.  
Rationale for change:
To align with the definitions adopted in the other phase 3 trials in the study program, this 
analysis set will be required for some Ex-US submissions.
8.3.5 Subjects who will not be included in any analysis sets
This section is newly added to specify subjects not in any of analysis sets and the reason of 
their exclusion is stated.  
Rationale for change:


Clinical Study Protocol
Drug Substance Roxadustat
Study Code D5740C00002
Version 8.0
Date 19 September 2018
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Not included in previous editions of the CSP.
8.4 Outcome measures for analyses
The text structure of this section is re-organized and subsections specific to primary and 
secondary efficacy endpoints efficacy are added.
Rationale for change:
For structure clarification. 
Here are the changes in texts related to “primary efficacy endpoint” as follows: 
1. A specific subsection with two parts, one for US FDA and the other for EU health 
authority, is created. 
2. The previous primary efficacy endpoint is designated for US FDA, and its description 
is moved under its corresponding part with the following clarification:  
a.
The texts, “Details of the ANCOVA multiple imputation will be provided in 
Section 8.5.2.”, are changed to “Details of the ANCOVA multiple imputation will 
be provided in the SAP”.
b. Hb measurement from the central lab is specified.  Calculation of baseline Hb and 
the censoring rule for the post baseline Hb are defined.   
3. Another primary efficacy endpoint designated for EU health authority is added as a 
separate part. 
Rationale for change:
For clarification and to be harmonized with the primary efficacy objective of the other phase 3
studies in the program.
Here are the changes in texts related to “efficacy related endpoint” as follows: 
1. The texts, “efficacy related endpoint”, are removed.
2. The secondary efficacy endpoints are presented in four subsections, 8.4.2-8.4.5, 
four for Hb-related response, one for lipid reduction, one for RBC rescue therapy 
and one for IV iron use.    
3. Texts under “Evaluation of the need for rescue therapy” together with its bullet 
point on time-to-first administration of RBC are moved under the subsection 
specific for RBC rescue therapy with more details added. The other bullet point on 
time-to-first receiving RBC transfusion or ESA as rescue therapy is now an 
exploratory, rather than a secondary, efficacy endpoint (see SAP).
4. Additional secondary efficacy endpoints are added, three related to Hb response, 
one to lipid reduction, one to RBC rescue therapy use and one to IV iron use. 
Rationale for change:
To harmonize with the secondary efficacy objectives of the other phase 3 studies in the 
program with clinically important variables for this indication.
Here are the changes in texts under “Primary safety endpoint” and “Additional safety 
composite endpoints” as follows: 


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Drug Substance Roxadustat
Study Code D5740C00002
Version 8.0
Date 19 September 2018
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1. A specified section, Section 8.5 entitled “Adjudicated CV Events Analyses for 
Safety Assessments”, is created to address CV safety of the study.
2. Previous texts under these two parts are moved under this section and replaced by 
new texts, in which CV safety endpoint analyses according to the PSAP using 
adjudicated events are emphasized.    
Rationale for change:
To harmonize with the primary safety objectives of the other phase 3 studies in the program.
8.5. Methods for statistical analyses
The section number is changed from 8.5 to 8.6, and all its subsection numbers are changed 
from 8.5.X to 8.6.X.    
Rationale for change:
For clarification, a new section, entitled “Adjudicated CV Event Analyses for Safety 
Assessments”, is added as Section 8.5. 
Change that finalization of the SAP will take place before database lock instead of the first 
subject in, which includes further details of the statistical analyses.
Rationale for change:
To align with the timing for SAP finalization in the other phase 3 studies.
8.5.1 Stratification variables
Here are the changes as follows: 
1. The section number is changed from 8.5.1 to 8.6.1.
2. Baseline Hb is added to the list of “stratification variables”.  
3. How to handle baseline Hb in the analysis is specified. 
4. CV history is defined in more details.
Rationale for change:
To harmonize with the other phase 3 studies in the program.
8.5.2. Analysis of the primary efficacy variable
Here are the changes as follow:
1. This section is split into two sections, 8.6.2 is entitled “Analysis of primary efficacy 
endpoint for US”, and 8.6.3 “Analysis of primary efficacy endpoint for EU”, 
respectively. 
2. The word, “variable”, is changed to “endpoint”.
3. Previous texts under this section are shortened and moved under Section 8.6.2,specific 
for the endpoint designated for US FDA. The analysis data set is changed from FAS to 
ITT. 
4. New texts on the analysis of the primary efficacy endpoint designated for EU authority 
are added under Section 8.6.3. 
Rationale for change:
For clarification and to harmonize with the primary efficacy objective of the other phase 3 


Clinical Study Protocol
Drug Substance Roxadustat
Study Code D5740C00002
Version 8.0
Date 19 September 2018
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studies in the program.
8.5.3 Analysis of the primary safety variable
Here are the changes as follow:
1. The section number is changed from 8.5.3 to 8.6.4.
2. The title of this section “Analysis of the primary safety variable”, is changed to “CV 
safety endpoint analyses”
3. Previous texts under this section are replaced by new texts on CV safety endpoint 
analyses according to the PSAP using adjudicated pooled data across the all phase 3 
studies in the program are added.
Rationale for change:
Strategic change in the approach to address CV safety for the project. 
8.5.4 Analysis of the secondary variables
Here are the changes as follow:
1. The section number is changed from 8.5.4 to 8.6.5  
2. The section title is changed to “Analysis of the secondary efficacy endpoints”.
3. PPS is used for the first secondary efficacy endpoint on non-inferiority, on 
treatment analysis for the endpoint of RBC transfusion as rescue therapy, and ITT 
for the remaining secondary efficacy endpoints.
4. Time-to-event analyses including time-to-first MACE+, time-to-first CSE and 
time-to-first rescue therapy (composite) are removed.
5. Additional secondary efficacy endpoints are added, three related to Hb-response, 
one to LDL cholesterol, and one to IV iron use and one related to RBC transfusion 
as rescue therapy.
6. The list of the secondary endpoints is re-ordered.
8.5.5 Additional Secondary Analyses
This section is removed.
Rationale for change:
All the secondary analyses are highlighted in “Analysis of the secondary efficacy endpoints”. 
8.5.6 Testing order
This section is removed.
Rationale for change:
To avoid repeating the related texts specified in “Analysis of the secondary efficacy 
endpoints”
Changes relevant only between Clinical Study Protocol version 7.0 (Outside of US) and
version 8.0:
Synopsis - International Co-ordinating Investigator (ICI)
Exchange of International Coordinating Investigator (ICI). The new International 
Co-ordinating Investigator is Dr Steven Fishbane:
Steven Fishbane, MD


Clinical Study Protocol
Drug Substance Roxadustat
Study Code D5740C00002
Version 8.0
Date 19 September 2018
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Chief Division of Kidney Diseases and Hypertension 
North Shore University Hospital
100 Community Drive, 2nd Floor
Great Neck, NY 11021
USA
Rationale for change:
Replacement for the previous International Co-ordinating Investigator that resigned from the 
International Co-ordinating Investigator role.
Clinical Study Protocol version 7.0 (US) and Clinical Study Protocol version 7.0 (Outside 
of US) were arising from:
Outside of US
Clinical Study Protocol edition 1.0 (version 5.0)
US (only)
Clinical Study Protocol version 6.0
Clinical Study Protocol version 7.0 (US) and Clinical Study Protocol version 7.0 (Outside of 
US) were the protocols for the recruitment of Incident Dialysis patients. 
Clinical Study Protocol version 7.0 (US only)
Summary of main changes from Clinical Study Protocol version 6.0 US only to version 
7.0 US only:
All below changes are updated in relevant sections of the study protocol.
Synopsis - International Co-ordinating Investigator (ICI)
Exchange of International Coordinating Investigator (ICI). The new International 
Co-ordinating Investigator is Dr Steven Fishbane:
Steven Fishbane, MD
Chief Division of Kidney Diseases and Hypertension 
North Shore University Hospital
100 Community Drive, 2nd Floor
Great Neck, NY 11021
USA
Rationale for change:
Replacement for the previous International Co-ordinating Investigator that resigned from the 
International Co-ordinating Investigator role.
Synopsis and Study objectives
Addition of a primary efficacy objective, “Evaluate the efficacy of roxadustat for the treatment 


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Drug Substance Roxadustat
Study Code D5740C00002
Version 8.0
Date 19 September 2018
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of anemia in CKD subjects on dialysis”, with a corresponding outcome measure.
Rationale for change: 
Harmonization of D5740C00002 with the other phase 3 trials in the roxadustat dialysis 
program, allowing the program to demonstrate both efficacy and safety across all populations 
studied.
Inclusion Criteria
Inclusion Criteria #4 has been changed, (new criteria is italicized):
Two central laboratory Hb values during the screening period, obtained at least 7 days apart, 
must be <12 g/dL in patients currently treated with an erythropoietin analogue or <10 g/dL in 
patients not currently treated with an erythropoietin analogue. Patients are considered not 
currently treated if they have not received either Mircera® for at least 8 weeks or any other 
erythropoietin analogue for at least 4 weeks prior to visit 1.
Rationale for change:
This inclusion criteria is modified to allow more incident subjects to participate by relaxing 
the screening Hb for subjects on an erythropoietin analogue.
Dose and schedule and Dosing of epoetin alfa (active control)
Deleted paragraphs covering self-administration.
Rationale for change:
Accommodate sites where patients are dialyzed at hours when site staff cannot be present.
Statistical considerations
Text has been added to clarify that there may be changes to endpoints and analyses to satisfy 
specific Regulatory Authorities in addition to what is described in this protocol.
Rationale for change:
Text has been added for clarification.
Per Protocol Set (PPS)
Section clarified with regards to important protocol deviation.
Rationale for change:
Changed nomenclature from “major protocol deviation” to “important protocol deviation”. 
Have also clarified the important protocol deviations.
Safety analysis set (SAS)
Addition of "All available data will be included for the patients in SAS up until 28 days after 
last intake of study drug, or at the start of non-study drug ESA treatment, whichever is earlier. 
Subsequent results will be excluded."
Rationale for change:
Clarification of when patients will be censored from the SAS, e.g. for the analysis of MACE.
Outcome measures for analyses and Methods for statistical analyse
Primary efficacy and safety objectives separated and clarified.
Rationale for change:
Harmonization of D5740C00002 with the other phase 3 trials in the roxadustat dialysis 


Clinical Study Protocol
Drug Substance Roxadustat
Study Code D5740C00002
Version 8.0
Date 19 September 2018
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program, allowing the program to demonstrate both efficacy and safety across all 
populations studied.
Rationale for amendment:
The primary intent of this amendment is to add a primary efficacy objective to harmonize 
Study D5740C00002 with the other studies in the program and by changing the Hb 
Inclusion Criteria #4 to further support the enrolment of incident dialysis patients to 
improve representation of incident dialysis patients for the pooled analysis in the roxadustat 
phase 3 program. Furthermore, the amendment is updated with the name of the new 
International Co-ordinating Investigator and with changes and clarifications to the Dosing 
and Statistical sections.
Clinical Study Protocol version 7.0– (Outside of US)
Summary of main changes from Clinical Study Protocol edition 1.0 (version 5.0) to 
version 7.0:
All below changes are updated in relevant sections of the study protocol.
Synopsis and Study objectives
Addition of a primary efficacy objective, “Evaluate the efficacy of roxadustat for the treatment 
of anemia in CKD subjects on dialysis”, with a corresponding outcome measure.
Rationale for change: 
Harmonization of D5740C00002 with the other phase 3 trials in the roxadustat dialysis 
program, allowing the program to demonstrate both efficacy and safety across all populations 
studied.
Synopsis, Study Design, Randomization and Sample size estimate
Sample size increased to approximately 2000 patients.
Rationale for change: 
The sample size has been increased to allow for randomization of additional incident dialysis 
patients and to account for the lower than anticipated MACE event rate.
Synopsis, Treatment duration and dosing and Treatment Period
The expected duration of treatment is estimated to be up to 4 years.
Rationale for change: 
Accounts for extension of study in Q1 2018.
Synopsis and Study timetable and end of study
Extension of study in Q1 2018.
Rationale for change: 
The study end date has been changed to allow for randomization of additional incident 
dialysis patients.


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Drug Substance Roxadustat
Study Code D5740C00002
Version 8.0
Date 19 September 2018
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Inclusion Criteria
Added text to modify Inclusion Criteria # 3, specifically it now reads as follows (added text is 
italicized):
Receiving or initiating hemodialysis or peritoneal dialysis for treatment of native kidney end-
stage renal disease (ESRD) for a minimum of 2 weeks and a maximum of 4 months prior to 
randomization. Patients treated with hemodialysis must have access consisting of an 
arteriovenous fistula, AV graft, or tunneled (permanent) catheter. Patients on peritoneal 
dialysis must have a functioning peritoneal dialysis catheter in place.
Rationale for change:
Study D5740C00002 (Rockies) was designed to allow for both incident and stable dialysis 
patients to be enrolled. The incident dialysis population is recognized to have higher
cardiovascular event rates, higher mortality rates, and higher ESA dose requirement for 
anemia therapy. Because the stable dialysis (conversion) patients were enrolled at a much 
more rapid rate in this phase 3 program than incident dialysis patients, there were few 
incident dialysis patients enrolled when the original target for this study was reached. The
primary intent for this amendment is to further support the enrolment of incident dialysis 
patients to improve representation of incident dialysis patients for the pooled analysis in the 
roxadustat phase 3 program. The definition of incident dialysis patients has been modified 
to insure that the period of highest risk, 2 wks to 4 months, is captured.
Dose and treatment regimens 
Initial dosing of Roxadustat and Epoetin Alfa will be based upon current dose at screening 
visit 1 for patients already receiving erythropoietin analogue therapy.
Rationale for change:
Incident dialysis patients frequently are on titrated dosing of ESA and this change simplifies 
the initial dosing strategy.
Dose and schedule and Dosing of epoetin alfa (active control)
Deleted paragraphs covering self-administration.
Rationale for change:
Accommodate sites where patients are dialyzed at hours when site staff cannot be present.
Per Protocol Set (PPS)
Section clarified with regards to important protocol deviation.
Rationale for change:
Changed nomenclature from “major protocol deviation” to “important protocol deviation”. 
Have also clarified the important protocol deviations.
Safety analysis set (SAS)
Addition of "All available data will be included for the patients in SAS up until 28 days after 
last intake of study drug, or at the start of non-study drug ESA treatment, whichever is earlier. 
Subsequent results will be excluded."
Rationale for change:
Clarification of when patients will be censored from the SAS, e.g. for the analysis of MACE.


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Drug Substance Roxadustat
Study Code D5740C00002
Version 8.0
Date 19 September 2018
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Outcome measures for analyses and Methods for statistical analyse
Primary efficacy and safety objectives separated and clarified.
Rationale for change:
Harmonization of D5740C00002 with the other phase 3 trials in the roxadustat dialysis 
program, allowing the program to demonstrate both efficacy and safety across all populations 
studied.
Appendix A Signatories
Removed and replaced by electronic signatures.
Appendix E - National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0
Removed and replaced by a reference to the document.
Rationale for amendment:
Study D5740C00002 was designed to allow for both incident and stable dialysis patients to 
be enrolled. The incident dialysis population is recognized to have higher cardiovascular
event rates, higher mortality rates, and higher ESA dose requirement for anemia therapy. 
Because the stable dialysis (conversion) patients were enrolled at a much more rapid rate in 
this phase 3 program than incident dialysis patients, there were few incident dialysis 
patients enrolled when the original target for this study was reached. The primary intent is 
to further support the enrolment of incident dialysis patients to improve representation of 
incident dialysis patients for the pooled analysis in the roxadustat phase 3 program. 
The incidence dialysis patient population is an important subset of the intended patient 
population for the roxadustat Phase 3 dialysis studies; including these patients will help 
evaluate the safety and efficacy of roxadustat in all dialysis patients.
The primary purpose of this protocol amendment is harmonization of D5740C00002 with the 
other phase 3 trials in the roxadustat dialysis program, allowing the program to demonstrate 
both efficacy and safety across populations studied. Additionally, the amendment allows 
further recruitment of newly initiated (incident) dialysis patients (on dialysis ≥2 weeks but ≤4 
months at randomization).
Clinical Study Protocol version 6.0 (US only)
Summary of main changes from Clinical Study Protocol version 5.0 to version 6.0 US 
only:

Adjustments in inclusion and exclusion criteria and dosing schedule for 


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Drug Substance Roxadustat
Study Code D5740C00002
Version 8.0
Date 19 September 2018
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Incident Dialysis patients. 

Duration of dialysis: Minimum of 2 weeks and a maximum of 4 months 
prior to randomization

Hb: Two central laboratory Hb values during the screening period must be 
<10.5 g/dL

Previous ESA treatment: Maximum 3 months at the time of informed 
consent

Sample size increased to approximately 2000 patients

Prolongation of study period up to 4 years.

Initial dosing of Roxadustat and Epoetin Alfa will be based upon current 
dose at screening visit 1 for subjects already receiving erythropoietin 
analogue therapy.

Clarification of EPO given as concomitant medication.

CSP version 5 Appendix A Signatories has been removed and replaced by 
electronic signatures.

CSP version 5 Appendix E - National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 has been removed and replaced by a reference to the 
document.
Rationale for amendment:
Rockies was designed to allow for both incident and stable dialysis patients to be enrolled. 
The incident dialysis population is recognized to have higher cardiovascular event rates, 
higher mortality rates, and higher ESA dose requirement for anemia therapy. Because the 
stable dialysis (conversion) patients were enrolled at a much more rapid rate in this phase 3 
program than incident dialysis patients, there were few incident dialysis patients enrolled, 
especially incident dialysis patients from the US, when the original target for this study was 
reached. The primary intent for this US-only amendment is to further support the enrolment 
of US incident dialysis patients to improve representation of incident dialysis patients in the 
US for the pooled analysis in the roxadustat phase 3 program.
Version History up until Clinical Study Protocol edition 1.0 (version 5.0), globally
Clinical Study Protocol edition 1.0 (version 5.0), 21 December 2015


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Study Code D5740C00002
Version 8.0
Date 19 September 2018
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An administrative change was approved (dated 21 December 2015), correcting errors and 
clarifying operational aspects of the protocol.  Revised protocol Edition 1.0 was the resulting 
version number, as this was the first revision of the protocol.
Clinical Study Protocol edition 4.0, 26 September 2014
Edition 4.0 was the original protocol submitted and approved globally.
Summary of main changes from edition  3.0 to 4.0:
Concomitant medications
Deleted text `Due to a potential…at the healthcare providers discretion`
Added text to new section Statins 7.7.1.1
`When coadministered with roxadustat, hydroxymethylglutaryl coenzyme A reductase 
inhibitor (statin) exposure was increased 2- to 3-fold. For patients randomized to roxadustat, 
investigators should consider this interaction and local prescribing information when deciding 
on the appropriate statin dose for individual patients, bearing in mind the impact of ethnicity, 
other concomitant medications, renal and hepatic function. Goals of lipid lowering treatment 
should be maintained as clinically indicated. The recommended maximum daily statin doses 
are: simvastatin 20 mg, atorvastatin 40 mg, rosuvastatin 10 mg, pravastatin 40 mg, fluvastatin 
40 mg (20 mg if eGFR<30), pitavastatin 2 mg (1 mg if eGFR<30)
Rationale:
In vitro studies indicated an inhibitory potential of roxadustat for transporters OATP1B1 and 
BCRP, so formal drug: drug interaction studies with simvastatin, atorvastatin and rosuvastatin 
were conducted. When preliminary results became available, the Clinical Study Protocol 
concomitant medication section was updated:
simvastatin
2-fold increase in Cmax and AUC
atorvastatin
1.3-fold increase in Cmax, 2-fold increase in AUC
rosuvastatin
4-fold increase in Cmax, 3-fold increase in AUC
The CSP already included maximum recommended statin doses based on in vitro data; 
rosuvastatin exposure when administered with roxadustat was higher than predicted, so the 
maximum recommended rosuvastatin dose was reduced from 20 mg to 10 mg daily. To avoid 
undertreatment of patients at high CV risk who might be randomized to placebo, investigators 
are asked to consider this interaction in the context of local prescribing information and lipid 
guidelines. Recommendations for pravastatin, pitavastatin and fluvastatin are based on 
predicted exposure as clinical studies were not conducted with these medications.
Concomitant medications
Addition of 


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Drug Substance Roxadustat
Study Code D5740C00002
Version 8.0
Date 19 September 2018
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7.7.1.2 Phosphate binders
When coadministered with phosphate binders, roxadustat exposure was reduced. Patients should be 
advised to discuss with the investigator before changing their phosphate binder dose or dosing time. To 
optimize absorption of roxadustat, subjects should take roxadustat at least 1 hour before or 3 hours 
after their phosphate binder.
Rationale:
In addition to new statin data, preliminary results of a drug: drug interaction study with sevelamer 
carbonate and calcium acetate indicate 40-50% reduced roxadustat exposure with concurrent
administration. A recommendation to take roxadustat at least 1 hour before or 3 hours after phosphate 
binder was also added to the concomitant medication section.
Concomitant medications
Moved herbal medicine text “ Use of herbal medicine…to continue at the same dose” from 
7.7.1 to a new section 7.7.1.3 Herbal medicine
Rationale:
In addition, preliminary results of a drug: drug interaction study with sevelamer carbonate and 
calcium acetate indicate 40-50% reduced roxadustat exposure with concurrent administration. 
A recommendation to take roxadustat at least 1 hour before or 3 hours after phosphate binder 
was also added to the concomitant medication section.
Liver enzymes
Liver enzyme text exchange " For cases where a patient shows an AST or ALT ≥3xULN or total 
bilirubin ≥2xULN please refer to Appendix D for further instruction in cases of combined increase of 
aminotransferase and total bilirubin." to “If a patient meets any of the following criteria, please refer to 
Appendix D for further instruction:
AST≥3xULN, ALT≥3xULN, total bilirubin ≥2xULN."
Rationale:
Clarification
Clinical Study Protocol edition 3.0, 22 August 2014
Edition 3.0 was finalized but never used. Czech Republic & Russia submitted this edition to 
HA , but have only enrolled patients on Edition 4.0.
Summary of main changes from edition  2.0 to 3.0:
Dosing:


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Study Code D5740C00002
Version 8.0
Date 19 September 2018
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Starting dose and dose adjustment; 
Start doses: 120 mg dose removed
120 and 350 mg dose steps removed
Dosing algorithm changes; 0.8 changed to 1.0
Single dose adjustment algorithm used throughout treatment period instead of separate 
algorithms for Correction and Maintenance
Maximum dose reduced from lower of 3.5 mg/kg or 400 mg to 3.0 mg/kg or 400 mg
Rationale:
Dosing simplified to reduce risk of prescriber/patient error and provide slow, steady Hb rise to 
and maintenance within desired range of 11+1 g/dL. 
Dose algorithm was adjusted to reflect results of pharmacometric modeling and simulation 
using the simplified dosing regimen
Mg/kg dose cap lowered from 3.5 to align with non-dialysis. The 400 mg cap is retained, 
reflecting weight distribution of dialysis patients.
Definition of excessive erythropoiesis
Definition of excessive erythropoiesis simplified from before week 20 ‘Hb increases by >2.0 
g/dL within a 2 week period’ and after week 20 ’Hb increases by >2.5 g/dL within a 4 week 
period’ to a single definition, ’Hb increases by >2.0 g/dL within a 4 week period’
Rationale:
Revised to less complicated and more conservative definition of excessive erythropoiesis.
Self-administration of study drug :
Specify self-administration of study drug or epoetin alfa allowed in PD and home HD patients
Rationale:
Clarification to homogenize prescription in dialysis patients
Visit schedule 
Exchange visit week 1 with phone call
Removed visits at week 3,5,7. Also after week 52, visits every 4 weeks
Visit window +-2 days to –4 days to 2
Rationale:
Enhance retention, reduce patient burden. Visits every 4 weeks align with standard of care for 
measurements of Hb and drug dose adjustments in dialysis patients 
The visit window was lengthen to improve patient retention by making sure that investigators 
in dialysis clinics can capture necessary data from patients who may miss dialysis treatments 
that fall on scheduled visit days
Study objectives


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Drug Substance Roxadustat
Study Code D5740C00002
Version 8.0
Date 19 September 2018
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‘Vascular access thrombosis or hypertensive emergency’ added to definition of composite 
safety endpoint
Rationale:
Consistent with list of adjudicated CV events in section 5.2.1.7
Inclusion criteria 
#5-6 Ferritin & TSAT thresholds raised 
Ferritin raised to ≥100ng/mL
TSAT raised to ≥20%
Rationale:
Encourage iron repletion before randomization in line with standard of care
Exclusion criteria 
Deleted exclusion criteria # 3
“Current treatment with an average weekly dose of epoetin alfa……..exceeding 225μg/month`
Rationale:
Enhance patient recruitment
Exclusion criteria
#9 changed from Bosniak II to IIF
#10 added definition of uncontrolled hypertension in dialysis patients
#13 added ‘that is determined to be the principal cause of anemia’
Rationale:
Allow patients with Bosniak II cysts, which are not associated with increased risk of renal cell 
carcinoma. Continue to exclude Bosniak IIF cysts which are associated with cancer risk.
Clarification specifying need to measure post-dialysis blood pressure and accounting for 
higher blood pressures observed in dialysis patients
Allows participation of patients with inflammatory disease if cause of anemia is CKD
Temporary discontinuation 
Deleted study medication discontinuation for thrombocytopenia or bleeding
Rationale:
These patients may benefit from roxadustat; they will also be able to receive appropriate 
concomitant therapy including transfusion
Temporary discontinuation
Updated text with” Need for more than one cycle of erythropoietin analogue rescue”
Rationale:


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Drug Substance Roxadustat
Study Code D5740C00002
Version 8.0
Date 19 September 2018
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Clarification
Supplemental iron use 
Added recommendation for oral iron supplementation.
For IV iron, ferritin/TSAT thresholds changed from <30 ng/ml/<5% to <100/<20; discontinue 
IV iron when patient no longer iron deficient
Rationale:
Consistent with standard of care
Revised IV iron management to align with guidelines and current standard of care.
Rescue continues to be reserved for patients who are not responsive to study medication, oral 
& IV iron and who do not have acute blood loss, which should be managed with transfusion. 
To maintain as many patients as possible on study medication, one cycle of epoetin alfa rescue 
is permitted before permanent discontinuation of study medication.
Erythropoietin analogue administration
For erythropoietin analogue rescue, added statement that clinical judgment should not suggest 
iron deficiency or bleeding. Also, rescue should be discontinued when Hb >9 g/dL or (new 
text) ‘after a 4-week cycle has been completed, whichever comes first.’ Allow one cycle of 
rescue before permanent discontinuation of study drug.
Added statement regarding rescue with different erythropoietin analogue in epoetin alfa 
treated patients
Rationale:
Rescue continues to be reserved for patients who are not responsive to study medication, oral 
& IV iron and who do not have acute blood loss, which should be managed with transfusion. 
To maintain as many patients as possible on study medication, one cycle of epoetin alfa rescue 
is permitted before permanent discontinuation of study medication
Study plan
EQ-5D-5L continued every 24 weeks after week 52 and added at next visit after CSE event
Specify visits with triplicate HR, BP recording
Clarify complete physical exam at randomization and EOT visits
Added optional for pharmacogenetic sampling & biomarker sampling
Rationale:
More complete quality of life assessment
Safety assessments Thromboembolic events added to list of adjudicated CV events
Rationale:
For consistency
Protocol synopsis


Clinical Study Protocol
Drug Substance Roxadustat
Study Code D5740C00002
Version 8.0
Date 19 September 2018
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Priority order of Secondary Objectives change
Rescue therapy before self reported health status
Rationale:
To reflect the pre-planned statistical testing order
Vascular access thrombosis and hypertensive emergency
Text exchanged to “Hypertensive emergency and vascular access thrombosis will be reported
as AE and adjudicated by the IERC”
Rationale:
Clarification
Clinical Study Protocol edition 2.0, 21 May 2014
Rockies protocol Edition 2.0 was submitted and approved in the United States only, as the 
study began in that market.
Clinical Study Protocol edition 1.0, 25 March 2014
Initial creation
Was never submitted in any country.


Clinical Study Protocol
Drug Substance Roxadustat
Study Code D5740C00002
Version 8.0
Date 19 September 2018
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This submission document contains confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object.
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The clinical study protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


PROTOCOL SYNOPSIS
A Phase 3, Multicenter, Randomized, Open-Label, Active-Controlled Study 
of the Safety and Efficacy of Roxadustat in the Treatment of Anemia in 
Dialysis Patients
International Co-ordinating Investigator (ICI)
Steven Fishbane, MD
Chief Division of Kidney Diseases and Hypertension 
North Shore University Hospital
100 Community Drive, 2nd Floor
Great Neck, NY 11021
USA
Study site(s) and number of subjects planned
Approximately 2000 patients will be randomized from approximately 250 centres worldwide.
Study period
Phase of development
Estimated date of first subject enrolled
Q2 2014
III
Estimated date of last subject completed
Q3 2018
Study design
This is a Phase 3, multicenter, randomized, open-label, active-controlled study to evaluate the 
efficacy and safety of roxadustat compared to epoetin alfa for the treatment of anemia in dialysis 
patients. Patients on hemodialysis (HD) or peritoneal dialysis (PD) who have been treated with 
an erythropoietin analogue or have an indication for treatment with an erythropoietin analogue 
will be evaluated for eligibility and randomized at a 1:1 ratio to treatment with roxadustat (with 
discontinuation of prior erythropoietin analogue therapy) or to an active-control group treated 
with epoetin alfa.


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Drug Substance Roxadustat
Study Code D5740C00002
Version 8.0
Date 19 September 2018
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Objectives
Primary Efficacy Objective:
Outcome Measure:
Evaluate the efficacy of Roxadustat for the 
treatment of anemia in CKD subjects on 
dialysis.
US FDA: Mean change from baseline in Hb 
averaged over week 28 to week 52.
EU health authorities: The EU (EMA) primary 
efficacy endpoint is change in Hb from BL to the 
average level during the evaluation period 
(defined as week 28 until week 36), without 
having received rescue therapy (i.e. RBC 
transfusion for all subjects or ESA for subjects 
treated with roxadustat) within 6 weeks prior to 
and during this 8-week evaluation period.
Primary Safety Objective:
Outcome Measure:
Contribute CV safety data to pooled safety 
analyses across the phase 3 program
Adjudicated CV safety data. Analyses of the 
adjudicated events are described in a separate 
pooled statistical analysis plan.
Secondary Efficacy Objectives:
Outcome Measure:
The efficacy of roxadustat as compared to 
epoetin alfa based on Hb response and 
level during the study
Proportion of total time of Hb ≥ 10 g/dL from 
week 28 to week 52.
Proportion of total time of Hb within the interval 
of 10-12 g/dL from week 28 to week 52
The effect of roxadustat on Low-density 
lipoprotein (LDL) cholesterol as compared 
to epoetin alfa
Mean change from baseline in LDL cholesterol
from baseline to week 24
The efficacy of roxadustat based on Hb 
response in inflamed subjects
Mean change in Hb from baseline to the subjects 
mean level between week 28 to week 52 in 
subjects with baseline high-sensitivity C-reactive 
protein (hsCRP) greater than the Upper Limit 
Normal (ULN)
The need for IV iron use in subjects treated 
with roxadustat as compared to epoetin 
alfa
Average monthly IV iron use
The need for RBC transfusion as rescue 
therapy in subjects treated with roxadustat 
as compared to epoetin alfa
Time-to-first (and proportion of subjects 
receiving) administration of red blood cell (RBC) 
transfusion as rescue therapy


Clinical Study Protocol
Drug Substance Roxadustat
Study Code D5740C00002
Version 8.0
Date 19 September 2018
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Secondary Safety Objectives:
Outcome Measure:
To evaluate the safety and tolerability of 
roxadustat.
Adverse events (AEs), serious adverse events
(SAEs).
Changes in vital signs, electrocardiogram (ECG) 
and laboratory values.
Target subject population
Approximately 2000 anemic patients with chronic kidney disease (CKD) receiving hemodialysis 
or peritoneal dialysis with an indication for treatment with an erythropoietin analogue.
Duration of treatment
The study will consist of three study periods as follows:

Screening Period: Up to 6 weeks

Treatment Period: Patients will be randomized (1:1) to open-label treatment with 
either roxadustat or epoetin alfa. A study end date will be declared and common close-
out will occur when the target number of CV events has been accrued. The expected 
duration of treatment is estimated to be up to 4 years

Post-Treatment Follow-Up Period: 4 weeks
Investigational product, dosage and mode of administration
Roxadustat
Roxadustat will be administered orally three times a week (TIW). Study drug doses must be 
administered at least 2 days apart but no more than 4 days apart (e.g., Monday, Wednesday, 
Friday). Selection of roxadustat starting dose will utilize a conversion table (Section 7) for 
patients currently treated with an erythropoietin analogue. Patients not currently treated with an 
erythropoietin analogue will initiate roxadustat using a tiered weight-based dosing scheme. 
Patients with dry weights between 45 and 70 kg will receive 70 mg of roxadustat as starting 
dose. Patients with dry weights between 71 and 160 kg will receive 100 mg of roxadustat for 
initial dosing. Dose adjustments are permitted starting at week 4 and at intervals of every 
4 weeks thereafter in order to achieve an Hb level of 11 g/dL and maintain an Hb of 11±1 g/ dL . 
However, dose adjustments can be done at any time if dose reduction is required for excessive 
erythropoiesis. Study drug will be dosed TIW throughout the study treatment period unless 
downward dose adjustment requires a change to twice or once weekly.
Epoetin alfa 
Initial dose selection of epoetin alfa for patients treated with an erythropoietin analogue will be 
determined using a conversion table based on the patient’s current erythropoietin analogue dose


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Study Code D5740C00002
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at screening visit 1. Initial dosing of epoetin alfa for patients not currently receiving any
erythropoietin at study entry will be 50 IU/kg TIW with subsequent dose adjustments to achieve 
an Hb level of 11 g/dL and maintain an Hb of 11±1 g/dL, consistent with approved prescribing 
information or the Summary of Product Characteristics for epoetin alfa.
Rescue therapy guidelines are provided to optimize standardization of the use of rescue therapy 
by investigators and to ensure safety of the individual study patients.
In the event of excessive erythropoiesis, the dose may be adjusted or put on hold at any time.
Statistical methods
Sample size determination
Primary efficacy variable: With at least 600 subjects, the study will provide at least 99% power 
to demonstrate non-inferiority of roxadustat versus epoetin alfa for the primary efficacy endpoint 
(i.e., Hb change from baseline to the average level during the evaluation period defined as Week 
28 until Week 52). This assumes a difference (roxadustat minus epoetin alfa) of -0.30 g/dL, a 
non-inferiority margin for this difference of -0.75 g/dL and a standard deviation of 1.25 g/dL.
To contribute adjudicated CV events for the pooled CV analyses across the phase 3 program: 
approximately 2000 subjects will be randomized in a 1:1 ratio to either roxadustat or active 
control, i.e. epoetin alfa. The sample size for this study is driven by the overall requirement of 
adjudicated CV events for the phase 3 program in dialysis-treated CKD subjects (which consists 
of four studies in total targeting 611 subjects with MACE events). The three other studies in the 
study program are FG-4592-064, 1517-CL-0613, FG-4592-063. 
Further information related to the sample size determination can be found in the study statistical 
analysis plan and the pooled statistical analysis plan.


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Study Code D5740C00002
Version 8.0
Date 19 September 2018
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TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
VERSION HISTORY..........................................................................................2
PROTOCOL SYNOPSIS................................................................................... 22
TABLE OF CONTENTS................................................................................... 26
1.
INTRODUCTION ............................................................................................. 35
1.1
Background and rationale for conducting this study ........................................... 35
1.2
Rationale for study design, doses and control groups.......................................... 35
1.2.1
Rationale for study design.................................................................................. 35
1.2.2
Rationale for doses............................................................................................. 35
1.2.3
Rationale for control group ................................................................................ 36
1.2.4
Rationale for hemoglobin level .......................................................................... 36
1.3
Benefit/risk and ethical assessment .................................................................... 37
1.4
Study Design...................................................................................................... 38
1.4.1
Treatment duration and dosing ........................................................................... 38
1.4.2
Randomization................................................................................................... 38
1.4.3
Starting dose of study drug................................................................................. 39
2.
STUDY OBJECTIVES...................................................................................... 41
2.1
Primary objectives ............................................................................................. 41
2.2
Secondary objectives.......................................................................................... 41
3.
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL..................... 42
3.1
Inclusion criteria ................................................................................................ 42
3.2
Exclusion criteria ............................................................................................... 43
3.3
Subject enrolment and randomization................................................................. 45
3.4
Procedures for handling incorrectly enrolled or randomized subjects.................. 45
3.5
Methods for assigning treatment groups............................................................. 46
3.6
Methods for ensuring blinding (Not applicable) ................................................. 46
3.7
Methods for unblinding (Not applicable)............................................................ 46
3.8
Restrictions........................................................................................................ 46
3.9
Discontinuation of investigational product ......................................................... 46
3.9.1
Temporary discontinuation from investigational product.................................... 46
3.9.2
Permanent discontinuation from investigational product..................................... 47


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Study Code D5740C00002
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3.9.3
Procedures for discontinuation of a patient from investigational product ............ 47
3.9.3.1
Patient agrees to undergo the Premature Treatment Discontinuation Visit 
and then continue in-person study visits ............................................................. 48
3.9.3.2
Patient refuses to continue in-person study visits but agrees to undergo 
modified follow-up ............................................................................................ 48
3.9.3.3
Patient refuses any form of follow-up................................................................. 49
3.9.3.4 
Restart of study medication................................................................................ 49
3.9.3.5 
End of study procedures..................................................................................... 49
3.10
Criteria for withdrawal....................................................................................... 49
3.10.1
Screen failures ................................................................................................... 50
3.10.2
Withdrawal of Informed Consent ....................................................................... 50
3.11
Discontinuation of the study............................................................................... 50
4.
STUDY PLAN AND TIMING OF PROCEDURES........................................... 50
4.1
Enrolment/screening period................................................................................ 55
4.1.1
Screening Visits................................................................................................. 55
4.1.2
Additional screening assessments....................................................................... 55
4.2
Treatment period................................................................................................ 56
4.3
Follow-up period................................................................................................ 56
5.
STUDY ASSESSMENTS.................................................................................. 56
5.1
Efficacy assessments.......................................................................................... 57
5.1.1
Efficacy assessments.......................................................................................... 57
5.1.1.1
Hemoglobin level............................................................................................... 57
5.1.1.2
Use of rescue therapy......................................................................................... 57
5.2
Safety assessments............................................................................................. 57
5.2.1
Cardiovascular events ........................................................................................ 57
5.2.2
Laboratory assessments...................................................................................... 58
5.2.3
Physical examination ......................................................................................... 59
5.2.4
ECG................................................................................................................... 60
5.2.4.1
Resting 12-lead ECG ......................................................................................... 60
5.2.5
Vital signs.......................................................................................................... 60
5.2.5.1
Heart rate and blood pressure............................................................................. 60
5.3
Other assessments.............................................................................................. 60
5.3.1
Patient reported outcomes .................................................................................. 60
5.3.1.1
EuroQol Health Utility Index – EQ-5D-5L......................................................... 61
5.3.1.2
Administration of patient-reported outcome ....................................................... 61
5.3.2
Hospitalizations ................................................................................................. 61
5.4
Pharmacokinetics ............................................................................................... 62
5.4.1
Collection of samples......................................................................................... 62
5.4.2
Determination of drug concentration.................................................................. 62
5.4.3
Storage and destruction of pharmacokinetic samples.......................................... 62


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Study Code D5740C00002
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5.5
Pharmacodynamics ............................................................................................ 63
5.5.1
Collection of samples......................................................................................... 63
5.5.2
Storage, re-use and destruction of pharmacodynamic samples............................ 63
5.6
Pharmacogenetics .............................................................................................. 63
5.6.1
Collection of pharmacogenetic samples.............................................................. 63
5.6.2
Storage, re-use and destruction of pharmacogenetic samples.............................. 63
5.7
Biomarker analysis............................................................................................. 64
5.7.1
Storage, use, re-use and destruction of biological samples.................................. 64
5.7.2
Labelling and shipment of biological samples .................................................... 64
5.7.3
Chain of custody of biological samples .............................................................. 64
5.7.4
Withdrawal of Informed Consent for donated biological samples....................... 65
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 65
6.1
Definition of adverse events............................................................................... 65
6.2
Definitions of serious adverse event ................................................................... 66
6.3
Recording of adverse events............................................................................... 66
6.3.1
Time period for collection of adverse events ...................................................... 66
6.3.2
Follow-up of unresolved adverse events............................................................. 66
6.3.3
Variables............................................................................................................ 66
6.3.4
Causality collection............................................................................................ 68
6.3.5
Adverse events based on signs and symptoms.................................................... 68
6.3.6
Adverse events based on examinations and tests ................................................ 69
6.3.7
Liver enzymes.................................................................................................... 69
6.3.8
Disease progression............................................................................................ 69
6.4
Reporting of serious adverse events ................................................................... 69
6.5
Overdose............................................................................................................ 70
6.6
Pregnancy .......................................................................................................... 70
6.6.1
Maternal exposure.............................................................................................. 70
6.6.2
Paternal exposure............................................................................................... 71
6.7
Management of IP related toxicities ................................................................... 71
6.8
Study governance and oversight......................................................................... 71
6.8.1
International coordinating investigator ............................................................... 71
6.8.2
Independent Endpoint Review Committee.......................................................... 71
6.8.3
Data Safety Monitoring Board............................................................................ 72
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................... 72
7.1
Identity of investigational product(s).................................................................. 72
7.1.1
Roxadustat......................................................................................................... 72
7.1.2
Epoetin alfa........................................................................................................ 73
7.2
Dose and treatment regimens ............................................................................. 73
7.2.1
Randomization................................................................................................... 73


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7.2.2
Dose and schedule.............................................................................................. 73
7.2.3
Dosing of Roxadustat......................................................................................... 73
7.2.3.1
Patients treated with erythropoietin analogue at study entry................................ 73
7.2.3.2
Patients not treated with erythropoietin analogue at study entry.......................... 74
7.2.3.3
Roxadustat dose adjustments.............................................................................. 74
7.2.3.4
Dose adjustment for excessive erythropoiesis..................................................... 75
7.2.3.5
Dose adjustments for excessive Hb ≥ 13.0g/dL .................................................. 75
7.2.4
Dosing of epoetin alfa (active control)................................................................ 75
7.2.4.1
Patients treated with epoetin alfa or beta at study entry....................................... 75
7.2.4.2
Patients treated with darbepoetin alfa or Mircera® at study entry........................ 76
7.2.4.3
Patients not treated with erythropoietin at study entry ........................................ 76
7.3
Labelling............................................................................................................ 76
7.4
Storage............................................................................................................... 76
7.5
Compliance........................................................................................................ 76
7.6
Accountability.................................................................................................... 77
7.7
Concomitant and other treatments ...................................................................... 77
7.7.1
Concomitant medications................................................................................... 77
7.7.1.1
Statins................................................................................................................ 77
7.7.1.2
Phosphate binders .............................................................................................. 77
7.7.1.3
Herbal medicine................................................................................................. 77
7.7.2
Prohibited medications....................................................................................... 78
7.7.3
Supplemental iron use........................................................................................ 78
7.7.4
Rescue therapy guidelines.................................................................................. 78
7.7.4.1
Red blood cell transfusion.................................................................................. 78
7.7.4.2
Erythropoietin analogue administration in patients randomized to 
roxadustat .......................................................................................................... 79
7.7.4.3
Therapeutic Phlebotomy .................................................................................... 79
7.7.5
Other concomitant treatment .............................................................................. 80
7.8
Post Study Access to Study Treatment ............................................................... 80
8.
STATISTICAL ANALYSES BY ASTRAZENECA.......................................... 80
8.1
Statistical considerations .................................................................................... 80
8.2
Sample size estimate .......................................................................................... 80
8.3
Definitions of analysis sets................................................................................. 81
8.3.1
Intention to Treat Analysis Set (ITT).................................................................. 81
8.3.2
Per Protocol Set (PPS) ....................................................................................... 81
8.3.3
Safety analysis set (SAS) ................................................................................... 81
8.3.4
Full Analysis Set (FAS) ..................................................................................... 81
8.3.5
Subjects who will not be included in any analysis sets........................................ 81
8.4
Outcome measures for analyses.......................................................................... 82
8.4.1
Primary efficacy endpoint: ................................................................................. 82
8.4.2
Hb related secondary efficacy endpoints: ........................................................... 82


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Study Code D5740C00002
Version 8.0
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8.4.3
Lipid related secondary efficacy endpoints......................................................... 82
8.4.4
IV iron related secondary efficacy variable endpoints:........................................ 83
8.4.5
Rescue therapy related secondary efficacy endpoints:......................................... 83
8.5
Adjudicated CV Events Analyses for Safety Assessments.................................. 83
8.6
Methods for statistical analyses.......................................................................... 83
8.6.1
Stratification variables ....................................................................................... 83
8.6.2
Analysis of the primary efficacy endpoint for US............................................... 84
8.6.3
Analysis of the primary efficacy endpoint for EU (Secondary Endpoint for 
FDA) ................................................................................................................. 84
8.6.4
CV safety endpoint analyses .............................................................................. 85
8.6.5
Analysis of the secondary efficacy endpoints ..................................................... 85
8.6.6
Subgroup analysis.............................................................................................. 86
8.6.7
Interim analysis.................................................................................................. 86
8.6.8
Sensitivity analysis............................................................................................. 86
8.6.9
Exploratory analysis........................................................................................... 86
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA......................... 86
9.1
Training of study site personnel ......................................................................... 86
9.2
Monitoring of the study...................................................................................... 86
9.2.1
Source data ........................................................................................................ 87
9.2.2
Study agreements............................................................................................... 87
9.2.3
Archiving of study documents............................................................................ 87
9.3
Study timetable and end of study........................................................................ 87
9.4
Data management by AstraZeneca ..................................................................... 88
10.
ETHICAL AND REGULATORY REQUIREMENTS....................................... 89
10.1
Ethical conduct of the study ............................................................................... 89
10.2
Patient data protection........................................................................................ 89
10.3
Ethics and regulatory review .............................................................................. 89
10.4
Informed consent ............................................................................................... 90
10.5
Changes to the protocol and informed consent form........................................... 90
10.6
Audits and inspections ....................................................................................... 91
11.
LIST OF REFERENCES ................................................................................... 91


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LIST OF TABLES
Table 1
Study Plan.............................................................................................51
Table 2
Laboratory Safety Variables..................................................................58
Table 3
Identity of investigational product.........................................................72
Table 4
Initial dosing of roxadustat for patients treated with an 
erythropoietin  analogue at study entry..................................................74
Table 5
Initial dosing of roxadustat dose for patients not taking 
erythropoietin analogue at study entry...................................................74
Table 6
Roxadustat dose adjustments.................................................................75
Table 7
Initial dosing of epoetin alfa for patients treated with darbepoetin 
alfa or Mircera® at study entry...............................................................76
LIST OF FIGURES
Figure 1
Study Flowchart....................................................................................40
LIST OF APPENDICES
Appendix B
Additional Safety Information...............................................................94
Appendix C
International Airline Transportation Association (IATA) 6.2 
Guidance Document..............................................................................96
Appendix D
Actions Required in Cases of Combined Increase of 
Aminotransferase and Total Bilirubin - Hy’s Law .................................97


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance model
Anti-HCV antibody
Anti-hepatitis C virus antibody
AST
Aspartate aminotransferase
BP
Blood pressure
CABG
Coronary artery bypass graft surgery
CBC
Complete Blood Count
CKD
Chronic kidney disease
CMH
Cochran-Mantel-Haenszel
CSA
Clinical Study Agreement
CSE
Composite safety endpoint
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Event
CV
Cardiovascular 
DILI
Drug induced liver injury
DSMB
Data Safety Monitoring Board
DVT
Deep vein thrombosis
EC
Ethics Committee, synonymous to Institutional Review Board (IRB)
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eGFR
Estimated glomerular filtration rate
EOS
End of Study
EOT
End of Treatment
EQ-5D-5L
EuroQol Health Utility Index
ESRD
End-stage Renal Disease
FAS
Full Analysis Set
GGT
Gamma-glutamyl transferase
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
Hb
Hemoglobin
HBsAg
Hepatitis B surface antigen


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Abbreviation or 
special term
Explanation
hCG
Human chorionic gonadotropin
HD
Hemodialysis 
HIF
Hypoxia-inducible factor
HIF-PHI
Hypoxia-inducible factor prolyl hydroxylase inhibitor
HIV
Human Immunodeficiency Virus
HR
Heart rate
HRQoL
Health related quality of life
hsCRP
High-sensitivity C-reactive protein
IB
Investigator’s brochure
ICF
Informed Consent form
ICH
International Conference on Harmonisation
ICI
International Co-ordinating Investigator, if a study is conducted in several 
countries the International Co-ordinating Investigator is the Investigator co-
ordinating the investigators and/or activities internationally.
ID
Incident Dialysis
IERC
Independent Endpoint Review Committee
iPTH
Intact parathyroid hormone
IP
Investigational Product 
IRB
Institutional Review Board
ITT
Intention To Treat 
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
KDIGO
Kidney Disease Improving Global Outcomes
LDL
Low-density lipoprotein
LFT
Liver Function Test
LLN
Lower limit of normal
MACE
Major adverse cardiovascular events; defined as a composite endpoint of 
death from any cause, non-fatal myocardial infarction (MI) or non-fatal 
stroke
MACE+
Major adverse cardiovascular events+; A composite endpoint of death from 
any cause, non-fatal MI, non-fatal stroke, congestive heart failure requiring 
hospitalisation and unstable angina requiring hospitalisation.
MI
Myocardial Infarction
MMRM
Mixed Model of Repeated Measures
NCI
National Cancer Institute 
PCI
Percutanous coronary intervention
PD
Peritoneal dialysis


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Abbreviation or 
special term
Explanation
PE
Pulmonary embolism
PI
Principal Investigator 
PK
Pharmacokinetic
PPS
Per Protocol Set
PRO
Patient-reported outcome
PSAP
Pooled Statistical Analysis Plan
PTDV
Premature Treatment Discontinuation Visit
QoL
Quality of life 
RBC
Red blood cell
SAE
Serious adverse event 
SAP
Statistical analysis plan
SAS
Safety Analysis Set
Tbili
Total bilirubin
TIBC
Total iron binding capacity
TIW
Three times a week
TSAT
Transferrin saturation
ULN
Upper limit of normal
URL
Upper reference limit
VAT
Vascular access thrombosis
WBDC
Web Based Data Capture


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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Roxadustat is an orally administered investigational novel drug in development for the 
treatment of anemia associated with chronic kidney disease (CKD), including end-stage renal 
disease (ESRD). It is currently in global Phase 3 clinical development and has not been 
marketed in any country. Roxadustat is a potent and reversible orally active hypoxia-inducible 
factor prolyl hydroxylase inhibitor (HIF-PHI) that transiently induces hypoxia-inducible factor 
(HIF) stabilization and leads to a functional HIF transcriptional response that mimics the 
erythropoietic response associated with exposure of humans to intermittent hypoxia 
(Semenza 1998). HIF induces expression not only of erythropoietin, but also the
erythropoietin receptor and proteins that promote iron reabsorption 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 
hypoxia, but under normoxic conditions. Potential advantages of roxadustat compared with 
erythropoietin analogues for treatment of anemia in patients with CKD treated with dialysis 
include oral administration, greater cardiovascular (CV) safety and reduced need for 
intravenous (IV) iron therapy. The clinical data collected thus far suggest that roxadustat is 
generally safe and well tolerated in healthy adult patients, and in dialysis and non-dialysis 
CKD patients with anemia treated up to 60 weeks. Information from the clinical studies 
conducted with roxadustat can be found in the Investigator’s Brochure. 
The objective of the current study is to assess the efficacy, safety and tolerability, with the 
primary focus on Hemoglobin efficacy and CV safety of roxadustat in patients with ESRD 
treated by dialysis (hemodialysis [HD] or peritoneal dialysis [PD]).
1.2
Rationale for study design, doses and control groups
1.2.1
Rationale for study design
The study is designed to evaluate the efficacy and safety of roxadustat in the treatment of 
anemia associated with CKD in dialysis patients. The study is a randomized, open-label study 
with two treatment groups, roxadustat or epoetin alfa, and includes hemodialysis or peritoneal 
dialysis patients that have been treated with an erythropoietin analogue or have an indication 
for treatment with an erythropoietin analogue.
1.2.2
Rationale for doses 
Starting doses of roxadustat were studied in three ways in the Phase 2 program: mg per kg 
weight-based dosing, tiered weight-based dosing or a fixed starting dose regardless of weight.


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Dose adjustments were allowed at regular 4-week intervals to maintain, increase or decrease 
the dose according to pre-specified rules. Additional rules were provided to minimize 
excessive erythropoiesis. These dose adjustment rules are adopted in this study with minor 
modifications. 
For patients treated with an erythropoietin analogue at study entry, selection of initial 
roxadustat dose in this study will utilize a conversion table based on the patient’s current 
erythropoietin analogue dose at screening visit 1. Patients not currently treated with 
erythropoietin analogue will initiate roxadustat using a tiered weight-based dose dosing 
scheme. Patients with dry weights between 45 and 70 kg will receive 70 mg of roxadustat as 
starting dose.  Patients with dry weights between 71 and 160 kg will receive 100 mg of 
roxadustat for initial dosing.
Doses will be administered at a frequency of three times a week (TIW) throughout the study 
treatment period unless downward dose adjustment requires a change to twice or once weekly.
In the event of excessive erythropoiesis, the dose may be adjusted at any time. The maximum 
dose of roxadustat allowed will be the lower of 3.0 mg/kg or 400 mg per dose.
Patients randomized to the epoetin alfa group will receive an epoetin alfa dosing regimen with 
initial and subsequent dose adjustments in accordance with accepted clinical practice 
guidelines and approved prescribing information for epoetin alfa. The initial dose of epoetin 
alfa will be selected based on the erythropoietin analogue regimen used prior to the entry into 
the study.  Patients who were not receiving an erythropoietin analogue at study entry will 
initially receive epoetin alfa at a dose of 50 IU/kg three times weekly.  Adjustments in the 
total weekly dose or frequency of epoetin alfa dosing should subsequently be made to achieve 
an Hb of 11 g/dL and maintain Hb levels of 11±1 g/dL.
1.2.3
Rationale for control group
The control group will be treated with epoetin alfa in accordance with accepted clinical 
practice guidelines and approved prescribing information for epoetin alfa in this patient 
population. Epoetin alfa is a frequently used erythropoietin analogue agent and is approved for 
use in treatment of anemia associated with CKD in dialysis patients. 
1.2.4
Rationale for hemoglobin level
This study seeks to achieve and maintain Hb within the range of 11±1 g/dL. This level is 
chosen to improve the clinical manifestations of anemia, reduce RBC transfusion and improve 
quality of life, without affecting CV risk. Systematic reviews have found that anemia
correction in patients with CKD improved exercise tolerance, energy and physical functions 
(Gandra et al 2010, Johansen et al 2010). Also, a number of studies and meta analyses have
addressed the issue of clinical benefit versus potential risk upon anemia correction in CKD 
(Phrommintikul et al 2010, Strippoli et al 2004). In a recent update, the 2012 KDIGO 
guidelines suggest that erythropoietin analogues be started at Hb below 10 g/dL and should 
generally not be used to maintain Hb above 11.5 g/dL (Johansen et al 2010, KDIGO 2012). In 


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contrast, the Cleveland Clinic recommends target hemoglobin level for both predialysis CKD 
and ESRD patients should be 11 to 12 g/dL (Lascano et al 2010).
Unlike Hb levels above 13 g/dL where the data indicates CV harm (Pfeffer et al 2009), there 
is a paucity of data on the potential risk of CV adverse events when Hb below 12 g/dL is 
achieved. Further, other factors than the exact Hb level may contribute to the CV risk 
associated with erythropoietin analogue use. These include toxic effects of higher doses of 
erythropoietin analogue (Andrews et al 201) and a too rapid increase in hemoglobin upon 
anemia correction (Singh 2010).
Roxadustat acts via a different mechanism of action than erythropoietin analogues and supra-
physiologic erythropoietin concentrations have not been observed in patients treated with 
roxadustat (Yu et al 2013). With the proposed dosing regimen, the risk of rapid rises of Hb 
levels is minimized. Finally, in clinical practice, it is difficult to maintain individual patient 
Hb values within a very narrow range and the proposed range (11±1 g/dL) is in line with 
achievable levels in practice.
1.3
Benefit/risk and ethical assessment
The primary benefit for patients randomized to roxadustat is expected to be the correction of 
anemia, including the relief of associated signs and symptoms and an improved quality of life. 
Roxadustat is expected to be at least as safe as parenteral erythropoietin analogues.
An established dose adjustment algorithm will be used during the study to titrate roxadustat 
doses to enable patients to achieve and maintain Hb levels, while closely monitoring the rate 
of rise of Hb levels. Roxadustat doses may be held and therapeutic phlebotomy is allowed in 
the event of excessive erythropoiesis. 
Dosing of epoetin alfa in the epoetin alfa group will be consistent with approved prescribing 
information. Adverse and serious adverse events, and laboratory parameters including 
electrolytes, liver enzymes, and iron indices, will be closely monitored to ensure the safety of 
treatment with roxadustat or epoetin alfa. 
In studies with healthy subjects, headache and dizziness were common events which occurred 
at a higher frequency with roxadustat compared to placebo. An increased frequency of mild to 
moderate musculoskeletal pain was also noted with high doses of roxadustat. These findings 
were not observed at the usual therapeutic dose range in the Phase 2 studies in the target 
populations.
Treatment with roxadustat was associated with increases in heart rate which were most 
pronounced at supra-therapeutic doses (5 mg/kg). At the high clinical dose of 2.75 mg/kg, the 
increase was modest (about 10 bpm from baseline, placebo corrected). In the Phase 2 studies, 
there were no adverse effects on hemodynamics with repeat dose administration in the 
therapeutic dose range. The cumulative safety data to date have not identified any major risks 
related to roxadustat, which was well tolerated by healthy subjects and patients with CKD.


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The safety of treatment with roxadustat and epoetin alfa will be carefully monitored and an 
independent Data Safety Monitoring Board (DSMB) will perform periodic assessments of 
safety data to detect any potential safety signals that may arise during the study and advise the 
International Coordinating Investigator and Sponsor accordingly. 
Based on data so far obtained, treatment with roxadustat is expected to be efficacious in 
treating anemia in patients with CKD. The safety profile of the compound, together with the 
safety monitoring implemented would minimize the risk to study participants. The benefit-risk 
in this study is therefore deemed acceptable.
More detailed information about the efficacy and safety profile of roxadustat is provided in 
the IB.
1.4
Study Design 
This is a Phase 3, multicenter, randomized, open-label, active-controlled study to evaluate the 
efficacy and safety of roxadustat compared to epoetin alfa for the treatment of anemia due to 
CKD in dialysis patients (hemodialysis or peritoneal dialysis). This study is planned to 
randomize approximately 2000 patients from approximately 250 centers worldwide.
1.4.1
Treatment duration and dosing
The study periods are as follows:

Screening Period: Up to 6 weeks
Treatment Period: Patients will be randomized (1:1) to open-label treatment with 
roxadustat or epoetin alfa. Roxadustat will be started at doses of 70 mg for patients 
with dry weights between 45 and 70 kg and 100 mg for patients with dry weights 
between 71 and 160 kg. This dose will be subsequently titrated. Patients currently 
treated with an erythropoietin analogue and randomized to receive roxadustat will 
discontinue prior erythropoietin analogue therapy and initiate treatment with 
roxadustat at a starting dose according to Table 4 Section 7 to achieve and maintain
Hb 11±1 g/dL. Epoetin alfa dosing will be done in accordance with accepted 
clinical practice guidelines and approved prescribing information.
The expected duration of treatment is estimated to be up to 4 years. A study end 
date will be declared and common closeout will occur when the target number of 
CV events has been accrued.

Post-Treatment Follow-Up Period: 4 weeks. Patients who discontinue study 
medication or protocol-specified study visits will be followed up for CV events, 
vital status and hospitalizations until the end of the study (EOS), unless consent to 
participate is withdrawn.
1.4.2
Randomization
A total of approximately 2000 patients will be randomized at 1:1 ratio to roxadustat or epoetin 
alfa via an Interactive Web Response System (IWRS)/ Interactive Voice Response System 
(IVRS). 


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1.4.3
Starting dose of study drug
For more details see Section 7.  
Roxadustat
Patients currently treated with an erythropoietin analogue who are randomized to the 
roxadustat group will discontinue prior erythropoietin analogue therapy and initiate treatment 
with roxadustat at a starting dose according to Section 7. Patients not currently treated with an
erythropoietin analogue will initiate roxadustat with dose selection based on body weight. 
Roxadustat will be dosed orally three times a week (TIW) throughout the Treatment Period 
unless dose reduction is required based on Hb levels.
Epoetin alfa
Patients currently treated with erythropoietin analogue who are randomized to the epoetin alfa 
active control group will be treated with epoetin alfa dosing regimen as described in Section 7. 
Initial dosing of epoetin alfa in patients not currently treated with erythropoietin analogue will 
be 50 IU/kg TIW with subsequent dose adjustments of erythropoietin analogue made based on 
Hb levels consistent with approved prescribing information.
During the screening period, eligibility will be confirmed at a minimum of 2 screening visits. 
If eligible, the patient will be randomized at the randomization visit. During the treatment 
period, patients will be contacted by telephone at week 1, and will attend study visits every 
two weeks from weeks 2 to 20. After week 20, study visits will occur every four weeks until 
the end of treatment period. A study end date will be defined based on when the planned 
number of events are estimated to be accrued; the end of treatment (EOT) visit will occur as 
soon as possible after that date. An end of study (EOS) visit will be performed 4 weeks after 
the EOT.
Detailed information about study visits and assessments is found in Section 4.


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Figure 1
Study Flowchart
Screening 
period
Treatment period
Randomization
-6
20
Roxadustat 
Every 2nd week
visits
Visits every 4th week
Epoetin alfa
Screening visits
End of Treatment (EOT) visit
End of Study 
(EOS) visit 
Post-Treatment follow-up 
period (4 weeks)
1st week 
phone/contact
2


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2.
STUDY OBJECTIVES
2.1
Primary objectives
Primary Efficacy Objective:
Outcome Measure:
Evaluate the efficacy of Roxadustat for the 
treatment of anemia in CKD subjects on 
dialysis.
US FDA: Mean change from baseline in Hb 
averaged over week 28 to week 52.
EU health authorities: The EU (EMA) primary 
efficacy endpoint is change in Hb from BL to the 
average level during the evaluation period 
(defined as week 28 until week 36), without 
having received rescue therapy (i.e. RBC 
transfusion for all subjects or ESA for subjects 
treated with roxadustat) within 6 weeks prior to 
and during this 8-week evaluation period.
Primary Safety Objective:
Outcome Measure:
Contribute CV safety data to pooled safety 
analyses across the phase 3 program
Adjudicated CV safety data. Analyses of the 
adjudicated events are described in a separate 
pooled statistical analysis plan.
2.2
Secondary objectives
Secondary Efficacy Objectives:
Outcome Measure:
The efficacy of roxadustat as compared to 
epoetin alfa based on Hb response and 
level during the study
Proportion of total time of Hb ≥ 10 g/dL from 
week 28 to week 52.
Proportion of total time of Hb within the interval 
of 10-12 g/dL from week 28 to week 52
The effect of roxadustat on Low-density 
lipoprotein (LDL) cholesterol as compared 
to epoetin alfa
Mean change from baseline in LDL cholesterol 
from baseline to week 24
The efficacy of roxadustat based on Hb 
response in inflamed subjects
Mean change in Hb from baseline to the subjects 
mean level between week 28 to week 52 in 
subjects with baseline high-sensitivity C-reactive 
protein (hsCRP) greater than the Upper Limit 
Normal (ULN)
The need for IV iron use in subjects treated 
with roxadustat as compared to epoetin 
alfa
Average monthly IV iron use


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Secondary Efficacy Objectives:
Outcome Measure:
The need for RBC transfusion as rescue 
therapy in subjects treated with roxadustat 
as compared to epoetin alfa
Time-to-first (and proportion of subjects 
receiving) administration of red blood cell (RBC) 
transfusion as rescue therapy
Secondary Safety Objectives:
Outcome Measure:
To evaluate the safety and tolerability of 
roxadustat.
Adverse events (AEs), serious adverse events
(SAEs).
Changes in vital signs, electrocardiogram (ECG) 
and laboratory values.
3.
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.
3.1
Inclusion criteria
For inclusion in the study subjects should fulfil the following criteria:
1.
Provision of Informed Consent prior to any study specific procedures
2.
Age ≥18 years at screening visit 1
3.
Previous versions of the protocol prior to US amendment ver 6.0 and outside of 
US amendment ver 7.0:
Receiving or initiating hemodialysis or peritoneal dialysis for treatment of native 
kidney end-stage renal disease (ESRD) at least 30 days prior to visit 1. Patients 
treated with hemodialysis must have access consisting of an arteriovenous fistula, 
AV graft, or tunneled (permanent) catheter. Patients on peritoneal dialysis must 
have a functioning peritoneal dialysis catheter in place.
Starting with US amendment ver. 6.0 and outside of US amendment ver 7.0
(changed to recruit incident dialysis patients only):
Receiving or initiating hemodialysis or peritoneal dialysis for treatment of native 
kidney end-stage renal disease (ESRD) for a minimum of 2 weeks and a maximum 
of 4 months prior to randomization. Patients treated with hemodialysis must have 
access consisting of an arteriovenous fistula, AV graft, or tunneled (permanent) 
catheter. Patients on peritoneal dialysis must have a functioning peritoneal dialysis 
catheter in place.


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4.
Two central laboratory Hb values during the screening period, obtained at least 7 
days apart, must be <12 g/dL in patients currently treated with an erythropoietin 
analogue or <10 g/dL in patients not currently treated with an erythropoietin 
analogue. Patients are considered not currently treated if they have not received 
either Mircera® for at least 8 weeks or any other erythropoietin analogue for at least 
4 weeks prior to visit 1.
5.
Ferritin ≥100 ng/mL at randomization (obtained from screening visit)
6.
TSAT ≥20% at randomization (obtained from screening visit)
7.
Serum folate level ≥ lower limit of normal (LLN) at randomization (obtained from 
screening visit)
8.
Serum vitamin B12 level ≥ LLN at randomization (obtained from screening visit)
9.
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3x upper 
limit of normal (ULN), and total bilirubin (Tbili) ≤1.5 x ULN at randomization 
(obtained from screening visit)
10.
Body weight 45 to 160 kg (prescribed dry weight)
3.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site)
2.
Previous randomisation in the present study
3.
New York Heart Association Class III or IV congestive heart failure at enrolment
4.
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
5.
History of chronic liver disease (e.g., chronic infectious hepatitis, chronic auto-
immune liver disease, cirrhosis or fibrosis of the liver)
6.
Known hereditary hematologic disease such as thalassemia, sickle cell anemia, a 
history of pure red cell aplasia or other known causes for anemia other than CKD
7.
Known and untreated retinal vein occlusion or known and untreated proliferative 
diabetic retinopathy (risk for retinal vein thrombosis)
8.
Diagnosis or suspicion (e.g. complex kidney cyst of Bosniak Category IIF, III or 
IV) of renal cell carcinoma on renal ultrasound (or other imaging procedure e.g. CT 
scan or MRI) conducted at screening or within 12 weeks prior to randomization.


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9.
Uncontrolled hypertension at the time of randomization (defined as systolic BP 
≥180 mmHg or diastolic BP ≥100 mmHg on repeated measurement post-dialysis in 
hemodialysis patients or at any time in peritoneal dialysis patients), contraindication 
to epoetin alfa treatment (e.g., pure red cell aplasia, hypersensitivity or know 
inability to tolerate epoetin alfa) 
10.
History of prostate cancer, breast cancer or any other malignancy, except the 
following: cancers determined to be cured or in remission for ≥5 years, curatively 
resected basal cell or squamous cell skin cancers, cervical cancer in situ or resected 
colonic polyps.
11.
Positive for any of the following: human immunodeficiency virus (HIV), hepatitis B 
surface antigen (HBsAg) or anti-hepatitis C virus antibody (anti-HCV Ab)
12.
Chronic inflammatory diseases such as rheumatoid arthritis, SLE, ankylosing 
spondylitis, psoriatic arthritis or inflammatory bowel disease that is determined to 
be the principal cause of anemia
13.
Known hemosiderosis, hemochromatosis or hypercoagulable condition
14.
Any prior organ transplant with the exception of an autologous renal transplant or a 
renal transplant that was subsequently removed (“explanted”) or scheduled organ 
transplantation date
15.
Any red blood cell (RBC) transfusion during the screening period
16.
Any current condition leading to active significant blood loss
17.
Any prior treatment with roxadustat or a hypoxia-inducible factor prolyl 
hydroxylase inhibitor (HIF-PHI)
18.
Has received another new chemical entity (defined as a compound which has not 
been approved for marketing) or has participated in any other clinical study that 
included drug treatment within the month preceding the first administration of IP in 
this study. (Note: patients consented and screened, but not randomized in this study 
or a previous study are not excluded)
19.
History of alcohol or drug abuse within 2 years prior to randomization
20.
Females of childbearing potential, unless using contraception as detailed in the 
protocol or sexual abstinence (see Section 3.8)
21.
Pregnant or breastfeeding females
22.
Known allergy to the investigational product or any of its ingredients


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23.
Any medical condition, including active, clinically significant infection, that in the 
opinion of the investigator or Sponsor may pose a safety risk to a patient in this 
study, which may confound efficacy or safety assessment, or may interfere with 
study participation
Procedures for withdrawal of incorrectly enrolled subjects see Section 3.4.
3.3
Subject enrolment and randomization
Investigator(s) should keep a record, the subject screening log, of subjects who entered pre-
study screening.
The Investigator(s) will:

Obtain signed Informed Consent from the potential patient before any study specific 
procedures are performed.

Assign potential patient a unique enrolment number, beginning with ‘E#’, through 
the IVRS/IWRS

Determine patient eligibility, see Section 3.1and 3.2.

Assign eligible patient unique randomization code through the IVRS/IWRS
If a patient withdraws from participation in the study, his/her enrolment/randomization code 
cannot be reused.
Randomization codes will be assigned strictly sequentially as patients become eligible for 
randomization. Randomization of qualified patients within the IVRS/IWRS system must take 
place prior to administration of study drug.  Randomization procedures must be completed 
within 72 hours.  The first dose of study drug defines Day 1. The randomization visit should 
be scheduled after the study drug has arrived at the study site.
3.4
Procedures for handling incorrectly enrolled or randomized 
subjects
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication. There can be no exceptions to this rule. Patients who are 
enrolled, but subsequently found not to meet all the eligibility criteria must not be randomized
or initiated on treatment, and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is randomized in error or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca study 
physician immediately, and a discussion should occur between the AstraZeneca study 
physician and the investigator regarding whether to continue or discontinue the patient from 
treatment. The AstraZeneca study physician must ensure all decisions are appropriately 
documented.


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3.5
Methods for assigning treatment groups
Randomization schedules will be prospectively prepared. Automated randomization and 
treatment assignments will be provided by an IWRS /IVRS. The randomization codes will be 
computer generated by AstraZeneca R&D using GRand (AZ Global Randomization system) 
and loaded into the IVRS/IWRS database. A blocked randomization schedule by country will 
be produced.
3.6
Methods for ensuring blinding (Not applicable)
3.7
Methods for unblinding (Not applicable)
3.8
Restrictions
The following restrictions apply in the study:
Female patients of childbearing potential and male patients (non-surgically sterile i.e., 
vasectomy) with a female partner of childbearing potential must, if not practicing complete 
sexual abstinence, agree to practice a dual method of contraception, for example, a 
combination of the following: (1) oral contraceptive, depo progesterone or intrauterine device; 
and (2) a barrier method (condom or diaphragm).
Contraceptive methods must be practiced upon being randomized to the study and through 
12 weeks after the last dose of study treatment. If a patient discontinues prematurely, the 
contraceptive method must be practiced for 12 weeks following final administration of study 
drug.
Pregnancy, spontaneous or therapeutic abortion, or events related to pregnancy must be 
reported (see Section 6.6).
For high dose statins use, see Section 7.7.1.1.
If epoetin alfa is supplied by AstraZeneca, see Section 7.1.2 for dose restrictions at study 
entry. 
3.9
Discontinuation of investigational product
Patients should be discontinued from investigational product (IP) in the following situations:
3.9.1
Temporary discontinuation from investigational product
For patients needing treatment with prohibited concomitant medications, study medication 
must be discontinued or interrupted temporarily.
For decisions around discontinuation the AstraZeneca study physician can be consulted as 
appropriate.


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3.9.2
Permanent discontinuation from investigational product
1.
Patient decision: The patient is at any time free to discontinue treatment, without 
prejudice to further treatment.
2.
Investigator’s decision, including but not limited to these examples:

Incorrectly randomized patient in whom the inclusion/exclusion criteria 
violation would put the patient at undue risk

Adverse event (AE) for which the investigator thinks continued treatment may 
put the patient at undue risk

Severe non-compliance to study protocol 

Pregnancy

Need for more than one cycle of erythropoietin analogue rescue in patients 
treated with Roxadustat

Patients who receive organ transplantation during the study
Each permanent discontinuation from study medication should be communicated to the study 
team. For decisions around permanent discontinuation the AstraZeneca study physician can be 
consulted as appropriate. Study assessments or follow-up should be continued in all cases if 
possible, see Section 4.
3.9.3
Procedures for discontinuation of a patient from investigational product 
Patients permanently discontinuing study medication should be given conventional therapy, if 
applicable, and should always be asked to continue the regular study visits as described below.
A patient who decides to discontinue study medication will always be asked about the 
reason(s) to discontinue study medication and the presence of AEs (if any). These data will be 
ascertained and documented by the investigator and recorded in the eCRF as appropriate. AEs 
will be followed up (see Sections 4 and 6.4); and the patient should return all study 
medications.
Discontinuation from study medication is not the same as complete withdrawal from the 
study (withdrawal of consent), which has a direct impact on the potential validity of all 
study data, and should be avoided wherever possible. It is essential to collect as much 
data as possible for all patients throughout the study and especially all potential 
endpoint events.
All discontinued patients unless consent withdrawal will be followed up for vital status and 
hospitalizations until study closure (see Section 3.9.3.2).
If the patient permanently discontinues study medication prior to closure of the study, there 
should be several different options for their continuation in the study as described below:


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3.9.3.1
Patient agrees to undergo the Premature Treatment Discontinuation Visit and 
then continue in-person study visits
The patient agrees to undergo the Premature Treatment Discontinuation Visit (PTDV) and 
then continue in-person study visits according to plan. This is the preferred option and 
patients who discontinue study medication will always be asked if they agree to this approach. 
If agreed, as above, the patient will undergo their PTDV within 15 days after the study 
medication is stopped. The PTDV includes the same assessments as the EOT visit. The patient 
will continue attending subsequent study visits according to schedule (Table 1), or if needed 
with reduced frequency until end of study is declared (i.e., when the prespecified number of 
primary events has been reached). The patient will then return for their EOS visit as soon as 
feasible, but no later than 60 days after the study closure has been declared. It is essential that 
the patients attend the EOS visit in person whenever possible.
At PTDV, the physicians caring for the patient will decide upon treatment the patient should 
receive as part of his/her ongoing clinical care.
3.9.3.2
Patient refuses to continue in-person study visits but agrees to undergo 
modified follow-up
If the patient agrees, the PTDV should be done. In all subjects permanently discontinuing 
study drug, all adverse events and potential endpoints should be captured during the 28 days 
following study drug discontinuation. Beyond 28 days following study drug discontinuation, 
for subjects who refuse to continue in-person study visits but agree to modified follow-up, all 
SAEs should be captured as well as any information (for example, hospitalization records) 
relevant to the following adjudicated events:

Death

Non-fatal MI

Non-fatal stroke

Heart failure requiring hospitalization

Unstable angina leading to hospitalization

Deep vein thrombosis (DVT)

Pulmonary embolism (PE)

Vascular access thrombosis (VAT)

Hypertensive emergency
Additionally, information about anemia treatment following study drug discontinuation (for 
example, erythropoietin analogue use) should be documented in the eCRF.
Examples of modified follow-up include in-person study visits occurring at a different 
frequency and/or with fewer study procedures (for example, without laboratory assessments) 


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than that listed in Table 1; periodic telephone contact with the subject, subject’s spouse, or the 
subject’s treating physician; and periodic medical record review. 
3.9.3.3
Patient refuses any form of follow-up
If the patient refuses any form of follow-up, he/she officially withdraws from the study and 
withdraws consent. This approach should be avoided if possible and is further described in 
Section 3.10. All available follow-up options (including modified follow-up as described in 
section 3.9.3.2) should be discussed with the patient, and the patient’s refusal of all follow-up 
options should be documented. Patients who agree to any form of follow-up or contact with 
the site (for example, one phone call during the study closeout period), have not withdrawn 
consent. At the end of the study, vital status on all such patients will be collected from 
publicly available sources, in accordance with local regulations.
3.9.3.4 
Restart of study medication
Whenever possible, restart of randomized study medication should be encouraged. However,
if a patient has permanently discontinued study drug and a PTDV has been performed, study 
drug should not be restarted.
If patient has been treated with erythropoietin analogue as rescue, see Section 7.7.4 for 
guidance on when study drug treatment can be restarted. 
3.9.3.5 
End of study procedures
If a patient is unable to attend the EOS visit in person, telephone contact for CSE events, 
hospitalization, SAEs and vital status, should be made to ascertain endpoint and AE 
information. 
3.10
Criteria for withdrawal 
Patients are at any time free to withdraw from the study (i.e., discontinue study medication 
permanently and withdraw from visit assessments), without prejudice to further treatment 
(withdrawal of consent). Withdrawal of consent from the study must be ascertained and 
documented by the investigator and recorded in the eCRF as well as in the withdrawal 
addendum to the informed consent form (ICF). The withdrawal addendum to ICF should be 
signed and dated by both the patient and the investigator, if possible. Such patients will always 
be asked about the reason(s) and the presence of any AEs. The reason for permanent 
discontinuation of treatment with the study medication and the date of the last intake of the 
study medication must be documented in the eCRF. 
To ensure validity of study data, it is very important to collect as much data as possible 
throughout the study and especially vital status (dead or alive) at the EOS. The investigator or 
delegate will therefore attempt to collect information on all patients’ vital status from publicly 
available sources at the EOS visit, in accordance with local regulations, even if Informed 
Consent has been withdrawn completely.


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3.10.1
Screen failures 
Screening failures are patients who do not fulfil the eligibility criteria for the study, and 
therefore must not be randomized. These patients should have the reason for study withdrawal 
recorded as ‘Incorrect Enrolment’ (i.e., patient does not meet the required inclusion/exclusion 
criteria). This reason for study withdrawal is only valid for screen failures (not randomized
patients).
3.10.2
Withdrawal of Informed Consent
Patients are free to withdraw from the study at any time (investigational product and 
assessments), without prejudice to further treatment.
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AEs. The Investigator will follow up AEs outside of the clinical study. 
If a patient withdraws from participation in the study, then his/her enrolment/randomization 
code cannot be reused. Withdrawn patients will not be replaced. Patients who agree to 
continued study participation following investigational product discontinuation, 
including modified follow-up such as telephone calls or medical record review, have not 
withdrawn consent.
3.11
Discontinuation of the study
A study end date will be defined based on when the planned number of events are estimated to 
be accrued.
The study may be stopped earlier if, in the judgment of AstraZeneca, the patients are placed at 
undue risk because of clinically significant findings or for other reasons.
Regardless of the reason for study termination, all data available for the patient at the time of 
discontinuation and follow-up must be recorded in the eCRF. All reasons for discontinuation 
of treatment must be documented.
If terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests.
The independent DSMB will monitor the study to ensure patient safety.
4.
STUDY PLAN AND TIMING OF PROCEDURES 
During study visits, all assessments including laboratory tests and physical examinations 
should be completed prior to initiation of the hemodialysis (HD) procedure in patients 
receiving HD. The EQ-5D-5L quality of life assessments should be completed prior to any 
intervention (e.g., start of dialysis in HD patients) and at approximately the same time of the 
day. Blood samples for Hb measurement and safety laboratory tests will be obtained 
according to Study Plan, Table 1.


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Table 1
Study Plan
Screeninga
Treatment (-4d to +2d)
EOT 
(-4d 
to 
+2d)
EOS 
(4wks 
after 
EOT+4d)
Up to 6 wks
Rand 
(wk 
0)
wk 
1 
Wk
2
4
6
8
10 12 14 16 18 20 24 28 32 36 40 44 48 52 56 60 every 4 
wks
Visito
1
2
3
4
5
7
9
11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 etc
Written informed 
consent
X
Eligibility criteria
X
X
X
Demographics and 
medical history
X
Physical 
examination
Xb
X
Xb
Xb
X
Heightc, weightd
X
X
X
X
X
X
every 24
wkst
X
12-lead ECG
X
X
X
X
Blood pressure, 
Heart rate
Xe
X
Xe,q
X
X
Xe
X
X
Xe
X
X
X
X
X
X
Xe
X
X
X, 
every
24 wks 
Xe,t
Xe
Renal ultrasound 
if none performed 
within 12 weeks 
prior to 
randomization
X
Serum hCG 
pregnancy testf
X
X
X
X
X
X
X
X
X
every
8 wks
X


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Table 1
Study Plan
Screeninga
Treatment (-4d to +2d)
EOT 
(-4d 
to 
+2d)
EOS 
(4wks 
after 
EOT+4d)
Up to 6 wks
Rand 
(wk 
0)
wk 
1 
Wk
2
4
6
8
10 12 14 16 18 20 24 28 32 36 40 44 48 52 56 60 every 4 
wks
Visito
1
2
3
4
5
7
9
11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 etc
Serology (HIV, 
Hepatitis B and 
C), Vitamin B12, 
folate
X
Hemocue 
assessmentg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hemoglobin 
(Central lab)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete blood 
count (CBC)h
X
X
X
X
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Iron, Ferritin, 
TIBC, TSAT
X
X
X
X
X
X
X
X
Lipids (non 
fasting)
X
X
X
Intact parathyroid 
hormone (PTH)
X
X
X
every
24wkst
Population PK 
samplingp
Xi
X
Pharmacogenetic 
sampling 
(optional)
X


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Study Code D5740C00002
Version 8.0
Date 19 September 2018
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Table 1
Study Plan
Screeninga
Treatment (-4d to +2d)
EOT 
(-4d 
to 
+2d)
EOS 
(4wks 
after 
EOT+4d)
Up to 6 wks
Rand 
(wk 
0)
wk 
1 
Wk
2
4
6
8
10 12 14 16 18 20 24 28 32 36 40 44 48 52 56 60 every 4 
wks
Visito
1
2
3
4
5
7
9
11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 etc
Biomarker 
sampling(optional)
hsCRP, hepcidin
Xj
X
  EQ-5D-5Lk
X
X
X
X
every 
24 wkst
SAE recording
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE recording
Xl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
V
X
X
X
X
Concomitant 
medication 
recording
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dose adjustment 
reviewm
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Confirm study 
drug being taken 
correctly
X
Study drug 
dispensingn
Xr
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Rand. = Randomization; EOT = End of Treatment; EOS= End of Study; Wk = Week 
a
Additional screening visit(s) may be conducted as needed (see Section 4.1.2)
b
Targeted physical examination only.
c
Height measured only at screening visit 1.
d
Dry weight; the dry weight measured after the patient’s most recent dialysis can be recorded.
e
BP should be measured prior to the hemodialysis procedure. HR and BP should be measured in triplicate after being comfortably at rest in a seated 
position quietly for at least 5 min 


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f
Collect from female patients of childbearing potential only. 
g 
For Hemocue Hb , use blood sample from lavender top tube collected for central laboratory Hb or CBC, not fingerstick
h
Hemoglobin is included in the CBC testing panel.
i
Only at week 4: patients should NOT take their morning dose on the day of PK collection. The medication should be taken after the sampling. Sample 
should be taken predose.
j
Collect pre-dose. 
k
After suspected CSE event (MI, stroke, unstable angina, heart failure, DVT, PE, hypertensive emergency or vascular access thrombosis), collect EQ-5D-
5L at next regularly scheduled visit.
l
Baseline dialysis related signs and symptoms will be recorded at randomization and AEs will be recorded starting from the first dose administration
m
Dose adjustment review every 4 weeks. Hemocue values measured from venous blood samples, collected in lavender tube, will be used for all dose 
adjustments with baseline value from Hemocue values at randomization. In the event of excessive erythropoiesis dose can be adjusted at any time see 
Section 7.2.3.4.
n
Dispensation every second week from Day 1 to week 20, every 4 weeks thereafter. In the event of excessive erythropoiesis dose can be adjusted at any 
time see Section 7.2.3.4.
o
Please be attentive to visit # which are not consecutive due to removal of some visits from Study plan
p
PK sampling is done only for patients assigned to the roxadustat treatment arm.
q
Refer to exclusion criterion 1: if ANY of the 3 measurements is exclusionary before dialysis on the day of randomization, then a BP measurement 
should be done after dialysis to confirm eligibility.
r
Receipt of the first dose of study drug defines Study Day 1.
s
Randomization may occur up to 2 weeks after the screening period ends, in order to allow for synchronization with the patient`s existing dosing schedule
t
Every 24 weeks should be calculated from week 48 for Intact parathyroid hormone (PTH) and from week 52 for Weight, Blood pressure/Heart rate and 
EQ-5D-5L.


4.1
Enrolment/screening period
During the screening period, consenting patients are assessed to ensure that they meet eligibility 
criteria. Patients who do not meet these criteria must not be randomized in the study. Patients 
must provide written Informed Consent before any screening tests or assessments are performed. 
Patients in screening currently treated with erythropoietin analogue will continue their existing 
erythropoietin analogue therapy during the enrolment/screening period.
4.1.1
Screening Visits
Procedures will be performed according to the Study Plan, Table 1.
The screening period will consist of a minimum of two visits to be performed at least 7 days 
apart. All screening procedures should be completed within 6 weeks. The site must ensure that 
roxadustat and epoetin alfa are available at study site before the randomization visit is scheduled. 
The Hb inclusion criteria will be based on central laboratory assessments and may be repeated 
during the screening period. Eligible patients should have two central laboratory Hb values 7 
days apart (during the screening period). <12. g/dL in patients currently treated with an 
erythropoietin analogue or <10.0 g/dL in patients not currently treated with an erythropoietin 
analogue.
4.1.2
Additional screening assessments
If a patient’s laboratory results do not meet the eligibility criteria or the patient is considered to 
have uncontrolled hypertension, the laboratory assessment may be repeated within the screening 
period. The visits must be at least 7 days apart. 
For example, an additional central laboratory Hb may be collected, if necessary, at least 7 days 
after the second screening visit if the screening visit 1 or visit 2 Hb level is ≥12 g/dL in patients 
currently treated with an erythropoietin analogue. Similarly an additional central laboratory Hb 
may be collected, if necessary, at least 7 days after the second screening visit if the screening 
visit 1 or visit 2 Hb level is ≥10 in patients not treated with epoetin alpha or other erythropoietin 
analogue for at least 4 weeks prior to visit 1.
Iron, vitamin B12 and folate laboratory tests may be repeated during the screening period after 
supplementation, if necessary. The liver function test (LFT) parameters may not be repeated if 
found exclusionary at screening without a prior approval from the AstraZeneca study physician 
unless the Investigator has a valid reason to believe that the original lab result is due to an error 
(e.g. possible sample mix-up). Such repeat should be communicated to the AstraZeneca study 
physician as soon as possible. 
Instructions will be provided for collection and recording of baseline dialysis symptoms.
A screen-fail patient may be re-screened if deemed appropriate by the investigator. Where 
possible, an approval should be obtained from the AstraZeneca study physician prior to re-
screening. Two rescreening periods are allowed.


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For all screen failures, the reason(s) will be documented.
4.2
Treatment period
Procedures will be performed according to the Study Plan in Table 1.
The treatment period begins on the first day of dosing with study treatment (Day 1, week 0). Day 
1 is preferably a scheduled treatment date according to the existing erythropoietin analogue 
treatment regimen.
The first day of dosing should not occur less than 2 days from the last dose of epoetin alfa or 
epoetin beta, less than 7 days since the last dose of darbepoetin alfa or less than 14 days since the 
last dose of Mircera®. All Day 1 study assessments are to be performed prior to first study drug 
administration; in hemodialysis patients, study assessments should also be performed prior to or 
at initiation of the dialysis procedure for patients treated with epoetin alfa prior to randomization. 
During the treatment period, the patient will be contacted by telephone at week 1. Patient will 
attend study visits every 2 weeks from randomization to week 20 and every 4 weeks thereafter 
until study closure is declared. The patient’s next scheduled visit will then be the EOT visit, 
marking the end of the treatment period. At the EOT visit, the physicians caring for the patient 
will decide upon treatment the patient should receive as part of his/her ongoing clinical care.
The study is event-driven and will be closed when the target number of CV events has been 
accrued. Treatment duration is estimated to be up to 4 years. 
In case of premature discontinuation of study medication, see Section 3.9.
4.3
Follow-up period
Procedures will be performed according to the Study Plan, Table 1.
After the treatment period (ending with the EOT visit), patients will proceed to the 4-week post-
treatment follow-up period (ending with the EOS visit).
5.
STUDY ASSESSMENTS
The Rave Web Based Data Capture (WBDC) system will be used for data collection and query 
handling. The investigator will ensure that data are recorded in the electronic Case Report Forms 
(eCRF) as specified in the study protocol and in accordance with the instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and of 
the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRFs. A copy of the completed eCRF will be archived at 
the study centre.


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5.1
Efficacy assessments
5.1.1
Efficacy assessments
5.1.1.1
Hemoglobin level
Assessment of the efficacy of study treatments will be based on Hb assessed by central 
laboratory. Dose adjustments will be based on Hb assessed by Hemocue using the blood sample 
from lavender top tube collected for central laboratory Hb or CBC, not by fingerstick. For 
timings of the Hb assessments, see Table 1.
5.1.1.2
Use of rescue therapy
Use of rescue medication (erythropoietin analogue use in the roxadustat group only or RBC 
transfusion) will be identified using standard questioning of the patient at each visit or by 
information that the investigator may receive as part of standard medical practice. The use will 
be recorded in the appropriate section in the eCRF. For further information see Section 7.7.4.
5.2
Safety assessments
Safety will be assessed throughout the study. A complete baseline profile of each patient will be 
established through demographics, medical history, clinical laboratory values, vital signs, 
physical assessments, and electrocardiograms (ECGs). During the course of the study, vital 
signs, complete and targeted physical assessments, laboratory tests, and ECGs will be performed 
at regular intervals. 
Adverse events (AE), serious adverse events (SAEs) and ongoing concomitant medication usage 
will be monitored and recorded throughout the study. SAE reports will be evaluated individually 
to assess for the impact of the event, if any, on the overall safety of the product and on the study 
itself. Cumulative AEs will be monitored throughout the study. SAEs and AEs will be followed 
until resolved, stable, or until the patient’s EOS visit. See Section 6 for details on AE and SAE 
reporting.
Safety will be assessed through:

Adverse events

Laboratory parameters 

Vital signs (blood pressure, heart rate, ECG)

Adjudicated cardiovascular, cerebrovascular and thrombotic/thromboembolic events
5.2.1
Cardiovascular events
MACE+ events (death, non-fatal MI, non-fatal stroke, heart failure requiring hospitalization and 
unstable angina leading to hospitalization) should be reported as SAEs in the eCRF and will be 
adjudicated. Deep vein thrombosis, pulmonary embolism, vascular access thrombosis and 
hypertensive emergencies will also be reported and adjudicated. SAEs will be screened against a 
pre-specified list of MedDRA preferred terms to identify potential MACE+ events plus the rest 


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of the CV events listed above. When a potential CV event is identified, the Principal Investigator 
will be contacted to collect supporting medical records; once the clinical endpoint packet is 
compiled, blinded adjudication of candidate CV events will be conducted by the Independent 
Endpoint Review Committee (IERC) as described in the IERC charter. 
Independent Event Review Committee Charter (IERC) contains complete information regarding 
the cardiovascular events and criteria for adjudication.
5.2.2
Laboratory assessments
Blood samples for determination of clinical chemistry, hematology, lipid panel, serology, 
vitamin B12, folate and serum iron profile will be taken at the times indicated in Table 1 and 
analyzed by Covance Central Laboratory Services. 
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.
The following laboratory variables will be measured (blood, serum or plasma will be specified in
the laboratory manual):
Table 2
Laboratory Safety Variables
Hematology/Hemostasis
Clinical Chemistry
Hemoglobin (Hb)
Creatinine
Hematocrit
Creatinine kinase
Leukocyte count
Bilirubin, total
Leukocyte differential count (absolute count)
Alkaline phosphatase (ALP)
Platelet count
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Serology
Gamma-glutamyl transferase (GGT)
Hepatitis B surface antigen
Albumin
Hepatitis C antibody
Potassium
Human immunodeficiency virus (HIV)
Calcium, total
Sodium
Additional Laboratory Analyses
Chloride
Vitamin B12
Magnesium
Folate
Bicarbonate
Intact Parathyroid hormone (iPTH)
Phosphorus
hsCRP*, hepcidin*
Glucose
Lipid Panel
Uric Acid


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Total cholesterol
Total protein
HDL
Lactate dehydrogenase
Triglycerides
Blood urea nitrogen
Calculated low-density lipoprotein (LDL)
Serum hCG pregnancy test
Iron Profile
Iron
Ferritin
Total iron binding capacity (TIBC)
Transferrin saturation (TSAT)
* = will be analysed from specimens obtained in subjects who consent to biobanking blood 
samples
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be signed and dated and retained at centre 
as source data for laboratory variables. For information on how AEs based on laboratory tests 
should be recorded and reported, see Section 6.3.
Note: In case a patient shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN please refer 
to Appendix D ‘Actions required in cases of combined increase of Aminotransferase and Total 
Bilirubin - Hy’s Law’, for further instructions.
Additional laboratory assessments performed for purposes other than general safety evaluation 
are also listed in Table 2
5.2.3
Physical examination
A comprehensive physical examination will be conducted according to the Study Plan, Table 1,
and recorded in the source documents. This examination will include general appearance and the 
following body regions and systems: General appearance, skin, head and neck, lymph nodes, 
thyroid, musculoskeletal/extremities, cardiovascular, respiratory, abdomen, neurological and any 
other, if deemed necessary.
Height is measured only at screening. Weight is recorded at screening, randomization visit, and 
then at specific time points as described in the Study Plan, Table 1. A targeted physical 
examination (general appearance, cardiovascular, respiratory and abdomen) will be conducted 
throughout the study as described in the Study Plan, Table 1.
Any clinically relevant adverse change will be recorded as an AE in the eCRF (see 
Section 6.3.6).


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5.2.4
ECG
5.2.4.1
Resting 12-lead ECG
Standard 12-lead ECGs will be performed on all patients at specific time points as described in 
the Study Plan, Table 1, as to local routines. A single ECG will be taken after the patient has 
been resting in the supine position for 5 minutes. Any abnormalities must be evaluated in clinical 
context (based on patient’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, heart rate (HR), RR Interval, PR Interval, QRS Interval, QT Interval, 
overall interpretation and relevant comments will be recorded in the eCRF. ECG recordings will 
be kept as source documents.
5.2.5
Vital signs
The vital signs, blood pressure and heart rate, will be assessed at the visits as described in the 
Study Plan, Table 1 and recorded in the eCRF.
5.2.5.1
Heart rate and blood pressure
At most visits, HR and BP will be measured according to usual clinical practice and recorded.
On specific visits indicated in Table 1, HR and BP will be measured in triplicate after the patient 
has been comfortably at rest in a seated position for at least 5 min. The position of the patient 
should be comfortable with the arm where the blood pressure is recorded to be within the level of 
heart (the middle of the cuff on the upper arm is at the level of the right atrium (the midpoint of 
the sternum). The patient will be instructed to relax as much as possible and to not talk during 
the measurement procedure. Preferably measurement will be done with an electronic automated 
oscillometric device. The same device should preferably be used for the patient during the course 
of the study and in the same arm. Blood pressure will be measured in triplicate with at least one-
minute intervals between measurements. In HD patients BP and HR will be assessed prior to 
initiation of the dialysis procedures. In peritoneal dialysis (PD) patients BP and HR will be 
assessed when they come to the clinic. All the three readings will be reported in the eCRF. 
The heart rate will be assessed by pulse palpation of radial artery for 30 s immediately after each 
recording of the blood pressure. It could be also performed with an oscillometric device if this is 
used for blood pressure measurement. The triplicate heart rate assessments will recorded in the 
eCRF.
Blood pressure measurements are to be obtained prior to initiation of each dialysis procedure.
5.3
Other assessments
5.3.1
Patient reported outcomes
All study patients will be asked to complete the Euro Quality of life (QoL) Health Utility Index 
questionnaire at time points indicated in the Study Plan, Table 1. The questionnaires should be 
completed by the patient prior any other intervention.


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5.3.1.1
EuroQol Health Utility Index – EQ-5D-5L
The EQ-5D-5L is a self-reported questionnaire measuring 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, and 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 range from 1 for full health to 0 for being dead, but it 
can also be below 0 indicating a health state worse than being dead.
5.3.1.2
Administration of patient-reported outcome
All patient-reported outcomes (PROs) are paper-based and will be administered at baseline and 
according to Study plan, Table 1 and recorded in the eCRF.
Each center must allocate the responsibility for the administration of the questionnaire to a 
specific individual (e.g., a research nurse, study coordinator) and if possible assign a back-up 
person to cover if that individual is absent. The AstraZeneca Study Team (or delegate) will 
provide relevant training in administration of the questionnaire. The significance and relevance 
of the data need to be explained carefully to participating patients so that they are motivated to 
comply with data collection.
The instructions for completion of the PRO questionnaire are as follows:

The EQ-5D-5L must be completed prior to any other study procedures (following 
Informed Consent) and before discussion of disease progress to avoid biasing the 
patient’s responses to the questions. They must be completed in private by the patient

The patient should be given sufficient time to complete at their own speed

The patient should not receive help from relatives, friends or clinic staff to answer the 
questionnaire. However, if the patient is unable to read the questionnaire (e.g. is 
visually impaired) the questionnaire may be read out by trained clinic staff and 
responses recorded

On completion of the questionnaire it should be handed back to the person responsible 
for questionnaire who should check for completeness

Only one answer should be recorded for each question
5.3.2
Hospitalizations 
Details on hospitalizations (including emergency room/skilled nursing facility use) will be 
collected at each study visit. Reason, admission, discharge dates and type and reason for 
hospitalization will be recorded in the eCRF. Details on hospitalizations will also be collected at 


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follow-up visits in patients who prematurely discontinued treatment (only if they have taken at 
least one dose of study drug), until the projected date of the EOS visit.
5.4
Pharmacokinetics
5.4.1
Collection of samples
Venous blood samples (4 mL) for determination of roxadustat concentration in plasma will be 
collected at week 4 and week 8, only for patients taking roxadustat. Patients will be instructed 
NOT to take the study medication on the day of week 4 visit (not necessary for week 8). If a 
dose of the study medication is scheduled for that day, the dose can be given AFTER the 
collection of the blood sample. For both visits the date and time of sample collection will be 
recorded as well as the last dosing date and time of study medication. 
Samples will be collected into appropriately labelled tubes containing sodium-heparin as 
anticoagulant. Immediately after collection, blood samples will be kept on melting ice until ready 
for centrifugation, which must be done within 30 minutes of collection. Blood samples will be 
centrifuged at 1500 g for 10 minutes at room temperature in order to obtain plasma. Plasma will 
be harvested and transferred into an appropriately labelled amber polypropylene storage tube and 
stored at -20°C or below, within 30 minutes of centrifugation. Samples will be stored frozen at 
the site until shipment. Samples will be sent to the central laboratory packed with sufficient dry 
ice to keep the samples frozen. All applicable shipping regulations will be followed. Further 
details will be provided in the laboratory manual.
5.4.2
Determination of drug concentration
For the patients receiving roxadustat, samples for pharmacokinetic (PK) determination will be 
analysed by Covance on behalf of Clinical Bioanalysis Alliance, AstraZeneca R&D, using 
validated bioanalytical methods. Full details of the analytical methods used will be described in a 
separate bioanalytical report.
The plasma concentration data will be listed, summarized on the basis of time intervals and 
plotted in scattering with time relative to the immediate preceding roxadustat dosing time. A 
population PK analysis of data collected in the CKD dialysis program will be performed using 
the non-linear mixed-effects modelling technique as outlined in a population PK analysis plan.
5.4.3
Storage and destruction of pharmacokinetic samples
PK samples will be disposed of after the Bioanalytical Report finalization or six months after 
issuance of the draft Bioanalytical Report (whichever is earlier), unless requested for future 
analyses.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis of 
the test samples. The results from the evaluation will not be reported in the Clinical Study Report 
but separately in a Bioanalytical Report.


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5.5
Pharmacodynamics
5.5.1
Collection of samples
For collection and assessment of the pharmacodynamics with respect to Hb, see Table 1 and 
Section 5.1.
5.5.2
Storage, re-use and destruction of pharmacodynamic samples
Pharmacodynamic samples will be disposed of during the study. 
5.6
Pharmacogenetics
Pharmacogenetic samples 
 
will be collected at baseline, i.e., at (week 0) randomization visit.
5.6.1
Collection of pharmacogenetic samples
The patient’s consent to participate in the pharmacogenetic research components of the study is 
mandatory. Patients may participate in the study without participating in genetic sampling. 
The blood sample for genetic research will be obtained from the patients at (week 0) 
randomization visit.  Although genotype is a stable parameter, early sample collection is 
preferred to avoid introducing bias through excluding patients who may withdraw due to an AE, 
such patients would be important to include in any genetic analysis. If for any reason the sample 
is not drawn at the randomization visit it may be taken at any visit until the last study visit, 
before starting the closure period. Only one sample should be collected per patient for genetics 
during the study. 
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual.
5.6.2
Storage, re-use and destruction of pharmacogenetic samples
 
 
 The 
results of any further analyses will be reported either in the Clinical Study Report itself or as an 
addendum or separately in a scientific report or publication.
 
 
  
 
 
CCI
CCI
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5.7
Biomarker analysis 
The patient’s consent to the use of donated biological samples is mandatory. Patients may 
participate in the study without participating in biomarker sampling.  
Blood samples will be collected at baseline, i.e., at (week0, pre-dose) randomization visit and at 
week 24 (at any time), and may be analysed for exploratory biomarkers to assess correlations 
with disease activity, effects of study drug and clinical outcomes (including CV risk).
5.7.1
Storage, use, re-use and destruction of biological samples
Biological samples will be used for analyses of hsCRP and hepcidin. Samples for future research 
will be retained at AstraZeneca or its designee for a maximum of 15 years from the date of the 
Last Patient’s Last Visit, after which they will be destroyed.  The results of this biomarker 
research will be reported either in the Clinical Study Report itself or as an addendum, or 
separately in a scientific report or publication. The results of this biomarker research may be 
pooled with biomarker data from other studies with the study drug to generate hypotheses to be 
tested in future research.
5.7.2
Labelling and shipment of biological samples
The Principal Investigator ensures that samples are labelled and shipped in accordance with the 
Laboratory Manual and the Biological Substance, Category B Regulations (materials containing 
or suspected to contain infectious substances that do not meet Category A criteria), see Appendix 
C ‘IATA 6.2 Guidance Document’.
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the patient unless agreed with AstraZeneca and appropriate labelling, 
shipment and containment provisions are approved.
5.7.3
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle. The Principal 
Investigator at each centre keeps full traceability of collected biological samples from the 
patients while in storage at the centre until shipment or disposal (where appropriate) and keeps 
documentation of receipt of arrival.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
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AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers.
Samples retained for further use are registered in the AstraZeneca Biobank during the entire life 
cycle.
5.7.4
Withdrawal of Informed Consent for donated biological samples 
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed and the action documented. If samples are already analysed, AstraZeneca 
is not obliged to destroy the results of this research.
As collection of the biological samples is an optional part of the study, then the patient may 
continue in the study.
The Principal Investigator:

Ensures patients’ withdrawal of Informed Consent to the use of donated samples is 
notified immediately to AstraZeneca

Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed and the action documented

Ensures the laboratory (ies) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action 
documented and the signed document returned to the study site

Ensures that the patient and AstraZeneca are informed about the sample disposal
AstraZeneca ensures the central laboratory (ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
6.1
Definition of adverse events
An adverse event is the development of an undesirable medical condition or the deterioration of 
a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition can 
be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal 
results of an investigation (e.g., laboratory findings, electrocardiogram). In clinical studies, an 
AE can include an undesirable medical condition occurring at any time, including run-in or 
washout periods, even if no study treatment has been administered.


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The term AE is used to include both serious and non-serious AEs.
6.2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (i.e., screening, treatment and 
follow-up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalisation or prolongation of existing hospitalisation 

Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the subject or may require medical 
intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix B to the Clinical Study Protocol.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
Serious Adverse Events (SAEs) will be collected from the time of signature of Informed Consent 
throughout the treatment period and including the follow-up period.
Adverse Events (AEs) will be collected from randomization (after first dose of investigational 
product) throughout the treatment period and including the follow-up period.
6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at the follow up visit in the study are followed up by 
the Investigator for as long as medically indicated, but without further recording in 
the eCRF. AstraZeneca retains the right to request additional information for any 
patient with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
6.3.3
Variables 
The following variables will be collect for each AE;

AE (verbatim)

The date when the AE started and stopped

Intensity or changes in intensity.


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
The investigator should use the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0. For terms not 
specified as part of NCI-CTCAE, the following guidelines should be used to determine 
grade: 

Grade 1, Mild: Asymptomatic or mild symptoms that the patient finds easily 
tolerated. The event is of little concern to the patient and/or of little-or-no clinical 
significance; clinical or diagnostic observations only; intervention not indicated

Grade 2, Moderate: The patient has enough discomfort to cause interference with or 
change in some of their age-appropriate instrumental activities of daily living (e.g. 
preparing meals, shopping for groceries or clothes, using the telephone, managing 
money); local or non-invasive intervention indicated

Grade 3, Severe: The patient is incapacitated and unable to work or participate in 
many or all usual activities. The event is of definite concern to the patient and/or poses 
substantial risk to the patient’s health or well-being; Likely to require medical 
intervention and/or close follow-up, including but not limited to hospitalization or 
prolongation of hospitalization

Grade 4, Life-threatening: The patient was at immediate risk of death from the event 
as it occurred

Grade 5, Death: Related to AE
Grade 4 & 5 are SAE criteria and are collected as SAE in the AE eCRF module. The following 
variables will be collected:

Whether the AE is serious or not

Investigator causality rating against the Investigational Product (yes or no)

Action taken with regard to investigational product

AE caused patient’s withdrawal from study (yes or no)

Outcome
In addition, the following variables will be collected for SAEs:


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
Date AE met criteria for serious AE

Date Investigator became aware of serious AE

AE is serious due to

Date of hospitalization

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to Study procedure(s)

Description of AE
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Section 6.2. An AE of severe intensity need not 
necessarily be considered serious. For example, nausea that persists for several hours may be 
considered severe nausea, but not a SAE unless it meets the criteria shown in Section 6.2. On the 
other hand, a stroke that results in only a limited degree of disability may be considered a mild 
stroke but would be a SAE when it satisfies the criteria shown in Section 6.2.
6.3.4
Causality collection
The Investigator will assess causal relationship between Investigational Product and each 
Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’
For SAEs causal relationship will also be assessed for other medication, study procedures and 
additional study drug. Note that for SAEs that could be associated with any study procedure the 
causal relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix D to the Clinical 
Study Protocol.
6.3.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient, care provider or reported in response to the open 
question from the study personnel: ‘Have you had any health problems since the previous 
Visit/you were last asked?’ or revealed by observation will be collected and recorded in the 
eCRF. When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms. However, if a diagnosis is known and there are other 
signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately.


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6.3.6
Adverse events based on examinations and tests
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
clinical study report. Deterioration as compared to baseline in protocol-mandated laboratory 
values, vital signs should therefore only be reported as AEs if they fulfil any of the SAE criteria 
or are the reason for discontinuation of treatment with the investigational product.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign will 
be considered as additional information. Wherever possible the reporting Investigator uses the 
clinical, rather than the laboratory term (e.g. anemia versus low hemoglobin value). In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the baseline assessment will be reported as an AE.
6.3.7
Liver enzymes
If a patient meets any of the following criteria, please refer to Appendix D for further instruction: 
AST≥3x ULN, ALT≥3x ULN, total bilirubin ≥2x ULN.
6.3.8
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to the 
disease for which the investigational product is being studied. It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. Worsening 
of CKD should be considered a disease progression and not an AE and events, which are 
unequivocally due to disease progression, should not be reported as an AE during the study.
6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform the 
appropriate AstraZeneca representatives within one day i.e., immediately but no later than 24 
hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided within 1 calendar day of initial receipt for fatal and life 
threatening events and within 5 calendar days of initial receipt for all other SAEs.
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately. Investigators or other site personnel inform 


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AstraZeneca representatives of any follow-up information on a previously reported SAE within 
one calendar day i.e., immediately but no later than 24 hours of when he or she becomes aware 
of it.
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, an 
automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site personnel reports a 
SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site personnel how to proceed.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug.
6.5
Overdose
The maximum tolerated dose of roxadustat has not been established in humans. For the purposes 
of this study, exceeding the maximum allowed dose specified in this CSP (3.0 mg/kg or 400 mg 
per administration, whichever is lower) represents an overdose.
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the relevant AE 
modules in the eCRF and on the Overdose eCRF module.
An overdose without associated symptoms is only reported on the Overdose eCRF module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives immediately, 
or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is provided to AstraZeneca.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4. For 
other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca or its 
representative on the pregnancy form.
6.6.1
Maternal exposure
If a patient becomes pregnant during the course of the study investigational product should be 
discontinued immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
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medication. Congenital abnormalities/birth defects and spontaneous miscarriages should be 
reported and handled as SAEs. Elective abortions without complications should not be handled 
as AEs. The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth or congenital abnormality) should be followed up and documented even 
if the patient was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1day i.e., immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is provided within 1 or 5 calendar days for SAEs (see Section 6.4) and within 
30 days for all other pregnancies.
The same timelines apply when outcome information is available.
6.6.2
Paternal exposure 
Pregnancy of the patient’s partners is not considered to be an adverse event. However, the 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should if possible be followed up and documented as 
described in Section 6.6.1. To capture information about a pregnancy from the partner of a male 
patient, the male patient’s partner consent must be obtained to collect information related to the 
pregnancy and outcome; the male patient should not be asked to provide this information.
6.7
Management of IP related toxicities 
Observed adverse effects demonstrated in nonclinical safety studies (refer to Section 4 of the IB) 
following administration of roxadustat are primarily caused by an exaggerated pharmacological 
response, which can be managed in the clinical setting. The dose algorithm will mitigate 
excessive Hb levels. 
If there are clinical concerns for excessive elevation in Hb levels, the investigator may decide to 
perform a therapeutic phlebotomy instead of, or in addition to, a dose hold. For overdose, see 
Section 6.5.
6.8
Study governance and oversight
6.8.1
International coordinating investigator 
The International coordinating investigator in collaboration with the sponsor will be responsible 
for the overall design, interpretation, supervision, and reporting (presented at international 
congresses and published in peer reviewed journals) of the study, including the development of 
the protocol and any protocol amendments.
6.8.2
Independent Endpoint Review Committee 
An Independent Endpoint Review Committee (IERC) will be appointed and will adjudicate 
potential endpoint events. The committee members will not have access to individual treatment 


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codes for any patient or clinical efficacy and safety event. The precise responsibilities and 
procedures applicable for the IERC will be detailed in a separate IERC charter.
6.8.3
Data Safety Monitoring Board
An independent Data Safety Monitoring Board (DSMB) committee will be appointed and will 
report to the International Coordinating Investigator and sponsor. 
The DSMB will be responsible for safeguarding the interests of the patients in the outcome study 
by assessing the safety of the intervention during the study, and for reviewing the overall conduct 
of the clinical study. The DSMB will have access to the individual treatment codes and will be 
able to merge these with the collected study data while the study is ongoing.
The DSMB charter will be prepared to detail precise roles and responsibilities and procedures to 
ensure the integrity of the study in the review of accumulating data and interactions with the 
International Coordinating Investigator and sponsor.
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
Table 3
Identity of investigational product
Investigational product
Dosage form and strength
Manufacturer
Roxadustat
Oral tablets 20mg, 50mg and 100mg
FibroGen
The formulation number and batch number will be recorded in the study master file and 
identified in the clinical study report (CSR).
The only epoetin alfa to be used in the study is Procrit®, Eprex® and Epogen®, will be 
reimbursed in countries where this is possible, or otherwise centrally supplied by AstraZeneca.
7.1.1
Roxadustat
Roxadustat oral tablets will be packed in bottles and supplied by AstraZeneca. The tablet 
strengths are different in size. The tablets should remain in original packaging until 
administration. The tablets must not be chewed, crushed or divided but should be swallowed 
whole with water.
The excipients include lactose monohydrate, microcrystalline cellulose, povidone, 
croscarmellose sodium, magnesium stearate, and colorant Red Opadry II (contains Lecithin 
(Soya), FD&C Red #40 Aluminium Lake).


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7.1.2
Epoetin alfa
The only epoetin alfa to be used in the study is Procrit®, Eprex® and Epogen®.
In countries where epoetin alfa is not expected to be marketed for the duration of study, or where 
local regulations prevent reimbursement, Eprex will be centrally supplied by AstraZeneca. In 
these centrally supplied countries only, patients requiring Eprex doses >45,000 IU/week or 
15,000IU/administration should not be enrolled.
7.2
Dose and treatment regimens
7.2.1
Randomization
Eligible patients will be randomized to receive either roxadustat or epoetin alfa in a 1:1 ratio. 
Randomization schedules will be prospectively prepared. Automated randomization and 
assignment to treatment arm will be provided by IWRS/IVRS. The randomization in this study 
will be stratified by country.
The number of tablet bottles (or amount of epoetin alfa supplied by AstraZeneca) that will be 
dispensed may vary depending on the dose. Dispensation will be managed by IWRS/IVRS. The 
administration will be detailed on a dosing card. Doses administered will be recorded in the 
eCRF.
7.2.2
Dose and schedule
The first dose of study drug should be administered on Day 1 (week 0), and will mark the 
beginning of the treatment period. This should correspond to a day when the next dose of 
erythropoietin analogue would have been administered in patient currently treated with 
erythropoietin analogue. All randomization visit study procedures including laboratory blood 
draws are to be completed prior to administration of the first dose of study drug. All dose 
adjustments should be based on Hb values using Hemocue, a point-of-care device, at visits 
specified in Table 1. Hb values will be recorded in the eCRF (screening) and IWRS (during 
treatment period).
Missed dose should not be replaced.
7.2.3
Dosing of Roxadustat
Roxadustat will be dosed orally three times a week (TIW) throughout the treatment period unless 
dose reduction is required based on Hb levels. For hemodialysis patients, it is recommended that 
roxadustat is taken after completion of the hemodialysis session.
7.2.3.1
Patients treated with erythropoietin analogue at study entry 
Patients randomized to roxadustat will discontinue any prior erythropoietin analogue therapy and 
start roxadustat. The starting dose of roxadustat will be based on the current erythropoietin 
analogue dose at screening visit 1 (Table 4). If the mean hemoglobin during the screening phase 
(e.g. the average of central laboratory values at visit 1 and visit 2 or the average of the values at 
visit 2 and the retest of visit 2 value, if applicable) is less than 10 g/dL, the starting dose will be 


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increased by one dose step.  For example, a patient being treated with an average of 10,000 IU of 
epoetin alfa per week with a Hb value of 11 g/dL during the screening period would take 
roxadustat 150 mg orally, three times a week (TIW). In contrast, a patient being treated with an 
average of 10,000 IU of epoetin alfa per week who had a screening Hb of 9 g/dL during the 
screening period would take roxadustat 200 mg orally TIW.
Table 4
Initial dosing of roxadustat for patients treated with an erythropoietin 
analogue at study entry
Epoetin alfaor beta a
(IU/week)
Darbepoetin alfa a,b
(µg/week)
Mircera® c
(µg/month)
Roxadustat dose d
(mg/dose) TIW
<5,000
<25
<80
70
5,000 to ≤8,000
25-40
80-120
100
>8,000 to 16,000
40-80
120-200
150
>16,000
>80
>200
200e
a 
Current weekly dose at screening visit 1
b
If darbepoetin is used once every 2 weeks, use half dose given every 2 weeks to determine the roxadustat 
starting dose.
c 
Current monthly dose at screening visit 1.
d
Starting dose will be 1 step higher if the mean central Hb value from the last 2 screening visits is <10 g/dL.
e
If the initial dose of 200 mg exceeds the maximum dose of 3.0 mg/kg, then 150 mg should be chosen as the 
starting dose
7.2.3.2
Patients not treated with erythropoietin analogue at study entry
The initial roxadustat dose (administered TIW) is based on a tiered, weight-based dosing scheme 
(Table 5). For example, a patient that has a dry weight of 80 kg would initiate roxadustat 
treatment with 100 mg orally TIW.
Table 5
Initial dosing of roxadustat dose for patients not taking erythropoietin
analogue at study entry
Dry Weight (kg)
Roxadustat dose, mg TIW 
45-70
70
>70-160
100
7.2.3.3
Roxadustat dose adjustments
Roxadustat dose will remain constant during the first 4 weeks of the treatment period, unless a 
dose reduction is required for excessive erythropoiesis. Dose may be adjusted at week 4 and 
every 4 weeks thereafter in accordance b to achieve and maintain Hb 11±1 g/dL. Dose 
adjustment is based on Hb assessed by Hemocue.


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Table 6
Roxadustat dose adjustments
Changes in Hb 
over past 4 weeks
Hb 
<10.5g/dL
Hb 10.5 to 
11.9g/dL
Hb 12.0 to 
12.9g/dL
Hb ≥13.0g/dL
<-1.0
↑
↑
No change
Hold, then resume dosing when 
Hb≤11.9 g/dL, at a dose that is 
reduced by two dose steps
-1.0 to 1.0
↑
No change
↓
>1.0
No change
↓
↓
Dose Increases and Reductions:
Dose increases (↑) and reductions (↓) are pre-set according to dose steps.
The dose steps are as follows: 20, 40, 50, 70, 100, 150, 200, 250, 300, and 400 mg. 
Example: A dose increase at a dose of 70 mg results in 100 mg as the new dose. A dose reduction at a dose150 mg 
results in 100 mg as the new dose. 
If patients on 20 mg TIW need dose reduction, change frequency to twice a week, i.e. 20 mg administered twice a 
week. If further dose reduction is needed, reduce frequency to once weekly, i.e. 20 mg administered once a week.
Note: Maximum dose is capped at the lower of 3.0 mg/kg or 400 mg per dose administration. 
Dose Adjustment for Excessive Erythropoiesis:
  If Hb increases by >2.0 g/dL within a 4 week period, the dose should be reduced by one dose step.
7.2.3.4
Dose adjustment for excessive erythropoiesis 
Excessive erythropoiesis is defined in Table 6. In the event of excessive erythropoiesis, the dose 
may be adjusted, even on visits without a dose adjustment review. In such cases, dose adjustment 
reviews are then resumed at 4-week intervals. If a dose adjustment review is scheduled on week 
18, then the next dose adjustment review will be scheduled on week 24, since there is no 
scheduled visit on week 22.
7.2.3.5
Dose adjustments for excessive Hb ≥ 13.0g/dL
In the event of Hb value ≥13.0g/dL, dosing will immediately be put on hold. Resume dosing at a 
subsequent visit when Hb ≤11.9 g/dL, at a dose that is reduced by two dose steps. After dosing 
has been resumed, the dose adjustment reviews are then continued at 4-week intervals following 
the same principle as for excessive erythropoiesis.
7.2.4
Dosing of epoetin alfa (active control)
7.2.4.1
Patients treated with epoetin alfa or beta at study entry
All patients who are randomized to the epoetin alfa group should initially receive epoetin alfa 
TIW with the exception of patients who were treated with epoetin alfa using a less frequent 
dosing regimen (for example, twice weekly dosing) prior to study entry.  The initial dose of 
epoetin alfa will be the actual dose given at the time of screening visit 1.


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7.2.4.2
Patients treated with darbepoetin alfa or Mircera® at study entry
Patients treated with darbepoetin alfa or Mircera® who are randomized to the epoetin alfa group 
will initially receive epoetin alfa at doses based on a conversion factor as described in Table 7. 
Table 7
Initial dosing of epoetin alfa for patients treated with darbepoetin alfa or 
Mircera® at study entry
Conversion Ratio
Examples of converted initial 
epoetin alfa dose (IU/week)d
Darbepoetin alfa (μg/week) a
x 200   
40 μg/week x 200 = 8,000 IU/week
Mircera® (μg/month) b
x 70 to 80
(Lower conversion ratio can be 
used for lower Mircera® dose)c
100 μg/month x 70=7,000 IU/week
200 μg/month x 80=16,000 IU/week
a
Current weekly dose at screening visit 1
b
Current monthly dose at screening visit 1
c
Per discretion of investigator
d
May be rounded if deemed necessary
7.2.4.3
Patients not treated with erythropoietin at study entry
Patients who are not currently treated with erythropoietin analogue at study entry who are 
randomized to the epoetin alfa group will be treated with epoetin alfa with an initial dose of 
50 IU/kg TIW. Dose adjustments should not occur more frequently than every 4 weeks and be 
made in a manner consistent with local approved prescribing information for epoetin alfa. In 
countries where no local guideline is available, Handling Instruction including Summary of 
Product Characteristics will be provided as guideline for dosing by AstraZeneca.
7.3
Labelling
Labelling of roxadustat and centrally sourced epoetin alfa will be carried out by AstraZeneca or 
their designee in accordance with current Good Manufacturing Practise (GMP). The labels will 
fulfil GMPAnnex 13 requirements for labelling and local regulatory guidelines. The label text 
will be translated into local language. 
7.4
Storage
All study drugs should be kept in a secure place under appropriate storage conditions. The 
investigational product label on the bottle specifies the appropriate storage.
7.5
Compliance
The administration of all study drugs (including investigational products) should be recorded in 
the appropriate sections of the eCRF.


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7.6
Accountability
The study drug provided for this study will be used only as directed in the study protocol.
The study personnel will account for all study drugs dispensed to and returned from the patient.
Study site personnel, if applicable, or the AstraZeneca monitor will account for all study drugs 
received at the site, unused study drugs and for appropriate destruction. Certificates of delivery, 
destruction and return should be signed. Unused and/or returned investigational products should 
be destroyed at the site according to local regulations.
7.7
Concomitant and other treatments 
7.7.1
Concomitant medications
Concomitant medications are any prescription or over-the-counter preparations, including herbal 
products and “natural remedies”, used by a patient while participating in this clinical study. 
For all concomitant medications, an indication for its use should be provided. 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 patient’s clinical study records as source documentation.
7.7.1.1
Statins
When coadministered with roxadustat, hydroxymethylglutaryl coenzyme A reductase inhibitor 
(statin) exposure was increased 2- to 3-fold. For patients randomized to roxadustat, investigators 
should consider this interaction and local prescribing information when deciding on the 
appropriate statin dose for individual patients, bearing in mind the impact of ethnicity, other 
concomitant medications, renal and hepatic function. Goals of lipid lowering treatment should be 
maintained as clinically indicated. The recommended maximum daily statin doses are: 
simvastatin 20 mg, atorvastatin 40 mg, rosuvastatin 10 mg, pravastatin 40 mg, fluvastatin 40 mg 
(20 mg if eGFR<30), pitavastatin 2 mg (1 mg if eGFR<30).
7.7.1.2
Phosphate binders
When coadministered with phosphate binders, roxadustat exposure was reduced. Patients should 
be advised to discuss with the investigator before changing their phosphate binder dose or dosing 
time. To optimize absorption of roxadustat, subjects should take roxadustat with at least 1 hour 
separation from their phosphate binder.
7.7.1.3
Herbal medicine
Use of herbal medicine during the study is not prohibited but strongly discouraged. All herbal 
and natural remidies should be reviewed by the investigator and if considered safe, may be 
allowed to continue at the same dose.


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7.7.2
Prohibited medications
The following treatments/medications are prohibited during the study: 

Any other investigational drug: from randomization until EOS.

Any erythropoietin analogue during the treatment period except for study medication 
or rescue medication (see Section 7.7.4.2) 

Iron-chelating agents (e.g. deferoxamine/desferrioxamine, deferiprone, or deferaxirox 
therapy): from 4 weeks prior to screening until EOS

Androgens: from randomization onwards until EOS

Dapsone (at any dose) from randomization onwards until EOS

Chronic doses of acetaminophen/paracetamol >2.0 g/day from randomization until 
EOS
7.7.3
Supplemental iron use
Oral iron supplementation is allowed for both treatment arms without restriction. Oral iron is 
recommended for dietary supplementation to support erythropoiesis and as the first line for 
prevention and treatment of iron deficiency, unless the patient is intolerant to this route of 
treatment.
In subjects receiving roxadustat, the investigator may initiate the use of an approved IV iron 
supplement if:

A patient’s Hb level has not sufficiently responded to two or more dose increases of 
study drug, and

Ferritin <100 ng/ml or transferring saturation (TSAT) <20%
Study treatment may continue during IV iron administration. Discontinuation of IV iron 
supplementation is recommended once the patient is no longer considered to be iron deficient 
(ferritin >100 ng/mL and TSAT >20%). Use of IV iron will be recorded in the eCRF. In subjects 
receiving epoetin alfa, IV iron supplementation will be given according to standard of care. 
In addition to scheduled assessments (Table 1) iron indices may be assessed anytime (via central 
lab) to evaluate iron storage status of the patients, if considered necessary by the investigator.
7.7.4
Rescue therapy guidelines
Rescue therapy guidelines are provided to optimize the standardization of rescue therapy by 
investigators and to ensure the safety of individual study patients. Rescue therapy should be 
recorded in the eCRF. 
7.7.4.1
Red blood cell transfusion 
Red blood cell (RBC) transfusion is allowed in either roxadustat or epoetin alfa treated patients if 
rapid correction of anemia is required to stabilize the patient’s condition (e.g., acute hemorrhage) 


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or the investigator is of the opinion that the blood transfusion is a medical necessity. Study drug 
treatment may continue during or after RBC transfusion administration. Transfusion will be 
recorded in the eCRF.
7.7.4.2
Erythropoietin analogue administration in patients randomized to roxadustat
For patients randomized to roxadustat, the investigator may initiate use of an approved 
erythropoietin analogue if all of the following criteria are met:

A patient’s Hb level has not sufficiently responded to two or more dose increases or 
the maximum dose limit of the study drug has been reached, and

The patient’s Hb is <8.5 g/dL on two consecutive measurements drawn at least five 
days apart; and

Clinical judgment does not suggest iron deficiency or bleeding as a cause of lack of 
response or rapid decline in Hb (see 7.7.4.1 and 7.7.4.2 above for addressing these 
conditions), and

Reducing the risk of all immunization in transplant eligible patients and/or reduction 
of other RBC transfusion-related risks is a goal
The patient is not allowed to be administered both an erythropoietin analogue and study drug at 
the same time. Treatment with an erythropoietin analogue should be stopped when Hb >9 g/dL 
or after a 4-week cycle has been completed, whichever comes first. Study treatment should be 
resumed after the following intervals:

Two days after stopping epoetin 

One week after stopping darbepoetin alfa 

Two weeks after stopping methoxy polyethylene glycol-epoetin beta (Mircera)
If more than one cycle of erythropoietin analogue rescue is required, the investigator should 
permanently discontinue study drug. Use of erythropoietin analogues will be recorded in the 
eCRF.
Note: For patients randomized to epoetin alfa, the investigator may initiate use of a different 
erythropoietin analogue if clinically indicated. Use of the different erythropoietin analogue will 
be recorded in the eCRF and will be considered rescue therapy.
7.7.4.3
Therapeutic Phlebotomy
If there are clinical concerns for a patient due to excessive elevation in Hb levels, the investigator 
may decide to perform a therapeutic phlebotomy instead of, or in addition to, a dose hold. This 
should be documented and discussed with the study AstraZeneca study physician.


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7.7.5
Other concomitant treatment
Other medication than described above, which is considered necessary for the patient’s safety 
and well-being, may be given at the discretion of the Investigator and recorded in the appropriate 
sections in the eCRF.
7.8
Post Study Access to Study Treatment
After end of treatment with study drug, patients should be managed according to local standard 
of care.
8.
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
Analyses will be performed by AstraZeneca or its representatives. A comprehensive SAP will be 
prepared prior to database lock.  It is recognized that Regulatory Authorities might require 
different efficacy and/or safety endpoints or alternate analyses for approval. The endpoints and 
analyses described in this protocol are intended for the US (FDA) submission. Regional SAPs 
will fully describe any changes to endpoints or analyses that differ from those described in this 
protocol. 
8.2
Sample size estimate
Primary efficacy variable: With at least 600 subjects, the study will provide at least 99% power 
to demonstrate non-inferiority of roxadustat versus epoetin alfa for the primary efficacy endpoint 
(i.e., Hb change from baseline to the average level during the evaluation period defined as Week 
28 until Week 52). This assumes a difference (roxadustat minus epoetin alfa) of -0.30 g/dL, a 
non-inferiority margin for this difference of -0.75 g/dL and a standard deviation of 1.25 g/dL.
To contribute adjudicated CV events for the pooled CV analyses across the phase 3 program: 
approximately 2000 subjects will be randomized in a 1:1 ratio to either roxadustat or active 
control, i.e. epoetin alfa. The sample size for this study is driven by the overall requirement of 
adjudicated CV events for the phase 3 program in dialysis-treated CKD subjects (which consists 
of four studies in total targeting 611 subjects with MACE events). The three other studies in the 
study program are FG-4592-064, 1517-CL-0613, FG-4592-063. 
Further information related to the sample size determination can be found in the study statistical 
analysis plan and the pooled statistical analysis plan.


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8.3
Definitions of analysis sets
8.3.1
Intention to Treat Analysis Set (ITT)
All subjects who have been randomized to study treatment will be included irrespective of 
their protocol adherence and continued participation in the study. Subjects will be analysed 
according to their randomized study medication irrespective of intake of study medication.
8.3.2
Per Protocol Set (PPS)
All randomized subjects without important protocol deviations and who have received at least 
8 weeks of study treatment and have valid corresponding Hb measurements from the central 
laboratory will be included in the PPS. Subjects will be analysed according to their 
randomized study medication irrespective of intake of study medication. Subjects with an 
important protocol deviation will be included in the PPS up to the time point when the 
violation was met. For criteria for PPS exclusion, see Table 1 in the SAP. Further details of 
important protocol deviations are available in a Protocol Deviation Plan. Subjects will be 
censored at the earliest of date of an important protocol deviation, the EOS visit, or last intake 
of study drug. 
8.3.3
Safety analysis set (SAS)
All subjects who received at least one dose of randomized study drug will be included in the 
Safety Analysis Set. Throughout the safety results sections, erroneously treated subjects will 
be accounted for in the actual treatment group. If a subject has received both treatments, only 
the initial period will be utilized. On-treatment analyses will be emphasized.
8.3.4
Full Analysis Set (FAS)
The FAS consists of all subjects in the ITT analysis set who received at least one dose of 
study drug and have baseline and at least one post-dose Hb assessment. If actual study 
medication received differs from the randomized treatment arm, the randomized treatment 
arm will be used for analysis for the FAS.  This analysis set is primarily used for EX-US 
submissions
8.3.5
Subjects who will not be included in any analysis sets
Subjects or sites identified prior to Database lock (breaking of Sponsor blindness, open-label 
study) with major Good Clinical Practice violations and where the integrity of the data is 
strongly questioned through thorough independent investigations will be excluded from all 
analyses and all analysis sets. This includes but are not limited to subjects who have been 
identified to be part of a potential fraud investigation, subjects who have not signed an 
informed consent, subjects randomized in error (e.g. a subject considered to be a screen fail 
but by mistake randomized in the IWRS due to a technical error). Further, subjects being 
randomized more than once will only contribute to the analysis one time. These patients will 
be analyzed according to their first assigned randomization number and treatment code. All 
AE’s reported for the subjects will be assigned to the subject´s first randomization number. 
All subjects excluded from all analysis sets will be properly documented


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8.4
Outcome measures for analyses
8.4.1
Primary efficacy endpoint:
US FDA: The primary efficacy endpoint is the mean change from baseline in Hb averaged 
over week 28 to week 52. A multiple imputation approach with analysis of covariance 
(ANCOVA) will be applied as a method to handle missing data. Details of the ANCOVA 
multiple imputation are provided in the SAP.
Hb results obtained from the central laboratory will be used for all Hb efficacy analyses. 
Baseline Hb is defined as the mean of the three last central laboratory Hb values from the 
screening and randomization visits.
Hb values under the influence of a rescue therapy will not be censored.
EU health authorities: The primary efficacy endpoint is the mean change from baseline in 
Hb averaged over week 28 to week 36, without having received rescue therapy (i.e. RBC 
transfusion for all subjects or ESA for subjects treated with roxadustat) within 6 weeks prior 
to and during this 8-week evaluation period.
8.4.2
Hb related secondary efficacy endpoints:
The Hb related secondary efficacy endpoints are:

The EU primary endpoint is the first secondary efficacy endpoint.

Mean change in Hb from baseline to the subjects mean level between week 28 to week 
52 in subjects with baseline high-sensitivity C-reactive protein (hsCRP) greater than 
the Upper Limit Normal (ULN)

Proportion of total time of Hb ≥10 g/dL from week 28 to week 52. The proportion of 
total time will be computed as follows: For each subject, the recorded Hb values will 
first be linearly interpolated between measurements. The time this interpolated curve is 
≥10 g/dL will be computed and subsequently divided by the time between the 
measurements at week 28 and week 52. Patients without any Hb measurements from 
week 28 will not be considered for this variable.

Proportion of total time of Hb within the interval of 10-12 g/dL from week 28 to week 
52. The proportion of total time will be computed as follows: For each subject, the 
recorded Hb values will first be linearly interpolated between measurements. The time 
this interpolated curve is within 10-12 g/dL will be computed and subsequently 
divided by the time between the measurement at week 28 and week 52. Patients 
without any Hb measurements from week 28 will not be considered for this variable.
8.4.3
Lipid related secondary efficacy endpoints
To evaluate the roxadustat effect on lipids, the following variable will be evaluated


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
Mean change from baseline in LDL cholesterol to week 24.
8.4.4
IV iron related secondary efficacy variable endpoints: 
The use of IV iron will be investigated with the variable:

Average monthly IV iron use per subject during, week 36 to EOS (monthly 
defined as a period of 4 weeks). 
8.4.5
Rescue therapy related secondary efficacy endpoints:
The need for rescue therapy will be evaluated as

Time-to-first (and proportion of subjects receiving) administration of red blood 
cell (RBC) transfusion as rescue therapy (rescue therapy guidelines are 
specified in the CSP, Section 7.7.4).
8.5
Adjudicated CV Events Analyses for Safety Assessments 
The CV events described in Section 5.2.1 will be adjudicated by the Independent Event
Review Committee (IERC) according to the IERC charter. The same adjudication committee
will be used four phase 3 studies, FG-4592-064, 1517-CL-0613, FG-4592-063, and 
D5740C00002, in the CKD-DD program. Analyses of these adjudicated events are described 
in a separate pooled analysis plan.
8.6
Methods for statistical analyses
A detailed Statistical Analysis Plan (SAP) will be finalized prior to database lock. Any 
significant changes to the analyses described in this protocol will be highlighted in the SAP 
and the Clinical Study Report (CSR). Moreover, further details of the statistical analyses are 
provided in the SAP. 
8.6.1
Stratification variables
The randomization in this study will be stratified by country. The stratification variables for 
the other two studies in the program will be used in the analyses for this study as covariates,
with addition of incident vs stable dialysis. The stratification variables are:
1.
Baseline Hb (≤10.5 g/dL vs > 10.5 g/dL)
2.
cardiovascular/cerebrovascular/thromboembolic medical history (Yes vs. No)
3.
geographical region (US vs. Ex-US)
4.
incident vs. stable dialysis (dialysis duration ≤4 months vs >4 months from the 
randomization date)
Baseline Hb will be included in the analyses as a continuous covariate, hence, not as a 
dichotomous factor, unless specified otherwise. Throughout this document, the variable 


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cardiovascular/cerebrovascular/thromboembolic medical history will be shortened as CV 
history, and the variable incident vs stable dialysis will be shortened as dialysis duration
CV history at baseline will be defined for subjects with history of any of the following 
diseases:

Myocardial infarction

Percutaneous coronary intervention

Coronary artery bypass

Cardiac failure congestive

Ischaemic stroke

Haemorrhagic stroke

Cerebrovascular accident 
8.6.2
Analysis of the primary efficacy endpoint for US
Mean change in Hb from baseline to the subjects mean level from week 28 to week 52 will 
analyzed with multiple imputation ANCOVA as described in the SAP. The model will contain 
terms for the baseline Hb measurement, treatment arm, CV history, geographic region and 
dialysis duration. Non-inferiority of roxadustat compared to epoetin alfa will be declared, and 
this test as successful, if the lower bound of the 2-sided 95% confidence interval of the 
difference between roxadustat and epoetin alfa exceeds -0.75 g/dL. The ITT analysis set will 
be used.
8.6.3
Analysis of the primary efficacy endpoint for EU (Secondary Endpoint for 
FDA)
The primary efficacy endpoint for EU is Hb change from baseline (BL) to the average Hb of 
weeks 28 to 36, without having received rescue therapy (i.e. RBC transfusion for all subjects 
and ESA for roxadustat subjects) within 6 weeks prior to and during this 8-week evaluation 
period and will be analysed using MMRM. The model will contain terms for the baseline Hb 
measurement, treatment arm, visit, visit by treatment, CV history, geographic region and 
dialysis duration. Data up to visit of Week 52 will be included in the model. Non-inferiority of 
roxadustat compared to epoetin alfa will be declared, and this test as successful, if the lower 
bound of the 2-sided 95% confidence interval of the difference between roxadustat and 
epoetin alfa exceeds -0.75 g/dL. The PPS will be used for non-inferiority. In addition to the 
comparison based on the PPS population, to address the formal test for non-inferiority, results 
will also be provided based on the FAS population, to allow also for a potential superiority 
comparison. The latter test is not part of the formal testing sequence.


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8.6.4
CV safety endpoint analyses 
The CV safety evaluation strategy is to conduct pooled analyses of adjudicated data across the 
study program to ensure that the overall number of events is high enough to provide adequate 
power. Thus, all analyses of CV safety will be conducted in accordance with the PSAP.
8.6.5
Analysis of the secondary efficacy endpoints
Secondary efficacy endpoints will be tested using a fixed sequence approach to adjust for 
multiple testing. If the p-value from a test is less than 0.05, the test will be declared as 
successful and the analysis will continue to the next comparison in the sequence. Formal 
statistical hypothesis testing will be stopped as soon as a test is accompanied by a p-value 
≥0.05. The PPS will be used on the first secondary endpoint for non-inferiority, on treatment 
analysis will be used on the secondary endpoint related to RBC transfusion as rescue therapy, 
and the ITT analysis set will be used for all the remaining secondary endpoints. 
1. The EU primary endpoint for non-inferiority is the first secondary efficacy endpoint 
for FDA (see above).
2. Mean change from baseline in LDL cholesterol to week 24 will be analysed using 
ANCOVA. Baseline Hb and baseline LDL will be used as covariates and treatment 
groups, CV history, geographic region and dialysis duration as fixed effects. 
Superiority will be declared if the upper bound of the 2-sided 95% confidence interval 
of the difference between roxadustat and epoetin alfa exceeds 0. 
3. Mean change in Hb from baseline to the subjects mean level from week 28 to week 52 
in subjects with baseline hsCRP greater than the Upper Limit Normal (ULN) will be 
analysed analogously as the primary efficacy endpoint. Superiority of roxadustat 
compared to epoetin alfa will be declared, and this test as successful, if the lower 
bound of the 2-sided 95% confidence interval of the difference between roxadustat and 
epoetin alfa exceeds 0 g/dL.
4. Proportion of total time of interpolated Hb values ≥10 g/dL from week 28 until week 
52 will be estimated for each subject and used as dependent variable. The difference 
between roxadustat and epoetin alfa will be compared using ANCOVA. Baseline Hb 
will be used as a covariate and the treatment groups, CV history, geographic region 
and dialysis duration as fixed effects. Non-inferiority between the groups will be 
declared, and this test as successful, if the lower bound of the 2-sided 95% confidence 
interval of the difference between roxadustat and epoetin alfa exceeds -0.15.
5. Proportion of total time of interpolated Hb values within the interval 10-12 g/dL from 
week 28 until week 52 will be estimated for each subject and used as dependent 
variable. The difference between roxadustat and epoetin alfa will be compared using 
ANCOVA. Baseline Hb will be used as a covariate and the treatment groups, CV 
history, geographic region and dialysis duration as fixed effects. Non-inferiority 
between the groups will be declared, and this test as successful, if the lower bound of 


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the 2-sided 95% confidence interval of the difference between roxadustat and epoetin 
alfa exceeds -0.15. 
6. The average monthly IV iron use during Week 36 to EOS will be compared between 
the two treatment groups using a Wilcoxon Rank Sum test. Superiority will be 
declared if the p-value is less than 0.05.
7. Time-to-first (and proportion of subjects receiving) RBC transfusion as rescue therapy. 
The baseline Hb, geographic region, dialysis duration and CV history will be included 
as covariates.
8.6.6
Subgroup analysis
Defined in the SAP.
8.6.7
Interim analysis
No interim analysis specific to this study will be conducted. 
8.6.8
Sensitivity analysis 
As defined in the SAP.
8.6.9
Exploratory analysis 
Exploratory analyses are specified in the SAP.
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site personnel
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and the WBDC 
system utilized.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to:

Provide information and support to the Investigators


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
Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks 
are being performed

Perform source data verification (a comparison of the data in the eCRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of Informed Consent of participating patients. This 
will require direct access to all original records for each patient (e.g., clinic charts)

Ensure withdrawal of Informed Consent to the use of the patient’s biological 
samples is reported and biological samples are identified and disposed of/destroyed 
accordingly, and the action is documented, and reported to the patient
The AstraZeneca representative will be available between visits if the Investigators or other 
staff at the centre needs information and advice about the study conduct.
9.2.1
Source data
Refer to the Clinical Study Agreement for location of source data.
9.2.2
Study agreements
The Principal Investigator at each centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of patients and in all other respects, not relating to study conduct or treatment of 
patients, the terms of the Clinical Study Agreement shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled.
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the Clinical Study Agreement (CSA).
9.3
Study timetable and end of study
The end of the study is defined as ‘the last visit of the last patient undergoing the study’.
The study is expected to start in Q2 2014 and is estimated to end by Q3 2018.
The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or if recruitment is slow. AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with roxadustat.


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9.4
Data management by AstraZeneca
Data management will be performed by AstraZeneca Data Management Centre staff.
Data will be entered in the WBDC system at the study site. Trained site staff will be 
responsible for entering the data on the observation, tests and assessments specified in the 
protocol into the WBDC system and according to the eCRF instructions. Data entered in the 
WBDC system will be immediately saved to a central database and changes tracked to provide 
an audit trail. The data will then be Source Data Verified, reviewed/queried and updated as 
needed. 
The Principal Investigator is responsible for signing the eCRF and this can be delegated to a 
trained sub-investigator. 
The data will be validated as defined in the Data Management Plan. Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
When all data have been coded, validated, signed and locked, a clean file will be declared. 
Any treatment revealing data may thereafter be added and the final database will be locked. A 
copy of the eCRF will be archived at the study site when the study has been locked.
When the completed paper Case Report Forms for the PRO questionnaire has been completed 
by the Patients, the data are to be entered ongoing into the eCRF by the site staff.
Dictionary coding
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version the Medical Dictionary for Regulatory Activities (MedDRA). Medications 
will be classified according to the latest version of the AstraZeneca Drug Dictionary. 
Classification coding will be performed by the Medical Coding Team at the AstraZeneca Data 
Management Centre.
Serious Adverse Event (SAE) Reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site.
Data associated with human biological samples
Data associated with biological samples will be transferred from laboratory(ies) internal or 
external to AstraZeneca. 
Management of external data
The data collected through third party sources will be obtained and reconciled against study 
data. The AstraZeneca Data Management Centre determines the format of the data to be 
received from external vendors and coordinates the flow of data to an external environment or 
clinical database (if applicable). The AstraZeneca Data Management Centre will ensure that 


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the data collection tool (IVRS/ IWRS, etc) will be tested/validated as needed. External 
reconciliation will be done with the clinical database as applicable.
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples.
10.2
Patient data protection
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
AstraZeneca will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, general physician or any other third party, unless 
required to do so by law.
Precautions are taken to preserve confidentiality and prevent genetic data being linked to the 
identity of the subject. In exceptional circumstances, however, certain individuals might see 
both the genetic data and the personal identifiers of a subject. For example, in the case of a 
medical emergency, an AstraZeneca physician or an Investigator might know a subject’s 
identity and also have access to his or her genetic data. Also Regulatory authorities may 
require access to the relevant files, though the subject’s medical information and the genetic 
files would remain physically separate.
10.3
Ethics and regulatory review
An Ethics Committee/Institutional Review Board (IRB) should approve the final study 
protocol, including the final version of the Informed Consent Forms and any other written 
information and/or materials to be provided to the patients. The Investigator will ensure the 
distribution of these documents to the applicable Ethics Committee, and to the study site staff.
The opinion of the Ethics Committee/Institutional Review Board should be given in writing. 
The Investigator should submit the written approval to AstraZeneca before enrolment of any 
patient into the study. 
The Ethics Committee/Institutional Review Board should approve all advertising used to 
recruit patients for the study.
AstraZeneca should approve any modifications to the Informed Consent Forms that are 
needed to meet local requirements.


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If required by local regulations, the protocol should be re-approved by the Ethics Committee 
annually.
Before enrolment of any patient into the study, the national regulatory authority will approve 
the final study protocol, including the final version of the Informed Consent Forms, or a 
notification to the national regulatory authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, Ethics Committees and Principal 
Investigators with safety updates/reports according to local requirements.
Each Principal Investigator is responsible for providing the Ethics Committees/IRB with 
reports of any serious and unexpected adverse drug reactions from any other study conducted 
with the investigational product. AstraZeneca will provide this information to the Principal 
Investigator so that he/she can meet these reporting requirements.
10.4
Informed consent
The Principal Investigator(s) at each centre will:

Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study

Ensure each patient is notified that they are free to discontinue from the study at any 
time

Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided

Ensure each patient provides signed and dated Informed Consent before conducting 
any procedure specifically for the study

Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File

Ensure a copy of the signed Informed Consent Form(s) is/are given to the patient

Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the Informed Consent form that is approved by an Ethics Committee
10.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the International co-
ordinating Investigator and AstraZeneca.


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If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol).
The amendment is to be approved by the relevant Ethics Committee and if applicable, also the 
national regulatory authority approval, before implementation. Local requirements are to be 
followed for revised protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s). For distribution to Ethics Committee see 10.3.
If a protocol amendment requires a change to a centre’s Informed Consent Form, AstraZeneca 
and the centre’s Ethics Committee are to approve the revised Informed Consent Form before 
the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by each Ethics Committee.
10.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification. The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analysed, and accurately reported according to the protocol, Good Clinical 
Practice (GCP), guidelines of the International Conference on Harmonisation (ICH), and any 
applicable regulatory requirements. The Investigator will contact AstraZeneca immediately if 
contacted by a regulatory agency about an inspection at the centre.
11.
LIST OF REFERENCES
Andrews et al 2014
Andrews DA, Pyrah ITG, Boren BM, Tannehill-Gregg SH, Lightfoot-Dunn RM. High 
Hematocrit Resulting from Administration of Erythropoiesis-stimulating Agents Is Not Fully 
Predictive of Mortality or Toxicities in Preclinical Species. 
Toxicol Pathol 2014;42(3):510-23
Gandra et al 2010
Gandra SR, Finkelstein FO, Bennett AV, Lewis EF, Brazg T, Martin ML. Impact of 
erythropoiesis-stimulating agents on energy and physical function in nondialysis CKD 
patients with anemia: A systematic review. Am J Kidney Dis 2010;55(3):519-34
Hicks et al 2014
Hicks KA, Tcheng JE, Bozkurt B, Chaitman BR, Cutlip DE, Farb A et al. ACC/AHA Key 
Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials: A 
Report of the American College of Cardiology/American Heart Association Task Force on 


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Clinical Data Standards Writing Committee to Develop Cardiovascular Endpoints Data 
Standards. Circulation 2015; 131: 1-109 
Johansen et al 2010
Johansen KL, Finkelstein FO, Revicki DA, Gitlin M, Evans C, Mayne TJ. Systematic Review 
and Meta-analysis of Exercise Tolerance and Physical Functioning in Dialysis Patients 
Treated With Erythropoiesis-Stimulating Agents. Am J Kidney Dis 2010;55(3):535-48
KDIGO 2012
Kidney Disease Improving Global Outcomes (KDIGO) 2012. Clinical Practice Guideline for 
Anaemia in Chronic Kidney Disease. Kidney International Supplements 2012;2(4):279-335
Lascano et al 2010
Lascano ME, Schreiber MJ, Nurko S. Chronic Kidney Disease. Cleveland Clinic 2010. 
Available at: 
http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/nephrology/chronic-
kidney-disease/ 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0
Peyssonnaux et al 2008
Peyssonnaux CV, Nizet, Johnson RS. Role of the hypoxia inducible factors HIF in iron 
metabolism. Cell Cycle 2008;7(1):28-32
Pfeffer et al 2009
Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU et al. A trial of 
darbepoeitin alfa in type 2 diabetes and chronic kidney disease. 
N Engl J Med 2009;361(21):2019-32
Phrommintikul et al 2010
Phrommintikul A, Haas SJ, Elsik M, Krum H. Mortality and target haemoglobin 
concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a 
meta-analysis.
The Lancet 2010;369(9559):381-8
Semenza 1998
Semenza GL. Hypoxia-inducible factor 1: master regulator of O2 homeostasis. 
Curr Opin Genet Dev 1998;8(5):588-94
Singh 2010
Singh AK. The FDA’s Perspective on the Risk for Rapid Rise in Haemoglobin in Treating 
CKD Anaemia: Quo Vadis. Renal Division, Brigham and Women’s Hospital and Harvard 
Medical School, Boston, Massachusetts. Clin J Am Soc Nephrol 2010;5:553-6
Skali et al 2011


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Skali H, Parving H-H, Parfrey PS, Burdmann EA, Lewis EF, Ivanovich P et al . Stroke in 
Patients With Type 2 Diabetes Mellitus, Chronic Kidney Disease, and Anemia Treated With 
Darbepoetin Alfa. The Trial to Reduce Cardiovascular Events With Aranesp Therapy 
(TREAT) Experience. Circulation 2011;124:2903-2908
Strippoli et al 2004
Strippoli GFM, Craig JC, Manno C, Schena FP. Haemoglobin Targets for the Anemia of 
Chronic Kidney Disease: A Meta-analysis of Randomized, Controlled Trials. 
J Am Soc Nephrol 2004;15(12):3154-65
Yu et al 2013
Yu P, Chou J, Zong M, Neff T, Schaddelee M. Similar PK/PD profiles were observed 
following comparable doses of FG-4592 in haemodialysis (HD) patients. World Congress of 
Nephrology Hong Kong 31 May - 4 June 2013, Poster SU437


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Appendix B
Additional Safety Information
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation
Development of drug dependency or drug abuse


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A GUIDE TO INTERPRETING THE CAUSALITY QUESTION
When making an assessment of causality consider the following factors when deciding if there
is a ‘reasonable possibility’ that an AE may have been caused by the drug.

Time Course.  Exposure to suspect drug.  Has the subject actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug?

Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience.  Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug?

No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience.  Did the AE reoccur if the suspected drug was 
reintroduced after having been stopped? AstraZeneca would not normally 
recommend or support a re-challenge.

Laboratory tests.  A specific laboratory investigation (if performed) has confirmed 
the relationship.
In difficult cases, other factors could be considered such as:

Is this a recognized feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.


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Appendix C
International Airline Transportation Association (IATA) 6.2 
Guidance Document
Labelling and shipment of biohazard samples
International Airline Transportation Association (IATA) classifies biohazardous agents into 
3 categories (http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm).
For transport purposes the classification of infectious substances according to risk groups was 
removed from the Dangerous Goods Regulations (DGR) in the 46th edition (2005). Infectious 
substances are now classified either as Category A, Category B or Exempt. There is no direct 
relationship between Risk Groups and categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. Category A pathogens are eg, Ebola, Lassa fever virus:

are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2. They are assigned the following UN 
number and proper shipping name:

UN 3373 - Biological Substance, Category B

are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens

Clinical trial samples will fall into Category B or exempt under IATA regulations

Clinical trial samples will routinely be packed and transported at ambient 
temperature in IATA 650 compliant packaging 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm)

Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as 
applicable

Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times. The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport 
is used.


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Appendix D
Actions Required in Cases of Combined Increase of 
Aminotransferase and Total Bilirubin - Hy’s Law
1.
INTRODUCTION
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
2.
DEFINITIONS
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study 
following the start of study medication  irrespective of an increase in Alkaline Phosphatase 
(ALP). The elevations do not have to occur at the same time or within a specified time frame.
Hy’s Law (HL)
AST or ALT ≥ 3x ULN  together with TBL ≥ 2xULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  The elevations do not have to occur at the same time 
or within a specified time frame.
3.
IDENTIFICATION OF POTENTIAL HY’S LAW CASES
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3xULN

AST ≥ 3xULN

TBL ≥ 2xULN
When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative). 


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98(100)
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will:

Request a repeat of the test (new blood draw) by the central laboratory

Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:

Determine whether the patient meets PHL criteria (see Section 2 of this Appendix 
for definition) by reviewing laboratory reports from all previous visits (including 
both central and local laboratory results)
4.
FOLLOW-UP
4.1
Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:

Inform the AstraZeneca representative that the patient has not met PHL criteria.

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
4.2
Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data. Subsequent to 
this contact the Investigator will:

Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated 

Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician

Complete the three Liver CRF Modules as information becomes available 

If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures


Clinical Study Protocol Appendix D
Drug Substance Roxadustat
Study Code D5740C00002
Version 8.0
Date 19 September 2018
99(100)
5.
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW 
CASES
The instructions in this Section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP. The AstraZeneca Medical Science Director and Global Safety Physician will also be 
involved in this review together with other subject matter experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF

If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly and follow the AZ standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:

Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above

Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are met. Update the SAE report according to the 
outcome of the review
6.
REFERENCES


Clinical Study Protocol Appendix D
Drug Substance Roxadustat
Study Code D5740C00002
Version 8.0
Date 19 September 2018
100(100)
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d5740c00002-csp-v8
Document Title:
D5740C00002-Clinical Study Protocol version 8
Document ID:
Doc ID-003839910
Version Label:
1.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
19-Sep-2018 23:32 UTC
Mark Houser
Author Approval
19-Sep-2018 15:37 UTC
Lars Frison
Author Approval
19-Sep-2018 18:35 UTC
Liselotte Holmgren
Qualified Person Approval
19-Sep-2018 18:42 UTC
Maksym Pola
Author Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.

SAP_001.pdf: 
Statistical Analysis Plan
Study Code
D5740C00002
Edition Number
4.0
Date
28 September 2018
A Phase 3, Multicenter, Randomized, Open-Label, Active-Controlled Study 
of the Safety and Efficacy of Roxadustat in the Treatment of Anemia in 
Dialysis Patients


PPD


PPD


Statistical Analysis Plan 
Study Code D5740C00002
Edition Number 4.0
Date 28 September 2018
4
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................................1
SIGNATURE OF STUDY STATISTICIAN........................................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN ..................................................3
TABLE OF CONTENTS.....................................................................................................4
LIST OF ABBREVIATIONS ..............................................................................................7
SAP AMENDMENT HISTORY........................................................................................ 10
1.
STUDY DETAILS............................................................................................. 12
1.1
Study objectives................................................................................................. 12
1.1.1
Primary efficacy objective.................................................................................. 12
1.1.2
Primary safety objective..................................................................................... 12
1.1.3
Secondary efficacy objectives ............................................................................ 12
1.1.4
Secondary safety objectives ............................................................................... 13
1.2
Study design ...................................................................................................... 13
1.2.1
Dosing ............................................................................................................... 13
Roxadustat......................................................................................................................... 13
Epoetin alfa........................................................................................................................ 13
1.2.2
Scheduled visits during treatment....................................................................... 14
1.2.3
Stratification variables ....................................................................................... 14
1.3
Number of subjects ............................................................................................ 15
2.
ANALYSIS SETS ............................................................................................. 16
2.1
Definition of analysis sets .................................................................................. 16
2.1.1
Intention To Treat Analysis Set (ITT) ................................................................ 16
2.1.2
Per Protocol Set (PPS) ....................................................................................... 16
2.1.3
Safety Analysis Set ............................................................................................ 16
2.1.4
Full Analysis Set (FAS) ..................................................................................... 16
2.1.5
Subjects who will not be included in any analysis sets........................................ 16
2.2
Violations and deviations ................................................................................... 17
3.
PRIMARY AND SECONDARY VARIABLES................................................. 17
3.1
Efficacy variables............................................................................................... 17
3.1.1
Primary efficacy endpoint .................................................................................. 17
3.1.2
Hb related secondary efficacy variables.............................................................. 18
3.1.3
Lipid related secondary efficacy variables.......................................................... 18
3.1.4
Rescue therapy related secondary efficacy variables........................................... 19
3.1.5
IV iron related secondary efficacy variables....................................................... 19


Statistical Analysis Plan 
Study Code D5740C00002
Edition Number 4.0
Date 28 September 2018
5
3.1.6
Exploratory variables ......................................................................................... 19
3.1.6.1
Hb related exploratory variables......................................................................... 19
3.1.6.2
RBC transfusion related exploratory variables.................................................... 20
3.1.6.3
Quality of life related exploratory efficacy variables .......................................... 20
European Quality of Life Questionnaire in Five Dimensions, Five Levels (EQ-5D-
5L)..................................................................................................................... 20
3.1.6.4
Hospitalization related exploratory variables...................................................... 20
3.1.6.5
Other exploratory variables ................................................................................ 21
3.2
Safety assessments............................................................................................. 21
3.3
Adjudicated CV Events Analyses for Safety Assessments.................................. 22
3.4
Treatment compliance........................................................................................ 22
4.
ANALYSIS METHODS.................................................................................... 22
4.1
General principles.............................................................................................. 22
4.1.1
Censoring........................................................................................................... 23
4.1.2
Premature permanent discontinuation of study medication ................................. 24
4.1.3
Choice of the non-inferiority margins................................................................. 24
4.2
Analysis methods............................................................................................... 25
4.2.1
Demography ...................................................................................................... 25
4.2.2
Confirmatory analysis for the efficacy endpoints................................................ 25
4.2.3
Time to event analysis........................................................................................ 25
4.2.4
Difference in proportions analysis...................................................................... 26
4.2.5
Analysis of Covariance (ANCOVA) .................................................................. 26
4.2.6
Multiple imputation ANCOVA.......................................................................... 26
4.2.7
Mixed Model of Repeated Measures (MMRM).................................................. 28
4.2.8
Pattern Mixture Models...................................................................................... 28
4.2.8.1
PMM –Last Mean Carried Forward.................................................................... 28
4.2.8.2
PMM –Baseline Carried Forward (roxadustat only and both groups).................. 29
4.3
Statistical Analyses ............................................................................................ 30
4.3.1
CV safety endpoints analyses............................................................................. 30
4.3.2
Primary efficacy endpoint analysis for US.......................................................... 30
4.3.3
Primary efficacy endpoint analysis for EU (First Secondary endpoint for 
FDA) ................................................................................................................. 30
4.3.4
Secondary efficacy endpoints analyses............................................................... 30
4.3.5
Exploratory endpoint analysis ............................................................................ 31
4.3.5.1
Hb related exploratory endpoint analysis............................................................ 32
4.3.5.2
Rescue therapy related exploratory endpoint analysis......................................... 33
4.3.5.3
Quality of life related exploratory endpoint analysis........................................... 33
4.3.5.4
Hospitalization related exploratory endpoint analysis......................................... 34
4.3.5.5
Other exploratory endpoint analysis ................................................................... 34
4.3.6
Sensitivity analysis of efficacy endpoints ........................................................... 35
4.3.7
Subgroup analyses ............................................................................................. 36
4.3.8
Safety assessment analysis ................................................................................. 37


Statistical Analysis Plan 
Study Code D5740C00002
Edition Number 4.0
Date 28 September 2018
6
4.3.8.1
Adverse events................................................................................................... 37
4.3.8.2
Laboratory variables .......................................................................................... 38
4.3.8.3
Vital signs.......................................................................................................... 38
4.3.8.4
Electrocardiogram.............................................................................................. 39
4.3.8.5
Physical examination ......................................................................................... 40
4.3.9
Population PK analysis ...................................................................................... 40
5.
INTERIM ANALYSES ..................................................................................... 40
6.
CHANGES OF ANALYSIS FROM PROTOCOL ............................................. 40
6.1
Changes of analysis from previous edition of the SAP ....................................... 40
7.
REFERENCES .................................................................................................. 45
8.
APPENDIX ....................................................................................................... 46
LIST OF TABLES 
Table 1
Criteria for Assessing Important Protocol Deviations ............................17
Table 2
Criteria for Potentially Clinically Significant Vital Signs.......................39
Table 3
Criteria for Potentially Clinically Significant ECG................................39
Table 4 
Major changes of analysis from SAP Edition 3.0...................................40
LIST OF FIGURES
Figure 1
Study Flowchart....................................................................................14


Statistical Analysis Plan 
Study Code D5740C00002
Edition Number 4.0
Date 28 September 2018
7
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
AE
Adverse Event
ALT
Alanine aminotransferase
AST
Aspartate transaminase
ANCOVA
Analysis of Covariance
BIW
Twice weekly
BP
Blood pressure
CHr
Reticulocyte hemoglobin content
CKD
Chronic kidney disease
CKD-DD
Chronic kidney disease with subject on dialysis
CKD-ND
Chronic kidney disease with subject not on dialysis
CMH
Cochran-Mantel-Haenszel
CRF
Case report form
CRP
C-reactive protein
CS
Clinically significant
CSE
Composite safety endpoint 
CSP
Clinical study protocol 
CSR
Clinical study report
DSMB
Data and safety monitoring board
ECG
Electrocardiogram
ECRF
Electronic case report form
EOS
End of study
EOT
End of treatment
EQ-5D-5L
EuroQol Health Utility Index, 5 dimensions 5 levels
ESA
Erythropoiesis-stimulating agent
FAS
Full Analysis Set
FDA
Food and Drug Administration 
Hb
Hemoglobin
HDL
High-density lipoprotein
HR
Hazard ratio
HRQoL
Health Related Quality of Life


Statistical Analysis Plan 
Study Code D5740C00002
Edition Number 4.0
Date 28 September 2018
8
Abbreviation or 
special term
Explanation
ITT
Intention To Treat
IV
Intravenous
KM
Kaplan-Meier 
LDL
Low-density lipoprotein
LTFU
Lost to follow up
MACE
Major Adverse Cardiovascular Event
MAP
Mean Arterial Pressure
MAR
Missing At Random
MCH
Mean Corpuscular Hemoglobin 
MCHC
Mean Corpuscular Hemoglobin Concentration
MCMC
Markov Chain Monte Carlo
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Model of Repeated Measures
MNAR
Missing Not At Random
N (or n)
Sample size
NCS
Not clinically significant
PCS
Potentially clinically significant
PEY
Patient-exposure-year
PMM
Pattern Mixture Model
PPS
Per-protocol set
PSAP
Pooled Statistical Analysis Plan
RBC
Red blood cell
SAE
Serious adverse event
SAP
Statistical Analysis Plan
TEAE
Treatment Emergent Adverse Event 
TESAE
Treatment Emergent Serious Adverse Event
TIBC
Total iron binding capacity
TIW
Three times weekly
TSAT
Transferrin saturation
US
United States
VAS
Visual analogue scale


Statistical Analysis Plan 
Study Code D5740C00002
Edition Number 4.0
Date 28 September 2018
9
Abbreviation or 
special term
Explanation
WBC
White blood cell


Statistical Analysis Plan 
Study Code D5740C00002
Edition Number 4.0
Date 28 September 2018
10
SAP AMENDMENT HISTORY
Date
Brief description of change
28 September 2018
The primary safety objective of this study is to contribute to the safety 
data in the pool safety analysis. Thus, analyses of CV safety will be 
conducted in accordance with the pooled safety analysis plan (PSAP).. 
These analyses will be made by study, as described in the PSAP, then 
pooled adopting meta-analysis techniques. 
The primary efficacy endpoint has been specified as the primary 
efficacy endpoint for the FDA. The first secondary efficacy endpoint for 
the FDA has been specified as the primary endpoint for the EU health 
authorities.
Another change in this SAP is the ordering of the secondary efficacy 
endpoints to align with the order of the other phase 3 studies in the DD 
program.  
The censoring criteria at a primary analysis censoring date has been 
omitted to align with the censoring rules in the PSAP. 
A full list of the major changes are listed in Section 6. 
25 January 2018
The most important change in edition 3.0 is how the analysis of the 
primary safety composite endpoint MACE is conducted. There has been 
a strategic change in how to address CV safety in the project. No 
hypothesis testing, and no formal NI-margin for the safety endpoints 
will be adopted for this SAP. In alignment with the pooled SAP (PSAP)
the focus will be on estimation and in providing a complete and 
transparent pattern of results for CV safety through the adoption of the 
“Totality of Evidence” approach. For full details regarding the ”Totality 
of Evidence” approach, please refer to the PSAP. 
Other main changes are the addition of a primary efficacy endpoint, and 
addition of further secondary endpoints, as well as ordering of the 
secondary endpoints, done to harmonize with the other pivotal studies 
in this indication. 
A comprehensive list of changes from the previous edition of the SAP 
is available in Section 6.


Statistical Analysis Plan 
Study Code D5740C00002
Edition Number 4.0
Date 28 September 2018
11
Date
Brief description of change
08 July 2016
Changes from SAP Edition 1.0: Following comments from the US Food and 
Drug Administration (FDA) on the CSP on March 13, 2015, it was decided 
that the analysis method for the first secondary endpoint regarding Hb change 
to be a multiple imputation ANCOVA. Furthermore, additional changes have 
been made to align with the CSP amendment, edition 6.0. For all major 
changes from SAP Edition 1.0, see Section 6.


Statistical Analysis Plan 
Study Code D5740C00002
Edition Number 4.0
Date 28 September 2018
12
1.
STUDY DETAILS
1.1
Study objectives
This study is part of a study program for chronic kidney disease dialysis dependent (CKD-
DD) subjects. The other phase 3 studies in the study program are the FibroGen FG-4592-063
and FG-4592-064 studies and the Astellas 1517-CL-613 study. There is a separate pooled 
statistical analysis plan (PSAP) for the statistical considerations concerning the overall 
program. The primary objective of this study is to evaluate the efficacy of roxadustat and to 
contribute CV safety data to the pooled safety analysis evaluating the safety of roxadustat for 
the treatment of anemia in CKD subjects on dialysis. 
The objectives of the current study are to evaluate the safety and efficacy of roxadustat 
compared to epoetin alfa for the treatment of anemia in subjects receiving dialysis. Subjects 
on hemodialysis (HD) or peritoneal dialysis (PD) who have been treated with an 
erythropoietin analogue or have an indication for treatment with an erythropoietin analogue 
will be evaluated for eligibility and randomized at a 1:1 ratio to treatment with roxadustat 
(with discontinuation of prior erythropoietin analogue therapy) or to an active-control group 
treated with epoetin alfa. This study is also known as “ROCKIES”.
1.1.1
Primary efficacy objective
The primary efficacy objective is to evaluate the efficacy of roxadustat as compared to epoetin 
alfa based on Hb response during the study.
1.1.2
Primary safety objective
The primary safety objective is to contribute adjudicated CV safety data to pooled safety 
analyses across the phase 3 program per pooled SAP. 
1.1.3
Secondary efficacy objectives
The secondary efficacy objectives are to evaluate:

The efficacy of roxadustat as compared to epoetin alfa based on Hb response and 
level during the study.

The efficacy of roxadustat based on Hb response in inflamed subjects.

The effect of roxadustat on low-density lipoprotein (LDL) cholesterol as compared to 
epoetin alfa.

The need for IV iron use in subjects treated with roxadustat as compared to epoetin 
alfa.

The need for RBC transfusion as rescue therapy in subjects treated with roxadustat 
as compared to epoetin alfa.


Statistical Analysis Plan 
Study Code D5740C00002
Edition Number 4.0
Date 28 September 2018
13
1.1.4
Secondary safety objectives
The secondary safety objective is to evaluate the safety and tolerability of roxadustat as 
compared to epoetin alfa..
1.2
Study design
This is a Phase 3, multicenter, randomized, open-label, active-controlled study to evaluate the 
safety and efficacy of roxadustat compared to epoetin alfa for the treatment of anemia in 
dialysis subjects. Subjects on hemodialysis (HD) or peritoneal dialysis (PD) who have been 
treated with an erythropoietin analogue or have an indication for treatment with an
erythropoietin analogue will be evaluated for eligibility and randomized at a 1:1 ratio to 
treatment with roxadustat (with discontinuation of prior erythropoietin analogue therapy) or to 
an active control group treated with epoetin alfa.
The study periods are as follows:

Screening Period:  Up to 6 weeks. 

Treatment Period:  Subjects will be randomized (1:1) to open-label treatment with 
either roxadustat or epoetin alfa. Treatment duration is variable for individual 
subjects (estimated treatment up to 4 years). A common closeout will occur when 
the target number of MACE events has been accrued.

Post-Treatment Follow-Up Period: 4 weeks from the end of treatment (EOT) visit 
to the end of study (EOS) visit. Subjects who discontinue study medication 
prematurely will be followed up for CV events, Hb measurements, vital status and 
hospitalizations until the end of the study (EOS), according to ITT principles, unless 
consent to participate is withdrawn.
1.2.1
Dosing
Roxadustat
Subjects currently treated with an erythropoietin analogue who are randomized to the 
roxadustat group will discontinue prior erythropoietin analogue therapy and initiate treatment 
with roxadustat at a starting dose according to Section 7 in the Clinical Study Protocol (CSP).
Moreover, the dose is subsequently adjusted to achieve and maintain Hb levels between 10 
and 12 g/dL. Subjects not currently treated with erythropoietin analogue will initiate 
roxadustat with dose selection based on body weight. Roxadustat will be administered orally 
three times a week (TIW) throughout the Treatment Period unless dose frequency reduction is 
required based on Hb levels.
Epoetin alfa
Initial dose selection of epoetin alfa for subjects treated with an erythropoietin analogue will 
be determined using a conversion table based on the subject’s average prescribed 


Statistical Analysis Plan 
Study Code D5740C00002
Edition Number 4.0
Date 28 September 2018
14
erythropoietin analogue dose during the preceding 4-8 weeks prior to enrollment in the study. 
Initial dosing of epoetin alfa for subjects not currently receiving an erythropoietin at study 
entry will be 50 IU/kg TIW with subsequent dose adjustments to achieve an Hb level of 11 
g/dL and maintain an Hb level between 10 and 12 g/dL, consistent with approved prescribing 
information or the Summary of Product Characteristics for epoetin alfa.
Dosing for both treatment groups
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. In the event of 
excessive erythropoiesis or excessive Hb levels equal or greater than 13 g/dL, the dose will be 
adjusted or put on hold at any time. Excessive erythropoiesis is defined as an Hb increase by 
>2.0 g/dL within a 4 week period. 
1.2.2
Scheduled visits during treatment
During the treatment period, subjects will be contacted by telephone at week 1, and will attend 
study visits every two weeks from weeks 2 to 20. After week 20, study visits will occur every 
four weeks until the end of treatment period. A study end date will be defined based on when 
the planned number of events are estimated to be accrued; the EOT visit will occur as soon as 
possible after that date. An EOS visit will be performed 4 weeks after the EOT.
Figure 1
Study Flowchart
Screening 
period
Treatment period
Randomization
-6
20
Roxadustat 
Every 2nd week
visits
Visits every 4th week
Epoetin alfa
Screening visits
End of Treatment (EOT) visit
End of Study 
(EOS) visit 
Post-Treatment follow-up 
period (4 weeks)
1st week 
phone/contact
2
1.2.3
Stratification variables 
The randomization in this study will be stratified by country. The stratification variables for 
the other studies in the program will be used in the analyses for this study as covariates, with 
addition of incident vs stable dialysis. The stratification variables are:


Statistical Analysis Plan 
Study Code D5740C00002
Edition Number 4.0
Date 28 September 2018
15
1.
Baseline Hb (≤10.5 g/dL vs > 10.5 g/dL)
2.
cardiovascular/cerebrovascular/thromboembolic medical history (Yes vs. No)
3.
geographical region (US vs. Ex-US)
4.
incident vs. stable dialysis (dialysis duration ≤4 months vs >4 months from the 
randomization date)
Baseline Hb will be included in the analyses as a continuous covariate, hence, not as a 
dichotomous factor, unless specified otherwise. Throughout this document, the variable 
cardiovascular/cerebrovascular/thromboembolic medical history will be shortened as CV 
history, and the variable incident vs stable dialysis will be shortened as dialysis duration
CV history at baseline will be defined for subjects with history of any of the following 
diseases:

Myocardial infarction

Percutaneous coronary intervention

Coronary artery bypass

Cardiac failure congestive

Ischaemic stroke

Haemorrhagic stroke

Cerebrovascular accident 
1.3
Number of subjects
Primary efficacy variable: With at least 600 subjects, the study will provide at least 99% 
power to demonstrate non-inferiority of roxadustat versus epoetin alfa for the primary efficacy 
endpoint (i.e., Hb change from baseline to the average level during the evaluation period 
defined as Week 28 until Week 52). This assumes a difference (roxadustat minus epoetin alfa) 
of -0.30 g/dL, a non-inferiority margin for this difference of -0.75 g/dL and a standard 
deviation of 1.25 g/dL.
To contribute adjudicated CV events for the pooled CV analyses across the phase 3 program: 
approximately 2000 subjects will be randomized in a 1:1 ratio to either roxadustat or active 
control, i.e. epoetin alfa. The sample size for this study is driven by the overall requirement of 
adjudicated CV events for the phase 3 program in dialysis-treated CKD subjects (which 
consists of four studies in total targeting 611 subjects with MACE events). The three other 
studies in the study program are FG-4592-064, 1517-CL-0613, FG-4592-063. 
,.


Statistical Analysis Plan 
Study Code D5740C00002
Edition Number 4.0
Date 28 September 2018
16
2.
ANALYSIS SETS
2.1
Definition of analysis sets
2.1.1
Intention To Treat Analysis Set (ITT) 
All subjects who have been randomized to study treatment will be included irrespective of 
their protocol adherence and continued participation in the study. Subjects will be analyzed 
according to their randomized study medication irrespective of intake of study medication. 
2.1.2
Per Protocol Set (PPS)
All randomized subjects without important protocol deviations and who have received at least 
8 weeks of study treatment and who have valid corresponding Hb measurements will be 
included in the PPS. A valid corresponding Hb is defined as an Hb value from the central 
laboratory that is measured at least 2 weeks after the first dose and was either before the last 
study drug intake or at maximum three days after the last drug intake. Subjects will be 
analysed according to their randomized study medication irrespective of intake of study 
medication. Subjects with an important protocol deviation will be included in the PPS up to 
the time point when the violation was met. For criteria for PPS exclusion, see Table 1 in 
Section 2.2. Further details of important protocol deviations are available in a Protocol 
Deviation Plan. Subjects will be censored at the earliest of date of violating an important 
protocol deviation, the EOS visit, or at last intake of study drug. 
2.1.3
Safety Analysis Set 
All subjects who received at least one dose of randomized study drug will be included in the 
Safety Analysis Set. Throughout the safety results sections, erroneously treated subjects will 
be accounted for in the actual treatment group. If a subject has received both treatments, only 
the initial period will be utilized. Subjects will be censored at either, 7, 3 or 0 days after last 
intake of study drug. Consequently, there will be three versions of the Safety Analysis Set, 
and they will be referred to as On-treatment+7 (OT+7), OT+3 and OT+0 respectively. 
2.1.4
Full Analysis Set (FAS)
The FAS consists of all patients in the ITT analysis set who received at least one dose of study 
drug and have baseline and at least one post-dose Hb assessment. If actual study medication 
received differs from the randomized treatment arm, the randomized treatment arm will be 
used for analysis for the FAS. This analysis set is primarily used for EX-US submissions.
2.1.5
Subjects who will not be included in any analysis sets
Subjects or sites identified prior to database lock (breaking of Sponsor blindness, open-label 
study) with major Good Clinical Practice violations and where the integrity of the data is 
strongly questioned through thorough independent investigations will be excluded from all 
analyses and all analysis sets. This includes but are not limited to subjects who have been 
identified to be part of a potential fraud investigation, subjects who have not signed an 
informed consent, subjects randomized in error (e.g. a subject considered to be a screen fail 
but by mistake randomized in the IWRS due to a technical error). Further, subjects being


Statistical Analysis Plan 
Study Code D5740C00002
Edition Number 4.0
Date 28 September 2018
17
randomized more than once will only contribute to the analysis one time. These patients will 
be analyzed according to their first assigned randomization number and treatment code. All 
AE’s reported for the subjects will be assigned to the subject´s first randomization number. 
All subjects excluded from all analysis sets will be properly documented.
2.2
Violations and deviations
The important protocol deviations are defined in Table 1. Protocol deviations will be 
presented in a data listing.
Table 1
Criteria for Assessing Important Protocol Deviations
Number
Important Protocol Deviations
Level of Deviation1
1
Study drug compliance <75% where drug compliance is 
measured by comparing dispensed and returned drug (see Section 
3.4). 
Subject
2
Administration of wrong type of study drug (i.e. the one not 
randomized to) cumulatively more than 1 week
Visit
3
Administration of prohibited concomitant medication or non-
drug therapy as defined in the protocol.
Visit
4
Administration of rescue therapy deviating from the protocol
Visit
6
Violation of inclusion or exclusion criteria. The key inclusion 
criteria are numbers 3-8. The key exclusion criteria are numbers 
1-6, 9-16, 18 and 23. The full inclusion and exclusion criteria is 
available in the CSP.
Subject
3.
PRIMARY AND SECONDARY VARIABLES
3.1
Efficacy variables
3.1.1
Primary efficacy endpoint  
US FDA: The primary efficacy endpoint for the US is the mean change from baseline in Hb 
averaged over week 28 to week 52. A multiple imputation approach with analysis of 
                                               
1 Subject-level deviations refer to important protocol deviations that will cause subjects to be excluded from the 
Per Protocol set, and therefore all their collected data from analyses based on this population.
Visit-level deviations refer to important protocol deviations that will cause only some data for subjects to be 
excluded from analyses based on the Per Protocol set, while the subjects remain in the Per Protocol set given that 
they did not meet any subject-level deviations. Data to be excluded from the Per Protocol analyses could be 
either data from a certain date, at which the deviation was met for the first time, onwards to the end of the study, 
or data during a period defined by the start and end dates of the deviation.


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covariance (ANCOVA) will be applied as a method to handle missing data. Details of the 
multiple imputation ANCOVA are provided in Sections 4.2.4 and 4.2.5.
Hb results obtained from the central laboratory will be used for all Hb efficacy analyses. 
Baseline Hb is defined as the mean of the three last central laboratory Hb values from the 
screening and randomization visits. 
Hb values under the influence of a rescue therapy will not be censored.
EU health authorities: The primary efficacy endpoint for the EU health authorities is the 
mean change from baseline in Hb averaged over week 28 to week 36, without having received 
rescue therapy within 6 weeks prior to and during this 8-week evaluation period.
3.1.2
Hb related secondary efficacy variables
The Hb related secondary efficacy variables are:

The EU primary endpoint as specified in Section 3.1.1 is the first secondary 
efficacy endpoint in the analysis for FDA

Mean change in Hb from baseline to the subjects mean level between week 28 to 
week 52 in subjects with baseline high-sensitivity C-reactive protein (hsCRP) 
greater than the Upper Limit Normal (ULN) 

Proportion of total time of Hb ≥10 g/dL from week 28 to week 52. The proportion 
of total time will be computed as follows: For each subject, the recorded Hb values 
will first be linearly interpolated between measurements. The time this interpolated 
curve is ≥10 g/dL will be computed and subsequently divided by the time between 
the measurements at week 28 and week 52. Subjects without any Hb measurements 
from week 28 will not be considered for this variable.

Proportion of total time of Hb within the interval of 10-12 g/dL from week 28 to 
week 52. The proportion of total time will be computed as follows: For each 
subject, the recorded Hb values will first be linearly interpolated between 
measurements. The time this interpolated curve is within 10-12 g/dL will be 
computed and subsequently divided by the time between the measurement at week 
28 and week 52. Patients without any Hb measurements from week 28 will not be 
considered for this variable.
3.1.3
Lipid related secondary efficacy variables
To evaluate the roxadustat effect on lipids, the following variable will be evaluated

Mean change from baseline in LDL cholesterol to week 24.


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3.1.4
Rescue therapy related secondary efficacy variables
The need for rescue therapy will be evaluated as

Time-to-first (and proportion of subjects who received) administration of red blood 
cell (RBC) transfusion as rescue therapy (rescue therapy guidelines are specified in 
the CSP, Section 7.7.4).
For analyses based on the Safety Analysis set, time to the event will be calculated as the 
number of days plus one between the day of first dose of study drug and date of the first 
occurrence of the event, or if no event has occurred before censoring, the date of censoring 
(see Section 4.1.1). For analyses based on the ITT analysis set, FAS and PPS, time will be 
calculated as the number of days plus one between the day of randomization and date of the 
first occurrence of the event, or if no event has occurred before censoring, the date of 
censoring.
3.1.5
IV iron related secondary efficacy variables
The use of IV iron will be investigated with the variable:

Average monthly IV iron use per subject during, week 36 to EOS (monthly defined 
as a period of 4 weeks). 
3.1.6
Exploratory variables
The exploratory variables are:
3.1.6.1
Hb related exploratory variables 
Mean change from baseline in Hb, utilizing all Hb values from week 28 until the 
EOT visit. An imputation for mean change in baseline will only be applied for 
subjects with no Hb values from week 28 to the EOT visit. 

Time to achieving target Hb for anemic (Hb<10 g/dL at baseline) subjects not 
receiving ESA <= 4 weeks prior to randomization and were ESA-naïve or near 
ESA-naïve (no ESA use <=4 weeks prior to randomization). Time will be computed 
analogously as time to first rescue therapy. Target Hb is achieved when Hb level is 
within 10-12 g/dL at two consecutive measurements. This will be repeated for 
subjects with no ESA use <= 4 weeks prior to randomization. 

Proportion of ESA-naïve anemic patients achieved Hb response by Week 24 in the 
subset of patients who were anemic (Hb< 10 g/dL at baseline) and were ESA-naïve 
or near ESA-naïve (no ESA use <=4 weeks prior to randomization). 
Hb response (Yes/No), where Yes is defined as: 
o
Hb ≥ 11.0 g/dL and Hb increase from baseline by ≥ 1.0 g/dL, for subjects with 
baseline Hb > 8.0 g/dL; or


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o
Hb increase from baseline by ≥ 2.0 g/dL, for subjects with baseline Hb ≤ 8.0 g/dL
at two consecutive visits [dates] (with available data) separated at least 5 days 
during the first 24 weeks of treatment without having received rescue therapy 
(RBC transfusion, ESA, or IV iron) prior to Hb response. The first date of the two 
consecutive visits will be used as the date of response. The second date of the two 
consecutive visits will be used when evaluating the presence or absence of rescue 
therapy. 

Percent of total patient exposure time with achieved Hb level <9, 9-<10, 10-<11, 11 
- <12, 12-<13, >=13 g/dL during treatment.
3.1.6.2
RBC transfusion related exploratory variables

Number of rescue therapy treatments given, RBC transfusion per patient exposure 
year (PEY). 

Proportion of subjects with RBC transfusions during week 28 to week 52. 
3.1.6.3
Quality of life related exploratory efficacy variables 
European Quality of Life Questionnaire in Five Dimensions, Five Levels (EQ-5D-5L)
The EQ- 5D-5L consists of the EQ-5D-5L descriptive system and the EQ visual analogue 
scale (VAS). The EQ-5D-5L 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 visual analogue scale records the respondent's self-rated health status on a graduated (0–
100) scale, where the endpoints are labelled ‘Best imaginable health state’ and ‘Worst 
imaginable health state’ with higher scores for higher HRQoL. The EQ-5D-5L variables are:

Change from baseline in EQ-5D-5L index value 

Change from baseline in EQ VAS 
and will be computed according to the EQ-5D-5L documentation.
Results from the EQ-5D-5L questionnaire will also be summarized descriptively.
3.1.6.4
Hospitalization related exploratory variables

Number of hospitalization(s) and number of days of hospitalizations per PEY. 

Number of days spent in Intensive Care Unit (ICU) per PEY.

Proportion of subjects who are re-admitted to hospital within 30 days per PEY. 


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
Proportion of subjects who are re-admitted to hospital within 30 days due to heart 
failure per PEY following a preceding hospitalization due to heart failure. 

Proportion and number of on treatment days of hospitalization-free survival.

Proportion and number of on treatment days of hospitalization-free, emergency 
room- free, and skilled nursing facility-free survival. Number of days spent in a 
Skilled Nursing Facility that follow hospitalizations per PEY, and the total number 
of days covering both hospitalizations and subsequent days in Skilled Nursing 
Facility.
3.1.6.5
Other exploratory variables

Variables concerning serum iron profiles: Iron, TIBC, Ferritin and TSAT. Mean 
value at each time-point tested, and change from baseline.

Variables concerning lipids: total cholesterol, high-density lipoprotein (HDL) and 
triglyceride: mean values and change from baseline at each timepoint tested; 
percent of subjects who achieved target LDL level <100 mg/dL, at each timepoint ; 
subgroup analyses on patients on statins and those not on statins

Variables concerning heart rate and blood pressure: heart rate, systolic blood 
pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP).

Variables concerning concomitant medication: Usage of statins and types of statins, 
initiation of ESA therapy post study drug discontinuation

Change from baseline in hepcidin to week 24. 
3.2
Safety assessments
Safety will be further assessed by evaluating the following:

Occurrence of treatment emergent adverse events (TEAEs) and treatment emergent 
serious adverse events (TESAEs) 

Changes from baseline in vital signs and physical examinations. 

Mean change from baseline in clinical laboratory values.

Occurrence of clinically significant changes from baseline in vital signs and ECG
values.


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3.3
Adjudicated CV Events Analyses for Safety Assessments 
The CV events being analysed in the PSAP will be adjudicated by the Independent Event 
Review Committee (IERC) according to the IERC charter. The same adjudication committee
will be used for all the phase 3 studies (FG-4592-064, 1517-CL-0613, FG-4592-063, and 
D5740C00002) in the CKD-NDD program. Analyses of these adjudicated events are 
described in a separate pooled analysis plan.
3.4
Treatment compliance
Subjects will be asked to return all unused study medication and empty packages to the clinic 
at each visit.  The amount of dispensed and returned study medication will be recorded in the 
eCRF.  The percentage treatment compliance will be calculated as: 
((Overall amount of dose actually taken)/(Overall amount of dose to be taken))*100%
Subjects taking ≥75% and ≤125% of planned study medication are considered to be 
compliant.
Compliance will be summarized as follows:

Descriptive statistics will be summarized by the two treatment groups 

Percent compliance will be categorized according to the following three categories:

<50% (significant drug non-compliance)

≥50%, <75%, >125% (moderate drug non-compliance)

≥75%, ≤125% (drug compliance)
4.
ANALYSIS METHODS
Statistical analyses will be performed by IQVIA™using SAS® Version 9.4 or higher and, 
where appropriate, additional validated software.
4.1
General principles
All study data will be listed by treatment group, centre, and subject number. Throughout 
subject data listings, figures and tables, treatment groups will be labelled as “Roxadustat” and 
“Epoetin alfa”.
Study Day will be listed in all data listings whenever an assessment date is presented. Study 
Day is a relative number, relative to the date of first dose of study drug. Week is also a relative 
number, relative to the number of weeks from the first dose of study drug. Study Days 1-7 is 
defined as Week 0, Days 8-14 as Week 1, etc. Clinical events and other variables reported 
after the EOT visit for a subject will not be included in the primary efficacy and safety 


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analysis. If collected, these events will be included in tables. Events that are recorded as 
beginning prior to the date and time of randomization will not be included in a listing.
In addition to specific analyses and presentations that are detailed in the following sections, 
results will be summarised using descriptive statistics, including the number of subjects (n), 
mean, standard deviation (SD), median and range (i.e. minimum and maximum) as 
appropriate. For categorical variables counts and percentage n (%) per treatment group will be 
presented. Summaries of continuous variables will be based on non-missing observations. For 
time to event data, the number and percentage of subjects recording the event will be 
summarised. Ninety-five percent confidence intervals will also be included where appropriate, 
as a measure of precision. Demographic characteristics, qualifying risk factors and other 
specific medical and surgical history will be summarised for the ITT analysis set using 
descriptive statistics. Mean Hb values over time will be graphically displayed and grouped by 
treatment.
Dates will be presented in the format YYYY-MM-DD.
When the last dose date is missing, it will be imputed as the earliest date of last drug dispense 
date + number of days of drug dispensed, date of death, date of EOT visit or date of EOS visit. 
4.1.1
Censoring
For analyses based on OT+7, subjects will be censored at 7 days after last intake of study 
drug, or the EOS visit, whichever is earliest.
For analyses based on OT+3, subjects will be censored at 3 days after last intake of study 
drug, or the EOS visit, whichever is earliest.
For analyses based on OT+0, subjects will be censored at last intake of study drug, or the EOS 
visit, whichever is earliest.
For analyses based on the ITT analysis set and FAS, subjects will be censored at their 
individual EOS visit, regardless of if they have discontinued study drug or not. Complete 
endpoint information will be pursued with every effort for all subjects, unless they exercise 
their right to withdraw consent. Subjects who withdraw consent will be censored at date of 
withdrawal of consent, and subjects who are lost to follow up (LTFU) will be censored at last 
available contact. 
Subjects who withdraw consent and for whom only vital status (known to be alive at study 
closure, or date of death) may be obtained from public records, the occurrence of all 
components of the primary endpoint cannot be assessed, and will thus be censored at date of 
consent withdrawn for all analyses. However, the determination of all-cause death will utilize 
all publicly known mortality data, even that extending beyond date of consent withdrawal. 
The vital status information will be included in the analysis of all-cause death as a single
endpoint, and in sensitivity analysis and tabulations. Similarly, complete information on the 
endpoint may not be obtained for subjects who are LTFU. Any such subject will be censored 
in the analysis at the last contact where all elements of the endpoint were assessed. A subject 


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will not be recorded as LTFU until the end of the study, after every allowable effort to get in 
contact has been made. Hence, it is anticipated that the number of subjects LTFU will be 
limited.
4.1.2
Premature permanent discontinuation of study medication
Premature discontinuation from study medication is not the same as withdrawal from the 
study. As described in Section 3.9 in the CSP there are several options for continuing the 
study. 
It is expected that complete information on the safety composite endpoint events, and as much 
as possible of the remaining eCRF data, will be obtained for all subjects who prematurely 
discontinue study medication, unless they refuse any form of follow-up and withdraw consent 
or are LTFU. 
4.1.3
Choice of the non-inferiority margins
Non-inferiority for the Hb efficacy endpoint will be established if the lower limit of the two-
sided 95% CI for the difference between the means of the primary endpoint (roxadustat minus 
control epoetin alfa) is ≥-0.75 g/dL, see Section 0. In other words, a non-inferiority margin 
of -0.75 g/dL will be used in the Hb efficacy assessments.
Support for the use of a non-inferiority margin of -1.0 g/dL in the peginesatide submission for 
the dialysis studies was initially provided by estimating the magnitude of the effect of 
erythropoietin analogue therapy. This estimate was based on summary information from the 
darbepoetin alfa development program (Aranesp 2001, Omontys 2012), with publicly 
available summary data. Based on these data, the estimated treatment effect of erythropoietin 
analogue therapy in the dialysis population was approximately 2.0 g/dL. Based on these data, 
the estimated treatment effect of erythropoietin analogue therapy in the dialysis population 
with a 10-12 g/dL target range (at least 2.0 g/dL and was considered to be appreciably larger 
than 1.0 g/dL, thus supporting the choice of a non-inferiority margin of -1.0 g/dL. 
Therefore, the choice of -0.75 g/dL as non-inferiority is more conservative than prior 
programs, and consequently, an appropriate margin to use.
The comparison between the study drugs for the time-to-first instance of receiving RBC 
transfusion, or erythropoietin analogue (for roxadustat subjects only) as rescue therapy is also 
based on a NI evaluation. For this purpose, in the lack of support for the choice from the 
literature, a 1.8 margin has been selected. NI will thus be claimed if the upper bound of the 2-
sided 95% CI for the hazard ratio (roxadustat/epoetin alfa) is less than or equal 1.8.
The analysis of the proportion of total time of Hb within the interval of 11±1 g/dL from week 
28 until week 52 between the treatment groups also relies on a non-inferiority evaluation. For 
this purpose a NI margin of -0.15 has been adopted, i.e. the 2-sided 95% CI around the 
difference between roxadustat and epoetin alfa has to exceed -0.15. No support from the 
literature has been found for this selection. 


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4.2
Analysis methods
4.2.1
Demography
The following will be reported on subjects who are randomised: sex, age, race and ethnic 
group, baseline Hb value, geographical region, incident vs stable dialysis (dialysis duration ≤4
months vs >4 months from the randomization date), dialysis type, 
cardiovascular/cerebrovascular/thromboembolic medical history, congestive heart failure 
history, coronary artery disease history and cerebrovascular history, other relevant medical 
and surgical history, concomitant medication, weight, height, BMI, tobacco use, CKD
diagnosis, diabetes history and baseline blood pressure. Continuous and categorical 
demographic variables will be presented as described in Section 4.1. The following 
continuous variables will also be presented as range-based categories: 

baseline Hb value (≤10.5g/dL vs >10.5g/dL), 

age (≥18 - < 50, ≥50 - < 65, ≥65 - < 75, ≥75 years), 

BMI (<30, ≥30 kg/m2), and 

weight (<70, >=70 - <100, >=100 kg)).
4.2.2
Confirmatory analysis for the efficacy endpoints
To address the issue of multiple testing while maintaining the overall type-I error, adopting a 
5% two-sided significance level, a closed testing sequence will be used for the efficacy 
endpoints. First, the primary efficacy endpoint analysis according to Section 0 will be 
performed. If successful, the testing will continue with the secondary efficacy endpoints in the 
order as specified in Section 4.3.4. Confirmatory statistical hypothesis testing will continue 
until the first statistically non-significant treatment difference is observed. However, treatment 
comparisons following and including the first non-significant comparison will be examined in 
an exploratory manner.
All analyses other than part of this confirmatory analysis will be interpreted descriptively. 
Consequently, no adjustments for multiplicity will be necessary for such analyses. Ninety-five 
percent confidence intervals will be calculated, where appropriate, as measures of study 
precision. P-values may be calculated but are to be regarded as descriptive.
4.2.3
Time to event analysis 
For time to event variables, treatments will be compared using a Cox proportional hazards
model. Unless specified otherwise baseline Hb as a continuous variable will be used as a 
covariate, and treatment group, CV history, dialysis duration and geographic region as fixed 
effects for all analyses. The Efron method will be used for ties. The p-values (calculated using 
the Wald test), hazard ratio (HR) and 95% confidence intervals for the HR will be reported. 
Summary tables of these analyses will also include the number of subjects with an event and 
Kaplan-Meier estimates of the event rates per treatment group estimated at a time point 
determined on the basis of the available follow-up. Kaplan-Meier estimates of the cumulative 
proportion of subjects with events will be estimated and plotted, with the number of subjects 
at risk indicated below the plot at specific time points.


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4.2.4
Difference in proportions analysis
For analysis of difference in proportions the approach by Miettinen & Nurminen 1985 will be 
used and a 2-sided 95% confidence interval for the difference of two proportions (roxadustat 
vs epoetin alfa) will be computed, adjusting for stratification factors. The model will include 
the terms of baseline Hb, treatment group, cardiovascular history, geographic region and 
dialysis duration. The stratified statistics will be based on the standard normal statistic 
proposed by Gart and Nam 1990. 
4.2.5
Analysis of Covariance (ANCOVA)
When using ANCOVA in analysis of change from baseline for a continuous variable, the 
mean value of all change from baseline values available within the pre-specified timeframe 
will be used as the dependent variable. Unless specified otherwise, baseline Hb will be used as 
a covariate and treatment group, cardiovascular history, geographic region and dialysis 
duration as fixed effects for all analyses. Any further details will be given case-by-case for 
each endpoint (see Section 4.3). The least squares mean estimates of change from baseline for 
each treatment group and their difference, and associated 95% CI will be provided.
4.2.6
Multiple imputation ANCOVA
For the primary efficacy analysis, a multiple imputation ANCOVA method (O’Kelly & 
Ratitch, 2014) will be used. It will be conducted with the following steps:
1. 200 datasets will be generated, using seed number 326154, where non-monotone missing 
Hb data will be imputed, meaning intermediate visits that subjects skip, but return for 
evaluations at subsequent visits. The data points are imputed assuming MAR, using the 
MCMC imputation model baseline Hb, CV history, geographic region and dialysis 
duration, and the available non-missing Hb for each scheduled week are used as 
covariates, by treatment group. The MCMC statement in the SAS PROC MI procedure 
with monotone option will be used. As a result, each dataset will only have a monotone 
missing data pattern. 
2. For each dataset from step 1, the missing monotone data points will be imputed, which is 
when a subject misses one visit, and all subsequent visits. As a result, 200 imputed 
complete datasets will be generated.

Missing data at Week 2 will be imputed using the regression imputation model with 
baseline Hb and Hb from Week 2, CV history, geographic region and dialysis duration 
as terms in the model, by treatment group This will be performed with the SAS PROC 
MI procedure with the REGRESSION option in the MONOTONE statement. 

Repeat for all other scheduled weeks sequentially. Subjects whose missing data were 
imputed for previous weeks will contribute to the imputation for the current week. 

The regression imputation model includes an intercept and the slopes of the Hb from 
previous weeks.


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3. Fit an ANCOVA model on each of the 200 datasets where the average of the imputed and 
observed Hb values between weeks 28 to 52 for each subject is taken as the dependent 
variable and baseline Hb, treatment group, CV history, geographic region and dialysis 
duration as covariates. 
4. Combine the results of all 200 ANCOVA models using Rubin’s rules (Rubin, 1987) with 
the SAS PROC MI ANALYZE procedure.
The least squares mean estimates of change from baseline for each treatment group and their 
difference, together with their associated 95% CI and p-value will be reported. 
The exploratory efficacy endpoint of Hb change from baseline to the average between week 
28 to the EOT visit will be conducted in the following steps:
1. 200 datasets will be generated, using seed number 326154, assuming a return-to-baseline 
values, with imputed values being sampled from a posterior Bayesian distribution of 
baseline Hb for all treatment groups combined, using a regression imputation model with
stratification variables as predictor variables. 
2. The imputations will be obtained using SAS PROC MI as follows. The input dataset will 
contain a set of temporary records to be used for imputation model estimation, where a 
new record is created for each subject, assigning their baseline Hb value to a variable 
representing mean Hb values from week 28 to EOT. This variable will be used as a 
dependent variable in a regression imputation model, thus estimating a distribution of 
baseline values. The MONOTONE REG statement will be used to estimate the imputation 
model, and the MNAR statement with MODEL option will be used to specify the subset 
of temporary records as described above from which the imputation model will be 
estimated. Once the imputation is complete, the temporary records will be removed prior 
to analyzing the imputed data, and for subjects whose mean Hb values from week 28 to 
EOT were imputed, a change from baseline will be calculated as the imputed value minus 
baseline Hb value.
3. Fit an ANCOVA model on each of the resulting 200 datasets where the mean change in 
Hb from baseline from weeks 28 to EOT for each patient is taken as the dependent 
variable and baseline Hb, treatment group, CV history, geographic region and dialysis 
duration as covariates. 
4. Combine the results of all 200 ANCOVA models using Rubin’s rules (Rubin, 1987) with 
the SAS PROC MIANALYZE.
5. Non-inferiority between roxadustat compared to epoetin alfa will be declared, and this test 
successful, if the lower bound of the 2-sided 95% confidence interval of the difference 
between roxadustat and epoetin alfa exceeds -0.75 g/dL.


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4.2.7
Mixed Model of Repeated Measures (MMRM)
As one of the sensitivity analyses, the mixed model of repeated measures (MMRM) will be 
used. Longitudinal models with correlated errors, otherwise widely known as MMRMs, have 
been increasingly used for the analysis of clinical trials with missing data. A longitudinal 
model is often used even though the primary objective is to estimate a treatment effect and test
a null hypothesis of no treatment effect at a single specific time-point (typically at the end of 
double-blind period). The advantage of using an MMRM analysis in this context (compared to 
ANCOVA at the primary time-point) is that longitudinal models include all randomized 
subjects regardless of whether they completed the study (provided data for the primary time-
point) or not. Model estimation and inference is done without performing any imputation of 
the missing data for subjects who discontinued early, yet partial data available for these 
subjects is fully utilized and contributes to the estimation of effects and to the variance-
covariance structure of the longitudinal model.
The MMRM can contain terms for baseline measurement, treatment arm, visit, treatment by 
visit interaction, and the stratification variables. Details will be given case-by-case for each 
endpoint. The least squares mean estimates of change from baseline for each treatment group 
and their difference, and associated 95% CI will be provided. Due to the large amount of visits 
to include in the model, the unstructured covariance pattern model will be selected first. If the 
algorithm for unstructured covariance pattern does not converge, then the heterogeneous 
Toeplitz structure will be used instead. If this second model also does not converge, then the 
(homogeneous) Toeplitz structure will be selected, thereafter the compound symmetry and 
finally the first order autoregressive covariance structure will be used to achieve convergence.
4.2.8
Pattern Mixture Models
To address the possibility of the Hb data being missing not at random (MNAR), Pattern 
Mixture Models (PMM) will be implemented as sensitivity analyses. Pattern Mixture Models 
(PMM) provide a general and flexible framework for sensitivity analyses that allows 
formulating assumptions regarding missing data in a transparent and clinically interpretable 
manner. A variety of PMMs with different types of MNAR assumptions will be implemented.    
4.2.8.1
PMM –Last Mean Carried Forward
A pattern-mixture model using a last mean carried forward multiple imputation method 
(Carpenter et al, 2013) will be used as another sensitivity analysis to explore the robustness of 
the ANCOVA results for the primary efficacy variables. Using this method, missing data after 
ending Week will be imputed based on the last non-missing mean from its own treatment 
group.
The steps to implement this sensitivity method is the same as for the multiple imputation 
ANCOVA method described in Section 4.2.6 with the exception of step 2, where the 
monotone datasets are imputed. The procedure for that is as follows. Parameters below refer 
to the parameters of the multivariate normal distribution for baseline and post baseline Hb 
measurement. 


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1.
Create posterior distribution of parameters: Separately for each treatment group, take 
all subjects observed data and assuming MAR to fit a multivariate normal distribution 
with unstructured mean (i.e. a separate mean for each of the baseline plus post-
baseline scheduled weeks and unstructured variance covariance matrix using a 
Bayesian approach with an improper prior for the mean and an uninformative Jereys' 
prior for the variance-covariance matrix (Schafer, 1997, p. 155). 
2.
Draw parameters: Separately for each treatment group, draw variance-covariance 
matrix from the posterior distribution for the parameters using seed 453628. The mean 
Vector would be set to the marginal mean for their randomized treatment arm at their 
last non-missing measurement.
3.
Build joint distribution of missing data and observed data: For each subject with 
missing data, using the draws for the parameter to build the joint distribution of their 
observed and missing data.
4.
Construct conditional distribution of missing data give observed data: For each 
subject with missing data, use their joint distribution in previous step to construct their 
conditional distribution of missing given observed outcome data. Sample their 
missing data from this conditional distribution, to create a “completed” data set, using 
seed 732545.
Repeat the above steps for 200 times and resulting in 200 fully imputed data sets. Then fit an 
ANCOVA model for each imputation data set, and combine the resulting parameter estimates 
and standard errors using Rubin’s rules (Rubin, 1987) for final inference. 
4.2.8.2
PMM –Baseline Carried Forward (roxadustat only and both groups)
The analysis is similar to PMM – Last Mean Carried Forward, with a different assumption in
imputing the missing data. The imputation data will be generated similarly as last mean 
carried forward method described above but instead of using post-baseline observed data, only 
baseline data will be used. The similar analyses will be conducted in two scenarios.

The baseline carried forward imputation will be performed for the roxadustat 
treatment group only, while for active control group, the imputation data will be 
generated using the last mean carried forward described above. 

The baseline carried forward imputation will be performed for both treatment groups.
Similarly, the Rubin’s method will be then used to combine the estimates and the differences 
between the least square mean differences between the two treatment groups from each of the 
ANCOVA analysis. 


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4.3
Statistical Analyses
4.3.1
CV safety endpoints analyses
The CV safety evaluation strategy is to conduct pooled analyses of adjudicated data across the 
study program to ensure that the overall number of events is high enough to provide adequate 
power. Thus, all analyses of CV safety will be conducted in accordance with the PSAP.
4.3.2
Primary efficacy endpoint analysis for US
Mean change in Hb from baseline to the subjects mean level from week 28 to week 52 will 
analyzed with multiple imputation ANCOVA as described in Section 4.2.5 and 4.2.6. The 
model will contain terms for the baseline Hb measurement, treatment arm, CV history, 
geographic region and dialysis duration. Non-inferiority of roxadustat compared to epoetin 
alfa will be declared, and this test as successful, if the lower bound of the 2-sided 95% 
confidence interval of the difference between roxadustat and epoetin alfa exceeds -0.75 g/dL.
The ITT analysis set will be used.
4.3.3
Primary efficacy endpoint analysis for EU (First Secondary endpoint for FDA)
Mean change in Hb from baseline to the subjects mean level from week 28 to week 36, 
without having received rescue therapy within 6 weeks prior to and during this 8-week 
evaluation period and will be analysed using MMRM. The model will contain terms for the 
baseline Hb measurement, treatment arm, visit, visit by treatment, CV history, geographic 
region and dialysis duration. Data up to visit of Week 52 will be included in the model.
Non-inferiority of roxadustat compared to epoetin alfa will be declared, and this test as 
successful, if the lower bound of the 2-sided 95% confidence interval of the difference 
between roxadustat and epoetin alfa exceeds -0.75 g/dL. The PPS will be used for non-
inferiority. In addition to the comparison based on the PPS population, to address the formal 
test for non-inferiority, results will also be provided based on the FAS population, to allow 
also for a potential superiority comparison. The latter test is not part of the formal testing 
sequence.
4.3.4
Secondary efficacy endpoints analyses
Secondary efficacy endpoints will be tested using a fixed sequence approach to adjust for 
multiple testing. If the p-value from a test is less than 0.05, the test will be declared as 
successful and the analysis will continue to the next comparison in the sequence. Formal 
statistical hypothesis testing will be stopped as soon as a test is accompanied by a p-value 
≥0.05. The PPS will be used for the first secondary endpoint for non-inferiority, OT+3
analysis set will be used for the secondary endpoints related to RBC transfusion as rescue 
therapy, and the ITT analysis data set will be used for all the remaining secondary endpoints.
1. The EU primary endpoint for non-inferiority is the first secondary efficacy endpoint 
for FDA (see above). 


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2. Mean change from baseline in LDL cholesterol to week 24 will be analysed using 
ANCOVA. Baseline Hb and baseline LDL will be used as covariates and treatment 
groups, CV history, geographic region and dialysis duration as fixed effects. 
Superiority will be declared if the upper bound of the 2-sided 95% confidence interval 
of the difference between roxadustat and epoetin alfa falls below 0. 
3. Mean change in Hb from baseline to the subjects mean level from week 28 to week 52 
in subjects with baseline hsCRP greater than the Upper Limit Normal (ULN) will be 
analysed analogously as the primary efficacy endpoint. Superiority of roxadustat 
compared to epoetin alfa will be declared, and this test as successful, if the lower 
bound of the 2-sided 95% confidence interval of the difference between roxadustat and 
epoetin alfa exceeds 0 g/dL. 
4. Proportion of total time of interpolated Hb values ≥10 g/dL from week 28 until week 
52 will be estimated for each subject and used as dependent variable. The difference 
between roxadustat and epoetin alfa will be compared using ANCOVA. Baseline Hb
will be used as a covariate and the treatment groups, CV history, geographic region 
and dialysis duration as fixed effects. Non-inferiority between the groups will be 
declared, and this test as successful, if the lower bound of the 2-sided 95% confidence 
interval of the difference between roxadustat and epoetin alfa exceeds -0.15.
5. Proportion of total time of interpolated Hb values within the interval 10-12 g/dL from 
week 28 until week 52 will be estimated for each subject and used as dependent 
variable. The difference between roxadustat and epoetin alfa will be compared using 
ANCOVA. Baseline Hb will be used as a covariate and the treatment groups, CV 
history, geographic region and dialysis duration as fixed effects. Non-inferiority 
between the groups will be declared, and this test as successful, if the lower bound of 
the 2-sided 95% confidence interval of the difference between roxadustat and epoetin 
alfa exceeds -0.15. 
6. The average monthly IV iron use during Week 36 to EOS will be compared between 
the two treatment groups using a Wilcoxon Rank Sum test. Superiority will be 
declared if the p-value is less than 0.05.
7. Time-to-first (and proportion of subjects who received) RBC transfusion as rescue 
therapy, will be analysed using Cox proportional hazard model. The baseline Hb, 
geographic region, dialysis duration and CV history will be included as covariates. 
Non-inferiority will be claimed, and this test successful, if the upper bound of the 2-
sided 95% CI for the hazard ratio (roxadustat/epoetin alfa) is less than or equal to 1.8. 
4.3.5
Exploratory endpoint analysis
The baseline value for each exploratory variable is defined as the last measurement of the 
variable prior to randomization, including the measurement from the randomization visit, 
unless stated otherwise. 


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The analysis set to be used for all exploratory analyses will be ITT analysis set, unless 
specified otherwise. The variables will be analysed as follows:
4.3.5.1
Hb related exploratory endpoint analysis 

Mean change from baseline in Hb to the subjects mean level from week 28 to EOT 
will be analyzed using multiple imputation with ANCOVA as described in Section 
4.2.6. The mean change from baseline will only be imputed for subjects with no 
measurements from week 28 to EOT. Non-inferiority of roxadustat compared to 
epoetin alfa will be declared, and this test as successful, if the lower bound of the 2-
sided 95% confidence interval of the difference between roxadustat and epoetin alfa 
exceeds -0.75 g/dL.

Mean change in Hb from baseline to the subjects mean level from week 28 to week 
36 in subjects with baseline hsCRP greater than the Upper Limit Normal (ULN) 
will be analysed analogously as the primary efficacy endpoint. PPS will be used.

Proportion of total time of interpolated Hb values ≥10 g/dL from week 28 until 
week 36 will be estimated for each subject and used as dependent variable. The 
difference between roxadustat and epoetin alfa will be compared using ANCOVA 
with treatment group, geographic region and CV history as fixed factors and 
baseline Hb and baseline eGFR as covariates. PPS will be used.

Time to achieving target Hb for anemic (Hb<10 g/dL at baseline) subjects who
were ESA-naïve or near ESA-naïve (no ESA use <=4 weeks prior to 
randomization). This will be analyzed analogously as Time to first rescue therapy 
(composite). Target Hb is achieved when Hb level is within 10-12 g/dL at two 
consecutive measurements.

Estimation of median time (in weeks) to achieve target Hb for anemic (Hb<10 g/dL 
who were ESA-naïve or near ESA-naïve (no ESA use <=4 weeks prior to 
randomization), based on the definition of two consecutive Hb levels within 10-12 
g/dl, by treatment arm.

Proportion of ESA-naïve anemic patients achieved Hb response by Week 24 in the 
subset of patients who were anemic (Hb< 10 g/dL at baseline) and were ESA-naïve 
or near ESA-naïve (no ESA use <=4 weeks prior to randomization). 
Hb response (Yes/No), where Yes is defined as: 
o
Hb ≥ 11.0 g/dL and Hb increase from baseline by ≥ 1.0 g/dL, for subjects with 
baseline Hb > 8.0 g/dL; or
o
Hb increase from baseline by ≥ 2.0 g/dL, for subjects with baseline Hb ≤ 8.0 g/dL
at two consecutive visits [dates] (with available data) separated at least 5 days 
during the first 24 weeks of treatment without having received rescue therapy 


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(RBC transfusion, ESA, or IV iron) prior to Hb response. The proportion of 
responders in the primary efficacy variable will be compared using Miettinen & 
Nurminen model, adjusting for the region, history of CV, baseline Hb (<=8, >8 
g/dL) and dialysis duration, comparing roxadustat to epoetin alfa. 
4.3.5.2
Rescue therapy related exploratory endpoint analysis

Time-to-first instance rescue therapy (composite) of receiving RBC transfusions, or 
erythropoietin analogue as rescue therapy will be analysed analogously as Time to 
first RBC transfusion in Section 4.3.4. The OT+3 will be used. 

Number of rescue therapy treatments given; RBC transfusion or erythropoietin 
analogue per PEY will be reported descriptively, together and separately. The OT+3 
will be used. 

Proportion of subjects receiving RBC transfusion during week 28 to week 52 will 
be analysed using Miettinen & Nurminen model adjusting for the region, history of 
CV and baseline Hb (<=8, >8 g/dL) and dialysis duration, comparing roxadustat to 
epoetin alfa. The OT+3 will be used.
4.3.5.3
Quality of life related exploratory endpoint analysis

Mean change in EQ-5D-5L index value from baseline to average EQ-5D-5L index 
value of weeks 28-52 will be analyzed using MMRM with treatment, visit, 
treatment-by-visit interaction, and baseline covariates, including the baseline index 
value, baseline Hb, CV history, geographic region and dialysis duration, as fixed 
effects and subject as a random effect. 

Change in EQ-5D-5L index value from baseline at weeks 12, 28 and 52 will be 
analyzed using the same MMRM as specified in Section 4.3.4 for this variable.

Shift tables of EQ-5D-5L levels 1-5 by dimension and treatment arm. 

Mean change in EQ-5D-5L VAS value from baseline to average EQ-5D-5L VAS 
value of weeks 28-52 will be analyzed using MMRM with treatment, visit, 
treatment-by-visit interaction, and baseline covariates, including the baseline VAS 
value, baseline Hb, CV history, geographic region and dialysis duration, as fixed 
effects and subject as a random effect. 

Change in EQ-5D-5L VAS value from baseline at weeks 12, 28 and 52 will be 
analyzed using the same MMRM as specified above for this variable.

EQ index value and VAS mean values (+SD) and median values (+ 25th & 75th
percentiles) at baseline and each visit per treatment arm. 


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4.3.5.4
Hospitalization related exploratory endpoint analysis
All endpoints in this subsection will use OT+7. 

Proportion of subjects with hospitalizations and number of days of hospitalizations 
per PEY will be reported descriptively.

Number of days spent in ICU per PEY for each treatment arm will be reported 
descriptively. 

Proportion of subjects who are re-admitted to hospital within 30 days per patient-
exposure year for each arm will be reported descriptively.

Proportion of subjects who are re-admitted to hospital within 30 days due to heart 
failure preceding a hospitalization due to heart failure per PEY for each arm will be 
reported descriptively.

Proportion of subjects by number of days spent in a Skilled Nursing Facility that 
follow hospitalizations per PEY will be reported descriptively. 

Proportion and number of days of hospitalization-free survival on treatment will be 
reported descriptively. 

Proportion and number of days of hospitalization-free, emergency room- free, and 
skilled nursing facility-free survival on treatment will be reported descriptively. 
Proportion of subjects with days spent in a Skilled Nursing Facility that follow 
hospitalization and number of days spent in a Skilled Nursing Facility that follow 
hospitalizations per PEY will be reported descriptively. The total number of days 
covering both hospitalizations and subsequent days in Skilled Nursing Facility will 
also be reported.
4.3.5.5
Other exploratory endpoint analysis

The average monthly IV iron use during Week 0 to 36 and week 28 to 36 will be 
compared between the two treatment groups analogously as the secondary efficacy 
endpoint of IV iron. 

Average monthly IV iron usage per PEY per arm will be reported descriptively.

Mean change in heart rate from baseline throughout week 28 to the EOT visit. For 
each subject, the change from baseline to the mean level across all heart rate values 
from week 28 until the EOT visit will be used as the dependent variable. An
ANCOVA approach will be used with baseline heart rate, baseline Hb as covariates
and the treatment groups, CV history, geographic region and dialysis duration as 
fixed effects. 


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
Change in blood pressure (DBP, SBP and MAP) from baseline throughout week 28 
to the EOT visit. Analysis will be conducted using ANCOVA analogously as the 
analysis of change in heart rate.

Iron parameters: Serum iron, TIBC, Ferritin and TSAT level at each testing time-
point and mean change from baseline throughout week 28 to the EOT visit. For 
each of the serum profiles, analysis will be conducted using ANCOVA analogously 
as the analysis of change in heart rate. 

Change in variables concerning lipids: Total cholesterol, LDL, HDL and 
triglyceride. For each of the lipids, analysis will be conducted using ANCOVA 
analogously as the analysis of change in heart rate, from week 24 to the EOT visit. 
Percent of subjects who achieved target LDL level <100 mg/dL will also be 
compared at all available time points

The usage of statins, types of statins and statin dose levels will be reported 
descriptively.

Subject initiation of ESA therapy post study drug discontinuation will be reported 
descriptively. 

Change from baseline in hepcidin to week 24. Analysis will be conducted using 
ANCOVA analogously as the analysis of change in heart rate.  
4.3.6
Sensitivity analysis of efficacy endpoints

The analysis of the primary efficacy endpoint for US will be repeated but will 
exclude Hb values 6 weeks after the use of rescue therapy. ITT analysis set will be 
used. 

The analyses of primary efficacy endpoint and the secondary efficacy endpoints
will be repeated using the OT+7.

The analysis of the US primary efficacy endpoint and the Hb related secondary 
efficacy endpoints will be repeated using the PPS.

The secondary endpoint of RBC transfusion as rescue therapy will be repeated 
using the ITT analysis set. 

Change in Hb from baseline using MMRM. Mean change from baseline across all 
Hb values from week 28 to week 52 will be analysed using baseline Hb as a 
covariate and treatment group, visit, visit by treatment interaction, CV history, 
geographic region and dialysis duration as fixed effects. ITT analysis set will be 
used.


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
Proportion of total time of interpolated Hb within the interval of 10-12 g/dL from 
week 28 to the EOT visit. The difference between roxadustat and epoetin alfa will 
be compared using an ANCOVA model with baseline Hb as a covariate, and CV 
history, geographic region and dialysis duration, as fixed effects. ITT analysis set 
will be used.

Change in Hb from baseline using PMM – Last Mean Carried Forward, as specified 
in Section 4.2.8.1. ITT analysis set will be used.

Change in Hb from baseline using PMM – PMM – Baseline Mean Carried Forward 
(ANCOVA), as specified in Section 4.2.8.2. ITT analysis set will be used.

Change in Hb from baseline using PMM – Baseline Mean Carried Forward for 
roxadustat subjects, MAR assumption for epoetin alfa group (ANCOVA), as 
specified in Section 4.2.8.2. ITT analysis set will be used.
4.3.7
Subgroup analyses
Subgroup analysis will be performed for both the primary efficacy endpoints of Hb, with the 
ITT analysis set for the primary endpoint for US and the PPS for the primary endpoint for EU.

Age: <65 and ≥65; <75 and ≥75 years 

Gender: Male vs Female 

Race: White, Black or African American, Asian, Native Hawaiian or other Pacific 
Islander, American Indian or Alaska native, other 

Weight: <70 kg vs ≥70 kg; and <100 kg vs ≥ 100 kg

Weight by gender-specific median (4 groups)

Body mass index (BMI): <30 and ≥30 kg/m2

Geographical region: US vs Ex-US

Geographical region:

North America

South America 

Asia and Australia 

Europe 

Peritoneal dialysis vs. Hemodialysis 


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
Cardiovascular/cerebrovascular/thromboembolic history: Yes or No 

Baseline Hb value: ≤10.5g/dL and >10.5g/dL

Incident vs stable dialysis: dialysis duration ≤4 months vs >4 months from the 
randomization date

Diabetes history: Yes vs No

Epoetin alfa dose prior to randomization: ≤ 12,500 IU/week and >12,500 IU/week

Baseline hsCRP (≤ULN vs >ULN). 
4.3.8
Safety assessment analysis
The safety analysis will be performed using the OT+7. Safety variables include adverse events 
(AE), laboratory variables, vital signs, ECG variables and physical examinations. For each 
safety variable, the last assessment made on the screening visits or the randomization visit will 
be used as the baseline for all analyses, unless specified otherwise.
4.3.8.1
Adverse events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) version 20.0 higher. 
An AE (classified by preferred term) started during the treatment period will be considered a 
treatment-emergent adverse event (TEAE) if it was not present prior to the first dose of study 
medication. An AE that starts more than 7 days after the last dose of study medication will not 
be counted as a TEAE.
The number, percentage and percentage per PEY of subjects reporting TEAEs in each 
treatment group will be tabulated by system organ class and preferred term; by system organ 
class; by preferred term and by system organ class, 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. In addition to reporting TEAEs by number of subjects, the table by system organ 
class and preferred term will also be reported by patient years and event rates. Thus, allowing 
for potential systematic differences in mean exposure between the treatment groups. The event 
rate for a particular AE will be derived as the number of subjects with the AE, divided by total 
number of days at risk for the AE across all subjects in given group, multiplied by 365.25 
multiplied by 100.
The distribution of TEAEs by severity and relationship to study medication will be 
summarized by treatment group.


Statistical Analysis Plan 
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The incidence of common (≥5% of subjects in any treatment group) TEAEs, common 
treatment-emergent serious AEs (TESAE), and AEs leading to discontinuation of study 
medication will be summarized by preferred term and treatment group, sorted in decreasing 
overall (across treatments) frequency. Moreover, TEAEs leading to hospitalization by system 
organ class and preferred term will be presented. In addition, related deaths and fatal SAEs 
(i.e., events that caused death) will be summarized separately by treatment group, system 
organ class and preferred term. TEAEs with outcome of deaths and TESAEs will also be 
presented for the ITT analysis set.
TEAEs and TESAEs by system organ class and preferred term will also be reported with 
OT+3 and OT+0. 
Listings will be presented of subjects with serious adverse events (SAEs), subjects with 
adverse events leading to discontinuation, and subjects who died.
4.3.8.2
Laboratory variables
Descriptive statistics for laboratory values and mean percent changes from baseline at each 
assessment time point will be presented by treatment group for the following laboratory 
variables collected in the study:

Hematology: Hemoglobin, hematocrit, RBC count, MCV, MCH, MCHC, WBC 
count, WBC differential, platelet counts and Reticulocyte count

Chemistry: Alkaline phosphatase, ALT, AST, total bilirubin, LDH, total protein, 
albumin, fasting glucose, phosphate, uric acid, BUN, creatinine, sodium, and 
potassium.

Serum iron, ferritin, TIBC, TSAT

CHr

Hepcidin and hsCRP
The laboratory values will be presented in SI units, except for Hb, ALT, AST, ALP and 
Gamma Glutamyl Transferase, which will be presented in conventional units
4.3.8.3
Vital signs
Blood pressure baselines are defined as the average of all measurements from the screening 
visits and randomization visit. For subjects on hemodialysis, vital signs should be recorded 
pre-dialysis. For subjects on peritoneal dialysis, vital signs may be recorded at any time during 
the visit.
Descriptive statistics for vital signs (e.g., systolic and diastolic blood pressure and MAP) and 
their changes from baseline at each visit and at the end of study will be presented by treatment 
group.


Statistical Analysis Plan 
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Vital sign values are potentially clinically significant (PCS) if they meet both the observed
value criteria and the change from baseline criteria listed in Table 2 below.  The number and 
percentage of subjects with post-baseline PCS values will be tabulated by treatment group. 
Table 2
Criteria for Potentially Clinically Significant Vital Signs
Vital Sign Parameter
Flag
Criteria*
Observed Value
Change
Systolic Blood Pressure 
(mmHg)
High
≥170
Increase of ≥20
Low
≤90
Decrease of ≥20
Diastolic Blood 
Pressure (mmHg)
High
≥110
Increase of ≥15
Low
≤45
Decrease of ≥15
Pulse Rate (bpm)
High
≥120
Increase of ≥20
Low
≤50
Decrease of ≥20
*
A post-baseline pre-dialysis or post-dialysis value is considered as a PCS value if it meets both criteria for 
observed value and change from pre-dialysis or post-dialysis baseline
4.3.8.4
Electrocardiogram
QTc interval will be calculated using both Bazett (QTcB = QT/(RR)1/2) and Fridericia (QTcF 
= QT/(RR)1/3) corrections; and if RR is not available, it will be replaced with 60/HR in the 
correction formula. 
Box plots for each variable versus visit will be produced by treatment group (roxadustat vs. 
epoetin alfa).  
ECG values are PCS if they meet or exceed the upper limit values listed in Table 3 below.  
The number and percentage of subjects with post-baseline PCS values will be tabulated by 
treatment group. The percentages are to be calculated relative to the number of subjects with 
available baseline and at least one post-baseline assessment. The numerator is the total 
number of subjects with at least one post-baseline PCS ECG value. 
Table 3
Criteria for Potentially Clinically Significant ECG
ECG Parameter
Unit
High Limit
QRS interval
Msec
≥150
PR interval
Msec
≥250
QTc interval
Msec
>500;
Change from baseline >30 and >60


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4.3.8.5
Physical examination
Incidence of physical examination abnormalities will be summarized for the randomization 
visit and the EOT visit by treatment group. Shift tables of baseline vs last observation will be 
provided.
4.3.9
Population PK analysis 
A population PK analysis of data collected in the CKD-dialysis dependent
program will be performed as outlined in a separate population PK analysis plan.
5.
INTERIM ANALYSES
No interim analysis specific to this study will be conducted. 
6.
CHANGES OF ANALYSIS FROM PROTOCOL
There are no changes of analysis from protocol version 8.0, 19 September 2018.
6.1
Changes of analysis from previous edition of the SAP
Table 4
Major changes of analysis from SAP Edition 3.0
SAP Section
Description of change
Rationale
1.1 
The objectives of the study have been 
split to efficacy objectives and safety 
objectives. 
For clarification.
1.1.4
A secondary objective to evaluate the 
efficacy of roxadustat based on Hb 
response in inflamed subjects has been 
added
A secondary objective to evaluate the 
effect of roxadustat on LDL 
cholesterol has been added.
The secondary objective of the effect 
on self-reported health status has been 
removed.
To harmonize with the 
secondary objectives of the 
other phase III studies in the 
program.
1.3
The description of the determination 
of the sample size related to CV safety
has been shortened
Reference to a more detailed 
description of the 
requirements for sample size 
to address CV safety for this 


Statistical Analysis Plan 
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indication is made to the 
pooled statistical analysis 
plan.
2.1.1
FAS is renamed as ITT analysis set. 
To align with the definition 
and terminology adopted in 
the other phase 3 trials in the 
study program.
2.1.2
An additional criteria to PPS has been 
added, which requires subjects to be 
on study drug for at least 8 weeks.
To align with the definitions 
adopted in the other phase 3 
trials in the study program, 
and for clarification.
2.1.3
Added additional safety analysis sets; 
OT+7, OT+3 and OT+0. Removed 
OT+28.
To align with safety analysis 
sets in the PSAP. 
Full analysis set (FAS) is newly 
defined in a new section, Section 
2.1.4.  
To align with the definitions 
and terminology adopted in 
the other phase 3 trials in the 
study program, this analysis 
set will be required for the EU 
submission.
Have added a subsection 2.1.5 that 
describes how subjects who will not 
be included in any analysis sets will be 
handled.
Not included in previous 
editions of the SAP. 
2.2
Changed the level of deviation for the 
important protocol deviation of 
compliance to subject level from visit 
level.
To simplify the derivation of 
compliance and harmonize 
with the other phase III studies 
in the program
3
The structure of this section and its 
subsections are rearranged.
The subsection on primary efficacy 
variables is split into two parts, one for 
US FDA and the other for EU health 
authority. 
The subsections on primary and 
secondary safety variables is renamed 
as “Adjudicated CV events Analyses 
To harmonize with the 
primary variables of the other 
phase III studies in the 
program


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for Safety Assessments” and its 
description is replaced by new texts on 
the pooling of the adjudicated 
composite safety endpoints from all 
the phase 3 studies of the program. 
Subsections of 
Section 3 related 
to secondary and 
exploratory 
efficacy variables
The primary efficacy variable 
designated for EU health authority is 
added as the first Hb-related 
secondary efficacy variable designated 
for US FDA.  
Changed the timing of the hsCRP 
variable to the average level between 
week 28 to week 52.
Added a variable for proportion of 
total time of interpolated Hb values 
≥10 g/dL from week 28 until week 52 
to the secondary variables. A 
corresponding analysis has been added 
to Section 4 as a secondary efficacy 
analysis.
Downgraded the secondary variables 
of mean change from baseline in Hb, 
averaged over week 28 to EOT visit, 
Hb response, FACT-An variable, 
PGIC variable and EQ-5D-5L variable 
to exploratory variables and their 
corresponding analyses to exploratory 
in Section 4. 
Added a new section for lipid related 
secondary efficacy variables. A 
corresponding analysis has been added 
as a secondary efficacy analysis in 
Section 4. 
Added exploratory endpoint of 
proportion of subjects with RBC 
transfusion within weeks 28-52 in 
To harmonize with the 
secondary variables of the 
other phase III studies in the 
program
To investigate the added 
secondary objective to 
evaluate LDL cholesterol.


Statistical Analysis Plan 
Study Code D5740C00002
Edition Number 4.0
Date 28 September 2018
43
Section 3 and the corresponding 
exploratory analysis in Section 4.
Added exploratory endpoint of 
proportion of anemic ESA-naïve 
subjects in Section 3 and the 
corresponding exploratory analysis in 
Section 4.
Added exploratory variables related to 
hospitalization-free, emergency room-
free, and skilled nursing facility-free 
survival in Section 3 and their 
corresponding exploratory analysis in 
Section 4.
Added exploratory variables for 
measuring the proportion of time 
subjects were on different Hb levels in 
Section 3 and their corresponding 
exploratory analysis in Section 4.
Added exploratory variables that 
repeat the secondary endpoints 
number 3, 4 and 6 on the time period 
week 28 to week 36. 
Exploratory variables and 
analyses of interest
3.4
Changed the derivation of compliance
To harmonize with the 
definition with the other phase 
3 studies in the program
4.1
A method to impute the last dose date, 
if missing, has been added.
To handle missing last dose 
dates. 
4.1.1
The criteria to censor at PACD has 
been removed.
Subjects will be censored at the EOS 
instead of EOT for FAS.
To harmonize with the 
censoring rules of the PSAP.
4.1.4
Deleted Section “Investigation of 
informative censoring”.
Not applicable since the CV 
analyses will not be performed 
for the individual CSR. 


Statistical Analysis Plan 
Study Code D5740C00002
Edition Number 4.0
Date 28 September 2018
44
4.2.6
Decreased the number of multiple 
imputations to 200 from 1000.
To reduce the computational 
runtime. 
Subsections of 
Section 4 related 
to statistical 
analyses on CV 
Safety
Removed the statistical analyses of the 
adjudicated CV events from this SAP. 
Deleted section “Model checking”.
All analyses of CV safety will 
be conducted in accordance 
with the PSAP, and will not be 
done for the individual CSR.
Not applicable since the CV 
analyses will not be performed 
for the individual CSR.
Subsections of 
Section 4 related 
to statistical 
analysis on 
efficacy 
The section on primary efficacy 
endpoint analysis is split into two 
sections, one for US FDA and the 
other for EU health authority.
The primary efficacy endpoint 
designated for EU health authority is 
added as the first secondary efficacy 
endpoint designated for US FDA
Changed the ordering of the secondary 
efficacy endpoints.
The PPS will be used for the first 
secondary endpoint, OT+3 analysis set 
will be used for the secondary 
endpoints related to RBC transfusion 
as rescue therapy, and the ITT analysis 
data set will be used for all the 
remaining secondary endpoints.
Changed the analysis model of IV iron 
to Wilcoxon Rank Sum test. 
Analyses of the exploratory efficacy 
endpoints newly added in Section 3 
are specified accordingly.
To harmonize with the 
primary variables of the other 
phase III studies in the 
program
To harmonize with the 
secondary endpoints of the 
other phase III studies in the 
program. A decision based on 
balancing clinical importance 
of different endpoints together 
with the likelihood for 
success.
To better the fit the 
distribution of the IV iron 
data.
Analyses of interest


Statistical Analysis Plan 
Study Code D5740C00002
Edition Number 4.0
Date 28 September 2018
45
The analysis data sets of individual 
sensitivity analyses are updated, and 
new sensitivity analyses are added. 
To harmonize with the 
sensitivity analyses of the 
other phase III studies in the 
program
4.3.10.1
The sentence “Finally, TESAEs that 
occurred during the 4-week period 
preceding an excessive erythropoiesis 
event will be presented by system 
organ class, preferred term and 
treatment group” is removed. 
Change the safety analyses to be on 
OT+7 instead of OT+28.
Added analyses on key safety 
variables for OT+7, OT+3 and OT+0.
To align with safety analysis 
sets in the PSAP and the 
safety analysis in the other 
phase 3 studies in the 
program. 
Analyses of interest.
4.3.10.3  
Vital sign baseline definition has 
changed from using the last 
assessment prior to the first dose to the 
average of all measurements from the 
screening visits and randomization 
visit.
Deemed to be a more 
meaningful definition of the 
baseline from a clinical 
perspective. 
7.
REFERENCES
Aranesp 2001
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Accessed on 22MAY2014. 
Carpenter et al. 2013
Carpenter JR, Roger JH and Kenward MG, Analysis of longitudinal trials with protocol 
deviation: - A Framework for Relevant, Accessible Assumptions, and Inference via Multiple 
Imputation. Journal of Biopharmaceutical Statistics, issue 6 (November/December) in volume 
23 (2013). 1352-137
Gart & Nam 1990
Gart J., and Nam J. Approximate Interval Estimation of the Difference in Binomial
Parameters: Correction for Skewness and Extension to Multiple Tables. Biometrics


Statistical Analysis Plan 
Study Code D5740C00002
Edition Number 4.0
Date 28 September 2018
46
1990, 46: 637-643.
Miettinen & Nurminen 1985
Miettinen O, Nurminen M. Comparative analysis of two rates. Statistics in Medicine; 4(2), 
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O’Kelly & Ratitch, 2014
O’Kelly M, Ratitch B, 2014. Clinical Trials with Missing Data – A Guide for Practitioners.
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Omontys Product Approval Information Summary. Available at 
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Rubin, 1987
Rubin, D. B. Multiple imputation for nonresponse in surveys. New York: Wiley.
Schafer, 1997
Schafer, J. L. Analysis of incomplete multivariate data. London: Chapman and Hall.
8.
APPENDIX
Not applicable.