Conditions: Anemia
Keywords: Renal, CKD, Roxadustat, anemia, non-dialysis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2781
Healthy volunteers: no

Brief summary:
The purpose of the study is to evaluate the safety and efficacy of roxadustat for treatment of anemia in patients with chronic kidney disease not on dialysis

Detailed description:
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study in anemic patients with Stage 3, 4 or 5 chronic kidney disease (CKD) who are not on dialysis.

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Roxadustat intervention 2: Placebo
Intervention descriptions: intervention 1: The initial study drug dose is 70 mg three times a week (TIW). The dose is subsequently adjusted to achieve and maintain Hb 11±1 g/dL. intervention 2: The initial study drug dose is 70 mg three times a week (TIW). The dose is subsequently adjusted to achieve and maintain Hb 11±1 g/dL.

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol 
Drug Substance
Roxadustat
Study Code
D5740C00001
Version
6.0
Date
31 August 2018
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled
Study Evaluating the Safety and Efficacy of Roxadustat for the
Treatment of Anemia in Chronic Kidney Disease Patients not on Dialysis
Sponsor: AstraZeneca AB, S-151 85 Södertälje, Sweden


Clinical Study Protocol
Drug Substance Roxadustat
Study Code D5740C00001
Version 6
Date 31 August 2018
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VERSION HISTORY
Clinical Study Protocol version 6.0 (current version)
Rationale for protocol amendment:
A primary efficacy objective has been added, with specification of accompanying variables 
and analyses, in order to harmonize D5740C00001 with the other phase 3 trials in the 
roxadustat CKD non-dialysis program (FG-4592-060 and 1517-CL-0608). This will allow 
D5740C00001 to serve as a pivotal study to support both efficacy and safety of roxadustat 
for the treatment of CKD anemia. Furthermore, additional secondary efficacy objectives, 
with specification of accompanying variables and analyses, have been added and the 
corresponding ordering of secondary endpoints has been updated.
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), and will not be reported in 
the individual CSR. However, all these analyses of adjudicated CV events will be made by 
individual study and then pooled and analyzed, as described in the PSAP, adopting meta-
analysis techniques. Hence, all analyses of CV safety for this study will be reported in 
conjunction with the pooled analyses. Consequently, these analyses will not be duplicated 
separately for this individual study.
Summary of changes from Revised Clinical Study Protocol Edition 1.0 (Version 5.0), 
21 December 2015 to version 6.0:
All below changes are updated in relevant sections of the study protocol.
Throughout the document:
Hematopoiesis changed to erythropoiesis.
Rationale: 
Clarification.
Synopsis and section 2.1. Primary Objectives
Here are the changes as follows:
1. Previous primary objective is now specified as  primary safety objective. 
2. Primary efficacy objective and its two outcome measures, one for US FDA and one 
for EU health authority, are added.  
3. The previous texts on primary objective are moved to the section on primary safety 
objective. New texts stating that pooled CV safety analyses are now described in the 
PSAP.
Rationale: 
Harmonizes D5740C00001 with the other phase 3 trials in the roxadustat CKD non-dialysis 
program, to serve as a pivotal study for confirming efficacy and safety, and facilitates 
assessement of pooled efficacy and safety across the phase 3 trials.


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Synopsis and section 2.2. Secondary objectives
Here are the changes as follows:
1. The secondary objectives are split into the secondary efficacy and secondary safety 
objectives.   
2. The two previous CV-related secondary objectives (MACE+ and CSE) are removed  
as all analyses of CV safety will be conducted in accordance with the Pooled SAP 
(PSAP), and will not be done for the individual CSRs.  
3. The previous secondary objective with its outcome measures related to anaemia 
symptoms using FACT-An is removed.
4. The previous secondary objective with its outcome measures related to self-reported 
health status using EQ-5D-5L and PGIC is removed.   
5. “Proportion of total time of Hb ≥10 g/dL from week 28 to week 52”, is added for 
the secondary efficacy objective based on Hb response and level during the study.   
6. The time-frame to evaluate the proportion of total time of Hb measurements within 
the interval of 11±1 g/dL is changed from “from week 28 until end of treatment 
visit” to “from Week 28 to week 52”.
7. 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.
8. The previous rescue therapy related secondary objective is moved to the secondary 
efficacy objective together with its corresponding composite outcome measures, 
including IV, RBC or ESA as rescue therapy. Also, additional outcome measure, 
including RBC only as rescue therapy, is added to this secondary objective.
Proportion and number of subjects receiving rescue therapy (composite or RBC
only) are aslo reported.
9. The previous health-related quality of life related secondary objective is moved to 
the secondary efficacy objective together with its outcome measure.
10. The previous secondary objective related to CKD progression is moved to the 
secondary efficacy objective. Its outcome measure is the annual rate of eGFR 
change in log scale, calculated as the linear slope of log (eGFR values) to prior to 
initiation of dialysis/kidney transplant
11. The secondary efficacy objectives with its outcome measure related to LDL 
cholesterol is added.
Rationale for change:
To harmonize with the secondary objectives of the other phase 3 studies in the program.
Synopsis, Study Period and Treatment Period
Expansion of the study duration. Enrollment is anticipated to occur over approximately a 3 
year period followed by an additional 1-2 year treatment period. 
Rationale:
Study duration prolonged to observe requisite number of patients with adjudicated CV 
endpoint events in the phase 3 study program.
Synopsis, Sample Size Determination and 8.2 Sample Size estimate


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The sample size determination has been revised, allowing now also for primary efficacy 
objective.  
Rationale for change:
Harmonization with the strategy for the analyses of efficacy and CV safety for the study 
program as described in the PSAP.
Synopsis and 9.3 Study timetable and end of study
Extension of study in Q3 2018.
Rationale: 
The study end date has been changed to reflect a common study end date across the phase 3 
trials when the requisite number of patients with adjudicated CV endpoints is anticipated.
Section 1.4.1 Treatment duration and dosing and 4.2 Treatment period
Removal of the statement, “Treatment duration is expected to vary between 1 and 2 years.
Rationale: 
Some patients will be treated for up to 4 years.
Section 1.4.4 Visits
Change from “During the treatment period, patients will be contacted by telephone at week 
1, and will attend study visits every two weeks from week 2 to 20.” To “During the 
treatment period, patients will be contacted by telephone at week 1, and will attend study 
visits every two weeks from weeks 0 to 20.”
Rationale: Clarification.
Section 3.9.1 Temporary discontinuation from investigational product
Added statement clarifying that study drug should be withheld for subjects receiving 
erythropoietin analogue rescue therapy.
Rationale: Clarification
Section 3.9.2 Permanent discontinuation from investigational product
Added the following: 
!
Patients who have received two courses of erythropoietin analogue rescue 
therapy, and for whom there is a need for a third course of rescue with 
erythropoietin analogue
!
For patients initiating dialysis during the study; and for whom there is a 
need for rescue with erythropoietin analogue
Rationale: 
Clarification to make this section of the protocol consistent with section 7.7.4.3 which states 
that the above are reasons for permanent discontinuation from investigational product.
Section 3.9.3 Procedures for discontinuation of a patient from investigational product
Added statements clarifying that subjects who are permanently discontinued from study 
drug prior to study closure, should be followed until study closure; and that subjects who 
permanenty discontinue study drug prior to study closure may be followed via modified 


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follow-up schedules. 
Rationale: Clarification 
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: Clarification.
Section 3.9.3.3 Patient refuses any form of follow-up
Entire section clarified and elaborated.
Rationale: Clarification.
Section 3.10: Criteria for withdrawal
Entire section clarified and elaborated.
Rationale: Clarification.
Section 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: Clarification
Section 3.11 Discontinuation of the study and Section 4 Study Plan and timing of 
procedures
“The independent DSMB will monitor the study to ensure patient safety” moved from 
section 4 to section 3.11.
Rationale: 
To improve clarity.
Table 1 Study Plan
Randomization visit footnote removed. 
Rationale: 
Error correction.
Table 1 Laboratory Values table from Section 5.2, and Section 5.7.1
Added that hepcidin and hsCRP will be analyzed from biomarker samples
Rationale: To enable evaluation of hepcidin and hsCRP in the clinical program. 
Section 4.1.2: Additional screening assessments
Deleted the following text, “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.”
Rationale: Clarification 
Section 5.1.1 Secondary efficacy assessments


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The title of this section is changed to “Efficacy assessment”.
Rationale: 
Assement of Hemoglobin level specified in 5.1.1.1 is for both the primary and some of the 
secondary efficacy endpoints.   
Section 5.1.1.2: Use of rescue therapy
Changed “Use of rescue medications” to “Use of rescue therapy”
Rationale: Section refers to rescue medications as well as red blood cell transfusion
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.
Section 5.7.3: Chain of custody of biological samples
Added the following statement: “Samples retained for future use are registered within the 
relevant sample tracking system at AstraZeneca.”
Section 5.7.4 Samples retained for future use are registered within the relevant sample 
tracking system at AstraZeneca. Withdrawal of informed consent for donated 
biological samples
Insertion of “However, this does not result in withdrawal of the patient from the study and 
patient should continue until the end of study”.
Removal of “As collection of the biological samples is an optional part of the study, 
then the patient may continue in the study.”
Rationale: 
Clarification.
Section 6.1 Definition of adverse event
Addition of the following language defining Treatment Emergent Adverse Event:
“An AE (classified by preferred term) that occurs during the double-blind treatment period 
will be considered a TEAE (Treatment Emergent Adverse Event) if it was not present prior 
to the first dose of study drug, or it was present prior to the first dose of study drug but 
increased in severity during the double-blind treatment period. An AE that occurs more than 
28 days after the last dose of study medication will not be counted as a TEAE.”
Rationale: 
Need for definition of TEAE (treatment emergent AE).
Section 6.3.1 Time period for collection of adverse events
Reference to section 3.9.3.2 added.
Rationale: 
Clarification.
Section 6.3.8 Disease progression


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Section reworded, to clarify that both worsening of anemia and CKD progression should be 
considered disease progression and not AEs. Also, added the following text at the end of the 
section: “Acute kidney injury, when meeting diagnostic criteria (i.e. based on serum 
creatinine values or urine output), can be considered an AE or SAE. AEs or SAEs that cause 
anemia should be recorded, but anemia for which no cause is found other than CKD should 
not be reported as an AE or SAE.”
Rationale: 
Clarification to disease progression and AE reporting.
Section 6.3.9 Patients initiating dialysis during the treatment period
Section reworded. Addition of protocol specific reasons. Removal of dose adjustment 
wording.
Rationale: 
Clarification to be more specific.
Section 7.2.5 Patients initiating dialysis during the treatment period
Section reworded. Addition of protocol specific reasons. Removal of dose adjustment 
wording.
Rationale: 
Clarification of language.
Section 7.7.4.3 Initiation of Rescue with an approved erythropoietin analogue
Deleted “For patients initiating dialysis, study drug should be permanently discontinued.” 
and added, “Study drug should be permanently discontinued for subjects who initiate 
dialysis and who are clinically judged to require erythropoietin analogue therapy.”
Rationale: Clarification
Statistical methods and Statistical analyses
Change to outcome measures and the evaluation of the data.
Rationale: 
Harmonization of D5740C00001 with the other phase 3 trials in the roxadustat non-dialysis 
program.
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.
Section 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. 


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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.
Section 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
Section 8.3.3 Safety Analysis Set (SAS)
Here are the changes as follows:
1. Treatment groups to which SAS subjects belong is further clarified.
2. The Censoring rule for SAS subjects is specified.    
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.
Section 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:
Not included in previous editions of the CSP.
Section 8.4 Outcome measures for analyses
Here are the changes as follows: 
1. Texts under “primary endpoint” and “Additional safety composite endpoints” are 
replaced by new texts and moved under a new section, 8.5, entitled “Adjudicated 
composite safety endpoint events” 
2. A subsection, 8.4.1, specific to the primary efficacy endpoint with two outcome 
measures, one for US and one for EU health authorities, is added.


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3. Texts under “Secondary points” are re-structured with the following changes:
a.
“Efficacy related endpoints” are re-structured into five new subsections, 
8.4.2-8.4.6, one related to Hb, one to lipid, one to rescue therapy, one to 
health-related quality of life by SF-36 (Version 2, standard) and one to 
CKD progression, each with corresponding outcome measures specified. 
b.
“Mean change in Hb from baseline to the end of treatment period (EOT), 
utilizing all Hb values from week 28 until the EOT”, is moved under the 
primary efficacy endpoint for US FDA, and its timeframe is changed from 
“Week 28 to EOT” to “Week 28 to Week 52”. The missing value 
imputation is changed from MMRM to MI ANCOVA with its details in 
SAP.
c.
EU primary endpoint is added as a secondary endpoint for the analysis for 
FDA.
d. 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) is added as
Hb related secondary efficacy endpoint  
e.
Proportion of total time of Hb ≥10 g/dL from week 28 to week 52 is 
added as Hb related secondary efficacy endpoint. 
f.
“Proportion of total time of Hb measurements within the interval of 10-12
g/dL from week 28 until end of treatment visit”, is moved under the 
Section 8.4.2, and its timeframe is changed from “Week 28 until end of 
treatment visit” to “Week 28 to Week 52”. 
g. “Endpoints related to HRQoL and health status” except the one related to 
health-related quality of life by SF-36 (Version 2, standard) under Section 
8.4.5, are moved from secondary endpoint to exploratory endpoint.
h.
“Evaluation of the need for rescue therapy” related to IV iron is removed. 
The other two points are moved under the section 8.4.4, with more details 
specified.
Rationale for change:
For structure clarification and to harmonize with the other phase III studies in the program. 
Section 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 Events 
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 
trials.


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Section 8.5.1 Stratification variables
Here are the changes as follows: 
1.
The section number is changed 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 be in agreement with the other studies in the program
Section 8.5.2. Analysis of the primary variable
Here are the changes as follows: 
1. This section is split into two sections, 8.6.2 and 8.6.3, entitled “Analysis of primary 
efficacy endpoint for US” and “Analysis of primary efficacy endpoint for EU”, 
respectively.
2. New texts on the analysis of the primary efficacy endpoint for US and EU are added.  
3. Previous texts in this section are removed.
Rationale for change:
To be in agreement with the other studies in the program
Section 8.5.3 Analysis of the secondary variables
Here are the changes as follows: 
1.
The section number is changed to 8.6.4. 
2. The title of this section is changed to “CV safety endpoint analyses”. 
3. New texts on CV safety endpoint analyses according to the PSAP using adjudicated 
pooled data across the study program are added.      
4. Previous texts in this section are moved to the Section 8.6.5 with changes specified 
below. 
Rationale for change:
Strategic change in the approach to address CV safety for the project. 
Section 8.5.4 Additional Secondary Analyses
Here are the changes as follow:
1. The section number is changed to 8.6.5. 
2. The title of this section is changed to “Analysis of the secondary efficacy 
endpoints”.
3. Previous texts in this section are removed. 
4. Previous texts in Section 8.5.3 were moved to this section with the following 
changes:
a.
ITT analysis date set is used for all the secondary efficacy endpoints except 
for the first secondary efficacy endpoint and the two rescue related 
endpoints. 
b. The secondary efficacy endpoint related to mean change in Hb from baseline 
to average Hb from week 28 until EOT is removed. 


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c.
Time-to-event analyses including time-to-first MACE+ and time-to-first CSE 
are referred to the PSAP.
d. IV iron use is now an exploratory, rather than a secondary, efficacy endpoint
(see SAP).
e.
The erythropoietin analogues use as rescue therapy is now an exploratory, 
rather than a secondary, efficacy endpoint (see SAP). 
f.
The EU primary endpoint is added as a secondary endpoint for the analysis 
for FDA
g. The time-frame of the secondary efficacy endpoint related to the proportion 
of total time of Hb within the interval of 10-12 g/dL is changed, from “week 
28 to EOT” to “week 28 to week 52”.
h. The secondary efficacy endpoint related to FACT-An is moved to 
exploratory analyses (see SAP). 
i.
The secondary efficacy endpoints related to EQ-5D-5L and PGIC are moved 
to exploratory analyses (see SAP).
j.
The secondary efficacy endpoint related to SF-36 is split into two secondary 
efficacy endpoints.
k. FAS will not be used for the secondary efficacy endpoint related to 
composite and RBC-only rescue therapy. Instead, the OT+28 censoring rule 
will be used.
5. Additional secondary efficacy endpoints are added, two related to Hb-response, 
one to LDL cholesterol, and one to CKD progression. 
6. The list of the secondary endpoints is re-ordered.
Rationale for change:
To harmonize with the secondary efficacy endpoints of the other phase III studies in the 
program.
Section 8.5.5 Testing order
This section is removed.
Rationale for change:
To avoid repeating the related texts specified in “Analysis of the secondary efficacy 
endpoints”.
Section 8.5.9 Exploratory analysis
The section number is changed to 8.6.9 and the previous texts in this section are changed to 
indicate that the analysis details are specified in SAP.
Rationale for change:
For clarificaction
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.


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Revised Clinical Study Protocol Edition 1.0 (Version 5.0), 21 December 2015
An administrative change was approved (dated 21 December 2015), correcting errors and 
clarifying operational aspects of the protocol. Revised Clinical Study Protocol Edition 1.0 
was the resulting version number, as this was the first revision of the protocol.
History of the changes is included in the previous CSP versions.
Clinical Study Protocol Version 4.0, 26 September 2014
Edition 4.0 was the protocol submitted and approved globally.
History of the changes is included in the previous CSP versions.
Clinical Study Protocol Version 3.0, 22 August 2014
Version 3.0 was finalized but never used. Czech Republic & Russia submitted this edition to 
HA, but have only enrolled patients on Edition 4.0. 
History of the changes is included in the previous CSP versions.
Clinical Study Protocol Version 2.0, 21 May 2014
Olympus protocol Edition 2.0 was submitted and approved in the United States only, 
as the study began in that market.
History of the changes is included in the previous CSP versions.
Clinical Study Protocol Version 1.0, 25 March 2014
Initial creation.
Was never submitted in any country.


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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.


Clinical Study Protocol Synopsis
Drug Substance Roxadustat
Study Code D5740C00001
Version 6.0
Date 31 August 2018
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PROTOCOL SYNOPSIS
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Study Evaluating the Safety and Efficacy of Roxadustat for the Treatment 
of Anemia in Chronic Kidney Disease Patients not on Dialysis
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 patients planned
Approximately 2600 patients will be randomized at approximately 400 study centers 
worldwide.
Study period
Phase of development
Date of first patient enrolled
Q2 2014
III
Estimated date of last subject completed
Q3 2018
Study design
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate 
efficacy and safety in anemic patients with Stage 3, 4 or 5 chronic kidney disease (CKD) who
are not on dialysis.


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Study Objectives
Primary Efficacy Objective:
Outcome Measure:
Evaluate the efficacy of roxadustat compared 
to placebo for the treatment of anemia in CKD 
subjects not on dialysis.
US FDA: The primary efficacy endpoint for the US is 
the mean change from baseline in Hb averaged over 
week 28 to week 52. 
EU health authorities: The primary efficacy 
endpoint is whether patients achieved 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 (RBC transfusion, ESA, or IV iron) prior to 
Hb response. 
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 compared to 
placebo 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 efficacy of roxadustat compared to 
placebo 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 effect of roxadustat compared to placebo 
on Low-density lipoprotein (LDL) cholesterol
Mean change in LDL cholesterol from baseline to 
week 24


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Secondary Efficacy Objectives:
Outcome Measure:
The need for rescue therapy in subjects treated 
with roxadustat compared to placebo
Time-to-first (and proportion of subjects receiving)
instance of receiving intravenous (IV) iron, red blood 
cell (RBC) transfusions, or erythropoietin analogue as 
rescue therapy.
Time-to-first (and proportion of subjects receiving)
instance of receiving red blood cell (RBC) 
transfusions as rescue therapy.
The effect of roxadustat on anemia symptoms 
and health-related quality of life (HRQoL) 
based on comparison with placebo
Changes in generic HRQoL as measured by the
SF-36 (Vital Status and Physical Functioning)
The effect on the CKD progression of 
roxadustat as compared to placebo 
Annual rate of eGFR change in log scale, calculated 
as the linear slope of log (eGFR values) to prior to 
initiation of dialysis/kidney transplant
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 patient population
Anemic patients (Hb <10 g/dL) with Stage 3, 4 or 5 CKD who are not on dialysis.
Duration of treatment
This study will consist of three study periods as follows:
!
Screening Period: Up to 6 weeks
!
Treatment Period: Patients will be randomized (1:1) to double-blind treatment 
with roxadustat or placebo. A study end date will be declared and common closeout 
will occur when the target number of CV events has been accrued. It is anticipated 
that enrollment will occur over approximately a 3 year period and that an additional 
1 to 2years may be required to accumulate the requisite number of patients with 
positively adjudicated endpoint events. 
!
Post-Treatment Follow-Up Period: 4 weeks.
Investigational product, dosage and mode of administration
The initial study drug dose is 70 mg three times a week (TIW). The dose is subsequently 
adjusted to achieve and maintain Hb 11±1 g/dL. Study drug doses must be administered at 
least 2 days apart and no more than 4 days apart, except in subjects who require dose hold or 
dose reduction to 20 mg once weekly.


Clinical Study Protocol Synopsis
Drug Substance Roxadustat
Study Code D5740C00001
Version 6.0
Date 31 August 2018
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Dose adjustments are permitted starting at week 4 and at intervals of every 4 weeks until week 
52, every 8 weeks thereafter, unless a dose reduction is required for excessive erythropoiesis 
(see Table 4). Study drug will be dosed TIW throughout the study treatment period unless 
downward dose adjustment requires a change to twice or once weekly.
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.
Statistical methods
Sample Size Determination
Primary efficacy endpoint: A sample size of 450 subjects will have > 99% power to detect a 
0.75 g/dL difference in mean Hb values between the two treatment groups, assuming that the 
common standard deviation is 1.2 g/dL, using an analysis of variance (ANOVA) test with a 
0.05 two-sided significance level.
To contribute adjudicated CV safety events for the pooled CV analyses across the phase 3 
program: approximately 2600 subjects are planned to be randomized in a 1:1 ratio to either 
roxadustat or placebo. The sample size in this study is driven by the overall requirement of 
adjudicated CV events for the phase 3 program in CKD-NDD (which consists of 3 studies in 
total targeting 465 subjects with MACE events). The two other placebo-controlled studies in 
the study program are FGCL-4592-060 and 1517-CL-0608.
Further information related to the sample size determination can be found in the study 
statistical analysis plan and the pooled statistical analysis plan.


Clinical Study Protocol
Drug Substance Roxadustat
Study Code D5740C00001
Version 6.0
Date 31 August 2018
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TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
VERSION HISTORY..........................................................................................2
PROTOCOL SYNOPSIS...................................................................................14
TABLE OF CONTENTS...................................................................................18
1.
INTRODUCTION .............................................................................................27
1.1
Background and rationale for conducting this study ...........................................27
1.2
Rationale for study design, doses and control groups..........................................27
1.2.1
Rationale for control group ................................................................................ 27
1.2.2
Rationale for doses.............................................................................................28
1.2.3
Rationale for hemoglobin level ..........................................................................28
1.3
Benefit/risk and ethical assessment ....................................................................29
1.4
Study Design...................................................................................................... 29
1.4.1
Treatment duration and dosing ...........................................................................30
1.4.2
Randomization...................................................................................................30
1.4.3
Blinding.............................................................................................................30
1.4.4
Visits .................................................................................................................30
2.
STUDY OBJECTIVES......................................................................................33
2.1
Primary objectives .............................................................................................33
2.2
Secondary objectives..........................................................................................33
3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL.....................34
3.1
Inclusion criteria ................................................................................................34
3.2
Exclusion criteria ............................................................................................... 35
3.3
Patient enrollment and randomization ................................................................36
3.4
Procedures for handling incorrectly enrolled or randomized patients..................37
3.5
Methods for assigning treatment groups.............................................................37
3.6
Methods for ensuring blinding ...........................................................................37
3.7
Methods for unblinding......................................................................................38
3.8
Restrictions........................................................................................................38
3.9
Discontinuation of investigational product .........................................................38
3.9.1
Temporary discontinuation from investigational product....................................38
3.9.2
Permanent discontinuation from investigational product.....................................39
3.9.3
Procedures for discontinuation of a patient from investigational product ............39


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Study Code D5740C00001
Version 6.0
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3.9.3.1
Patient agrees to undergo the Premature Treatment Discontinuation Visit 
and then continue in-person study visits .............................................................40
3.9.3.2
Patient refuses to continue in-person study visits but agrees to undergo 
modified follow-up ............................................................................................40
3.9.3.3
Patient refuses any form of follow-up................................................................. 41
3.9.3.4
Restart of study medication................................................................................41
3.9.3.5
End of study procedures..................................................................................... 41
3.10
Criteria for withdrawal.......................................................................................41
3.10.1
Screen failures ...................................................................................................41
3.10.2
Withdrawal of the informed consent...................................................................42
3.11
Discontinuation of the study............................................................................... 42
4.
STUDY PLAN AND TIMING OF PROCEDURES...........................................42
4.1
Enrollment/screening period ..............................................................................45
4.1.1
Screening visits..................................................................................................45
4.1.2
Additional screening assessments.......................................................................45
4.2
Treatment period................................................................................................ 45
4.3
Follow-up period................................................................................................ 46
5.
STUDY ASSESSMENTS..................................................................................46
5.1
Efficacy assessments.......................................................................................... 46
5.1.1
Efficacy assessments.......................................................................................... 46
5.1.1.1
Hemoglobin level...............................................................................................46
5.1.1.2
Use of rescue therapy.........................................................................................47
5.2
Safety assessments............................................................................................. 47
5.2.1
Cardiovascular events ........................................................................................47
5.2.2
Laboratory assessments...................................................................................... 48
5.2.3
Physical examination .........................................................................................49
5.2.4
ECG...................................................................................................................49
5.2.4.1
Resting 12-lead ECG..........................................................................................49
5.2.5
Vital signs..........................................................................................................50
5.2.5.1
Heart rate and Blood pressure ............................................................................50
5.3
Other assessments.............................................................................................. 50
5.3.1
Patient reported outcomes ..................................................................................50
5.3.1.1
Short Form 36 – (SF-36) ....................................................................................50
5.3.1.2
Functional Assessment of Cancer Therapy - Anemia (FACT-An) ......................51
5.3.1.3
Patients’ Global Impression of Change (PGIC) ..................................................51
5.3.1.4
EuroQol Health Utility Index - (EQ-5D-5L)....................................................... 51
5.3.1.5
Administration of patient-reported outcome .......................................................51
5.3.2
Hospitalizations .................................................................................................52
5.4
Pharmacokinetics ............................................................................................... 52
5.4.1
Collection of samples.........................................................................................52
5.4.2
Determination of study drug concentration.........................................................53


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Study Code D5740C00001
Version 6.0
Date 31 August 2018
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5.4.3
Storage and destruction of pharmacokinetic samples..........................................53
5.5
Pharmacodynamics ............................................................................................53
5.5.1
Collection of samples.........................................................................................53
5.5.2
Storage, re-use and destruction of pharmacodynamic samples............................53
5.6
Pharmacogenetics .............................................................................................. 53
5.6.1
Collection of pharmacogenetic samples..............................................................53
5.6.2
Storage, re-use and destruction of pharmacogenetic samples..............................54
5.7
Biomarker analysis............................................................................................. 54
5.7.1
Storage, use, re-use and destruction of biological samples..................................55
5.7.2
Labelling and shipment of biological samples ....................................................55
5.7.3
Chain of custody of biological samples ..............................................................55
5.7.4
Withdrawal of Informed Consent for donated biological samples.......................55
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 56
6.1
Definition of adverse events............................................................................... 56
6.2
Definitions of serious adverse event ...................................................................57
6.3
Recording of adverse events............................................................................... 57
6.3.1
Time period for collection of adverse events ......................................................57
6.3.2
Follow-up of unresolved adverse events.............................................................57
6.3.3
Variables............................................................................................................57
6.3.4
Causality collection............................................................................................59
6.3.5
Adverse events based on signs and symptoms....................................................59
6.3.6
Adverse events based on examinations and tests ................................................59
6.3.7
Liver enzymes....................................................................................................60
6.3.8
Disease progression............................................................................................60
6.3.9
Patients initiating dialysis during the treatment period........................................60
6.4
Reporting of serious adverse events ................................................................... 60
6.5
Overdose............................................................................................................61
6.6
Pregnancy .......................................................................................................... 61
6.6.1
Maternal exposure..............................................................................................62
6.6.2
Paternal exposure...............................................................................................62
6.7
Management of IP related toxicities ...................................................................62
6.8
Study governance and oversight.........................................................................63
6.8.1
International coordinating investigator ...............................................................63
6.8.2
Independent Endpoint Review Committee..........................................................63
6.8.3
Data Safety Monitoring Board............................................................................63
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ...................63
7.1
Identity of investigational product(s)..................................................................63
7.2
Dose and treatment regimens .............................................................................64
7.2.1
Randomization...................................................................................................64


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7.2.2
Starting dose and dose adjustment......................................................................64
7.2.3
Dose adjustment for excessive Erythropoiesis .................................................... 65
7.2.4
Dose adjustment for Hb ≥ 13.0g/dL....................................................................65
7.2.5
Patients initiating dialysis during the treatment period........................................65
7.3
Labelling............................................................................................................66
7.4
Storage............................................................................................................... 66
7.5
Compliance........................................................................................................ 66
7.6
Accountability....................................................................................................66
7.7
Concomitant and other treatments ......................................................................66
7.7.1
Concomitant medications...................................................................................66
7.7.1.1
Statins................................................................................................................66
7.7.1.2
Phosphate binders ..............................................................................................67
7.7.1.3
Herbal medicines ...............................................................................................67
7.7.2
Prohibited medications.......................................................................................67
7.7.3
Supplemental iron use........................................................................................67
7.7.4
Rescue therapy guidelines.................................................................................. 67
7.7.4.1
Intravenous iron supplementation.......................................................................68
7.7.4.2
Red blood cell transfusion..................................................................................68
7.7.4.3
Initiation of Rescue with an approved erythropoietin analogue........................... 68
7.7.4.4
Therapeutic Phlebotomy ....................................................................................69
7.7.4.5
Other concomitant treatment ..............................................................................69
7.8
Post Study Access to Study Treatment ............................................................... 69
8.
STATISTICAL ANALYSES BY ASTRAZENECA..........................................69
8.1
Statistical considerations....................................................................................69
8.2
Sample size estimate ..........................................................................................70
8.3
Definitions of analysis sets................................................................................. 70
8.3.1
Intention To Treat Analysis Set (ITT) ................................................................70
8.3.2
Per Protocol Set (PPS) .......................................................................................70
8.3.3
Safety analysis set..............................................................................................70
8.3.4
Full Analysis Set (FAS) .....................................................................................71
8.3.5
Subjects who will not be included in any analysis sets........................................71
8.4
Outcome measures for analyses..........................................................................71
8.4.1
Primary efficacy endpoint ..................................................................................71
8.4.2
Hb related secondary efficacy endpoints ............................................................72
8.4.3
Lipid related secondary efficacy endpoints.........................................................72
8.4.4
Rescue therapy related secondary efficacy endpoints.......................................... 73
8.4.5
36-Item Short Form Health Survey..................................................................... 73
8.4.6
CKD progression related secondary efficacy endpoints ...................................... 73
8.5
Adjudicated CV Events Analyses for Safety Assessments..................................73
8.6
Methods for statistical analyses..........................................................................74


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Study Code D5740C00001
Version 6.0
Date 31 August 2018
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8.6.1
Stratification variables ....................................................................................... 74
8.6.2
Analysis of the primary efficacy endpoint for US............................................... 74
8.6.3
Analysis of the primary efficacy endpoint for EU (Secondary Endpoint for 
FDA) .................................................................................................................75
8.6.4
CV safety endpoint analyses ..............................................................................75
8.6.5
Analysis of the secondary efficacy endpoints .....................................................75
8.6.6
Subgroup analysis..............................................................................................77
8.6.7
Interim analysis..................................................................................................77
8.6.8
Sensitivity analysis.............................................................................................77
8.6.9
Exploratory analysis...........................................................................................77
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA.........................77
9.1
Training of study site personnel .........................................................................77
9.2
Monitoring of the study...................................................................................... 78
9.2.1
Source data ........................................................................................................ 78
9.2.2
Study agreements............................................................................................... 78
9.2.3
Archiving of study documents............................................................................ 78
9.3
Study timetable and end of study........................................................................79
9.4
Data management by AstraZeneca .....................................................................79
10.
ETHICAL AND REGULATORY REQUIREMENTS.......................................80
10.1
Ethical conduct of the study ...............................................................................80
10.2
Patient data protection........................................................................................80
10.3
Ethics and regulatory review ..............................................................................80
10.4
Informed consent ...............................................................................................81
10.5
Changes to the protocol and informed consent form...........................................82
10.6
Audits and inspections .......................................................................................82
11.
LIST OF REFERENCES ...................................................................................82
1.
INTRODUCTION .............................................................................................90
2.
DEFINITIONS .................................................................................................. 90
3.
IDENTIFICATION OF POTENTIAL HY’S LAW CASES............................... 90
4.
FOLLOW-UP .................................................................................................... 91
4.1
Potential Hy’s Law Criteria not met ................................................................... 91
4.2
Potential Hy’s Law Criteria met ......................................................................... 91
5.
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES............ 92
6.
REFERENCES ..................................................................................................93


Clinical Study Protocol
Drug Substance Roxadustat
Study Code D5740C00001
Version 6.0
Date 31 August 2018
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LIST OF TABLES
Table 1
Study Plan...................................................................................................43
Table 2
Laboratory Variables...................................................................................48
Table 3
Identity of investigational products..............................................................63
Table 4
Dose adjustment algorithm..........................................................................65
LIST OF FIGURES
Figure 1
Study flow chart..........................................................................................32
LIST OF APPENDICES
Appendix A
Not Applicable............................................................................................86
Appendix B
Additional Safety Information .....................................................................87
Appendix C
International Airline Transportation Association (IATA) 6.2 Guidance 
Document....................................................................................................89
Appendix D
Actions Required in Cases of Combined Increase of Aminotransferase
and Total Bilirubin – Hy’s Law ...................................................................90


Clinical Study Protocol
Drug Substance Roxadustat
Study Code D5740C00001
Version 6.0
Date 31 August 2018
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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
CKD-NDD
Chronic kidney disease-non-dialysis dependent
CSA
Clinical Study Agreement
CSE
Composite safety endpoint
CSR
Clinical Study Report
CMH
Cochran-Mantel-Haenszel
CTCAE
Common Terminology Criteria for Adverse Event
CV
Cardiovascular
DSMB
Data and 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
FACT-An
Functional Assessment of Cancer Therapy-Anemia
ESRD
End-stage Renal Disease
FAS
Full Analysis Set
GGT
Gamma-glutamyl transferase
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice


Clinical Study Protocol
Drug Substance Roxadustat
Study Code D5740C00001
Version 6.0
Date 31 August 2018
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Abbreviation or 
special term
Explanation
Hb
Hemoglobin
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HIF
Hypoxia-inducible factor
HIF-PHI
HIF 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
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.
IERC
Independent Endpoint Review Committee
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
KDOQI
Kidney Disease Outcomes Quality Initiative
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 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 
hospitalization and unstable angina requiring hospitalization.
MI
Myocardial Infarction
NCI
National Cancer Institute
OT+28
On treatment plus 28 days


Clinical Study Protocol
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Study Code D5740C00001
Version 6.0
Date 31 August 2018
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Abbreviation or 
special term
Explanation
PCI
Percutaneous coronary intervention
PE
Pulmonary embolism
PEY
Person Exposure Year
PF
Physical Functioning subscale component of SF-36
PGIC
Patients’ Global Impression of Change
PI
Principal Investigator
PK
Pharmacokinetics
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
SF-36
Short Form 36
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


Clinical Study Protocol
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Study Code D5740C00001
Version 6.0
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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). It is currently in global 
Phase 3 clinical development and has not been marketed in any country. Roxadustat is a 
potent and reversible active hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) 
(Semenza 1998, Peyssonnaux et al 2008) 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. HIF 
induces expression of not only erythropoietin, but also the erythropoietin receptor and proteins 
that promote iron absorption and recycling (Peyssonnaux et al 2008). Thus, roxadustat 
pharmacologically stimulates erythropoiesis via the HIF pathway and in a manner consistent 
with the body’s normal homeostatic response to hypoxia, but under normoxic conditions. 
Potential advantages of roxadustat compared with erythropoietin analogues for treatment of 
anemia in patients with CKD 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 subjects 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 key objective of the study is to assess the efficacy and CV safety of roxadustat in patients 
with stage 3, 4, or 5 CKD who are anemic and not on dialysis.
1.2
Rationale for study design, doses and control groups
1.2.1
Rationale for control group
Currently available options for the treatment of anemia in patients with CKD and not on 
dialysis (erythropoietin analogues, IV iron, and red blood cell [RBC] transfusion) have 
significant disadvantages in terms of inconvenience to the patient, cost and adverse effects. 
Although clinical guidelines, e.g. KDIGO 2012 recommend the use of erythropoietin 
analogues in these patients if certain criteria are fulfilled, the use of these agents is still 
controversial (Breault 2011). The proportion of CKD patients with anemia who are treated 
with erythropoietin analogues was found to be about 8% (Veterans and Medicare data, Lawler 
et al 2011, Collins et al 2009, respectively). Thus, treatment with erythropoietin analogues is 
not considered a standard of care by the majority of practicing clinicians. Importantly, the use 
of erythropoietin analogues has been associated with increased CV risk (Besarab et al 1998, 
Drüeke et al 2006, Singh et al 2006) and this is likely to have hampered their broader use. 
Since it is still unclear whether this risk is due to a correction of Hb above a certain level, rate 
of Hb rise, toxic effects of erythropoietin analogues per se or a combination of these or other 
factors (Unger et al 2010), it is appropriate to investigate roxadustat, a compound with an 
entirely different mechanism of action, against placebo. Finally, no clinically justified anemia 
therapy will be withheld in patients on placebo for whom oral iron and, if necessary rescue
therapy (erythropoietin analogue, IV iron, RBC transfusion) will be available. Thus, placebo is 
deemed to be the appropriate comparator in this study.


Clinical Study Protocol
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Study Code D5740C00001
Version 6.0
Date 31 August 2018
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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 (45 to 60 kg, >60 to 90 kg, >90 to 140 kg) or 
a fixed starting dose regardless of body weight.
Dose adjustments were allowed at regular 4-week intervals to maintain, increase or decrease 
the dose according to pre-specified rules based on absolute Hb levels and change of Hb in the 
previous 4 weeks. Additional rules were provided to minimize excessive erythropoiesis. These 
dose adjustments are adopted in this study with minor modifications.
The starting dose for this study will be 70mg TIW. Doses will be administered three times 
weekly throughout the study unless downward dose adjustment requires a change to twice or 
once weekly. Dose adjustment is allowed at 4-week intervals to achieve and maintain 
Hb 11±1 g/dLIn the event of excessive erythropoiesis, the dose may be adjusted at any time. 
The maximum dose allowed will be the lower of 3.0 mg/kg or 300 mg per dose.
1.2.3
Rationale for hemoglobin level
This study seeks to achieve and maintain Hb 11±1 g/dLThis 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 KDIGO 2012 guidelines suggest that 
erythropoietin analogues to be started at Hb below 10 g/dL and should generally not be used 
to maintain Hb above 11.5 g/dL (KDIGO 2012). In contrast, the Cleveland Clinic 
recommends target hemoglobin level for both predialysis CKD and end-stage renal disease 
(ESRD) patients should be 11 to 12 g/dL (Lascano et al 2010).
Unlike Hb levels above 13 g/dL where the data indicate 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 analogues (Andrews et al 2013) 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). 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.


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Study Code D5740C00001
Version 6.0
Date 31 August 2018
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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.
Patients treated with placebo may not obtain any benefit in terms of anemia correction, but 
may benefit from the closer follow-up and will receive alternative therapies whenever 
clinically indicated.
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.
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 repeated 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.
The safety of treatment with roxadustat and placebo 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, double-blind, placebo-controlled study in anemic 
patients with stage 3, 4 or 5 CKD who are not on dialysis. This study is planned to recruit 
approximately 2600 patients from approximately 400 centers worldwide.


Clinical Study Protocol
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Study Code D5740C00001
Version 6.0
Date 31 August 2018
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1.4.1
Treatment duration and dosing
This study will consist of three study periods:
!
Screening Period: Up to 6 weeks
!
Treatment Period: Patients will be randomized (1:1) to double-blind treatment 
with roxadustat or placebo, started at 70mg TIW and titrated to achieve and 
maintain Hb 11±1 g/dL. Treatment duration is variable for individual patients. 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 2600 patients will be randomized at 1:1 ratio to roxadustat or placebo 
via an Interactive Web Response System (IWRS)/ Interactive Voice Response System (IVRS).
1.4.3
Blinding
This is a double blind, placebo-controlled study. The investigator, study site staff and the
patient, are blinded to study treatment, but not to the dose or dosing frequency. The Sponsor 
and designees except the personnel analyzing the pharmacokinetic (PK) samples are blinded 
to study treatment, dose and dosing frequency. Sponsor study team members responsible for 
IWRS system are blinded to study treatment and can in special cases be unblinded to dose and 
dosing frequency.
Roxadustat tablets and matching placebo tablets will be identical in appearance, packaging 
and labelling in order to maintain the blind. Treatment assignments will be unblinded after 
database lock.
Any intentional or unintentional breaking of the blind should be reported and documented. 
Breaking the blind (for a single patient) should be considered only when knowledge of the 
treatment assignment is deemed essential by the investigator for the patient’s care. Unplanned 
unblinding will result in the discontinuation of patient participation from the study treatment 
but follow up for CV events will continue until the study closes.
1.4.4
Visits
During the screening period, eligibility will be confirmed at a minimum of 2 screening visits. 
During the treatment period, patients will be contacted by telephone at week 1, and will attend 
study visits every two weeks from weeks 0 to 20. After week 20, study visits will occur every 
four weeks until week 52, then every 8 weeks until the end of the treatment period. A study
end date will be defined based on when the planned number of events are estimated to be 
accrued, and the end of treatment (EOT) visit will occur as soon as possible after that date. An 


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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 flow chart


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2.
STUDY OBJECTIVES
2.1
Primary objectives
Primary Efficacy Objective:
Outcome Measure:
Evaluate the efficacy of roxadustat compared 
to placebo for the treatment of anemia in CKD 
subjects not on dialysis.
US FDA: The primary efficacy endpoint for the US is 
the mean change from baseline in Hb averaged over 
week 28 to week 52. 
EU health authorities: The primary efficacy 
endpoint is whether patients achieved 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 (RBC transfusion, ESA, or IV iron) prior 
to Hb response. 
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


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Secondary Efficacy Objectives:
Outcome Measure:
The efficacy of roxadustat compared to 
placebo 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 efficacy of roxadustat compared to 
placebo 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 effect of roxadustat compared to placebo 
on Low-density lipoprotein (LDL) cholesterol
Mean change in LDL cholesterol from baseline to 
week 24
The need for rescue therapy in subjects treated 
with roxadustat as compared to placebo
Time-to-first (and proportion of subjects receiving)
instance of receiving intravenous (IV) iron, red blood 
cell (RBC) transfusions, or erythropoietin analogue as 
rescue therapy.
Time-to-first (and proportion of subjects receiving)
instance of receiving red blood cell (RBC) 
transfusions as rescue therapy.
The effect of roxadustat on anemia symptoms 
and health-related quality of life (HRQoL) 
based on comparison with placebo
Changes in generic HRQoL as measured by the
SF-36 (Version 2, standard)
The effect on the CKD progression of 
roxadustat as compared to placebo 
Annual rate of eGFR change in log scale, calculated as 
the linear slope of log (eGFR values) to prior to 
initiation of dialysis/kidney transplant
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.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Patients will be recruited from academic and community specialty and primary care practices. 
Each patient 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 patients should fulfill the following criteria:
1.
Provision of informed consent prior to any study specific procedures. 
2.
Age ≥18 years at screening visit 1


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2.
3.
eGFR <60 mL/min/1.73 m2, (calculated by central lab) corresponding to stage 
or 5CKD according to the Kidney Disease Outcomes Quality Initiative (KDOQI), 
not receiving dialysis (Levey et al 2006, National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0
National Kidney Foundation 2002)
4.
Mean of 2 most recent central laboratory Hb values during the screening period, 
obtained at least 7 days apart, must be <10.0 g/dL
5.
Ferritin ≥50 ng/mL at randomization (obtained from screening visit)
6.
TSAT ≥15 % 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) ≤3 x 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 
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 randomization in the present study
3.
Any erythropoietin analogue treatment within 6 weeks of randomization
4.
New York Heart Association Class III or IV congestive heart failure at enrollment
5.
Myocardial infarction (MI), acute coronary syndrome, stroke, seizure or a 
thrombotic/thromboembolic event (e.g., deep vein thrombosis or pulmonary 
embolism) within 12 weeks prior to randomization
6.
History of chronic liver disease (e.g., chronic infectious hepatitis, chronic auto-
immune liver disease, cirrhosis or fibrosis of the liver)
7.
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
8.
Known and untreated retinal vein occlusion or known and untreated proliferative 
diabetic retinopathy (risk for retinal vein thrombosis)


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9.
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
10.
Systolic BP ≥160 mmHg or diastolic BP ≥95 mmHg (confirmed by repeated 
measurement), within 2 weeks prior to randomization. Patients may be rescreened 
once BP controlled
11.
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
12.
Positive for any of the following: human immunodeficiency virus (HIV), hepatitis B 
surface antigen (HBsAg) or anti-hepatitis C virus antibody (anti-HCV Ab)
13.
Chronic inflammatory diseases such as rheumatoid arthritis, systemic lupus 
erythematosus (SLE)ankylosing spondylitis, psoriatic arthritis or inflammatory
bowel disease that is determined to be the principal cause of anemia
14.
Known hemosiderosis, hemochromatosis or hypercoagulable condition
15.
Any prior organ transplant or a scheduled organ transplantation date
16.
Any red blood cell transfusion (RBC) during the screening period
17.
Any current condition leading to active significant blood loss
18.
Any treatment with roxadustat or a hypoxia-inducible factor prolyl hydroxylase 
inhibitor (HIF-PHI)
19.
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 at least 1 month of 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)
20.
History of alcohol or drug abuse within 2 years prior to randomization
21.
Females of childbearing potential, unless using contraception as detailed in the 
protocol or sexual abstinence (see Section 3.8)
22.
Pregnant or breastfeeding females
23.
Known allergy to the investigational product or any of its ingredients
24.
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 patients see Section 3.4.


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3.3
Patient enrollment and randomization
Investigator(s) should keep a record, the patient screening log, of patients 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 enrollment number, beginning with ‘E#’ through 
the IWRS/IVRS
!
Determine patient eligibility, see Section 3.1 and 3.2
!
Assign eligible patients unique randomization code through the IWRS/IVRS
If a patient withdraws from participation in the study, his/her enrollment/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 
patients
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.
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 block randomization schedule by country will be 
produced.


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3.6
Methods for ensuring blinding
The investigator, study site staff, and the patient are blinded to study treatment, but not to the 
dose or dosing frequency. The Sponsor and designees except the personnel analyzing the 
pharmacokinetic (PK) samples are blinded to study treatment, dose and dosing frequency. 
Sponsor study team members responsible for IWRS system are blinded to study treatment and 
can in special cases be unblinded to dose and dosing frequency. The patient will also be 
blinded to study Hb values. Neither the patients nor the investigators and their staff can 
distinguish the roxadustat tablets from the matching placebo tablets. Both will be identical in 
appearance, packaging and labeling in order to maintain the blind.
3.7
Methods for unblinding 
Individual treatment codes, indicating the treatment randomization for each randomized 
patient, will be available to the Investigators or pharmacists from the IWRS/ IVRS. Routines 
for this will be described in the IWRS/ IVRS user manual that will be provided to each center.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomization. The 
Investigator documents and reports the action to AstraZeneca, without revealing the treatment 
assignment to the AstraZeneca staff.
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.
3.9
Discontinuation of investigational product
Patients should be discontinued from investigational product (IP) in the following situations:


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3.9.1
Temporary discontinuation from investigational product
For patients needing treatment with prohibited concomitant medications or receiving 
erythropoietin analogue rescue therapy, study medication must be discontinued or interrupted 
temporarily.
The AstraZeneca study physician should be consulted for all decisions around IP 
discontinuation.
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
!
Patients who have received two courses of erythropoietin analogue rescue 
therapy, and for whom there is a need for a third course of rescue with 
erythropoietin analogue
!
For patients initiating dialysis during the study; and for whom there is a need 
for rescue with erythropoietin analogue
Each permanent discontinuation from study medication should be communicated to the study 
team. For decisions around permanent discontinuation the AstraZeneca study physician should 
be consulted. 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.
Each patient who permanently discontinued study medication prior to closure of the study, 
should be followed up for vital status and hospitalizations until study closure (see Section 


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3.9.3.2), unless he/she decides to withdraw consent for the study completely (see Section 
3.9.3.3).
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.
There are several different options (methods of follow-up) for the continuation in the study as 
described below.
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 (see Table 1) until end 
of study is declared (i.e., when the prespecified number of primary events has been reached).
At PTDV, the physicians caring for the patient will decide upon treatment the patient should 
receive as part of his/her ongoing clinical care. Patients who have permanently discontinued 
study drug may receive prohibited concomitant medications such as erythropoietin analogues.
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)


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!
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) 
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 withdrawal of consentpatients 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. 
If patient has been treated with erythropoietin analogues as rescue therapy, see Section 7.7.4
for guidance on when study drug 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 discontinue investigational product and/or withdraw consent 
for participation in the study, without prejudice to further treatment. Whether or not 
withdrawal of consent from the study has occurred must be ascertained in subjects for whom 
investigational product is permanently discontinued, and this must be 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.


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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 visit. 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.
3.10.1
Screen failures
Screening failures are patients who do not fulfill the eligibility criteria for the study and 
therefore must not be randomized. These patients should have the reason for study withdrawal 
recorded as Incorrect Enrollment’ (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 the 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 enrollment/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.


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4.
STUDY PLAN AND TIMING OF PROCEDURES 
Study assessments and procedures are summarized in Study Plan, Table 1. At visits when 
PRO questionnaires (SF-36, FACT-An, EQ-5D-5L and PGIC) are scheduled, they should be 
completed prior to any other intervention. Blood samples for Hb measurement, safety
laboratory tests and other laboratory assessments will be obtained according to the 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
60
every 8 wks
Visitb
1
2
3
4
5
7
9
11 12 13 14 15 16 17 18
19 20 21 22 23 24
25
27 29, 31, 33, 35, 
37, 39 etc…
Written informed consent
X
Eligibility criteria
X
X
X
Demographics and medical history
X
Physical examination
Xc
X
Xc
Xc
X
Heightd, weight
X
X
X
X
X
X
every 24 wk
X
12-lead ECG
X
X
X
X
Blood pressure, Heart rate
Xe
Xo
Xe
X
X
Xe
X
X
Xe
X
X
X
X
X
X
Xe
XX, every 24 wks
Xe
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
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
Hemoglobin (Central lab)
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
every 24 wks
X
Clinical chemistry
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
Population PK sampling
Xi
X
Pharmacogenetic 
sampling(optional)
X
Biomarker sampling (optional)
hsCRP, hepcidin
Xj
X
PRO questionnaires: FACT-An, SF-
36
X
X
X
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
60
every 8 wks
Visitb
1
2
3
4
5
7
9
11 12 13 14 15 16 17 18
19 20 21 22 23 24
25
27 29, 31, 33, 35, 
37, 39 etc…
PGIC
X
X
X
EQ-5D-5Lk
X
X
X
X
every 24 wks
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
AE recording
X
X
X
X
X
X
X
X
X X X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication recording
X
X
X
X
X
X
X
X
X
X X X
X
X
X
X
X
X
X
X
X
X
X
X
Dose adjustment reviewl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Confirm study drug being taken 
correctly
X
Study drug dispensingm
Xn
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
Please be attentive to visit # which are not consecutive due to removal of some visits from Study Plan. 
c
Targeted physical examination only.
d
Height measured only at screening visit 1.
e
Perform HR and BP measurements in triplicates after being comfortably at rest in a seated position quietly for at least 5 min.
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 pre-dose.
j
Collect pre-dose.
k
After suspected CSE event (MI, stroke, unstable angina, heart failure, DVT, PE, vascular access thrombosis or hypertensive emergency), collect EQ-5D-
5L at next regularly scheduled visit
l
Dose adjustment review every 4 weeks until week 52, every 8th week thereafter. Hemocue values will be used for all dose adjustments, with baseline 
values from Hemocue values at randomization. In the event of excessive erythropoiesis dose can be adjusted at any time, see Section 7.2.3.
m
Dispensation every second week from Day 1 to week 20, every 4 weeks from week 20 to 52, every 8 weeks thereafter. In the event of excessive 
erythropoiesis dose can be adjusted at any time, see Section 7.2.3.
n
Receipt of the first dose of study drug defines Day 1
o
BP measurements in triplicates if one of the BP at visit 1 was out of range


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4.1
Enrollment/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.
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 screening visits to be performed at 
least 7 days apart. All screening procedures should be completed within 6 weeks. The site 
must ensure that study drug is available at study site before the randomization visit is 
scheduled.
The Hb inclusion criteria will be based on central laboratory assessment and may be repeated 
during the screening period. Eligible patients should have a mean (calculated by the 
Investigator) of two most recent central laboratory Hb values during the screening period, 
obtained at least 7 days apart, that is <10.0 g/dL.
4.1.2
Additional screening assessments
If a patient’s laboratory results or blood pressure (BP) do not meet the eligibility criteria, the 
laboratory assessment or BP may be repeated within the screening period. The visits must be 
at least 7 days apart.
For example, an additional central laboratory Hb value may be collected if necessary. The 
mean of two most recent Hb values during the screening period, obtained at least 7 days apart, 
will be used to calculate the patient’s eligibility. Iron, vitamin B12 and folate laboratory tests
may be repeated during the screening period after supplementation if necessary. Similarly BP
may be repeated after adjustment of antihypertensive medications. Liver function test (LFT) 
parameters may not be repeated if found exclusionary at screening without a prior approval 
from the AstraZeneca study physician. 
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 re-screening periods are allowed.
For all screen failures, the reason(s) will be documented.
4.2
Treatment period
Procedures for this period are included in the Study Plan, Table 1.


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The treatment period begins on the first day of dosing with study treatment (Day 1, week 0).
Day 1 is the first treatment day. All Randomization study assessments are to be performed 
prior to first study drug administration.
During the treatment period, patients will be contacted by phone at week 1 to assure that study 
drug is being taken correctly. The patients will attend study visits every 2 weeks from week 0
to 20, every 4 weeks thereafter until week 52, and every 8 weeks from week 52 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. 
In case of premature discontinuation of study medication, see Section 3.9.
4.3
Follow-up period
After the treatment period (ending with the EOT visit), study patients will proceed to the 
4-week post-treatment follow-up period (ending with the EOS visit).
Procedures will be performed according to the Study Plan, Table 1.
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 center.
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.


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5.1.1.2
Use of rescue therapy
Use of rescue therapy (erythropoietin analogue, IV iron and 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 of 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, 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. 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 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.


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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):
Laboratory 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 Analytes
Chloride
Vitamin B12
Magnesium
Folate
Bicarbonate
hsCRP*, hepcidin*
Phosphorus
Lipid Panel
Glucose
Total cholesterol
Uric Acid
HDL
Total protein
Triglycerides
Lactate dehydrogenase
Calculated low-density lipoprotein (LDL)
Blood urea nitrogen
Serum hCG pregnancy test
Iron Profile
Iron


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Laboratory Variables
Hematology/Hemostasis
Clinical Chemistry
Ferritin
Total iron binding capacity (TIBC)
Transferrin saturation (TSAT)
* = will be analyzed using biomarker specimens
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 
center 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 Study Plan, Table 1. 
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 measured at screening, at randomization 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 Study Plan, Table 1. Any
clinically relevant adverse change will be recorded as an AE in the eCRF (see Section 6.3.6).
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, RR Interval, PR Interval,


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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. On specific 
visits indicated in Table 1, HR and BP will be measured in triplicates 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. BP will be measured in triplicate 
with at least one-minute intervals between measurements. All the three readings will be 
reported in the eCRF.
The HR will be assessed by pulse palpation of radial artery for 30 seconds immediately after 
each recording of the BP. It could be also performed with an oscillometric device if this is 
used for BP measurement. The triplicate HR assessments will be recorded in the eCRF.
5.3
Other assessments
5.3.1
Patient reported outcomes
All study patients will be asked to complete the Health Related Quality of life (HRQoL) 
questionnaires at time points indicated in the Study Plan, Table 1.
5.3.1.1
Short Form 36 – (SF-36)
The SF-36 version 2, standard is a general HRQoL instrument designed to assess generic 
health concepts relevant across age, disease and treatment groups. It is aimed at both adults 
and adolescents aged eighteen years and older. The SF-36 consists of eight domains of health 
status: Physical functioning (PF) - 10 items; Role-physical - RP - 4 items; Bodily pain -
2 items; General health (GH) - 5 items; Vitality (VT) - 4 items; Social functioning (SF) -
2 items; Role emotional (RE) - 3 items; and Mental health (MH) - 5 items. Two component 
scores, the Physical Component Summary (PCS) and the Mental Component Summary (MCS) 
can also be calculated. For both the SF-36 domain scores and summary scores, higher scores 
indicate better health status. The SF-36 standard version has a recall period of the ‘past four 
weeks’.


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5.3.1.2
Functional Assessment of Cancer Therapy - Anemia (FACT-An)
The FACT-General (FACT-G) version 4 contains 27 items that cover four dimensions of 
disease-specific HRQoL: Physical well-being (PWB) - 7 items; Functional well-being (FWB) 
- 7 items; Social/family well-being (SWB) - 7 items; Emotional well-being (EWB) - 6 items. 
A subscale of 13 fatigue specific items (the Fatigue Subscale) plus seven additional items 
related to anemia were developed for use in conjunction with the FACT-G. The 13 fatigue 
items plus the seven additional items related to anemia comprise the Anemia Subscale 
(Additional Concerns). Administration of the FACT-G plus the Anemia Subscale is referred to 
as the FACT-An. The FACT-An has a recall period of the ‘past seven days’. Respondents are 
asked to provide responses (i.e. ‘Not at all’, ‘A little bit’, ‘Somewhat’, ‘Quite a bit’ and ‘Very 
much’), to a list of statements which are either positively or negatively phrased. For all FACT-
An scales, a higher score indicates better HRQoL.
5.3.1.3
Patients’ Global Impression of Change (PGIC)
The PGIC is an instrument where patients rate change in their overall health status compared 
to the start of the study treatment. Ratings are done on a 7-point scale ranging from 1 (very
much improved) to 7 (very much worse).
5.3.1.4
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.
5.3.1.5
Administration of patient-reported outcome
All patient-reported outcomes (PRO)s are paper-based and will be administered at baseline 
and according to Study Plan, Table 1 and recorded in the eCRF. The questionnaires should be 
completed by the patient prior to any other intervention.
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 questionnaires. 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.


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The instructions for completion of the PRO questionnaires are as follows:
!
The SF-36 should be completed first, thereafter the FACT-An, EQ-5D-5L and
PGIC at scheduled visits
!
They 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 questionnaires
!
On completion, the questionnaires should be handed back to the person responsible 
for questionnaires 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, type and reason for 
hospitalization will be recorded in the eCRF. Details on hospitalizations will also be collected 
at follow-up visits in patients who prematurely discontinued treatment (only if they have taken 
at least one dose of study drug), until EOS.
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. 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 date and time of the 
study last dosing 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.


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5.4.2
Determination of study drug concentration
For the patients receiving roxadustat, samples for pharmacokinetic (PK) determination will be 
analyzed 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 and summarized on the basis of time intervals 
and plotted in scattering with time relative to the immediately preceding roxadustat dosing 
time. A population PK analysis of data collected in the CKD- non-dialysis dependent (CKD-
NDD) 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.
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 randomization visit (week 0).
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 randomization 
visit (week 0). Although genotype is a stable parameter, early sample collection is preferred 
to avoid introducing bias through excluding patients who may withdraw due to an adverse 
event (AE), such patients would be important to include in any genetic analysis. If for any 
CCI


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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.
 
 
 
 
 
 
 
 
 
 
 
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. pre first dose in the study (week 0, pre-dose)
and at week 24 (at any time), and may be analyzed for exploratory biomarkers to assess 
correlations with disease activity, effects of study drug and clinical outcomes (including CV 
risk).
CCI
CCI
CCI


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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 center keeps full traceability of collected biological samples from the 
patients while in storage at the center 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.
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers.
Samples retained for future use are registered within the relevant sample tracking system at 
AstraZeneca.
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. However, this does not result in 
withdrawal of the patient from the study and patient should continue until the end of study. If 
samples are already analyzed, AstraZeneca is not obliged to destroy the results of this 
research.


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The Principal Investigator:
!
Ensures patients’ withdrawal of informed consent to the use of donated samples is 
communicated 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 is 
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.
The term AE is used to include both serious and non-serious AEs.
An AE (classified by preferred term) that occurs during the double-blind treatment period will 
be considered a TEAE (Treatment Emergent Adverse Event) if it was not present prior to the 
first dose of study drug, or it was present prior to the first dose of study drug but increased in 
severity during the double-blind treatment period. An AE that occurs more than 28 days after 
the last dose of study medication will not be counted as a TEAE. 


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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 hospitalization or prolongation of existing hospitalization
!
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 jeopardize the patient 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 throughout the treatment period 
and including the follow-up period. See Section 3.9.3.2 for details regarding AE collection for 
subjects who are followed by modified follow-up after premature discontinuation of IP. 
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 collected 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 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:
!
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


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!
Probable cause of death, if applicable
!
Date of death, if applicable
!
Autopsy performed, if applicable
!
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 and 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 B to the Clinical 
Study Protocol.
6.3.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient 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.
6.3.6
Adverse events based on examinations and tests
The results from protocol mandated laboratory tests and vital signs will be summarized in the 
clinical study report. Deterioration as compared to baseline in protocol-mandated laboratory 
values and 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.


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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≥3xULN, ALT≥3xULN, total bilirubin ≥2xULN.
6.3.8
Disease progression
Changes in patient condition that are due to progression of the disease for which the 
investigational product is being studied (for example, anemia or CKD) should not be 
considered AEs or SAEs. This includes an increase in the severity of the disease under study, 
and an increase in the symptoms of the disease under study. Roxadustat is being studied for 
the treatment of anemia in CKD. CKD progression should therefore not be considered an AE 
or SAE. Acute kidney injury, when meeting diagnostic criteria (i.e. based on serum creatinine 
values or urine output), can be considered an AE or SAE. AEs or SAEs that cause anemia 
should be recorded, but anemia for which no cause is found other than CKD should not be 
reported as an AE or SAE. 
6.3.9
Patients initiating dialysis during the treatment period
In patients judged on clinical grounds to require dialysis during the study, study medication 
should be continued until study closure, unless protocol specified reasons for investigational 
product discontinuation are present. Initiation of chronic dialysis should be recorded in the 
eCRF.
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 eCRF.
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.


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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 
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 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 300 mg per administration, whichever is lower) represents an overdose.
An overdose with associated AE(s) 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 AE(s) 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.


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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 
investigational product under study may have interfered with the effectiveness of a 
contraceptive 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 elevation.
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. For overdose see Section 6.5.


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6.8
Study governance and oversight
6.8.1
International coordinating investigator
The International coordinating investigator (ICI) in collaboration with AstraZeneca 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 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) 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 maintenance of the blinding and 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 products
Investigational product
Dosage form and strength
Manufacturer
Roxadustat
Oral tablets 20mg, 50mg and 100mg
FibroGen
Placebo
Oral tablets to match 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).
Roxadustat and matching placebo oral tablets will be packaged in bottles supplied by 
AstraZeneca. The tablet strengths are different in size and each strength has a matching 
placebo. The tablets should remain in original packaging until administration. The tablets 


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should be swallowed whole with water. The tablets must not be chewed, crushed or divided. 
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).
7.2
Dose and treatment regimens
7.2.1
Randomization
Patients will be randomized to receive roxadustat or placebo in a 1:1 ratio in a double-blind 
manner. 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 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.
The administration of the first dose of study drug would mark the beginning of the treatment 
period. Hemocue values will be used for all dose adjustments, including baseline values from 
Hemocue values at randomization. Missed doses should not be replaced.
7.2.2
Starting dose and dose adjustment
The initial study drug dose (per dose occasion) is 70 mg orally administered three times a 
week (TIW).
The first study drug administration will be on Day 1 (week 0). Study drug doses must be 
administered at least 2 days apart and no more than 4 days apart (e.g., Monday , Wednesday, 
Friday). Study drug will be dosed TIW throughout the study treatment period unless 
downward dose adjustment requires a change to twice or once weekly.
Dose adjustments are permitted starting at week 4 and at intervals of every 4 weeks until 
week 52, every 8 weeks thereafter using the dose adjustment algorithm (see Table 4). If dose 
reduction is required for excessive erythropoiesis, the dose may be adjusted at any time. All 
dose adjustments are based on Hb values using Hemocue, a point-of-care device. Hb values 
will be recorded in the eCRF (during the screening period) and in IWRS (during the treatment 
period).


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Table 4
Dose adjustment algorithm
Changes in Hb over
past 4a 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 and 300mg.
Example: A dose increase at a dose of 70 mg results in 100 mg as the new dose. A dose reduction at a dose of
150 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 300 mg per dose administration
Dose Adjustment for Excessive erythropoiesis
! If Hb increases by >2.0 g/dL within a 4 week period, reduce dose by one step.
a
After week 52, adjust dose based on current Hb (increase 1 dose step if <10.5g/dL, no change if 10.5 to
11.9 g/dL, decrease 1 dose step if 12 to 12.9 g/dL)
7.2.3
Dose adjustment for excessive Erythropoiesis
Excessive erythropoiesis is defined in Table 4. In the event of excessive erythropoiesis, the 
dose may be adjusted at any time, even on visits without a dose adjustment review. In such 
cases, dose adjustment reviews are then resumed at 4-week intervals until week 52, where 
after there will be 8-week intervals. If a dose adjustment review is performed on week 18, 
then the next dose adjustment review will be scheduled on week 24, since there is no 
scheduled visit on week 22.
7.2.4
Dose adjustment for Hb ≥ 13.0g/dL
In the event of Hemocue 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 until week 52, where after there will be 8-week intervals, following the same 
principle as for excessive erythropoiesis.
7.2.5
Patients initiating dialysis during the treatment period
In patients judged on clinical grounds to require dialysis during the study, study medication 
will be continued until study closure, unless protocol specified reasons for investigational 
product discontinuation are present. See Section 7.7.4 for criteria for rescue therapy in dialysis 
patients. Initiation of dialysis should be recorded in the eCRF.


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7.3
Labelling
Labelling of the investigational products will be carried out by AstraZeneca or their designee 
in accordance with current Good Manufacturing Practice (GMP). The labels will fulfil GMP 
Annex 13 requirements for labelling and local regulatory guidelines. 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.
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 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.  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).


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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 with at 
least 1 hour separation from their phosphate binder.
7.7.1.3
Herbal medicines
Use of herbal medicine during the study is not prohibited but strongly discouraged. All herbal 
and natural remedies should be reviewed by the investigator and if considered safe, may be 
allowed to continue at the same dose.
7.7.2
Prohibited medications
The following medications/therapies are prohibited during the study:
!
Any other investigational drug: from randomization until EOS
!
Any erythropoietin analogues during the treatment period, except as rescue 
medication (Section 7.7.4.3)
!
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 randomisation to 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 
treatment.
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 standardization of the use of rescue 
therapy by investigators and to ensure safety of the individual study patients. Rescue therapy
should be recorded in the eCRF.


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7.7.4.1
Intravenous iron supplementation
The use of intravenous iron is not encouraged in the setting of this placebo-controlled study. 
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 
treatment.
The investigator may initiate the use of an approved IV iron supplement if:
!
the patient is receiving or does not tolerate oral iron, and
!
Hb < 8.5 g/dL and
!
Ferritin <100 ng/ml or Transferrin saturation (TSAT) <20%
Study treatment may continue during IV iron administration. Ferritin and TSAT assessment is 
recommended 4 weeks after 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%) or Hb >9 g/dL, whichever comes first. Use of IV iron 
will be recorded in the eCRF.
7.7.4.2
Red blood cell transfusion
Red blood cell (RBC) transfusion is allowed if rapid correction of anemia is required to 
stabilize the patient’s condition (e.g. acute hemorrhage) 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.
7.7.4.3
Initiation of Rescue with an approved erythropoietin analogue
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 <8.0 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 alloimmunization 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 erythropoietin analogue and study drug at 
the same time. For patients not on dialysis, treatment with erythropoietin analogue should be 


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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)
Use of erythropoietin analogues will be recorded in the eCRF.
Patients may receive 2 cycles of rescue with erythropoietin analogues. If they meet the above 
criteria for erythropoietin rescue for a third time, study drug should be permanently 
discontinued (see Section 3.9.3). Study drug should be permanently discontinued for subjects 
who initiate dialysis and who are clinically judged to require erythropoietin analogue therapy.
7.7.4.4
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.
7.7.4.5
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
All personnel involved with the analysis of the study will remain blinded until database lock 
and protocol violators identified. Analyses will be performed by AstraZeneca or its 
representatives.
A comprehensive SAP will be prepared prior to database lock.


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8.2
Sample size estimate
Primary efficacy endpoint: A sample size of 450 subjects will have > 99% power to detect a 
0.75 g/dL difference in mean Hb values between the two treatment groups, assuming that the 
common standard deviation is 1.2 g/dL, using an analysis of variance (ANOVA) test with a 
0.05 two-sided significance level.
To contribute adjudicated CV safety events for the pooled CV analyses across the phase 3 
program: approximately 2600 subjects are planned to be randomized in a 1:1 ratio to either 
roxadustat or placebo. The sample size in this study is driven by the overall requirement of 
adjudicated CV events for the phase 3 program in CKD-NDD (which consists of 3 studies in 
total targeting 465 subjects with MACE events). The two other placebo-controlled studies in 
the study program are FGCL-4592-060 and 1517-CL-0608.
Further information related to the sample size determination can be found in the study 
statistical analysis plan and the pooled statistical analysis plan.
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 28 days 
after last intake of study drug.
8.3.3
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 28 days after last intake of study 
drug. The Safety Analysis Set may also be referred to as On-treatment+28 (OT+28).


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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 unblinding 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. 
8.4
Outcome measures for analyses
8.4.1
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 
covariance (ANCOVA) will be applied as a method to handle missing data. Details of the 
multiple imputation ANCOVA 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 whether patients achieved Hb 
response as described below.


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!
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 (RBC 
transfusion, ESA, or IV iron) prior to Hb response. Subjects who have discontinued 
study medication or received rescue therapy before a Hb response could be achieved 
will be considered as a non-responder.
8.4.2
Hb related secondary efficacy endpoints
The Hb related secondary efficacy variables are:
!
The EU primary endpoint is the first secondary efficacy endpoint 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. 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 measurements 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
!
Mean change in LDL cholesterol from baseline to week 24. 


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8.4.4
Rescue therapy related secondary efficacy endpoints
The need for rescue therapy will be evaluated as:
!
Time-to-first (and proportion of subjects receiving) instance of receiving intravenous 
(IV) iron, red blood cell (RBC) transfusions, or erythropoietin analogue as rescue 
therapy (rescue therapy guidelines are specified in the clinical study protocol (CSP), 
Section 7.7.4).
!
Time-to-first (and proportion of subjects receiving) instance of receiving red blood cell 
(RBC) transfusions as rescue therapy. 
and will be computed, as the number of days plus one between the day of first dose of study 
drug and the date of the first occurrence of rescue therapy, or if no event has occurred before 
censoring, the date of censoring. 
8.4.5
36-Item Short Form Health Survey
The SF-36 is a QoL instrument designed to assess generic health concepts relevant across
age, disease, and treatment groups. It is aimed at both adults and adolescents aged eighteen
years and older. The SF-36 consists of eight domains of health status: Physical functioning
(10 items), Role-physical (4 items), Bodily pain (2 items), General health (5 items), Vitality (4 
items), Social functioning (2 items), Role emotional (3 items) and Mental health (5 items).
Two component scores, the Physical Component Summary and the Mental Component
Summary can also be calculated. For both the SF-36 domain scores and summary scores,
higher scores indicate better health status. The SF-36 has a recall period of the ‘past four
weeks’.
•
Change from baseline in SF-36 Physical Functioning (PF) sub-score 
•
Change from baseline in SF-36 Vitality (VT) sub-score 
The SF-36 scores will be computed according to its documentation
8.4.6
CKD progression related secondary efficacy endpoints
To evaluate the effect of roxadustat on the CKD progression prior to initiation of 
dialysis/kidney transplant, the following variable will be analyzed:
!
Annual rate of eGFR change in log scale, calculated as the slope of log (eGFR values), 
prior to initiation of dialysis/kidney transplant
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 for 
three phase 3 studies, FG-4592-060, 1517-CL-608 and D5740C00001, in the CKD-NDD program. 
Analyses of these adjudicated events are described in a separate pooled analysis plan.


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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 only 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. The variables are: 
1.
Baseline eGFR (≤ 30 mL/min/1.73 m2 vs > 30 mL/min/1.73 m2) 
2.
Baseline Hb (≤ 8 g/dL vs > 8 g/dL)
3.
cardiovascular/cerebrovascular/thromboembolic medical history (Yes vs. No)
4.
geographical region (US vs Ex-US)
Baseline Hb and baseline eGFR will be included in the analyses as continuous covariates, not 
as dichotomous factors, unless specified otherwise. Throughout this document, the variable 
cardiovascular/cerebrovascular/thromboembolic medical history will be shortened as CV 
history.
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 
analysed with multiple imputation ANCOVA as described in the SAP. The model will contain 


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terms for the treatment, baseline Hb measurement, baseline eGFR, geographic region and CV 
history. Superiority of roxadustat compared to placebo 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 placebo exceeds 0 g/dL. The ITT analysis set will be used.
8.6.3
Analysis of the primary efficacy endpoint for EU (Secondary 
Endpoint for FDA)
Hb response (Yes/No), where Yes is defined as: 
-
Hb ≥ 11.0 g/dL and Hb increase from baseline by ≥ 1.0 g/dL, for subjects with 
baseline Hb > 8.0 g/dL; or
-
Hb increase from baseline by ≥2.0 g/dL, for subjects with baseline Hb ≤ 8.0 g/dL
at two consecutive visits [dates] (with available data) separated at least 5 days during the first 
24 weeks of treatment without having received rescue therapy (RBC transfusion, ESA, or IV 
iron) prior to Hb response. 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. The proportion of responders in the primary efficacy 
variable will be compared using a Cochran–Mantel–Haenszel (CMH) test adjusting for the 
region, history of CV, baseline Hb (<=8, >8 g/dL) and baseline eGFR (<=30, >30 
mL/min/1.73 m2), comparing roxadustat to placebo. The FAS will be used. 
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 FAS will be used on the first secondary endpoint, OT+28 will be used for the two 
secondary endpoints related to rescue therapy, and the ITT analysis set will be used for all the 
remaining secondary endpoints.
1. The EU primary endpoint is the first secondary efficacy endpoint for FDA (see above)
2. 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 placebo 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 placebo 
exceeds 0 g/dL. 
3. 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 placebo will be compared using ANCOVA with treatment 
group, geographic region and CV history as fixed factors and baseline Hb and baseline 
eGFR as covariates. Superiority between the groups will be declared, and this test as 
successful, if the lower bound of the 2-sided confidence interval of the difference 
between roxadustat and placebo exceeds 0. 
4. 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 placebo will be compared using 
ANCOVA with treatment group, geographic region and CV history as fixed factors 
and baseline Hb and baseline eGFR as covariates. Superiority between the groups will 
be declared, and this test as successful, if the lower bound of the 2-sided confidence 
interval of the difference between roxadustat and placebo exceeds 0.
5. Mean change from baseline in LDL cholesterol to week 24 will be analysed using 
ANCOVA. Baseline Hb, baseline eGFR and baseline LDL will be used as covariates 
and treatment arm, CV history and geographic region as fixed effects. Superiority will 
be declared if the upper bound of the 2-sided 95% confidence interval of the difference 
between roxadustat and placebo exceeds 0. 
6. Time-to-first (and proportion of subjects receiving) rescue therapy (composite) of any 
of IV iron, RBC transfusion or erythropoietin analogue as rescue therapy, will be 
analyzed using the Cox proportional hazard model with OT+28. Baseline Hb, baseline 
eGFR, geographic region, and CV history will be included as covariates. Superiority 
will be claimed, and this test successful, if the upper limit of the 2-sided 95% CI for 
the hazard ratio is less than or equal 1.0.
7. Time-to-first (and proportion of subjects receiving) RBC transfusion as rescue therapy, 
will be analyzed using the Cox proportional hazard model with OT+28. Baseline Hb, 
baseline eGFR, geographic region, and CV history will be included as covariates. 
Superiority will be claimed, and this test successful, if the upper limit of the 2-sided 
95% CI for the hazard ratio is less than or equal 1.0.
8. Mean change in SF-36 Vitality (VT) sub-score from baseline to average VT sub-score 
of weeks 12-28 will be analyzed using MMRM with treatment, visit, treatment-by-visit 
interaction, and baseline covariates, including the baseline score, baseline Hb, baseline 
eGFR, and geographic region and CV history, as fixed effects and subject as a random 
effect. Superiority between roxadustat and placebo will be declared, and this test 


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successful, if the lower bound of the 2-sided confidence interval for the difference 
between roxadustat and placebo exceeds 0.
9. Annual rate of eGFR change in log scale prior to initiation of dialysis/kidney 
transplant will be estimated with MMRM using all post-baseline log (eGFR values) 
prior to initiation of dialysis/kidney transplant. Baseline eGFR in log scale, baseline 
Hb and geographic region, CV history, treatment group and post-baseline eGFR 
measurement time will be treated as fixed effects, and subject and time as random 
effects, i.e. random intercept and slope.
10. Mean change in SF-36 Physical Functioning (PF) sub-score from baseline to average 
PF sub-score of weeks 12-28 will be analyzed using MMRM with treatment, visit, 
treatment-by-visit interaction, and baseline covariates, including the baseline score, 
baseline Hb, baseline eGFR, and geographic region and CV history, as fixed effects 
and subject as a random effect. Superiority between roxadustat and placebo will be 
declared, and this test successful, if the lower bound of the 2-sided confidence interval 
for the difference between roxadustat and placebo exceeds 0.
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
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(s) 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.


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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
!
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 center 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 center 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. 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).


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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 centers 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.
9.4
Data management by AstraZeneca
Data management will be performed by AstraZeneca Data Management Center 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 questionnaires have 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 Center.
Serious Adverse Event (SAE) Reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database
and/or the investigational site.


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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 Center 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 Center will ensure that 
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 form and any other written 


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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/IRB should be given in writing. The Investigator should 
submit the written approval to AstraZeneca before enrollment of any patient into the study.
The Ethics Committee/IRB 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.
If required by local regulations, the protocol should be re-approved by the Ethics Committee 
annually.
Before enrollment of any patient into the study, the national regulatory authority approves 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/ Institutional 
Review Board (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 center 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 is given to the patient


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!
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.
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 Section10.3.
If a protocol amendment requires a change to a center’s informed consent form, AstraZeneca 
and the center’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
Authorized representatives of AstraZeneca, a regulatory authority or an Ethics Committee 
may perform audits or inspections at the center, 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, analyzed 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 center.
11.
LIST OF REFERENCES
Andrews et al 2013
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 2013 May 14. 
[Epub ahead of print] doi: 10.1177/0192623313486317


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Besarab et al 1998
Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM et al. The effects 
of normal as compared with low hematocrit values in patients with cardiac disease who are 
receiving hemodialysis and epoetin. N Engl J Med 1998;339(9):584-90
Breault 2011
Breault R. Should Erythropoiesis-Stimulating Agents Be Used in Predialysis Patients? 
Can J Hosp Pharm 2011;64(2):149-50
Collins et al 2009
Collins AJ, Guo H, Gilbertson DT Bradbury BD. Predictors of ESA Use in the non-dialysis 
chronic kidney disease population with anemia. Nephron Clin Pract 2009;111(2):c141-8
Drüeke et al 2006
Drüeke TB, Locatelli F, Clyne N, Eckardt K-U, Macdougall IC, Tsakiris D et al. 
Normalization of hemoglobin level in patients with chronic kidney disease and anemia. 
N Engl J Med 2006;355(20):2071-84
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 
Clinical data Standards Writing Committee to Develop Cardiovascular Endpoint 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 
Anemia 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/


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Lawler et al 2011
Lawler EV, Gagnon DR, Fink J, Seliger S, Fonda J, Do TP et al. Initiation of Anaemia 
Management in Patients with Chronic Kidney Disease not on Dialysis in the Veterans Health 
Administration. Nephrol Dial Transplant 2011;25(7):2237-44
Levey et al 2006
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S et al. Using 
standardized serum creatinine values in the modification of diet in renal disease study
equation for estimating glomerular filtration rate. Ann Intern Med 2006;145(4):247-54
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0
National Kidney Foundation 2002
KDOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification 
and Stratification, Am J Kidney Dis 2002;39(2)(Suppl 1):S46-75
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 et al 2006
Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M et al. Correction of anemia 
with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355(20):2085-98
Singh 2010
Singh AK. The FDA’s Perspective on the Risk for Rapid Rise in Hemoglobin in Treating 
CKD Anemia: Quo Vadis. Renal Division, Brigham and Women’s Hospital and Harvard 
Medical School, Boston, Massachusetts. Clin J Am Soc Nephrol 2010;5:553-6


Clinical Study Protocol
Drug Substance Roxadustat
Study Code D5740C00001
Version 6.0
Date 31 August 2018
86(93)
Skali et al 2011
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. Hemoglobin Targets for the Anemia of 
Chronic Kidney Disease: A Meta-analysis of Randomized, Controlled Trials. 
J Am Soc Nephrol 2004;15(12):3154-65
Unger et al 2010
Unger EF, Thompson AM, Blank MJ, Temple R. Erythropoiesis-Stimulating Agents - Time 
for a Reevaluation. N Engl J Med 2010;362;(3)189-92
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 hemodialysis (HD) patients. World Congress of 
Nephrology Hong Kong 31 May - 4 June 2013, Poster SU437


Clinical Study Protocol Appendix A
Drug Substance Roxadustat
Study Code D5740C00001
Version 6.0
Date 31 August 2018
87(93)
Appendix A
Not Applicable


Clinical Study Protocol Appendix B
Drug Substance Roxadustat
Study Code D5740C00001
Version 6.0
Date 31 August 2018
88(93)
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


Clinical Study Protocol Appendix B
Drug Substance Roxadustat
Study Code D5740C00001
Version 6.0
Date 31 August 2018
89(93)
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 ‘yes’ 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 ‘no’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.


Clinical Study Protocol Appendix C
Drug Substance Roxadustat
Study Code D5740C00001
Version 6.0
Date 31 August 2018
90(93)
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.


Clinical Study Protocol Appendix D
Drug Substance Roxadustat
Study Code D5740C00001
Version 6.0
Date 31 August 2018
91(93)
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) and Total Bilirubin (TBL) ≥2xULN at any point during the study 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 and 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 while there is no alternative causation:
!
ALT ≥3xULN
!
AST ≥3xULN
!
TBL ≥2xULN


Clinical Study Protocol Appendix D
Drug Substance Roxadustat
Study Code D5740C00001
Version 6.0
Date 31 August 2018
92(93)
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).
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


Clinical Study Protocol Appendix D
Drug Substance Roxadustat
Study Code D5740C00001
Version 6.0
Date 31 August 2018
93(93)
!
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
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


Clinical Study Protocol Appendix D
Drug Substance Roxadustat
Study Code D5740C00001
Version 6.0
Date 31 August 2018
94(94)
!
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
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: d5740c00001-csp-v6
Document Title:
D5740C00001 Clinical Study Protocol version 6
Document ID:
Doc ID-003310384
Version Label:
1.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
01-Sep-2018 10:20 UTC
Mark Houser
Author Approval
31-Aug-2018 18:50 UTC
Dustin Little
Author Approval
31-Aug-2018 19:28 UTC
Lars Frison
Author Approval
31-Aug-2018 18:52 UTC
Liselotte Holmgren
Qualified Person Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.

SAP_001.pdf: 
Statistical Analysis Plan
Study Code
D5740C00001
Edition Number
3.0
Date
28 September 2018
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Study Evaluating the Safety and Efficacy of Roxadustat for the Treatment 
of Anemia in Chronic Kidney Disease Patients not on Dialysis


PPD


PPD


Statistical Analysis Plan 
Study Code D5740C00001
Edition Number 3.0
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
PROTOCOL AMENDMENT HISTORY .......................................................................... 10
1.
STUDY DETAILS............................................................................................. 11
1.1
Study objectives................................................................................................. 11
1.1.1
Primary efficacy objective.................................................................................. 11
1.1.2
Primary safety objective..................................................................................... 11
1.1.3
Secondary efficacy objectives ............................................................................ 11
1.1.4
Secondary safety objectives ............................................................................... 12
1.2
Study design ...................................................................................................... 12
1.2.1
Dosing ............................................................................................................... 12
1.2.1.1
Investigational product, dosage and mode of administration............................... 12
1.2.2
Scheduled visits during treatment....................................................................... 12
1.2.3
Stratification variables ....................................................................................... 13
1.3
Number of subjects ............................................................................................ 14
2.
ANALYSIS SETS ............................................................................................. 14
2.1
Definition of analysis sets .................................................................................. 14
2.1.1
Intention To Treat Analysis Set (ITT) ................................................................ 14
2.1.2
Per Protocol Set (PPS) ....................................................................................... 14
2.1.3
Safety Analysis Set ............................................................................................ 15
2.1.4
Full Analysis Set (FAS) ..................................................................................... 15
2.1.5
Subjects who will not be included in any analysis sets........................................ 15
2.2
Violations and deviations ................................................................................... 15
3.
PRIMARY AND SECONDARY VARIABLES................................................. 16
3.1
Efficacy variables............................................................................................... 16
3.1.1
Primary efficacy endpoint .................................................................................. 16
3.1.2
Hb related secondary efficacy variables.............................................................. 17
3.1.3
Lipid related secondary efficacy variables.......................................................... 17
3.1.4
Rescue therapy related secondary efficacy variables........................................... 18
3.1.5
36-Item Short Form Health Survey..................................................................... 18
3.1.6
CKD progression related secondary efficacy variables ....................................... 19


Statistical Analysis Plan 
Study Code D5740C00001
Edition Number 3.0
Date 28 September 2018
5
3.1.7
Exploratory variables ......................................................................................... 19
3.1.7.1
Hb related exploratory variables......................................................................... 19
3.1.7.2
Rescue therapy related exploratory variables...................................................... 19
3.1.7.3
CKD progression related exploratory variables .................................................. 19
3.1.7.4
Quality of life related exploratory efficacy variables .......................................... 20
3.1.7.5
Hospitalization related exploratory variables...................................................... 21
3.1.7.6
Other exploratory variables ................................................................................ 22
3.2
Safety assessment............................................................................................... 22
3.3
Adjudicated CV Events Analyses for Safety Assessments.................................. 22
3.4
Treatment compliance........................................................................................ 23
4.
ANALYSIS METHODS.................................................................................... 23
4.1
General principles.............................................................................................. 23
4.1.1
Censoring........................................................................................................... 24
4.1.2
Premature permanent discontinuation of study medication ................................. 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
4.2.3.1
Cox regression adopting Inverse of Probability of Censoring Weights................ 26
4.2.4
Analysis of Covariance (ANCOVA) .................................................................. 26
4.2.5
Multiple imputation ANCOVA.......................................................................... 26
4.2.6
Mixed Model of Repeated Measures (MMRM).................................................. 27
4.2.7
Pattern Mixture Models...................................................................................... 27
4.2.7.1
PMM – Last Mean Carried Forward................................................................... 28
4.2.7.2
PMM – Baseline Mean Carried Forward (roxadustat group only and both 
groups)............................................................................................................... 28
4.2.7.3
PMM – Jump to Control..................................................................................... 29
4.3
Statistical Analyses ............................................................................................ 29
4.3.1
CV safety endpoints analyses............................................................................. 29
4.3.2
Primary efficacy endpoint analysis for US.......................................................... 29
4.3.3
Primary efficacy endpoint analysis for EU (First Secondary endpoint for 
FDA) ................................................................................................................. 29
4.3.4
Secondary Efficacy Endpoints:........................................................................... 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......................................... 32
4.3.5.3
CKD progression related exploratory endpoint analysis ..................................... 32
4.3.5.4
Quality of life related exploratory endpoint analysis........................................... 33
4.3.5.5
Hospitalization related exploratory endpoint analysis......................................... 34
4.3.5.6
Other exploratory endpoint analysis ................................................................... 34
4.3.6
Sensitivity analysis of efficacy endpoints ........................................................... 35
4.3.7
Subgroup analyses ............................................................................................. 36


Statistical Analysis Plan 
Study Code D5740C00001
Edition Number 3.0
Date 28 September 2018
6
4.3.8
Safety assessment analysis ................................................................................. 37
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 ......................................................................................... 39
4.3.9
Population PK analysis ...................................................................................... 39
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 .................................................................................................. 46
8.
APPENDIX ....................................................................................................... 46
LIST OF TABLES 
Table 1
Criteria for Assessing Important Protocol Deviations ............................15
Table 2
Criteria for Potentially Clinically Significant Vital Signs.......................38
Table 3
Criteria for Potentially Clinically Significant ECG................................39
Table 4 
Major changes in the SAP from edition 2, 25 January 2018...................40
LIST OF FIGURES
Figure 1
Study flow chart....................................................................................13


Statistical Analysis Plan 
Study Code D5740C00001
Edition Number 3.0
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 model
BIW
Twice weekly
BP
Blood pressure
CHr
Reticulocyte hemoglobin content
CKD
Chronic kidney disease
CKD-DD
Chronic kidney disease with subject on dialysis
CKD-NDD
Chronic kidney disease with subject not on dialysis
CMH
Cochran-Mantel-Haenszel
CRF
Case report form
hsCRP
High-sensitivity C-reactive protein
CS
Clinically significant
CSE
Composite Safety Endpoint
CSR
Clinical Study Report
DSMB
Data and Safety Monitoring Board
ECG
Electrocardiogram
eGFR
Estimated glomerular filtration rate
EOS
End of study
EQ-5D-5L
EuroQol Health Utility Index, 5 dimensions 5 levels
FACT-An
Functional Assessment of Cancer Therapy-Anemia
EOS 
End of study
EOT 
End of treatment
ESA
Erythropoiesis-stimulating agent
ESRD
End-stage renal disease
FACT-An
Functional Assessment of Cancer Therapy - Anemia
FAS
Full Analysis Set


Statistical Analysis Plan 
Study Code D5740C00001
Edition Number 3.0
Date 28 September 2018
8
Abbreviation or 
special term
Explanation
FDA
Food and Drug Administration
Hb
Hemoglobin
HDL
High-density lipoprotein
HR
Hazard ratio
HRQoL
Health Related Quality of Life
ICU
Intensive Care Unit
IPCW
Inverse Probability of Censoring Weights
ITT
Intention to Treat
IV
Intravenous
LDL
Low-density lipoprotein
LOCF
Last observation carried forward
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
PF
Physical Functioning subscale component of SF-36
PGIC
Patients’ Global Impression of Change
PPS
Per-protocol Set
PMM
Pattern Mixture Model


Statistical Analysis Plan 
Study Code D5740C00001
Edition Number 3.0
Date 28 September 2018
9
Abbreviation or 
special term
Explanation
PSAP
Pooled Statistical Analysis Plan
QW
Once weekly
RBC
Red blood cell
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SF-36
Short Form 36
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
WBC
White blood cell


Statistical Analysis Plan 
Study Code D5740C00001
Edition Number 3.0
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 adjudicated CV 
safety data to the pool safety analysis across the study program to ensure 
sufficient data. 
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 choice of secondary objectives and 
variables, as well as the ordering of the secondary efficacy endpoints in 
the hierarchical testing, to align with the order of the other phase 3 studies 
in the NDD 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 is listed in Section 6. 
25 January 2018
An important change in edition 2.0 is on the analysis of adjudicate safety 
data which will be conducted according to the pooled statistical analysis 
(PSAP) on studies across the phase 3 program. 
Another important change is the addition of a primary efficacy endpoint, 
and addition of further secondary endpoints, as well as ordering of the 
secondary endpoints, done to test efficacy of roxadustat and 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, Changes of Analysis from Protocol.


Statistical Analysis Plan 
Study Code D5740C00001
Edition Number 3.0
Date 28 September 2018
11
1.
STUDY DETAILS
1.1
Study objectives
This study is part of the study program for subjects with Chronic Kidney Disease who are not 
dependent on dialysis (CKD-NDD). The other studies in the study program are FG-4592-060 
and 1517-CL-0608 which are also placebo-controlled. 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 provide MACE 
events required for the pooled safety analysis evaluating the safety of roxadustat for the 
treatment of anemia in CKD patients not on dialysis. This study is also known as 
“OLYMPUS”.
The objectives of the current study are to evaluate the efficacy and safety of roxadustat 
compared to placebo for the treatment of anemia in subjects with Stage 3, 4 or 5 CKD who are 
not on dialysis. 
1.1.1
Primary efficacy objective
The primary efficacy objective is to evaluate the efficacy of roxadustat compared to placebo
for the treatment of anemia in CKD subjects not on dialysis.
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 placebo based on Hb response and level
during the study

The efficacy of roxadustat compared to placebo based on Hb response in inflamed 
subjects 

The effect of roxadustat on Low-density lipoprotein (LDL) cholesterol as compared 
to placebo.

The need for rescue therapy in subjects treated with roxadustat as compared to 
placebo.

The effect of roxadustat on anemia symptoms and health-related quality of life 
(HRQoL) based on comparison with placebo.


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
The effect on the CKD progression of roxadustat as compared to placebo.
1.1.4
Secondary safety objectives
The secondary safety objective is to evaluate the safety and tolerability of roxadustat as 
compared to placebo.
1.2
Study design
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study in anemic 
subjects (Hb <10 g/dL) with Stage 3, 4, or 5 CKD who are not on dialysis.
This study will consist of three study periods as follows:

Screening Period: Up to 6 weeks

Treatment Period: Subjects will be randomized (1:1) to double-blind treatment with
roxadustat or placebo. 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. 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
1.2.1.1
Investigational product, dosage and mode of administration
The initial study drug dose (per dose occasion) is 70 mg orally administered three times a 
week (TIW). Moreover, the dose is subsequently adjusted to achieve and maintain Hb levels 
between 10 and 12 g/dL. Study drug will be dosed TIW throughout the study treatment period 
unless downward dose adjustment requires a change to twice or once weekly.
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 ≥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 screening period, eligibility will be confirmed at a minimum of 2 screening visits. 
If eligible, the subject will be randomized at the randomization visit. During the treatment 
period, subjects will be contacted by telephone at week 1, and will attend study visits every 


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two weeks from weeks 2 to 20. After week 20, study visits will occur every four weeks until 
week 52, then every 8 weeks until the end of the 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 EOS visit will be 
performed 4 weeks after the EOT.
Figure 1
Study flow chart
Screening 
period
Treatment period
Randomization
Week -6
2
52
Roxadustat 
1st  week phone/contact
Every 8th week
Placebo
Screening visits
Post-Treatment follow-up 
period (4 weeks)
End of treatment (EOT) visit
End of Study 
visit (EOS) 
20
Every 4th week
Every 2nd  week
1.2.3
Stratification variables
The randomization in this study will only 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. The variables are: 
1.
Baseline eGFR (≤30 mL/min/1.73 m2 vs > 30 mL/min/1.73 m2)
2.
Baseline Hb (≤8 g/dL vs > 8 g/dL)
3.
Cardiovascular/cerebrovascular/thromboembolic medical history (Yes vs. No)
4.
geographical region (US vs Ex-US)
Baseline Hb and baseline eGFR will be included in the analyses as continuous covariates, not 
as dichotomous factors, unless specified otherwise. Throughout this document, the variable 
cardiovascular/cerebrovascular/thromboembolic medical history will be shortened as CV 
history.
CV history at baseline will be defined for subjects with history of any of the following 
diseases:


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
Myocardial infarction

Percutaneous coronary intervention

Coronary artery bypass

Cardiac failure congestive 

Ischaemic stroke

Haemorrhagic stroke

Cerebrovascular accident 
1.3
Number of subjects
Primary efficacy endpoint: A sample size of 450 subjects will have > 99% power to detect a 
0.75 g/dL difference in mean Hb values between the two treatment groups, assuming that the 
common standard deviation is 1.2 g/dL, using an analysis of variance (ANOVA) test with a 
0.05 two-sided significance level.
To contribute an adequate number of adjudicated CV events for the pooled CV analyses 
across the phase 3 program, approximately 2600 subjects are planned to be randomized in this 
study in a 1:1 ratio to either roxadustat or placebo. This sample size is driven by the overall 
requirement of adjudicated CV events for the overall study program in CKD-NDD (which 
consists of 3 studies in total targeting 465 subjects with MACE events), all evaluating the 
cardiovascular safety of roxadustat compared to placebo. The two other placebo-controlled 
studies in the study program are FGCL-4592-060 and 1517-CL-0608.
All event numbers in this section refer to events accrued in the Safety Analysis Set.
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 analysed
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. Subjects with an important protocol 


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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 2.1.4. 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 28 days after 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 28 days after last intake of study 
drug. The Safety Analysis Set may also be referred to as On-treatment+28 (OT+28). 
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 Hb 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 unblinding 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, and 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. 
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 


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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-
7, 10-17, 19 and 24. 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 
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 
whether subjects achieved Hb response as described below.
                                               
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 patient-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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
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 [according to 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. Subjects who 
have discontinued study medication or received rescue therapy before a Hb 
response could be achieved will be considered as a non-responder.  
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 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 within the interval of ≥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 measurements at week 
28 and week 52. Subjects 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 in LDL cholesterol from baseline to week 24. 


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3.1.4
Rescue therapy related secondary efficacy variables
The need for rescue therapy will evaluated as

Time-to-first (and proportion of subjects who received) instance of receiving 
intravenous (IV) iron, red blood cell (RBC) transfusions, or erythropoietin analogue
(composite) as rescue therapy (rescue therapy guidelines are specified in the clinical 
study protocol (CSP), Section 7.7.4)

Time-to-first (and proportion of subjects who received) administration of RBC 
transfusion as rescue therapy
For analyses based on the OT+28, 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.
Furthermore, the other components of the above composite will be analyzed separately as 
exploratory endpoints: 

Time-to-first (and proportion of subjects who received) administration of 
erythropoietin analogue as rescue therapy

Time-to-first (and proportion of subjects who received) administration of IV iron as 
rescue therapy
3.1.5
36-Item Short Form Health Survey
The SF-36 is a QoL instrument designed to assess generic health concepts relevant across
age, disease, and treatment groups. It is aimed at both adults and adolescents aged eighteen
years and older. The SF-36 consists of eight domains of health status: Physical functioning
(10 items), Role-physical (4 items), Bodily pain (2 items), General health (5 items), Vitality (4 
items), Social functioning (2 items), Role emotional (3 items) and Mental health (5 items).
Two component scores, the Physical Component Summary and the Mental Component
Summary can also be calculated. For both the SF-36 domain scores and summary scores,
higher scores indicate better health status. The SF-36 has a recall period of the ‘past four
weeks’.

Change from baseline in SF-36 Vitality (VT) sub-score 

Change from baseline in SF-36 Physical Functioning (PF) sub-score 
The SF-36 scores will be computed according to its documentation.


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3.1.6
CKD progression related secondary efficacy variables
To evaluate the effect of roxadustat on the CKD progression prior to initiation of dialysis or 
kidney transplant, the following variable will be analyzed:

Annual rate of eGFR change, calculated as the slope of eGFR values to prior to 
initiation of dialysis/kidney transplant
Baseline eGFR is defined as the mean of all available central lab values prior to 
randomization, including the value from the randomization visit. 
3.1.7
Exploratory variables 
The exploratory variables are:
3.1.7.1
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 11 g/dL. 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. Time will be computed analogously as time to first 
rescue therapy.

Proportion of time on study with Hb <7, 7 to <8, 8 to < 9, 9 to <10, 10 -<11, 11-
<12, 12-<13, >13g/dL; proportion of time on study with Hb < 10 g/dL after week 
12; proportion of time on study with Hb < 10 g/dL after week 24;  
3.1.7.2
Rescue therapy related exploratory variables

Number of rescue therapy treatments given, IV iron, RBC transfusion or 
erythropoietin analogue, per patient exposure year (PEY). 
3.1.7.3
CKD progression related exploratory variables
All eGFR values obtained after the initiation of dialysis or renal transplant will be censored.

Time to a renal composite endpoint which is defined by the components: 

Doubling of creatinine or 

Initiating chronic dialysis treatment or 

All-cause mortality,


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for subjects with eGFR >15 ml/min/1.73m2 at baseline. A doubling of creatinine
from baseline is confirmed with two consecutive measurements separated at least 
21 days apart. The date of the first measurement will be used as the date when the 
event was reached. Time will be computed analogously as time to first rescue 
therapy.

Time to initiation of chronic dialysis. Time will be computed analogously as time to 
first rescue therapy. This will be analysed in all patients and in subgroups with 
eGFR >15, >20, >30 mL/min/1.73 m2.

Time to an eGFR decrease of 30%, 40% and 50% from baseline, prior to initiation 
of dialysis or renal transplant, and will be analysed using the Cox model 
analogously as Time to-first rescue therapy (composite) in Section 4.3.4, this will 
be analysed in all patients and in subgroups with eGFR >15, >20, >30 mL/min/1.73 
m2. A eGFR decrease of 30%, 40% or 50% from baseline is confirmed with two 
consecutive measurements separated at least 21 days apart. The date of the first 
measurement will be used as the date when the event was reached. Time will be 
computed analogously as time to first rescue therapy.
3.1.7.4
Quality of life related exploratory efficacy variables 
Evaluate the effect of roxadustat on anaemia symptoms and disease-specific health-related 
quality of life (HRQoL) and overall health status: The variables are:

Changes in anaemia symptoms as measured by the Functional Assessment of 
Cancer Therapy-Anemia (FACT-An).

Changes in self-reported health status as measured by the EuroQol Health Utility 
Index, 5 dimensions, 5 levels (EQ-5D-5L) and 

Patients’ Global Impression of Change (PGIC).

Change from baseline in SF-36 Vitality (VT) sub-score in subjects with baseline VT 
subscore in subjects with with baseline VT subscore below 50   

Change from baseline in SF-36 Physical Functioning (PF) sub-score in subjects 
with with baseline PF subscore below 35
The FACT-An, EQ-5D-5L, and PGIC scores will be computed according to their respective 
documentation.
Patient Global Impression of Change Scale (PGIC)
The PGIC is a subject-rated instrument that measures change in subjects’ overall status on a 7-
point scale ranging from 1 (very much improved) to 7 (very muchworse), when compared to 
the start of the study treatment.


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FACT-An
The Functional Assessment of Cancer Therapy- General (FACT-G) Version 4 contains
27 items that cover four dimensions of well-being: physical (PWB)—7 items, functional
(FWB)—7 items, social/family (SWB)—7 items each, and emotional (EWB)—6 items. A
subscale of 13 fatigue specific items (the Fatigue Subscale) plus seven additional items
related to anemia were developed for use in conjunction with the FACT-G. The 13 fatigue 
items plus the seven additional items related to anemia comprise the Anemia Subscale (AnS). 
Administration of the FACT-G plus the AnS is referred to as the FACT-An. The FACT-An 
has a recall period of the ‘past seven days’. Respondents are asked to provide responses, (i.e., 
‘Not at all’, ‘A little bit’, ‘Somewhat’, ‘Quite a bit’ and ‘Very much’), to a list of statements 
which are either positively or negatively phrased. For all FACT-An scales, a higher score 
indicates better QoL.

Changes in the score of the FACT-An in total score and anemia subscale.
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 
3.1.7.5
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 and number of on-treatment days hospitalization-free

Proportion and number of on-treatment days hospitalization-free, emergency room-
free, and skilled nursing facility-free. 

Proportion of subjects who are re-admitted to hospital within 30 days per PEY. 

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.


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
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.
3.1.7.6
Other exploratory variables

Variables concerning lipids: total cholesterol, high-density lipoprotein (HDL) and 
triglycerides. Lipid levels at all available timepoints and change from baseline to 
testing timepoints. Percent of subjects who achieved LDL target of <100 mg/dL
will also be compared at all available time points.

Variables concerning heart rate and blood pressure: heart rate, systolic blood 
pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP).

Change from baseline in hepcidin to week 24. 

Initiation of ESA therapy post study drug discontinuation

Usage of statins and types of statins
3.2
Safety assessment 
Safety will be assessed by evaluating the following:

Occurrence and event rates 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, and proportion of values 
above, within or below normal ranges

Occurrence of clinically significant changes from baseline in electrocardiogram
(ECG) values.
3.3
Adjudicated CV Events Analyses for Safety Assessments 
The CV events to be analyzed according to 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-4592-060, 1517-CL-608 and 
D5740C00001) in the CKD-NDD program. Analyses of these adjudicated events are 
described in a separate pooled analysis plan.


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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 analysis 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 
“Placebo”. 
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 
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 


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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 the Safety Analysis Set, subjects will be censored at the 28 days after 
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.
In analyses of eGFR and creatinine, all eGFR and creatinine measurements after initiation of
dialysis or renal transplant will be censored.
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 
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. 


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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. 
4.2
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, baseline eGFR, geographical region, 
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, baseline iron replete 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 <=8, >8 - <=9, >9 g/dL

baseline eGFR; <10, 10 to <15, 15 to <30, 30 to <45, 45 to <60, ≥60 mL/min/1.73m2, 

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 4.3.2 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 as described in detail below. Unless specified otherwise baseline Hb, baseline eGFR as 
continuous variables will be used as covariates, and treatment group, CV history 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 


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estimated at a time point determined based on 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.
4.2.3.1
Cox regression adopting Inverse of Probability of Censoring Weights
A separate document will describe the IPCW specification to be used to adjust for potential 
asymmetric dropout due to informative censoring.
4.2.4
Analysis of Covariance (ANCOVA)
When using ANCOVA for the 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, baseline eGFR
will be used as covariates, and treatment group, cardiovascular history and geographic region 
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.
4.2.5
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 with baseline Hb, baseline eGFR, CV history and geographic 
region, and the available non-missing Hb for each scheduled week are used as covariates, 
and 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, baseline eGFR, CV history and geographic region 
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 observed and 
imputed Hb values between weeks 28 to 52 for each subject is taken as the dependent 
variable and baseline Hb, baseline eGFR, treatment group, CV history and geographic 
region 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. 
4.2.6
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 are 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 at the end of the double 
blind period and to the variance-covariance structure of the longitudinal model.
The MMRM can contain terms for baseline measurements, 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 number 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.
4.2.7
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. 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. 
  


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4.2.7.1
PMM – Last Mean Carried Forward
A PMM 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 variable. 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 method is the same as for multiple imputation ANCOVA 
described in Section 4.2.5 with the exception of step 2, where the monotone datasets are 
imputed. Parameter below refers to the parameter of the multi-normal distribution for baseline 
and post baseline Hb measurement. 
1. Create posterior distribution of parameter: Separately for each treatment arm, 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) using a Bayesian approach with an improper prior. Moreover, fit an
unstructured variance covariance matrix using an uninformative Jeffrey’s' prior (Schafer, 
1997, p. 155). 
2. Draw parameters: Separately for each treatment arm, draw variance-covariance matrix 
from the posterior distribution for the parameters. The mean vector is 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 given observed data: For each subject
with missing data, use their joint distribution in previous step to construct their conditional 
distribution of missing data given observed data. Sample the missing data from this
conditional distribution, to create a “completed” data set.
Repeat the above steps 200 times, which will result 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 for final inference.
4.2.7.2
PMM – Baseline Mean Carried Forward (roxadustat group only and both 
groups)
The analysis is the same as PMM – Last Mean Carried Forward except 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 the placebo group, the imputation data will be 
generated using the last mean carried forward described above. 


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
The baseline carried forward imputation will be performed for both treatment 
groups.
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. 
4.2.7.3
PMM – Jump to Control 
A PMM using jump to control multiple imputation method (Carpenter et al, 2013) will also be 
used as another sensitivity analysis similar to the PMM-Last Mean Carried Forward with the 
exception of step 3. The joint distribution of the subjects observed and missing data are 
considered multivariate normal with mean and covariance matrix from following the placebo 
treatment arm. 
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 
analysed with multiple imputation ANCOVA as described in Section 4.2.4 and 4.2.5. The 
model will contain terms for the treatment, baseline Hb measurement, baseline eGFR, 
geographic region and CV history. Superiority of roxadustat compared to placebo 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 placebo exceeds 0 g/dL. The ITT analysis set will be 
used.
4.3.3
Primary efficacy endpoint analysis for EU (First Secondary endpoint for FDA)
Hb response (Yes/No), where Yes is defined as: 
-
Hb ≥ 11.0 g/dL and Hb increase from baseline by ≥ 1.0 g/dL, for subjects with 
baseline Hb > 8.0 g/dL; or
-
Hb increase from baseline by ≥ 2.0 g/dL, for subjects with baseline Hb ≤ 8.0 g/dL
at two consecutive visits [dates] (with available data) separated at least 5 days during 
the first 24 weeks of treatment without having received rescue therapy (RBC 
transfusion, ESA, or IV iron) prior to Hb response. 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 


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therapy. The proportion of responders in the primary efficacy variable will be 
compared using a Cochran–Mantel–Haenszel (CMH) test adjusting for the region, 
history of CV, baseline Hb (<=8, >8 g/dL) and baseline eGFR (<=30, >30 
mL/min/1.73 m2), comparing roxadustat to placebo. The FAS will be used. 
4.3.4
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 FAS will be used on the first secondary endpoint, OT+28 analysis set will be used 
for the two secondary endpoints related to rescue therapy, and the ITT analysis data set will be 
used for all the remaining secondary endpoints.”
1.
Hb response as noted for EU Primary Endpoint.
2.
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 for US. Superiority of 
roxadustat compared to placebo 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 placebo exceeds 0 g/dL. 
3.
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 placebo will be compared using ANCOVA with treatment 
group, geographic region and CV history as fixed factors and baseline Hb and 
baseline eGFR as covariates. Superiority between the groups will be declared, and this 
test as successful, if the lower bound of the 2-sided confidence interval of the 
difference between roxadustat and placebo exceeds 0. 
4.
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 placebo will be compared using 
ANCOVA with treatment group, geographic region and CV history as fixed factors 
and baseline Hb and baseline eGFR as covariates. Superiority between the groups will 
be declared, and this test as successful, if the lower bound of the 2-sided confidence 
interval of the difference between roxadustat and placebo exceeds 0. 
5.
Mean change from baseline in LDL cholesterol to week 24 will be analysed using 
ANCOVA. Baseline Hb, baseline eGFR and baseline LDL will be used as covariates 
and treatment arm, CV history and geographic region as fixed effects. Superiority will 


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be declared if the upper bound of the 2-sided 95% confidence interval of the 
difference between roxadustat and placebo exceeds 0. 
6.
Time-to-first rescue therapy (composite) of any of IV iron, RBC transfusion or 
erythropoietin analogue (and proportion of subjects who received) as rescue therapy, 
will be analyzed using the Cox proportional hazard model with OT+28. Baseline Hb, 
baseline eGFR, geographic region, and CV history will be included as covariates. 
Superiority will be claimed, and this test successful, if the upper limit of the 2-sided 
95% CI for the hazard ratio is less than or equal 1.0. 
7.
Time-to-first RBC transfusion (and proportion of subjects who received) as rescue 
therapy, will be analyzed using the Cox proportional hazard model with OT+28. 
Baseline Hb, baseline eGFR, geographic region, and CV history will be included as 
covariates. Superiority will be claimed, and this test successful, if the upper limit of 
the 2-sided 95% CI for the hazard ratio is less than or equal 1.0.
8.
Mean change in SF-36 Vitality (VT) sub-score from baseline to average VT sub-
score of weeks 12-28 will be analyzed using MMRM with treatment, visit, treatment-
by-visit interaction, and baseline covariates, including the baseline score, baseline Hb, 
baseline eGFR, and geographic region and CV history, as fixed effects and subject as 
a random effect. Superiority between roxadustat and placebo will be declared, and this 
test successful, if the lower bound of the 2-sided confidence interval for the difference 
between roxadustat and placebo exceeds 0.
9.
Annual rate of eGFR change prior to initiation of Dialysis/Transplant will be estimated 
with MMRM using all post-baseline eGFR values prior to initiation of dialysis/kidney 
transplant. Baseline eGF, baseline Hb and geographic region, CV history, treatment 
group and post-baseline eGFR measurement time will be treated as fixed effects, and 
subject and time as random effects, i.e. random intercept and slope. 
10.
Mean change in SF-36 Physical Functioning (PF) sub-score from baseline to 
average PF sub-score of weeks 12-28 will be analyzed using MMRM with treatment, 
visit, treatment-by-visit interaction, and baseline covariates, including the baseline 
score, baseline Hb, baseline eGFR, and geographic region and CV history, as fixed 
effects and subject as a random effect. Superiority between roxadustat and placebo 
will be declared, and this test successful, if the lower bound of the 2-sided confidence 
interval for the difference between roxadustat and placebo exceeds 0.
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 the ITT analysis set, unless 
specified otherwise. The variables will be analysed as follows:
4.3.5.1
Hb related exploratory endpoint analysis

Mean change in Hb from baseline to the subjects mean level from week 28 until the 
EOT visit will be analysed with ANCOVA where the mean change in Hb from 
baseline of all available values from week 28 to the EOT visit for each subject will 
be the dependent variable. The mean change from baseline will be imputed for 
subjects with no measurements from week 28 to the EOT visit with a multiple 
imputation ANCOVA approach and a MAR assumption. The model will contain 
terms for the baseline Hb measurement, baseline eGFR, CV history and geographic 
region and treatment arm. 

Time to achieving target Hb will be analyzed analogously as Time to first rescue 
therapy (composite) in Section 4.3.3. Target Hb is achieved when Hb level is within 
10-12 g/dL at two consecutive measurements.

Proportion of time on study with Hb <7, 7 to <8, 8 to < 9, 9 to <10 g/dL, 10-12, 12-
<13, >13 g/dL; proportion of time on study with Hb < 10 g/dL after week 12; 
proportion of time on study with Hb < 10 g/dL after week 24. These will be 
reported descriptively.  

Estimation of median time (in weeks) to achieve target Hb, based on the definition 
of two consecutive Hb levels within 10-12 g/dl, by study drug.
4.3.5.2
Rescue therapy related exploratory endpoint analysis

Number of rescue therapy treatments given; RBC transfusion, IV iron or 
erythropoietin analogue per PEY will be reported descriptively, together and 
separately. OT+28 will be used. 
4.3.5.3
CKD progression related exploratory endpoint analysis

Time to the renal composite endpoint for subjects with baseline eGFR >15 will be 
analysed using the Cox proportional hazard model. Baseline Hb, baseline eGFR, 
geographic region, and CV history will be included as covariates. 

The secondary efficacy endpoint of annual rate of eGFR change will be repeated for 
subjects with baseline eGFR >30 and >20 mL/min/1.73 m2. 

Time to initiation of dialysis will be analyzed using the Cox model analogously as 
analogously as Time to-first rescue therapy (composite) in Section 4.3.4.   This will 
be analysed in all patients and in subgroups with eGFR>15, >20, >30 
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
Time to an eGFR decrease of 30%, 40% and 50% from baseline, prior to initiation 
of dialysis or renal transplant, will be analysed using the Cox model analogously as 
Time to-first rescue therapy (composite) in Section 4.3.4, this will be analysed in all 
patients and in subgroups with eGFR >15, >20, >30 mL/min/1.73 m2.
4.3.5.4
Quality of life related exploratory endpoint analysis

Mean change in FACT-An score from baseline to average FACT-An score of weeks 
28-52 will be analyzed using MMRM with treatment, visit, treatment-by-visit 
interaction, and baseline covariates, including the baseline score, baseline Hb, 
baseline eGFR, and geographic region and CV history, as fixed effects and subject 
as a random effect. 

Mean change in FACT-An subscale score of anemia from baseline to average score 
of weeks 28-52 will be analyzed using MMRM with treatment, visit, treatment-by-
visit interaction, and baseline covariates, including the baseline score, baseline Hb, 
baseline eGFR, CV history and geographic region, as fixed effects and subject as a 
random effect.

Change in FACT-An score 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.

Change in SF-36 PF and VT score 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.

Change in PGIC 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.

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.

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, baseline eGFR, CV history and geographic region 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.

Shift tables of EQ-5D-5L levels 1-5 by dimension and treatment arm. 

EQ index value and VAS mean values (+SD) and median values (+ 25th & 75th
percentiles) at baseline and each visit per treatment arm. (descriptive)


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
Mean change in PGIC score from baseline to average PGIC score of weeks 28-52 
will be analyzed using MMRM with treatment, visit, treatment-by-visit interaction, 
and baseline covariates, including the baseline Hb, baseline eGFR, and geographic 
region and CV history, as fixed effects and subject as a random effect. Superiority 
between roxadustat and placebo will be declared, and this test successful, if the 
lower bound of the 2-sided confidence interval for the difference between 
roxadustat and placebo exceeds 0.   
4.3.5.5
Hospitalization related exploratory endpoint analysis
All endpoints in this subsection will use OT+28.

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 and number of days of hospitalization-free days on treatment will be 
reported descriptively. 

Proportion of hospitalization-free, emergency room- free, and skilled nursing 
facility-free days 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.
4.3.5.6
Other exploratory endpoint analysis

Change in heart rate from baseline throughout week 28 to the EOT visit. For each 
subject, the mean change from baseline across all heart rate values from week 28 to 
the EOT visit will be used as the dependent variable. An ANCOVA approach will 
be used with baseline Hb, baseline eGFR, baseline heart rate, treatment arm, CV 
history and geographic region as covariates. 


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
Change in blood pressure (DBP, SBP and MAP) from baseline throughout week 28 
to EOT visit. Analysis will be conducted using ANCOVA analogously as the 
analysis of change in heart rate.

Change in the serum iron profiles: Ferritin, TIBC and TSAT from baseline 
throughout week 28 to 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 
triglycerides. For each of the lipids, analysis will be conducted using ANCOVA
analogously as the analysis of change in heart rate, from week 24 to EOT. Percent 
of subjects achieved target LDL of <100 at the various time points that lipids were 
measured. Subgroup analysis will be conducted in subjects on statin and/or other 
cholesterol-lowering drug

Subjects 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 analysis of the primary efficacy endpoint and the secondary efficacy endpoints 
(with the exception of the rescue therapy secondary endpoints) will be repeated 
using OT+28.

The analysis of the primary efficacy endpoint and the Hb related secondary efficacy 
endpoints will be repeated using the PPS.

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, baseline 
eGFR, visit and visit by treatment interaction, treatment arm, CV history and 
geographic region as covariates. ITT analysis set will be used.

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 placebo will be 
compared using an ANCOVA model with baseline Hb and eGFR, CV history and 
geographic region as covariates. ITT analysis set will be used.


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
Change in Hb from baseline using PMM – Last Mean Carried Forward, as specified 
in Section 4.2.7.1. ITT analysis set will be used.

Change in Hb from baseline using PMM – Baseline Mean Carried Forward, as 
specified in Section 4.2.7.2. ITT analysis set will be used. 

Change in Hb from baseline using PMM – Jump to Control as specified in Section 
4.2.7.3. ITT analysis set will be used. 

The analyses of the time to rescue therapy endpoints will be repeated using IPCW
instead of the standard Cox regression. 
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 FAS 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 vs ≥30 kg/m2

Geographical region: US vs Ex-US

Geographical region:

North America

South America 

Asia 

Europe 

Cardiovascular/cerebrovascular/thromboembolic history: Yes or No 

Baseline Hb value: ≤8g/dL vs >8 g/dL and ≤9 vs >9 g/dL

Baseline eGFR value: <30 vs ≥30 and <15 vs ≥15, <10 vs ≥10 mL/min/1.73m2


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
Diabetes history: Yes vs No

Baseline hsCRP (≤ULN vs >ULN). 

Iron replete at baseline: (Ferritin>100 and TSAT>20%)
4.3.8
Safety assessment analysis 
The safety analysis will be performed using the OT+28. Safety parameters include adverse 
events (AE), laboratory parameters, 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 or 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 28 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; by system organ class, preferred term, and relationship to study 
medication; and by system organ class and the baseline eGFR categories <10, 10 to <15, 15 to 
<30, 30 to <45, 45 to <60 mL/min/1.73m2. 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.
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 


Statistical Analysis Plan 
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organ class and preferred term. TEAEs with outcome of deaths and TESAEs will also be 
presented for the ITT analysis set.
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.
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.
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 
High
≥170
Increase of ≥20


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Vital Sign Parameter
Flag
Criteria*
Observed Value
Change
(mmHg)
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 value is considered as a PCS value if it meets both criteria for observed value and change 
from 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. 
placebo).  
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
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- non-dialysis dependent 


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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
Changes of analysis from protocol version 6.0, 31 August 2018. 
The analysis of eGFR rate will not use log transformation of eGFR values.
6.1
Changes of analysis from previous edition of the SAP
Table 4 Major changes in the SAP from edition 2, 25 January 2018. 
SAP 
Section of 
previous 
edition
Description of change
Rationale
1.1 
The objectives of the study have been 
split to efficacy objectives and safety 
objectives. 
For clarification.
1.1.2
The safety objectives have been revised.
Harmonizes D5740C00001 with the 
other phase 3 trials in the roxadustat 
CKD non-dialysis program, to serve 
as a pivotal study for confirming 
efficacy and safety, and facilitates 
assessment of pooled safety across 
the phase 3 trials.
1.1.3 
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 (PGIC) is now 
To harmonize with the secondary 
objectives of the other phase 3 
studies in the program.


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defined as an exploratory efficacy 
endpoint. 
1.3
The sample size determination text has 
been revised
Harmonization with the strategy for 
the analyses of CV safety for the 
study program as described in the 
PSAP.
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.
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 3 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 for 
Safety Assessments” and its description 
is replaced by new texts on the pooling of 
To harmonize with the primary 
variables of the other phase III 
studies in the program


Statistical Analysis Plan 
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the adjudicated composite safety 
endpoints from all the phase 3 studies of 
the program. 
Added a new section for lipid related 
secondary efficacy variables. A 
corresponding analysis has been added as 
a secondary efficacy analysis in Section 
4. 
To investigate the added secondary 
objective to evaluate LDL 
cholesterol.
3.3.4.1/
3.3.4.3/
3.3.4.4
Moved the sections of the secondary 
variables FACT-An, EQ-5D-5L and 
PGIC, section numbers 3.3.4.1, 3.3.4.3 
and 3.3.4.4 respectively to exploratory 
variables and set their corresponding 
analysis as exploratory in Section 4. 
These variables have been 
downgraded to exploratory 
variables. 
3.3
The secondary efficacy variable of Hb 
response has been specified as the 
primary efficacy endpoint for EU. 
The primary efficacy variable designated 
for EU health authority is added as the 
first Hb-related secondary efficacy 
variable designated for US FDA.   
Downgraded the secondary variables of 
mean change from baseline in Hb, 
averaged over week 28 to EOT visit, 
FACT-An variable, PGIC variable and 
EQ-5D-5L variable to exploratory 
variables. 
Upgraded the exploratory variable of 
time-to-first (proportion of subjects 
receiving) RBC transfusion as rescue 
therapy to the secondary efficacy variable 
and set its corresponding analysis as 
secondary efficacy analysis in Section 4. 
To harmonize with the secondary 
variables of the other phase 3 
studies in the program
3.3.2
Changed the timing of the hsCRP 
variable to the average level between 
week 28 to week 52.
To harmonize with the primary 
efficacy variable
To harmonize with the secondary 


Statistical Analysis Plan 
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Added a variable for proportion of total 
time of interpolated Hb values ≥10 g/dL 
from week 28 until week 52. A 
corresponding analysis has been added to 
Section 4 as a secondary efficacy 
analysis. 
variables of the other phase 3 
studies in the program
3.3.5
Set the annual rate of eGFR change as a 
secondary variable and its corresponding 
analysis in Section 4 as a secondary 
efficacy analysis. Set the renal composite 
endpoint as an exploratory variable and 
its corresponding analysis as an 
exploratory in Section 4.
Added all-cause mortality as a 
component to the renal composite 
endpoint. Replaced the component of 
40% eGFR decrease with doubling of 
creatinine. 
To harmonize with the secondary 
variables of the other phase 3 
studies in the program
3.3.6/
4.3.6
Added analyses of proportion of time on 
study with different Hb categories over 
various timeframes 
Added further analyses of hospitalization-
free, emergency room- free, skilled 
nursing facility-free survival and LDL as 
exploratory variables in Section 3 and 
exploratory analysis in Section 4.
Added an analysis measuring the 
proportion of time subjects were on 
different Hb levels as exploratory 
variables in Section 3 and exploratory 
analysis in Section 4. 
Updated individual analyses of CKD 
progression related endpoints
Removed analyses of proportion of 
subjects with at least one occurrence of 
excessive erythropoiesis, Hb≥12, Hb≥13 
and Hb≥14. 
Analyses of interest and also to 
harmonize with other phase 3 
studies in the program.


Statistical Analysis Plan 
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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. 
4.1.2
Removed the subsection and the criteria 
to censor at PACD. 
Subjects will be censored at the EOS 
instead of EOT for ITT and FAS.
eGFR and creatinine values will also be 
censored at time of renal transplant. 
To harmonize with the censoring 
rules of the PSAP.
To harmonize with the censoring 
rules of the PSAP.
To include another renal 
replacement therapy which 
influences eGFR and creatinine 
values. 
4.1.4
Deleted Section “Investigation of 
informative censoring”.
Not applicable since the CV 
analyses will not be performed for 
the individual CSR. 
4.2.5
Decreased the number of multiple 
imputations to 200 from 1000.
To reduce the computational 
runtime. 
4.2.8
Referred the specification of the IPCW to 
a separate document.
To harmonize the analysis with the 
other phase III studies in the 
program.
4.3.1/
4.3.2/
4.3.3
Removed the statistical analyses of the 
adjudicated CV events from this SAP. 
All analyses of CV safety will be 
conducted in accordance with the 
PSAP, and will not be done for the 
individual CSR
4.3.5
The ITT analysis set will be used for the 
primary efficacy endpoint for the US 
FDA. FAS will be used for the primary 
efficacy endpoint for the EU health 
authority.  
To be in agreement with the other 
studies in the program.
4.3.2
The section on primary efficacy endpoint 
analysis is split into two sections, one for 
US FDA and the other for EU health 
authority.
To harmonize with the primary 
variables of the other phase 3 
studies in the program


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4.3.4
The analysis of Hb response (Y/N) during 
the first 24 weeks of treatment without 
having received any rescue therapy is 
moved to the primary efficacy endpoint 
analysis for EU health authority and the 
first secondary efficacy analysis for US 
FDA. 
This efficacy endpoint is now the 
primary for EU health authority and 
the first secondary for US FDA.
4.3.5
Changed the ordering of the secondary 
efficacy endpoints.
The primary efficacy endpoint designated 
for EU health authority is added as the 
first secondary efficacy endpoint 
designated for US FDA
ITT analysis set is used for all the 
secondary efficacy endpoints except for 
the first secondary efficacy endpoint and 
the two rescue therapy related endpoints. 
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. 
4.3.7
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.
4.3.8
Added a subgroup of iron replete subjects
Subgroup if interest
4.3.9
Deleted section “Model checking”.
Not applicable since the CV 
analyses will not be performed for 
the individual CSR.
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. 


Statistical Analysis Plan 
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Edition Number 3.0
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7.
REFERENCES
Aranesp 2001
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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 
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23 (2013). 1352-137
O’Kelly & Ratitch, 2014
O’Kelly M, Ratitch B, 2014. Clinical Trials with Missing Data – A Guide for Practitioners.
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Omontys 2012
Omontys Product Approval Information Summary. Available at 
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cfm.  Accessed on 22MAY2014.
Royston & Finkelstein 2000
Robins J, Finkelstein D. Correcting for Noncompliance and Dependent Censoring in an AIDS 
Clinical Trial with Inverse Probability of Censoring Weighted (IPCW) Log-Rank Tests.
Biometrics 779-788 September 2000
Rubin, 1987
Rubin, D. B. Multiple imputation for nonresponse in surveys. New York: Wiley.
Schafer, 1997
Schafer, J. L. (1997) Analysis of incomplete multivariate data. London: Chapman and Hall.
8.
APPENDIX
Not applicable.